WO2001001960A1 - Clear oil-containing pharmaceutical compositions - Google Patents

Clear oil-containing pharmaceutical compositions Download PDF

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Publication number
WO2001001960A1
WO2001001960A1 PCT/US2000/015133 US0015133W WO0101960A1 WO 2001001960 A1 WO2001001960 A1 WO 2001001960A1 US 0015133 W US0015133 W US 0015133W WO 0101960 A1 WO0101960 A1 WO 0101960A1
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WO
WIPO (PCT)
Prior art keywords
peg
oil
pharmaceutical composition
glyceryl
triglyceride
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PCT/US2000/015133
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French (fr)
Inventor
Feng-Jing Chen
Mahesh V. Patel
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Lipocine, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lipocine, Inc. filed Critical Lipocine, Inc.
Priority to CA2375083A priority Critical patent/CA2375083C/en
Priority to NZ516521A priority patent/NZ516521A/en
Priority to AU53131/00A priority patent/AU783077B2/en
Priority to EP00938039A priority patent/EP1194120A4/en
Priority to JP2001507455A priority patent/JP2003503440A/en
Publication of WO2001001960A1 publication Critical patent/WO2001001960A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • A61K9/107Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0087Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release

Definitions

  • the present invention relates to drug and nutrient delivery systems, and in particular to pharmaceutical compositions and methods for the improved solubilization of triglycerides and improved delivery of therapeutic agents.
  • a wide variety of therapeutic agents such as drugs, nutritional agents, and cosmeceuticals, are conventionally formulated in oil/water emulsion systems. These conventional emulsions take advantage of the increased solubility of many therapeutic agents in oils (triglycerides).
  • oils triglycerides
  • one conventional approach is to solubilize a therapeutic agent in a bioacceptable triglyceride solvent, such as a digestible vegetable oil, and disperse this oil phase in an aqueous solution.
  • the dispersion may be stabilized by emulsifying agents and provided in emulsion form.
  • the therapeutic agent can be provided in a water-free formulation, with an aqueous dispersion being formed in vivo in the gastrointestinal environment.
  • a triglyceride-containing formulation suitable for delivering therapeutic agents through an aqueous environment is an oil-in-water emulsion.
  • Such emulsions contain the hydrophobic therapeutic agent solubilized in an oil phase which is dispersed in an aqueous environment with the aid of a surfactant.
  • the surfactant may be present in the oil-based formulation itself, or may be a compound provided in the gastrointestinal system, such as bile salts, which are known to be in vivo emulsifying agents.
  • colloidal oil particles sizes are relatively large, ranging from several hundred nanometers to several microns in diameter, in a broad particle size distribution. Since the particle sizes are on the order of or greater than the wavelength range of visible light, such emulsions, when prepared in an emulsion dosage form, are visibly “cloudy” or “milky” to the naked eye.
  • Emulsions are thermodynamically unstable, and colloidal emulsion particles will spontaneously agglomerate, eventually leading to complete phase separation.
  • the tendency to agglomerate and phase separate presents problems of storage and handling, and increases the likelihood that pharmaceutical emulsions initially properly prepared will be in a less optimal, less effective, and poorly-characterized state upon ultimate administration to a patient.
  • Uncharacterized degradation is particularly disadvantageous, since increased particle size slows the rate of transport of the colloidal particle and digestion of the oil component, and hence the rate and extent of absorption of the therapeutic agent.
  • a further disadvantage of conventional triglyceride-containing compositions is the dependence of therapeutic agent absorption on the rate and extent of lipolysis.
  • colloidal emulsion particles can transport therapeutic agents through the aqueous environment of the gastrointestinal tract, ultimately the triglyceride must be digested and the therapeutic agent must be released in order to be absorbed through the intestinal mucosa.
  • the triglyceride carrier is emulsified by bile salts and hydrolyzed, primarily by pancreatic lipase. The rate and extent of lipolysis, however, are dependent upon several factors that are difficult to adequately control.
  • the amount and rate of bile salt secretion affect the lipolysis of the triglycerides, and the bile salt secretion can vary with stomach contents, with metabolic abnormalities, and with functional changes of the liver, bile ducts, gall bladder and intestine.
  • Lipase availability in patients with decreased pancreatic secretory function, such as cystic fibrosis or chronic pancreatitis may be undesirably low, resulting in a slow and incomplete triglyceride lipolysis.
  • the activity of lipase is pH dependent, with deactivation occurring at about pH 3, so that the lipolysis rate will vary with stomach contents, and may be insufficient in patients with gastric acid hyper-secretion.
  • surfactants commonly used in the preparation of pharmaceutical emulsions such as polyethoxylated castor oils
  • certain surfactant combinations when used in combination with digestible oils in emulsion preparations, can substantially decrease the lipolysis-inhibiting effect of some common pharmaceutical surfactants (see, U.S. Patent No. 5,645,856), such formulations are still subject to the other disadvantages of pharmaceutical emulsions and triglyceride-based formulations.
  • microemulsions Like an emulsion, a microemulsion is a liquid dispersion of oil in water, stabilized by surfactants. Conventional microemulsions, however, present several safety and efficiency problems. The amount of triglyceride that can be solubilized in a conventional microemulsion is generally quite small, resulting in a poor loading capacity. In order to solubilize significant amounts of triglycerides, large amounts of hydrophilic surfactant and/or solvents must be used. These high concentrations of hydrophilic surfactant and solvents raise questions of safety, since the levels of hydrophilic surfactant and solvent needed can approach or exceed bioacceptable levels.
  • the present invention provides pharmaceutical compositions for improved solubilization of triglycerides, and improved delivery of therapeutic agents. It has been surprisingly found that pharmaceutical compositions containing significant amounts of triglycerides can be formed without the disadvantages of conventional triglyceride- containing compositions by using a combination of surfactants and triglycerides in amounts such that when the pharmaceutical composition is mixed with an aqueous solution, a clear aqueous dispersion is formed. Such compositions can be co-administered with a therapeutic agent to increase the rate and/or extend of bioabsorption of the therapeutic agent, or can be provided with a therapeutic agent in the preconcentrate composition or in the diluent solution.
  • the present invention relates to pharmaceutical compositions having a triglyceride and a carrier, the carrier including at least two surfactants, at least one of which is hydrophilic.
  • the triglyceride and surfactants are present in amounts such that upon mixing with an aqueous solution, either in vitro or in vivo, the composition forms a clear aqueous dispersion.
  • the composition is capable of containing more triglyceride than can be solubilized in a clear aqueous dispersion having only one surfactant, the surfactant being hydrophilic.
  • the present invention relates to pharmaceutical compositions having a triglyceride and a carrier, the carrier including at least one hydrophilic surfactant and at least one hydrophobic surfactant.
  • the triglyceride and surfactants are present in amounts such that upon mixing with an aqueous solution, either in vitro or in vivo, the composition forms a clear aqueous dispersion.
  • the composition is capable of containing more triglyceride than can be solubilized in a clear aqueous dispersion having a hydrophilic surfactant but not having a hydrophobic surfactant..
  • the triglyceride itself can have therapeutic value as, for example, a nutritional oil, or absorption-promoting value as, for example, a long-chain triglyceride ("LCT", having fatty acid chains longer than C 10 and preferably Cj 2 - C 22 ) or a medium-chain triglyceride ("MCT", having C 6 -C 10 fatty acid chains).
  • LCT long-chain triglyceride
  • MCT medium-chain triglyceride
  • the present invention provides pharmaceutical compositions including a triglyceride having nutritional and/or absorption-promoting value, and a carrier.
  • the carrier includes at least two surfactants, at least one of which is hydrophilic.
  • the carrier can include at least one hydrophilic surfactant and at least one hydrophobic surfactant.
  • the triglyceride and surfactants are present in amounts such that upon dilution with an aqueous solution, either in vitro or in vivo, the composition forms a clear
  • the present invention relates to methods of increasing the amount of triglyceride that can be solubilized in an aqueous system, by providing a composition including a triglyceride and a carrier, the carrier including at least two surfactants, at least one of which is hydrophilic, and dispersing the composition in an aqueous solution so that a clear aqueous dispersion is formed.
  • the triglyceride is capable of being solubilized in an amount greater than the amount of the triglyceride that remains solubilized in an aqueous dispersion of the triglyceride and a carrier having only one surfactant and having the same total surfactant concentration.
  • the carrier can include at least one hydrophilic surfactant and at least one hydrophobic surfactant.
  • the present invention relates to triglyceride-containing pharmaceutical compositions as described in the preceding embodiments, which further include a therapeutic agent.
  • the therapeutic agent is a hydrophobic drug or a hydrophilic drug.
  • the therapeutic agent is a nutritional agent.
  • the therapeutic agent is a cosmeceutical agent.
  • the present invention relates to methods of increasing the solubilization of a therapeutic agent in a composition, by providing the therapeutic agent in a composition ofthe present invention.
  • the present invention relates to a pharmaceutical composition which includes a therapeutic agent, a triglyceride and a carrier.
  • the carrier includes at least two surfactants, at least one of which is hydrophilic.
  • the carrier includes at least one hydrophilic surfactant and at least one hydrophobic surfactant.
  • the triglyceride, and surfactants are present in amounts such that upon dilution with an aqueous solution, either in vitro or in vivo, the composition forms a clear aqueous dispersion.
  • the therapeutic agent is present in two amounts, a first amount of the therapeutic agent solubilized in the clear aqueous dispersion, and a second amount of the therapeutic agent that remains non-solubilized but dispersed.
  • the present invention relates to methods of increasing the rate and/or extent of absorption of therapeutic agents by administering to a patient a pharmaceutical composition of the present invention.
  • the therapeutic agent can be present in the pharmaceutical composition pre-concentrate, in the diluent, or in a second pharmaceutical composition, such as a conventional commercial formulation, which is co-administered with a pharmaceutical composition ofthe present invention.
  • the present invention overcomes the problems described above characteristic of conventional triglyceride-containing formulations by providing unique pharmaceutical compositions which form clear aqueous dispersions upon mixing with an aqueous solution.
  • compositions including triglycerides and a combination of surfactants can solubilize therapeutically effective amounts of therapeutic agents in homogeneous, single-phase systems which are thermodynamically stable and optically clear.
  • the optical clarity is indicative of a very small particle size within the aqueous dispersions, and this small particle size substantially reduces lipolysis dependence of the rate of bioabsorption, and other disadvantages of conventional triglyceride-containing formulations.
  • compositions of the present invention are surprisingly able to solubilize greater amounts of triglycerides than conventional formulations, even when the total surfactant concentration is the same as in a conventional formulation.
  • the present invention provides a pharmaceutical composition including a triglyceride and a carrier.
  • the carrier includes at least two surfactants, at least one of which is a hydrophilic surfactant.
  • the carrier includes at least one hydrophilic surfactant and at least one hydrophobic surfactant.
  • the triglyceride and surfactants are present in amounts such that upon dilution with an aqueous solution, either in vitro or in vivo, the composition forms a clear aqueous dispersion. It is a particular and surprising feature of the present invention that the composition is homogeneous and optically clear, despite the presence of substantial amounts of triglycerides, thereby providing surprising and important advantages over conventional triglyceride-containing formulations.
  • compositions of the present invention include one or more pharmaceutically acceptable triglycerides.
  • triglycerides suitable for use in the present invention are shown in Table 1. In general, these triglycerides are readily available from commercial sources. For several triglycerides, representative commercial products and/or commercial suppliers are listed. Table 1 : Triglycerides
  • Glyceryl triarchidate (Sigma)
  • Glyceryl trimyristoleate (Sigma)
  • Glyceryl tricaprylate/caprate Captex 300 (Abitec); Captex 355 (Abitec); Miglyol 810 (H ⁇ ls); Miglyol 812 (H ⁇ ls)
  • Glyceryl tricaprylate/caprate/laurate Captex 350 (Abitec)
  • Glyceryl tricaprylate/caprate/linoleate Captex 810 (Abitec); Miglyol 818 (H ⁇ ls)
  • Glyceryl tricaprylate/caprate/stearate Softisan 378 H ⁇ ls; (Larodan) Glyceryl tricaprylate/laurate/stearate (Larodan) Glyceryl l,2-caprylate-3-linoleate (Larodan) Glyceryl l,2-caprate-3-stearate (Larodan) Glyceryl l,2-laurate-3-myristate (Larodan) Glyceryl l,2-myristate-3-laurate (Larodan) Glyceryl l,3-palmitate-2-butyrate (Larodan) Glyceryl l,3-stearate-2-caprate (Larodan) Glyceryl l,2-linoleate-3-caprylate (Larodan) "
  • Fractionated triglycerides modified triglycerides, synthetic triglycerides, and mixtures of triglycerides are also within the scope ofthe invention.
  • Preferred triglycerides include vegetable oils, fish oils, animal fats, hydrogenated vegetable oils, partially hydrogenated vegetable oils, medium and long-chain triglycerides, and structured triglycerides. It should be appreciated that several commercial surfactant compositions contain small to moderate amounts of triglycerides, typically as a result of incomplete reaction of a triglyceride starting material in, for example, a transesterification reaction. Such commercial surfactant compositions, while nominally referred to as "surfactants”, may be suitable to provide all or part of the triglyceride component for the compositions of the present invention. Examples of commercial surfactant compositions containing triglycerides include some members of the surfactant families Gelucires (Gattefosse), Maisines (Gattefosse), and Imwitors (H ⁇ ls). Specific examples of these compositions are:
  • Gelucire 50/13 saturated polyglycolized glycerides
  • Gelucire 53/10 saturated polyglycolized glycerides
  • Gelucire 33/01 (semi-synthetic triglycerides of C 8 -C 18 saturated fatty acids)
  • Gelucire 39/01 (semi-synthetic glycerides) other Gelucires, such as 37/06, 43/01, 35/10, 37/02, 46/07, 48/09, 50/02, 62/05, etc.
  • Maisine 35-1 (linoleic glycerides)
  • Imwitor 742 (caprylic/capric glycerides)
  • compositions having significant triglyceride content are known to those skilled in the art. It should be appreciated that such compositions, which contain triglycerides as well as surfactants, may be suitable to provide all or part of the triglyceride component of the compositions of the present invention, as well as all or part of the surfactant component, as described below. Of course, none of the commonly known triglyceride-containing commercial surfactants alone provides the unique pharmaceutical compositions and characteristics as recited in the appended claims.
  • preferred triglycerides include: almond oil; babassu oil; borage oil; blackcurrant seed oil; canola oil; castor oil; coconut oil; com oil; cottonseed oil; evening primrose oil; grapeseed oil; groundnut oil; mustard seed oil; olive oil; palm oil; palm kernel oil; peanut oil; rapeseed oil; safflower oil; sesame oil; shark liver oil; soybean oil; sunflower oil; hydrogenated castor oil; hydrogenated coconut oil; hydrogenated palm oil; hydrogenated soybean oil; hydrogenated vegetable oil; hydrogenated cottonseed and castor oil; partially hydrogenated soybean oil; partially soy and cottonseed oil; glyceryl tricaproate; glyceryl tricaprylate; glyceryl tricaprate; glyceryl triundecanoate; glyceryl trilaurate; glyceryl trioleate; glyceryl trilinoleate; glyceryl trilinooleate; glyceryl trilin
  • triglycerides are saturated polyglycolized glycerides (Gelucire 44/14, Gelucire 50/13 and Gelucire 53/10), linoleic glycerides (Maisine 35-1), and caprylic/capric glycerides (Imwitor 742).
  • more preferred triglycerides include: coconut oil; com oil; olive oil; palm oil; peanut oil; safflower oil; sesame oil; soybean oil; hydrogenated castor oil; hydrogenated coconut oil; partially hydrogenated soybean oil; glyceryl tricaprate; glyceryl trilaurate; glyceryl trioleate; glyceryl trilinoleate; glyceryl tricaprylate/caprate; glyceryl tricaprylate/caprate/laurate; glyceryl tricaprylate/caprate/linoleate; glyceryl tricaprylate/caprate/stearate; saturated polyglycolized glycerides (Gelucire 44/14, Gelucire 50/13 and Gelucire 53/10); linoleic glycerides (Maisine 35-1); and caprylic/capric glycerides (Imwitor 742).
  • the carrier includes a combination of surfactants, at least one of which is a hydrophilic surfactant, with the remaining surfactant or surfactants being hydrophilic or hydrophobic.
  • hydrophilic and “hydrophobic” are relative terms.
  • a compound must necessarily include polar or charged hydrophilic moieties as well as non-polar hydrophobic (lipophilic) moieties; i.e., a surfactant compound must be amphiphilic.
  • An empirical parameter commonly used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (the "HLB” value).
  • HLB hydrophilic-lipophilic balance
  • hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable.
  • hydrophobic surfactants are compounds having an HLB value less than about 10.
  • HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.
  • HLB values can differ by as much as about 8 HLB units, depending upon the empirical method chosen to determine the HLB value (Schott, J. Pharm. Sciences, 79(1), 87-88 (1990)).
  • polypropylene oxide containing block copolymers polypropylene oxide containing block copolymers, available commercially as PLURONIC® surfactants, BASF Corp.
  • the HLB values may not accurately reflect the true physical chemical nature of the compounds.
  • the carrier of the present invention includes at least one hydrophilic surfactant.
  • the hydrophilic surfactant can be any surfactant suitable for use in pharmaceutical compositions. Suitable hydrophilic surfactants can be anionic, cationic, zwitterionic or non-ionic, although non-ionic hydrophilic surfactants are presently preferred.
  • the carrier includes a mixture of two or more hydrophilic surfactants, more preferably two or more non-ionic hydrophilic surfactants. Also preferred are mixtures of at least one hydrophilic surfactant, preferably non-ionic, and at least one hydrophobic surfactant.
  • surfactants should be made keeping in mind the particular triglycerides and optional therapeutic agents to be used in the composition, and the range of polarity appropriate for the chosen therapeutic agent. With these general principles in mind, a very broad range of surfactants is suitable for use in the present invention. Such surfactants can be grouped into the following general chemical classes detailed in the Tables herein.
  • the HLB values given in the Tables below generally represent the HLB value as reported by the manufacturer of the corresponding commercial product. In cases where more than one commercial product is listed, the HLB value in the Tables is the value as reported for one of the commercial products, a rough average of the reported values, or a value that, in the judgment ofthe present inventors, is more reliable.
  • PEG polyethylene glycol
  • PEG-fatty acid esters have useful surfactant properties.
  • PEG-fatty acid monoesters esters of lauric acid, oleic acid, and stearic acid are especially useful.
  • preferred hydrophilic surfactants include PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG- 10 laurate, PEG- 10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20 laurate and PEG-20 oleate. Examples of polyethoxylated fatty acid monoester surfactants commercially available are shown in Table 2.
  • PEG-8 oleate Mapeg® 400 MO PPG
  • Emulgante A8 Condea
  • Kessco PEG 400 12 MO Steppan
  • Kessco® PEG 1000 MO 15 PEG-20 stearate Mapeg® 1000 MS (PPG), Kessco® PEG 1000 MS (Stepan), Myrj 16
  • Polyethylene glycol (PEG) fatty acid diesters are also suitable for use as surfactants in the compositions of the present invention.
  • preferred hydrophilic surfactants include PEG-20 dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate and PEG-32 dioleate.
  • Representative PEG-fatty acid diesters are shown in Table 3.
  • Table 3 PEG-Fatty Acid Diester Surfactants
  • PEG-4 dilaurate Mapeg® 200 DL PPG
  • Kessco® PEG 200 DL Steppan
  • LIPOPEG 7 2-DL Lipo Chem.
  • PEG-8 dilaurate Mapeg® 400 DL PPG
  • Kessco® PEG 400 DL Steppan
  • LIPOPEG 11 4 DL LIPOPEG 11 4 DL
  • mixtures of surfactants are also useful in the present invention, including mixtures of two or more commercial surfactant products.
  • PEG-fatty acid esters are marketed commercially as mixtures or mono- and diesters.
  • Representative surfactant mixtures are shown in Table 4.
  • Suitable PEG glycerol fatty acid esters are shown in Table 5.
  • preferred hydrophilic surfactants are PEG-20 glyceryl laurate, 0 PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, and PEG-30 glyceryl oleate.
  • a large number of surfactants of different degrees of hydrophobicity or hydrophilicity can be prepared by reaction of alcohols or polyalcohols with a variety of natural and/or hydrogenated oils.
  • the oils used are castor oil or hydrogenated castor oil, or an edible vegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil, apricot kernel oil, or almond oil.
  • Preferred alcohols include glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, and pentaerythritol.
  • preferred hydrophilic surfactants are PEG-35 castor oil (Incrocas-35), PEG-40 hydrogenated castor oil (Cremophor RH 40), PEG-25 trioleate (TAGAT® TO), PEG-60 com glycerides (Crovol M70), PEG-60 almond oil (Crovol A70), PEG-40 palm kernel oil (Crovol PK70), PEG-50 castor oil (Emalex C- 50), PEG-50 hydrogenated castor oil (Emalex HC-50), PEG-8 caprylic/capric glycerides (Labrasol), and PEG-6 caprylic/capric glycerides (Softigen 767).
  • Preferred hydrophobic surfactants in this class include PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6 com oil (Labrafil® M 2125 CS), PEG-6 almond oil (Labrafil® M 1966 CS), PEG-6 apricot kernel oil (Labrafil® M 1944 CS), PEG-6 olive oil (Labrafil® M 1980 CS), PEG-6 peanut oil (Labrafil® M 1969 CS), PEG- 6 hydrogenated palm kernel oil (Labrafil® M 2130 BS), PEG-6 palm kernel oil (Labrafil® M 2130 CS), PEG-6 triolein (Labrafil® M 2735 CS), PEG-8 com oil (Labrafil® WL 2609 BS), PEG-20 com glycerides (Crovol M40), and PEG-20 almond glycerides (Crovol A40).
  • PEG-40 hydrogenated castor oil Cremophor RH 40 (BASF), Croduret (Croda), Emulgin HRE 40 13 (Henkel)
  • PEG-8 caprylic/capric glycerides Labrasol (Gattefosse),Labrafac CM 10 (Gattefosse) >10
  • Pentaerythrityl Liponate PE-810 (Lipo Chem.), Crodamol PTC (Croda) ⁇ 10 tetracaprylate/tetracaprate
  • oils in this category of surfactants are oil-soluble vitamins, such as vitamins A, D, E, K, etc.
  • derivatives of these vitamins such as tocopheryl PEG- 15 1000 succinate (TPGS, available from Eastman), are also suitable surfactants.
  • TPGS tocopheryl PEG- 15 1000 succinate
  • Polyglycerol esters of fatty acids are also suitable surfactants for the present invention.
  • preferred hydrophobic surfactants include polyglyceryl oleate (Plurol Oleique), polyglyceryl-2 dioleate (Nikkol DGDO), and 0 polyglyceryl-10 trioleate.
  • Preferred hydrophilic surfactants include polyglyceryl-10 laurate (Nikkol Decaglyn 1-L), polyglyceryl-10 oleate (Nikkol Decaglyn l-O), and polyglyceryl-10 mono, dioleate (Caprol® PEG 860).
  • Polyglyceryl polyricinoleates Polymuls
  • Examples of suitable polyglyceryl esters are shown in Table 7. 5
  • Polyglyceryl-6 pentaoleate Nikkol Hexaglyn 5-0 (Nikko) ⁇ 10 Polyglyceryl-3 dioleate Cremophor G032 (BASF) ⁇ 10 Polyglyceryl-3 distearate Cremophor GS32 (BASF) ⁇ 10 Polyglyceryl-4 pentaoleate Nikkol Tetraglyn 5-0 (Nikko) ⁇ 10 Polyglyceryl-6 dioleate Caprol® 6G20 (ABITEC); Hodag PGO-62 (Calgene), PLUROL 8.5 OLEIQUE CC 497 (Gattefosse)
  • esters of propylene glycol and fatty acids are suitable surfactants for use in the present invention.
  • preferred hydrophobic surfactants include propylene glycol monolaurate (Lauroglycol FCC), propylene glycol ricinoleate (Propymuls), propylene glycol monooleate (Myverol P-O6), propylene glycol dicaprylate/dicaprate (Captex® 200), and propylene glycol dioctanoate (Captex® 800). Examples of surfactants of this class are given in Table 8.
  • Propylene glycol LABRAFAC PG (Gattefosse) >6 caprylate/caprate Propylene glycol dilaurate >6 Propylene glycol distearate Kessco® PGDS (Stepan) >6 Propylene glycol dicaprylate Nikkol Sefsol 228 (Nikko) >6 Propylene glycol dicaprate Nikkol PDD (Nikko) >6
  • mixtures of surfactants are also suitable for use in the present invention.
  • mixtures of propylene glycol fatty acid esters and glycerol fatty acid esters are suitable and are commercially available.
  • One preferred mixture is composed of the oleic acid esters of propylene glycol and glycerol (Arlacel 186). Examples of these surfactants are shown in Table 9.
  • a particularly important class of surfactants is the class of mono- and diglycerides.
  • surfactants are generally hydrophobic.
  • Preferred hydrophobic surfactants in this class of compounds include glyceryl monooleate (Peceol), glyceryl ricinoleate, glyceryl laurate, glyceryl dilaurate (Capmul® GDL), glyceryl dioleate (Capmul® GDO), glyceryl mono/dioleate (Capmul® GMO-K), glyceryl caprylate/caprate (Capmul® MCM), caprylic acid mono/diglycerides (Imwitor® 988), and mono- and diacetylated monoglycerides
  • Glyceryl monooleate C 18 : 1
  • PECEOL Geattefosse
  • Hodag GMO-D Hodag GMO-D
  • Nikkol MGO Nikko
  • Glyceryl monooleate RYLO series (Danisco), DIMODAN series (Danisco), EMULDAN 3-4 (Danisco), ALDO® MO FG (Lonza), Kessco GMO (Stepan), MONOMULS® series (Henkel), TEGIN O, DREWMULSE GMO (Stepan), Atlas G-695 (ICI), GMOrphic 80 (Eastman), ADM DMG-40, 70, and 100 (ADM), Myverol (Eastman)
  • Glycerol monolinoleate Maisine (Gattefosse), MYVEROL 18-92, Myverol 18-06 (Eastman) 3-4
  • Glyceryl ricinoleate Softigen® 701 Hiils
  • HODAG GMR-D Calgene
  • Glycerol monostearate Capmul® GMS (ABITEC), Myvaplex (Eastman), IMWITOR® 191 5-9 (H ⁇ ls), CUTINA GMS, Aldo® MS (Lonza), Nikkol MGS series (Nikko)
  • Glyceryl acetate Lamegin® EE (Griinau GmbH) ⁇ 10 Glyceryl laurate Imwitor® 312 (H ⁇ ls), Monomuls® 90-45 (Gr ⁇ nau GmbH), Aldo® MLD (Lonza)
  • Glyceryl caprylate Imwitor® 308 H ⁇ ls
  • Capmul® MCMC8 (ABITEC) 5-6
  • Lactic acid esters of LAMEGIN GLP (Henkel) ⁇ 10 mono,diglycerides
  • Glycerol esters of fatty acids GELUCIRE 39/01 (Gattefosse), GELUCIRE 43/01 (Gattefosse) 1
  • Sterols and derivatives of sterols are suitable surfactants for use in the present invention. These surfactants can be hydrophilic or hydrophobic. Preferred derivatives include the polyethylene glycol derivatives. A preferred hydrophobic surfactant in this class is cholesterol. A preferred hydrophilic surfactant in this class is PEG-24 cholesterol
  • PEG-sorbitan fatty acid esters are available and are suitable for use as surfactants in the present invention.
  • these surfactants are hydrophilic, although several hydrophobic surfactants of this class can be used.
  • preferred hydrophilic surfactants include PEG-20 sorbitan monolaurate
  • Tween-20 PEG-20 sorbitan monopalmitate (Tween-40), PEG-20 sorbitan monostearate (Tween-60), and PEG-20 sorbitan monooleate (Tween-80).
  • Tween-20 PEG-20 sorbitan monopalmitate
  • Tween-60 PEG-20 sorbitan monostearate
  • Tween-80 PEG-20 sorbitan monooleate
  • Ethers of polyethylene glycol and alkyl alcohols are suitable surfactants for use in the present invention.
  • Preferred hydrophobic ethers include PEG-3 oleyl ether (Volpo 3) and PEG-4 lauryl ether (Brij 30). Examples of these surfactants are shown in Table 13.
  • esters of sugars are suitable surfactants for use in the present invention.
  • Preferred hydrophilic surfactants in this class include sucrose monopalmitate and sucrose monolaurate. Examples of such surfactants are shown in Table 14.
  • Sucrose distearate SUCRO ESTER 7 (Gattefosse), Crodesta F- 10 (Croda) 3
  • Sucrose distearate/monostearate SUCRO ESTER 11 (Gattefosse), Crodesta F-l 10 (Croda) 12 Sucrose dipalmitate 7.4
  • hydrophilic PEG-alkyl phenol surfactants are available, and are suitable for use in the present invention. Examples of these surfactants are shown in Table 15.
  • the POE-POP block copolymers are a unique class of polymeric surfactants.
  • the unique stmcture of the surfactants, with hydrophilic POE and hydrophobic POP moieties in well-defined ratios and positions, provides a wide variety of surfactants suitable for use in the present invention.
  • These surfactants are available under various trade names, including Synperonic PE series (ICI); Pluronic® series (BASF), Emkalyx, Lutrol (BASF),
  • polystyrene resin (CAS 9003-11-6). These polymers have the formula:
  • Preferred hydrophilic surfactants of this class include Poloxamers 108, 188, 217,
  • hydrophobic surfactants in this class include
  • Poloxamers 124, 182, 183, 212, 331, and 335 examples of suitable surfactants of this class are shown in Table 16. Since the compounds are widely available, commercial sources are not listed in the Table. The compounds are listed by generic name, with the corresponding "a" and "b" values.
  • Sorbitan Fatty Acid Esters Sorbitan esters of fatty acids are suitable surfactants for use in the present invention. Among these esters, preferred hydrophobic surfactants include sorbitan monolaurate (Arlacel 20), sorbitan monopalmitate (Span-40), sorbitan monooleate (Span- 80), sorbitan monostearate, and sorbitan tristearate. Examples of these surfactants are shown in Table 17.
  • Sorbitan monolaurate Span-20 (Atlas/ICI), Crill 1 (Croda), Arlacel 20 (ICI) 8.6 Sorbitan monopalmitate Span-40 (Atlas/ICI), Crill 2 (Croda), Nikkol SP-10 (Nikko) 6.7
  • Sorbitan monostearate Span-60 (Atlas/ICI), Crill 3 (Croda), Nikkol SS-10 (Nikko) 4.7
  • Sorbitan sesquioleate Arlacel-C (ICI), Crill 43 (Croda), Nikkol SO- 15 (Nikko) 3.7
  • Esters of lower alcohols (C to C 4 ) and fatty acids (C 8 to 8 ) are suitable surfactants for use in the present invention.
  • preferred hydrophobic surfactants include ethyl oleate (Crodamol EO), isopropyl myristate (Crodamol IPM), and isopropyl palmitate (Crodamol IPP). Examples of these surfactants are shown in Table 18.
  • Ionic surfactants including cationic, anionic and zwitterionic surfactants, are suitable hydrophilic surfactants for use in the present invention.
  • Preferred anionic surfactants include fatty acid salts and bile salts.
  • Preferred cationic surfactants include carnitines.
  • preferred ionic surfactants include sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, sodium cholate, sodium taurocholate; lauroyl camitine; palmitoyl camitine; and myristoyl camitine. Examples of such surfactants are shown in Table 19. For simplicity, typical counterions are shown in the entries in the Table.
  • any bioacceptable counterion may be used.
  • the fatty acids are shown as sodium salts, other cation counterions can also be used, such as alkali metal cations or ammonium.
  • these ionic surfactants are generally available as pure compounds, rather than commercial (proprietary) mixtures. Because these compounds are readily available from a variety of commercial suppliers, such as Aldrich, Sigma, and the like, commercial sources are not generally listed in the Table.
  • Ether carboxylates (by oxidation of terminal OH group of fatty alcohol ethoxylates)
  • Citric acid esters of mono-, diglycerides are Citric acid esters of mono-, diglycerides
  • Acyl lactylates lactylic esters of fatty acids calcium/sodium stearoyl-2-lactylate calcium/sodium stearoyl lactylate r.p. Alginate salts
  • Betaines (trialkylglycine):
  • Ionizable surfactants when present in their unionized (neutral, non-salt) form, are hydrophobic surfactants suitable for use in the compositions and methods of the present invention.
  • Particular examples of such surfactants include free fatty acids, particularly C 6 - C 22 fatty acids, and bile acids.
  • suitable unionized ionizable surfactants include the free fatty acid and bile acid forms of any of the fatty acid salts and bile salts shown in Table 19.
  • the carrier includes at least one hydrophilic surfactant.
  • Preferred non-ionic hydrophilic surfactants include alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene- polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols with fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sugar esters, sugar ethers; sucroglycerides
  • the non-ionic hydrophilic surfactant is selected from the group consisting of polyoxyethylene alkylethers; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglyceryl fatty acid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils; and polyoxyethylene hydrogenated vegetable oils.
  • the glyceride can be a monoglyceride, diglyceride, triglyceride, or a mixture.
  • non-ionic hydrophilic surfactants that are reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils or sterols. These reaction mixtures are largely composed of the transesterification products of the reaction, along with often complex mixtures of other reaction products.
  • the polyol is preferably glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.
  • carrier compositions are those which include as a non-ionic hydrophilic surfactant PEG- 10 laurate, PEG-12 laurate, PEG-20 laurate, PEG- 32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl
  • PEG-20 laurate PEG-20 oleate
  • PEG-35 castor oil PEG-40 palm kernel oil
  • PEG-40 hydrogenated castor oil PEG- 60 com oil
  • PEG-25 glyceryl trioleate polyglyceryl-10 laurate
  • PEG-6 caprate/caprylate glycerides PEG-8 caprate/caprylate glycerides
  • PEG-30 cholesterol polysorbate 20
  • polysorbate 80 POE-9 lauryl ether
  • POE-23 lauryl ether POE- 10 oleyl ether
  • PEG-24 cholesterol sucrose monostearate
  • sucrose monolaurate and poloxamers PEG-20 laurate
  • PEG-40 hydrogenated castor oil PEG- 60 com oil
  • PEG-25 glyceryl trioleate polyglyceryl-10 laurate
  • PEG-6 caprate/caprylate glycerides PEG-8
  • PEG-35 castor oil PEG-40 hydrogenated castor oil, PEG-60 com oil, PEG-25 glyceryl trioleate, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polysorbate 20, polysorbate 80, tocopheryl PEG-1000 succinate, PEG-24 cholesterol, and hydrophilic poloxamers.
  • the hydrophilic surfactant can also be, or include as a component, an ionic surfactant.
  • Preferred ionic surfactants include alkyl ammonium salts; bile acids and salts, analogues, and derivatives thereof; fusidic acid and derivatives thereof; fatty acid derivatives of amino acids, ohgopeptides, and polypeptides; glyceride derivatives of amino acids, ohgopeptides, and polypeptides; acyl lactylates; mono-,diacetylated tartaric acid esters of mono-,diglycerides; succinylated monoglycerides; citric acid esters of mono- jdiglycerides; alginate salts; propylene glycol alginate; lecithins and hydrogenated lecithins; lysolecithin and hydrogenated lysolecithins; lysophospholipids and derivatives thereof; phospholipids and derivatives thereof; salts of alky
  • More preferable ionic surfactants include bile acids and salts, analogues, and derivatives thereof; lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; salts of alkylsulfates; salts of fatty acids; sodium docusate; acyl lactylates; mono-,diacetylated tartaric acid esters of mono-,diglycerides; succinylated monoglycerides; citric acid esters of mono-,diglycerides; camitines; and mixtures thereof.
  • prefe ⁇ ed ionic surfactants are lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholate, taurocholate, glycocholate, deoxycholate, tau
  • Particularly prefe ⁇ ed ionic surfactants are lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, lysophosphatidylcholine, PEG-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholate, taurocholate, glycocholate, deoxycholate, taurodeoxycholate, glycodeoxycholate, cholylsarcosine, caproate, caprylate, caprate, laurate, oleate, lauryl sulfate, docusate, and salts and mixtures thereof, with the most preferred ionic surfactants being le
  • the carrier of the present compositions includes at least two surfactants, at least one of which is hydrophilic.
  • the present invention includes at two surfactants that are hydrophilic, and preferred hydrophilic surfactants are listed above.
  • the carrier includes at least one hydrophilic surfactant and at least one hydrophobic surfactant.
  • preferred hydrophobic surfactants are alcohols; polyoxyethylene alkylethers; fatty acids; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polypropylene glycol fatty acid esters; polyoxyethylene glycerides; lactic acid derivatives of mono/diglycerides; propylene glycol diglycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; transesterified vegetable oils; sterols; sterol derivatives; sugar esters; sugar ethers; sucroglycerides; polyoxyethylene vegetable oils; and polyoxyethylene hydrogenated vegetable oils.
  • hydrophobic surfactants can be reaction mixtures of polyols and fatty acids, glycer
  • the hydrophobic surfactant is selected from the group consisting of fatty acids; lower alcohol fatty acid esters; polyethylene glycol glycerol fatty acid esters; polypropylene glycol fatty acid esters; polyoxyethylene glycerides; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lactic acid derivatives of mono/diglycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene- polyoxypropylene block copolymers; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; and reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
  • lower alcohol fatty acids esters More preferred are lower alcohol fatty acids esters; polypropylene glycol fatty acid esters; propylene glycol fatty acid esters; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lactic acid derivatives of mono/diglycerides; sorbitan fatty acid esters; polyoxyethylene vegetable oils; and mixtures thereof, with glycerol fatty acid esters and acetylated glycerol fatty acid esters being most preferred.
  • the esters are preferably mono- or diglycerides, or mixtures of mono- and diglycerides, where the fatty acid moiety is a C 6 to C 22 fatty acid.
  • hydrophobic surfactants which are the reaction mixture of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
  • Preferred polyols are polyethylene glycol, sorbitol, propylene glycol, and pentaerythritol.
