CA2282906C - Stable complexes of poorly soluble compounds - Google Patents
Stable complexes of poorly soluble compounds Download PDFInfo
- Publication number
- CA2282906C CA2282906C CA2282906A CA2282906A CA2282906C CA 2282906 C CA2282906 C CA 2282906C CA 2282906 A CA2282906 A CA 2282906A CA 2282906 A CA2282906 A CA 2282906A CA 2282906 C CA2282906 C CA 2282906C
- Authority
- CA
- Canada
- Prior art keywords
- compound
- polymer
- therapeutically active
- ionic polymer
- insoluble
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Abstract
Stable water-insoluble complexes of poorly soluble compounds molecularly dispersed in water-insoluble ionic polymers are disclosed. Useful insoluble ionic polymers have a molecular weight greater than about 80,000 D and a glass transition temperature equal to or greater than about 50°. The compounds are microprecipitated in the ionic polymers in amorphous form. The complexes according to the present invention significantly increase the bioavailability of poorly soluble therapeutically active compounds.
Description
r Case 20227 The present invention provides pharmaceutical compositions comprising a stable water-insoluble complex composed of an amorphous therapeutically active compound (e.g. a drug) dispersed in an ionic polymer. The complexes according to the present invention provide significant increases in bioavailability of poorly soluble s therapeutically active compounds.
The bioavailability of a therapeutically active compound is generally affected by (i) the solubility/dissolution rate of the compound, and (ii) the partition coefficient/permeability of the compound through a subject's gastrointestinal to membrane. The major cause of poor bioavailability of a therapeutically active compound is the poor solubility/dissolution rate of said compound. Poor bioavailability is also often accompanied with undesirably high rates of patient variability and unpredictable dose/therapy effects due to erratic absorption of the therapeutically active compound (e.g. drug) by the patient.
Several techniques are used to improve the bioavailability of poorly soluble therapeutically active compounds. These techniques are summarized below.
1. Particle Size Reduction: A poorly soluble therapeutically active compound often is mechanically ground to reduce the particle size of the compound and thereby increase the surface area. See Lachman et al., The Theory and Practice of Industrial Pharmacy, Chapter 2, p. 45 (1986). Particle size reduction into micron size particles can be achieved using a jet mill. The mean particle size obtained by the jet mill is typically in the range of 1-10 p.m. Similarly, wet milling of a therapeutically active 2s compound in the presence of protective colloids or polymers typically yields particle sizes of compound in the range of about 300-800 nm. According to this technique, a therapeutically active compound and a polymer are dispersed in water and ground by DV/cp/13.07.1999 grinding media such as tiny beads (0.2-0.5 mm). See U.S. Patent No. 5,494,683.
Particle size reduction however, can only . improve the dissolution rate of the therapeutically active compound, but not the total amount of compound in solution at equilibrium.
s 2. Solid Dispersion 2.1 Fusion method: According to this technique, a therapeutically active compound is dispersed into a non-ionic polymer to form a solid dispersion.
Typically, the non-ionic polymer (e.g. Pluronic~ and Polyethylene Glycol) is melted to a io temperature above its melting point and the therapeutically active compound is dissolved, with stirring, into the molten polymer. See U.S. Patent No.
5,281,420. The resulting molten mass is then cooled to room temperature. As a result of this process, the therapeutically active compound is fused into the polymer and on cooling, precipitates out in amorphous form. The amorphous form of the compound generally is has a faster dissolution rate then the initial crystalline form of the compound. Thus, by rendering the compound in amorphous form this process improves bioavailability.
However, due to the greater aqueous solubility and low melting point of non-ionic polymers, the amorphous form of the therapeutically active compound, can not maintain its stability and eventually converts back to the crystalline form after 2o exposure to high humidity and elevated temperatures often encountered during long term storage. See Yoshioka et al., J. Pharm. Sci. 83:1700-1705 (1994).
Therefore, this technique is not suitable for most dosage forms of therapeutically active compounds, and certainly not for those therapeutically active compounds having poor solubility.
2.2 Co-precipitation: In another existing method for improving the bioavailability of a poorly soluble therapeutically active compound, the compound and a non-ionic hydrophilic polymer, such as polyvinyl pyrrolidone, are dissolved in an organic solvent. The solvent is removed by evaporation during which the therapeutically 3o active compound precipitates into the hydrophilic polymer matrix. See, H.G.
Britain, Physical Characterization of Pharmaceutical Solids, Drugs and the Pharmaceutical _3_ Sciences, Vol. 70 (Marcel Dekker, Inc., N.Y., 1995). Due to the hygroscopic nature and aqueous solubility of the polymer, this type of polymer does not protect the amorphous form of the therapeutically active compound from heat and moisture.
Thus, the therapeutically active compound in the hydrophilic polymer matrix does not s stay in amorphous form and eventually converts to a crystalline form during storage.
Therefore, this approach also is not practical to improve the bioavailability of poorly soluble therapeutically active compounds.
The bioavailability of a therapeutically active compound is generally affected by (i) the solubility/dissolution rate of the compound, and (ii) the partition coefficient/permeability of the compound through a subject's gastrointestinal to membrane. The major cause of poor bioavailability of a therapeutically active compound is the poor solubility/dissolution rate of said compound. Poor bioavailability is also often accompanied with undesirably high rates of patient variability and unpredictable dose/therapy effects due to erratic absorption of the therapeutically active compound (e.g. drug) by the patient.
Several techniques are used to improve the bioavailability of poorly soluble therapeutically active compounds. These techniques are summarized below.
1. Particle Size Reduction: A poorly soluble therapeutically active compound often is mechanically ground to reduce the particle size of the compound and thereby increase the surface area. See Lachman et al., The Theory and Practice of Industrial Pharmacy, Chapter 2, p. 45 (1986). Particle size reduction into micron size particles can be achieved using a jet mill. The mean particle size obtained by the jet mill is typically in the range of 1-10 p.m. Similarly, wet milling of a therapeutically active 2s compound in the presence of protective colloids or polymers typically yields particle sizes of compound in the range of about 300-800 nm. According to this technique, a therapeutically active compound and a polymer are dispersed in water and ground by DV/cp/13.07.1999 grinding media such as tiny beads (0.2-0.5 mm). See U.S. Patent No. 5,494,683.
Particle size reduction however, can only . improve the dissolution rate of the therapeutically active compound, but not the total amount of compound in solution at equilibrium.
s 2. Solid Dispersion 2.1 Fusion method: According to this technique, a therapeutically active compound is dispersed into a non-ionic polymer to form a solid dispersion.
Typically, the non-ionic polymer (e.g. Pluronic~ and Polyethylene Glycol) is melted to a io temperature above its melting point and the therapeutically active compound is dissolved, with stirring, into the molten polymer. See U.S. Patent No.
5,281,420. The resulting molten mass is then cooled to room temperature. As a result of this process, the therapeutically active compound is fused into the polymer and on cooling, precipitates out in amorphous form. The amorphous form of the compound generally is has a faster dissolution rate then the initial crystalline form of the compound. Thus, by rendering the compound in amorphous form this process improves bioavailability.
However, due to the greater aqueous solubility and low melting point of non-ionic polymers, the amorphous form of the therapeutically active compound, can not maintain its stability and eventually converts back to the crystalline form after 2o exposure to high humidity and elevated temperatures often encountered during long term storage. See Yoshioka et al., J. Pharm. Sci. 83:1700-1705 (1994).