  • hydrophobic surfactants include myristic acid; oleic acid; lauric acid; stearic acid; palmitic acid; PEG 1-4 stearate; PEG 2-4 oleate; PEG-4 dilaurate; PEG-4 dioleate; PEG-4 distearate; PEG-6 dioleate; PEG-6 distearate; PEG-8 dioleate; PEG 3-16 castor oil; PEG 5-10 hydrogenated castor oil; PEG 6-20 com oil; PEG 6-20 almond oil; PEG-6 olive oil; PEG-6 peanut oil; PEG-6 palm kernel oil; PEG-6 hydrogenated palm kernel oil; PEG-4 capric/caprylic triglyceride, mono, di, tri, tetra esters of vegetable oil and sorbitol; pentaerythrityl di, tetra stearate, isostearate, oleate, caprylate, or caprate; polyglyceryl 2-4 oleate
  • hydrophobic surfactants most preferred are oleic acid; lauric acid; glyceryl monocaprate; glyceryl monocaprylate; glyceryl monolaurate; glyceryl monooleate; glyceryl dicaprate; glyceryl dicaprylate; glyceryl dilaurate; glyceryl dioleate; acetylated monoglycerides; propylene glycol oleate; propylene glycol laurate; polyglyceryl-3 oleate; polyglyceryl-6 dioleate; PEG-6 com oil; PEG-20 com oil; PEG-20 almond oil; sorbitan monooleate; sorbitan monolaurate; POE-4 lauryl ether; POE-3 oleyl ether; ethyl oleate; and poloxamers. 3. Therapeutic Agents
  • the therapeutic agents suitable for use in the pharmaceutical compositions and methods of the present invention are not particularly limited, as the compositions are surprisingly capable of solubilizing and delivering a wide variety of therapeutic agents.
  • the therapeutic agents can be hydrophilic, lipophilic, amphiphilic or hydrophobic, and can be solubilized in the triglyceride; solubilized in the carrier; solubilized in both the triglyceride and the carrier; or present in the diluent.
  • the therapeutic agent can be present in a first, solubilzed amount, and a second, non-solubilized (suspended) amount.
  • Such therapeutic agents can be any agents having therapeutic or other value when administered to an animal, particularly to a mammal, such as drugs, nutrients, and cosmetics (cosmeceuticals). It should be understood that while the invention is described with particular reference to its value in the form of aqueous dispersions, the invention is not so limited. Thus, dmgs, nutrients or cosmetics which derive their therapeutic or other value from, for example, topical or transdermal administration, are still considered to be suitable for use in the present invention.
  • therapeutic agents that can be used in the pharmaceutical compositions of the present invention include analgesics and anti- inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-asthma agents, antibacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-
  • the therapeutic agent is a nutritional agent. In another embodiment, the therapeutic agent is a cosmeceutical agent.
  • the therapeutic agent is a protein, peptide or oligonucleotide.
  • the therapeutic agent is a protein, peptidomimetic, DNA, RNA, ohgodeoxynucleotide, genetic material, peptide or oligonucleotide having a molecular weight of less than about 1000 g/mol.
  • the therapeutic agent is hydrophobic. Hydrophobic therapeutic agents are compounds with little or no water solubility. Intrinsic water solubilities (i.e., water solubility of the unionized form) for hydrophobic therapeutic agents are less than about 1% by weight, and typically less than about 0.1% or 0.01% by weight. In a particular aspect of this embodiment, the therapeutic agent is a hydrophobic
  • the therapeutic agent is a hydrophobic dmg having a molecular weight of less than about 1000 g/mol.
  • the therapeutic agent is hydrophilic.
  • Amphiphilic therapeutic agents are included within the class of hydrophilic therapeutic agents.
  • Apparent water solubilities for hydrophilic therapeutic agents are greater than about 1% by
  • the therapeutic agent is a hydrophilic dmg.
  • the therapeutic agent is a hydrophilic dmg having a molecular weight of less than about 1000 g/mol.
  • therapeutic agents suitable for use in the compositions and methods of the present invention include the following representative compounds, as well as their pharmaceutically acceptable salts, isomers, esters, ethers and other derivatives: abacavir, acarbose, acebutolol, acetazolamide, acetohexamide, acrivastine, acutretin, acyclovir, alatrofloxacin, albendazole, albuterol, alclofenac, alendronate, allopurinol, aloxiprin, alprazolam, alprenolol, alprostadil, amantadine, amiloride, aminoglutethimide, amiodarone, amiodarone HCl, amitriptyline, amlodipine, , amodiaquine, amoxapine, amoxapine, amphetamine, amphotericin, amprenavir, amrinone
  • the components of the pharmaceutical compositions of the present invention in amounts such that upon dilution with an aqueous solution, the composition forms a clear, aqueous dispersion.
  • concentrations of components to form clear aqueous dispersions are the concentrations of triglyceride and surfactants, with the amount of the therapeutic agent, if present, being chosen as described below.
  • the relative amounts of triglycerides and surfactants are readily determined by observing the properties of the resultant dispersion; i.e., when the relative amounts of these components are within a suitable range, the resultant aqueous dispersion is optically clear.
  • the resulting dispersion is visibly "cloudy", resembling a conventional emulsion or multiple-phase system.
  • a visibly cloudy solution may be potentially useful for some applications, such a system would suffer from many of the same disadvantages as conventional prior art formulations, as described above.
  • a convenient method of determining the appropriate relative concentrations for any particular triglyceride is as follows. A convenient working amount of a hydrophilic surfactant is provided, and a known amount of the triglyceride is added. The mixture is sti ⁇ ed, with the aid of gentle heating if desired, then is diluted with purified water to prepare an aqueous dispersion. Any dilution amount can be chosen, but convenient dilutions are those within the range expected in vivo, about a 10 to 250-fold dilution. In the Examples herein, a convenient dilution of 100-fold was chosen. The aqueous dispersion is then assessed qualitatively for optical clarity.
  • the procedure can be repeated with incremental variations in the relative amount of triglyceride added, to determine the maximum relative amount of triglyceride that can be present to form a clear aqueous dispersion with a given hydrophilic surfactant. I.e., when the relative amount of triglyceride is too great, a hazy or cloudy dispersion is formed.
  • the amount of triglyceride that can be solubilized in a clear aqueous dispersion is increased by repeating the above procedure, but substituting a second hydrophilic surfactant, or a hydrophobic surfactant, for part of the originally-used hydrophilic surfactant, thus keeping the total surfactant concentration constant.
  • a second hydrophilic surfactant or a hydrophobic surfactant, for part of the originally-used hydrophilic surfactant, thus keeping the total surfactant concentration constant.
  • this procedure is merely exemplary, and the amounts of the components can be chosen using other methods, as desired.
  • mixtures of surfactants including two hydrophilic surfactants can solubilize a greater relative amount of triglyceride than a single surfactant.
  • mixtures of surfactants including a hydrophilic surfactant and a hydrophobic surfactant can solubilize a greater relative amount of triglyceride than either surfactant by itself. It is particularly surprising that when the surfactant mixture includes a hydrophilic surfactant and a hydrophobic surfactant, the solubility of the triglyceride is greater than, for example, in the hydrophilic surfactant itself.
  • 4,719,239 shows optically clear compositions containing water, oil, and a 3:7 mixture of PEG-glycerol monooleate and caprylic-capric acid glycerol esters, but the compositions contain no more that about 75% by weight water, or a dilution of the pre- concentrate of no more than 3 to 1.
  • the compositions of the cited reference phase-separate into multi-phase systems as is shown, for example, in the phase diagram of Figure 2 in the '239 patent.
  • compositions of the present invention when diluted to values typical of dilutions encountered in vivo, or when diluted in vivo upon administration to a patient, remain as clear aqueous dispersions.
  • the clear aqueous dispersions ofthe present invention are formed upon dilution of about 10 to about 250- fold or more.
  • the optical clarity of the aqueous dispersion can be measured using standard quantitative techniques for turbidity assessment.
  • One convenient procedure to measure turbidity is to measure the amount of light of a given wavelength transmitted by the solution, using, for example, a UV-visible spectrophotometer. Using this measure, optical clarity corresponds to high transmittance, since cloudier solutions will scatter more ofthe incident radiation, resulting in lower transmittance measurements. If this procedure is used, care should be taken to insure that the composition itself does not absorb light of the chosen wavelength, as any tme absorbance necessarily reduces the amount of transmitted light and falsely increases the quantitative turbidity value.
  • suitable dispersions at a dilution of 100X should have an apparent absorbance of less than about 0.3, preferably less than about 0.2, and more preferably less than about 0.1.
  • optical clarity such as direct particle size measurement and other methods known in the art may also be used.
  • the therapeutic agent is solubilized in the triglyceride, the carrier, or in both the triglyceride and the carrier.
  • the therapeutic agent can be solubilized in the aqueous medium used to dilute the preconcentrate to form an aqueous dispersion.
  • the maximum amount of therapeutic agent that can be solubilized is readily determined by simple mixing, as the presence of any non-solubilized therapeutic agent is apparent upon visual examination.
  • the therapeutic agent is present in an amount up to the maximum amount that can be solubilized in the composition.
  • the therapeutic agent is present in a first amount which is solubilized, and a second amount that remains unsolubilized but dispersed. This may be desirable when, for example, a larger dose of the therapeutic agent is desired.
  • a composition presents advantages over conventional compositions, since at least a portion of the therapeutic agent is present in the clear aqueous dispersion phase.
  • the optical clarity of the resultant aqueous dispersion is determined before the second non-solubilized amount ofthe therapeutic agent is added.
  • the pharmaceutical compositions of the present invention can optionally include additional compounds to enhance the solubility of the therapeutic agent or the triglyceride in the composition.
  • additional compounds include: 0 alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; 5 ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofur
  • solubilizers are also within the scope of the invention. Except as indicated, these compounds are readily available from standard commercial sources.
  • Prefe ⁇ ed solubilizers include triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide.
  • Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
  • the amount of solubilizer that can be included in compositions of the present invention is not particularly limited.
  • the amount of a given solubilizer is limited to a bioacceptable amount, which is readily determined by one of skill in the art.
  • the solubilizer can be in a concentration of 50%, 100%, 200%, or up to about 400% by weight, based on the amount of surfactant.
  • solubilizers may also be used, such as 25%, 10%, 5%, 1% or even less.
  • solubilizer will be present in an amount of about 1% to about 100%, more typically about 5% to about 25% by weight or about 10% to about 25%o by weight.
  • the compositions can include an enzyme inhibiting agent.
  • Enzyme inhibiting agents are shown for example, in Bemskop-Schnurch, A., "The use of inhibitory agents to overcome enzymatic barrier to perorally administered therapeutic peptides and proteins", J. Controlled Release 52, 1-16 (1998), the disclosure of which is incorporated herein by reference.
  • inhibitory agents can be divided into the following classes: Inhibitors that are not based on amino acids, such as P-aminobenzamidine, FK- 448, camostat mesylate, sodium glycocholate;
  • Amino acids and modified amino acids such as aminoboronic acid derivatives and n-acetylcysteine
  • Peptides and modified peptides such as bacitracin, phosphinic acid dipeptide derivatives, pepstatin, antipain, leupeptin, chymostatin, elastatin, bestatin, hosphoramindon, puromycin, cytochalasin potatocarboxy peptidase inhibitor, and amastatin;
  • Polypeptide protese inhibitors such as aprotinin (bovine pancreatic trypsin inhibitor), Bowman-Birk inhibitor and soybean trypsin inhibitor, chicken egg white trypsin inhibitor, chicken ovoinhibitor, and human pancreatic trypsin inhibitor.
  • Complexing agents such as EDTA, EGTA, 1,10- phenanthroline and hydroxychinoline;
  • Mucoadhesive polymers and polymer-inhibitor conjugates such as polyacrylate derivatives, chitosan, cellulosics, chitosan-EDTA, chitosan-EDTA-antipain, polyacrylic acid-bacitracin, carboxymethyl cellulose-pepstatin, polyacrylic acid-B woman-Birk inhibitor.
  • the choice and levels of the enzyme inhibitor are based on toxicity, specificity of the proteases and the potency of the inhibition.
  • the inhibitor can be suspended or solubilized in the composition preconcentrate, or added to the aqueous diluent or as a beverage.
  • an inhibitor can function solely or in combination as: a competitive inhibitor, by binding at the substrate binding site of the enzyme, thereby preventing the access to the substrate; examples of inhibitors believed to operate by this mechanism are antipain, elastatinal and the Bowman Birk inhibitor; a non-competitive inhibitor which can be simultaneously bound to the enzyme site along with the substrate, as their binding sites are not identical; and/or a complexing agent due to loss in enzymatic activity caused by deprivation of essential metal ions out ofthe enzyme stmcture. 7.
  • a competitive inhibitor by binding at the substrate binding site of the enzyme, thereby preventing the access to the substrate
  • examples of inhibitors believed to operate by this mechanism are antipain, elastatinal and the Bowman Birk inhibitor
  • a non-competitive inhibitor which can be simultaneously bound to the enzyme site along with the substrate, as their binding sites are not identical
  • a complexing agent due to loss in enzymatic activity caused by deprivation of essential metal ions out ofthe enzyme s
  • additives conventionally used in pharmaceutical compositions can be included, and these additives are well known in the art.
  • additives include detackifiers, anti-foaming agents, buffering agents, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.
  • the amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired. 8. Dosage Forms
  • compositions of the present invention can be formulated as a preconcentrate in a liquid, semi-solid, or solid form, or as an aqueous or organic diluted preconcentrate.
  • the diluent can be water, an aqueous solution, a buffer, an organic solvent, a beverage, a juice, or mixtures thereof.
  • the diluent can include components soluble therein, such as a therapeutic agent, an enzyme inhibitor, solubilizers, additives, and the like.
  • compositions can be processed according to conventional processes known to those skilled in the art, such as lyophilization, encapsulation, compression, melting, extmsion, drying, chilling, molding, spraying, coating, comminution, mixing, homogenization, sonication and granulation, to produce the desired dosage form.
  • compositions of the present invention can be formulated as pills, capsules, caplets, tablets, granules, beads or powders. Granules, beads and powders can, of course, be further processed to form pills, capsules, caplets or tablets.
  • the capsule can be a hard or soft gelatin capsule, a starch capsule, or a cellulosic capsule.
  • Such dosage forms can further be coated with, for example, a seal coating or an enteric coating.
  • enteric coated capsule as used herein means a capsule coated with a coating resistant to acid; i.e., an acid resistant enteric coating.
  • Enteric coated compositions of this invention protect therapeutic peptides or proteins in a restricted area of dmg liberation and absorption, and reduce or even exclude extensive dilution effects.
  • solubilizers are typically used to enhance the solubility of a hydrophobic therapeutic agent, they may also render the compositions more suitable for encapsulation in hard or soft gelatin capsules.
  • a solubilizer such as those described above is particularly preferred in capsule dosage forms of the pharmaceutical compositions. If present, these solubilizers should be added in amounts sufficient to impart to the compositions the desired solubility enhancement or encapsulation properties.
  • compositions of the present invention can also be formulated for topical, transdermal, buccal, ocular, pulmonary, vaginal, rectal, transmucosal or parenteral administration, as well as for oral administration.
  • the dosage form can be a solution, suspension, emulsion, cream, ointment, lotion, suppository, spray, aerosol, paste, gel, drops, douche, ovule, wafer, troche, cachet, symp, elixer, or other dosage form, as desired. If formulated as a suspension, the composition can further be processed in capsule form.
  • a dosage form of a multiparticulate carrier coated onto a substrate with the pharmaceutical compositions described herein can be used.
  • the substrate can be a granule, a particle, or a bead, for example, and formed of a therapeutic agent or a pharmaceutically acceptable material.
  • the multiparticulate carrier can be enteric coated with a pharmaceutically acceptable material as is well known to those skilled in the art.
  • the triglyceride and surfactants are present in amounts such that upon mixing with an aqueous solution, either in vitro or in vivo, a clear, aqueous dispersion is formed.
  • This optical clarity in an aqueous dispersion defines the appropriate relative concentrations of the triglyceride and surfactant components, but does not restrict the dosage form of the compositions to an aqueous dispersion, nor does it limit the compositions of the invention to optically clear dosage forms.
  • the appropriate concentrations of the triglyceride and surfactants are determined by the optical clarity of a dispersion formed by the composition preconcentrate and an aqueous solution in a dilution of about 10 to about 250-fold, as a preliminary matter.
  • the pharmaceutical compositions can be formulated as described in the preceding section, without regard to the optical clarity of the ultimate formulation.
  • optically clear aqueous dispersions, and their preconcentrates are preferred formulations.
  • the present invention relates to pharmaceutical compositions having a triglyceride and a carrier, the carrier including at least two surfactants, at least one of which is hydrophilic.
  • the triglyceride and surfactants are present in amounts such that upon mixing with an aqueous solution, either in vitro or in vivo, the composition forms a clear aqueous dispersion.
  • the composition can contain more triglyceride than can be solubilized in a clear aqueous dispersion having only one surfactant, the surfactant being hydrophilic.
  • this embodiment provides a higher concentration of triglyceride than is achievable with a single hydrophilic surfactant, resulting in a reduced triglyceride to hydrophilic surfactant ratio and enhanced biocompatibility.
  • the present invention relates to pharmaceutical compositions having a triglyceride and a carrier, the carrier including at least one hydrophilic surfactant and at least one hydrophobic surfactant.
  • the triglyceride and surfactants are present in amounts such that upon mixing with an aqueous solution, either in vitro or in vivo, the composition forms a clear aqueous dispersion.
  • the composition contains more triglyceride than can be solubilized in a clear aqueous dispersion having a hydrophilic surfactant but not having a hydrophobic surfactant..
  • the triglyceride itself can have therapeutic value as, for example, a nutritional oil, or absorption-promoting value as, for example, a long-chain triglyceride (LCT) or a medium-chain triglyceride (MCT).
  • a triglyceride having nutritional and/or absorption-promoting value and a carrier.
  • the carrier includes at least two surfactants, at least one of which is hydrophilic.
  • the carrier can include at least one hydrophilic surfactant and at least one hydrophobic surfactant.
  • the present invention relates to a pharmaceutical composition which includes a therapeutic agent, a triglyceride and a carrier.
  • the carrier includes at least two surfactants, at least one of which is hydrophilic.
  • the carrier includes at least one hydrophilic surfactant and at least one hydrophobic surfactant.
  • the triglyceride, and surfactants are present in amounts such that upon dilution with an aqueous solution, either in vitro or in vivo, the composition forms a clear aqueous dispersion.
  • the therapeutic agent is present in two amounts, a first amount of the therapeutic agent solubilized in the clear aqueous dispersion, and a second amount of the therapeutic agent that remains non-solubilized but dispersed.
  • the present invention relates to triglyceride-containing pharmaceutical compositions as described in the preceding embodiments, which further include a therapeutic agent.
  • the therapeutic agent is a hydrophobic drug or a hydrophilic dmg.
  • the therapeutic agent is a nutritional agent.
  • the therapeutic agent is a cosmeceutical agent.
  • compositions of the present invention can be prepared by conventional methods well known to those skilled in the art. Of course, the specific method of preparation will depend upon the ultimate dosage form.
  • dosage forms substantially free of water i.e., when the composition is provided in a pre-concentrate form for later dispersion in vitro or in vivo in an aqueous system, the composition is prepared by simple mixing of the components to form a pre-concentrate. The mixing process can be aided by gentle heating, if desired.
  • the pre-concentrate form is prepared, then the appropriate amount of an aqueous solution is added. Upon gentle mixing, a clear aqueous dispersion is formed.
  • any water-soluble enzyme inhibitors or additives may be included, these may be added first as part of the pre-concentrate, or added later to the clear aqueous dispersion, as desired.
  • the compositions can be prepared with or without a therapeutic agent, and a therapeutic agent may also be provided in the diluent, if desired.
  • the present invention includes a multi-phase dispersion containing a therapeutic agent.
  • a pharmaceutical composition includes a triglyceride and a carrier, which forms a clear aqueous dispersion upon mixing with an aqueous solution, and an additional amount of non-solubilized therapeutic agent.
  • multi-phase as used herein to describe these compositions of the present invention means a composition which when mixed with an aqueous solution forms a clear aqueous phase and a particulate dispersion phase.
  • the carrier and triglycerides are as described above, and can include any of the surfactants, therapeutic agents, solubilizers and additives previously described. An additional amount of therapeutic agent is included in the composition.
  • the composition contains two phases: a clear aqueous dispersion of the triglyceride and surfactants containing a first, solubilized amount of the therapeutic agent, and a second, non-solubilized amount of the therapeutic agent dispersed therein.
  • a clear aqueous dispersion of the triglyceride and surfactants containing a first, solubilized amount of the therapeutic agent, and a second, non-solubilized amount of the therapeutic agent dispersed therein.
  • the resultant multi-phase dispersion will not have the optical clarity of a dispersion in which the therapeutic agent is fully solubilized, but will appear to be cloudy, due to the presence of the non-solubilized phase.
  • Such a formulation may be useful, for example, when the desired dosage of a therapeutic agent exceeds that which can be solubilized in the carrier and/or triglyceride.
  • the formulation may also contain additives, as described above.
  • a therapeutic agent may have a greater solubility in the pre-concentrate composition than in the aqueous dispersion, so that meta- stable, supersaturated solutions having apparent optical clarity but containing a therapeutic agent in an amount in excess of its solubility in the aqueous dispersion can be formed.
  • Such super-saturated solutions whether characterized as clear aqueous dispersions (as initially formed) or as multi-phase solutions (as would be expected if the meta-stable state breaks down), are also within the scope ofthe present invention.
  • the multi-phase formulation can be prepared by the methods described above.
  • a pre-concentrate is prepared by simple mixing of the components, with the aid of gentle heating, if desired. It is convenient to consider the therapeutic agent as divided into two portions, a first solubilizable portion which will be solubilized and contained within the clear aqueous dispersion upon dilution, and a second non-solubilizable portion which will remain non-solubilized. When the ultimate dosage form is non-aqueous, the first and second portions of the therapeutic agent are both included in the pre-concentrate mixture.
  • the composition can be prepared in the same manner, and upon dilution in an aqueous system, the composition will form the two phases as described above, with the second non-solubilizable portion of the therapeutic agent dispersed or suspended in the aqueous system, and the first solubilizable portion of the therapeutic agent solubilized in the composition.
  • the pre-concentrate can be prepared including only the first, solubilizable portion of the therapeutic agent. This pre-concentrate can then be diluted in an aqueous system to form a clear aqueous dispersion, to which is then added the second, non- solubilizable portion ofthe therapeutic agent to form a multi-phase aqueous composition.
  • the present invention relates to methods of increasing the solubilization of a therapeutic agent in a composition, by providing the therapeutic agent in a composition of the present invention.
  • the composition can be any of the compositions described herein, with or without a therapeutic agent. It is surprisingly found that by using the combinations of triglycerides and surfactants described herein, greater amounts of triglycerides can be solubilized, without resort to unacceptably high concentrations of hydrophilic surfactants.
  • the present invention relates to methods of increasing the rate and/or extent of absorption of therapeutic agents by administering to a patient a pharmaceutical composition of the present invention.
  • the therapeutic agent can be present in the pharmaceutical composition pre-concentrate, in the diluent, or in a second pharmaceutical composition, such as a conventional commercial formulation, which is co-administered with a pharmaceutical composition ofthe present invention.
  • a second pharmaceutical composition such as a conventional commercial formulation
  • the delivery of therapeutic agents in conventional pharmaceutical compositions can be improved by co-administering a pharmaceutical composition of the present invention with a conventional composition.
  • compositions of the present invention have the following characteristics:
  • Rapid formation upon dilution with an aqueous solution, the composition forms a clear dispersion very rapidly; i.e., the clear dispersion appears to form instantaneously.
  • the dispersions are essentially optically clear to the naked eye, and show no readily observable signs of heterogeneity, such as turbidity or cloudiness. More quantitatively, dispersions of the pharmaceutical compositions of the present invention have absorbances (400 nm) of less than about 0.3, and often less than about 0.1, at 100X dilution, as described more fully in the Examples herein. In the multi-phase embodiment ofthe compositions described herein, it should be appreciated that the optical clarity ofthe aqueous phase will be obscured by the dispersed particulate non-solubilized therapeutic agent.
  • the dispersions are surprisingly stable to dilution in aqueous solution.
  • the hydrophobic therapeutic agent remains solubilized for at least the period of time relevant for absorption.
  • conventional triglyceride-containing formulations suffer the disadvantage that bioabsorption of the therapeutic agents contained therein is dependent upon enzymatic degradation (lipolysis) of the triglyceride components.
  • the solubilization of the triglyceride in an aqueous medium is usually limited if only a hydrophilic surfactant is used to disperse the triglyceride, as is conventional.
  • the triglyceride is present in the form of relatively large oil droplets.
  • the large size of the triglyceride particles impedes the transport and absorption of the triglyceride or therapeutic agent solubilized in the triglyceride or in the carrier.
  • the large, thermodynamically unstable triglyceride particles could further impose a risk when the compositions are administered intravenously, by plugging the blood capillaries.
  • To achieve a high level of fully-solubilized triglyceride would require an amount of the hydrophilic surfactant exceeding that which would be bioacceptable.
  • compositions of the present invention solve these and other problems of the prior art by adding a third component, a hydrophobic surfactant or a second hydrophilic surfactant.
  • a third component a hydrophobic surfactant or a second hydrophilic surfactant.
  • the solubilization ofthe triglyceride in the aqueous system is thereby unexpectedly enhanced. It is also unexpectedly found that the total amount of solubilized water-insoluble components, the triglyceride and hydrophobic surfactant, can greatly exceed the amount of the hydrophobic surfactant alone that can be solubilized using the same amount ofthe hydrophilic surfactant.
  • compositions and methods of the present invention present a number of significant and unexpected advantages, including:
  • the present compositions and methods allow for increased levels of triglyceride relative to hydrophilic surfactants, thereby reducing the need for excessively large amounts of hydrophilic surfactant. Further, the triglyceride-containing compositions of the present invention present small particle sizes, thus avoiding the problems of large particle size in conventional triglyceride-containing formulations and the concomitant safety concerns in parenteral administration.
  • Efficient transport The particle sizes in the aqueous dispersions of the present invention are much smaller than the larger particles characteristic of vesicular, emulsion or microemulsion phases. This reduced particle size enables more efficient dmg transport through the intestinal aqueous boundary layer, and through the absorptive b sh border membrane. More efficient transport to absorptive sites leads to improved and more consistent absorption of therapeutic agents.
  • Less-dependence on lipolysis The lack of large particle-size triglyceride components provides pharmaceutical compositions less dependent upon lipolysis, and upon the many poorly characterized factors which affect the rate and extent of lipolysis, for effective presentation of a therapeutic agent to an absorptive site.
  • compositions which may inhibit lipolysis include the presence of composition components which may inhibit lipolysis; patient conditions which limit production of lipase, such as pancreatic lipase secretory diseases; and dependence of lipolysis on stomach pH, endogenous calcium concentration, and presence of co-lipase or other digestion enzymes.
  • the reduced lipolysis dependence further provides transport which is less prone to suffer from any lag time between administration and absorption caused by the lipolysis process, enabling a more rapid onset of therapeutic action and better bioperformance characteristics.
  • pharmaceutical compositions of the present invention can make use of hydrophilic surfactants which might otherwise be avoided or limited due to their potential lipolysis inhibiting effects.
  • Non-dependence on bile and meal fat contents Due to the higher solubilization potential over bile salt micelles, the present compositions are less dependent on endogenous bile and bile related patient disease states, and meal fat contents. These advantages overcome meal-dependent absorption problems caused by poor patient compliance with meal-dosage restrictions.
  • compositions of the present invention enable superior loading capacity over conventional formulations.
  • particular combination of surfactants used can be optimized for a specific therapeutic agent to more closely match the polarity distribution of the therapeutic agent, resulting in still further enhanced solubilization.
  • the therapeutic agents Due to the robustness of compositions of the present invention to dilution, the therapeutic agents remain solubilized and thus do not suffer problems of precipitation of the therapeutic agent in the time frame relevant for absorption.
  • the therapeutic agent is presented in small particle carriers, and is not limited in dilution rate by entrapment in emulsion carriers. These factors avoid liabilities associated with the poor partitioning of lipid solubilized dmg in to the aqueous phase, such as large emulsion droplet surface area, and high interfacial transfer resistance, and enable rapid completion ofthe critical partitioning step.
  • Aqueous dispersions of the present invention are thermodynamically stable for the time period relevant for absorption, and can be more predictably reproduced, thereby limiting variability in bioavailability— a particularly important advantage for therapeutic agents with a narrow therapeutic index.
  • Efficient release The compositions of the present invention are designed with components that help to keep the therapeutic agent or absorption promoter, such as a permeation enhancer, an enzyme inhibitor, etc., solubilized for transport to the absorption site, but readily available for absorption, thus providing a more efficient transport and release.
  • Less prone to gastric emptying delays Unlike conventional triglyceride- containing formulations, the present compositions are less prone to gastric emptying delays, resulting in faster absorption. Further, the particles in dispersions of the present invention are less prone to unwanted retention in the gastro-intestinal tract.
  • the pharmaceutical compositions of the present invention allow for faster transport of the therapeutic agent through the aqueous boundary layer.
  • a simple pre-concentrate is prepared as follows. Predetermined weighed amounts of the surfactants and triglyceride are stirred together to form a homogeneous mixture. For combinations that are poorly miscible, the mixture can be gently heated to aid in formation of the homogeneous mixture. If the composition is to include a therapeutic agent, the chosen therapeutic agent in a predetermined amount is added and stirred until solubilized. Optionally, solubilizers or additives are included by simple mixing.
  • a predetermined amount of purified water, buffer solution, or aqueous simulated physiological solution is added to the pre-concentrate, and the resultant mixture is stirred to form a clear, aqueous dispersion.
  • Example 2 Triglyceride Solubilization in Conventional Formulations
  • compositions of the present invention Conventional formulations of a triglyceride and a hydrophilic surfactant were prepared for comparison to compositions of the present invention. For each surfactant- triglyceride pair, multiple dispersions were prepared with differing amounts of the two components, to determine the maximum amount of the triglyceride that can be present while the composition still forms a clear dispersion upon a 100-fold dilution with distilled water. No therapeutic agent was included in these compositions, since it is believed that the presence ofthe therapeutic agent does not substantially affect the clear, aqueous nature of composition. For the same reason, these compositions were free of additional solubilizers and other additives. The optical clarity was determined by visual inspection and/or by UV absorption (at 400 nm). When UV absorption was used, compositions were considered to be clear when the absorption was less than about 0.2.
  • Table 20 shows the maximum amount of triglyceride present in such binary mixtures forming clear aqueous dispersions.
  • the numerical entries in the Table are in units of grams of triglyceride per 100 grams of hydrophilic surfactant.
  • Example 2 The procedure of Example 2 was repeated for compositions containing PEG-40 hydrogenated castor oil (Cremophor RH 40) or polysorbate 80 (Tween 80) as the hydrophilic surfactant, but substituting a second hydrophilic surfactant (compositions number 6-7 and 14-16) or a hydrophobic surfactant (compositions number 4-5, 8-9, and ⁇ ⁇ 17-18) for part of the hydrophilic surfactant. The total amount of hydrophilic surfactant was kept constant. The results are summarized in Table 21.
  • Tween 80 100 100 100 100 100 67 67 67 67 67 67 67 67 67
  • the clear or hazy appearance noted in the Table is that of the pre-concentrate, not of the aqueous dispersion.
  • the clarity of the aqueous dispersion is shown quantitatively by UV absorption ofthe 100X dilution at 400 nm.
  • compositions 1-3 a binary com oil-Cremophor RH-40 mixture having
  • compositions 4-5 show the surprising result that when part of the hydrophilic Cremophor RH-40 is replaced by a hydrophobic surfactant 0 (Peceol), keeping the total surfactant concentration constant, compositions having a much higher amount of triglyceride (40 grams) still form clear aqueous dispersions, with absorbances less than 0.2 and dramatically less than the comparable binary composition number 3.
  • a similar result is shown in compositions 8-9 for a different hydrophobic surfactant, Crovol M-40.
  • part of the hydrophilic surfactant is replaced by a hydrophobic surfactant 0 (Peceol)
  • compositions 6-7 25 a second hydrophilic surfactant in compositions 6-7, it is surprisingly found that the amount of triglyceride solubilized is similarly increased.
  • Table 2 IB shows a similar surprising result for a different hydrophilic surfactant, Tween 80.
  • Simple binary com oil-Tween 80 mixtures form clear aqueous dispersions with 10 grams of com oil, but are cloudy and multi -phasic
  • Example 3 Effect of Surfactant Combinations Example 3 was repeated, using different triglyceride-surfactant combinations. In particular, medium-chain triglycerides (MCTs) were used instead of com oil, a long-chain triglyceride (LCT). The results are shown in the three-part Table 22.
  • MCTs medium-chain triglycerides
  • LCT long-chain triglyceride
  • Table 22 shows that the increased solubilization of the triglyceride is observed for MCTs as well as for LCTs, with a variety of surfactants. Table 22 additionally shows that the same effect is observed in the presence of increased amounts of surfactants (compositions 23 and 27) and solubilizers (composition 23).
  • Example 5 Characterization of Compositions Various compositions were prepared and characterized by visual observation as well as by UV absorbance at 400 nm. Each composition was diluted 100-fold with distilled water. The results are shown in Table 23. Table 23: Visual and Spectroscopic Characterization
  • compositions of the present invention Prior art formulations were prepared for comparison with the compositions of the present invention. As in Example 5, the compositions were diluted 100-fold with distilled water, and characterized by visual observation and by UV absorbance. The results are shown in Table 24.
  • Patent No. 5,645,856 form milky suspensions rather than the clear aqueous dispersions of the present invention.
  • Example 7 Formulations with Therapeutic Agents Table 25 shows several formulations of compositions that can be prepared according to the present invention, using a variety of therapeutic agents.

Abstract

The present invention relates to pharmaceutical compositions and methods for improved solubilization of triglycerides and improved delivery of therapeutic agents. Compositions of the present invention include a triglyceride and a carrier, where the carrier is formed from a combination of at least two surfactants, at least one of which is hydrophilic. Upon dilution with an aqueous solvent, the composition forms a clear, aqueous dispersion of the triglyceride and surfactants. An optional therapeutic agent can be incorporated into the composition, or can be co-administered with the composition. The invention also provides methods of enhancing triglyceride solubility and methods of treatment with therapeutic agents using these compositions.

Description

CLEAR OIL-CONTAINING
PHARMACEUTICAL COMPOSITIONS
FIELD OF THE INVENTION The present invention relates to drug and nutrient delivery systems, and in particular to pharmaceutical compositions and methods for the improved solubilization of triglycerides and improved delivery of therapeutic agents.
BACKGROUND A wide variety of therapeutic agents, such as drugs, nutritional agents, and cosmeceuticals, are conventionally formulated in oil/water emulsion systems. These conventional emulsions take advantage of the increased solubility of many therapeutic agents in oils (triglycerides). Thus, one conventional approach is to solubilize a therapeutic agent in a bioacceptable triglyceride solvent, such as a digestible vegetable oil, and disperse this oil phase in an aqueous solution. The dispersion may be stabilized by emulsifying agents and provided in emulsion form. Alternatively, the therapeutic agent can be provided in a water-free formulation, with an aqueous dispersion being formed in vivo in the gastrointestinal environment. The properties of these oil-based formulations are determined by such factors as the size of the triglyceride/therapeutic agent colloidal particles and the presence or absence of surfactant additives. In simplest form, a triglyceride-containing formulation suitable for delivering therapeutic agents through an aqueous environment is an oil-in-water emulsion. Such emulsions contain the hydrophobic therapeutic agent solubilized in an oil phase which is dispersed in an aqueous environment with the aid of a surfactant. The surfactant may be present in the oil-based formulation itself, or may be a compound provided in the gastrointestinal system, such as bile salts, which are known to be in vivo emulsifying agents. The colloidal oil particles sizes are relatively large, ranging from several hundred nanometers to several microns in diameter, in a broad particle size distribution. Since the particle sizes are on the order of or greater than the wavelength range of visible light, such emulsions, when prepared in an emulsion dosage form, are visibly "cloudy" or "milky" to the naked eye.
Although conventional triglyceride-based pharmaceutical compositions are useful in solubilizing and delivering some therapeutic agents, such compositions are subject to a number of significant limitations and disadvantages. Emulsions are thermodynamically unstable, and colloidal emulsion particles will spontaneously agglomerate, eventually leading to complete phase separation. The tendency to agglomerate and phase separate presents problems of storage and handling, and increases the likelihood that pharmaceutical emulsions initially properly prepared will be in a less optimal, less effective, and poorly-characterized state upon ultimate administration to a patient. Uncharacterized degradation is particularly disadvantageous, since increased particle size slows the rate of transport of the colloidal particle and digestion of the oil component, and hence the rate and extent of absorption of the therapeutic agent. These problems lead to poorly-characterized and potentially harmful changes in the effective dosage received by the patient. Moreover, changes in colloidal emulsion particle size are also believed to render absorption more sensitive to and dependent upon conditions in the gastrointestinal tract, such as pH, enzyme activity, bile components, and stomach contents. Such uncertainty in the rate and extent of ultimate absorption of the therapeutic agent severely compromises the medical professional's ability to safely administer therapeutically effective dosages. In addition, when such compositions are administered parenterally, the presence of large particles can block blood capillaries, further compromising patient safety.
A further disadvantage of conventional triglyceride-containing compositions is the dependence of therapeutic agent absorption on the rate and extent of lipolysis. Although colloidal emulsion particles can transport therapeutic agents through the aqueous environment of the gastrointestinal tract, ultimately the triglyceride must be digested and the therapeutic agent must be released in order to be absorbed through the intestinal mucosa. The triglyceride carrier is emulsified by bile salts and hydrolyzed, primarily by pancreatic lipase. The rate and extent of lipolysis, however, are dependent upon several factors that are difficult to adequately control. For example, the amount and rate of bile salt secretion affect the lipolysis of the triglycerides, and the bile salt secretion can vary with stomach contents, with metabolic abnormalities, and with functional changes of the liver, bile ducts, gall bladder and intestine. Lipase availability in patients with decreased pancreatic secretory function, such as cystic fibrosis or chronic pancreatitis, may be undesirably low, resulting in a slow and incomplete triglyceride lipolysis. The activity of lipase is pH dependent, with deactivation occurring at about pH 3, so that the lipolysis rate will vary with stomach contents, and may be insufficient in patients with gastric acid hyper-secretion. Moreover, certain surfactants commonly used in the preparation of pharmaceutical emulsions, such as polyethoxylated castor oils, may themselves act as inhibitors of lipolysis. Although recent work suggests that certain surfactant combinations, when used in combination with digestible oils in emulsion preparations, can substantially decrease the lipolysis-inhibiting effect of some common pharmaceutical surfactants (see, U.S. Patent No. 5,645,856), such formulations are still subject to the other disadvantages of pharmaceutical emulsions and triglyceride-based formulations.
Yet another approach is based on formation of "microemulsions." Like an emulsion, a microemulsion is a liquid dispersion of oil in water, stabilized by surfactants. Conventional microemulsions, however, present several safety and efficiency problems. The amount of triglyceride that can be solubilized in a conventional microemulsion is generally quite small, resulting in a poor loading capacity. In order to solubilize significant amounts of triglycerides, large amounts of hydrophilic surfactant and/or solvents must be used. These high concentrations of hydrophilic surfactant and solvents raise questions of safety, since the levels of hydrophilic surfactant and solvent needed can approach or exceed bioacceptable levels.
Thus, there is a need for pharmaceutical compositions that overcome the limitations and safety concerns of conventional triglyceride-containing formulations, but without suffering from the disadvantages described above.
SUMMARY OF THE INVENTION The present invention provides pharmaceutical compositions for improved solubilization of triglycerides, and improved delivery of therapeutic agents. It has been surprisingly found that pharmaceutical compositions containing significant amounts of triglycerides can be formed without the disadvantages of conventional triglyceride- containing compositions by using a combination of surfactants and triglycerides in amounts such that when the pharmaceutical composition is mixed with an aqueous solution, a clear aqueous dispersion is formed. Such compositions can be co-administered with a therapeutic agent to increase the rate and/or extend of bioabsorption of the therapeutic agent, or can be provided with a therapeutic agent in the preconcentrate composition or in the diluent solution. In one embodiment, the present invention relates to pharmaceutical compositions having a triglyceride and a carrier, the carrier including at least two surfactants, at least one of which is hydrophilic. The triglyceride and surfactants are present in amounts such that upon mixing with an aqueous solution, either in vitro or in vivo, the composition forms a clear aqueous dispersion. In a particular aspect of this embodiment, the composition is capable of containing more triglyceride than can be solubilized in a clear aqueous dispersion having only one surfactant, the surfactant being hydrophilic.
In another embodiment, the present invention relates to pharmaceutical compositions having a triglyceride and a carrier, the carrier including at least one hydrophilic surfactant and at least one hydrophobic surfactant. The triglyceride and surfactants are present in amounts such that upon mixing with an aqueous solution, either in vitro or in vivo, the composition forms a clear aqueous dispersion. In a particular aspect of this embodiment, the composition is capable of containing more triglyceride than can be solubilized in a clear aqueous dispersion having a hydrophilic surfactant but not having a hydrophobic surfactant..
In another embodiment, the triglyceride itself can have therapeutic value as, for example, a nutritional oil, or absorption-promoting value as, for example, a long-chain triglyceride ("LCT", having fatty acid chains longer than C10 and preferably Cj2 - C22) or a medium-chain triglyceride ("MCT", having C6-C10 fatty acid chains). Thus, in this embodiment, the present invention provides pharmaceutical compositions including a triglyceride having nutritional and/or absorption-promoting value, and a carrier. The carrier includes at least two surfactants, at least one of which is hydrophilic. Optionally, the carrier can include at least one hydrophilic surfactant and at least one hydrophobic surfactant. The triglyceride and surfactants are present in amounts such that upon dilution with an aqueous solution, either in vitro or in vivo, the composition forms a clear aqueous dispersion.
In another embodiment, the present invention relates to methods of increasing the amount of triglyceride that can be solubilized in an aqueous system, by providing a composition including a triglyceride and a carrier, the carrier including at least two surfactants, at least one of which is hydrophilic, and dispersing the composition in an aqueous solution so that a clear aqueous dispersion is formed. Within the clear aqueous dispersion, the triglyceride is capable of being solubilized in an amount greater than the amount of the triglyceride that remains solubilized in an aqueous dispersion of the triglyceride and a carrier having only one surfactant and having the same total surfactant concentration. Optionally, the carrier can include at least one hydrophilic surfactant and at least one hydrophobic surfactant. In another aspect, the present invention relates to triglyceride-containing pharmaceutical compositions as described in the preceding embodiments, which further include a therapeutic agent. In particular embodiments, the therapeutic agent is a hydrophobic drug or a hydrophilic drug. In other embodiments, the therapeutic agent is a nutritional agent. In still further embodiments, the therapeutic agent is a cosmeceutical agent.
In another embodiment, the present invention relates to methods of increasing the solubilization of a therapeutic agent in a composition, by providing the therapeutic agent in a composition ofthe present invention.
In another embodiment, the present invention relates to a pharmaceutical composition which includes a therapeutic agent, a triglyceride and a carrier. The carrier includes at least two surfactants, at least one of which is hydrophilic. Optionally, the carrier includes at least one hydrophilic surfactant and at least one hydrophobic surfactant. The triglyceride, and surfactants are present in amounts such that upon dilution with an aqueous solution, either in vitro or in vivo, the composition forms a clear aqueous dispersion. The therapeutic agent is present in two amounts, a first amount of the therapeutic agent solubilized in the clear aqueous dispersion, and a second amount of the therapeutic agent that remains non-solubilized but dispersed.
In another embodiment, the present invention relates to methods of increasing the rate and/or extent of absorption of therapeutic agents by administering to a patient a pharmaceutical composition of the present invention. In this embodiment, the therapeutic agent can be present in the pharmaceutical composition pre-concentrate, in the diluent, or in a second pharmaceutical composition, such as a conventional commercial formulation, which is co-administered with a pharmaceutical composition ofthe present invention.
These and other features of the present invention will become more fully apparent from the following description and appended claims, or may be learned by the practice of the invention as set forth hereinafter. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention overcomes the problems described above characteristic of conventional triglyceride-containing formulations by providing unique pharmaceutical compositions which form clear aqueous dispersions upon mixing with an aqueous solution. Surprisingly, the present inventors have found that compositions including triglycerides and a combination of surfactants can solubilize therapeutically effective amounts of therapeutic agents in homogeneous, single-phase systems which are thermodynamically stable and optically clear. The optical clarity is indicative of a very small particle size within the aqueous dispersions, and this small particle size substantially reduces lipolysis dependence of the rate of bioabsorption, and other disadvantages of conventional triglyceride-containing formulations. Use of these formulations is thus believed to result in an enhanced rate and/or extent of absorption of the therapeutic agent. Advantageously, the compositions of the present invention are surprisingly able to solubilize greater amounts of triglycerides than conventional formulations, even when the total surfactant concentration is the same as in a conventional formulation. A. Pharmaceutical Compositions
In one embodiment, the present invention provides a pharmaceutical composition including a triglyceride and a carrier. The carrier includes at least two surfactants, at least one of which is a hydrophilic surfactant. Optionally, the carrier includes at least one hydrophilic surfactant and at least one hydrophobic surfactant. The triglyceride and surfactants are present in amounts such that upon dilution with an aqueous solution, either in vitro or in vivo, the composition forms a clear aqueous dispersion. It is a particular and surprising feature of the present invention that the composition is homogeneous and optically clear, despite the presence of substantial amounts of triglycerides, thereby providing surprising and important advantages over conventional triglyceride-containing formulations.
1. Triglycerides
The compositions of the present invention include one or more pharmaceutically acceptable triglycerides. Examples of triglycerides suitable for use in the present invention are shown in Table 1. In general, these triglycerides are readily available from commercial sources. For several triglycerides, representative commercial products and/or commercial suppliers are listed. Table 1 : Triglycerides
Triglyceride Commercial Source
Aceituno oil Almond oil Super Refined Almond Oil (Croda)
Araehis oil
Babassu oil
Blackcurrant seed oil Borage oil
Buffalo ground oil
Candlenut oil
Canola oil Lipex 108 (Abitec)
Castor oil
Chinese vegetable tallow oil
Cocoa butter
Coconut oil Pureco 76 (Abitec)
Coffee seed oil
Com oil Super Refined Com Oil (Croda)
Cottonseed oil Super Refined Cottonseed Oil (Croda)
Crambe oil
Cuphea species oil
Evening primrose oil
Grapeseed oil
Groundnut oil
Hemp seed oil
Illipe butter Kapok seed oil Linseed oil Menhaden oil Super Refined Menhaden Oil (Croda) Mowrah butter Mustard seed oil Oiticica oil
Olive oil Super Refined Olive Oil (Croda)
Palm oil
Palm kernel oil
Peanut oil Super Refined Peanut Oil (Croda)
Poppy seed oil
Rapeseed oil
Rice bran oil
Safflower oil Super Refined Safflower Oil (Croda)
Sal fat
Sesame oil Super Refined Sesame Oil (Croda)
Shark liver oil Super Refined Shark Liver Oil (Croda)
Shea nut oil
Soybean oil Super Refined Soybean Oil (Croda)
Stillingia oil
Sunflower oil
Tall oil
Tea seed oil
Tobacco seed oil
Tung oil (China wood oil) Ucuhuba
Vemonia oil
Wheat germ oil Super Refined Wheat Germ Oil (Croda) Hydrogenated castor oil Castorwax
Hydrogenated coconut oil Pureco 100 (Abitec)
Hydrogenated cottonseed oil Dritex C (Abitec)
Hydrogenated palm oil Dritex PST (Abitec); Softisan 154 (Hϋls)
Hydrogenated soybean oil Sterotex HM NF (Abitec); Dritex S (Abitec)
Hydrogenated vegetable oil Sterotex NF (Abitec); Hydrokote M (Abitec)
Hydrogenated cottonseed and castor oil Sterotex K (Abitec)
Partially hydrogenated soybean oil Hydrokote AP5 (Abitec)
Partially soy and cottonseed oil Apex B (Abitec)
Glyceryl tributyrate (Sigma)
Glyceryl tricaproate (Sigma)
Glyceryl tricaprylate (Sigma)
Glyceryl tricaprate Captex 1000 (Abitec)
Glyceryl triundecanoate Captex 8227 (Abitec)
Glyceryl trilaurate (Sigma)
Glyceryl trimyristate Dynasan 114 (Hiils)
Glyceryl tripalmitate Dynasan 116 (Hiils)
Glyceryl tristearate Dynasan 118 (Hϋls)
Glyceryl triarchidate (Sigma) Glyceryl trimyristoleate (Sigma)
Glyceryl tripalmitoleate (Sigma)
Glyceryl trioleate (Sigma) Glyceryl trilinoleate (Sigma)
Glyceryl trilinolenate (Sigma)
Glyceryl tricaprylate/caprate Captex 300 (Abitec); Captex 355 (Abitec); Miglyol 810 (Hϋls); Miglyol 812 (Hϋls)
Glyceryl tricaprylate/caprate/laurate Captex 350 (Abitec)
Glyceryl tricaprylate/caprate/linoleate Captex 810 (Abitec); Miglyol 818 (Hϋls)
Glyceryl tricaprylate/caprate/stearate Softisan 378 (Hϋls); (Larodan) Glyceryl tricaprylate/laurate/stearate (Larodan) Glyceryl l,2-caprylate-3-linoleate (Larodan) Glyceryl l,2-caprate-3-stearate (Larodan) Glyceryl l,2-laurate-3-myristate (Larodan) Glyceryl l,2-myristate-3-laurate (Larodan) Glyceryl l,3-palmitate-2-butyrate (Larodan) Glyceryl l,3-stearate-2-caprate (Larodan) Glyceryl l,2-linoleate-3-caprylate (Larodan) "
Fractionated triglycerides, modified triglycerides, synthetic triglycerides, and mixtures of triglycerides are also within the scope ofthe invention.
Preferred triglycerides include vegetable oils, fish oils, animal fats, hydrogenated vegetable oils, partially hydrogenated vegetable oils, medium and long-chain triglycerides, and structured triglycerides. It should be appreciated that several commercial surfactant compositions contain small to moderate amounts of triglycerides, typically as a result of incomplete reaction of a triglyceride starting material in, for example, a transesterification reaction. Such commercial surfactant compositions, while nominally referred to as "surfactants", may be suitable to provide all or part of the triglyceride component for the compositions of the present invention. Examples of commercial surfactant compositions containing triglycerides include some members of the surfactant families Gelucires (Gattefosse), Maisines (Gattefosse), and Imwitors (Hϋls). Specific examples of these compositions are:
Gelucire 44/14 (saturated polyglycolized glycerides)
Gelucire 50/13 (saturated polyglycolized glycerides) Gelucire 53/10 (saturated polyglycolized glycerides)
Gelucire 33/01 (semi-synthetic triglycerides of C8-C18 saturated fatty acids) Gelucire 39/01 (semi-synthetic glycerides) other Gelucires, such as 37/06, 43/01, 35/10, 37/02, 46/07, 48/09, 50/02, 62/05, etc. Maisine 35-1 (linoleic glycerides)
Imwitor 742 (caprylic/capric glycerides)
Still other commercial surfactant compositions having significant triglyceride content are known to those skilled in the art. It should be appreciated that such compositions, which contain triglycerides as well as surfactants, may be suitable to provide all or part of the triglyceride component of the compositions of the present invention, as well as all or part of the surfactant component, as described below. Of course, none of the commonly known triglyceride-containing commercial surfactants alone provides the unique pharmaceutical compositions and characteristics as recited in the appended claims. Among the above-listed triglycerides, preferred triglycerides include: almond oil; babassu oil; borage oil; blackcurrant seed oil; canola oil; castor oil; coconut oil; com oil; cottonseed oil; evening primrose oil; grapeseed oil; groundnut oil; mustard seed oil; olive oil; palm oil; palm kernel oil; peanut oil; rapeseed oil; safflower oil; sesame oil; shark liver oil; soybean oil; sunflower oil; hydrogenated castor oil; hydrogenated coconut oil; hydrogenated palm oil; hydrogenated soybean oil; hydrogenated vegetable oil; hydrogenated cottonseed and castor oil; partially hydrogenated soybean oil; partially soy and cottonseed oil; glyceryl tricaproate; glyceryl tricaprylate; glyceryl tricaprate; glyceryl triundecanoate; glyceryl trilaurate; glyceryl trioleate; glyceryl trilinoleate; glyceryl trilinolenate; glyceryl tricaprylate/caprate; glyceryl tricaprylate/caprate/laurate; glyceryl tricaprylate/caprate/linoleate; and glyceryl tricaprylate/caprate/stearate. Other preferred triglycerides are saturated polyglycolized glycerides (Gelucire 44/14, Gelucire 50/13 and Gelucire 53/10), linoleic glycerides (Maisine 35-1), and caprylic/capric glycerides (Imwitor 742).
Among the preferred triglycerides, more preferred triglycerides include: coconut oil; com oil; olive oil; palm oil; peanut oil; safflower oil; sesame oil; soybean oil; hydrogenated castor oil; hydrogenated coconut oil; partially hydrogenated soybean oil; glyceryl tricaprate; glyceryl trilaurate; glyceryl trioleate; glyceryl trilinoleate; glyceryl tricaprylate/caprate; glyceryl tricaprylate/caprate/laurate; glyceryl tricaprylate/caprate/linoleate; glyceryl tricaprylate/caprate/stearate; saturated polyglycolized glycerides (Gelucire 44/14, Gelucire 50/13 and Gelucire 53/10); linoleic glycerides (Maisine 35-1); and caprylic/capric glycerides (Imwitor 742). 2. Surfactants
The carrier includes a combination of surfactants, at least one of which is a hydrophilic surfactant, with the remaining surfactant or surfactants being hydrophilic or hydrophobic. As is well known in the art, the terms "hydrophilic" and "hydrophobic" are relative terms. To function as a surfactant, a compound must necessarily include polar or charged hydrophilic moieties as well as non-polar hydrophobic (lipophilic) moieties; i.e., a surfactant compound must be amphiphilic. An empirical parameter commonly used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (the "HLB" value). Surfactants with lower HLB values are more hydrophobic, and have greater solubility in oils, whereas surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.
Using HLB values as a rough guide, hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, hydrophobic surfactants are compounds having an HLB value less than about 10.
It should be appreciated that the HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions. For many important surfactants, including several polyethoxylated surfactants, it has been reported that HLB values can differ by as much as about 8 HLB units, depending upon the empirical method chosen to determine the HLB value (Schott, J. Pharm. Sciences, 79(1), 87-88 (1990)). Likewise, for certain polypropylene oxide containing block copolymers (poloxamers, available commercially as PLURONIC® surfactants, BASF Corp.), the HLB values may not accurately reflect the true physical chemical nature of the compounds. Finally, commercial surfactant products are generally not pure compounds, but are often complex mixtures of compounds, and the HLB value reported for a particular compound may more accurately be characteristic of the commercial product of which the compound is a major component. Different commercial products having the same primary surfactant component can, and typically do, have different HLB values. In addition, a certain amount of lot-to-lot variability is expected even for a single commercial surfactant product. Keeping these inherent difficulties in mind, and using HLB values as a guide, one skilled in the art can readily identify surfactants having suitable hydrophilicity or hydrophobicity for use in the present invention, as described herein.
The carrier of the present invention includes at least one hydrophilic surfactant. The hydrophilic surfactant can be any surfactant suitable for use in pharmaceutical compositions. Suitable hydrophilic surfactants can be anionic, cationic, zwitterionic or non-ionic, although non-ionic hydrophilic surfactants are presently preferred. Preferably, the carrier includes a mixture of two or more hydrophilic surfactants, more preferably two or more non-ionic hydrophilic surfactants. Also preferred are mixtures of at least one hydrophilic surfactant, preferably non-ionic, and at least one hydrophobic surfactant.
The choice of specific surfactants should be made keeping in mind the particular triglycerides and optional therapeutic agents to be used in the composition, and the range of polarity appropriate for the chosen therapeutic agent. With these general principles in mind, a very broad range of surfactants is suitable for use in the present invention. Such surfactants can be grouped into the following general chemical classes detailed in the Tables herein. The HLB values given in the Tables below generally represent the HLB value as reported by the manufacturer of the corresponding commercial product. In cases where more than one commercial product is listed, the HLB value in the Tables is the value as reported for one of the commercial products, a rough average of the reported values, or a value that, in the judgment ofthe present inventors, is more reliable.
It should be emphasized that the invention is not limited to the surfactants in the Tables, which show representative, but not exclusive, lists of available surfactants. 2.1. Polyethoxylated Fatty Acids
Although polyethylene glycol (PEG) itself does not function as a surfactant, a variety of PEG-fatty acid esters have useful surfactant properties. Among the PEG-fatty acid monoesters, esters of lauric acid, oleic acid, and stearic acid are especially useful. Among the surfactants of Table 2, preferred hydrophilic surfactants include PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG- 10 laurate, PEG- 10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20 laurate and PEG-20 oleate. Examples of polyethoxylated fatty acid monoester surfactants commercially available are shown in Table 2.
Table 2: PEG-Fatty Acid Monoester Surfactants
COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG 4-100 monolaurate Crodet L series (Croda) >9
PEG 4-100 monooleate Crodet O series (Croda) >8
PEG 4-100 monostearate Crodet S series (Croda), Myrj Series (Atlas/ICI) >6
PEG 400 distearate Cithrol 4DS series (Croda) >10
PEG 100,200,300 monolaurate Cithrol ML series (Croda) >10
PEG 100,200,300 monooleate Cithrol MO series (Croda) >10
PEG 400 dioleate Cithrol 4DO series (Croda) >10
PEG 400-1000 monostearate Cithrol MS series (Croda) >10
PEG-1 stearate Nikkol MYS-1EX (Nikko), Coster Kl (Condea) 2
PEG-2 stearate Nikkol MYS-2 (Nikko) 4
PEG-2 oleate Nikkol MYO-2 (Nikko) 4.5
PEG-4 laurate Mapeg® 200 ML (PPG), Kessco® PEG 200ML (Stepan), LIPOPEG 9.3 2L (LIPO Chem.)
PEG-4 oleate Mapeg® 200 MO (PPG), Kessco® PEG200 MO (Stepan), 8.3
PEG-4 stearate Kessco® PEG 200 MS (Stepan), Hodag 20 S (Calgene), Nikkol 6.5
MYS-4 (Nikko) PEG-5 stearate Nikkol TMGS-5 (Nikko) 9.5
PEG-5 oleate Nikkol TMGO-5 (Nikko) 9.5
PEG-6 oleate Algon OL 60 (Auschem SpA), Kessco® PEG 300 MO (Stepan), 8.5 Nikkol MYO-6 (Nikko), Emulgante A6 (Condea)
PEG-7 oleate Algon OL 70 (Auschem SpA) 10.4
PEG-6 laurate Kessco® PEG300 ML (Stepan) 11.4
PEG-7 laurate Lauridac 7 (Condea) 13
PEG-6 stearate Kessco® PEG300 MS (Stepan) 9.7
PEG-8 laurate Mapeg® 400 ML (PPG), LIPOPEG 4DL(Lipo Chem.) 13
PEG-8 oleate Mapeg® 400 MO (PPG), Emulgante A8 (Condea); Kessco PEG 400 12 MO (Stepan)
PEG-8 stearate Mapeg® 400 MS (PPG), Myrj 45 12 PEG-9 oleate Emulgante A9 (Condea) >10 PEG-9 stearate Cremophor S9 (BASF) >10 PEG- 10 laurate Nikkol MYL-10 (Nikko), Lauridac 10 (Croda) 13 PEG-10 oleate Nikkol MYO-10 (Nikko) 11 PEG- 10 stearate Nikkol MYS-10 (Nikko), Coster K100 (Condea) 11
PEG-12 laurate Kessco® PEG 600ML (Stepan) 15
PEG-12 oleate Kessco® PEG 600MO (Stepan) 14
PEG-12 ricinoleate (CAS # 9004-97-1) >10
PEG-12 stearate Mapeg® 600 MS (PPG), Kessco® PEG 600MS (Stepan) 14
PEG-15 stearate Nikkol TMGS-15 (Nikko), Koster K15 (Condea) 14
PEG-15 oleate Nikkol TMGO-15 (Nikko) 15
PEG-20 laurate Kessco® PEG 1000 ML (Stepan) 17
PEG-20 oleate Kessco® PEG 1000 MO (Stepan) 15 PEG-20 stearate Mapeg® 1000 MS (PPG), Kessco® PEG 1000 MS (Stepan), Myrj 16
49
PEG-25 stearate Nikkol MYS-25 (Nikko) 15
PEG-32 laurate Kessco® PEG 1540 ML (Stepan) 16
PEG-32 oleate Kessco® PEG 1540 MO (Stepan) 17
PEG-32 stearate Kessco® PEG 1540 MS (Stepan) 17
PEG-30 stearate Myrj 51 >10 PEG-40 laurate Crodet L40 (Croda) 17.9
PEG-40 oleate Crodet O40 (Croda) 17.4
PEG-40 stearate Myrj 52, Emerest® 2715 (Henkel), Nikkol MYS-40 (Nikko) >10
PEG-45 stearate Nikkol MYS-45 (Nikko) 18 PEG-50 stearate Myrj 53 >10 PEG-55 stearate Nikkol MYS-55 (Nikko) 18 PEG- 100 oleate Crodet O- 100 (Croda) 18.8 PEG- 100 stearate Myrj 59, Arlacel 165 (ICI) 19 PEG-200 oleate Albunol 200 MO (Taiwan Surf.) >10 PEG-400 oleate LACTOMUL (Henkel), Albunol 400 MO (Taiwan Surf.) >10 PEG-600 oleate Albunol 600 MO (Taiwan Surf.) >10
2.2 PEG-Fatty Acid Diesters
Polyethylene glycol (PEG) fatty acid diesters are also suitable for use as surfactants in the compositions of the present invention. Among the surfactants in Table 3, preferred hydrophilic surfactants include PEG-20 dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate and PEG-32 dioleate. Representative PEG-fatty acid diesters are shown in Table 3. Table 3: PEG-Fatty Acid Diester Surfactants
COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-4 dilaurate Mapeg® 200 DL (PPG), Kessco® PEG 200 DL (Stepan), LIPOPEG 7 2-DL (Lipo Chem.)
PEG-4 dioleate Mapeg® 200 DO (PPG), 6
PEG-4 distearate Kessco® 200 DS (Stepan) 5
PEG-6 dilaurate Kessco® PEG 300 DL (Stepan) 9.8
PEG-6 dioleate Kessco® PEG 300 DO (Stepan) 7.2
PEG-6 distearate Kessco® PEG 300 DS (Stepan) 6.5
PEG-8 dilaurate Mapeg® 400 DL (PPG), Kessco® PEG 400 DL (Stepan), LIPOPEG 11 4 DL (Lipo Chem.)
PEG-8 dioleate Mapeg® 400 DO (PPG), Kessco® PEG 400 DO (Stepan), LIPOPEG 8.8 4 DO(Lipo Chem.)
PEG-8 distearate Mapeg® 400 DS (PPG), CDS 400 (Nikkol) 11
PEG- 10 dipalmitate Polyaldo 2PKFG >10 PEG-12 dilaurate Kessco® PEG 600 DL (Stepan) 11.7
PEG-12 distearate Kessco® PEG 600 DS (Stepan) 10.7
PEG-12 dioleate Mapeg® 600 DO (PPG), Kessco® 600 DO(Stepan) 10
PEG-20 dilaurate Kessco® PEG 1000 DL (Stepan) 15
PEG-20 dioleate Kessco® PEG 1000 DO (Stepan) 13
PEG-20 distearate Kessco® PEG 1000 DS (Stepan) 12
PEG-32 dilaurate Kessco® PEG 1540 DL (Stepan) 16
PEG-32 dioleate Kessco® PEG 1540 DO (Stepan) 15
PEG-32 distearate Kessco® PEG 1540 DS (Stepan) 15
PEG-400 dioleate Cithrol 4DO series (Croda) >10 PEG-400 distearate Cithrol 4DS series (Croda) >10
2.3 PEG-Fatty Acid Mono- and Di-ester Mixtures
In general, mixtures of surfactants are also useful in the present invention, including mixtures of two or more commercial surfactant products. Several PEG-fatty acid esters are marketed commercially as mixtures or mono- and diesters. Representative surfactant mixtures are shown in Table 4.
Table 4: PEG-Fatty Acid Mono- and Diester Mixtures
10
COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG 4-150 mono, dilaurate Kessco® PEG 200-6000 mono, dilaurate (Stepan)
PEG 4-150 mono, dioleate Kessco® PEG 200-6000 mono, dioleate (Stepan)
, c PEG 4-150 mono, distearate Kessco® 200-6000 mono, distearate (Stepan)
2.4 Polyethylene Glycol Glycerol Fatty Acid Esters
Suitable PEG glycerol fatty acid esters are shown in Table 5. Among the surfactants in the Table, preferred hydrophilic surfactants are PEG-20 glyceryl laurate, 0 PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, and PEG-30 glyceryl oleate.
Table 5: PEG Glycerol Fatty Acid Esters
COMPOUND COMMERCIAL PRODUCT (Supplier) HLB 5
PEG-20 glyceryl laurate Tagat® L (Goldschmidt) 16
PEG-30 glyceryl laurate Tagat® L2 (Goldschmidt) 16
PEG-15 glyceryl laurate Glycerox L series (Croda) 15
PEG-40 glyceryl laurate Glycerox L series (Croda) 15 0 PEG-20 glyceryl stearate Capmul® EMG (ABITEC), Aldo® MS-20 KFG (Lonza) 13
PEG-20 glyceryl oleate Tagat® O (Goldschmidt) >10 PEG-30 glyceryl oleate Tagat® 02 (Goldschmidt) >10
2.5. Alcohol - Oil Transesterification Products
A large number of surfactants of different degrees of hydrophobicity or hydrophilicity can be prepared by reaction of alcohols or polyalcohols with a variety of natural and/or hydrogenated oils. Most commonly, the oils used are castor oil or hydrogenated castor oil, or an edible vegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil, apricot kernel oil, or almond oil. Preferred alcohols include glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, and pentaerythritol. Among these alcohol-oil transesterified surfactants, preferred hydrophilic surfactants are PEG-35 castor oil (Incrocas-35), PEG-40 hydrogenated castor oil (Cremophor RH 40), PEG-25 trioleate (TAGAT® TO), PEG-60 com glycerides (Crovol M70), PEG-60 almond oil (Crovol A70), PEG-40 palm kernel oil (Crovol PK70), PEG-50 castor oil (Emalex C- 50), PEG-50 hydrogenated castor oil (Emalex HC-50), PEG-8 caprylic/capric glycerides (Labrasol), and PEG-6 caprylic/capric glycerides (Softigen 767). Preferred hydrophobic surfactants in this class include PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6 com oil (Labrafil® M 2125 CS), PEG-6 almond oil (Labrafil® M 1966 CS), PEG-6 apricot kernel oil (Labrafil® M 1944 CS), PEG-6 olive oil (Labrafil® M 1980 CS), PEG-6 peanut oil (Labrafil® M 1969 CS), PEG- 6 hydrogenated palm kernel oil (Labrafil® M 2130 BS), PEG-6 palm kernel oil (Labrafil® M 2130 CS), PEG-6 triolein (Labrafil® M 2735 CS), PEG-8 com oil (Labrafil® WL 2609 BS), PEG-20 com glycerides (Crovol M40), and PEG-20 almond glycerides (Crovol A40). The latter two surfactants are reported to have HLB values of 10, which is generally considered to be the approximate border line between hydrophilic and hydrophobic surfactants. For purposes of the present invention, these two surfactants are considered to be hydrophobic. Representative surfactants of this class suitable for use in the present invention are shown in Table 6.
Table 6: Transesterification Products of Oils and Alcohols
COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-3 castor oil Nikkol CO-3 (Nikko) 3 PEG-5, 9, and 16 castor oil ACCONON CA series (ABITEC) 6-7
PEG-20 castor oil Emalex C-20 (Nihon Emulsion), Nikkol CO-20 TX (Nikko) 1 1
PEG-23 castor oil Emulgante EL23 >10
PEG-30 castor oil Emalex C-30 (Nihon Emulsion), Alkamuls® EL 620 (Rhone- 11 Poulenc), Incrocas 30 (Croda)
PEG-35 castor oil Cremophor EL and EL-P (BASF), Emulphor EL, Incrocas-35 (Croda), Emulgin RO 35 (Henkel)
PEG-38 castor oil Emulgante EL 65 (Condea)
PEG-40 castor oil Emalex C-40 (Nihon Emulsion), Alkamuls® EL 719 (Rhone- 13 Poulenc)
PEG-50 castor oil Emalex C-50 (Nihon Emulsion) 14
PEG-56 castor oil Eumulgin® PRT 56 (Pulcra SA) >10
PEG-60 castor oil Nikkol CO-60TX (Nikko) 14
PEG- 100 castor oil Thornley >10
PEG-200 castor oil Eumulgin® PRT 200 (Pulcra SA) >10
PEG-5 hydrogenated castor oil Nikkol HCO-5 (Nikko) 6
PEG-7 hydrogenated castor oil Simusol® 989 (Seppic), Cremophor W07 (BASF) 6
PEG- 10 hydrogenated castor oil Nikkol HCO- 10 (Nikko) 6.5 PEG-20 hydrogenated castor oil Nikkol HCO-20 (Nikko) 11
PEG-25 hydrogenated castor oil Simulsol® 1292 (Seppic), Cerex ELS 250 (Auschem SpA) 11 PEG-30 hydrogenated castor oil Nikkol HCO-30 (Nikko) 11
PEG-40 hydrogenated castor oil Cremophor RH 40 (BASF), Croduret (Croda), Emulgin HRE 40 13 (Henkel)
PEG-45 hydrogenated castor oil Cerex ELS 450 (Auschem Spa) 14
PEG-50 hydrogenated castor oil Emalex HC-50 (Nihon Emulsion) 14
PEG-60 hydrogenated castor oil Nikkol HCO-60 (Nikko); Cremophor RH 60 (BASF) 15 PEG-80 hydrogenated castor oil Nikkol HCO-80 (Nikko) 15
PEG- 100 hydrogenated castor Nikkol HCO - 100 (Nikko) 17 oil
c PEG-6 corn oil Labrafil® M 2125 CS (Gattefosse) 4
PEG-6 almond oil Labrafil® M 1966 CS (Gattefosse) 4
PEG-6 apricot kernel oil Labrafil® M 1944 CS (Gattefosse) 4
PEG-6 olive oil Labrafil® M 1980 CS (Gattefosse) 4
10 PEG-6 peanut oil Labrafil® M 1969 CS (Gattefosse) 4
PEG-6 hydrogenated palm Labrafil® M 2130 BS (Gattefosse) 4 kernel oil
PEG-6 palm kernel oil Labrafil® M 2130 CS (Gattefosse) 4 j 5 PEG-6 triolein Labrafil® M 2735 CS (Gattefosse) 4 PEG-8 corn oil Labrafil® WL 2609 BS (Gattefosse) 6-7 PEG-20 corn glycerides Crovol M40 (Croda) 10 PEG-20 almond glycerides Crovol A40 (Croda) 10
20 PEG-25 trioleate TAGAT® TO (Goldschmidt) 11
PEG-40 palm kernel oil Crovol PK-70 >10
PEG-60 corn glycerides Crovol M70(Croda) 15 PEG-60 almond glycerides Crovol A70 (Croda) 15 5
PEG-4 caprylic/capric Labrafac® Hydro (Gattefosse), 4-5 triglyceride
PEG-8 caprylic/capric glycerides Labrasol (Gattefosse),Labrafac CM 10 (Gattefosse) >10
PEG-6 caprylic/capric glycerides SOFTIGEN® 767 (Huls), Glycerox 767 (Croda) 19 30 Lauroyl macrogol-32 glyceride GELUCIRE 44/14 (Gattefosse) 14
Stearoyl macrogol glyceride GELUCIRE 50/13 (Gattefosse) 13 Mono, di, tri, terra esters of SorbitoGlyceride (Gattefosse) <10 vegetable oils and sorbitol
Pentaerythrityl tetraisostearate Croda ol PTIS (Croda) <10 c Pentaerythrityl distearate Albunol DS (Taiwan Surf.) <10
Pentaerythrityl tetraoleate Liponate PO-4 (Lipo Chem.) <10
Pentaerythrityl tetrastearate Liponate PS-4 (Lipo Chem.) <10
Pentaerythrityl Liponate PE-810 (Lipo Chem.), Crodamol PTC (Croda) <10 tetracaprylate/tetracaprate
10
Pentaerythrityl tetraoctanoate Nikkol Pentarate 408 (Nikko)
Also included as oils in this category of surfactants are oil-soluble vitamins, such as vitamins A, D, E, K, etc. Thus, derivatives of these vitamins, such as tocopheryl PEG- 15 1000 succinate (TPGS, available from Eastman), are also suitable surfactants. 2.6. Polyglycerized Fatty Acids
Polyglycerol esters of fatty acids are also suitable surfactants for the present invention. Among the polyglyceryl fatty acid esters, preferred hydrophobic surfactants include polyglyceryl oleate (Plurol Oleique), polyglyceryl-2 dioleate (Nikkol DGDO), and 0 polyglyceryl-10 trioleate. Preferred hydrophilic surfactants include polyglyceryl-10 laurate (Nikkol Decaglyn 1-L), polyglyceryl-10 oleate (Nikkol Decaglyn l-O), and polyglyceryl-10 mono, dioleate (Caprol® PEG 860). Polyglyceryl polyricinoleates (Polymuls) are also preferred hydrophilic and hydrophobic surfactants. Examples of suitable polyglyceryl esters are shown in Table 7. 5
Table 7: Polyglycerized Fatty Acids
COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
Polyglyceryl-2 stearate Nikkol DGMS (Nikko) 5-7
0 Polyglyceryl-2 oleate Nikkol DGMO (Nikko) 5-7
Polyglyceryl-2 isostearate Nikkol DGMIS (Nikko) 5-7 Polyglyceryl-3 oleate Caprol® 3GO (ABITEC), Drewpol 3-1-0 (Stepan) 6.5 Polyglyceryl-4 oleate Nikkol Tetraglyn 1-0 (Nikko) 5-7
Polyglyceryl-4 stearate Nikkol Tetraglyn l-S (Nikko) 5-6 Polyglyceryl-6 oleate Drewpol 6- 1 -O (Stepan), Nikkol Hexaglyn 1 -O (Nikko) 9 Polyglyceryl-10 laurate Nikkol Decaglyn 1 -L (Nikko) 15
Polyglyceryl-10 oleate Nikkol Decaglyn 1 -O (Nikko) 14 Polyglyceryl-10 stearate Nikkol Decaglyn 1 -S (Nikko) 12 Polyglyceryl-6 ricinoleate Nikkol Hexaglyn PR- 15 (Nikko) >8
Polyglyceryl-10 linoleate Nikkol Decaglyn 1 -LN (Nikko) 12
Polyglyceryl-6 pentaoleate Nikkol Hexaglyn 5-0 (Nikko) <10 Polyglyceryl-3 dioleate Cremophor G032 (BASF) <10 Polyglyceryl-3 distearate Cremophor GS32 (BASF) <10 Polyglyceryl-4 pentaoleate Nikkol Tetraglyn 5-0 (Nikko) <10 Polyglyceryl-6 dioleate Caprol® 6G20 (ABITEC); Hodag PGO-62 (Calgene), PLUROL 8.5 OLEIQUE CC 497 (Gattefosse)
Polyglyceryl-2 dioleate Nikkol DGDO (Nikko) 7
Polyglyceryl-10 trioleate Nikkol Decaglyn 3-0 (Nikko) 7
Polyglyceryl-10 pentaoleate Nikkol Decaglyn 5-0 (Nikko) 3.5 Polyglyceryl-10 septaoleate Nikkol Decaglyn 7-0 (Nikko) 3
Polyglyceryl-10 tetraoleate Caprol® 10G4O (ABITEC); Hodag PGO-62 (CALGENE), 6.2 Drewpol 10-4-O (Stepan)
Polyglyceryl-10 decaisostearate Nikkol Decaglyn 10-IS (Nikko) <10
Polyglyceryl- 101 decaoleate Drewpol 10-10-O (Stepan), Caprol 10G10O (ABITEC), Nikkol 3.5 Decaglyn 10-O
Polyglyceryl- 10 mono, dioleate Caprol® PGE 860 (ABITEC) 11 Polyglyceryl polyricinoleate Polymuls (Henkel) 3-20
2.7. Propylene Glycol Fatty Acid Esters
Esters of propylene glycol and fatty acids are suitable surfactants for use in the present invention. In this surfactant class, preferred hydrophobic surfactants include propylene glycol monolaurate (Lauroglycol FCC), propylene glycol ricinoleate (Propymuls), propylene glycol monooleate (Myverol P-O6), propylene glycol dicaprylate/dicaprate (Captex® 200), and propylene glycol dioctanoate (Captex® 800). Examples of surfactants of this class are given in Table 8.
Table 8: Propylene Glycol Fatty Acid Esters COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
Propylene glycol monocaprylate Capryol 90 (Gattefosse), Nikkol Sefsol 218 (Nikko) <10
Propylene glycol monolaurate Lauroglycol 90 (Gattefosse), Lauroglycol FCC (Gattefosse) <10
Propylene glycol oleate Lutrol OP2000 (BASF) <10
Propylene glycol myristate Mirpyl <10
Propylene glycol monostearate ADM PGME-03 (ADM), LIPO PGMS (Lipo Chem.), Aldo® 3-4
PGHMS (Lonza)
Propylene glycol hydroxy stearate <10
Propylene glycol ricinoleate PROPYMULS (Henkel) <10
Propylene glycol isostearate <10
Propylene glycol monooleate Myverol P-06 (Eastman) <10
Propylene glycol Captex® 200 (ABITEC), Miglyol® 840 (Hϋls), Neobee® M-20 >6 dicaprylate/dicaprate (Stepan)
Propylene glycol dioctanoate Captex® 800 (ABITEC) >6
Propylene glycol LABRAFAC PG (Gattefosse) >6 caprylate/caprate Propylene glycol dilaurate >6 Propylene glycol distearate Kessco® PGDS (Stepan) >6 Propylene glycol dicaprylate Nikkol Sefsol 228 (Nikko) >6 Propylene glycol dicaprate Nikkol PDD (Nikko) >6