Therefore, this technique is not suitable for most dosage forms of therapeutically active compounds, and certainly not for those therapeutically active compounds having poor solubility.
2.2 Co-precipitation: In another existing method for improving the bioavailability of a poorly soluble therapeutically active compound, the compound and a non-ionic hydrophilic polymer, such as polyvinyl pyrrolidone, are dissolved in an organic solvent. The solvent is removed by evaporation during which the therapeutically 3o active compound precipitates into the hydrophilic polymer matrix. See, H.G.
Britain, Physical Characterization of Pharmaceutical Solids, Drugs and the Pharmaceutical _3_ Sciences, Vol. 70 (Marcel Dekker, Inc., N.Y., 1995). Due to the hygroscopic nature and aqueous solubility of the polymer, this type of polymer does not protect the amorphous form of the therapeutically active compound from heat and moisture.
Thus, the therapeutically active compound in the hydrophilic polymer matrix does not s stay in amorphous form and eventually converts to a crystalline form during storage.
Therefore, this approach also is not practical to improve the bioavailability of poorly soluble therapeutically active compounds.
3. Self-Emulsifying Drug Delivery System (SEDDS): In this system, a io therapeutically active compound is dissolved in a mixture of a suitable oil and emulsifier. The resultant lipid formulation, upon exposure to gastrointestinal fluids, forms a very fine emulsion or microemulsion. Due to high surface area of the oil globules, the bioavailability of a poorly soluble therapeutically active compound dissolved in such oil is significantly increased. See, P.P. Constantinides, Pharm. Res.
is 12 11 : 1561-1572 (1995). The key requirement for use of this system is that the therapeutically active compound must be soluble in oil and once dissolved in oil, must remain in stable form in the solution. SEDDS is thus not a useful alternative for most therapeutically active compounds due to the limited solubility and unsatisfactory stability of these compounds in an oil-based solution.
We have surprisingly found that when a poorly soluble therapeutically active compound (typically in crystalline form) is molecularly dispersed in a water-insoluble ionic polymer having a molecular weight greater than about 80,000 D and a glass transition temperature equal to or greater than about 50 C, the physical stability of the 2s compound (now in amorphous form) is maintained for long periods of time even under high humidity and temperature storage conditions. Due to the high molecular weight and high glass transition temperature of the ionic polymer, as well as its relative insolubility in water, the ionic polymer immobilizes the therapeutically active compound in its amorphous form thereby providing excellent stabili of compound 3o which is superior to that afforded by currently available methods. In addition, due to the increased solubility of the compound in the compound/polymer complex, the bioavailabilitv of the therapeutically active compound is also significantly increased.
This method is therefore particularly useful for improving the bioavailability of poorly soluble therapeutically active compounds.
s The present invention provides a pharmaceutical composition comprising a stable, water-insoluble complex composed of a carrier macromolecule that is a water-insoluble ionic polymer having a molecular weight greater than about 80,000 D
and a glass transition temperature equal to or greater than about 50~C, and an amorphous therapeutically active compound, wherein the therapeutically active compound is io incorporated or dispersed in the ionic polymer in stable amorphous form to yield a compound/polymer complex. Another aspect of this invention is the water-insoluble compound/polymer complex. The complex of the invention is formed by the microprecipitation of the therapeutically active compound in the ionic carrier.
is The compound/polymer complex of the invention may be in the form of a solid (e.g. a paste, granules, a powder) which can be filled into capsules or compressed into tablets. The powdered form of the complex may also be pulverized or micronized sufficiently to form stable liquid suspensions or semi-solid dispersions.
The complex of the invention may be sterilized, such as by gamma irradiation or 2o electron beam irradiation, prior to administration in vivo for parenteral applications.
This invention relates to a stable water-insoluble complex composed of a water-insoluble ionic polymer carrier having a molecular weight greater than about 80,000 D and a glass transition temperature equal to or greater than about 50°C and 2s a therapeutically active compound in stable amorphous form. This invention also relates to methods of making such complexes and pharmaceutical formulations including such complexes. The advantage of the complexes of the invention include the ability to increase substantially the bioavailability of relatively insoluble therapeutically active compounds and the ability for delivery of such compounds for 3o prolonged periods of time (that is, a sustained release of such compounds into the bloodstream).
is 12 11 : 1561-1572 (1995). The key requirement for use of this system is that the therapeutically active compound must be soluble in oil and once dissolved in oil, must remain in stable form in the solution. SEDDS is thus not a useful alternative for most therapeutically active compounds due to the limited solubility and unsatisfactory stability of these compounds in an oil-based solution.
We have surprisingly found that when a poorly soluble therapeutically active compound (typically in crystalline form) is molecularly dispersed in a water-insoluble ionic polymer having a molecular weight greater than about 80,000 D and a glass transition temperature equal to or greater than about 50 C, the physical stability of the 2s compound (now in amorphous form) is maintained for long periods of time even under high humidity and temperature storage conditions. Due to the high molecular weight and high glass transition temperature of the ionic polymer, as well as its relative insolubility in water, the ionic polymer immobilizes the therapeutically active compound in its amorphous form thereby providing excellent stabili of compound 3o which is superior to that afforded by currently available methods. In addition, due to the increased solubility of the compound in the compound/polymer complex, the bioavailabilitv of the therapeutically active compound is also significantly increased.
This method is therefore particularly useful for improving the bioavailability of poorly soluble therapeutically active compounds.
s The present invention provides a pharmaceutical composition comprising a stable, water-insoluble complex composed of a carrier macromolecule that is a water-insoluble ionic polymer having a molecular weight greater than about 80,000 D
and a glass transition temperature equal to or greater than about 50~C, and an amorphous therapeutically active compound, wherein the therapeutically active compound is io incorporated or dispersed in the ionic polymer in stable amorphous form to yield a compound/polymer complex. Another aspect of this invention is the water-insoluble compound/polymer complex. The complex of the invention is formed by the microprecipitation of the therapeutically active compound in the ionic carrier.
is The compound/polymer complex of the invention may be in the form of a solid (e.g. a paste, granules, a powder) which can be filled into capsules or compressed into tablets. The powdered form of the complex may also be pulverized or micronized sufficiently to form stable liquid suspensions or semi-solid dispersions.
The complex of the invention may be sterilized, such as by gamma irradiation or 2o electron beam irradiation, prior to administration in vivo for parenteral applications.
This invention relates to a stable water-insoluble complex composed of a water-insoluble ionic polymer carrier having a molecular weight greater than about 80,000 D and a glass transition temperature equal to or greater than about 50°C and 2s a therapeutically active compound in stable amorphous form. This invention also relates to methods of making such complexes and pharmaceutical formulations including such complexes. The advantage of the complexes of the invention include the ability to increase substantially the bioavailability of relatively insoluble therapeutically active compounds and the ability for delivery of such compounds for 3o prolonged periods of time (that is, a sustained release of such compounds into the bloodstream).
As used herein, the following terms shall have the following meanings.
"Compound/polymer complex" or "water-insoluble complex" refer to a s physically stable product that forms upon the concurrent precipitation ("microprecipitation") of a therapeutically active compound and a water-insoluble ionic polymer according to the methods described herein.
"Dispersed" means random distribution of a therapeutically active compound io throughout an ionic polymer.