2.8. Mixtures of Propylene Glycol Esters - Glycerol Esters
In general, mixtures of surfactants are also suitable for use in the present invention.
In particular, mixtures of propylene glycol fatty acid esters and glycerol fatty acid esters are suitable and are commercially available. One preferred mixture is composed of the oleic acid esters of propylene glycol and glycerol (Arlacel 186). Examples of these surfactants are shown in Table 9.
Table 9: Glycerol/Propylene Glycol Fatty Acid Esters COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
Oleic ATMOS 300, ARLACEL 186 (ICI) 3-4
Stearic ATMOS 150 3-4
2.9. Mono- and Diglycerides
A particularly important class of surfactants is the class of mono- and diglycerides.
These surfactants are generally hydrophobic. Preferred hydrophobic surfactants in this class of compounds include glyceryl monooleate (Peceol), glyceryl ricinoleate, glyceryl laurate, glyceryl dilaurate (Capmul® GDL), glyceryl dioleate (Capmul® GDO), glyceryl mono/dioleate (Capmul® GMO-K), glyceryl caprylate/caprate (Capmul® MCM), caprylic acid mono/diglycerides (Imwitor® 988), and mono- and diacetylated monoglycerides
(Myvacet® 9-45). Examples of these surfactants are given in Table 10. Table 10: Mono- and Diglyceride Surfactants
COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
Monopalmitolein (C16: l) (Larodan) <10
Monoelaidin (C18:l) (Larodan) <10
Monocaproin (C6) (Larodan) <10
Monocaprylin (Larodan) <10
Monocaprin (Larodan) <10
Monolaurin (Larodan) <10
Glyceryl monomyristate (C14) Nikkol MGM (Nikko) 3-4
Glyceryl monooleate (C 18 : 1 ) PECEOL (Gattefosse), Hodag GMO-D, Nikkol MGO (Nikko) 3-4
Glyceryl monooleate RYLO series (Danisco), DIMODAN series (Danisco), EMULDAN 3-4 (Danisco), ALDO® MO FG (Lonza), Kessco GMO (Stepan), MONOMULS® series (Henkel), TEGIN O, DREWMULSE GMO (Stepan), Atlas G-695 (ICI), GMOrphic 80 (Eastman), ADM DMG-40, 70, and 100 (ADM), Myverol (Eastman)
Glycerol monooleate/linoleate OLICINE (Gattefosse) 3-4
Glycerol monolinoleate Maisine (Gattefosse), MYVEROL 18-92, Myverol 18-06 (Eastman) 3-4
Glyceryl ricinoleate Softigen® 701 (Hiils), HODAG GMR-D (Calgene), ALDO® MR 6
(Lonza)
Glyceryl monolaurate ALDO® MLD (Lonza), Hodag GML (Calgene) 6.8 Glycerol monopalmitate Emalex GMS-P (Nihon)
Glycerol monostearate Capmul® GMS (ABITEC), Myvaplex (Eastman), IMWITOR® 191 5-9 (Hϋls), CUTINA GMS, Aldo® MS (Lonza), Nikkol MGS series (Nikko)
Glyceryl mono-,dioleate Capmul® GMO-K (ABITEC) <10
Glyceryl palmitic/stearic CUTINA MD-A, ESTAGEL-G18 <10
Glyceryl acetate Lamegin® EE (Griinau GmbH) <10 Glyceryl laurate Imwitor® 312 (Hϋls), Monomuls® 90-45 (Grϋnau GmbH), Aldo® MLD (Lonza)
Glyceryl citrate/lactate/oleate/ Imwitor® 375 (Hϋls) <10 linoleate
Glyceryl caprylate Imwitor® 308 (Hϋls), Capmul® MCMC8 (ABITEC) 5-6
Glyceryl caprylate/caprate Capmul® MCM (ABITEC) 5-6
Caprylic acid mono,diglycerides Imwitor® 988 (Hϋls) 5-6
Caprylic/capric glycerides Imwitor® 742 (Hϋls) <10
Mono-and diacetylated Myvacet® 9-45, Myvacet® 9-40, Myvacet® 9-08 (Eastman), 3.8-4 monoglycerides Lamegin® (Grϋnau)
Glyceryl monostearate Aldo® MS, Arlacel 129 (ICI), LIPO GMS (Lipo Chem.), Imwitor® 4.4 191 (Hϋls), Myvaplex (Eastman)
Lactic acid esters of LAMEGIN GLP (Henkel) <10 mono,diglycerides
Dicaproin (C6) (Larodan) <10
Dicaprin (ClO) (Larodan) <10
Dioctanoin (C8) (Larodan) <10
Dimyristin (C14) (Larodan) <10
Dipalmitin (C16) (Larodan) <10
Distearin (Larodan) <10
Glyceryl dilaurate (C12) Capmul® 3-4
Glyceryl dioleate Capmul® 3-4
Glycerol esters of fatty acids GELUCIRE 39/01 (Gattefosse), GELUCIRE 43/01 (Gattefosse) 1
GELUCIRE 37/06 (Gattefosse) 6
Dipalmitolein (C16:l) (Larodan) <10 l,2 and l,3-diolein (C18:l) (Larodan) <10 Dielaidin (C18:l) (Larodan) <10
Dilinolein (C18:2) (Larodan) <10
5 2.10. Sterol and Sterol Derivatives
Sterols and derivatives of sterols are suitable surfactants for use in the present invention. These surfactants can be hydrophilic or hydrophobic. Preferred derivatives include the polyethylene glycol derivatives. A preferred hydrophobic surfactant in this class is cholesterol. A preferred hydrophilic surfactant in this class is PEG-24 cholesterol
10 ether (Solulan C-24). Examples of surfactants of this class are shown in Table 11.
Table 11 : Sterol and Sterol Derivative Surfactants
COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
Cholesterol, sitosterol, lanosterol <10
15 PEG-24 cholesterol ether Solulan C-24 (Amerchol) >10 PEG-30 cholestanol Nikkol DHC (Nikko) >10
Phytosterol GENEROL series (Henkel) <10
.r, PEG-25 phyto sterol Nikkol BPSH-25 (Nikko) >10
PEG-5 soya sterol Nikkol BPS-5 (Nikko) <10
PEG- 10 soya sterol Nikkol BPS- 10 (Nikko) <10
PEG-20 soya sterol Nikkol BPS-20 (Nikko) <10
25 PEG-30 soya sterol Nikkol BPS-30 (Nikko) >10
2.11. Polyethylene Glycol Sorbitan Fatty Acid Esters
A variety of PEG-sorbitan fatty acid esters are available and are suitable for use as surfactants in the present invention. In general, these surfactants are hydrophilic, although several hydrophobic surfactants of this class can be used. Among the PEG-sorbitan fatty acid esters, preferred hydrophilic surfactants include PEG-20 sorbitan monolaurate
(Tween-20), PEG-20 sorbitan monopalmitate (Tween-40), PEG-20 sorbitan monostearate (Tween-60), and PEG-20 sorbitan monooleate (Tween-80). Examples of these surfactants are shown in Table 12.
Table 12: PEG-Sorbitan Fatty Acid Esters
COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG- 10 sorbitan laurate Liposorb L-10 (Lipo Chem.) >10
PEG-20 sorbitan monolaurate Tween-20 (Atlas/ICI), Crillet 1 (Croda), DACOL MLS 20 (Condea) 17
PEG-4 sorbitan monolaurate Tween-21 (Atlas/ICI), Cπllet 11 (Croda) 13
PEG-80 sorbitan monolaurate Hodag PSML-80 (Calgene); T-Maz 28 >10
PEG-6 sorbitan monolaurate Nikkol GL-1 (Nikko) 16
PEG-20 sorbitan monopalmitate Tween-40 (Atlas/ICI), Cπllet 2 (Croda) 16
PEG-20 sorbitan monostearate Tween-60 (Atlas/ICI), Cπllet 3 (Croda) 15 PEG-4 sorbitan monostearate Tween-61 (Atlas/ICI), Crillet 31 (Croda) 9.6 PEG-8 sorbitan monostearate DACOL MSS (Condea) >10
PEG-6 sorbitan monostearate Nikkol TS 106 (Nikko) 11
PEG-20 sorbitan tπstearate Tween-65 (Atlas/ICI), Cπllet 35 (Croda) 11
PEG-6 sorbitan tetrastearate Nikkol GS-6 (Nikko) 3
PEG-60 sorbitan tetrastearate Nikkol GS-460 (Nikko) 13
PEG-5 sorbitan monooleate Tween-81 (Atlas/ICI), Crillet 41 (Croda) 10
PEG-6 sorbitan monooleate Nikkol TO- 106 (Nikko) 10
PEG-20 sorbitan monooleate Tween-80 (Atlas/ICI), Cπllet 4 (Croda) 15
PEG-40 sorbitan oleate Emalex ET 8040 (Nihon Emulsion) 18
PEG-20 sorbitan tπoleate Tween-85 (Atlas/ICI), Cπllet 45 (Croda) 11
PEG-6 sorbitan tetraoleate Nikkol GO-4 (Nikko) 8.5
PEG-30 sorbitan tetraoleate Nikkol GO-430 (Nikko) 12 PEG-40 sorbitan tetraoleate Nikkol GO-440 (Nikko) 13
PEG-20 sorbitan Tween- 120 (Atlas/ICI), Crillet 6 (Croda) >10 monoisostearate
PEG sorbitol hexaoleate Atlas G-1086 (ICI) 10
PEG-6 sorbitol hexastearate Nikkol GS-6 (Nikko)
2.12. Polyethylene Glycol Alkyl Ethers
Ethers of polyethylene glycol and alkyl alcohols are suitable surfactants for use in the present invention. Preferred hydrophobic ethers include PEG-3 oleyl ether (Volpo 3) and PEG-4 lauryl ether (Brij 30). Examples of these surfactants are shown in Table 13.
Table 13: Polyethylene Glycol Alkyl Ethers
COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-2 oleyl ether,oleth-2 Brij 92/93 (Atlas/ICI) 4.9
PEG-3 oleyl ether,oleth-3 Volpo 3 (Croda) <10
PEG-5 oleyl ether,oleth-5 Volpo 5 (Croda) <10
PEG-10 oleyl ether,oleth-10 Volpo 10 (Croda), Brij 96/97 (Atlas/ICI) 12
PEG-20 oleyl ether,oleth-20 Volpo 20 (Croda), Brij 98/99 (Atlas/ICI) 15
PEG-4 lauryl ether, laureth-4 Brij 30 (Atlas/ICI) 9.7
PEG-9 lauryl ether >10
PEG-23 lauryl ether, laureth-23 Brij 35 (Atlas/ICI) 17
PEG-2 cetyl ether Brij 52 (ICI) 5.3
PEG- 10 cetyl ether Brij 56 (ICI) 13
PEG-20 cetyl ether Brij 58 (ICI) 16
PEG-2 stearyl ether Brij 72 (ICI) 4.9
PEG- 10 stearyl ether Brij 76 (ICI) 12 PEG-20 stearyl ether Brij 78 (ICI) 15
PEG- 100 stearyl ether Brij 700 (ICI) >10
2.13. Sugar Esters
Esters of sugars are suitable surfactants for use in the present invention. Preferred hydrophilic surfactants in this class include sucrose monopalmitate and sucrose monolaurate. Examples of such surfactants are shown in Table 14.
Table 14: Sugar Ester Surfactants
COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
Sucrose distearate SUCRO ESTER 7 (Gattefosse), Crodesta F- 10 (Croda) 3
Sucrose distearate/monostearate SUCRO ESTER 11 (Gattefosse), Crodesta F-l 10 (Croda) 12 Sucrose dipalmitate 7.4
Sucrose monostearate Crodesta F-l 60 (Croda) 15
Sucrose monopalmitate SUCRO ESTER 15 (Gattefosse) >10
Sucrose monolaurate Saccharose monolaurate 1695 (Mitsubishi-Kasei) 15
2.14. Polyethylene Glycol Alkyl Phenols
Several hydrophilic PEG-alkyl phenol surfactants are available, and are suitable for use in the present invention. Examples of these surfactants are shown in Table 15.
Table 15 : Polyethylene Glycol Alkyl Phenol Surfactants
COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-10-100 nonyl phenol Triton X series (Rohm & Haas), Igepal CA series (GAF, USA), >10
Antarox CA series (GAF, UK)
PEG-15-100 octyl phenol ether Triton N-series (Rohm & Haas), Igepal CO series (GAF, USA), >10
Antarox CO series (GAF, UK) 2.15. Polyoxyethylene-Polyoxypropylene Block Copolymers
The POE-POP block copolymers are a unique class of polymeric surfactants. The unique stmcture of the surfactants, with hydrophilic POE and hydrophobic POP moieties in well-defined ratios and positions, provides a wide variety of surfactants suitable for use in the present invention. These surfactants are available under various trade names, including Synperonic PE series (ICI); Pluronic® series (BASF), Emkalyx, Lutrol (BASF),
Supronic, Monolan, Pluracare, and Plurodac. The generic term for these polymers is
"poloxamer" (CAS 9003-11-6). These polymers have the formula:
HO(C2H4O)a(C3H6O)b(C2H4O)aH where "a" and "b" denote the number of polyoxyethylene and polyoxypropylene units, respectively.
Preferred hydrophilic surfactants of this class include Poloxamers 108, 188, 217,
238, 288, 338, and 407. Preferred hydrophobic surfactants in this class include
Poloxamers 124, 182, 183, 212, 331, and 335. Examples of suitable surfactants of this class are shown in Table 16. Since the compounds are widely available, commercial sources are not listed in the Table. The compounds are listed by generic name, with the corresponding "a" and "b" values.
Table 16: POE-POP Block Copolymers COMPOUND a, b values in HO(C2H O)a(C3H6O)b(C2H4O)aH HLB
Poloxamer 105 a = l l b = 16
Poloxamer 108 a = 46 b = 16 >10
Poloxamer 122 a = 5 b = 21 3
Poloxamer 123 a = 7 b = 21 7
Poloxamer 124 a = 11 b = 21 >7
Poloxamer 181 a = 3 b = 30
Poloxamer 182 a = 8 b = 30
Poloxamer 183 a = 10 b = 30
Poloxamer 184 a = 13 b = 30 Poloxamer 185 a = 19 b = 30
Poloxamer 188 a = 75 b = 30 29
Poloxamer 212 a = 8 b = 35
Poloxamer 215 a = 24 b = 35
Poloxamer 217 a = 52 b = 35
Poloxamer 231 a = 16 b = 39
Poloxamer 234 a = 22 b = 39
Poloxamer 235 a = 27 b = 39
Poloxamer 237 a = 62 b = 39 24
Poloxamer 238 a = 97 b = 39
Poloxamer 282 a = 10 b = 47
Poloxamer 284 a = 21 b = 47
Poloxamer 288 a = 122 b = 47 >10
Poloxamer 331 a = 7 b = 54 0.5
Poloxamer 333 a = 20 b = 54
Poloxamer 334 a = 31 b = 54
Poloxamer 335 a = 38 b = 54
Poloxamer 338 a = 128 b = 54
Poloxamer 401 a = 6 b = 67
Poloxamer 402 a = 13 b = 67
Poloxamer 403 a = 21 b = 67
Poloxamer 407 a = 98 b = 67
2.16. Sorbitan Fatty Acid Esters Sorbitan esters of fatty acids are suitable surfactants for use in the present invention. Among these esters, preferred hydrophobic surfactants include sorbitan monolaurate (Arlacel 20), sorbitan monopalmitate (Span-40), sorbitan monooleate (Span- 80), sorbitan monostearate, and sorbitan tristearate. Examples of these surfactants are shown in Table 17.
Table 17: Sorbitan Fatty Acid Ester Surfactants
COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
Sorbitan monolaurate Span-20 (Atlas/ICI), Crill 1 (Croda), Arlacel 20 (ICI) 8.6 Sorbitan monopalmitate Span-40 (Atlas/ICI), Crill 2 (Croda), Nikkol SP-10 (Nikko) 6.7
Sorbitan monooleate Span-80 (Atlas/ICI), Crill 4 (Croda), Crill 50 (Croda) 4.3
Sorbitan monostearate Span-60 (Atlas/ICI), Crill 3 (Croda), Nikkol SS-10 (Nikko) 4.7
Sorbitan trioleate Span-85 (Atlas/ICI), Crill 45 (Croda), Nikkol SO-30 (Nikko) 4.3
Sorbitan sesquioleate Arlacel-C (ICI), Crill 43 (Croda), Nikkol SO- 15 (Nikko) 3.7
Sorbitan tristearate Span-65 (Atlas/ICI) Crill 35 (Croda), Nikkol SS-30 (Nikko) 2.1
Sorbitan monoisostearate Crill 6 (Croda), Nikkol SI-10 (Nikko) 4.7
Sorbitan sesquistearate Nikkol SS-15 (Nikko) 4.2
2.17. Lower Alcohol Fatty Acid Esters
Esters of lower alcohols (C to C4) and fatty acids (C8 to 8) are suitable surfactants for use in the present invention. Among these esters, preferred hydrophobic surfactants include ethyl oleate (Crodamol EO), isopropyl myristate (Crodamol IPM), and isopropyl palmitate (Crodamol IPP). Examples of these surfactants are shown in Table 18.
Table 18: Lower Alcohol Fatty Acid Ester Surfactants
COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
Ethyl oleate Crodamol EO (Croda), Nikkol EOO (Nikko) <10
Isopropyl myristate Crodamol IPM (Croda) <10
Isopropyl palmitate Crodamol IPP (Croda) <10
Ethyl linoleate Nikkol VF-E (Nikko) <10 Isopropyl linoleate Nikkol VF-IP (Nikko) <10
2.18. Ionic Surfactants
Ionic surfactants, including cationic, anionic and zwitterionic surfactants, are suitable hydrophilic surfactants for use in the present invention. Preferred anionic surfactants include fatty acid salts and bile salts. Preferred cationic surfactants include carnitines. Specifically, preferred ionic surfactants include sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, sodium cholate, sodium taurocholate; lauroyl camitine; palmitoyl camitine; and myristoyl camitine. Examples of such surfactants are shown in Table 19. For simplicity, typical counterions are shown in the entries in the Table. It will be appreciated by one skilled in the art, however, that any bioacceptable counterion may be used. For example, although the fatty acids are shown as sodium salts, other cation counterions can also be used, such as alkali metal cations or ammonium. Unlike typical non-ionic surfactants, these ionic surfactants are generally available as pure compounds, rather than commercial (proprietary) mixtures. Because these compounds are readily available from a variety of commercial suppliers, such as Aldrich, Sigma, and the like, commercial sources are not generally listed in the Table.
Table 19: Ionic Surfactants 0
COMPOUND HLB
FATTY ACID SALTS >10
Sodium caproate
Sodium caprylate c Sodium caprate
Sodium laurate
Sodium myristate
Sodium myristolate
Sodium palmitate 0 Sodium palmitoleate
Sodium oleate 18
Sodium ricinoleate Sodium linoleate Sodium linolenate Sodium stearate
Sodium lauryl sulfate (dodecyl) 40
Sodium tetradecyl sulfate Sodium lauryl sarcosinate
Sodium dioctyl sulfosuccinate [sodium docusate (Cytec)] BILE SALTS >10
Sodium cholate
10
Sodium taurocholate
Sodium glycocholate
Sodium deoxycholate
Sodium taurodeoxycholate
Sodium glycodeoxycholate
Sodium ursodeoxycholate
Sodium chenodeoxycholate
Sodium taurochenodeoxycholate
Sodium glyco cheno deoxycholate
Sodium cholylsarcosinate
Sodium N-methyl taurocholate
Sodium lithocholate
PHOSPHOLIPIDS
Egg/Soy lecithin [Epikuron™ (Lucas Meyer), Ovothin™ (Lucas Meyer)] Lyso egg/soy lecithin
Hydroxylated lecithin
Lysophosphatidylcholine
Cardiolipin
Sphingomyelin 30 Phosphatidylcholine
Phosphatidyl ethanolamine
Phosphatidic acid Phosphatidyl glycerol Phosphatidyl serine PHOSPHORIC ACID ESTERS
Diethanolammonium polyoxyethylene- 10 oleyl ether phosphate
Esterification products of fatty alcohols or fatty alcohol ethoxylates with phosphoric acid or anhydride
CARBOXYLATES
Ether carboxylates (by oxidation of terminal OH group of fatty alcohol ethoxylates)
10 Succinylated monoglycerides [LAMEGIN ZE (Henkel)]
Sodium stearyl fumarate
Stearoyl propylene glycol hydrogen succinate
Mono/diacetylated tartaric acid esters of mono- and diglycerides
Citric acid esters of mono-, diglycerides
15 Glyceryl-lacto esters of fatty acids (CFR ref. 172.852)
Acyl lactylates: lactylic esters of fatty acids calcium/sodium stearoyl-2-lactylate calcium/sodium stearoyl lactylate r.p. Alginate salts
Propylene glycol alginate
SULFATES AND SULFONATES
Ethoxylated alkyl sulfates
Alkyl benzene sulfones 25 α-olefin sulfonates
Acyl isethionates
Acyl taurates
Alkyl glyceryl ether sulfonates
Octyl sulfosuccinate disodium 30 Disodium undecylenamideo-MEA-sulfosuccinate
CATIONIC Surfactants >10
Lauroyl camitine Palmitoyl camitine Myristoyl camitine Hexadecyl triammonium bromide Decyl trimethyl ammonium bromide Cetyl trimethyl ammonium bromide Dodecyl ammonium chloride Alkyl benzyldimethylammonium salts Diisobutyl phenoxyethoxydimethyl benzylammonium salts
Alkylpyridinium salts
Betaines (trialkylglycine):
Lauryl betaine (N-lauryl,N,N-dimethylglycine)
Ethoxylated amines:
Polyoxyethylene- 15 coconut amine
2.19 Unionized Ionizable Surfactants
Ionizable surfactants, when present in their unionized (neutral, non-salt) form, are hydrophobic surfactants suitable for use in the compositions and methods of the present invention. Particular examples of such surfactants include free fatty acids, particularly C6- C22 fatty acids, and bile acids. More specifically, suitable unionized ionizable surfactants include the free fatty acid and bile acid forms of any of the fatty acid salts and bile salts shown in Table 19.
2.20 Preferred Surfactants and Surfactant Combinations
Among the above-listed surfactants, several combinations are preferred. In all of the preferred combinations, the carrier includes at least one hydrophilic surfactant. Preferred non-ionic hydrophilic surfactants include alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene- polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols with fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sugar esters, sugar ethers; sucroglycerides; and mixtures thereof.
More preferably, the non-ionic hydrophilic surfactant is selected from the group consisting of polyoxyethylene alkylethers; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglyceryl fatty acid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils; and polyoxyethylene hydrogenated vegetable oils. The glyceride can be a monoglyceride, diglyceride, triglyceride, or a mixture. Also preferred are non-ionic hydrophilic surfactants that are reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils or sterols. These reaction mixtures are largely composed of the transesterification products of the reaction, along with often complex mixtures of other reaction products. The polyol is preferably glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.
Several particularly preferred carrier compositions are those which include as a non-ionic hydrophilic surfactant PEG- 10 laurate, PEG-12 laurate, PEG-20 laurate, PEG- 32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 com oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE- 10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG- 100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, or a poloxamer. Among these preferred surfactants, more prefeπed are PEG-20 laurate, PEG-20 oleate, PEG-35 castor oil, PEG-40 palm kernel oil, PEG-40 hydrogenated castor oil, PEG- 60 com oil, PEG-25 glyceryl trioleate, polyglyceryl-10 laurate, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, PEG-30 cholesterol, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE- 10 oleyl ether, PEG-24 cholesterol, sucrose monostearate, sucrose monolaurate and poloxamers. Most preferred are PEG-35 castor oil, PEG-40 hydrogenated castor oil, PEG-60 com oil, PEG-25 glyceryl trioleate, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polysorbate 20, polysorbate 80, tocopheryl PEG-1000 succinate, PEG-24 cholesterol, and hydrophilic poloxamers.
The hydrophilic surfactant can also be, or include as a component, an ionic surfactant. Preferred ionic surfactants include alkyl ammonium salts; bile acids and salts, analogues, and derivatives thereof; fusidic acid and derivatives thereof; fatty acid derivatives of amino acids, ohgopeptides, and polypeptides; glyceride derivatives of amino acids, ohgopeptides, and polypeptides; acyl lactylates; mono-,diacetylated tartaric acid esters of mono-,diglycerides; succinylated monoglycerides; citric acid esters of mono- jdiglycerides; alginate salts; propylene glycol alginate; lecithins and hydrogenated lecithins; lysolecithin and hydrogenated lysolecithins; lysophospholipids and derivatives thereof; phospholipids and derivatives thereof; salts of alkylsulfates; salts of fatty acids; sodium docusate; camitines; and mixtures thereof.
More preferable ionic surfactants include bile acids and salts, analogues, and derivatives thereof; lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; salts of alkylsulfates; salts of fatty acids; sodium docusate; acyl lactylates; mono-,diacetylated tartaric acid esters of mono-,diglycerides; succinylated monoglycerides; citric acid esters of mono-,diglycerides; camitines; and mixtures thereof. More specifically, prefeπed ionic surfactants are lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholate, taurocholate, glycocholate, deoxycholate, taurodeoxycholate, chenodeoxycholate, glycodeoxycholate, glycochenodeoxycholate, taurochenodeoxycholate, ursodeoxycholate, tauroursodeoxycholate, glycoursodeoxycholate, cholylsarcosine, N-methyl taurocholate, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl camitines, palmitoyl camitines, myristoyl camitines, and salts and mixtures thereof.
Particularly prefeπed ionic surfactants are lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, lysophosphatidylcholine, PEG-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholate, taurocholate, glycocholate, deoxycholate, taurodeoxycholate, glycodeoxycholate, cholylsarcosine, caproate, caprylate, caprate, laurate, oleate, lauryl sulfate, docusate, and salts and mixtures thereof, with the most preferred ionic surfactants being lecithin, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, taurocholate, caprylate, caprate, oleate, lauryl sulfate, docusate, and salts and mixtures thereof.
The carrier of the present compositions includes at least two surfactants, at least one of which is hydrophilic. In one embodiment, the present invention includes at two surfactants that are hydrophilic, and preferred hydrophilic surfactants are listed above. In another embodiment, the carrier includes at least one hydrophilic surfactant and at least one hydrophobic surfactant. In this embodiment, preferred hydrophobic surfactants are alcohols; polyoxyethylene alkylethers; fatty acids; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polypropylene glycol fatty acid esters; polyoxyethylene glycerides; lactic acid derivatives of mono/diglycerides; propylene glycol diglycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; transesterified vegetable oils; sterols; sterol derivatives; sugar esters; sugar ethers; sucroglycerides; polyoxyethylene vegetable oils; and polyoxyethylene hydrogenated vegetable oils. As with the hydrophilic surfactants, hydrophobic surfactants can be reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
Preferably, the hydrophobic surfactant is selected from the group consisting of fatty acids; lower alcohol fatty acid esters; polyethylene glycol glycerol fatty acid esters; polypropylene glycol fatty acid esters; polyoxyethylene glycerides; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lactic acid derivatives of mono/diglycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene- polyoxypropylene block copolymers; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; and reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
More preferred are lower alcohol fatty acids esters; polypropylene glycol fatty acid esters; propylene glycol fatty acid esters; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lactic acid derivatives of mono/diglycerides; sorbitan fatty acid esters; polyoxyethylene vegetable oils; and mixtures thereof, with glycerol fatty acid esters and acetylated glycerol fatty acid esters being most preferred. Among the glycerol fatty acid esters, the esters are preferably mono- or diglycerides, or mixtures of mono- and diglycerides, where the fatty acid moiety is a C6 to C22 fatty acid.
Also preferred are hydrophobic surfactants which are the reaction mixture of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols. Preferred polyols are polyethylene glycol, sorbitol, propylene glycol, and pentaerythritol.
Specifically prefeπed hydrophobic surfactants include myristic acid; oleic acid; lauric acid; stearic acid; palmitic acid; PEG 1-4 stearate; PEG 2-4 oleate; PEG-4 dilaurate; PEG-4 dioleate; PEG-4 distearate; PEG-6 dioleate; PEG-6 distearate; PEG-8 dioleate; PEG 3-16 castor oil; PEG 5-10 hydrogenated castor oil; PEG 6-20 com oil; PEG 6-20 almond oil; PEG-6 olive oil; PEG-6 peanut oil; PEG-6 palm kernel oil; PEG-6 hydrogenated palm kernel oil; PEG-4 capric/caprylic triglyceride, mono, di, tri, tetra esters of vegetable oil and sorbitol; pentaerythrityl di, tetra stearate, isostearate, oleate, caprylate, or caprate; polyglyceryl 2-4 oleate, stearate, or isostearate; polyglyceryl 4-10 pentaoleate; polyglyceryl-3 dioleate; polyglyceryl-6 dioleate; polyglyceryl-10 trioleate; polyglyceryl-3 distearate; propylene glycol mono- or diesters of a C6 to C20 fatty acid; monoglycerides of C6 to C20 fatty acids; acetylated monoglycerides of C6 to C20 fatty acids; diglycerides of C6 to C 0 fatty acids; lactic acid derivatives of monoglycerides; lactic acid derivatives of diglycerides; cholesterol; phytosterol; PEG 5-20 soya sterol; PEG-6 sorbitan tetra, hexastearate; PEG-6 sorbitan tetraoleate; sorbitan monolaurate; sorbitan monopalmitate; sorbitan mono, trioleate; sorbitan mono, tristearate; sorbitan monoisostearate; sorbitan sesquioleate; sorbitan sesquistearate; PEG 2-5 oleyl ether; POE 2-4 lauryl ether; PEG-2 cetyl ether; PEG-2 stearyl ether; sucrose distearate; sucrose dipalmitate; ethyl oleate; isopropyl myristate; isopropyl palmitate; ethyl linoleate; isopropyl linoleate; and poloxamers. Among the specifically preferred hydrophobic surfactants, most preferred are oleic acid; lauric acid; glyceryl monocaprate; glyceryl monocaprylate; glyceryl monolaurate; glyceryl monooleate; glyceryl dicaprate; glyceryl dicaprylate; glyceryl dilaurate; glyceryl dioleate; acetylated monoglycerides; propylene glycol oleate; propylene glycol laurate; polyglyceryl-3 oleate; polyglyceryl-6 dioleate; PEG-6 com oil; PEG-20 com oil; PEG-20 almond oil; sorbitan monooleate; sorbitan monolaurate; POE-4 lauryl ether; POE-3 oleyl ether; ethyl oleate; and poloxamers. 3. Therapeutic Agents
In the embodiments of the present invention which include therapeutic agents, the therapeutic agents suitable for use in the pharmaceutical compositions and methods of the present invention are not particularly limited, as the compositions are surprisingly capable of solubilizing and delivering a wide variety of therapeutic agents. The therapeutic agents can be hydrophilic, lipophilic, amphiphilic or hydrophobic, and can be solubilized in the triglyceride; solubilized in the carrier; solubilized in both the triglyceride and the carrier; or present in the diluent. Optionally, the therapeutic agent can be present in a first, solubilzed amount, and a second, non-solubilized (suspended) amount. Such therapeutic agents can be any agents having therapeutic or other value when administered to an animal, particularly to a mammal, such as drugs, nutrients, and cosmetics (cosmeceuticals). It should be understood that while the invention is described with particular reference to its value in the form of aqueous dispersions, the invention is not so limited. Thus, dmgs, nutrients or cosmetics which derive their therapeutic or other value from, for example, topical or transdermal administration, are still considered to be suitable for use in the present invention. 1 Specific non-limiting examples of therapeutic agents that can be used in the pharmaceutical compositions of the present invention include analgesics and anti- inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-asthma agents, antibacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-
5 epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents and immunosuppressants, anti-protozoal agents, anti-thyroid agents, anti-tussives, anxiolytic, sedatives, hypnotics and neuroleptics, β -Blockers, cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastro-intestinal agents, histamine H,- receptor antagonists, keratolytics, lipid regulating agents, muscle relaxants, anti-anginal agents, nutritional agents, analgesics, sex hormones, stimulants, peptides, peptidomimetics, DNA, RNA, oligodeoxynucleotides, genetic material, proteins, oligonucleotides, and vaccines.
In one embodiment, the therapeutic agent is a nutritional agent. In another embodiment, the therapeutic agent is a cosmeceutical agent.
In another embodiment, the therapeutic agent is a protein, peptide or oligonucleotide. In a particular aspect of this embodiment, the therapeutic agent is a protein, peptidomimetic, DNA, RNA, ohgodeoxynucleotide, genetic material, peptide or oligonucleotide having a molecular weight of less than about 1000 g/mol. U In another embodiment, the therapeutic agent is hydrophobic. Hydrophobic therapeutic agents are compounds with little or no water solubility. Intrinsic water solubilities (i.e., water solubility of the unionized form) for hydrophobic therapeutic agents are less than about 1% by weight, and typically less than about 0.1% or 0.01% by weight. In a particular aspect of this embodiment, the therapeutic agent is a hydrophobic
7 dmg. In another particular aspect, the therapeutic agent is a hydrophobic dmg having a molecular weight of less than about 1000 g/mol.
In another embodiment, the therapeutic agent is hydrophilic. Amphiphilic therapeutic agents are included within the class of hydrophilic therapeutic agents.
Apparent water solubilities for hydrophilic therapeutic agents are greater than about 1% by
J 30j weight, and typically greater than about 0.1% by weight. In a particular aspect of this embodiment, the therapeutic agent is a hydrophilic dmg. In another particular aspect, the therapeutic agent is a hydrophilic dmg having a molecular weight of less than about 1000 g/mol.
Although the invention is not limited thereby, examples of therapeutic agents suitable for use in the compositions and methods of the present invention include the following representative compounds, as well as their pharmaceutically acceptable salts, isomers, esters, ethers and other derivatives: abacavir, acarbose, acebutolol, acetazolamide, acetohexamide, acrivastine, acutretin, acyclovir, alatrofloxacin, albendazole, albuterol, alclofenac, alendronate, allopurinol, aloxiprin, alprazolam, alprenolol, alprostadil, amantadine, amiloride, aminoglutethimide, amiodarone, amiodarone HCl, amitriptyline, amlodipine, , amodiaquine, amoxapine, amoxapine, amphetamine, amphotericin, amprenavir, amrinone, amsacrine, amyl nitrate, amylobarbital, amylobarbitone, aspirin, astemizole, atenolol, atorvastatin, atovaquone, atropine, auranofin, azapropazone, azathioprine, azelastine, azithromycin, baclofen, barbital, barbitone, becaplermin, beclamide, beclomethasone, bendrofluazide, benethamine, benethamine penicillin, benezepril, benidipine, benorylate, bentazepam, benzhexol, benzhexol HCl, benznidazole, benzonatate, benztropine, bephenium hydroxynaphthoate, betamethasone, bezafibrate, bicalutamide, biperiden, bisacodyl, bisanthrene, bovine growth hormone, bromazepam, bromfenac, bromocriptine, bromocriptine mesylate, bromperidol, brompheniramine, brotizolam, budesonide, bumetanide, bupropion, busulphan, butenafine, butenafine HCl, butobarbital, butobarbitone, butoconazole, butoconazole nitrate, calcifediol, calciprotiene, calcitonin, calcitriol, cambendazole, camptothecan, camptothecin, candesartan, capecitabine, capsacin, capsaicin, captopril, carbamazepine, carbimazole, carbinoxamine, carbromal, carotenes, cefazolin, cefoxitin sodium, celecoxib, cephadrine, cephalexin, cerivistatin, cetrizine, chlopheniramine, chlophenisamine, chloproguanil, chlorambucil, chlordiazepoxide, chlormethiazole, chloroquine, chlorothiazide, chlorproguanil HCl, chlorpromazine, chlorpropamide, chlorprothiocene, chlorprothixene, chlorthalidone, cholecalciferol, cilostazol, cimetidine, cinnarizine, cinoxacin, ciprofloxacin, ciprofloxacin HCl, cisapride, citalopram, citrizine, clarithromycin, clemastine, clemastine fumarate, clemizole, clenbuterol, clinofibrate, clioquinol, clobazam, clofazimine, clofibrate, clomiphene, clomiphene citrate, clomipramine, clonazepam, clopidrogel, clotiazepam, clotrimazole, cloxacillin, clozapine, codeine, conjugated estrogens, cortisone acetate, cortisone acetate, cromalyn sodium, cromoglicate, cromolyn, cyclizine, cyclosporin, cyproheptadine, cyproheptadine HCl, dacarbazine, danazol, dantrolene, dantrolene sodium, darodipine, decoquinate, delavirdine, demeclocycline, desoxymethasone, dexamphetamine, dexchlopheniramine, dexfenfluramine, dextropropyoxyphene, diamorphine, diazepam, diazoxide, dichlorophen, diclofenac, dicloxacillin, dicoumarol, dicumarol, didanosine, diethylpropion, diflunisal, digitoxin, digoxin, dihydro epiandrosterone, dihydrocodeine, dihydroergotamine, dihydroergotamine mesylate, dihydrotachysterol, diiodohydroxyquinoline, dilitazem, dilitazem HCl, diloxanide furoate, dimenhydrinate, dinitolmide, diphenhydramine, diphenooxylate, diphenoxylate HCl, diphenylimidazole, diphenylpyrallin, dipyridamole, dirithromycin, disopyramide, divalproen, docusate, dolasetron, domperidone, donepezil, donepezil HCl, doxazosin, doxazosin HCl, doxycycline, dronabinol, droperidol, econazole, econazole nitrate, editronate, efavirenz, elanapril, ellipticine, enalapril, enkephalin, enoxacin, enoximone, enrofloxacin, epalrestate, eperisone, ephedrine, eposartan, eposartan losartan, ergocalciferol, ergotamine, ergotamine tartrate, erythromycin, erythropoietin, essential fatty acids, estramustine, ethacrynic acid, ethambutol, ethinamate, ethinyloestradiol, ethionamide, ethopropazine, ethopropazine HCl, ethotoin, etodolac, etoperidone, etoposide, etretinate, famcyclovir, famotidine, felbamate, felodipine, fenbendazole, fenbufen, fenfluramine, fenofibrate, fenolclopam, fenoldopam, fenoprofen, fenoprofen calcium, fentanyl, fexofenadine, finasteride, flecainide, flecainide acetate, fluconazole, flucortolone, flucytosine, fludrocortisone, fludrocortisone acetate, fluexetine HCl, flunanisone, flunarizine, flunarizine HCl, flunisolide, flunitrazepam, fluopromazine, fluoxetine, fluoxymisterone, flupenthixol decanoate, flupentixol, flupentixol decanoate, fluphenazine, fluphenazine decanoate, flurazepam, flurbiprofen, flurithromycin, fluticasone propionate, fluvastatin, foscamet sodium, fosinopril, fosphenytoin, fosphenytoin sodium, frovatriptan, frusemide, fumagillin, furazolidone, furosemide, furzolidone, gabapentin, gancyclovir, gemfibrozil, gentamycin, glibenclamide, gliclazide, glipizide, glucagon, glybenclamide, glyburide, glyceryl trinitrate, glymepiride, glymepride, granisetron, granulocyte stimulating factor, grepafloxacin, griseofulvin, guanabenz, guanabenz acetate, halofantrine, halofantrine HCl, haloperidol, hydrocortisone, hyoscyamine, ibufenac, ibuprofen, imipenem, indinavir, indivir, indomethacin, insulin, interleukin-3, irbesartan, irinotecan, isosorbide dinitrate, isosorbide mononitrate, isotretinoin, isoxazole, isradipine, itraconazole, ivermectin, ketoconazole, ketoprofen, ketorolac, ketotifen, labetalol, lamivudine, lamotrigine, lanatoside C, lanosprazole, leflunomide, levofloxacin, levothyroxine, lisinopril, lomefloxacin, lomustine, loperamide, loratadine, lorazepam, lorefloxacin, lormetazepam, losartan, lovastatin, L-thryroxine, lysuride, lysuride maleate, maprotiline, maprotiline HCl, mazindol, mebendazole, meclofenamic acid, meclozine, meclozine HCl, medazepam, medigoxin, medroxyprogesterone acetate, mefenamic acid, mefloquine, mefloquine HCl, megesterol acetate, melonicam, melphalan, mepacrine, mepenzolate bromide, meprobamate, meptazinol, mercaptopurine, mesalazine, mesoridazine, mesoridiazine, mestranol, mesylate, metformin, methadone, methaqualone, methoin, methotrexate, methoxsalen, methsuximide, methylphenidate, methylphenobarbital, methylphenobarbitone, methylprednisolone, methyltestosterone, methysergide, methysergide maleate, metoclopramide, metolazone, metoprolol, metronidazole, mianserin, mianserin HCl, miconazole, midazolam, miglitol, minoxidil, mitomycins, mitotane, mitoxantrone, mofetil, molindone, montelukast, morphine, mortriptyline, moxifloxacin, moxifloxacin HCl, mycophenolate, nabumetone, nadolol, nalbuphine, nalidixic acid, naproxen, naratriptan, naratriptan HCl, natamycin, nedocromil sodium, nefazodone, nelfinavir, nerteporfin, neutontin, nevirapine, nicardipine, nicardipine HCl, nicotine, nicoumalone, nifedipine, nilutamide, nimesulide, nimodipine, nimorazole, nisoldipine, nitrazepam, nitrofurantoin, nitrofurazone, nizatidine, non-essential fatty acids, norethisterone, norfloxacin, norgestrel, nortriptyline HCl, nystatin, oestradiol, ofloxacin, olanzapine, omeprazole, ondansetron, ondansetron HCL, oprelvekin, omidazole, oxacillin, oxamniquine, oxantel, oxantel embonate, oxaprozin, oxatomide, oxazepam, oxcarbazepine, oxfendazole, oxiconazole, oxprenolol, oxybutynin, oxyphenbutazone, oxyphencylcimine, oxyphencylcimine HCl, paclitaxel, pamidronate, paramethadione, paricalcitol, paroxetine, paroxetine HCl, penicillins, pentaerythritol tetranitrate, pentazocine, pentobarbital, pentobarbitone, pentoxifylline, perchloperazine, perfloxacin, pericyclovir, perphenazine, perphenazine pimozide, phenacemide, phenbenzamine, phenindione, pheniramine, phenobarbital, phenobarbitone, phenoxybenzamine, phenoxybenzamine HCl, phensuximide, phentermine, phenylalanine, phenylbutazone, phenytoin, physostigmine, phytonodione, pimozide, pindolol, pioglitazone, piroxicam, pizotifen, pizotifen maleate, pramipexol, pramipexole, pranlukast, pravastatin, praziquantel, prazosin, prazosin HCl, prednisolone, prednisone, pregabalin, primidone, probenecid, probucol, procarbazine, procarbazine HCl, prochlorperazine, progesterone, proguanil, proguanil HCl, propofol, propranolol, propylthiouracil, pseudoephedrine, pyrantel, pyrantel embonate, pyridostigmine, pyrimethamine, quetiapine, quinapril, quinidine, quinidine sulfate, quinine, quinine sulfate, rabeprazole, rabeprazole sodium, raloxifene, raloxifene HCl, ranitidine, ranitidine HCl, recombinant human growth hormone, refocoxib, remifentanil, repaglinide, reserpine, residronate, retinoids, ricobendazole, rifabutin, rifabutine, rifampicin, rifampin, rifapentine, rimantadine, rimexolone, risperodone, ritonavir, rizatriptan, rizatriptan benzoate, robinirole HCl, ropinirole, rosiglitazone, roxatidine, roxithromycin, salbutamol, salmon calcitonin (sCT), saquinavir, selegiline, sertindole, sertraline, sertraline HCl, sibutramine, sibutramine HCl, sildenafil, sildenafil citrate, simvastatin, sirolimus, sodium cefazoline, somatostatin, sparfloxacin, spiramycins, spironolactone, stanozolol, stavudine, stavueline, stiboestrol, sulconazole, sulconazole nitrate, sulfabenzamide, sulfacetamide, sulfadiazine, sulfadoxine, sulfafurazole, sulfamerazine, sulfamethoxazole, sulfapyridine, sulfasalazine, sulindac, sulphabenzamide, sulphacetamide, sulphadiazine, sulphadoxine, sulphafurazole, sulphamerazine, sulphamethoxazole, sulphapyridine, sulphasalazine, sulphin-pyrazone, sulpiride, sulthiame, sumatriptan, sumatriptan succinate, tacrine, tacrolimus, tamoxifen, tamoxifen citrate, tamsulosin, tamsulosin HCl, targretin, tazarotene, telmisartan, temazepam, teniposide, terazosin, terazosin HCl, terbinafine HCl, terbutaline, terbutaline sulfate, terconazole, terenadine, terfenadine, testolactone, testosterone, tetracycline, tetrahydrocannabinol, tetramisole, thiabendazole, thioguanine, thioridazine, tiagabine, tiagabine HCl, tibolone, ticlidopine, ticlopidine, tiludronate, timolol, tinidazole, tioconazole, tirofibran, tizanidine, tizanidine HCl, tolazamide, tolbutamide, tolcapone, tolmetin, tolterodine, topiramate, topotecan, topotecan HCl, toremifene, toremifene citrate, tramadol, trazodone, trazodone HCl, tretinoin, triamcinolone, triamterene, triazolam, trifluoperazine, trimethoprim, trimipramine, trimipramine maleate, troglitazone, tromethamine, tropicamide, trovafloxacin, tumor necrosisi factor, undecenoic acid, ursodeoxycholic acid, valacylcovir, valproic acid, valsartan, vancomycin, vasopressin, venlafaxine HCl, verteporfin, vigabatrin, vinblastine, vincristine, vinorelbine, vitamin A, vitamin B2, vitamin D, vitamin E and vitamin K, vitamin K5, vitamin K$, vitamin K7, vitamin K-S (II), zafirlukast, zileuton, zolmitriptan, zolpidem, and zopiclone. Of course, salts, metabolic precursors, derivatives and mixtures of therapeutic agents may also be used where desired. 4. Concentrations
The components of the pharmaceutical compositions of the present invention in amounts such that upon dilution with an aqueous solution, the composition forms a clear, aqueous dispersion. The determining concentrations of components to form clear aqueous dispersions are the concentrations of triglyceride and surfactants, with the amount of the therapeutic agent, if present, being chosen as described below. The relative amounts of triglycerides and surfactants are readily determined by observing the properties of the resultant dispersion; i.e., when the relative amounts of these components are within a suitable range, the resultant aqueous dispersion is optically clear. When the relative amounts are outside the suitable range, the resulting dispersion is visibly "cloudy", resembling a conventional emulsion or multiple-phase system. Although a visibly cloudy solution may be potentially useful for some applications, such a system would suffer from many of the same disadvantages as conventional prior art formulations, as described above.