"Dissolution Rate" means the speed with which a particular compound dissolves in physiological fluids in vitro.
is "Ionic polymer" or "ionic carrier polymer" includes both anionic (negatively charged) and cationic (positively charged) polymers.
"Microprecipitation" means any method by which a compound, in particular a therapeutically active compound, is molecularly dispersed in a polymer.
"Molecularly dispersed" means that the therapeutically active compounds) is present in the polymer in a final state of subdivision. See, e.g., M.G. Vachon et al., J.
Microencapsulation 14 3 : 281-301 (1997); M.A. and Vandelli et al., J.
Microencapsulation 10 1 : 55-65 (1993).
"Patient" refers to a human subject.
"Poorly soluble therapeutically active compound" refers to therapeutically active compounds (e.g. drugs) having an aqueous solubility of less than about 3o mg/mL, often less than about 100 ~g/mL.
"Compound/polymer complex" or "water-insoluble complex" refer to a s physically stable product that forms upon the concurrent precipitation ("microprecipitation") of a therapeutically active compound and a water-insoluble ionic polymer according to the methods described herein.
"Dispersed" means random distribution of a therapeutically active compound io throughout an ionic polymer.
"Dissolution Rate" means the speed with which a particular compound dissolves in physiological fluids in vitro.
is "Ionic polymer" or "ionic carrier polymer" includes both anionic (negatively charged) and cationic (positively charged) polymers.
"Microprecipitation" means any method by which a compound, in particular a therapeutically active compound, is molecularly dispersed in a polymer.
"Molecularly dispersed" means that the therapeutically active compounds) is present in the polymer in a final state of subdivision. See, e.g., M.G. Vachon et al., J.
Microencapsulation 14 3 : 281-301 (1997); M.A. and Vandelli et al., J.
Microencapsulation 10 1 : 55-65 (1993).
"Patient" refers to a human subject.
"Poorly soluble therapeutically active compound" refers to therapeutically active compounds (e.g. drugs) having an aqueous solubility of less than about 3o mg/mL, often less than about 100 ~g/mL.
One aspect of the present invention pertains to pharmaceutical compositions comprising a stable water-insoluble complex composed of a carrier macromolecule that is an ionic polymer and a therapeutically active compound that is stable in its amorphous form. The use of such compound/polymer complex is particularly s preferable when the compound is otherwise poorly soluble making it difficult to obtain desirable oral bioavailability of said compound.
According to the present invention, when poorly soluble crystalline therapeutically active compound and a water-insoluble ionic polymer having a io molecular weight greater than about 80,000 D and a glass transition temperature equal to or greater than about 50°C are microprecipitated, the compound is molecularly dispersed in amorphous form, into the ionic polymer producing a stable, water insoluble complex. Microprecipitation may be accomplished, for example, by any one of the following methods, each of which is further described infra:
is a) Spray Drying or Lyophilization Method b) Solvent-Controlled Precipitation c) pH-Controlled Precipitation d) Hot Melt Extrusion Process e) Supercritical Fluid Technology Once the therapeutically active compound is so dispersed in the ionic polymer, it retains its amorphous structure even during long term storage, that is, it is "stable". In addition, the ionic polymer protects the compound from detrimental external environmental factors such as moisture and heat, thereby retaining increased 2s solubility and consequent increased bioavailabilitv.
A therapeutically active compound that is contained in a complex amorphous form according to the invention has significantly increase bioavailability in comparison to said compound in its crystalline form and is highly stable over a prolonged period of time. In addition, due to a controlled dissolution rate of the complex in the gastrointestinal fluids, the complex affords sustained release characteristics for the therapeutically active compound dispersed in the compound/polymer complex.
This invention is useful with any therapeutically active compound, but is especially useful for therapeutically active compounds having aqueous solubilities of less than about 1 mglmL, and especially for compounds having less then 100 ~g/mL.
s Such poorly soluble therapeutically active compounds include, for example, retinoids and protease inhibitors. In particular, this invention is especially useful with the following therapeutic compounds:
H
O O
\) \ / ~i ' Me M~ NO h \ C1 / N
CI O ~ /
O~
HN
/ O
'O
II, IS
_$_ ~S i N~ 1\
O
III, IV, J
i NOZ V
In its crystalline form, Compound I above has extremely poor aqueous solubility (<10 ~g/mL) and bioavailability.
This invention is also useful with the compound tolcapone (marketed by Roche Laboratories Inc. under the brand name Tasmar~), the compound 1,3-cis-retinoic acid (commercially from available from Roche Laboratories Inc. under the brand name ACCUTANE~), the compound saquinavir (marketed by Roche Laboratories s Inc. as FORTOVASET""), and with the following compounds:
VI
VII
VIII
- 1~-The ionic polymers suitable for use in accordance with this invention are either cationic or anionic polymers, have a molecular weight of above about 80,000 D, a glass transition temperature equal to or greater than about 50°C, are relatively insoluble in water and preferably have pH-dependent solubility. Examples of such s polymers include polyacrylates (e.g. Eudragit~, Rohm America), chitosan, Carbopol~
(BF Goodrich), polyvinyl acetate phthalate, cellulose acetate phthalate, polycyanoacrylates, hydroxypropylmethyl cellulose phthalate, cellulose acetate terphthalate, hydroxypropyl methyl cellulose acetyl succinate, carboxy methyl cellulose and low substituted hydroxy propyl cellulose. The water-insoluble io complexes according to present invention may also be comprised of mixtures of two or more above-described ionic polymers (see, e.g. Examples 9 and 10).
Particularly preferred anionic polymers include Eudragit~ L100-55 (methacrylic acid and ethyl acrylate copolymer) and Eudragit~ L100 or Eudragit~ S100 is (methacrylic acid and methyl methacrylate copolymers), all of which are available from Rohm America. Eudragit~ L100-55 is soluble at a pH above 5.5 and practically insoluble at pH below 5.5. The molecular weight of Eudragit~ L100-55 is approximately 250,000 D and the glass transition temperature is 110°C.
Eudragit~
L100 is soluble at pH above 6 and practically insoluble at pH below 6. The molecular 2o weight of Eudragit~ L100 is approximately 135,000 D and the glass transition temperature is about 150°C. Eudragit~ S100 is soluble at pH above 7 and practically insoluble at pH below 7. The molecular weight of Eudragit~ S100 is approximately 135,000 D and the glass transition temperature is about 160°C.
2s Particularly preferred cationic polymers include Eudragit~ E (Rohm America), which is a copolymer of dimethylaminoethylmethacrylate and neutral methacrylic esters. This polymer is soluble up to pH 4 and is practically insoluble at a pH above 4. The molecular weight of Eudragit~ E is approximately 150,000 D and the glass transition temperature is about 50~C.
Pharmaceutical compositions of the present invention comprising the water-insoluble complexes of the invention may be manufactured in a manner that is known in the art, e.g. by means of conventional mixing, milling, encapsulating, dissolving, compressing, granulating, or lyophilizing processes. In addition to the water-insoluble s complexes, these pharmaceutical compositions may also include therapeutically inert, inorganic or organic carriers ("pharmaceutically acceptable carriers"), other than the ionic polymer, and/or excipients. Pharmaceutically acceptable carriers for tablets, coated tablets, dragees and hard gelatin capsules include lactose, maize starch or derivatives thereof, talc, stearic acid or its salts. Suitable carriers for soft gelatin io capsules include vegetable oils, waxes, fats, and semi-solid or liquid polyols.