A convenient method of determining the appropriate relative concentrations for any particular triglyceride is as follows. A convenient working amount of a hydrophilic surfactant is provided, and a known amount of the triglyceride is added. The mixture is stiπed, with the aid of gentle heating if desired, then is diluted with purified water to prepare an aqueous dispersion. Any dilution amount can be chosen, but convenient dilutions are those within the range expected in vivo, about a 10 to 250-fold dilution. In the Examples herein, a convenient dilution of 100-fold was chosen. The aqueous dispersion is then assessed qualitatively for optical clarity. The procedure can be repeated with incremental variations in the relative amount of triglyceride added, to determine the maximum relative amount of triglyceride that can be present to form a clear aqueous dispersion with a given hydrophilic surfactant. I.e., when the relative amount of triglyceride is too great, a hazy or cloudy dispersion is formed.
The amount of triglyceride that can be solubilized in a clear aqueous dispersion is increased by repeating the above procedure, but substituting a second hydrophilic surfactant, or a hydrophobic surfactant, for part of the originally-used hydrophilic surfactant, thus keeping the total surfactant concentration constant. Of course, this procedure is merely exemplary, and the amounts of the components can be chosen using other methods, as desired.
It has been surprisingly found that mixtures of surfactants including two hydrophilic surfactants can solubilize a greater relative amount of triglyceride than a single surfactant. Similarly, mixtures of surfactants including a hydrophilic surfactant and a hydrophobic surfactant can solubilize a greater relative amount of triglyceride than either surfactant by itself. It is particularly surprising that when the surfactant mixture includes a hydrophilic surfactant and a hydrophobic surfactant, the solubility of the triglyceride is greater than, for example, in the hydrophilic surfactant itself. Thus, contrary to conventional knowledge in the art, the total amount of water-insoluble component (triglyceride plus hydrophobic surfactant) exceeds the amount of hydrophobic surfactant that can be solubilized by the same amount of hydrophilic surfactant. This unexpected finding shows a surprising and non-intuitive relationship between the hydrophilic and hydrophobic components. It should be emphasized that the optical clarity is determined in the diluted composition (the aqueous dispersion), and not in the pre-concentrate. Thus, for example, U.S. Patent No. 4,719,239 shows optically clear compositions containing water, oil, and a 3:7 mixture of PEG-glycerol monooleate and caprylic-capric acid glycerol esters, but the compositions contain no more that about 75% by weight water, or a dilution of the pre- concentrate of no more than 3 to 1. Upon dilution with water in a ratio of more than about 3 to 1, the compositions of the cited reference phase-separate into multi-phase systems, as is shown, for example, in the phase diagram of Figure 2 in the '239 patent. In contrast, the compositions of the present invention, when diluted to values typical of dilutions encountered in vivo, or when diluted in vivo upon administration to a patient, remain as clear aqueous dispersions. Thus, the clear aqueous dispersions ofthe present invention are formed upon dilution of about 10 to about 250- fold or more.
As an alternative to qualitative visual assessment of optical clarity, the optical clarity of the aqueous dispersion can be measured using standard quantitative techniques for turbidity assessment. One convenient procedure to measure turbidity is to measure the amount of light of a given wavelength transmitted by the solution, using, for example, a UV-visible spectrophotometer. Using this measure, optical clarity corresponds to high transmittance, since cloudier solutions will scatter more ofthe incident radiation, resulting in lower transmittance measurements. If this procedure is used, care should be taken to insure that the composition itself does not absorb light of the chosen wavelength, as any tme absorbance necessarily reduces the amount of transmitted light and falsely increases the quantitative turbidity value. In the absence of chromophores at the chosen wavelength, suitable dispersions at a dilution of 100X should have an apparent absorbance of less than about 0.3, preferably less than about 0.2, and more preferably less than about 0.1.
Other methods of characterizing optical clarity, such as direct particle size measurement and other methods known in the art may also be used.
It should be emphasized that any or all of the available methods may be used to ensure that the resulting aqueous dispersions possess the requisite optical clarity. For convenience, however, the present inventors prefer to use the simple qualitative procedure; i.e., simple visible observation. However, in order to more fully illustrate the practice of the present invention, both qualitative observation and spectroscopic measures are used to assess the dispersion clarity in the Examples herein. If present, the therapeutic agent is solubilized in the triglyceride, the carrier, or in both the triglyceride and the carrier. Altematively, the therapeutic agent can be solubilized in the aqueous medium used to dilute the preconcentrate to form an aqueous dispersion. The maximum amount of therapeutic agent that can be solubilized is readily determined by simple mixing, as the presence of any non-solubilized therapeutic agent is apparent upon visual examination.
In one embodiment, the therapeutic agent is present in an amount up to the maximum amount that can be solubilized in the composition. In another embodiment, the therapeutic agent is present in a first amount which is solubilized, and a second amount that remains unsolubilized but dispersed. This may be desirable when, for example, a larger dose of the therapeutic agent is desired. Although not all of the therapeutic agent is solubilized, such a composition presents advantages over conventional compositions, since at least a portion of the therapeutic agent is present in the clear aqueous dispersion phase. Of course, in this embodiment, the optical clarity of the resultant aqueous dispersion is determined before the second non-solubilized amount ofthe therapeutic agent is added. Other considerations well known to those skilled in the art will further inform the choice of specific proportions of surfactants and triglycerides. These considerations include the degree of bioacceptability of the compounds, and the desired dosage of therapeutic agent to be provided. In some cases, the amount of triglyceride or therapeutic agent actually used in a pharmaceutical composition according to the present invention will be less than the maximum that can be solubilized, and it should be apparent that such compositions are also within the scope ofthe present invention. 5. Solubilizers
If desired, the pharmaceutical compositions of the present invention can optionally include additional compounds to enhance the solubility of the therapeutic agent or the triglyceride in the composition. Examples of such compounds, referred to as "solubilizers", include: 0 alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; 5 ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol, available commercially from BASF under the trade name Tetraglycol) or methoxy PEG (Union Carbide); amides, such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, 0υ N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, and polyvinylpyrrolidone; esters, such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ- 5 valerolactone and isomers thereof, β-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide (Arlasolve DMI (ICI)), N-methyl pyrrolidones (Pharmasolve (ISP)), monooctanoin, diethylene glycol monoethyl ether (available from Gattefosse under the trade name Transcutol), and water. 0
Mixtures of solubilizers are also within the scope of the invention. Except as indicated, these compounds are readily available from standard commercial sources. Prefeπed solubilizers include triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
The amount of solubilizer that can be included in compositions of the present invention is not particularly limited. Of course, when such compositions are ultimately administered to a patient, the amount of a given solubilizer is limited to a bioacceptable amount, which is readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example, to maximize the concentration of therapeutic agent, with excess solubilizer removed prior to providing the composition to a patient using conventional techniques, such as distillation or evaporation. Thus, if present, the solubilizer can be in a concentration of 50%, 100%, 200%, or up to about 400% by weight, based on the amount of surfactant. If desired, very small amounts of solubilizers may also be used, such as 25%, 10%, 5%, 1% or even less. Typically, the solubilizer will be present in an amount of about 1% to about 100%, more typically about 5% to about 25% by weight or about 10% to about 25%o by weight. 6. Enzyme Inhibitors
When the therapeutic agent is subject to enzymatic degradation, the compositions can include an enzyme inhibiting agent. Enzyme inhibiting agents are shown for example, in Bemskop-Schnurch, A., "The use of inhibitory agents to overcome enzymatic barrier to perorally administered therapeutic peptides and proteins", J. Controlled Release 52, 1-16 (1998), the disclosure of which is incorporated herein by reference.
Generally, inhibitory agents can be divided into the following classes: Inhibitors that are not based on amino acids, such as P-aminobenzamidine, FK- 448, camostat mesylate, sodium glycocholate;
Amino acids and modified amino acids, such as aminoboronic acid derivatives and n-acetylcysteine;
Peptides and modified peptides, such as bacitracin, phosphinic acid dipeptide derivatives, pepstatin, antipain, leupeptin, chymostatin, elastatin, bestatin, hosphoramindon, puromycin, cytochalasin potatocarboxy peptidase inhibitor, and amastatin;
Polypeptide protese inhibitors , such as aprotinin (bovine pancreatic trypsin inhibitor), Bowman-Birk inhibitor and soybean trypsin inhibitor, chicken egg white trypsin inhibitor, chicken ovoinhibitor, and human pancreatic trypsin inhibitor.
Complexing agents, such as EDTA, EGTA, 1,10- phenanthroline and hydroxychinoline; and
Mucoadhesive polymers and polymer-inhibitor conjugates, such as polyacrylate derivatives, chitosan, cellulosics, chitosan-EDTA, chitosan-EDTA-antipain, polyacrylic acid-bacitracin, carboxymethyl cellulose-pepstatin, polyacrylic acid-Bwoman-Birk inhibitor.
The choice and levels of the enzyme inhibitor are based on toxicity, specificity of the proteases and the potency of the inhibition. The inhibitor can be suspended or solubilized in the composition preconcentrate, or added to the aqueous diluent or as a beverage.
Without wishing to be bound by theory, it is believed that an inhibitor can function solely or in combination as: a competitive inhibitor, by binding at the substrate binding site of the enzyme, thereby preventing the access to the substrate; examples of inhibitors believed to operate by this mechanism are antipain, elastatinal and the Bowman Birk inhibitor; a non-competitive inhibitor which can be simultaneously bound to the enzyme site along with the substrate, as their binding sites are not identical; and/or a complexing agent due to loss in enzymatic activity caused by deprivation of essential metal ions out ofthe enzyme stmcture. 7. Other Additives
Other additives conventionally used in pharmaceutical compositions can be included, and these additives are well known in the art. Such additives include detackifiers, anti-foaming agents, buffering agents, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof. The amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired. 8. Dosage Forms
The pharmaceutical compositions of the present invention can be formulated as a preconcentrate in a liquid, semi-solid, or solid form, or as an aqueous or organic diluted preconcentrate. In the diluted form, the diluent can be water, an aqueous solution, a buffer, an organic solvent, a beverage, a juice, or mixtures thereof. If desired, the diluent can include components soluble therein, such as a therapeutic agent, an enzyme inhibitor, solubilizers, additives, and the like.
The compositions can be processed according to conventional processes known to those skilled in the art, such as lyophilization, encapsulation, compression, melting, extmsion, drying, chilling, molding, spraying, coating, comminution, mixing, homogenization, sonication and granulation, to produce the desired dosage form.
The dosage form is not particularly limited. Thus, compositions of the present invention can be formulated as pills, capsules, caplets, tablets, granules, beads or powders. Granules, beads and powders can, of course, be further processed to form pills, capsules, caplets or tablets. When formulated as a capsule, the capsule can be a hard or soft gelatin capsule, a starch capsule, or a cellulosic capsule. Such dosage forms can further be coated with, for example, a seal coating or an enteric coating. The term "enteric coated capsule" as used herein means a capsule coated with a coating resistant to acid; i.e., an acid resistant enteric coating. Enteric coated compositions of this invention protect therapeutic peptides or proteins in a restricted area of dmg liberation and absorption, and reduce or even exclude extensive dilution effects. Although solubilizers are typically used to enhance the solubility of a hydrophobic therapeutic agent, they may also render the compositions more suitable for encapsulation in hard or soft gelatin capsules. Thus, the use of a solubilizer such as those described above is particularly preferred in capsule dosage forms of the pharmaceutical compositions. If present, these solubilizers should be added in amounts sufficient to impart to the compositions the desired solubility enhancement or encapsulation properties.
Although formulations specifically suited to oral administration are presently preferred, the compositions of the present invention can also be formulated for topical, transdermal, buccal, ocular, pulmonary, vaginal, rectal, transmucosal or parenteral administration, as well as for oral administration. Thus, the dosage form can be a solution, suspension, emulsion, cream, ointment, lotion, suppository, spray, aerosol, paste, gel, drops, douche, ovule, wafer, troche, cachet, symp, elixer, or other dosage form, as desired. If formulated as a suspension, the composition can further be processed in capsule form.
When formulated as a sprayable solution or dispersion, a dosage form of a multiparticulate carrier coated onto a substrate with the pharmaceutical compositions described herein can be used. The substrate can be a granule, a particle, or a bead, for example, and formed of a therapeutic agent or a pharmaceutically acceptable material. The multiparticulate carrier can be enteric coated with a pharmaceutically acceptable material as is well known to those skilled in the art.
Other additives may be included, such as are well-known in the art, to impart the desired consistency and other properties to the formulation. 9. Specific Embodiments
In all of the embodiments described herein, the triglyceride and surfactants are present in amounts such that upon mixing with an aqueous solution, either in vitro or in vivo, a clear, aqueous dispersion is formed. This optical clarity in an aqueous dispersion defines the appropriate relative concentrations of the triglyceride and surfactant components, but does not restrict the dosage form of the compositions to an aqueous dispersion, nor does it limit the compositions of the invention to optically clear dosage forms. Thus, the appropriate concentrations of the triglyceride and surfactants are determined by the optical clarity of a dispersion formed by the composition preconcentrate and an aqueous solution in a dilution of about 10 to about 250-fold, as a preliminary matter. Once the appropriate concentrations are determined, the pharmaceutical compositions can be formulated as described in the preceding section, without regard to the optical clarity of the ultimate formulation. Of course, optically clear aqueous dispersions, and their preconcentrates, are preferred formulations. In one embodiment, the present invention relates to pharmaceutical compositions having a triglyceride and a carrier, the carrier including at least two surfactants, at least one of which is hydrophilic. The triglyceride and surfactants are present in amounts such that upon mixing with an aqueous solution, either in vitro or in vivo, the composition forms a clear aqueous dispersion. In a particular aspect of this embodiment, the composition can contain more triglyceride than can be solubilized in a clear aqueous dispersion having only one surfactant, the surfactant being hydrophilic. Thus, this embodiment provides a higher concentration of triglyceride than is achievable with a single hydrophilic surfactant, resulting in a reduced triglyceride to hydrophilic surfactant ratio and enhanced biocompatibility.
In another embodiment, the present invention relates to pharmaceutical compositions having a triglyceride and a carrier, the carrier including at least one hydrophilic surfactant and at least one hydrophobic surfactant. The triglyceride and surfactants are present in amounts such that upon mixing with an aqueous solution, either in vitro or in vivo, the composition forms a clear aqueous dispersion. In a particular aspect of this embodiment, the composition contains more triglyceride than can be solubilized in a clear aqueous dispersion having a hydrophilic surfactant but not having a hydrophobic surfactant..
In another embodiment, the triglyceride itself can have therapeutic value as, for example, a nutritional oil, or absorption-promoting value as, for example, a long-chain triglyceride (LCT) or a medium-chain triglyceride (MCT). Thus, in this embodiment, the present invention provides pharmaceutical compositions including a triglyceride having nutritional and/or absorption-promoting value, and a carrier. The carrier includes at least two surfactants, at least one of which is hydrophilic. Optionally, the carrier can include at least one hydrophilic surfactant and at least one hydrophobic surfactant. The triglyceride and surfactants are present in amounts such that upon dilution with an aqueous solution, either in vitro or in vivo, the composition forms a clear aqueous dispersion. In another embodiment, the present invention relates to a pharmaceutical composition which includes a therapeutic agent, a triglyceride and a carrier. The carrier includes at least two surfactants, at least one of which is hydrophilic. Optionally, the carrier includes at least one hydrophilic surfactant and at least one hydrophobic surfactant. The triglyceride, and surfactants are present in amounts such that upon dilution with an aqueous solution, either in vitro or in vivo, the composition forms a clear aqueous dispersion. The therapeutic agent is present in two amounts, a first amount of the therapeutic agent solubilized in the clear aqueous dispersion, and a second amount of the therapeutic agent that remains non-solubilized but dispersed.
In another aspect, the present invention relates to triglyceride-containing pharmaceutical compositions as described in the preceding embodiments, which further include a therapeutic agent. In particular embodiments, the therapeutic agent is a hydrophobic drug or a hydrophilic dmg. In other embodiments, the therapeutic agent is a nutritional agent. In still further embodiments, the therapeutic agent is a cosmeceutical agent.
10. Preparation of Pharmaceutical Compositions
The pharmaceutical compositions of the present invention can be prepared by conventional methods well known to those skilled in the art. Of course, the specific method of preparation will depend upon the ultimate dosage form. For dosage forms substantially free of water, i.e., when the composition is provided in a pre-concentrate form for later dispersion in vitro or in vivo in an aqueous system, the composition is prepared by simple mixing of the components to form a pre-concentrate. The mixing process can be aided by gentle heating, if desired. For compositions in the form of an aqueous dispersion, the pre-concentrate form is prepared, then the appropriate amount of an aqueous solution is added. Upon gentle mixing, a clear aqueous dispersion is formed. If any water-soluble enzyme inhibitors or additives are included, these may be added first as part of the pre-concentrate, or added later to the clear aqueous dispersion, as desired. The compositions can be prepared with or without a therapeutic agent, and a therapeutic agent may also be provided in the diluent, if desired.
As previously noted, in another embodiment, the present invention includes a multi-phase dispersion containing a therapeutic agent. In this embodiment, a pharmaceutical composition includes a triglyceride and a carrier, which forms a clear aqueous dispersion upon mixing with an aqueous solution, and an additional amount of non-solubilized therapeutic agent. Thus, the term "multi-phase" as used herein to describe these compositions of the present invention means a composition which when mixed with an aqueous solution forms a clear aqueous phase and a particulate dispersion phase. The carrier and triglycerides are as described above, and can include any of the surfactants, therapeutic agents, solubilizers and additives previously described. An additional amount of therapeutic agent is included in the composition. This additional amount is not solubilized by the carrier, and upon mixing with an aqueous system is present as a separate dispersion phase. The additional amount is optionally a milled, micronized, or precipitated form. Thus, upon dilution, the composition contains two phases: a clear aqueous dispersion of the triglyceride and surfactants containing a first, solubilized amount of the therapeutic agent, and a second, non-solubilized amount of the therapeutic agent dispersed therein. It should be emphasized that the resultant multi-phase dispersion will not have the optical clarity of a dispersion in which the therapeutic agent is fully solubilized, but will appear to be cloudy, due to the presence of the non-solubilized phase. Such a formulation may be useful, for example, when the desired dosage of a therapeutic agent exceeds that which can be solubilized in the carrier and/or triglyceride. The formulation may also contain additives, as described above.
One skilled in the art will appreciate that a therapeutic agent may have a greater solubility in the pre-concentrate composition than in the aqueous dispersion, so that meta- stable, supersaturated solutions having apparent optical clarity but containing a therapeutic agent in an amount in excess of its solubility in the aqueous dispersion can be formed. Such super-saturated solutions, whether characterized as clear aqueous dispersions (as initially formed) or as multi-phase solutions (as would be expected if the meta-stable state breaks down), are also within the scope ofthe present invention.
The multi-phase formulation can be prepared by the methods described above. A pre-concentrate is prepared by simple mixing of the components, with the aid of gentle heating, if desired. It is convenient to consider the therapeutic agent as divided into two portions, a first solubilizable portion which will be solubilized and contained within the clear aqueous dispersion upon dilution, and a second non-solubilizable portion which will remain non-solubilized. When the ultimate dosage form is non-aqueous, the first and second portions of the therapeutic agent are both included in the pre-concentrate mixture. When the ultimate dosage form is aqueous, the composition can be prepared in the same manner, and upon dilution in an aqueous system, the composition will form the two phases as described above, with the second non-solubilizable portion of the therapeutic agent dispersed or suspended in the aqueous system, and the first solubilizable portion of the therapeutic agent solubilized in the composition. Alternatively, when the ultimate dosage form is aqueous, the pre-concentrate can be prepared including only the first, solubilizable portion of the therapeutic agent. This pre-concentrate can then be diluted in an aqueous system to form a clear aqueous dispersion, to which is then added the second, non- solubilizable portion ofthe therapeutic agent to form a multi-phase aqueous composition. B. Methods in another embodiment, the present invention relates to methods of increasing the solubilization of a therapeutic agent in a composition, by providing the therapeutic agent in a composition of the present invention. The composition can be any of the compositions described herein, with or without a therapeutic agent. It is surprisingly found that by using the combinations of triglycerides and surfactants described herein, greater amounts of triglycerides can be solubilized, without resort to unacceptably high concentrations of hydrophilic surfactants. In another embodiment, the present invention relates to methods of increasing the rate and/or extent of absorption of therapeutic agents by administering to a patient a pharmaceutical composition of the present invention. In this embodiment, the therapeutic agent can be present in the pharmaceutical composition pre-concentrate, in the diluent, or in a second pharmaceutical composition, such as a conventional commercial formulation, which is co-administered with a pharmaceutical composition ofthe present invention. For example, the delivery of therapeutic agents in conventional pharmaceutical compositions can be improved by co-administering a pharmaceutical composition of the present invention with a conventional composition.
C. Characteristics of the Pharmaceutical Compositions The dispersions formed upon dilution of the pharmaceutical compositions of the present invention have the following characteristics:
Rapid formation: upon dilution with an aqueous solution, the composition forms a clear dispersion very rapidly; i.e., the clear dispersion appears to form instantaneously.
Optical clarity: the dispersions are essentially optically clear to the naked eye, and show no readily observable signs of heterogeneity, such as turbidity or cloudiness. More quantitatively, dispersions of the pharmaceutical compositions of the present invention have absorbances (400 nm) of less than about 0.3, and often less than about 0.1, at 100X dilution, as described more fully in the Examples herein. In the multi-phase embodiment ofthe compositions described herein, it should be appreciated that the optical clarity ofthe aqueous phase will be obscured by the dispersed particulate non-solubilized therapeutic agent.
Robustness to dilution: the dispersions are surprisingly stable to dilution in aqueous solution. The hydrophobic therapeutic agent remains solubilized for at least the period of time relevant for absorption. As discussed above, conventional triglyceride-containing formulations suffer the disadvantage that bioabsorption of the therapeutic agents contained therein is dependent upon enzymatic degradation (lipolysis) of the triglyceride components. The solubilization of the triglyceride in an aqueous medium is usually limited if only a hydrophilic surfactant is used to disperse the triglyceride, as is conventional. Without a sufficiently high concentration of the hydrophilic surfactant, an emulsion or milky suspension of the triglyceride is formed, and the triglyceride is present in the form of relatively large oil droplets. In this case, the large size of the triglyceride particles impedes the transport and absorption of the triglyceride or therapeutic agent solubilized in the triglyceride or in the carrier. In addition, the large, thermodynamically unstable triglyceride particles could further impose a risk when the compositions are administered intravenously, by plugging the blood capillaries. To achieve a high level of fully-solubilized triglyceride would require an amount of the hydrophilic surfactant exceeding that which would be bioacceptable. The pharmaceutical compositions of the present invention, however, solve these and other problems of the prior art by adding a third component, a hydrophobic surfactant or a second hydrophilic surfactant. The solubilization ofthe triglyceride in the aqueous system is thereby unexpectedly enhanced. It is also unexpectedly found that the total amount of solubilized water-insoluble components, the triglyceride and hydrophobic surfactant, can greatly exceed the amount of the hydrophobic surfactant alone that can be solubilized using the same amount ofthe hydrophilic surfactant.
The unique pharmaceutical compositions and methods of the present invention present a number of significant and unexpected advantages, including:
Increased safety: The present compositions and methods allow for increased levels of triglyceride relative to hydrophilic surfactants, thereby reducing the need for excessively large amounts of hydrophilic surfactant. Further, the triglyceride-containing compositions of the present invention present small particle sizes, thus avoiding the problems of large particle size in conventional triglyceride-containing formulations and the concomitant safety concerns in parenteral administration.
Efficient transport: The particle sizes in the aqueous dispersions of the present invention are much smaller than the larger particles characteristic of vesicular, emulsion or microemulsion phases. This reduced particle size enables more efficient dmg transport through the intestinal aqueous boundary layer, and through the absorptive b sh border membrane. More efficient transport to absorptive sites leads to improved and more consistent absorption of therapeutic agents. Less-dependence on lipolysis: The lack of large particle-size triglyceride components provides pharmaceutical compositions less dependent upon lipolysis, and upon the many poorly characterized factors which affect the rate and extent of lipolysis, for effective presentation of a therapeutic agent to an absorptive site. Such factors include the presence of composition components which may inhibit lipolysis; patient conditions which limit production of lipase, such as pancreatic lipase secretory diseases; and dependence of lipolysis on stomach pH, endogenous calcium concentration, and presence of co-lipase or other digestion enzymes. The reduced lipolysis dependence further provides transport which is less prone to suffer from any lag time between administration and absorption caused by the lipolysis process, enabling a more rapid onset of therapeutic action and better bioperformance characteristics. In addition, pharmaceutical compositions of the present invention can make use of hydrophilic surfactants which might otherwise be avoided or limited due to their potential lipolysis inhibiting effects.
Non-dependence on bile and meal fat contents: Due to the higher solubilization potential over bile salt micelles, the present compositions are less dependent on endogenous bile and bile related patient disease states, and meal fat contents. These advantages overcome meal-dependent absorption problems caused by poor patient compliance with meal-dosage restrictions.
Superior solubilization: The triglyceride and surfactant combinations used in compositions of the present invention enable superior loading capacity over conventional formulations. In addition, the particular combination of surfactants used can be optimized for a specific therapeutic agent to more closely match the polarity distribution of the therapeutic agent, resulting in still further enhanced solubilization.
Faster dissolution and release: Due to the robustness of compositions of the present invention to dilution, the therapeutic agents remain solubilized and thus do not suffer problems of precipitation of the therapeutic agent in the time frame relevant for absorption. In addition, the therapeutic agent is presented in small particle carriers, and is not limited in dilution rate by entrapment in emulsion carriers. These factors avoid liabilities associated with the poor partitioning of lipid solubilized dmg in to the aqueous phase, such as large emulsion droplet surface area, and high interfacial transfer resistance, and enable rapid completion ofthe critical partitioning step. Consistent performance: Aqueous dispersions of the present invention are thermodynamically stable for the time period relevant for absorption, and can be more predictably reproduced, thereby limiting variability in bioavailability— a particularly important advantage for therapeutic agents with a narrow therapeutic index. Efficient release: The compositions of the present invention are designed with components that help to keep the therapeutic agent or absorption promoter, such as a permeation enhancer, an enzyme inhibitor, etc., solubilized for transport to the absorption site, but readily available for absorption, thus providing a more efficient transport and release. Less prone to gastric emptying delays: Unlike conventional triglyceride- containing formulations, the present compositions are less prone to gastric emptying delays, resulting in faster absorption. Further, the particles in dispersions of the present invention are less prone to unwanted retention in the gastro-intestinal tract.
Small size: Because of the small particle size in aqueous dispersion, the pharmaceutical compositions of the present invention allow for faster transport of the therapeutic agent through the aqueous boundary layer.
These and other advantages ofthe present invention, as well as aspects of preferred embodiments, are illustrated more fully in the Examples which follow.
EXAMPLES Example 1: Preparation of Compositions
A simple pre-concentrate is prepared as follows. Predetermined weighed amounts of the surfactants and triglyceride are stirred together to form a homogeneous mixture. For combinations that are poorly miscible, the mixture can be gently heated to aid in formation of the homogeneous mixture. If the composition is to include a therapeutic agent, the chosen therapeutic agent in a predetermined amount is added and stirred until solubilized. Optionally, solubilizers or additives are included by simple mixing.
To form an aqueous dispersion of the pre-concentrate, a predetermined amount of purified water, buffer solution, or aqueous simulated physiological solution, is added to the pre-concentrate, and the resultant mixture is stirred to form a clear, aqueous dispersion. Example 2: Triglyceride Solubilization in Conventional Formulations
Conventional formulations of a triglyceride and a hydrophilic surfactant were prepared for comparison to compositions of the present invention. For each surfactant- triglyceride pair, multiple dispersions were prepared with differing amounts of the two components, to determine the maximum amount of the triglyceride that can be present while the composition still forms a clear dispersion upon a 100-fold dilution with distilled water. No therapeutic agent was included in these compositions, since it is believed that the presence ofthe therapeutic agent does not substantially affect the clear, aqueous nature of composition. For the same reason, these compositions were free of additional solubilizers and other additives. The optical clarity was determined by visual inspection and/or by UV absorption (at 400 nm). When UV absorption was used, compositions were considered to be clear when the absorption was less than about 0.2.
Table 20 shows the maximum amount of triglyceride present in such binary mixtures forming clear aqueous dispersions. The numerical entries in the Table are in units of grams of triglyceride per 100 grams of hydrophilic surfactant.
Table 20: Binary Triglyceride-Surfactant Solubility
Figure imgf000065_0001
Figure imgf000066_0002
5 Example 3: Effect of Surfactant Combinations
The procedure of Example 2 was repeated for compositions containing PEG-40 hydrogenated castor oil (Cremophor RH 40) or polysorbate 80 (Tween 80) as the hydrophilic surfactant, but substituting a second hydrophilic surfactant (compositions number 6-7 and 14-16) or a hydrophobic surfactant (compositions number 4-5, 8-9, and ι ø 17-18) for part of the hydrophilic surfactant. The total amount of hydrophilic surfactant was kept constant. The results are summarized in Table 21.
Table 21 A: Effects of Surfactant Combinations on the Solubilization of Triglycerides
Composition in w/w ratio
15
Corn Oil 25 30 40 40 40 40 40 40 40
Cremophor RH-40 100 100 100 77 71 67 57 62 57
Peceol — — — 23 29 — — — — 0 Kessco PEG 400 MO — — — — — 33 43 — —
Crovol M-40 — — — — — — — 38 43
Appearance of the Concentrate Clear Hazy Hazy Clear Clear Clear Clear Hazy Hazy
5 Abs @ 400 nm ofthe 100X (w/v)
Dilution in Deiomzed Water
0 148 2 195 2 518 0 121 0 132 0 124 0 102 0 233 0 167
Table 21B
0 Composition in w/w ratio
10 11 12 13 14 15 16 17 18
Figure imgf000066_0001
Tween 80 100 100 100 100 67 67 67 67 67
Kessco PEG 400 MO — — — — 33 33 33 — —
Crovol M-40 — — — — — — — 33 33
Appearance ofthe Concentrate Clear Clear Hazy Hazy Clear Clear Clear Clear Clear
Abs @ 400 nm of the 100X (w/v)
Dilution in Deionized Water
0 002 1 314 1 613 1 654 0 041 0 019 0 194 0 057 0 158
10
The clear or hazy appearance noted in the Table is that of the pre-concentrate, not of the aqueous dispersion. The clarity of the aqueous dispersion is shown quantitatively by UV absorption ofthe 100X dilution at 400 nm.
Comparing compositions 1-3, a binary com oil-Cremophor RH-40 mixture having
15 25 grams of com oil per 100 grams of the surfactant is optically clear, having an absorption of 0.148. However, upon a slight increase of the amount of com oil to 30 grams, the dispersion becomes cloudy, with an absorbance of 2.195, indicating the formation of a conventional emulsion. Compositions 4-5 show the surprising result that when part of the hydrophilic Cremophor RH-40 is replaced by a hydrophobic surfactant 0 (Peceol), keeping the total surfactant concentration constant, compositions having a much higher amount of triglyceride (40 grams) still form clear aqueous dispersions, with absorbances less than 0.2 and dramatically less than the comparable binary composition number 3. A similar result is shown in compositions 8-9 for a different hydrophobic surfactant, Crovol M-40. Likewise, when part of the hydrophilic surfactant is replaced by
25 a second hydrophilic surfactant in compositions 6-7, it is surprisingly found that the amount of triglyceride solubilized is similarly increased.
The second part of the Table, Table 2 IB, shows a similar surprising result for a different hydrophilic surfactant, Tween 80. Simple binary com oil-Tween 80 mixtures form clear aqueous dispersions with 10 grams of com oil, but are cloudy and multi -phasic
30 with 15 grams or more of the triglyceride. As the Table shows, substitution of part of the hydrophilic surfactant with a second hydrophilic surfactant or a hydrophobic surfactant dramatically increases the amount of triglyceride that can be solubilized. Example 4: Effect of Surfactant Combinations Example 3 was repeated, using different triglyceride-surfactant combinations. In particular, medium-chain triglycerides (MCTs) were used instead of com oil, a long-chain triglyceride (LCT). The results are shown in the three-part Table 22.
Table 22 A: Solubilization of MCTs Composition in w/w ratio
19 20 21 22 23
Pureco 76 33 50 80 50 80
Cremophor RH-40 100 100 100 40 100
Imwitor 988 — — — 60 100
Ethanol — — — — 33
Appearance of the Concentrate Clear Clear Hazy Clear Clear
Abs @ 400 nm of the 100X (w/v) 0 201 0 346 2 522 0 204 0 098
Dilution in Deionized Water
Table 22B
Composition in w/w ratio
24 25 26 27
Captex 300 40 75 75 75
Cremophor RH-40 100 100 50 100
Imwitor 988 — — 50 75
Appearance of the Concentrate Clear Hazy Clear Clear
Abs @ 400 nm of the 100X (w/v) 0 180 0 557 0 208 0 078
Dilution in Deionized Water Table 22C
Composition in w/w ratio
28 29 30 31 32 33
Figure imgf000069_0001
Table 22 shows that the increased solubilization of the triglyceride is observed for MCTs as well as for LCTs, with a variety of surfactants. Table 22 additionally shows that the same effect is observed in the presence of increased amounts of surfactants (compositions 23 and 27) and solubilizers (composition 23).
Example 5: Characterization of Compositions Various compositions were prepared and characterized by visual observation as well as by UV absorbance at 400 nm. Each composition was diluted 100-fold with distilled water. The results are shown in Table 23. Table 23: Visual and Spectroscopic Characterization
Figure imgf000069_0002
Figure imgf000070_0001
Example 6: Comparative Example
Prior art formulations were prepared for comparison with the compositions of the present invention. As in Example 5, the compositions were diluted 100-fold with distilled water, and characterized by visual observation and by UV absorbance. The results are shown in Table 24.
Table 24: Compositions Not Forming Clear Aqueous Dispersions
Figure imgf000071_0001
Figure imgf000072_0001
As the Table shows, conventional formulations such as those disclosed in U.S.
Patent No. 5,645,856, form milky suspensions rather than the clear aqueous dispersions of the present invention.
Example 7: Formulations with Therapeutic Agents Table 25 shows several formulations of compositions that can be prepared according to the present invention, using a variety of therapeutic agents.
Table 25: Formulations
No. Composition (g)
43 Cremophor RH-40 0.75
Peceol 0.25
Com Oil NF 0.40
Fenofibrate 0.10
44 Cremophor RH-40 0.57
Crovol M-40 0.43
Com Oil NF 0.40
Rofecoxib 0.15 10
15
20
25
Figure imgf000073_0001
30 50 Crovol M-70 0.67
Crovol M-40 0.33
Captex 350 0.75
Progesterone 0.10
Ethanol 0.15
51 Labrasol 0.30
Gelucire 44/14 0.70
Dronabinol 0.02
Ethanol 0.10
52 Incrocas 35 0.80
Arlacel 186 0.20
Miglyol 818 0.45
Alendronate sodium 0.04
Water 0.10
53 Cremophor RH-40 0.62
Capmul MCM 0.38
Miglyol 810 0.25
Heparin sodium 0.03
Water 0.10
PEG 400 0.05
The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope. What is claimed is:

Claims

1. A pharmaceutical composition comprising:
(a) a triglyceride;
(b) a carrier comprising at least two surfactants, at least one of the surfactants being hydrophilic; and (c) a therapeutic agent which is capable of being solubilized in the triglyceride, the carrier, or both the triglyceride and the carrier, wherein the triglyceride and surfactants are present in amounts such that upon mixing with an aqueous solution the composition forms a clear aqueous dispersion.
2. The pharmaceutical composition of claim 1, wherein the triglyceride is selected from the group consisting of vegetable oils, fish oils, animal fats, hydrogenated vegetable oils, partially hydrogenated vegetable oils, synthetic triglycerides, modified triglycerides, fractionated triglycerides, and mixtures thereof.
3. The pharmaceutical composition of claim 1, wherein the triglyceride is selected from the group consisting of almond oil; babassu oil; borage oil; blackcurrant seed oil; canola oil; castor oil; coconut oil; com oil; cottonseed oil; evening primrose oil; grapeseed oil; groundnut oil; mustard seed oil; olive oil; palm oil; palm kernel oil; peanut oil; rapeseed oil; safflower oil; sesame oil; shark liver oil; soybean oil; sunflower oil; hydrogenated castor oil; hydrogenated coconut oil; hydrogenated palm oil; hydrogenated soybean oil; hydrogenated vegetable oil; hydrogenated cottonseed and castor oil; partially hydrogenated soybean oil; partially soy and cottonseed oil; glyceryl tricaproate; glyceryl tricaprylate; glyceryl tricaprate; glyceryl triundecanoate; glyceryl trilaurate; glyceryl trioleate; glyceryl trilinoleate; glyceryl trilinolenate; glyceryl tricaprylate/caprate; glyceryl tricaprylate/caprate/laurate; glyceryl tricaprylate/caprate/linoleate; glyceryl tricaprylate/caprate/stearate; saturated polyglycolized glycerides; linoleic glycerides; caprylic/capric glycerides; modified triglycerides; fractionated triglycerides; and mixtures thereof.
4. The pharmaceutical composition of claim 1, wherein the triglyceride is selected from the group consisting of coconut oil; com oil; olive oil; palm oil; peanut oil; safflower oil; sesame oil; soybean oil; hydrogenated castor oil; hydrogenated coconut oil; partially hydrogenated soybean oil; glyceryl tricaprate; glyceryl trilaurate; glyceryl trioleate; glyceryl trilinoleate; glyceryl tricaprylate/caprate; glyceryl tricaprylate/caprate/laurate; glyceryl tricaprylate/caprate/linoleate; glyceryl tricaprylate/caprate/stearate; saturated polyglycolized glycerides; linoleic glycerides; caprylic/capric glycerides; modified triglycerides; fractionated triglycerides; and mixtures thereof.
5. The pharmaceutical composition of claim 1, wherein the triglyceride is a medium chain triglyceride, a long chain triglyceride, a modified triglyceride, a fractionated triglyceride, or a mixture thereof.
6. The pharmaceutical composition of claim 1, wherein the hydrophilic surfactant comprises at least one non-ionic hydrophilic surfactant having an HLB value greater than or equal to about 10.
7. The pharmaceutical composition of claim 1, wherein the hydrophilic surfactant comprises at least one ionic surfactant.
8. The pharmaceutical composition of claim 6, which further comprises at least one ionic surfactant.
9. The pharmaceutical composition of claim 6, wherein the non-ionic surfactant is selected from the group consisting of alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene- polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sugar esters, sugar ethers; sucroglycerides; and mixtures thereof.
10. The pharmaceutical composition of claim 6, wherein the non-ionic hydrophilic surfactant is selected from the group consisting of polyoxyethylene alkylethers; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and mixtures thereof.
11. The pharmaceutical composition of claim 10, wherein the glyceride is a monoglyceride, diglyceride, triglyceride, or a mixture thereof.
12. The pharmaceutical composition of claim 10, wherein the reaction mixture comprises the transesterification products of a polyol and at least one member ofthe group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
13. The pharmaceutical composition of claim 10, wherein the polyol is glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, a saccharide, or a mixture thereof.
14. The pharmaceutical composition of claim 6, wherein the hydrophilic surfactant is PEG- 10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG- 40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 com oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE- 10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG- 100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, a poloxamer, or a mixture thereof.
15. The pharmaceutical composition of claim 6, wherein the hydrophilic surfactant is PEG-20 laurate, PEG-20 oleate, PEG-35 castor oil, PEG-40 palm kernel oil,
PEG-40 hydrogenated castor oil, PEG-60 com oil, PEG-25 glyceryl trioleate, polyglyceryl-10 laurate, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, PEG-30 cholesterol, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE- 23 lauryl ether, POE- 10 oleyl ether, PEG-24 cholesterol, sucrose monostearate, sucrose monolaurate, a poloxamer, or a mixture thereof.
16. The pharmaceutical composition of claim 6, wherein the hydrophilic surfactant is PEG-35 castor oil, PEG-40 hydrogenated castor oil, PEG-60 com oil, PEG-25 glyceryl trioleate, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polysorbate 20, polysorbate 80, tocopheryl PEG- 1000 succinate, PEG-24 cholesterol, a poloxamer, or a mixture thereof.
17. The pharmaceutical composition of claim 7, wherein the ionic surfactant is selected from the group consisting of alkyl ammonium salts; bile salts, analogues, and derivatives thereof; fusidic acid and derivatives thereof; fatty acid derivatives of amino acids, ohgopeptides, and polypeptides; glyceride derivatives of amino acids, ohgopeptides, and polypeptides; acyl lactylates; mono-,diacetylated tartaric acid esters of mono- ,diglycerides; succinylated monoglycerides; citric acid esters of mono-,diglycerides; alginate salts; propylene glycol alginate; lecithins and hydrogenated lecithins; lysolecithin and hydrogenated lysolecithins; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; phospholipids and derivatives thereof; salts of alkylsulfates; salts of fatty acids; sodium docusate; and mixtures thereof.
18. The pharmaceutical composition of claim 7, wherein the ionic surfactant is selected from the group consisting of bile acids and salts, analogues, and derivatives thereof; lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; camitine fatty acid ester salts; salts of alkylsulfates; salts of fatty acids; sodium docusate; acyl lactylates; mono-,diacetylated tartaric acid esters of mono-,diglycerides; succinylated monoglycerides; citric acid esters of mono-,di glycerides; and mixtures thereof.
19. The pharmaceutical composition of claim 7, wherein the ionic surfactant is selected from the group consisting of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP- phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholate, taurocholate, 1 glycocholate, deoxycholate, taurodeoxycholate, chenodeoxycholate, glycodeoxycholate, glycochenodeoxycholate, taurochenodeoxycholate, ursodeoxycholate, lithocholate, tauroursodeoxycholate, glycoursodeoxycholate, cholylsarcosine, N-methyl taurocholate, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate,
5 linolenate, stearate, lauryl sulfate, tetraacetyl sulfate, docusate, lauroyl camitine, palmitoyl camitine, myristoyl camitine, and salts and mixtures thereof.
20. The pharmaceutical composition of claim 7, wherein the ionic surfactant is selected from the group consisting of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, lysophosphatidylcholine, PEG-
10 phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholate, taurocholate, glycocholate, deoxycholate, chenodeoxycholate, lithocholate, ursodeoxycholate, taurodeoxycholate, glycodeoxycholate, cholylsarcosine, caproate, caprylate, caprate,
15 laurate, oleate, lauryl sulfate, docusate, lauroyl camitine, palmitoyl camitine, myristoyl camitine, and salts and mixtures thereof.
21. The pharmaceutical composition of claim 7, wherein the ionic surfactant is selected from the group consisting of lecithin, lactylic esters of fatty acids, stearoyl-2- lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid
20 esters of mono/diglycerides, citric acid esters of mono/diglycerides, chenodeoxycholate, lithocholate, ursodeoxycholate, taurocholate, caprylate, caprate, oleate, lauryl sulfate, docusate, lauroyl camitine, palmitoyl camitine, myristoyl camitine, and salts and mixtures thereof.
22. The pharmaceutical composition of claim 1, wherein the carrier comprises 25 at least two hydrophilic surfactants.
23. The pharmaceutical composition of claim 1, wherein the carrier comprises at least one hydrophilic surfactant and at least one hydrophobic surfactant.
24. The pharmaceutical composition of claim 1 wherein the hydrophobic surfactant is a compound or mixture of compounds having an HLB value less than about
30 10.
25. The pharmaceutical composition of claim 24, wherein the hydrophobic surfactant is selected from the group consisting of alcohols; polyoxyethylene alkylethers; fatty acids; bile acids; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polypropylene glycol fatty acid esters; polyoxyethylene glycerides; lactic acid derivatives of mono/diglycerides; propylene glycol diglycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene- polyoxypropylene block copolymers; transesterified vegetable oils; sterols; sterol derivatives; sugar esters; sugar ethers; sucroglycerides; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and mixtures thereof.
26. The pharmaceutical composition of claim 24, wherein the hydrophobic surfactant is selected from the group consisting of fatty acids; bile acids; lower alcohol fatty acid esters; polyethylene glycol glycerol fatty acid esters; polypropylene glycol fatty acid esters; polyoxyethylene glycerides; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lactic acid derivatives of mono/diglycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and mixtures thereof.
27. The pharmaceutical composition of claim 24, wherein the hydrophobic surfactant is selected from the group consisting of bile acids; lower alcohol fatty acids esters; polypropylene glycol fatty acid esters; propylene glycol fatty acid esters; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lactic acid derivatives of mono/diglycerides; sorbitan fatty acid esters; polyoxyethylene vegetable oils; and mixtures thereof.
28. The pharmaceutical composition of claim 24, wherein the hydrophobic surfactant is a glycerol fatty acid ester, an acetylated glycerol fatty acid ester, or a mixture thereof.
29. The pharmaceutical composition of claim 28, wherein the glycerol fatty acid ester is a monoglyceride, diglyceride, or a mixture thereof.
30. The pharmaceutical composition of claim 29, wherein the fatty acid of the glycerol fatty acid ester is a C6 to C22 fatty acid or a mixture thereof.
31. The pharmaceutical composition of claim 24, wherein the hydrophobic surfactant is a reaction mixture of a polyol and at least one member ofthe group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
32. The pharmaceutical composition of claim 31, wherein the reaction mixture is a transesterification product of a polyol and at least one member ofthe group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
33. The pharmaceutical composition of claim 31, wherein the polyol is polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, a saccharide, or a mixture thereof.
34. The pharmaceutical composition of claim 24, wherein the hydrophobic surfactant is selected from the group consisting of myristic acid; oleic acid; lauric acid; stearic acid; palmitic acid; PEG 1-4 stearate; PEG 2-4 oleate; PEG-4 dilaurate; PEG-4 dioleate; PEG-4 distearate; PEG-6 dioleate; PEG-6 distearate; PEG-8 dioleate; PEG 3-16 castor oil; PEG 5-10 hydrogenated castor oil; PEG 6-20 com oil; PEG 6-20 almond oil; PEG-6 olive oil; PEG-6 peanut oil; PEG-6 palm kernel oil; PEG-6 hydrogenated palm kernel oil; PEG-4 capric/caprylic triglyceride, mono, di, tri, tetra esters of vegetable oil and sorbitol; pentaerythrityl di, tetra stearate, isostearate, oleate, caprylate, or caprate; polyglyceryl 2-4 oleate, stearate, or isostearate; polyglyceryl 4-10 pentaoleate; polyglyceryl-3 dioleate; polyglyceryl-6 dioleate; polyglyceryl-10 trioleate; polyglyceryl-3 distearate; propylene glycol mono- or diesters of a C6 to C22 fatty acid; monoglycerides of a C6 to C22 fatty acid; acetylated monoglycerides of C6 to C22 fatty acid; diglycerides of C6 to C22 fatty acids; lactic acid derivatives of monoglycerides; lactic acid derivatives of diglycerides; cholesterol; phytosterol; PEG 5-20 soya sterol; PEG-6 sorbitan tetra, hexastearate; PEG-6 sorbitan tetraoleate; sorbitan monolaurate; sorbitan monopalmitate; sorbitan mono, trioleate; sorbitan mono, tristearate; sorbitan monoisostearate; sorbitan sesquioleate; sorbitan sesquistearate; PEG 2-5 oleyl ether; POE 2-4 lauryl ether; PEG-2 cetyl ether; PEG-2 stearyl ether; sucrose distearate; sucrose dipalmitate; ethyl oleate; isopropyl myristate; isopropyl palmitate; ethyl linoleate; isopropyl linoleate; poloxamers; cholic acid; ursodeoxycholic acid; glycocholic acid; taurocholic acid; lithocholic acid; deoxycholic acid; chenodeoxycholic acid; and mixtures thereof.
35. The pharmaceutical composition of claim 24, wherein the hydrophobic surfactant is selected from the group consisting of oleic acid; lauric acid; glyceryl monocaprate; glyceryl monocaprylate; glyceryl monolaurate; glyceryl monooleate; glyceryl dicaprate; glyceryl dicaprylate; glyceryl dilaurate; glyceryl dioleate; acetylated monoglycerides; propylene glycol oleate; propylene glycol laurate; polyglyceryl-3 oleate; polyglyceryl-6 dioleate; PEG-6 com oil; PEG-20 com oil; PEG-20 almond oil; sorbitan monooleate; sorbitan monolaurate; POE-4 lauryl ether; POE-3 oleyl ether; ethyl oleate; poloxamers; cholic acid; ursodeoxycholic acid; glycocholic acid; taurocholic acid; lithocholic acid; deoxycholic acid; chenodeoxycholic acid; and mixtures thereof.
36. The pharmaceutical composition of claim 1, wherein the therapeutic agent is a dmg, a vitamin, a nutritional supplement, a cosmeceutical, or a mixture thereof.
37. The pharmaceutical composition of claim 1, wherein the therapeutic agent is a hydrophobic dmg.
38. The pharmaceutical composition of claim 37, wherein the hydrophobic dmg has a molecular weight of less than about 1000 g/mol.
39. The pharmaceutical composition of claim 1, wherein the therapeutic agent is a hydrophilic dmg.
40. The pharmaceutical composition of claim 39, wherein the hydrophilic drag is a peptidomimetic, a peptide, a protein, an oligonucleotide, an ohgodeoxynucleotide, RNA, DNA, genetic material, derivatives or analogues thereof, or a mixture thereof.
41. The pharmaceutical composition of claim 39, wherein the hydrophilic dmg has a molecular weight of less than about 1000 g/mol.
42. The pharmaceutical composition of claim 1, wherein the surfactants are present in amounts such that the triglyceride can be present in an amount greater than the amount of the triglyceride that remains solubilized in an aqueous dispersion of the triglyceride and a carrier having only one surfactant, the surfactant being hydrophilic, and having the same total surfactant concentration.
43. The pharmaceutical composition of claim 22, wherein the surfactants are present in amounts such that the triglyceride can be present in an amount greater than the amount of the triglyceride that remains solubilized in an aqueous dispersion of the triglyceride and a carrier having only one surfactant, the surfactant being hydrophilic, and having the same total surfactant concentration.
44. The pharmaceutical composition of claim 23, wherein the surfactants are present in amounts such that the triglyceride can be present in an amount greater than the amount of the triglyceride that remains solubilized in an aqueous dispersion of the triglyceride and a carrier having a hydrophilic surfactant but not having a hydrophobic surfactant, and having the same total surfactant concentration.
45. The pharmaceutical composition of claim 1, wherein the triglyceride and surfactants are present in amounts such that upon mixing with an aqueous solution in an aqueous solution to composition ratio of about 10:1 by weight, the composition forms a clear aqueous dispersion.
46. The pharmaceutical composition of claim 1, wherein the triglyceride and surfactants are present in amounts such that upon mixing with an aqueous solution in an aqueous solution to composition ratio of about 100:1 by weight, the composition forms a clear aqueous dispersion.
47. The pharmaceutical composition of claim 46, wherein the clear aqueous dispersion has an absorbance of less than about 0.3 at about 400 nm.
48. The pharmaceutical composition of claim 47, wherein the absorbance is less than about 0.2.
49. The pharmaceutical composition of claim 47, wherein the absorbance is less than about 0.1.
50. The pharmaceutical composition of claim 1, which further comprises a solubilizer.
51. The pharmaceutical composition of claim 50, wherein the solubilizer is selected from the group consisting of alcohols, polyols, amides, esters, propylene glycol ethers and mixtures thereof.
52. The pharmaceutical composition of claim 51, wherein the alcohol or polyol is selected from the group consisting of ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, maltol, maltodextrins, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives, and mixtures thereof.
53. The pharmaceutical composition of claim 51, wherein the amide is selected from the group consisting of 2-pyrrolidone, 2-piperidone, ε-caprolactam, N- alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, polyvinylpyrrolidone, and mixtures thereof.
54. The pharmaceutical composition of claim 51, wherein the ester is selected from the group consisting of ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof, and mixtures thereof.
55. The pharmaceutical composition of claim 50, wherein the solubilizer is selected from the group consisting of ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and derivatives thereof, ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof, 2- pyrrolidone, 2-piperidone, ε-caprolactam, N-methylpyπolidone, N-ethylpyrrolidone, N- hydroxyethyl pyrrolidone, N-octylpyπolidone, N-laurylpyrrolidone, dimethylacetamide, polyvinylpyrrolidone, glycofurol, methoxy PEG, and mixtures thereof.
56. The pharmaceutical composition of claim 50, wherein the solubilizer is selected from the group consisting of ethanol, isopropanol, benzyl alcohol, ethylene glycol, propylene glycol, 1,3-butanediol, glycerol, pentaerythritol, sorbitol, glycofurol, transcutol, dimethyl isosorbide, polyethylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, hydroxypropylcyclodextrins, sulfobutyl ether derivatives of cyclodextrins, ethyl propionate, tributylcitrate, triethylcitrate, ethyl oleate, ethyl caprylate, triacetin, β-butyrolactone and isomers thereof, 2-pyπolidone, N- methylpyrrolidone, N-ethylpyrrolidone, N-hydroxyethylpyπolidone, N-octylpyπolidone, N-laurylpyrrolidone, dimethylacetamide, polyvinylpyrrolidone, and mixtures thereof.
57. The pharmaceutical composition of claim 50, wherein the solubilizer is triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N- methylpyπolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, dimethyl isosorbide, or a mixture thereof.
58. The pharmaceutical composition of claim 50, wherein the solubilizer is triacetin, ethanol, polyethylene glycol 400, glycofurol, propylene glycol or a mixture thereof.
59. The pharmaceutical composition of claim 1, which further comprises an antioxidant, a bufferant, an antifoaming agent, a detackifier, a preservative, a chelating agent, a viscomodulator, a tonicifier, a flavorant, a colorant, an odorant, an opacifier, a suspending agent, a binder, a filler, a plasticizer, a lubricant, or a mixture thereof.
60. The pharmaceutical composition of claim 1, which further comprises an amount of an enzyme inhibiting agent sufficient to at least partially inhibit enzymatic degradation ofthe therapeutic agent.
61. The pharmaceutical composition of claim 60, wherein the enzyme inhibitor is solubilized or suspended in the preconcentrate.
62. The pharmaceutical composition of claim 1, which further comprises an aqueous medium comprising water, an aqueous palatable diluent or an aqueous beverage.
63. The pharmaceutical composition of claim 62, wherein the therapeutic agent is provided to the composition in the aqueous medium.
64. The pharmaceutical composition of claim 62, wherein the aqueous medium further comprises an amount of an enzyme inhibiting agent sufficient to at least partially inhibit enzymatic degradation ofthe therapeutic agent.
65. The pharmaceutical composition of claim 1 in the form of a preconcentrate in a liquid, semi-solid, or solid form, or as an aqueous or organic diluted preconcentrate.
66. A dosage form comprising the pharmaceutical composition of claim 1 processed by lyophilization, encapsulation, extmding, compression, melting, molding, spraying, coating, comminution, mixing, homogenization, sonication, granulation, or a combination thereof.
67. A dosage form comprising the pharmaceutical composition of claim 1 formulated as a pill, capsule, caplet, tablet, granule, bead or powder.
68. The dosage form of claim 67, wherein the capsule is a starch capsule, a cellulosic capsule, a hard gelatin capsule or a soft gelatin capsule.
69. The dosage form of claim 67, wherein the capsule is a starch capsule, a cellulosic capsule, or a soft gelatin capsule.
70. The dosage form of claim 67, which further comprises an enteric coating, a seal coating, or both.
71. A dosage form comprising the pharmaceutical composition of claim 1 formulated as a solution, suspension, emulsion, cream, ointment, lotion, suppository, spray, aerosol, paste, gel, drops, douche, ovule, wafer, troche, cachet, symp or elixer.
72. A dosage form comprising a multiparticulate carrier coated onto a substrate with the pharmaceutical composition of claim 1.
73. The dosage form of claim 72, wherein the substrate is a particle, a granule or a bead, and is formed of the therapeutic agent, a pharmaceutically acceptable material, or a mixture thereof.
74. The dosage form of claim 72, wherein the multiparticulate carrier is enteric coated, seal coated, or both.
75. The pharmaceutical composition of claim 1, which further comprises an additional amount of the therapeutic agent, said additional amount not solubilized in the composition.
76. The dosage form of claim 72, wherein the dosage form is further processed by encapsulation, compression, extmsion or molding.
77. The dosage form of claim 72, wherein the capsule is a starch capsule, a cellulosic capsule, a hard gelatin capsule, or a soft gelatin capsule.
78. The dosage form of claim 72, wherein the capsule is a starch capsule, a cellulosic capsule, or a soft gelatin capsule.
79. A pharmaceutical composition comprising:
(a) a triglyceride;
(b) a carrier comprising at least one hydrophilic surfactant and at least one hydrophobic surfactant; and (c) a therapeutic agent which is capable of being solubilized in the triglyceride, the carrier, or both the triglyceride and the carrier, wherein the triglyceride and surfactants are present in amounts such that upon mixing with an aqueous solution the composition forms a clear aqueous dispersion.
80. The pharmaceutical composition of claim 79, wherein the triglyceride is selected from the group consisting of vegetable oils, fish oils, animal fats, hydrogenated vegetable oils, partially hydrogenated vegetable oils, synthetic triglycerides, modified triglycerides, fractionated triglycerides, and mixtures thereof.
81. The pharmaceutical composition of claim 79, wherein the triglyceride is selected from the group consisting of almond oil; babassu oil; borage oil; blackcurrant seed oil; canola oil; castor oil; coconut oil; com oil; cottonseed oil; evening primrose oil; grapeseed oil; groundnut oil; mustard seed oil; olive oil; palm oil; palm kernel oil; peanut oil; rapeseed oil; safflower oil; sesame oil; shark liver oil; soybean oil; sunflower oil; hydrogenated castor oil; hydrogenated coconut oil; hydrogenated palm oil; hydrogenated soybean oil; hydrogenated vegetable oil; hydrogenated cottonseed and castor oil; partially hydrogenated soybean oil; partially soy and cottonseed oil; glyceryl tricaproate; glyceryl tricaprylate; glyceryl tricaprate; glyceryl triundecanoate; glyceryl trilaurate; glyceryl trioleate; glyceryl trilinoleate; glyceryl trilinolenate; glyceryl tricaprylate/caprate; glyceryl tricaprylate/caprate/laurate; glyceryl tricaprylate/caprate/linoleate; glyceryl tricaprylate/caprate/stearate; saturated polyglycolized glycerides; linoleic glycerides; caprylic/capric glycerides; modified triglycerides; fractionated triglycerides; and mixtures thereof.
82. The pharmaceutical composition of claim 79, wherein the triglyceride is selected from the group consisting of coconut oil; com oil; olive oil; palm oil; peanut oil; safflower oil; sesame oil; soybean oil; hydrogenated castor oil; hydrogenated coconut oil; partially hydrogenated soybean oil; glyceryl tricaprate; glyceryl trilaurate; glyceryl trioleate; glyceryl trilinoleate; glyceryl tricaprylate/caprate; glyceryl tricaprylate/caprate/laurate; glyceryl tricaprylate/caprate/linoleate; glyceryl tricaprylate/caprate/stearate; saturated polyglycolized glycerides; linoleic glycerides; caprylic/capric glycerides; modified triglycerides; fractionated triglycerides; and mixtures thereof.
83. The pharmaceutical composition of claim 79, wherein the triglyceride is a medium chain triglyceride, a long chain triglyceride, a modified triglyceride, a fractionated triglyceride, or a mixture thereof.
84. The pharmaceutical composition of claim 79, wherein the hydrophilic surfactant comprises at least one non-ionic hydrophilic surfactant having an HLB value greater than or equal to about 10.
85. The pharmaceutical composition of claim 79, wherein the hydrophilic surfactant comprises at least one ionic surfactant.
86. The pharmaceutical composition of claim 84, which further comprises at least one ionic surfactant.
87. The pharmaceutical composition of claim 84, wherein the non-ionic surfactant is selected from the group consisting of alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene- polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sugar esters, sugar ethers; sucroglycerides; and mixtures thereof.
88. The pharmaceutical composition of claim 84, wherein the non-ionic hydrophilic surfactant is selected from the group consisting of polyoxyethylene alkylethers; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and mixtures thereof.
89. The pharmaceutical composition of claim 84, wherein the glyceride is a monoglyceride, diglyceride, triglyceride, or a mixture thereof.
90. The pharmaceutical composition of claim 88, wherein the reaction mixture comprises the transesterification products of a polyol and at least one member ofthe group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
5 91. The pharmaceutical composition of claim 88, wherein the polyol is glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, a saccharide, or a mixture thereof.
92. The pharmaceutical composition of claim 84, wherein the hydrophilic surfactant is PEG- 10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32
1° dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG- 1 40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 com oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20,
20 polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG- 100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, a poloxamer, or a mixture thereof.
2 93. The pharmaceutical composition of claim 84, wherein the hydrophilic surfactant is PEG-20 laurate, PEG-20 oleate, PEG-35 castor oil, PEG-40 palm kernel oil, PEG-40 hydrogenated castor oil, PEG-60 com oil, PEG-25 glyceryl trioleate, polyglyceryl-10 laurate, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, PEG-30 cholesterol, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-
30 23 lauryl ether, POE-10 oleyl ether, PEG-24 cholesterol, sucrose monostearate, sucrose monolaurate, a poloxamer, or a mixture thereof.
94. The pharmaceutical composition of claim 84, wherein the hydrophilic surfactant is PEG-35 castor oil, PEG-40 hydrogenated castor oil, PEG-60 com oil, PEG-25 glyceryl trioleate, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polysorbate 20, polysorbate 80, tocopheryl PEG- 1000 succinate, PEG-24 cholesterol, a poloxamer, or a mixture thereof.
95. The pharmaceutical composition of claim 85, wherein the ionic surfactant is selected from the group consisting of alkyl ammonium salts; bile salts, analogues, and derivatives thereof; fusidic acid and derivatives thereof; fatty acid derivatives of amino acids, ohgopeptides, and polypeptides; glyceride derivatives of amino acids, ohgopeptides, and polypeptides; acyl lactylates; mono-,diacetylated tartaric acid esters of mono- ,diglycerides; succinylated monoglycerides; citric acid esters of mono-,diglycerides; alginate salts; propylene glycol alginate; lecithins and hydrogenated lecithins; lysolecithin and hydrogenated lysolecithins; lysophospholipids and derivatives thereof; camitine fatty acid ester salts; phospholipids and derivatives thereof; salts of alkylsulfates; salts of fatty acids; sodium docusate; and mixtures thereof.
96. The pharmaceutical composition of claim 85, wherein the ionic surfactant is selected from the group consisting of bile salts, analogues, and derivatives thereof; lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; camitine fatty acid ester salts; salts of alkylsulfates; salts of fatty acids; sodium docusate; acyl lactylates; mono-,diacetylated tartaric acid esters of mono-,diglycerides; succinylated monoglycerides; citric acid esters of mono-,diglycerides; and mixtures thereof.
97. The pharmaceutical composition of claim 85, wherein the ionic surfactant is selected from the group consisting of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP- phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholate, chenodeoxycholate, lithocholate, ursodeoxycholate, taurocholate, glycocholate, deoxycholate, taurodeoxycholate, chenodeoxycholate, glycodeoxycholate, glycochenodeoxycholate, taurochenodeoxycholate, ursodeoxycholate, lithocholate, tauroursodeoxycholate, glycoursodeoxycholate, cholylsarcosine, N-methyl taurocholate, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, tetraacetyl sulfate, docusate, lauroyl camitine, palmitoyl camitine, myristoyl camitine, and salts and mixtures thereof.
98. The pharmaceutical composition of claim 85, wherein the ionic surfactant is selected from the group consisting of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, lysophosphatidylcholine, PEG- phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholate, taurocholate, glycocholate, deoxycholate, taurodeoxycholate, chenodeoxycholate, lithocholate, ursodeoxycholate, glycodeoxycholate, cholylsarcosine, caproate, caprylate, caprate, laurate, oleate, lauryl sulfate, docusate, lauroyl camitine, palmitoyl camitine, myristoyl camitine, and salts and mixtures thereof.
99. The pharmaceutical composition of claim 85, wherein the ionic surfactant is selected from the group consisting of lecithin, lactylic esters of fatty acids, stearoyl-2- lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, chenodeoxycholate, lithocholate, ursodeoxycholate, taurocholate, caprylate, caprate, oleate, lauryl sulfate, docusate, lauroyl camitine, palmitoyl camitine, myristoyl camitine, and salts and mixtures thereof.
100. The pharmaceutical composition of claim 79 wherein the hydrophobic surfactant is a compound or mixture of compounds having an HLB value less than about 10.
101. The pharmaceutical composition of claim 100, wherein the hydrophobic surfactant is selected from the group consisting of alcohols; polyoxyethylene alkylethers; fatty acids; bile acids; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polypropylene glycol fatty acid esters; polyoxyethylene glycerides; lactic acid derivatives of mono/diglycerides; propylene glycol diglycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene- polyoxypropylene block copolymers; transesterified vegetable oils; sterols; sterol derivatives; sugar esters; sugar ethers; sucroglycerides; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and mixtures thereof.
102. The pharmaceutical composition of claim 100, wherein the hydrophobic surfactant is selected from the group consisting of fatty acids; bile acids; lower alcohol fatty acid esters; polyethylene glycol glycerol fatty acid esters; polypropylene glycol fatty acid esters; polyoxyethylene glycerides; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lactic acid derivatives of mono/diglycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and mixtures thereof.
103. The pharmaceutical composition of claim 100, wherein the hydrophobic surfactant is selected from the group consisting of bile acids; lower alcohol fatty acids esters; polypropylene glycol fatty acid esters; propylene glycol fatty acid esters; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lactic acid derivatives of mono/diglycerides; sorbitan fatty acid esters; polyoxyethylene vegetable oils; and mixtures thereof.
104. The pharmaceutical composition of claim 100, wherein the hydrophobic surfactant is a glycerol fatty acid ester, an acetylated glycerol fatty acid ester, or a mixture thereof.
105. The pharmaceutical composition of claim 104, wherein the glycerol fatty acid ester is a monoglyceride, diglyceride, or a mixture thereof.
106. The pharmaceutical composition of claim 105, wherein the fatty acid of the glycerol fatty acid ester is a C6 to C 2 fatty acid or a mixture thereof.
107. The pharmaceutical composition of claim 100, wherein the hydrophobic surfactant is a reaction mixture of a polyol and at least one member ofthe group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
108. The pharmaceutical composition of claim 107, wherein the reaction mixture is a transesterification product of a polyol and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
109. The pharmaceutical composition of claim 107, wherein the polyol is polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, a saccharide, or a mixture thereof.
110. The pharmaceutical composition of claim 100, wherein the hydrophobic surfactant is selected from the group consisting of myristic acid; oleic acid; lauric acid; stearic acid; palmitic acid; PEG 1-4 stearate; PEG 2-4 oleate; PEG-4 dilaurate; PEG-4 dioleate; PEG-4 distearate; PEG-6 dioleate; PEG-6 distearate; PEG-8 dioleate; PEG 3-16 ° castor oil; PEG 5-10 hydrogenated castor oil; PEG 6-20 com oil; PEG 6-20 almond oil; PEG-6 olive oil; PEG-6 peanut oil; PEG-6 palm kernel oil; PEG-6 hydrogenated palm kernel oil; PEG-4 capric/caprylic triglyceride, mono, di, tri, tetra esters of vegetable oil and sorbitol; pentaerythrityl di, tetra stearate, isostearate, oleate, caprylate, or caprate; polyglyceryl 2-4 oleate, stearate, or isostearate; polyglyceryl 4-10 pentaoleate; 5 polyglyceryl-3 dioleate; polyglyceryl-6 dioleate; polyglyceryl-10 trioleate; polyglyceryl-3 distearate; propylene glycol mono- or diesters of a C6 to C22 fatty acid; monoglycerides of a C6 to C22 fatty acid; acetylated monoglycerides of C6 to C22 fatty acid; diglycerides of C6 to C22 fatty acids; lactic acid derivatives of monoglycerides; lactic acid derivatives of diglycerides; cholesterol; phytosterol; PEG 5-20 soya sterol; PEG-6 sorbitan tetra, hexastearate; PEG-6 sorbitan tetraoleate; sorbitan monolaurate; sorbitan monopalmitate; sorbitan mono, trioleate; sorbitan mono, tristearate; sorbitan monoisostearate; sorbitan sesquioleate; sorbitan sesquistearate; PEG 2-5 oleyl ether; POE 2-4 lauryl ether; PEG-2 cetyl ether; PEG-2 stearyl ether; sucrose distearate; sucrose dipalmitate; ethyl oleate; isopropyl myristate; isopropyl palmitate; ethyl linoleate; isopropyl linoleate; poloxamers; cholic acid; ursodeoxycholic acid; glycocholic acid; taurocholic acid; lithocholic acid; deoxycholic acid; chenodeoxycholic acid; and mixtures thereof.
111. The pharmaceutical composition of claim 100, wherein the hydrophobic surfactant is selected from the group consisting of oleic acid; lauric acid; glyceryl monocaprate; glyceryl monocaprylate; glyceryl monolaurate; glyceryl monooleate; 0 glyceryl dicaprate; glyceryl dicaprylate; glyceryl dilaurate; glyceryl dioleate; acetylated monoglycerides; propylene glycol oleate; propylene glycol laurate; polyglyceryl-3 oleate; polyglyceryl-6 dioleate; PEG-6 com oil; PEG-20 com oil; PEG-20 almond oil; sorbitan monooleate; sorbitan monolaurate; POE-4 lauryl ether; POE-3 oleyl ether; ethyl oleate; poloxamers; cholic acid; ursodeoxycholic acid; glycocholic acid; taurocholic acid; lithocholic acid; deoxycholic acid; chenodeoxycholic acid; and mixtures thereof.
112. The pharmaceutical composition of claim 79, wherein the therapeutic agent is a dmg, a vitamin, a nutritional supplement, a cosmeceutical, or a mixture thereof.
113. The pharmaceutical composition of claim 79, wherein the therapeutic agent is a hydrophobic dmg.
114. The pharmaceutical composition of claim 113, wherein the hydrophobic dmg has a molecular weight of less than about 1000 g/mol.
115. The pharmaceutical composition of claim 79, wherein the therapeutic agent is a hydrophilic dmg.
116. The pharmaceutical composition of claim 115, wherein the hydrophilic dmg is a peptidomimetic, a peptide, a protein, an oligonucleotide, an ohgodeoxynucleotide, RNA, DNA, genetic material, derivatives or analogues thereof, or a mixture thereof.
117. The pharmaceutical composition of claim 115, wherein the hydrophilic dmg has a molecular weight of less than about 1000 g/mol.
118. The pharmaceutical composition of claim 79, wherein the surfactants are present in amounts such that the triglyceride can be present in an amount greater than the amount of the triglyceride that remains solubilized in an aqueous dispersion of the triglyceride and a carrier having a hydrophilic surfactant but not having a hydrophobic surfactant, and having the same total surfactant concentration.
119. The pharmaceutical composition of claim 79, wherein the triglyceride and surfactants are present in amounts such that upon mixing with an aqueous solution in an aqueous solution to composition ratio of about 10:1 by weight, the composition forms a clear aqueous dispersion.
120. The pharmaceutical composition of claim 79, wherein the triglyceride and surfactants are present in amounts such that upon mixing with an aqueous solution in an aqueous solution to composition ratio of about 100:1 by weight, the composition forms a clear aqueous dispersion.
121. The pharmaceutical composition of claim 79, wherein the clear aqueous dispersion has an absorbance of less than about 0.3 at about 400 nm when the composition 1 is diluted with an aqueous solution in an aqueous solution to composition ratio of 100: 1 by weight.
122. The pharmaceutical composition of claim 121, wherein the absorbance is less than about 0.2. 5
123. The pharmaceutical composition of claim 121, wherein the absorbance is less than about 0.1.
124. The pharmaceutical composition of claim 79, which further comprises a solubilizer.
125. The pharmaceutical composition of claim 124, wherein the solubilizer is 10 selected from the group consisting of alcohols, polyols, amides, esters, propylene glycol ethers and mixtures thereof.
126. The pharmaceutical composition of claim 125, wherein the alcohol or polyol is selected from the group consisting of ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol,
15 pentaerythritol, sorbitol, mannitol, transcutol, maltol, maltodextrins, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives, and mixtures thereof.
127. The pharmaceutical composition of claim 125, wherein the amide is selected from the group consisting of 2-pyrrolidone, 2-piperidone, ε-caprolactam, N- alkylpyπolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, polyvinylpyπolidone, and mixtures thereof.
128. The pharmaceutical composition of claim 125, wherein the ester is selected from the group consisting of ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl
ΔJ tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof, and mixtures thereof.
129. The pharmaceutical composition of claim 124, wherein the solubilizer is
30 . . selected from the group consisting of ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and derivatives thereof, ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof, 2- pyrrolidone, 2-piperidone, ε-caprolactam, N-methylpyrrolidone, N-ethylpyrrolidone, N- hydroxyethyl pyrrolidone, N-octylpyrrolidone, N-laurylpyrrolidone, dimethylacetamide, polyvinylpyrrolidone, glycofurol, methoxy PEG, and mixtures thereof.
130. The pharmaceutical composition of claim 124, wherein the solubilizer is selected from the group consisting of ethanol, isopropanol, benzyl alcohol, ethylene glycol, propylene glycol, 1,3-butanediol, glycerol, pentaerythritol, sorbitol, glycofurol, transcutol, dimethyl isosorbide, polyethylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, hydroxypropylcyclodextrins, sulfobutyl ether derivatives of cyclodextrins, ethyl propionate, tributylcitrate, triethylcitrate, ethyl oleate, ethyl caprylate, triacetin, β-butyrolactone and isomers thereof, 2-pyrrolidone, N- methylpyrrolidone, N-ethylpyrrolidone, N-hydroxyethylpyrrolidone, N-octylpyrrolidone, N-laurylpyrrolidone, dimethylacetamide, polyvinylpyrrolidone, and mixtures thereof.
131. The pharmaceutical composition of claim 124, wherein the solubilizer is triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N- methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, dimethyl isosorbide, or a mixture thereof.
132. The pharmaceutical composition of claim 124, wherein the solubilizer is triacetin, ethanol, polyethylene glycol 400, glycofurol, propylene glycol or a mixture thereof.
133. The pharmaceutical composition of claim 79, which further comprises an antioxidant, a bufferant, an antifoaming agent, a detackifier, a preservative, a chelating agent, a viscomodulator, a tonicifier, a flavorant, a colorant, an odorant, an opacifϊer, a suspending agent, a binder, a filler, a plasticizer, a lubricant, or a mixture thereof.
134. The pharmaceutical composition of claim 79, which further comprises an amount of an enzyme inhibiting agent sufficient to at least partially inhibit enzymatic degradation ofthe therapeutic agent.
135. The pharmaceutical composition of claim 134, wherein the enzyme inhibitor is solubilized or suspended in the preconcentrate.
136. The pharmaceutical composition of claim 79, which further comprises an aqueous medium comprising water, an aqueous palatable diluent or an aqueous beverage.
137. The pharmaceutical composition of claim 136, wherein the therapeutic agent is provided to the composition in the aqueous medium.
138. The pharmaceutical composition of claim 136, wherein the aqueous medium further comprises an amount of an enzyme inhibiting agent sufficient to at least partially inhibit enzymatic degradation ofthe therapeutic agent.
139. The pharmaceutical composition of claim 79 in the form of a preconcentrate in a liquid, semi-solid, or solid form, or as an aqueous or organic diluted preconcentrate.
140. A dosage form comprising the pharmaceutical composition of claim 79 processed by lyophilization, encapsulation, extruding, compression, melting, molding, spraying, coating, comminution, mixing, homogenization, sonication, granulation, or a combination thereof.
141. A dosage form comprising the pharmaceutical composition of claim 79 formulated as a pill, capsule, caplet, tablet, granule, bead or powder.
142. The dosage form of claim 141, wherein the capsule is a starch capsule, a cellulosic capsule, a hard gelatin capsule or a soft gelatin capsule.
143. The dosage form of claim 141, wherein the capsule is a starch capsule, a cellulosic capsule, or a soft gelatin capsule.
144. The dosage form of claim 141, which further comprises an enteric coating, a seal coating, or both.
145. A dosage form comprising the pharmaceutical composition of claim 79 formulated as a solution, suspension, emulsion, cream, ointment, lotion, suppository, spray, aerosol, paste, gel, drops, douche, ovule, wafer, troche, cachet, symp or elixer.
146. A dosage form comprising a multiparticulate carrier coated onto a substrate with the pharmaceutical composition of claim 79.
147. The dosage form of claim 146, wherein the substrate is a particle, a granule or a bead, and is formed of the therapeutic agent, a pharmaceutically acceptable material, or a mixture thereof.
148. The dosage form of claim 146, wherein the multiparticulate carrier is enteric coated, seal coated, or both.
149. The pharmaceutical composition of claim 79, which further comprises an additional amount of the therapeutic agent, said additional amount not solubilized in the composition.
150. The dosage form of claim 146, wherein the dosage form is further processed by encapsulation, compression, extmsion or molding.
151. The dosage form of claim 146, wherein the capsule is a starch capsule, a cellulosic capsule, a hard gelatin capsule, or a soft gelatin capsule.
152. The dosage form of claim 146, wherein the capsule is a starch capsule, a cellulosic capsule, or a soft gelatin capsule.
153. A pharmaceutical composition comprising:
(a) a triglyceride;
(b) a carrier comprising at least two surfactants, at least one of the surfactants being hydrophilic, wherein the triglyceride and surfactants are present in amounts such that upon mixing with an aqueous solution the composition forms a clear aqueous dispersion;
(c) a first amount of a therapeutic agent, said first amount being solubilized in the triglyceride, the carrier, or both the triglyceride and the carrier; and
(d) a second amount of a therapeutic agent, said second amount not solubilized in the triglyceride or the carrier.
154. A pharmaceutical composition comprising: (a) a triglyceride; and (b) a carrier comprising at least two surfactants, at least one of the surfactants being hydrophilic, wherein the triglyceride and surfactants are present in amounts such that upon mixing with an aqueous solution the composition forms a clear aqueous dispersion, and wherein the triglyceride is present in an amount greater than the amount of the triglyceride that remains solubilized in an aqueous dispersion of the triglyceride and a carrier having only one surfactant, the surfactant being hydrophilic, and having the same total surfactant concentration.
155. The composition of claim 154, wherein the triglyceride comprises a digestible oil.
156. The pharmaceutical composition of claim 154, wherein the triglyceride is selected from the group consisting of vegetable oils, fish oils, animal fats, hydrogenated vegetable oils, partially hydrogenated vegetable oils, synthetic triglycerides, and mixtures thereof.
157. The pharmaceutical composition of claim 154, wherein the triglyceride is selected from the group consisting of almond oil; babassu oil; borage oil; blackcurrant seed oil; canola oil; castor oil; coconut oil; com oil; cottonseed oil; evening primrose oil; grapeseed oil; groundnut oil; mustard seed oil; olive oil; palm oil; palm kernel oil; peanut oil; rapeseed oil; safflower oil; sesame oil; shark liver oil; soybean oil; sunflower oil; hydrogenated castor oil; hydrogenated coconut oil; hydrogenated palm oil; hydrogenated soybean oil; hydrogenated vegetable oil; hydrogenated cottonseed and castor oil; partially hydrogenated soybean oil; partially soy and cottonseed oil; glyceryl tricaproate; glyceryl tricaprylate; glyceryl tricaprate; glyceryl triundecanoate; glyceryl trilaurate; glyceryl trioleate; glyceryl trilinoleate; glyceryl trilinolenate; glyceryl tricaprylate/caprate; glyceryl tricaprylate/caprate/laurate; glyceryl tricaprylate/caprate/linoleate; glyceryl tricaprylate/caprate/stearate; saturated polyglycolized glycerides; linoleic glycerides; caprylic/capric glycerides; and mixtures thereof.
158. The pharmaceutical composition of claim 154, wherein the triglyceride is selected from the group consisting of coconut oil; com oil; olive oil; palm oil; peanut oil; safflower oil; sesame oil; soybean oil; hydrogenated castor oil; hydrogenated coconut oil; partially hydrogenated soybean oil; glyceryl tricaprate; glyceryl trilaurate; glyceryl trioleate; glyceryl trilinoleate; glyceryl tricaprylate/caprate; glyceryl tricaprylate/caprate/laurate; glyceryl tricaprylate/caprate/linoleate; glyceryl tricaprylate/caprate/stearate; saturated polyglycolized glycerides; linoleic glycerides; caprylic/capric glycerides; and mixtures thereof.
159. The pharmaceutical composition of claim 154, wherein the triglyceride is a medium chain triglyceride, a long chain triglyceride, or a mixture thereof.
160. The pharmaceutical composition of claim 154, which further comprises a therapeutic agent.
161. A method of treating an animal with a therapeutic agent, the method comprising:
(a) providing a dosage form of a pharmaceutical composition comprising: (i) a triglyceride; and
(ii) a carrier comprising at least two surfactants, at least one of the surfactants being hydrophilic, wherein the triglyceride and surfactants are present in amounts such that upon mixing with an aqueous solution the composition forms a clear aqueous dispersion;
(b) providing a therapeutic agent; and
(c) administering said dosage form to said ammal.
162. The method of claim 161, wherein the dosage form comprises the pharmaceutical composition processed by lyophilization, encapsulation, extmding, compression, melting, molding, spraying, coating, comminution, mixing, homogenization, sonication, granulation, or a combination thereof.
163. The method of claim 161, wherein the dosage form comprises the pharmaceutical composition formulated as a pill, capsule, caplet, tablet, granule, bead or powder.
164. The method of claim 163, wherein the capsule is a starch capsule, a cellulosic capsule, a hard gelatin capsule or a soft gelatin capsule.
165. The method of claim 163, wherein the capsule is a starch capsule, a cellulosic capsule, or a soft gelatin capsule.
166. The method of claim 163, wherein the capsule further comprises an enteric coating, a seal coating, or both.
167. The method of claim 161, wherein the dosage form comprises the pharmaceutical composition formulated as a solution, suspension, emulsion, cream, ointment, lotion, suppository, spray, aerosol, paste, gel, drops, douche, ovule, wafer, troche, cachet, symp or elixer.
168. The method of claim 161, wherein the dosage form comprises a multiparticulate carrier coated onto a substrate with the pharmaceutical composition.
169. The method of claim 168, wherein the substrate is a particle, a granule or a bead, and is formed of the therapeutic agent, a pharmaceutically acceptable material or a mixture thereof.
170. The method of claim 168, wherein the multiparticulate carrier is enteric coated, seal coated, or both.
171. The method of claim 168, wherein the dosage form is further processed by encapsulation, compression, extmsion or molding.
172. The method of claim 168, wherein the capsule is a starch capsule, a cellulosic capsule, a hard gelatin capsule, or a soft gelatin capsule.
173. The method of claim 168, wherein the capsule is a starch capsule, a cellulosic capsule, or a soft gelatin capsule.
174. The method of claim 161, wherein the therapeutic agent is provided by solubihzing the therapeutic agent in the triglyceride, in the carrier, or in both the triglyceride and the carrier.
175. The method of claim 161, wherein the therapeutic agent is provided separately from the dosage form ofthe pharmaceutical composition.
176. The method of claim 161, wherein the dosage form is administered by an oral, parenteral, buccal, topical, transdermal, ocular, pulmonary, vaginal, rectal or transmucosal route.
177. The method of claim 161, wherein the animal is a mammal.
178. The method of claim 177, wherein the mammal is a human.
179. A method of increasing the amount of a triglyceride that can be solubilized in a clear aqueous dispersion, the method comprising:
(a) providing a composition comprising a triglyceride and a carrier, the carrier comprising at least two surfactants, at least one of the surfactants being hydrophilic; and
(b) dispersing the composition in an aqueous solution, wherein the triglyceride and surfactants are present in amounts such that upon mixing with an aqueous solution the composition forms a clear aqueous dispersion, and wherein the triglyceride is present in an amount greater than the amount of the triglyceride that remains solubilized in an aqueous dispersion of the triglyceride and a carrier having only one surfactant and having the same total surfactant concentration.
180. The method of claim 179, wherein the step of dispersing the composition comprises mixing the composition with an aqueous solution in vitro.
181. The method of claim 179, wherein the step of dispersing the composition comprises allowing the composition to contact an aqueous biological solution in vivo upon administering the composition to an animal.
182. A method of treating an animal with a therapeutic agent, the method comprising: (a) providing a dosage form of a pharmaceutical composition comprising:
(i) an effective amount of a triglyceride; and (ii) a carrier comprising at least two surfactants, at least one of the surfactants being hydrophilic, wherein the triglyceride and surfactants are present in amounts such that upon mixing with an aqueous solution the composition forms a clear aqueous dispersion; and (b) administering said dosage form to said animal.
183. The method of claim 182, wherein the effective amount of the triglyceride is a nutritionally effective amount of a digestible oil.
184. The method of claim 182, wherein the effective amount of the triglyceride is an amount sufficient to improve the bioabsorption of a therapeutic agent co- administered with the dosage form ofthe pharmaceutical composition.
PCT/US2000/015133 1999-06-30 2000-06-02 Clear oil-containing pharmaceutical compositions WO2001001960A1 (en)

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CA2375083A CA2375083C (en) 1999-06-30 2000-06-02 Clear oil-containing pharmaceutical compositions
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AU53131/00A AU783077B2 (en) 1999-06-30 2000-06-02 Clear oil-containing pharmaceutical compositions
EP00938039A EP1194120A4 (en) 1999-06-30 2000-06-02 Clear oil-containing pharmaceutical compositions
JP2001507455A JP2003503440A (en) 1999-06-30 2000-06-02 Pharmaceutical composition containing clear oil

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001054675A2 (en) * 2000-01-27 2001-08-02 Novartis Ag Pharmaceutical compositions comprising terbinafine
WO2001078724A1 (en) * 2000-04-18 2001-10-25 Pharmacia Corporation Rapid-onset formulation of a selective cyclooxigenase-2
WO2001091729A1 (en) * 2000-05-30 2001-12-06 Basf Aktiengesellschaft Formulation based on heparin, glycosaminoglycan or heparinoid, use of the formulation and the formulation base
WO2001093834A1 (en) * 2000-06-08 2001-12-13 Laboratoires Crinex Pharmaceutical composition in liquid form for oral administration of an active principle, with unpleasant, in particular bitter, taste
WO2003045357A1 (en) * 2001-11-27 2003-06-05 Transform Pharmaceuticals, Inc. Oral pharmaceutical formulations comprising paclitaxel, derivatives and methods of administration thereof
EP1363622A1 (en) * 2001-02-01 2003-11-26 Shire Laboratories Inc. Pharmaceutical compositions including sampatrilat dispersed in a lipoidic vehicle
WO2003097007A2 (en) * 2002-05-15 2003-11-27 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Aqueous ophthalmic composition comprising a lyotropic mesomorphic lipid
WO2003106592A2 (en) * 2002-06-12 2003-12-24 IFAC GmbH & Co. KG Institut für Angewandte Colloidtechnologie Ether alcohols used as solvents and emulsifiers and dispersions containing said ether alcohols
WO2004009076A1 (en) * 2002-07-20 2004-01-29 Korea Institute Of Science And Technology Paclitaxel composition for the intravesical treatment of bladder tumor and preparation method thereof
WO2004009075A1 (en) * 2002-07-20 2004-01-29 Korea Institute Of Science And Technology Composition for solubilization of paclitaxel and preparation method thereof
EP1406855A2 (en) 2001-06-13 2004-04-14 Biogal Gyogyszergyar Rt. Novel process for preparing rac-bicalutamide and its intermediates
WO2004052354A1 (en) * 2002-12-06 2004-06-24 Otsuka Pharmaceutical Factory, Inc. Propofol-containing fat emulsions
EP1452162A1 (en) * 2001-11-09 2004-09-01 The Nisshin Oil Mills, Ltd. Gel-form composition
EP1458359A1 (en) * 2001-12-27 2004-09-22 CJ Corporation Microemulsion preconcentrate
EP1498143A1 (en) * 2003-07-18 2005-01-19 Aventis Pharma S.A. Self-emulsifying and self-microemulsifying formulations for the oral administration of taxoids
WO2005053727A2 (en) * 2003-11-29 2005-06-16 Sangstat Medical Corporation Pharmaceutical compositions for bioactive peptide agents
US6919370B2 (en) 2000-11-28 2005-07-19 Transform Pharmaceuticals, Inc. Pharmaceutical formulations comprising paclitaxel, derivatives, and pharmaceutically acceptable salts thereof
JPWO2003097026A1 (en) * 2002-05-22 2005-09-15 日本製薬株式会社 Smooth muscle peristalsis inhibitor
JPWO2003097027A1 (en) * 2002-05-22 2005-10-06 日本製薬株式会社 L-menthol oil-in-water emulsion
EP1633326A1 (en) * 2003-06-17 2006-03-15 SK Corporation Transnasal microemulsions containing diazepam
JP2006160696A (en) * 2004-12-09 2006-06-22 Nof Corp Solubilizer composition for sparingly water-soluble medicine
JP2006160695A (en) * 2004-12-09 2006-06-22 Nof Corp Solubilizer composition for sparingly water-soluble medicine
WO2006133518A1 (en) * 2005-06-17 2006-12-21 Australian Nuclear Science And Technology Organisation Particles having hydrophobic material therein
WO2006133519A1 (en) * 2005-06-17 2006-12-21 Australian Nuclear Science And Technology Organisation Particles comprising a releasable dopant therein
US7306819B2 (en) 2002-06-12 2007-12-11 The Coca-Cola Company Beverages containing plant sterols
US7335389B2 (en) 2002-06-12 2008-02-26 The Coca-Cola Company Beverages containing plant sterols
US7345093B2 (en) 2004-04-27 2008-03-18 Formatech, Inc. Methods of enhancing solubility of compounds
WO2008077823A1 (en) * 2006-12-27 2008-07-03 Lek Pharmaceuticals D.D. Self-microemulsifying drug delivery systems
EP2003450A1 (en) * 2007-06-12 2008-12-17 Fujifilm Corporation Dry analytical element for lipase measurement
WO2009019604A2 (en) * 2007-08-09 2009-02-12 Ems S/A Delivery systems for solubilising water-insoluble pharmaceutical active ingredients
US7659310B2 (en) 2004-04-27 2010-02-09 Formatech, Inc. Methods of enhancing solubility of agents
EP2204167A1 (en) 2009-01-05 2010-07-07 Azad Pharma AG Pharmaceutical microemulsion for preventing supramolecular aggregation of amphiphilic molecules
WO2010015400A3 (en) * 2008-08-07 2010-08-12 Gp Pharm, S.A. Injectable taxane pharmaceutical composition
JP2011032287A (en) * 2002-03-12 2011-02-17 Galderma Research & Development Pharmaceutical composition comprising adapalene for treatment of dermatological disorder
US8241670B2 (en) * 2004-04-15 2012-08-14 Chiasma Inc. Compositions capable of facilitating penetration across a biological barrier
EP2514406A1 (en) * 2007-06-01 2012-10-24 Novo Nordisk A/S Spontaneously dispersible preconcentrates including a peptide drug in a solid or semisolid carrier
US8329198B2 (en) 2008-09-17 2012-12-11 Chiasma Inc. Pharmaceutical compositions and related methods of delivery
EP2540281A1 (en) 2011-06-30 2013-01-02 LEK Pharmaceuticals d.d. Solid self-microemulsifying systems
US8492369B2 (en) 2010-04-12 2013-07-23 Clarus Therapeutics Inc Oral testosterone ester formulations and methods of treating testosterone deficiency comprising same
RU2490016C1 (en) * 2012-06-13 2013-08-20 Федеральное государственное бюджетное учреждение "Научный центр неврологии" Российской академии медицинских наук (ФГБУ "НЦН" РАМН) Parenteral composition containing carbamazepine in form of submicron emulsion possessing anticonvulsant activity
US8530412B2 (en) 2005-03-30 2013-09-10 Canon Kabushiki Kaisha Ejection liquid, ejection method, method of making droplets from liquid, cartridge and ejection device
US8568748B2 (en) * 2001-12-14 2013-10-29 Jagotec Ag Pharmaceutical formulation comprising cyclosporin and use thereof
US8591942B2 (en) 2009-09-23 2013-11-26 Indu JAVERI Methods for the preparation of liposomes comprising docetaxel
US8592406B2 (en) 2008-05-14 2013-11-26 Sk Biopharmaceuticals Co., Ltd. Transnasal anticonvulsive pharmaceutical composition comprising poorly soluble anticonvulsant
US8778917B2 (en) 2005-04-15 2014-07-15 Clarus Therapeutics, Inc. Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same
US8802087B2 (en) 2004-03-22 2014-08-12 Abbott Products Gmbh Pharmaceutical compositions of lipase-containing products, in particular of pancreation
US8865695B2 (en) 2009-01-08 2014-10-21 Lipocine Inc. Steroidal compositions
US9034858B2 (en) 2010-11-30 2015-05-19 Lipocine Inc. High-strength testosterone undecanoate compositions
EP2878311A1 (en) * 2013-11-27 2015-06-03 Freund Pharmatec Ltd. Solubility Enhancement for Hydrophobic Drugs
US9173856B2 (en) 2010-04-19 2015-11-03 Qlt Inc. Therapeutic regimen and methods for treating or ameliorating visual disorders associated with an endogenous retinoid deficiency
US9198871B2 (en) 2005-08-15 2015-12-01 Abbott Products Gmbh Delayed release pancreatin compositions
CN105209476A (en) * 2013-09-25 2015-12-30 萨尼雷德有限公司 Method for preserving and stabilizing proteins, which can be used for industrial development of formulations of sanitary, pharmaceutical and cosmetic products
WO2016022936A1 (en) * 2014-08-07 2016-02-11 Murty Pharmaceuticals, Inc. An improved oral gastrointestinal dosage form delivery system of cannabinoids and/or standardized marijuana extracts
US9358241B2 (en) 2010-11-30 2016-06-07 Lipocine Inc. High-strength testosterone undecanoate compositions
US9481721B2 (en) 2012-04-11 2016-11-01 Novo Nordisk A/S Insulin formulations
US9498485B2 (en) 2014-08-28 2016-11-22 Lipocine Inc. Bioavailable solid state (17-β)-hydroxy-4-androsten-3-one esters
EP3124016A1 (en) 2015-07-31 2017-02-01 Warszawski Uniwersytet Medyczny Antipsoriatic emulsion composition comprising cefazolin
WO2017095736A1 (en) * 2015-12-01 2017-06-08 R.P. Scherer Technologies, Llc Aspirin soft gelatin capsule as a single active or in combination with other actives
US9688737B2 (en) 2008-03-18 2017-06-27 Novo Nordisk A/S Protease stabilized acylated insulin analogues
EP3169659A4 (en) * 2014-07-16 2018-01-31 Eastman Chemical Company Enzyme-catalyzed polyoxyalkylene esters
US10072256B2 (en) 2006-05-22 2018-09-11 Abbott Products Gmbh Process for separating and determining the viral load in a pancreatin sample
US10130606B2 (en) 2009-09-15 2018-11-20 Novelion Therapeutics Inc. Pharmaceutical formulations comprising 9-cis-retinyl esters in a lipid vehicle
US10143652B2 (en) 2009-09-23 2018-12-04 Curirx Inc. Methods for the preparation of liposomes
US10265385B2 (en) 2016-12-16 2019-04-23 Novo Nordisk A/S Insulin containing pharmaceutical compositions
US10376527B2 (en) 2015-05-28 2019-08-13 Dr. Reddy's Laboratories Ltd. Oral composition of celecoxib for treatment of pain
US10531671B2 (en) 2014-01-20 2020-01-14 Xeda International S.A. Anti-sprouting compositions for coating bulbs and tubers and the use thereof for anti-sprouting treatment
US10561615B2 (en) 2010-12-10 2020-02-18 Lipocine Inc. Testosterone undecanoate compositions
US10704037B2 (en) 2005-07-29 2020-07-07 Abbott Products Gmbh Processes for the manufacture and use of pancreatin
US10828267B2 (en) 2012-03-01 2020-11-10 Retinagenix Therapeutics, Inc. Therapeutic regimens and methods for improving visual function in visual disorders associated with an endogenous retinoid deficiency
US11266607B2 (en) 2005-08-15 2022-03-08 AbbVie Pharmaceuticals GmbH Process for the manufacture and use of pancreatin micropellet cores
US11338011B2 (en) 2015-02-03 2022-05-24 Amryt Endo, Inc. Method of treating diseases
US11337987B1 (en) 2021-05-07 2022-05-24 Lipocine Inc. Compositions and methods for treating central nervous system disorders
US11559530B2 (en) 2016-11-28 2023-01-24 Lipocine Inc. Oral testosterone undecanoate therapy
WO2023081786A1 (en) * 2021-11-04 2023-05-11 Vdf Futureceuticals, Inc Ketone precursors and methods therefor
US11707467B2 (en) 2014-08-28 2023-07-25 Lipocine Inc. (17-ß)-3-oxoandrost-4-en-17YL tridecanoate compositions and methods of their preparation and use
US11890316B2 (en) 2020-12-28 2024-02-06 Amryt Endo, Inc. Oral octreotide therapy and contraceptive methods