The pharmaceutical compositions of the invention may also contain preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for varying the osmotic is pressure, buffers, coating agents or antioxidants. These compositions may also contain additional therapeutically active compounds or more than one therapeutically active compound/polymer complex.
Methods of Preparation In one embodiment of the present invention, water-insoluble complexes of the invention are prepared using one of the following methods:
a) Spray Drying or Lyophilization Method: The therapeutically active 2s compound and the ionic polymer are dissolved in a common solvent having a low boiling point, e.g., ethanol, methanol, acetone, etc. By means of spray drying or lyophilization, the solvent is evaporated, leaving the therapeutically active compound microprecipitated in amorphous form in the ionic polymer matrix. This technique is not preferable for those therapeutically active compounds that do not have adequate 3o solubility (>5%) in the preferred solvents.
b) Solvent Controlled Precipitation: The therapeutically active compound and the ionic polymer are dissolved in a common solvent, e.g., dimethylacetamide, dimethylformamide, etc. The therapeutically active compound/
polymer solution is added to cold (2°-5°C) water adjusted to appropriate pH. The s desired pH is dependent on the polymer used and is readily asertainablebly one skilled in the art. This causes the therapeutically active compound to microprecipitate in the polymer matrix. The microprecipitate is washed several times with aqueous medium until the residual solvent falls below an acceptable limit for that solvent. An "acceptable limit" for each solvent is determined pursuant to the International io Conference on Harmonization (ICH) guidelines.
c) pH-Controlled Precipitation: In this process, microprecipitation of the therapeutically active compound in an ionic polymer is controlled by a drastic change in pH of the solution. The therapeutically active compound and the ionic polymer are is dissolved at a high pH (e.g. pH -. 9) and precipitated by lowering the pH
of the solution (e.g. to -- 1 ), or vice versa. This method is particularly suitable for therapeutically active compounds that have pH-dependent solubility.
d) Hot Melt Extrusion Process: Mircroprecipitation of a therapeutically 2o active compound in an ionic polymer having thermoplastic characteristics can be achieved by a hot melt extrusion process. The crystalline therapeutically active compound and the polymer are mixed in a suitable blender and fed continuously to a temperature-controlled extruder causing the therapeutically active compound to be molecularly dispersed in the molten ionic polymer. The resulting extrudates are 2s cooled to room temperature and milled into a fine powder.
e) Supercritical Fluid Technology: The therapeutically active compound and an ionic polymer are dissolved in a supercritical fluid such as liquid nitrogen or liquid carbon dioxide. The supercritical fluid is then removed by evaporation leaving 3o the therapeutically active compound microprecipitated in the polymer matrix. In another method, the therapeutic compound and an ionic polymer is dissolved in a suitable solvent. A microprecipitated powder can then be formed by spraying the solution in a supercritical fluid which acts as an antisolvent.
In another embodiment of the invention, pharmaceutical formulations may be s prepared according to any one of the foregoing steps by the addition of a final step during which the compound/polymer complexes of the invention are formulated by methods well-known in the art.
In a preferred embodiment of the invention, the therapeutically active io compound and the ionic polymer are dissolved in an organic solvent.
Thereafter, the compound and the ionic polymer are co-precipitated relatively concurrently, preferably in aqueous solution, and preferably at a pH where, independently, neither the compound nor the polymer are soluble.
is The organic solvent used to dissolve the therapeutically active compound and the ionic polymer should provide good solubility for both the poorly soluble compounds and the polymers used. These solvents include ethyl alcohol, methyl alcohol, acetone dimethyl sulfoxide, dimethyl acetamide, dimethyl formamide, N-methylpyrrolidone, Transcutol~ (Diethylene glycol monoethyl ether, Gattefosse, Inc.), 2o glycofural, propylene carbonate, tetrahydrofuran, polyethylene glycols and propylene glycols.
The pH selected to co-precipitate the therapeutically active compound and the ionic polymer depends on the solubility of each of the specific polymers and 2s compounds being precipitated. One skilled in the art can easily ascertain the preferred pH for co-precipitation for each combination of polymer and therapeutically active compound. In a preferred embodiment wherein an anionic polymer selected from Eudragit~ L100-55, Eudragit~ L100 and Eudragit~ S100 is used, the solution is precipitated at a pH lower than about 4. In another preferred embodiment wherein so the cationic polymer Eudragit~ E100 is used, the solution is precipitated preferably at a pH above 4.
The amounts of therapeutically active compounds) and polymer necessary to achieve the stable, water-insoluble complex of the invention may vary depending upon the particular compound and ionic polymers) used, as well as the particular s solvents) and precipitation parameters. By way of example, the compound may be present in the complex from about 0.1 % to about 80%, by weight. Analogously, the polymer is typically present in the complex in not less than about 20% by weight.
Preferably, the compound is present in the complex from about 30% to about 70%
by weight, more preferably from about 40% to about 60% by weight. Most preferably, io the compound is present in the complex at about 50% by weight. For a complex incorporating Compound I, the compound is present in the complex at about 30-70%
by weight, most preferably at about 50% by weight.
Once the compound/polymer complex precipitates out of solution, the resulting is complex can be recovered from the solution by procedures known to those skilled in the art, for example by filtration, centrifugation, washing, etc. The recovered mass can then be dried (in air, an oven, or a vacuum) and the resulting solid can be milled, pulverized or micronized to a fine powder by means known in the art. The powder form of the complex can then be dispersed in a carrier to form a pharmaceutical 2o preparation.
The pharmaceutical preparations according to the invention can be administered to a subject by any route suitable for achieving the desired therapeutic result(s). Preferred routes of administration include parenteral and oral 2s administration.
The pharmaceutical formulations according to the invention include a therapeutically effective amount of a therapeutically active compound. A
therapeutically effective amount means an amount, at such dosages and for such 3o periods of time, necessary to achieve the desired therapeutic result.
Moreover, such amount must be one in which the overall therapeutically beneficial effects outweigh the toxic or undesirable side effects. A therapeutically effective amount of a compound often varies according to disease state, age and weight of the subject being treated. Thus, dosage regimens are typically adjusted to the individual requirements in each particular case and are within the skill in the art.
s By way of example, for Compound I above, the appropriate daily dose for administration to an adult human weighing about 70 kg is from about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, although the upper limit may be exceeded when indicated.
io The daily dosage of the therapeutically active compound can be administered as a single dose, in divided doses, or for parenteral administration, it may be given as subcutaneous injection.
is The examples which follow refer to appended drawings wherein FIG 1 is a powder x-ray diffraction pattern of the compound/polymer complex of Example 4 compared to the bulk drug alone and compared to drug and polymer physical mixture.
FIG. 2 is a powder x-ray diffraction pattern of samples from the compound/polymer complex of Example 4 exposed to accelerated stress conditions compared to unstressed (initial) compound/polymer complex.
2s FIG 3 is a plasma concentration profile in dogs of the compound/polymer complex of Example 4.
FIG 4 is a powder x-ray diffraction pattern for Compound II "as is" and as compound/polymer complex (Example 11 ) after microprecipitation in accordance with 3o the invention.
FIG 5 is a powder x-ray diffraction pattern for Compound III "as is" and as compound/polymer complex (Example 13) after microprecipitation in accordance with the invention.
s FIG 6 is a powder x-ray diffraction pattern for Compound IV "as is" and as compound/polymer complex (Example 15) after microprecipitation in accordance with the invention.
FIG 7 is a powder x-ray diffraction pattern for Compound V "as is" and as io compound/polymer complex (Example 16) after microprecipitation in accordance with the invention.
EXAMPLES
is The following examples illustrate methods for making the water-insoluble compound/polymer(s) complexes of the present invention as well as pharmaceutical preparations incorporating said complexes.
2o For the examples reported herein, the therapeutically active compounds tested were Compounds I, II, III, IV and V, the structures for which are provided above.
These compounds are practically insoluble in gastrointestinal fluids. Prior to the current invention, the crystalline, insoluble form of Compound I was the only stable form of this Compound that could be obtained.
General Procedures Procedure Applicable to Example 1 ~micronized compound) Compound I was micronized using a fluid energy mill to yield an average 3o particle size of 10 microns. This procedure did not alter the crystalline form of the compound.
Procedure Applicable to Example 2 (nanosized compound) A 10% suspension of Compound I was wet milled in aqueous medium containing 5% Klucel EF~ (Hydroxypropylcellulose, Aqualon Corp.) as a protective s colloid to prevent aggregation. The milling was performed in batch mode in a Dynomill for 24 hours using 0.25 mm glass beads as milling media. The average particle size of the resultant suspension was 700 nm and the residue obtained after drying the suspension demonstrated that the compound was present in crystalline form.
io Procedure Applicable to Example 3 (Pluronic F 68 dispersion) A 10% dispersion of Compound I in 90% Pluronic F68 (polymer) was prepared using hot-melt technique. The compound was mixed into molten Pluronic F68 at 60°C
and the dispersion was then heated up to 180°C to dissolve Compound I.
The is solution was cooled to room temperature to yield a solid mass. The powder x-ray diffraction ("XRD") pattern of the molten dispersion was similar to that for Pluronic F68. This XRD shows that Compound I was thus present in the solid dispersion in amorphous form. The solid dispersion obtained by this technique was further dispersed in aqueous medium prior to use in dosing animals.
Procedure Applicable to Examples 4-12 and 15-16 (Molecular dispersion according to the invention) In accordance with the method of the invention, compounds I, II, IV or V and the specific polymer identified in each instance (i.e., Eudragit~ L100-55, Eudragit~
2s L100 or Eudragit~ S100) were dissolved in dimethylacetamide. The resulting solution was then slowly added to cold (2-10°C) aqueous solution at pH 2 causing the compound and the polymer to co-precipitate as an insoluble matrix wherein the compound was molecularly dispersed in the polymer. In each case, the precipitate was washed several times with cold (2-10°C) aqueous solution at pH 2 until the 3o residual dimethylacetamide was below 0.2%. The precipitate was dried in a forced air oven at 40°C for 24 hours to a moisture level of below 2% and milled using a Fitz Mill~ (Fitzpatrick) at slow speed using forward knives and size 0 screen into desirable particle sizes. The desired mean particle size ~nras 90% particles in the size range 50-400 p.m.
s Procedure applicable to Examples 13-14 (Compound III) In accordance with the methods described above, Compound III and a specific polymer identified in each instance (i.e., Eudragit~ L100-55, Eudragit~ L100, Hydroxypropylmethylcellulose phthalate (HP-50) or Eudragit~ S100) were dissolved in ethanol. The resulting solution was either dried in a vacuum oven at 40°C for 24 io hours until the weight loss on drying was less than 2%, or alternatively, the solution was spray dried. As a result of this process, the compound and the polymer co-precipitated as an insoluble complex wherein the compound was molecularly dispersed in the polymer. The resulting dried film was ground with a pestle/mortar and screened through 60 mesh screen.
is Data Table 1 below summarizes the results of Examples 1-16. Table 1 specifies the individual therapeutically active compounds and, where applicable, the compound/polymer complex that was prepared, the method of preparing the 2o compound/polymer complex, and the physical characteristics of the resulting products from each example.
Table 1: Summary of Examples 1-14 Example Composition (% w/w) Method of Characterization # of Pre aration Resultin Product 1 Compound I 100% Fluid energy XRD- crystalline, mill (micronized) Particle size:
50% - 10 ~m 2 Compound I 67% Wet milling usingXRD - crystalline, Klucel EF'~ 33% 0.25 mm glass Particle size:
beads 50% - 0.7 ~m 3 Compound I 10% Hot melt extrusionXRD - amorphous Pluronic F68 90% at about 180C
4 Compound I 30% Solvent-controlledXRD -Amorphous Eudra it L 100-55 reci itation (Figures: 1 and 70% 2) Compound I 50% Solvent-controlledXRD - Amorphous Eudra it L 100-55 reci itation 50%
6 Compound I 70% Solvent-controlledXRD - Amorphous Eudra it L 100-55 reci itation 30%
According to the present invention, when poorly soluble crystalline therapeutically active compound and a water-insoluble ionic polymer having a io molecular weight greater than about 80,000 D and a glass transition temperature equal to or greater than about 50°C are microprecipitated, the compound is molecularly dispersed in amorphous form, into the ionic polymer producing a stable, water insoluble complex. Microprecipitation may be accomplished, for example, by any one of the following methods, each of which is further described infra:
is a) Spray Drying or Lyophilization Method b) Solvent-Controlled Precipitation c) pH-Controlled Precipitation d) Hot Melt Extrusion Process e) Supercritical Fluid Technology Once the therapeutically active compound is so dispersed in the ionic polymer, it retains its amorphous structure even during long term storage, that is, it is "stable". In addition, the ionic polymer protects the compound from detrimental external environmental factors such as moisture and heat, thereby retaining increased 2s solubility and consequent increased bioavailabilitv.
A therapeutically active compound that is contained in a complex amorphous form according to the invention has significantly increase bioavailability in comparison to said compound in its crystalline form and is highly stable over a prolonged period of time. In addition, due to a controlled dissolution rate of the complex in the gastrointestinal fluids, the complex affords sustained release characteristics for the therapeutically active compound dispersed in the compound/polymer complex.
This invention is useful with any therapeutically active compound, but is especially useful for therapeutically active compounds having aqueous solubilities of less than about 1 mglmL, and especially for compounds having less then 100 ~g/mL.
s Such poorly soluble therapeutically active compounds include, for example, retinoids and protease inhibitors. In particular, this invention is especially useful with the following therapeutic compounds:
H
O O
\) \ / ~i ' Me M~ NO h \ C1 / N
CI O ~ /
O~
HN
/ O
'O
II, IS
_$_ ~S i N~ 1\
O
III, IV, J
i NOZ V
In its crystalline form, Compound I above has extremely poor aqueous solubility (<10 ~g/mL) and bioavailability.
This invention is also useful with the compound tolcapone (marketed by Roche Laboratories Inc. under the brand name Tasmar~), the compound 1,3-cis-retinoic acid (commercially from available from Roche Laboratories Inc. under the brand name ACCUTANE~), the compound saquinavir (marketed by Roche Laboratories s Inc. as FORTOVASET""), and with the following compounds:
VI
VII
VIII
- 1~-The ionic polymers suitable for use in accordance with this invention are either cationic or anionic polymers, have a molecular weight of above about 80,000 D, a glass transition temperature equal to or greater than about 50°C, are relatively insoluble in water and preferably have pH-dependent solubility. Examples of such s polymers include polyacrylates (e.g. Eudragit~, Rohm America), chitosan, Carbopol~
(BF Goodrich), polyvinyl acetate phthalate, cellulose acetate phthalate, polycyanoacrylates, hydroxypropylmethyl cellulose phthalate, cellulose acetate terphthalate, hydroxypropyl methyl cellulose acetyl succinate, carboxy methyl cellulose and low substituted hydroxy propyl cellulose. The water-insoluble io complexes according to present invention may also be comprised of mixtures of two or more above-described ionic polymers (see, e.g. Examples 9 and 10).