Families Citing this family (336)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5858401A (en) 1996-01-22 1999-01-12 Sidmak Laboratories, Inc. Pharmaceutical composition for cyclosporines
US6087350A (en) 1997-08-29 2000-07-11 University Of Pittsburgh Of The Commonwealth System Of Higher Education Use of pretreatment chemicals to enhance efficacy of cytotoxic agents
DE19834814A1 (en) * 1998-08-01 2000-02-03 Beiersdorf Ag Cosmetic and dermatological preparations with an effective content of bile acids, their salts and / or their derivatives
GB9822170D0 (en) * 1998-10-13 1998-12-02 Danbioyst Uk Ltd Novel formulations of fexofenadine
IL143604A0 (en) 1998-12-30 2002-04-21 Dexcel Ltd Dispersable concentrate for the delivery of cyclosporin
US20030104048A1 (en) * 1999-02-26 2003-06-05 Lipocine, Inc. Pharmaceutical dosage forms for highly hydrophilic materials
US6761903B2 (en) * 1999-06-30 2004-07-13 Lipocine, Inc. Clear oil-containing pharmaceutical compositions containing a therapeutic agent
JP2002537358A (en) * 1999-02-26 2002-11-05 サノフィ−サンテラボ Stable formulation containing fumagillin
US6616942B1 (en) * 1999-03-29 2003-09-09 Soft Gel Technologies, Inc. Coenzyme Q10 formulation and process methodology for soft gel capsules manufacturing
US20030236236A1 (en) * 1999-06-30 2003-12-25 Feng-Jing Chen Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs
NZ517706A (en) 1999-10-08 2004-01-30 Affinium Pharm Inc Fab I inhibitors
US6720001B2 (en) * 1999-10-18 2004-04-13 Lipocine, Inc. Emulsion compositions for polyfunctional active ingredients
US20060034937A1 (en) * 1999-11-23 2006-02-16 Mahesh Patel Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US7732404B2 (en) 1999-12-30 2010-06-08 Dexcel Ltd Pro-nanodispersion for the delivery of cyclosporin
EP1255565A1 (en) * 2000-01-13 2002-11-13 MERCK PATENT GmbH Pharmaceutical preparations containing 2-pyrrolidone as the dissolving intermediary
SE0000774D0 (en) * 2000-03-08 2000-03-08 Astrazeneca Ab New formulation
SE0000773D0 (en) * 2000-03-08 2000-03-08 Astrazeneca Ab New formulation
US7074803B2 (en) * 2001-03-02 2006-07-11 Durect Corporation Opioid formulations
KR100381834B1 (en) * 2000-05-20 2003-04-26 이상득 Solid dispersion system of pranlukast with improved dissolution, and the method thereof
US7678387B2 (en) * 2000-06-06 2010-03-16 Capricorn Pharma, Inc. Drug delivery systems
US6596306B1 (en) * 2000-07-07 2003-07-22 David Ho Sue San Ho Drug delivery system:formulation for fat-soluble drugs
WO2001097779A2 (en) * 2000-06-16 2001-12-27 Rtp Pharma Inc. Improved injectable dispersions of propofol
US7198801B2 (en) * 2000-08-03 2007-04-03 Antares Pharma Ipl Ag Formulations for transdermal or transmucosal application
EP1323431B1 (en) * 2000-08-03 2010-10-27 Antares Pharma IPL AG Composition for transdermal and/or transmucosal administration of active compounds that ensures adequate therapeutic levels
US20040198706A1 (en) * 2003-03-11 2004-10-07 Carrara Dario Norberto R. Methods and formulations for transdermal or transmucosal application of active agents
US8980290B2 (en) 2000-08-03 2015-03-17 Antares Pharma Ipl Ag Transdermal compositions for anticholinergic agents
US20070225379A1 (en) * 2001-08-03 2007-09-27 Carrara Dario Norberto R Transdermal delivery of systemically active central nervous system drugs
US6503894B1 (en) 2000-08-30 2003-01-07 Unimed Pharmaceuticals, Inc. Pharmaceutical composition and method for treating hypogonadism
CA2422580C (en) * 2000-09-18 2011-05-17 Rpg Life Sciences Limited Selfemulsifiable formulation having enhanced bioabsorption and immunosuppression activities
ATE270544T1 (en) * 2000-09-22 2004-07-15 Galephar M F SEMI-SOLID MEDICINAL PREPARATION CONTAINING ISOTRETINOIN
WO2002058689A1 (en) * 2000-12-05 2002-08-01 Childrens Hospital Los Angeles Pharmaceutical compositions of fenretinide having increased bioavailability and methods of using the same
US20020119237A1 (en) * 2000-12-22 2002-08-29 Hevey Maurice O. Medium and method for delivery of edible materials subject to degradation by oxidation and hydrolysis
FR2818905A1 (en) * 2000-12-28 2002-07-05 Cll Pharma MICELLAR COLLOIDAL PHARMACEUTICAL COMPOSITIONS COMPRISING A LIPOPHILIC ACTIVE INGREDIENT
GB0105772D0 (en) * 2001-03-08 2001-04-25 Sterix Ltd Use
DK1560584T3 (en) * 2001-04-06 2009-05-18 Affinium Pharm Inc Fab I inhibitors
SI1385498T1 (en) * 2001-04-18 2008-04-30 Prometic Biosciences Inc Fatty acids as neutrophil survival and activation factors.
EP1392272B1 (en) * 2001-05-11 2014-08-06 Merrion Research III Limited Permeation enhancers
AUPR510001A0 (en) * 2001-05-18 2001-06-14 Jupitar Pty Ltd Formulation and method
US20080058424A1 (en) * 2002-05-23 2008-03-06 Cephalon, Inc. Novel pharmaceutical formulations of modafinil
ATE357228T1 (en) * 2001-05-25 2007-04-15 Cephalon Inc SOLID PHARMACEUTICAL FORMULATION CONTAINING MODAFINIL
GB0114532D0 (en) * 2001-06-14 2001-08-08 Jagotec Ag Novel compositions
AR034813A1 (en) * 2001-07-20 2004-03-17 Novartis Ag PHARMACEUTICAL COMPOSITIONS AND USE OF THE SAME
GB0118300D0 (en) * 2001-07-26 2001-09-19 Cortendo Ab Formulations
CN1335182A (en) * 2001-08-08 2002-02-13 华中科技大学 Insulin spray for oral cavity and its prepn process
US7338971B2 (en) * 2001-08-30 2008-03-04 El-Naggar Mawaheb M Treatment of inflammatory, cancer, and thrombosis disorders
ATE322256T1 (en) * 2001-09-04 2006-04-15 Loders Croklaan Bv COMPOSITION CONTAINING A SUBSTITUTED FATTY ACID OR A SUBSTITUTED FATTY ACID DERIVATIVE
SE0102993D0 (en) 2001-09-07 2001-09-07 Astrazeneca Ab New self emulsifying drug delivery system
US20040234602A1 (en) * 2001-09-21 2004-11-25 Gina Fischer Polymer release system
EP1429744A1 (en) 2001-09-21 2004-06-23 Egalet A/S Morphine polymer release system
US20030059489A1 (en) * 2001-09-24 2003-03-27 Canolio Inc. Genital lubricating compositions and uses thereof
WO2003039583A1 (en) * 2001-11-08 2003-05-15 The Brigham And Women's Hospital, Inc. Lipoprotein lipase and lipoprotein lipase activators in the treatment of inflammatory conditions
EP1461044A4 (en) * 2001-12-03 2007-06-13 Novacea Inc Pharmaceutical compositions comprising active vitamin d compounds
ITBS20010111A1 (en) * 2001-12-20 2003-06-20 Paoli Ambrosi Gianfranco De COMPOSITION FOR TOPICAL USE BASED ON THE ETHYL ESTER OF LINOLEIC ACID AND OF THE TRIETYL ESTER OF CITRIC ACID ASSOCIATED WITH OPPORTUN
US7011846B2 (en) * 2001-12-21 2006-03-14 Shire Laboratories, Inc. Oral capsule formulation with increased physical stability
US20030228395A1 (en) * 2002-01-31 2003-12-11 Archer-Daniels Midland Company Isotropic transparent structured fluids
JP2005519075A (en) * 2002-02-25 2005-06-30 リフジャスロウン エイチエフ Absorption enhancer
US6623780B1 (en) * 2002-03-26 2003-09-23 Cargill, Inc. Aqueous dispersible sterol product
FR2837670A1 (en) * 2002-03-26 2003-10-03 Longechaud Veronique Fernandez Soft gelatin capsules filled with rice bran oil, useful for nutritional, cosmetic and therapeutic applications
CA2481384A1 (en) * 2002-04-10 2003-10-23 Cargill, Incorporated Aqueous dispersible steryl ester compositions
US6869939B2 (en) 2002-05-04 2005-03-22 Cydex, Inc. Formulations containing amiodarone and sulfoalkyl ether cyclodextrin
US7229644B2 (en) * 2002-05-23 2007-06-12 Cephalon, Inc. Pharmaceutical formulations of modafinil
US20040033257A1 (en) * 2002-05-30 2004-02-19 Strides Inc. Pharmaceutical formulation in a drug delivery system and process for preparing the same
KR20030095600A (en) * 2002-06-12 2003-12-24 환인제약 주식회사 Controlled release composition comprising felodipine, and method of the preparing thereof
DE10226990A1 (en) * 2002-06-18 2004-03-18 Sanguibiotech Ag Topically applicable micro-emulsions with binary phase and active substance differentiation, their production and their use, in particular for supplying the skin with bioavailable oxygen
US20040005339A1 (en) * 2002-06-28 2004-01-08 Shojaei Amir H. Formulations of fenofibrate and/or fenofibrate derivatives with improved oral bioavailability
US6855332B2 (en) * 2002-07-03 2005-02-15 Lyfjathroun Hf. Absorption promoting agent
US20040116532A1 (en) 2002-09-13 2004-06-17 Craig Heacock Pharmaceutical formulations of modafinil
ES2594758T3 (en) * 2002-10-23 2016-12-22 Glaxosmithkline Biologicals S.A. Vaccination procedures against malaria
US7544674B2 (en) 2002-10-25 2009-06-09 Galderma S.A. Topical skin care composition
US20050101576A1 (en) * 2003-11-06 2005-05-12 Novacea, Inc. Methods of using vitamin D compounds in the treatment of myelodysplastic syndromes
US7374772B2 (en) * 2002-11-07 2008-05-20 Bommarito Alexander A Topical antifungal treatment
US20050026877A1 (en) * 2002-12-03 2005-02-03 Novacea, Inc. Pharmaceutical compositions comprising active vitamin D compounds
TW200409644A (en) * 2002-12-04 2004-06-16 Bio Max Inc Improved carrier system for cyclosporin pharmaceutical compositions
WO2004052890A1 (en) * 2002-12-06 2004-06-24 Affinium Pharmaceuticals, Inc. Heterocyclic compounds, methods of making them and their use in therapy
US7385004B2 (en) * 2002-12-10 2008-06-10 Cellresin Technologies, Llc Enhanced lubrication in polyolefin closure with polyolefin grafted cyclodextrin
US7166671B2 (en) 2002-12-10 2007-01-23 Cellresin Technologies, Llc Grafted cyclodextrin
US8129450B2 (en) 2002-12-10 2012-03-06 Cellresin Technologies, Llc Articles having a polymer grafted cyclodextrin
US6635654B1 (en) 2003-01-09 2003-10-21 Allergan, Inc. Ophthalmic compositions containing loratadine
GEP20084540B (en) 2003-01-14 2008-11-25 Arena Pharm Inc 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prpphylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
JP5390070B2 (en) * 2003-02-07 2014-01-15 プロメティック、バイオサイエンシーズ、インコーポレーテッド Medium chain fatty acids, glycerides, and analogs as erythropoiesis stimulants
TWI323660B (en) 2003-02-25 2010-04-21 Otsuka Pharma Co Ltd Pten inhibitor or maxi-k channels opener
US7323206B1 (en) 2003-03-04 2008-01-29 B. Braun Medical Inc. Reagents and methods for all-in-one total parenteral nutrition for neonates and infants
FR2851918B1 (en) * 2003-03-06 2006-06-16 IMPREGNATED POWDER ENHANCING BIOAVAILABILITY AND / OR SOLUBILITY AND METHOD OF MANUFACTURE
EP1608377B1 (en) 2003-03-17 2008-10-01 Affinium Pharmaceuticals, Inc. Pharmaceutical compositions comprising inhibitors of fab i and further antibiotics
TWI338132B (en) * 2003-03-25 2011-03-01 Toppan Printing Co Ltd Analytic method for plating liquid for eletrolyzing copper and method for manufacturing a semiconductor product
DE602004031096D1 (en) 2003-03-26 2011-03-03 Egalet As MORPHINE SYSTEM WITH CONTROLLED RELEASE
US8298581B2 (en) * 2003-03-26 2012-10-30 Egalet A/S Matrix compositions for controlled delivery of drug substances
EP1608347B1 (en) * 2003-03-28 2014-08-13 Sigmoid Pharma Limited Solid oral dosage form containing seamless microcapsules
US20060189586A1 (en) * 2003-06-11 2006-08-24 Cleland Jeffrey L Pharmaceutical compositions comprising active vitamin D compounds
US20050020546A1 (en) * 2003-06-11 2005-01-27 Novacea, Inc. Pharmaceutical compositions comprising active vitamin D compounds
ZA200510025B (en) * 2003-06-11 2007-03-28 Novacea Inc Pharmaceutical compositions comprising active vitamin D compounds
EP1488785A1 (en) * 2003-06-18 2004-12-22 B. Braun Melsungen Ag Oil emulsion for postnatal substitution of hormones
CA2532971A1 (en) 2003-07-14 2005-01-27 Arena Pharmaceuticals, Inc. Fused-aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
US7169401B2 (en) * 2003-07-18 2007-01-30 Hill Dermaceuticals, Inc. Topical skin care composition containing refined peanut oil
US20070140999A1 (en) * 2003-07-18 2007-06-21 Hill Dermaceuticals, Inc. Topical skin care composition containing refined peanut oil
EP1651192A1 (en) * 2003-08-06 2006-05-03 Nirmal Mulye Pharmaceutical composition containing water soluble drug
JP3881640B2 (en) * 2003-08-08 2007-02-14 塩野義製薬株式会社 Dry syrup containing loratadine
JP2007502296A (en) * 2003-08-11 2007-02-08 アドバンシス ファーマスーティカル コーポレイション Robust pellet
US20080089877A1 (en) * 2003-08-14 2008-04-17 Udell Ronald G Super Absorption Coenzyme Q10
US20050187278A1 (en) * 2003-08-28 2005-08-25 Pharmacia Corporation Treatment or prevention of vascular disorders with Cox-2 inhibitors in combination with cyclic AMP-specific phosphodiesterase inhibitors
US8025899B2 (en) 2003-08-28 2011-09-27 Abbott Laboratories Solid pharmaceutical dosage form
US20050059583A1 (en) 2003-09-15 2005-03-17 Allergan, Inc. Methods of providing therapeutic effects using cyclosporin components
US20050058702A1 (en) * 2003-09-17 2005-03-17 Ben-Sasson Shmuel A. Compositions capable of facilitating penetration across a biological barrier
US7585517B2 (en) * 2003-09-18 2009-09-08 Macusight, Inc. Transscleral delivery
JP2007505927A (en) * 2003-09-19 2007-03-15 ドラッグテック コーポレイション Drug delivery system
US20060140990A1 (en) * 2003-09-19 2006-06-29 Drugtech Corporation Composition for topical treatment of mixed vaginal infections
US8124072B2 (en) 2003-09-29 2012-02-28 Soft Gel Technologies, Inc. Solubilized CoQ-10
US8105583B2 (en) 2003-09-29 2012-01-31 Soft Gel Technologies, Inc. Solubilized CoQ-10
US7387788B1 (en) 2003-10-10 2008-06-17 Antares Pharma Ipl Ag Pharmaceutical compositions of nicotine and methods of use thereof
MXPA06003316A (en) * 2003-10-10 2006-06-08 Antares Pharma Ipl Ag Transdermal pharmaceutical formulation for minimizing skin residues.
KR20060097020A (en) * 2003-10-31 2006-09-13 테바 파마슈티컬 인더스트리즈 리미티드 Nanoparticles for drug delivery
US20050096365A1 (en) * 2003-11-03 2005-05-05 David Fikstad Pharmaceutical compositions with synchronized solubilizer release
PE20050596A1 (en) * 2003-12-19 2005-10-18 Novartis Ag MICROEMULSION INCLUDING A RENIN INHIBITOR
US20070020298A1 (en) * 2003-12-31 2007-01-25 Pipkin James D Inhalant formulation containing sulfoalkyl ether gamma-cyclodextrin and corticosteroid
US20070020299A1 (en) * 2003-12-31 2007-01-25 Pipkin James D Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid
CA2552611A1 (en) * 2004-01-09 2005-08-04 Wyeth Microemulsions for pharmaceutical compositions
US20050171177A1 (en) * 2004-01-30 2005-08-04 Thompson Daniel J. Method of treatment of Candida isolates
KR101166394B1 (en) * 2004-02-06 2012-07-23 추가이 세이야쿠 가부시키가이샤 Ed-71 preparation
US20080241082A1 (en) * 2004-04-05 2008-10-02 Lonza Inc. Method for the Preparation of Cosmetic Emulsion
WO2005117911A2 (en) * 2004-05-06 2005-12-15 Cydex, Inc. Taste-masked formulations containing sertraline and sulfoalkyl ether cyclodextrin
US7425340B2 (en) * 2004-05-07 2008-09-16 Antares Pharma Ipl Ag Permeation enhancing compositions for anticholinergic agents
US8075910B2 (en) 2004-05-20 2011-12-13 Pbm Pharmaceuticals, Inc. Oral compositions comprising edible oils and vitamins and/or minerals and methods for making oral compositions
CN101691430B (en) * 2004-05-24 2012-10-10 细胞树脂技术有限责任公司 Amphoteric grafted barrier materials
DK1828167T3 (en) 2004-06-04 2014-10-20 Debiopharm Int Sa Acrylamide derivatives as antibiotic agents
BRPI0418885A (en) * 2004-06-07 2007-11-27 Strides Arcolab Ltd pharmaceutical composition containing a stable and clear solution of soft gelatin capsule anti-inflammatory drug and process for producing it
EP3326617A1 (en) 2004-06-12 2018-05-30 Collegium Pharmaceutical, Inc. Abuse-deterrent drug formulations
US20060051462A1 (en) * 2004-09-03 2006-03-09 Wang Jimmy X Self emulsifying compositions for delivering lipophilic coenzyme Q10 and other dietary ingredients
TWI365075B (en) * 2004-09-22 2012-06-01 Kao Corp Microemulsion
CA2581775A1 (en) * 2004-09-27 2006-04-06 Sigmoid Biotechnologies Limited Dihydropyrimidine microcapsule - formulations
JP4147235B2 (en) * 2004-09-27 2008-09-10 キヤノン株式会社 Discharge liquid, discharge method, droplet forming method, liquid discharge cartridge, and discharge apparatus
US8026281B2 (en) * 2004-10-14 2011-09-27 Lupin Atlantis Holdings, S.A. Treating metabolic syndrome with fenofibrate
KR101356335B1 (en) * 2004-12-06 2014-02-06 릴라이언트 파마슈티컬스 인코퍼레이티드 Omega-3 fatty acids and dyslipidemic agent for lipid therapy
WO2006062933A2 (en) * 2004-12-06 2006-06-15 Reliant Pharmaceuticals, Inc. Stable compositions of fenofibrate with fatty acid esters
KR20070118069A (en) * 2004-12-09 2007-12-13 인시스 테라퓨틱스, 인코포레이티드 Room-temperature stable dronabinol formulations
MY148521A (en) * 2005-01-10 2013-04-30 Arena Pharm Inc Substituted pyridinyl and pyrimidinyl derivatives as modulators of metabolism and the treatment of disorders related thereto
US8663639B2 (en) 2005-02-09 2014-03-04 Santen Pharmaceutical Co., Ltd. Formulations for treating ocular diseases and conditions
WO2006086750A1 (en) 2005-02-09 2006-08-17 Macusight, Inc. Liquid formulations for treatment of diseases or conditions
MX2007011031A (en) * 2005-03-08 2008-04-21 Reliant Pharmaceuticals Inc Treatment with statin and omega-3 fatty acids and a combination product thereof.
WO2006097938A1 (en) * 2005-03-16 2006-09-21 Strides Arcolab Limited Stable liquid suspension formulation comprising tibolone and process for producing the same
PL1885342T3 (en) * 2005-03-21 2016-10-31 Crystallization inhibitor and its use in gelatin capsules
CA2602525A1 (en) * 2005-03-21 2006-09-28 Macusight, Inc. Drug delivery systems for treatment of diseases or conditions
WO2006099877A1 (en) * 2005-03-24 2006-09-28 Atef Mohammed Mostafa Darwish Rectal and vaginal suppositories containing bioadhesive bromocriptine and poloxamer
US20060240051A1 (en) * 2005-04-26 2006-10-26 Singleton Andy H Eutectic blends containing a water soluble vitamin derivative
BRPI0608599A2 (en) * 2005-05-09 2010-01-19 Drugtech Corp Modified release pharmaceutical compositions
EP1893182B8 (en) * 2005-05-26 2012-04-04 Teva Women's Health, Inc. Oral dosage forms comprising progesterone and method of making and using the same
WO2006125642A1 (en) * 2005-05-27 2006-11-30 Antares Pharma Ipl Ag Methods and apparatus for transdermal or transmucosal application of testosterone
US7956031B2 (en) * 2005-05-31 2011-06-07 Naidu Lp Metallo-lactoferrin-coenzyme compositions for trigger and release of bioenergy
WO2006133045A1 (en) * 2005-06-03 2006-12-14 Elan Pharma International, Limited Nanoparticulate benidipine compositions
JP5161075B2 (en) * 2005-06-03 2013-03-13 エガレット エイ/エス Solid pharmaceutical composition having a first fraction of a dispersion medium and a second fraction of a matrix, wherein the second fraction is first at least partially exposed to gastrointestinal fluid
ATE415944T1 (en) * 2005-07-08 2008-12-15 Physica Pharma CLEAR PHARMACEUTICAL AQUEOUS MICROEMULSION WITH PROPOFOL AND PRODUCTION METHOD
KR100699582B1 (en) 2005-07-11 2007-03-23 삼성전기주식회사 Output buffer circuit
US7276476B2 (en) * 2005-07-13 2007-10-02 Allergan, Inc. Cyclosporin compositions
US20070015691A1 (en) * 2005-07-13 2007-01-18 Allergan, Inc. Cyclosporin compositions
US7202209B2 (en) * 2005-07-13 2007-04-10 Allergan, Inc. Cyclosporin compositions
US20070015693A1 (en) * 2005-07-13 2007-01-18 Allergan, Inc. Cyclosporin compositions
US7288520B2 (en) 2005-07-13 2007-10-30 Allergan, Inc. Cyclosporin compositions
US7297679B2 (en) 2005-07-13 2007-11-20 Allergan, Inc. Cyclosporin compositions
US8288348B2 (en) * 2005-07-13 2012-10-16 Allergan, Inc. Cyclosporin compositions
US7501393B2 (en) * 2005-07-27 2009-03-10 Allergan, Inc. Pharmaceutical compositions comprising cyclosporins
US20070082046A1 (en) * 2005-10-11 2007-04-12 Banner Pharmacaps, Inc. Enteric valproic acid
DK2450041T3 (en) 2005-10-12 2018-11-19 Unimed Pharmaceuticals Llc Enhanced testosterone gel for use in the treatment of hypogonadism
US9839667B2 (en) 2005-10-14 2017-12-12 Allergan, Inc. Prevention and treatment of ocular side effects with a cyclosporin
US7745400B2 (en) * 2005-10-14 2010-06-29 Gregg Feinerman Prevention and treatment of ocular side effects with a cyclosporin
US20090156578A1 (en) * 2005-12-05 2009-06-18 PAULS Henry 3-Heterocyclylacrylamide Compounds as Fab I Inhibitors and Antibacterial Agents
PT1957040E (en) * 2005-12-06 2015-01-14 Zoetis W Llc Benzimidazole non-aqueous compositions
JP2009522362A (en) * 2006-01-05 2009-06-11 ドラッグテック コーポレイション Drug delivery system
KR20080091793A (en) * 2006-01-05 2008-10-14 드러그테크 코포레이션 Composition and method of use thereof
CA2635797C (en) 2006-02-09 2015-03-31 Macusight, Inc. Stable formulations, and methods of their preparation and use
KR101520408B1 (en) 2006-03-23 2015-05-14 산텐 세이야꾸 가부시키가이샤 Formulations and methods for vascular permeability-related diseases or conditions
CA2646667C (en) * 2006-04-21 2014-03-11 Antares Pharma Ipl Ag Methods of treating hot flashes with formulations for transdermal or transmucosal application
US8021659B2 (en) 2006-04-28 2011-09-20 Naidu Lp Coenzyme Q10, lactoferrin and angiogenin compositions and uses thereof
JP5468899B2 (en) * 2006-07-20 2014-04-09 アフィニウム ファーマシューティカルズ, インク. Acrylamide derivatives as FABI inhibitors
SG10201503411QA (en) 2006-08-03 2015-06-29 Nitec Pharma Ag Delayed-release glucocorticoid treatment of rheumatoid disease
BRPI0715328A2 (en) * 2006-08-04 2013-07-09 Insys Therapeutics Inc formulation and unit dose or multiple dose device for sublingual administration of a drug
US20080098900A1 (en) * 2006-11-01 2008-05-01 Babatunde Aremu Beverage manufacture using a static mixer
GB0623838D0 (en) * 2006-11-29 2007-01-10 Malvern Cosmeceutics Ltd Novel compositions
US20080311093A1 (en) * 2006-12-07 2008-12-18 American Symbolic, Llc Stem cell secretions and related methods
WO2008067991A2 (en) * 2006-12-08 2008-06-12 Antares Pharma Ipl Ag Skin-friendly drug complexes for transdermal administration
WO2008086804A2 (en) * 2007-01-16 2008-07-24 Egalet A/S Use of i) a polyglycol and n) an active drug substance for the preparation of a pharmaceutical composition for i) mitigating the risk of alcohol induced dose dumping and/or ii) reducing the risk of drug abuse
US8263613B2 (en) * 2007-02-16 2012-09-11 Affinium Pharmaceuticals, Inc. Salts, prodrugs and polymorphs of fab I inhibitors
US8343541B2 (en) 2007-03-15 2013-01-01 Soft Gel Technologies, Inc. Ubiquinol and alpha lipoic acid compositions
WO2008122967A2 (en) 2007-04-04 2008-10-16 Sigmoid Pharma Limited An oral pharmaceutical composition
JP2010527285A (en) 2007-04-26 2010-08-12 シグモイド・ファーマ・リミテッド Production of multiple mini capsules
US20100239665A1 (en) * 2007-05-01 2010-09-23 Ivan Coulter Pharmaceutical nimodipine compositions
US8309129B2 (en) 2007-05-03 2012-11-13 Bend Research, Inc. Nanoparticles comprising a drug, ethylcellulose, and a bile salt
US8703204B2 (en) 2007-05-03 2014-04-22 Bend Research, Inc. Nanoparticles comprising a cholesteryl ester transfer protein inhibitor and anon-ionizable polymer
PT2157973E (en) * 2007-05-22 2015-10-14 Otsuka Pharma Co Ltd A medicament comprising a carbostyril derivative and donepezil for treating alzheimer's disease
MX2009012834A (en) 2007-05-29 2010-05-17 Intrexon Corp Chiral diachylhydrazine ligands for modulating the expression of exogenous genes via an ecdysone receptor complex.
WO2008145183A1 (en) * 2007-05-30 2008-12-04 Nestec S.A. Oil-in-water emulsion and its use for the delayed release of active elements
US9545384B2 (en) 2007-06-04 2017-01-17 Bend Research, Inc. Nanoparticles comprising drug, a non-ionizable cellulosic polymer and tocopheryl polyethylene glocol succinate
EP2155167A2 (en) 2007-06-04 2010-02-24 Egalet A/S Controlled release pharmaceutical compositions for prolonged effect
EP2162120B1 (en) 2007-06-04 2016-05-04 Bend Research, Inc Nanoparticles comprising a non-ionizable cellulosic polymer and an amphiphilic non-ionizable block copolymer
ES2493641T3 (en) * 2007-06-28 2014-09-12 Cydex Pharmaceuticals, Inc. Nasal administration of aqueous corticosteroid solutions
WO2009036368A2 (en) 2007-09-14 2009-03-19 Nitto Denko Corporation Drug carriers
WO2009042114A2 (en) 2007-09-21 2009-04-02 The Johns Hopkins University Phenazine derivatives and uses thereof
CN101827613A (en) 2007-09-27 2010-09-08 免疫疫苗技术有限公司 Use of liposomes in a carrier comprising a continuous hydrophobic phase for delivery of polynucleotides in vivo
WO2009045370A2 (en) 2007-09-28 2009-04-09 Intrexon Corporation Therapeutic gene-switch constructs and bioreactors for the expression of biotherapeutic molecules, and uses thereof
US20100209452A1 (en) * 2007-10-03 2010-08-19 Immunovaccine Technologies, Inc Compositions comprising an antigen, an amphipathic compound and a hydrophobic carrier, and uses thereof
CA2701482C (en) * 2007-10-08 2018-10-23 Lux Biosciences, Inc. Ophthalmic compositions comprising calcineurin inhibitors or mtor inhibitors
BRPI0705564B8 (en) * 2007-10-10 2021-05-25 Embrapa Pesquisa Agropecuaria continuous liquid crystal type system containing co-solvents carrying sparingly soluble substances in water, its process of obtaining and its uses
DK2205244T3 (en) * 2007-11-08 2013-11-25 Ambit Biosciences Corp METHODS FOR ADMINISTRATING N- (5-TERT-BUTYL-ISOXAZOL-3-YL) -N '- {4- [7- (2-MORPHOLIN-4-YL-ETHOXY-) IMIDAZO- [2,1-B] - [1,3] -BENZOTHIAZOL-2-YL] -PHENYL} URINE FOR TREATMENT OF PROLIFERATIVE DISEASE
US20090130063A1 (en) * 2007-11-15 2009-05-21 Solvay Pharmaceuticals Gmbh Process for separating and determining the viral load in a pancreatin sample
WO2009066299A2 (en) * 2007-11-23 2009-05-28 Rappaport Family Institute For Research Use of haptoglobin genotyping in diagnosis and treatment of cardiovascular disease
EP2231169B1 (en) 2007-12-06 2016-05-04 Bend Research, Inc. Pharmaceutical compositions comprising nanoparticles and a resuspending material
US9233078B2 (en) 2007-12-06 2016-01-12 Bend Research, Inc. Nanoparticles comprising a non-ionizable polymer and an Amine-functionalized methacrylate copolymer
EP2268274B1 (en) 2008-03-20 2012-05-16 Virun, Inc. Vitamin e derivatives and their uses
DK2268160T3 (en) 2008-03-20 2013-01-07 Virun Inc Emulsions comprising a PEG derivative of tocopherol
US8068218B2 (en) 2008-04-13 2011-11-29 Agilent Technologies, Inc. Water in oil measurement using stabilizer
SG157299A1 (en) 2008-05-09 2009-12-29 Agency Science Tech & Res Diagnosis and treatment of kawasaki disease
WO2009146523A1 (en) 2008-06-05 2009-12-10 Immunovaccine Technologies Inc. Compositions comprising liposomes, an antigen, a polynucleotide and a carrier comprising a continuous phase of a hydrophobic substance
US8173621B2 (en) 2008-06-11 2012-05-08 Gilead Pharmasset Llc Nucleoside cyclicphosphates
US8337931B2 (en) * 2008-06-23 2012-12-25 Virun, Inc. Compositions containing non-polar compounds
US20100041622A1 (en) * 2008-08-13 2010-02-18 Bromley Philip J Compositions containing aminoalkanes and aminoalkane derivatives
BRPI0919293A2 (en) * 2008-10-08 2020-12-01 Wyeth Llc anthelmintic benzimidazole compositions.
US10400118B2 (en) 2008-10-20 2019-09-03 Plastipak Packaging, Inc. Methods and compositions for direct print having improved recyclability
NZ593648A (en) 2008-12-23 2013-09-27 Gilead Pharmasset Llc Nucleoside phosphoramidates
PA8855701A1 (en) 2008-12-23 2010-07-27 NUCLEOSID ANALOGS
AU2009329872B2 (en) 2008-12-23 2016-07-07 Gilead Pharmasset Llc Synthesis of purine nucleosides
US9480691B1 (en) 2009-01-20 2016-11-01 Hill Dermaceuticals, Inc. Topical liquid containing refined peanut oil for treating skin proliferation or inflammation disorders
AU2010207740B2 (en) * 2009-01-26 2016-06-16 Nitec Pharma Ag Delayed-release glucocorticoid treatment of asthma
NZ582836A (en) * 2009-01-30 2011-06-30 Nitec Pharma Ag Delayed-release glucocorticoid treatment of rheumatoid arthritis by improving signs and symptoms, showing major or complete clinical response and by preventing from joint damage
WO2010089132A1 (en) 2009-02-06 2010-08-12 Egalet A/S Immediate release composition resistant to abuse by intake of alcohol
US20100297194A1 (en) * 2009-04-30 2010-11-25 Nathaniel Catron Formulation for oral administration of apoptosis promoter
US20100278921A1 (en) * 2009-04-30 2010-11-04 Fischer Cristina M Solid oral formulation of abt-263
US8362013B2 (en) * 2009-04-30 2013-01-29 Abbvie Inc. Salt of ABT-263 and solid-state forms thereof
US20100280031A1 (en) * 2009-04-30 2010-11-04 Paul David Lipid formulation of apoptosis promoter
US8728516B2 (en) * 2009-04-30 2014-05-20 Abbvie Inc. Stabilized lipid formulation of apoptosis promoter
JP5640079B2 (en) 2009-05-18 2014-12-10 シグモイド・ファーマ・リミテッドSigmoid Pharma Limited Oil droplet-containing composition
TWI598358B (en) 2009-05-20 2017-09-11 基利法瑪席特有限責任公司 Nucleoside phosphoramidates
TWI532484B (en) * 2009-06-08 2016-05-11 艾伯維有限公司 Solid dispersions containing an apoptosis-promoting agent
TWI540132B (en) * 2009-06-08 2016-07-01 亞培公司 Pharmaceutical dosage form for oral administration of a bcl-2 family inhibitor
MY154505A (en) * 2009-06-23 2015-06-30 Univ Putra Malaysia An emulsion system derives from engkabang fat esters
WO2010149169A2 (en) 2009-06-24 2010-12-29 Egalet A/S Controlled release formulations
US8735374B2 (en) * 2009-07-31 2014-05-27 Intelgenx Corp. Oral mucoadhesive dosage form
CN107582526A (en) 2009-08-12 2018-01-16 希格默伊德药业有限公司 Immune regulation composite comprising polymer substrate and oil phase
LT2501234T (en) * 2009-11-20 2017-12-11 Tonix Pharma Holdings Limited Methods and compositions for treating symptoms associated with post-traumatic stress disorder using cyclobenzaprine
US10610528B2 (en) 2009-12-08 2020-04-07 Intelgenx Corp. Solid oral film dosage forms and methods for making same
US20110136815A1 (en) * 2009-12-08 2011-06-09 Horst Zerbe Solid oral film dosage forms and methods for making same
US10668060B2 (en) 2009-12-10 2020-06-02 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opioids and other drugs
NZ599941A (en) * 2009-12-22 2014-06-27 Abbvie Inc Abt-263 capsule
CN102770121B (en) * 2009-12-22 2014-10-15 利奥制药有限公司 Pharmaceutical composition comprising solvent mixture and a vitamin D derivative or analogue
CN102781425B (en) 2009-12-22 2014-08-13 利奥制药有限公司 Cutaneous composition comprising vitamin d analogue and a mixture of solvent and surfactants
CA2822435C (en) 2009-12-31 2018-09-11 Differential Drug Development Associates, Llc Modulation of solubility, stability, absorption, metabolism, and pharmacokinetic profile of lipophilic drugs by sterols
US8603568B2 (en) 2010-01-15 2013-12-10 Kemin Industries, Inc. Hydrolyzed lecithin product to improve digestibility
EP4148045A1 (en) 2010-01-27 2023-03-15 Arena Pharmaceuticals, Inc. Intermediate compounds for the preparation of (r)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b] indol-3-yl)acetic acid and salts thereof
CN103037708B (en) 2010-03-23 2015-05-20 维尔恩公司 Nanoemulsion including sucrose fatty acid ester
EP2552933A1 (en) 2010-03-31 2013-02-06 Gilead Pharmasset LLC Purine nucleoside phosphoramidate
EP2552931B1 (en) 2010-03-31 2014-07-23 Gilead Pharmasset LLC Stereoselective synthesis of phosphorus containing actives
PL3290428T3 (en) 2010-03-31 2022-02-07 Gilead Pharmasset Llc Tablet comprising crystalline (s)-isopropyl 2-(((s)-(((2r,3r,4r,5r)-5-(2,4-dioxo-3,4-dihydropyrimidin-1 (2h)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate
EP2377556A1 (en) * 2010-04-14 2011-10-19 Cognis IP Management GmbH A compound
SG185389A1 (en) 2010-05-03 2012-12-28 Teikoku Pharma Usa Inc Non-aqueous taxane pro-emulsion formulations and methods of making and using the same
KR101205186B1 (en) 2010-06-04 2012-11-27 한불화장품주식회사 The cosmetic compositions with the improved permeation of hydrophilic active ingredients
WO2011162802A1 (en) 2010-06-21 2011-12-29 Virun, Inc. Compositions containing non-polar compounds
US20110319389A1 (en) 2010-06-24 2011-12-29 Tonix Pharmaceuticals, Inc. Methods and compositions for treating fatigue associated with disordered sleep using very low dose cyclobenzaprine
US8287904B2 (en) * 2010-08-19 2012-10-16 Lionel Borkan Stable soft capsule dosage form for acetylsalicylic acid
MY158809A (en) * 2010-09-22 2016-11-15 Craun Res Sdn Bhd Pharmaceutical compositions for calanolides, their derivatives and analogues, and process for producing the same
EP3323818A1 (en) 2010-09-22 2018-05-23 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
US8895537B2 (en) 2010-10-29 2014-11-25 Infirst Healthcare Ltd. Compositions and methods for treating cardiovascular diseases
UA113500C2 (en) 2010-10-29 2017-02-10 MEL EXTRUSION SOLID DISPERSIONS CONTAINING AN APOPTOSIS-INDUCING AGENT
US9504664B2 (en) 2010-10-29 2016-11-29 Infirst Healthcare Limited Compositions and methods for treating severe pain
US9308213B2 (en) 2010-10-29 2016-04-12 Infirst Healthcare Limited Solid solution compositions and use in chronic inflammation
US9744132B2 (en) 2010-10-29 2017-08-29 Infirst Healthcare Limited Solid solution compositions and use in chronic inflammation
US9271950B2 (en) 2010-10-29 2016-03-01 Infirst Healthcare Limited Compositions for treating chronic inflammation and inflammatory diseases
US10695431B2 (en) 2010-10-29 2020-06-30 Infirst Healthcare Limited Solid solution compositions and use in cardiovascular disease
US9737500B2 (en) 2010-10-29 2017-08-22 Infirst Healthcare Limited Compositions and methods for treating severe pain
US11730709B2 (en) 2010-10-29 2023-08-22 Infirst Healthcare Limited Compositions and methods for treating severe pain
US11202831B2 (en) 2010-10-29 2021-12-21 Infirst Healthcare Limited Solid solution compositions and use in cardiovascular disease
US11224659B2 (en) 2010-10-29 2022-01-18 Infirst Healthcare Limited Solid solution compositions and use in severe pain
US10695432B2 (en) 2010-10-29 2020-06-30 Infirst Healthcare Limited Solid solution compositions and use in severe pain
GB201020032D0 (en) * 2010-11-25 2011-01-12 Sigmoid Pharma Ltd Composition
WO2012075140A1 (en) 2010-11-30 2012-06-07 Pharmasset, Inc. Compounds
US20180153904A1 (en) 2010-11-30 2018-06-07 Lipocine Inc. High-strength testosterone undecanoate compositions
US20120232159A1 (en) 2011-03-07 2012-09-13 Tonix Pharmaceuticals, Inc. Methods and Compositions for Treating Depression using Cyclobenzaprine
US9610245B2 (en) * 2011-03-14 2017-04-04 Drug Delivery Solutions Limited Ophthalmic composition
DE102011108948A1 (en) 2011-07-29 2013-01-31 Achim Göpferich Aqueous, colloidal solutions of lipophilic substances, in particular drug solutions
MX350158B (en) 2011-09-08 2017-08-28 Intrexon Corp Crystalline diacylhydrazine and the use thereof.
CA2850857C (en) 2011-10-06 2022-07-26 Immunovaccine Technologies Inc. Liposome compositions comprising an adjuvant that activates or increases the activity of tlr2 and uses thereof
JP6174601B2 (en) * 2012-01-03 2017-08-02 オラムド エルティーディー. Methods and compositions for treating diabetes
US10342764B2 (en) 2012-02-01 2019-07-09 Oramed Ltd. Protease inhibitor-containing compositions, compositions comprising same, and methods for producing and using same
SG11201404640YA (en) 2012-02-10 2014-09-26 Virun Inc Beverage compositions containing non-polar compounds
WO2013182688A1 (en) 2012-06-08 2013-12-12 Leo Laboratories Limited A topical gel composition comprising an ingenol derivative and a solvent mixture
US9078925B2 (en) 2012-06-18 2015-07-14 Galephar Pharmaceutical Research, Inc. Pharmaceutical semi-solid composition of isotretinoin
SG11201408100YA (en) 2012-06-19 2015-01-29 Debiopharm Int Sa Prodrug derivatives of (e)-n-methyl-n-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide
GB201212010D0 (en) 2012-07-05 2012-08-22 Sigmoid Pharma Ltd Formulations
KR20150059167A (en) 2012-07-06 2015-05-29 에갈렛 리미티드 Abuse deterrent pharmaceutical compositions for controlled release
JP6260538B2 (en) * 2012-09-27 2018-01-17 大正製薬株式会社 Oral liquid composition
JO3685B1 (en) 2012-10-01 2020-08-27 Teikoku Pharma Usa Inc Non-aqueous taxane nanodispersion formulations and methods of using the same
MX360186B (en) 2012-12-20 2018-10-24 Solural Pharma ApS Solid oral dosage form of testosterone derivative.
CN104968330A (en) 2013-01-14 2015-10-07 因佛斯特医疗有限公司 Compositions and methods for treating severe pain
EP2950821A1 (en) 2013-02-04 2015-12-09 InFirst Healthcare Limited Compositions and methods for treating chronic inflammation and inflammatory diseases
GB201304662D0 (en) 2013-03-14 2013-05-01 Sigmoid Pharma Ltd Compositions
WO2014128564A2 (en) 2013-02-21 2014-08-28 Dr. Reddy's Laboratories Ltd. Pharmaceutical compositions of cetp inhibitors
TWI740136B (en) 2013-03-15 2021-09-21 愛爾蘭商托尼克製藥控股有限公司 Eutectic formulations of cyclobenzaprine hydrochloride and amitriptyline hydrochloride
CN105188670B (en) 2013-03-15 2018-11-02 马留斯医药有限责任公司 Emulsion formulations
US9351517B2 (en) 2013-03-15 2016-05-31 Virun, Inc. Formulations of water-soluble derivatives of vitamin E and compositions containing same
EP2983525B1 (en) 2013-03-15 2017-12-13 Virun, Inc. Compositions comprising water-soluble derivatives of vitamin e
US9693574B2 (en) 2013-08-08 2017-07-04 Virun, Inc. Compositions containing water-soluble derivatives of vitamin E mixtures and modified food starch
WO2015054448A1 (en) * 2013-10-11 2015-04-16 University Of Florida Research Foundation, Inc. Method of manufacturing stable emulsions and compositions containing the same
GB201319791D0 (en) 2013-11-08 2013-12-25 Sigmoid Pharma Ltd Formulations
JP6563922B2 (en) * 2013-11-14 2019-08-21 リピドール エービー Sprayable topical carrier and composition comprising phosphatidylcholine
HUE054467T2 (en) 2014-06-19 2021-09-28 Solural Pharma ApS Solid oral dosage form of lipophilic compounds
KR20170033442A (en) * 2014-08-09 2017-03-24 아반티 폴라 리피즈, 인코포레이티드 Oral composition for delivery of drugs and other substances
US9861611B2 (en) 2014-09-18 2018-01-09 Virun, Inc. Formulations of water-soluble derivatives of vitamin E and soft gel compositions, concentrates and powders containing same
US10016363B2 (en) 2014-09-18 2018-07-10 Virun, Inc. Pre-spray emulsions and powders containing non-polar compounds
EP3193854A4 (en) 2014-09-18 2018-05-02 Tonix Pharma Holdings Limited Eutectic formulations of cyclobenzaprine hydrochloride
JP6542519B2 (en) * 2014-09-29 2019-07-10 ロレアル Composition
WO2016066611A1 (en) * 2014-10-31 2016-05-06 Capsugel Belgium N.V. Pharmaceutical compositions containing cinacalcet and methods for their preparation and use
CA2966801A1 (en) 2014-11-07 2016-05-12 Sigmoid Pharma Limited Compositions comprising cyclosporin
AU2016205361C1 (en) 2015-01-06 2021-04-08 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US9649384B2 (en) * 2015-04-09 2017-05-16 Professional Compounding Centers Of America Natural solubilizer agent comprising a synergistic blend of heptyl glucoside and olive oil glycereth-8 esters for transdermal compositions
WO2016194942A1 (en) * 2015-06-05 2016-12-08 マルホ株式会社 External preparation for transdermal administration
EP3310760B8 (en) 2015-06-22 2022-10-19 Arena Pharmaceuticals, Inc. Crystalline l-arginine salt of (r)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid for use in s1p1 receptor-associated disorders
US10328087B2 (en) 2015-07-23 2019-06-25 Therapeuticsmd, Inc. Formulations for solubilizing hormones
US9872832B2 (en) * 2015-10-23 2018-01-23 LG Bionano, LLC Nanoemulsions having reversible continuous and dispersed phases
HUE052140T2 (en) 2016-02-26 2021-04-28 Debiopharm Int Sa Medicament for treatment of diabetic foot infections
WO2017173044A1 (en) 2016-04-01 2017-10-05 Therapeuticsmd Inc. Steroid hormone compositions in medium chain oils
AU2017239645A1 (en) 2016-04-01 2018-10-18 Therapeuticsmd, Inc. Steroid hormone pharmaceutical composition
WO2017168174A1 (en) 2016-04-02 2017-10-05 N4 Pharma Uk Limited New pharmaceutical forms of sildenafil
WO2017222575A1 (en) 2016-06-23 2017-12-28 Collegium Pharmaceutical, Inc. Process of making more stable abuse-deterrent oral formulations
WO2018002673A1 (en) 2016-07-01 2018-01-04 N4 Pharma Uk Limited Novel formulations of angiotensin ii receptor antagonists
JP7041067B2 (en) * 2016-10-19 2022-03-23 株式会社 資生堂 Detergent composition
AU2016247173B2 (en) * 2016-10-21 2023-02-16 LG Bionano, LLC Nanoemulsions having reversible continuous and dispersed phases
CN110022857A (en) 2016-11-18 2019-07-16 艾库里斯抗感染治疗有限公司 Based on the amidine of modified cyclodextrin and acidulant replace 'beta '-lactam compounds novel formulation, its preparation and as antimicrobial pharmceutical compositions purposes
MA47504A (en) 2017-02-16 2019-12-25 Arena Pharm Inc COMPOUNDS AND TREATMENT METHODS FOR PRIMITIVE BILIARY ANGIOCHOLITIS
WO2019014651A1 (en) 2017-07-13 2019-01-17 Tonix Pharmaceuticals Holding Corp. Analogs of cyclobenzaprine and amitryptilene
WO2019116091A1 (en) 2017-12-11 2019-06-20 Tonix Pharma Holdings Limited Cyclobenzaprine treatment for agitation, psychosis and cognitive decline in dementia and neurodegenerative conditions
CN111867567A (en) 2018-02-26 2020-10-30 R·P·舍勒科技有限责任公司 Pharmaceutical dosage form of an emulsion of dimethicone and loperamide
CA3095103A1 (en) 2018-04-27 2019-10-31 Johnson & Johnson Consumer Inc. Liquid oral pharmaceutical dosage form
US20220347122A1 (en) * 2019-03-15 2022-11-03 Ftf Pharma Private Limited Solutions for oral dosage
WO2020203733A1 (en) * 2019-03-29 2020-10-08 積水化学工業株式会社 Core-shell structure, preparation, medicine for external application, tape agent and cosmetic product
JP2022541874A (en) 2019-06-11 2022-09-28 サイファイ エス.ピー.エー. Microemulsion composition
US10590038B1 (en) 2019-07-01 2020-03-17 Maw-Tien Lee Producing cementitious materials with improved hydrophobicity and strength using reclaimed waste substances
US20210059278A1 (en) * 2019-09-04 2021-03-04 Pepsico, Inc. Process for preparing transparent emulsions
EP4025067A4 (en) * 2019-09-06 2023-09-13 Quicksilver Scientific, Inc. Microemulsion delivery systems for water-based beverages
WO2023209136A1 (en) 2022-04-29 2023-11-02 Sifi S.P.A. Microemulsion pharmaceutical composition for treatment of disorders of the anterior segment of the eye
CN115463070B (en) * 2022-06-27 2023-08-22 广东梵蜜琳生物科技有限公司 Hybrid flower extract and preparation method thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5817320A (en) * 1994-06-20 1998-10-06 The United States Of America As Represented By The Secretary Of The Agriculture In ovo immunization of avian embryos with oil-emulsion vaccines
US5948825A (en) * 1993-04-19 1999-09-07 Institute For Advanced Skin Research Inc. Microemulsion preparation containing a slightly absorbable substance