Particularly preferred anionic polymers include Eudragit~ L100-55 (methacrylic acid and ethyl acrylate copolymer) and Eudragit~ L100 or Eudragit~ S100 is (methacrylic acid and methyl methacrylate copolymers), all of which are available from Rohm America. Eudragit~ L100-55 is soluble at a pH above 5.5 and practically insoluble at pH below 5.5. The molecular weight of Eudragit~ L100-55 is approximately 250,000 D and the glass transition temperature is 110°C.
Eudragit~
L100 is soluble at pH above 6 and practically insoluble at pH below 6. The molecular 2o weight of Eudragit~ L100 is approximately 135,000 D and the glass transition temperature is about 150°C. Eudragit~ S100 is soluble at pH above 7 and practically insoluble at pH below 7. The molecular weight of Eudragit~ S100 is approximately 135,000 D and the glass transition temperature is about 160°C.
2s Particularly preferred cationic polymers include Eudragit~ E (Rohm America), which is a copolymer of dimethylaminoethylmethacrylate and neutral methacrylic esters. This polymer is soluble up to pH 4 and is practically insoluble at a pH above 4. The molecular weight of Eudragit~ E is approximately 150,000 D and the glass transition temperature is about 50~C.
Pharmaceutical compositions of the present invention comprising the water-insoluble complexes of the invention may be manufactured in a manner that is known in the art, e.g. by means of conventional mixing, milling, encapsulating, dissolving, compressing, granulating, or lyophilizing processes. In addition to the water-insoluble s complexes, these pharmaceutical compositions may also include therapeutically inert, inorganic or organic carriers ("pharmaceutically acceptable carriers"), other than the ionic polymer, and/or excipients. Pharmaceutically acceptable carriers for tablets, coated tablets, dragees and hard gelatin capsules include lactose, maize starch or derivatives thereof, talc, stearic acid or its salts. Suitable carriers for soft gelatin io capsules include vegetable oils, waxes, fats, and semi-solid or liquid polyols.
The pharmaceutical compositions of the invention may also contain preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for varying the osmotic is pressure, buffers, coating agents or antioxidants. These compositions may also contain additional therapeutically active compounds or more than one therapeutically active compound/polymer complex.
Methods of Preparation In one embodiment of the present invention, water-insoluble complexes of the invention are prepared using one of the following methods:
a) Spray Drying or Lyophilization Method: The therapeutically active 2s compound and the ionic polymer are dissolved in a common solvent having a low boiling point, e.g., ethanol, methanol, acetone, etc. By means of spray drying or lyophilization, the solvent is evaporated, leaving the therapeutically active compound microprecipitated in amorphous form in the ionic polymer matrix. This technique is not preferable for those therapeutically active compounds that do not have adequate 3o solubility (>5%) in the preferred solvents.
b) Solvent Controlled Precipitation: The therapeutically active compound and the ionic polymer are dissolved in a common solvent, e.g., dimethylacetamide, dimethylformamide, etc. The therapeutically active compound/
polymer solution is added to cold (2°-5°C) water adjusted to appropriate pH. The s desired pH is dependent on the polymer used and is readily asertainablebly one skilled in the art. This causes the therapeutically active compound to microprecipitate in the polymer matrix. The microprecipitate is washed several times with aqueous medium until the residual solvent falls below an acceptable limit for that solvent. An "acceptable limit" for each solvent is determined pursuant to the International io Conference on Harmonization (ICH) guidelines.
c) pH-Controlled Precipitation: In this process, microprecipitation of the therapeutically active compound in an ionic polymer is controlled by a drastic change in pH of the solution. The therapeutically active compound and the ionic polymer are is dissolved at a high pH (e.g. pH -. 9) and precipitated by lowering the pH
of the solution (e.g. to -- 1 ), or vice versa. This method is particularly suitable for therapeutically active compounds that have pH-dependent solubility.
d) Hot Melt Extrusion Process: Mircroprecipitation of a therapeutically 2o active compound in an ionic polymer having thermoplastic characteristics can be achieved by a hot melt extrusion process. The crystalline therapeutically active compound and the polymer are mixed in a suitable blender and fed continuously to a temperature-controlled extruder causing the therapeutically active compound to be molecularly dispersed in the molten ionic polymer. The resulting extrudates are 2s cooled to room temperature and milled into a fine powder.
e) Supercritical Fluid Technology: The therapeutically active compound and an ionic polymer are dissolved in a supercritical fluid such as liquid nitrogen or liquid carbon dioxide. The supercritical fluid is then removed by evaporation leaving 3o the therapeutically active compound microprecipitated in the polymer matrix. In another method, the therapeutic compound and an ionic polymer is dissolved in a suitable solvent. A microprecipitated powder can then be formed by spraying the solution in a supercritical fluid which acts as an antisolvent.
In another embodiment of the invention, pharmaceutical formulations may be s prepared according to any one of the foregoing steps by the addition of a final step during which the compound/polymer complexes of the invention are formulated by methods well-known in the art.
In a preferred embodiment of the invention, the therapeutically active io compound and the ionic polymer are dissolved in an organic solvent.
Thereafter, the compound and the ionic polymer are co-precipitated relatively concurrently, preferably in aqueous solution, and preferably at a pH where, independently, neither the compound nor the polymer are soluble.
is The organic solvent used to dissolve the therapeutically active compound and the ionic polymer should provide good solubility for both the poorly soluble compounds and the polymers used. These solvents include ethyl alcohol, methyl alcohol, acetone dimethyl sulfoxide, dimethyl acetamide, dimethyl formamide, N-methylpyrrolidone, Transcutol~ (Diethylene glycol monoethyl ether, Gattefosse, Inc.), 2o glycofural, propylene carbonate, tetrahydrofuran, polyethylene glycols and propylene glycols.
The pH selected to co-precipitate the therapeutically active compound and the ionic polymer depends on the solubility of each of the specific polymers and 2s compounds being precipitated. One skilled in the art can easily ascertain the preferred pH for co-precipitation for each combination of polymer and therapeutically active compound. In a preferred embodiment wherein an anionic polymer selected from Eudragit~ L100-55, Eudragit~ L100 and Eudragit~ S100 is used, the solution is precipitated at a pH lower than about 4. In another preferred embodiment wherein so the cationic polymer Eudragit~ E100 is used, the solution is precipitated preferably at a pH above 4.
The amounts of therapeutically active compounds) and polymer necessary to achieve the stable, water-insoluble complex of the invention may vary depending upon the particular compound and ionic polymers) used, as well as the particular s solvents) and precipitation parameters. By way of example, the compound may be present in the complex from about 0.1 % to about 80%, by weight. Analogously, the polymer is typically present in the complex in not less than about 20% by weight.
Preferably, the compound is present in the complex from about 30% to about 70%
by weight, more preferably from about 40% to about 60% by weight. Most preferably, io the compound is present in the complex at about 50% by weight. For a complex incorporating Compound I, the compound is present in the complex at about 30-70%
by weight, most preferably at about 50% by weight.
Once the compound/polymer complex precipitates out of solution, the resulting is complex can be recovered from the solution by procedures known to those skilled in the art, for example by filtration, centrifugation, washing, etc. The recovered mass can then be dried (in air, an oven, or a vacuum) and the resulting solid can be milled, pulverized or micronized to a fine powder by means known in the art. The powder form of the complex can then be dispersed in a carrier to form a pharmaceutical 2o preparation.
The pharmaceutical preparations according to the invention can be administered to a subject by any route suitable for achieving the desired therapeutic result(s). Preferred routes of administration include parenteral and oral 2s administration.
The pharmaceutical formulations according to the invention include a therapeutically effective amount of a therapeutically active compound. A
therapeutically effective amount means an amount, at such dosages and for such 3o periods of time, necessary to achieve the desired therapeutic result.
Moreover, such amount must be one in which the overall therapeutically beneficial effects outweigh the toxic or undesirable side effects. A therapeutically effective amount of a compound often varies according to disease state, age and weight of the subject being treated. Thus, dosage regimens are typically adjusted to the individual requirements in each particular case and are within the skill in the art.
s By way of example, for Compound I above, the appropriate daily dose for administration to an adult human weighing about 70 kg is from about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, although the upper limit may be exceeded when indicated.
io The daily dosage of the therapeutically active compound can be administered as a single dose, in divided doses, or for parenteral administration, it may be given as subcutaneous injection.
is The examples which follow refer to appended drawings wherein FIG 1 is a powder x-ray diffraction pattern of the compound/polymer complex of Example 4 compared to the bulk drug alone and compared to drug and polymer physical mixture.
FIG. 2 is a powder x-ray diffraction pattern of samples from the compound/polymer complex of Example 4 exposed to accelerated stress conditions compared to unstressed (initial) compound/polymer complex.
2s FIG 3 is a plasma concentration profile in dogs of the compound/polymer complex of Example 4.
FIG 4 is a powder x-ray diffraction pattern for Compound II "as is" and as compound/polymer complex (Example 11 ) after microprecipitation in accordance with 3o the invention.
FIG 5 is a powder x-ray diffraction pattern for Compound III "as is" and as compound/polymer complex (Example 13) after microprecipitation in accordance with the invention.
s FIG 6 is a powder x-ray diffraction pattern for Compound IV "as is" and as compound/polymer complex (Example 15) after microprecipitation in accordance with the invention.
FIG 7 is a powder x-ray diffraction pattern for Compound V "as is" and as io compound/polymer complex (Example 16) after microprecipitation in accordance with the invention.
EXAMPLES
is The following examples illustrate methods for making the water-insoluble compound/polymer(s) complexes of the present invention as well as pharmaceutical preparations incorporating said complexes.
2o For the examples reported herein, the therapeutically active compounds tested were Compounds I, II, III, IV and V, the structures for which are provided above.
These compounds are practically insoluble in gastrointestinal fluids. Prior to the current invention, the crystalline, insoluble form of Compound I was the only stable form of this Compound that could be obtained.
General Procedures Procedure Applicable to Example 1 ~micronized compound) Compound I was micronized using a fluid energy mill to yield an average 3o particle size of 10 microns. This procedure did not alter the crystalline form of the compound.
Procedure Applicable to Example 2 (nanosized compound) A 10% suspension of Compound I was wet milled in aqueous medium containing 5% Klucel EF~ (Hydroxypropylcellulose, Aqualon Corp.) as a protective s colloid to prevent aggregation. The milling was performed in batch mode in a Dynomill for 24 hours using 0.25 mm glass beads as milling media. The average particle size of the resultant suspension was 700 nm and the residue obtained after drying the suspension demonstrated that the compound was present in crystalline form.
io Procedure Applicable to Example 3 (Pluronic F 68 dispersion) A 10% dispersion of Compound I in 90% Pluronic F68 (polymer) was prepared using hot-melt technique. The compound was mixed into molten Pluronic F68 at 60°C
and the dispersion was then heated up to 180°C to dissolve Compound I.
The is solution was cooled to room temperature to yield a solid mass. The powder x-ray diffraction ("XRD") pattern of the molten dispersion was similar to that for Pluronic F68. This XRD shows that Compound I was thus present in the solid dispersion in amorphous form. The solid dispersion obtained by this technique was further dispersed in aqueous medium prior to use in dosing animals.
Procedure Applicable to Examples 4-12 and 15-16 (Molecular dispersion according to the invention) In accordance with the method of the invention, compounds I, II, IV or V and the specific polymer identified in each instance (i.e., Eudragit~ L100-55, Eudragit~
2s L100 or Eudragit~ S100) were dissolved in dimethylacetamide. The resulting solution was then slowly added to cold (2-10°C) aqueous solution at pH 2 causing the compound and the polymer to co-precipitate as an insoluble matrix wherein the compound was molecularly dispersed in the polymer. In each case, the precipitate was washed several times with cold (2-10°C) aqueous solution at pH 2 until the 3o residual dimethylacetamide was below 0.2%. The precipitate was dried in a forced air oven at 40°C for 24 hours to a moisture level of below 2% and milled using a Fitz Mill~ (Fitzpatrick) at slow speed using forward knives and size 0 screen into desirable particle sizes. The desired mean particle size ~nras 90% particles in the size range 50-400 p.m.
s Procedure applicable to Examples 13-14 (Compound III) In accordance with the methods described above, Compound III and a specific polymer identified in each instance (i.e., Eudragit~ L100-55, Eudragit~ L100, Hydroxypropylmethylcellulose phthalate (HP-50) or Eudragit~ S100) were dissolved in ethanol. The resulting solution was either dried in a vacuum oven at 40°C for 24 io hours until the weight loss on drying was less than 2%, or alternatively, the solution was spray dried. As a result of this process, the compound and the polymer co-precipitated as an insoluble complex wherein the compound was molecularly dispersed in the polymer. The resulting dried film was ground with a pestle/mortar and screened through 60 mesh screen.
is Data Table 1 below summarizes the results of Examples 1-16. Table 1 specifies the individual therapeutically active compounds and, where applicable, the compound/polymer complex that was prepared, the method of preparing the 2o compound/polymer complex, and the physical characteristics of the resulting products from each example.