Family Cites Families (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3886294A (en) * 1973-03-12 1975-05-27 Hoffmann La Roche Carotenoid coloring compositions and preparation thereof
US4073943A (en) * 1974-09-11 1978-02-14 Apoteksvarucentralen Vitrum Ab Method of enhancing the administration of pharmalogically active agents
US4146499A (en) * 1976-09-18 1979-03-27 Rosano Henri L Method for preparing microemulsions
SE445174B (en) * 1978-03-07 1986-06-09 Sandoz Ag PHARMACEUTICAL COMPOSITION CONTAINING A CYCLOSPORIN AND A HEALING SUBSTANCE
US4731384A (en) * 1983-07-01 1988-03-15 Troponwerke Gmbh & Co, Kg Etofenamate formulation
DE3406497A1 (en) * 1984-02-23 1985-09-05 Mueller Bernhard Willi Werner HIGHLY DISPERSAL PHARMACEUTICAL MULTI-COMPONENT SYSTEMS AND METHOD FOR THEIR PRODUCTION
US4713246A (en) * 1984-03-19 1987-12-15 Bristol-Myers Company Etoposide oral dosage form
US4572915A (en) * 1984-05-01 1986-02-25 Bioglan Laboratories Clear micellized solutions of fat soluble essential nutrients
US5639724A (en) 1984-07-24 1997-06-17 Sandoz Ltd. Cyclosporin galenic forms
DE3500103A1 (en) * 1985-01-04 1986-07-10 R.P. Scherer GmbH, 6930 Eberbach PHARMACEUTICAL PREPARATION WITH AN INTENSIVE SOLUTION IN WATER AND DIGESTIVE JUICES
US5071643A (en) * 1986-10-17 1991-12-10 R. P. Scherer Corporation Solvent system enhancing the solubility of pharmaceuticals for encapsulation
GB8630273D0 (en) * 1986-12-18 1987-01-28 Til Medical Ltd Pharmaceutical delivery systems
JP2588413B2 (en) * 1987-12-14 1997-03-05 ライオン株式会社 Method for producing oil-in-water emulsion
US5244925A (en) * 1987-12-18 1993-09-14 Kabi Pharmacia Aktiebolag Emulsion for parenteral administration
US5350741A (en) 1988-07-30 1994-09-27 Kanji Takada Enteric formulations of physiologically active peptides and proteins
KR0148748B1 (en) * 1988-09-16 1998-08-17 장 크라메르, 한스 루돌프 하우스 A multiphase cyclosporin composition
US5342625A (en) * 1988-09-16 1994-08-30 Sandoz Ltd. Pharmaceutical compositions comprising cyclosporins
GB8822857D0 (en) 1988-09-29 1988-11-02 Patralan Ltd Pharmaceutical formulations
US4994439A (en) * 1989-01-19 1991-02-19 California Biotechnology Inc. Transmembrane formulations for drug administration
US5364632A (en) 1989-04-05 1994-11-15 Yissum Research Development Company Of The Hebrew University Of Jerusalem Medicinal emulsions
DE3919982A1 (en) * 1989-06-19 1990-12-20 Liedtke Pharmed Gmbh ORAL LIPID MEDICINE FORM
US5532002A (en) 1989-08-17 1996-07-02 Cortecs Limited Gelatin pharmaceutical formulations
JP3273785B2 (en) 1990-08-13 2002-04-15 ダブリュー. イェスエア,デービッド Mixed lipid-bicarbonate colloid particles for drug or heat source delivery
US5665379A (en) 1990-09-28 1997-09-09 Pharmacia & Upjohn Aktiebolag Lipid particle forming matrix, preparation and use thereof
US5145684A (en) * 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
US5300529A (en) * 1991-02-12 1994-04-05 Isp Investments Inc. Stable, clear, efficacious aqueous microemulsion compositions containing a high loading of a water-insoluble, agriculturally active chemical
CA2108266C (en) 1991-04-19 2003-06-03 Albert J. Owen Convertible microemulsion formulations
US5206219A (en) * 1991-11-25 1993-04-27 Applied Analytical Industries, Inc. Oral compositions of proteinaceous medicaments
SE9200951D0 (en) 1992-03-27 1992-03-27 Kabi Pharmacia Ab PHARMACEUTICAL COMPOSITION CONTAINING A DEFINED LIPID SYSTEM
IT1255449B (en) 1992-06-30 1995-10-31 Fabio Berlati USE OF NOR- AND HOMO-DERIVATIVES OF BILE ACIDS AS DRUGS ABSORPTION PROMOTERS.
US5376688A (en) 1992-12-18 1994-12-27 R. P. Scherer Corporation Enhanced solubility pharmaceutical solutions
US5686105A (en) 1993-10-19 1997-11-11 The Procter & Gamble Company Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery
US5639474A (en) 1993-07-01 1997-06-17 Hanmi Pharm. Ind., Ltd. Cyclosporin soft capsule composition
WO1995014037A1 (en) 1993-11-17 1995-05-26 Ibah, Inc. Transparent liquid for encapsulated drug delivery
DE4340781C3 (en) 1993-11-30 2000-01-27 Novartis Ag Liquid preparations containing cyclosporin and process for their preparation
GB9405041D0 (en) * 1994-03-15 1994-04-27 Smithkline Beecham Plc Novel process
GB9405304D0 (en) 1994-03-16 1994-04-27 Scherer Ltd R P Delivery systems for hydrophobic drugs
US5731355A (en) 1994-03-22 1998-03-24 Zeneca Limited Pharmaceutical compositions of propofol and edetate
US5616330A (en) 1994-07-19 1997-04-01 Hemagen/Pfc Stable oil-in-water emulsions incorporating a taxine (taxol) and method of making same
IL129547A (en) * 1994-10-26 2001-01-11 Novartis Ag Pharmaceutical compositions comprising a macrolide and an acid
KR0167613B1 (en) 1994-12-28 1999-01-15 한스 루돌프 하우스, 니콜 케르커 Cyclosporin-containing soft capsule compositions
JP2740153B2 (en) 1995-03-07 1998-04-15 エフ・ホフマン−ラ ロシユ アーゲー Mixed micelle
US5653987A (en) 1995-05-16 1997-08-05 Modi; Pankaj Liquid formulations for proteinic pharmaceuticals
US5726181A (en) 1995-06-05 1998-03-10 Bionumerik Pharmaceuticals, Inc. Formulations and compositions of poorly water soluble camptothecin derivatives
US5766629A (en) 1995-08-25 1998-06-16 Sangstat Medical Corporation Oral cyclosporin formulations
GB9519468D0 (en) * 1995-09-23 1995-11-22 Smithkline Beecham Plc Novel process
US5858401A (en) 1996-01-22 1999-01-12 Sidmak Laboratories, Inc. Pharmaceutical composition for cyclosporines
KR0183449B1 (en) * 1996-06-19 1999-05-01 한스 루돌프 하우스, 니콜 케르커 Cyclosporin-containing soft capsule preparations
US6063762A (en) * 1997-12-05 2000-05-16 Chong Kun Dang Corp. Cyclosporin-containing microemulsion preconcentrate composition
CA2313024C (en) * 1997-12-10 2008-06-03 Severson, Mary L. Pharmaceutical compositions containing an omega-3 fatty acid oil
DE19939756A1 (en) * 1999-08-21 2001-02-22 Merck Patent Gmbh New 1-(1-ethyl-piperidin-4-yl)-1-(phenyl or heterocyclyl)-alkanol derivatives, are 5-HT(2A) receptor antagonists useful e.g. for treating schizophrenia, depression, memory disorders or eating disorders

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5948825A (en) * 1993-04-19 1999-09-07 Institute For Advanced Skin Research Inc. Microemulsion preparation containing a slightly absorbable substance
US5817320A (en) * 1994-06-20 1998-10-06 The United States Of America As Represented By The Secretary Of The Agriculture In ovo immunization of avian embryos with oil-emulsion vaccines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1194120A4 *

Cited By (148)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001054675A3 (en) * 2000-01-27 2002-02-14 Novartis Ag Pharmaceutical compositions comprising terbinafine
WO2001054675A2 (en) * 2000-01-27 2001-08-02 Novartis Ag Pharmaceutical compositions comprising terbinafine
WO2001078724A1 (en) * 2000-04-18 2001-10-25 Pharmacia Corporation Rapid-onset formulation of a selective cyclooxigenase-2
WO2001091729A1 (en) * 2000-05-30 2001-12-06 Basf Aktiengesellschaft Formulation based on heparin, glycosaminoglycan or heparinoid, use of the formulation and the formulation base
US7393840B2 (en) 2000-05-30 2008-07-01 Basf Aktiengesellschaft Formulation based on heparin, glycosaminoglycan or heparinoid, use of the formulation and the formulation base
WO2001093834A1 (en) * 2000-06-08 2001-12-13 Laboratoires Crinex Pharmaceutical composition in liquid form for oral administration of an active principle, with unpleasant, in particular bitter, taste
FR2809958A1 (en) * 2000-06-08 2001-12-14 Crinex Lab Masking taste of oral administered water-soluble active agent, e.g. ranitidine salt, by dissolution in aqueous phase of water-in-oil type microemulsion
US6919370B2 (en) 2000-11-28 2005-07-19 Transform Pharmaceuticals, Inc. Pharmaceutical formulations comprising paclitaxel, derivatives, and pharmaceutically acceptable salts thereof
EP1363622A1 (en) * 2001-02-01 2003-11-26 Shire Laboratories Inc. Pharmaceutical compositions including sampatrilat dispersed in a lipoidic vehicle
EP1363622A4 (en) * 2001-02-01 2005-04-13 Shire Lab Inc Pharmaceutical compositions including sampatrilat dispersed in a lipoidic vehicle
EP1406855A2 (en) 2001-06-13 2004-04-14 Biogal Gyogyszergyar Rt. Novel process for preparing rac-bicalutamide and its intermediates
EP1452162A4 (en) * 2001-11-09 2010-01-06 Nisshin Oillio Group Ltd Gel-form composition
EP1452162A1 (en) * 2001-11-09 2004-09-01 The Nisshin Oil Mills, Ltd. Gel-form composition
WO2003045357A1 (en) * 2001-11-27 2003-06-05 Transform Pharmaceuticals, Inc. Oral pharmaceutical formulations comprising paclitaxel, derivatives and methods of administration thereof
US8568748B2 (en) * 2001-12-14 2013-10-29 Jagotec Ag Pharmaceutical formulation comprising cyclosporin and use thereof
EP1458359A4 (en) * 2001-12-27 2007-05-30 Cj Corp Microemulsion preconcentrate
EP1458359A1 (en) * 2001-12-27 2004-09-22 CJ Corporation Microemulsion preconcentrate
JP2011032287A (en) * 2002-03-12 2011-02-17 Galderma Research & Development Pharmaceutical composition comprising adapalene for treatment of dermatological disorder
WO2003097007A2 (en) * 2002-05-15 2003-11-27 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Aqueous ophthalmic composition comprising a lyotropic mesomorphic lipid
WO2003097007A3 (en) * 2002-05-15 2004-07-22 Acraf Aqueous ophthalmic composition comprising a lyotropic mesomorphic lipid
JP4493018B2 (en) * 2002-05-22 2010-06-30 日本製薬株式会社 Smooth muscle peristalsis inhibitor
JPWO2003097026A1 (en) * 2002-05-22 2005-09-15 日本製薬株式会社 Smooth muscle peristalsis inhibitor
JPWO2003097027A1 (en) * 2002-05-22 2005-10-06 日本製薬株式会社 L-menthol oil-in-water emulsion
WO2003106592A2 (en) * 2002-06-12 2003-12-24 IFAC GmbH & Co. KG Institut für Angewandte Colloidtechnologie Ether alcohols used as solvents and emulsifiers and dispersions containing said ether alcohols
WO2003106592A3 (en) * 2002-06-12 2004-06-10 Ifac Gmbh & Co Kg Inst Fuer An Ether alcohols used as solvents and emulsifiers and dispersions containing said ether alcohols
US7335389B2 (en) 2002-06-12 2008-02-26 The Coca-Cola Company Beverages containing plant sterols
US7306819B2 (en) 2002-06-12 2007-12-11 The Coca-Cola Company Beverages containing plant sterols
WO2004009076A1 (en) * 2002-07-20 2004-01-29 Korea Institute Of Science And Technology Paclitaxel composition for the intravesical treatment of bladder tumor and preparation method thereof
US8075917B2 (en) 2002-07-20 2011-12-13 Daehwa Pharm. Co., Ltd. Composition for solubilization of paclitaxel and preparation method thereof
WO2004009075A1 (en) * 2002-07-20 2004-01-29 Korea Institute Of Science And Technology Composition for solubilization of paclitaxel and preparation method thereof
WO2004052354A1 (en) * 2002-12-06 2004-06-24 Otsuka Pharmaceutical Factory, Inc. Propofol-containing fat emulsions
EP1633326A4 (en) * 2003-06-17 2012-01-18 Sk Holdings Co Ltd Transnasal microemulsions containing diazepam
EP1633326A1 (en) * 2003-06-17 2006-03-15 SK Corporation Transnasal microemulsions containing diazepam
WO2005014048A1 (en) * 2003-07-18 2005-02-17 Aventis Pharma S.A. Self-emulsifying and self-microemulsifying formulations for the oral administration of taxoids
EP1498143A1 (en) * 2003-07-18 2005-01-19 Aventis Pharma S.A. Self-emulsifying and self-microemulsifying formulations for the oral administration of taxoids
WO2005053727A3 (en) * 2003-11-29 2006-05-26 Sangstat Medical Corp Pharmaceutical compositions for bioactive peptide agents
WO2005053727A2 (en) * 2003-11-29 2005-06-16 Sangstat Medical Corporation Pharmaceutical compositions for bioactive peptide agents
US7498309B2 (en) 2003-11-29 2009-03-03 Sangstat Medical Corporation Pharmaceutical compositions for bioactive peptide agents
US8802087B2 (en) 2004-03-22 2014-08-12 Abbott Products Gmbh Pharmaceutical compositions of lipase-containing products, in particular of pancreation
US8241670B2 (en) * 2004-04-15 2012-08-14 Chiasma Inc. Compositions capable of facilitating penetration across a biological barrier
US7659310B2 (en) 2004-04-27 2010-02-09 Formatech, Inc. Methods of enhancing solubility of agents
US7687458B2 (en) 2004-04-27 2010-03-30 Formatech, Inc. Pharmaceutical compositions of hydrophobic compounds
US7345093B2 (en) 2004-04-27 2008-03-18 Formatech, Inc. Methods of enhancing solubility of compounds
JP4734909B2 (en) * 2004-12-09 2011-07-27 日油株式会社 Solubilizer composition for poorly water-soluble drugs
JP2006160696A (en) * 2004-12-09 2006-06-22 Nof Corp Solubilizer composition for sparingly water-soluble medicine
JP2006160695A (en) * 2004-12-09 2006-06-22 Nof Corp Solubilizer composition for sparingly water-soluble medicine
JP4734910B2 (en) * 2004-12-09 2011-07-27 日油株式会社 Solubilizer composition for poorly water-soluble drugs
US8530412B2 (en) 2005-03-30 2013-09-10 Canon Kabushiki Kaisha Ejection liquid, ejection method, method of making droplets from liquid, cartridge and ejection device
US8828428B1 (en) 2005-04-15 2014-09-09 Clarus Therapeutics, Inc. Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same
US11179402B2 (en) 2005-04-15 2021-11-23 Clarus Therapeutics, Inc. Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same
US8778916B2 (en) 2005-04-15 2014-07-15 Clarus Therapeutics, Inc. Oral testosterone ester formulations and methods of treating testosterone deficiency comprising same
US11331325B2 (en) 2005-04-15 2022-05-17 Clarus Therapeutics, Inc. Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same
US8778917B2 (en) 2005-04-15 2014-07-15 Clarus Therapeutics, Inc. Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same
US8815291B2 (en) 2005-06-17 2014-08-26 Austrailian Nuclear Science & Technology Organisation Particles comprising a releasable dopant therein
WO2006133519A1 (en) * 2005-06-17 2006-12-21 Australian Nuclear Science And Technology Organisation Particles comprising a releasable dopant therein
WO2006133518A1 (en) * 2005-06-17 2006-12-21 Australian Nuclear Science And Technology Organisation Particles having hydrophobic material therein
US9131681B2 (en) 2005-06-17 2015-09-15 Australian Nuclear Science & Technology Organisation Particles comprising a releasable dopant therein
US9345667B2 (en) 2005-06-17 2016-05-24 Australian Nuclear Science And Technology Organisation Particles having hydrophobic material therein
US9017643B2 (en) 2005-06-17 2015-04-28 Australian Nuclear Science & Technology Organisation Particles comprising a releasable dopant therein
US10704037B2 (en) 2005-07-29 2020-07-07 Abbott Products Gmbh Processes for the manufacture and use of pancreatin
US11266607B2 (en) 2005-08-15 2022-03-08 AbbVie Pharmaceuticals GmbH Process for the manufacture and use of pancreatin micropellet cores
US9198871B2 (en) 2005-08-15 2015-12-01 Abbott Products Gmbh Delayed release pancreatin compositions
US10072256B2 (en) 2006-05-22 2018-09-11 Abbott Products Gmbh Process for separating and determining the viral load in a pancreatin sample
EP1961412A1 (en) * 2006-12-27 2008-08-27 LEK Pharmaceuticals D.D. Self-microemulsifying drug delivery systems
US8592490B2 (en) 2006-12-27 2013-11-26 Lek Pharmaceuticals D.D. Self-microemulsifying drug delivery systems
WO2008077823A1 (en) * 2006-12-27 2008-07-03 Lek Pharmaceuticals D.D. Self-microemulsifying drug delivery systems
EP2514406A1 (en) * 2007-06-01 2012-10-24 Novo Nordisk A/S Spontaneously dispersible preconcentrates including a peptide drug in a solid or semisolid carrier
US8216799B2 (en) 2007-06-12 2012-07-10 Fujifilm Corporation Dry analytical element for lipase measurement
EP2003450A1 (en) * 2007-06-12 2008-12-17 Fujifilm Corporation Dry analytical element for lipase measurement
WO2009019604A3 (en) * 2007-08-09 2009-07-23 Ems Sa Delivery systems for solubilising water-insoluble pharmaceutical active ingredients
US9278065B2 (en) 2007-08-09 2016-03-08 Ems S/A Delivery systems for solubilising water-insoluble pharmaceutical active ingredients
WO2009019604A2 (en) * 2007-08-09 2009-02-12 Ems S/A Delivery systems for solubilising water-insoluble pharmaceutical active ingredients
GB2451811A (en) * 2007-08-09 2009-02-18 Ems Sa Delivery composition for solubilising water-insoluble pharmaceutical active ingredients
US10259856B2 (en) 2008-03-18 2019-04-16 Novo Nordisk A/S Protease stabilized acylated insulin analogues
US9688737B2 (en) 2008-03-18 2017-06-27 Novo Nordisk A/S Protease stabilized acylated insulin analogues
US8592406B2 (en) 2008-05-14 2013-11-26 Sk Biopharmaceuticals Co., Ltd. Transnasal anticonvulsive pharmaceutical composition comprising poorly soluble anticonvulsant
US9962392B2 (en) 2008-05-14 2018-05-08 Sk Biopharmaceuticals Co., Ltd. Transnasal anticonvulsive pharmaceutical composition comprising poorly soluble anticonvulsant
WO2010015400A3 (en) * 2008-08-07 2010-08-12 Gp Pharm, S.A. Injectable taxane pharmaceutical composition
ES2344674A1 (en) * 2008-08-07 2010-09-02 Gp Pharm, S.A. Injectable taxane pharmaceutical composition
US8329198B2 (en) 2008-09-17 2012-12-11 Chiasma Inc. Pharmaceutical compositions and related methods of delivery
US11400159B2 (en) 2008-09-17 2022-08-02 Amryt Endo, Inc. Pharmaceutical compositions and related methods of delivery
US9265812B2 (en) 2008-09-17 2016-02-23 Chiasma, Inc. Pharmaceutical compositions and related methods of delivery
US9566246B2 (en) 2008-09-17 2017-02-14 Chiasma Inc. Pharmaceutical compositions and related methods of delivery
US8535695B2 (en) 2008-09-17 2013-09-17 Chiasma Inc. Pharmaceutical compositions and related methods of delivery
US9468602B2 (en) 2009-01-05 2016-10-18 Azad Pharma Ag Pharmaceutical microemulsion for preventing supramolecular aggregation of amphiphilic molecules
WO2010076340A1 (en) 2009-01-05 2010-07-08 Azad Pharma Ag Pharmaceutical microemulsion for preventing supramolecular aggregation of amphiphilic molecules
EP2606877A1 (en) 2009-01-05 2013-06-26 Azad Pharma AG Pharmaceutical microemulsion for preventing supramolecular aggregation of amphiphilic molecules
EP2204167A1 (en) 2009-01-05 2010-07-07 Azad Pharma AG Pharmaceutical microemulsion for preventing supramolecular aggregation of amphiphilic molecules
US8865695B2 (en) 2009-01-08 2014-10-21 Lipocine Inc. Steroidal compositions
US11304960B2 (en) 2009-01-08 2022-04-19 Chandrashekar Giliyar Steroidal compositions
US11052096B2 (en) 2009-01-08 2021-07-06 Lipocine Inc. Steroidal compositions
US10130606B2 (en) 2009-09-15 2018-11-20 Novelion Therapeutics Inc. Pharmaceutical formulations comprising 9-cis-retinyl esters in a lipid vehicle
US10736865B2 (en) 2009-09-15 2020-08-11 Retinagenix Therapeutics, Inc. Pharmaceutical formulations comprising 9-cis-retinyl esters in a lipid vehicle
US9402812B2 (en) 2009-09-23 2016-08-02 Indu JAVERI Methods for the preparation of liposomes
US10143652B2 (en) 2009-09-23 2018-12-04 Curirx Inc. Methods for the preparation of liposomes
US9655846B2 (en) 2009-09-23 2017-05-23 Indu JAVERI Methods for the preparation of liposomes comprising drugs
US8591942B2 (en) 2009-09-23 2013-11-26 Indu JAVERI Methods for the preparation of liposomes comprising docetaxel
US11179403B2 (en) 2010-04-12 2021-11-23 Clarus Therapeutics, Inc. Oral testosterone ester formulations and methods of treating testosterone deficiency comprising same
US10543219B2 (en) 2010-04-12 2020-01-28 Clarus Therapeutics, Inc. Oral testosterone ester formulations and methods of treating testosterone deficiency comprising same
US10617696B2 (en) 2010-04-12 2020-04-14 Clarus Therapeutics, Inc. Oral testosterone ester formulations and methods of treating testosterone deficiency comprising same
US11426416B2 (en) 2010-04-12 2022-08-30 Clarus Therapeutics, Inc. Oral testosterone ester formulations and methods of treating testosterone deficiency comprising same
US8492369B2 (en) 2010-04-12 2013-07-23 Clarus Therapeutics Inc Oral testosterone ester formulations and methods of treating testosterone deficiency comprising same
US9173856B2 (en) 2010-04-19 2015-11-03 Qlt Inc. Therapeutic regimen and methods for treating or ameliorating visual disorders associated with an endogenous retinoid deficiency
US9987245B2 (en) 2010-04-19 2018-06-05 Novelion Therapeutics Inc. Therapeutic regimen and methods for treating or ameliorating visual disorders associated with an endogenous retinoid deficiency
US10973833B2 (en) 2010-11-30 2021-04-13 Lipocine Inc. High-strength testosterone undecanoate compositions
US9480690B2 (en) 2010-11-30 2016-11-01 Lipocine Inc. High-strength testosterone undecanoate compositions
US9949985B2 (en) 2010-11-30 2018-04-24 Lipocine Inc. High-strength testosterone undecanoate compositions
US9205057B2 (en) 2010-11-30 2015-12-08 Lipocine Inc. High-strength testosterone undecanoate compositions
US9757390B2 (en) 2010-11-30 2017-09-12 Lipocine Inc. High-strength testosterone undecanoate compositions
US9358241B2 (en) 2010-11-30 2016-06-07 Lipocine Inc. High-strength testosterone undecanoate compositions
US10716794B2 (en) 2010-11-30 2020-07-21 Lipocine Inc. High-strength testosterone undecanoate compositions
US10226473B2 (en) 2010-11-30 2019-03-12 Lipocine Inc. High-strength testosterone undecanoate compositions
US9034858B2 (en) 2010-11-30 2015-05-19 Lipocine Inc. High-strength testosterone undecanoate compositions
US9943527B2 (en) 2010-11-30 2018-04-17 Lipocine Inc. High-strength testosterone undecanoate compositions
US10799513B2 (en) 2010-11-30 2020-10-13 Lipocine Inc. High-strength testosterone undecanoate compositions
US10561615B2 (en) 2010-12-10 2020-02-18 Lipocine Inc. Testosterone undecanoate compositions
EP2540281A1 (en) 2011-06-30 2013-01-02 LEK Pharmaceuticals d.d. Solid self-microemulsifying systems
US10828267B2 (en) 2012-03-01 2020-11-10 Retinagenix Therapeutics, Inc. Therapeutic regimens and methods for improving visual function in visual disorders associated with an endogenous retinoid deficiency
US9481721B2 (en) 2012-04-11 2016-11-01 Novo Nordisk A/S Insulin formulations
RU2490016C1 (en) * 2012-06-13 2013-08-20 Федеральное государственное бюджетное учреждение "Научный центр неврологии" Российской академии медицинских наук (ФГБУ "НЦН" РАМН) Parenteral composition containing carbamazepine in form of submicron emulsion possessing anticonvulsant activity
EP3050894A4 (en) * 2013-09-25 2017-04-19 Sani-Red, S.L. Method for preserving and stabilising proteins, which can be used for industrial development of formulations of sanitary, pharmaceutical and cosmetic products
CN105209476A (en) * 2013-09-25 2015-12-30 萨尼雷德有限公司 Method for preserving and stabilizing proteins, which can be used for industrial development of formulations of sanitary, pharmaceutical and cosmetic products
EP4241783A1 (en) * 2013-09-25 2023-09-13 Sani-Red, S.L. Method for preserving and stabilising proteins, which can be used for industrial development of formulations of sanitary, pharmaceutical and cosmetic products
RU2642277C2 (en) * 2013-09-25 2018-01-24 САНИ-РЕД, С.Л., Испания Method for conserving and stabilizing proteins
EP2878311A1 (en) * 2013-11-27 2015-06-03 Freund Pharmatec Ltd. Solubility Enhancement for Hydrophobic Drugs
WO2015078936A1 (en) * 2013-11-27 2015-06-04 Freund Pharmatec Ltd. Solubility enhancement for hydrophobic drugs
US10531671B2 (en) 2014-01-20 2020-01-14 Xeda International S.A. Anti-sprouting compositions for coating bulbs and tubers and the use thereof for anti-sprouting treatment
EP3169659A4 (en) * 2014-07-16 2018-01-31 Eastman Chemical Company Enzyme-catalyzed polyoxyalkylene esters
WO2016022936A1 (en) * 2014-08-07 2016-02-11 Murty Pharmaceuticals, Inc. An improved oral gastrointestinal dosage form delivery system of cannabinoids and/or standardized marijuana extracts
US9498485B2 (en) 2014-08-28 2016-11-22 Lipocine Inc. Bioavailable solid state (17-β)-hydroxy-4-androsten-3-one esters
US9757389B2 (en) 2014-08-28 2017-09-12 Lipocine Inc. Bioavailable solid state (17-β)-hydroxy-4-androsten-3-one esters
US11872235B1 (en) 2014-08-28 2024-01-16 Lipocine Inc. Bioavailable solid state (17-β)-Hydroxy-4-Androsten-3-one esters
US11298365B2 (en) 2014-08-28 2022-04-12 Lipocine Inc. Bioavailable solid state (17-β)-hydroxy-4-androsten-3-one esters
US11707467B2 (en) 2014-08-28 2023-07-25 Lipocine Inc. (17-ß)-3-oxoandrost-4-en-17YL tridecanoate compositions and methods of their preparation and use
US11857595B2 (en) 2015-02-03 2024-01-02 Amryt Endo, Inc. Method of treating diseases
US11510963B1 (en) 2015-02-03 2022-11-29 Amryt Endo, Inc. Method of treating diseases
US11338011B2 (en) 2015-02-03 2022-05-24 Amryt Endo, Inc. Method of treating diseases
US10376527B2 (en) 2015-05-28 2019-08-13 Dr. Reddy's Laboratories Ltd. Oral composition of celecoxib for treatment of pain
US10799517B2 (en) 2015-05-28 2020-10-13 Dr. Reddy's Laboratories Ltd Oral composition of celecoxib for treatment of pain
EP3124016A1 (en) 2015-07-31 2017-02-01 Warszawski Uniwersytet Medyczny Antipsoriatic emulsion composition comprising cefazolin
WO2017095736A1 (en) * 2015-12-01 2017-06-08 R.P. Scherer Technologies, Llc Aspirin soft gelatin capsule as a single active or in combination with other actives
US11559530B2 (en) 2016-11-28 2023-01-24 Lipocine Inc. Oral testosterone undecanoate therapy
US10596231B2 (en) 2016-12-16 2020-03-24 Novo Nordisk A/S Insulin containing pharmaceutical compositions
US10265385B2 (en) 2016-12-16 2019-04-23 Novo Nordisk A/S Insulin containing pharmaceutical compositions
US11890316B2 (en) 2020-12-28 2024-02-06 Amryt Endo, Inc. Oral octreotide therapy and contraceptive methods
US11337987B1 (en) 2021-05-07 2022-05-24 Lipocine Inc. Compositions and methods for treating central nervous system disorders
US11478485B1 (en) 2021-05-07 2022-10-25 Lipocine Inc. Compositions and methods for treating CNS disorders
WO2023081786A1 (en) * 2021-11-04 2023-05-11 Vdf Futureceuticals, Inc Ketone precursors and methods therefor

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