Table 1: Summary of Examples 1-14 Example Composition (% w/w) Method of Characterization # of Pre aration Resultin Product 1 Compound I 100% Fluid energy XRD- crystalline, mill (micronized) Particle size:
50% - 10 ~m 2 Compound I 67% Wet milling usingXRD - crystalline, Klucel EF'~ 33% 0.25 mm glass Particle size:
beads 50% - 0.7 ~m 3 Compound I 10% Hot melt extrusionXRD - amorphous Pluronic F68 90% at about 180C
4 Compound I 30% Solvent-controlledXRD -Amorphous Eudra it L 100-55 reci itation (Figures: 1 and 70% 2) Compound I 50% Solvent-controlledXRD - Amorphous Eudra it L 100-55 reci itation 50%
6 Compound I 70% Solvent-controlledXRD - Amorphous Eudra it L 100-55 reci itation 30%
7 Compound I 30% Solvent-controlledXRD - Amorphous Eudra it L 100 70% reci itation 8 Compound I 50% Solvent-controlledXRD - Amorphous Eudra it L 100 50% reci itation 9 Compound I 15% Solvent-controlledXRD - Amorphous Eudragit L100-55 42.5precipitation Eduragit S 100 42.5 Compound I 30% Solvent-controlledXRD -Amorphous Eduragit L 100-55 precipitation 35%
Eudra it S 100 35%
11 Compound II 30% Solvent -controlledXRD - Amorphous Eudra it L 100 70% reci itation (Figure 4) 12 Compound II 30% Solvent-controlledXRD - Amorphous HP-50* 70% reci itation 13 Compound III 30% Spray drying XRD - Amorphous Eudra it L 100 70% (Figure 5) 14 Compound III 50% Spray drying XRD - Amorphous Eudra it L 100 50%
Compound IV 20% Solvent-controlledXRD - Amorphous Eudra it L 100 80% reci itation (Figure 6) 16 Compound V 30% Solvent-controlledXRD - Amorphous Eudra it L 100 70% reci itation (Figure 7) * Hydroxypropylmethylcellulose phthalate As is shown in Figure 1 and Table 1, the powder x-ray diffraction (XRD) pattern of the complex resulting in Example 4_ (Table 1 ), that is when Compound I is included in an ionic polymer in accordance with the process of the current invention, it takes an amorphous form.
Table I and Figures 4-7 also show that the methods of the present invention are useful in rendering Compounds II, III, IV and V in amorphous form.
The inclusion of Compound I in the ionic polymer protected the compound io from external environmental effects such as moisture and heat. This result is demonstrated in Figure 2, wherein it is shown, by powder x-ray diffraction, that Compound I embedded in the polymer maintained its amorphous properties even under accelerated storage conditions. The ability of the complex to maintain Compound 1 in amorphous form even after storage at accelerated stress condition is is due to the high molecular weight (> 80,000), high glass transition temperature (>
50°C) and insolubility in water of the polymer(s).
Furthermore, as is shown in Table 2 below, the bioavailability in dogs of Compound I when it is molecularly dispersed in an ionic polymer in accordance with 2o the invention was unexpectedly higher than when the compound was administered to the animals in conventional forms (e.g. micronized and wet milled). Also shown in Table 2 are the bioavailability results obtained from solid dispersion of Compound I
prepared by hot-melt method with Pluronic F68~ (non-ionic water soluble polymer containing poly-oxyethylene and polyoxypropylene chains, BASF). While the -2s biovailability of the Compound in this solid dispersion was better than when the compound was micronized or in wet mill suspension, the physical stability of the solid dispersion was not satisfactory for a pharmaceutical product as is evident by the reversion of compound to its crystalline form within one month of storage at ambient conditions. The above-described results demonstrate the unsuitability for preparation 30 of a pharmaceutical product of the solid dispersion technique in non-ionic water soluble polymers.
Table 2: Bioavailabilitv of Compound.l in doss after single oral dose administration (10m4/k4)* for four animals (2 males and 2 females) Formulation AUCo.eJDose % Bioavailability**
(ng.h/ml)/(mg/kg) Micronized drug suspension29.5 8.3 3.85 Exam le 1 Wet milled drug suspension86.1 13.7 11.2 Exam le 2 Pluronic F68 532 152 69.5 Solid Dispersion***
Exam le 3 Compound (/Polymer Complex529 189 69.1 Exam le 4 Compound (/Polymer Complex560 72 73.1 Exam le 5 Compound (/Polymer Complex588 3gg 76.8 Exam le 6 Compound (/Polymer Complex604 124 78.9 Exam le 7 Compound (/Polymer Complex768 387 100.3 Exam le 8 Compound (/Polymer Complex415 152 54.2 Exam le 9 Compound (/Polymer Complex264 152 34.5 Exam le 10 s * Results are mean values (with standard deviations) for four animals (2 males and 2 females).
** Compared to Single Dose Intravenous Administration.
*** Converts to crystalline form after exposure to 40°C, 75%RH, 1 wk, open io condition.
Figure 3 shows plasma concentration-time profile of different batches of the compound/polymer complex produced in accordance to Example 4. The results of these tests (summarized in Figure 3), show batch to batch reproducibility and is consistency. Batch to batch reproducibility and consistency is an important aspect of any formulation that is intended for administration to human patients.
Figures 4-7 show that Compounds II, III, IV and V also can be converted into amorphous form using this invention.
In summary, as is shown by the data in Tables 1 and 2 above and in Figures s 1, 2, and 4-7, the powder x-ray diffraction patterns of the compound/polymer(s) complexes obtained in Examples 4-16 shows that molecularly dispersing a poorly soluble compound in an ionic polymers) according to the present invention converts the compounds into amorphous form and maintains excellent stability of the amorphous compound upon long-term storage.
io
Eudra it S 100 35%
11 Compound II 30% Solvent -controlledXRD - Amorphous Eudra it L 100 70% reci itation (Figure 4) 12 Compound II 30% Solvent-controlledXRD - Amorphous HP-50* 70% reci itation 13 Compound III 30% Spray drying XRD - Amorphous Eudra it L 100 70% (Figure 5) 14 Compound III 50% Spray drying XRD - Amorphous Eudra it L 100 50%
Compound IV 20% Solvent-controlledXRD - Amorphous Eudra it L 100 80% reci itation (Figure 6) 16 Compound V 30% Solvent-controlledXRD - Amorphous Eudra it L 100 70% reci itation (Figure 7) * Hydroxypropylmethylcellulose phthalate As is shown in Figure 1 and Table 1, the powder x-ray diffraction (XRD) pattern of the complex resulting in Example 4_ (Table 1 ), that is when Compound I is included in an ionic polymer in accordance with the process of the current invention, it takes an amorphous form.
Table I and Figures 4-7 also show that the methods of the present invention are useful in rendering Compounds II, III, IV and V in amorphous form.
The inclusion of Compound I in the ionic polymer protected the compound io from external environmental effects such as moisture and heat. This result is demonstrated in Figure 2, wherein it is shown, by powder x-ray diffraction, that Compound I embedded in the polymer maintained its amorphous properties even under accelerated storage conditions. The ability of the complex to maintain Compound 1 in amorphous form even after storage at accelerated stress condition is is due to the high molecular weight (> 80,000), high glass transition temperature (>
50°C) and insolubility in water of the polymer(s).
Furthermore, as is shown in Table 2 below, the bioavailability in dogs of Compound I when it is molecularly dispersed in an ionic polymer in accordance with 2o the invention was unexpectedly higher than when the compound was administered to the animals in conventional forms (e.g. micronized and wet milled). Also shown in Table 2 are the bioavailability results obtained from solid dispersion of Compound I
prepared by hot-melt method with Pluronic F68~ (non-ionic water soluble polymer containing poly-oxyethylene and polyoxypropylene chains, BASF). While the -2s biovailability of the Compound in this solid dispersion was better than when the compound was micronized or in wet mill suspension, the physical stability of the solid dispersion was not satisfactory for a pharmaceutical product as is evident by the reversion of compound to its crystalline form within one month of storage at ambient conditions. The above-described results demonstrate the unsuitability for preparation 30 of a pharmaceutical product of the solid dispersion technique in non-ionic water soluble polymers.
Table 2: Bioavailabilitv of Compound.l in doss after single oral dose administration (10m4/k4)* for four animals (2 males and 2 females) Formulation AUCo.eJDose % Bioavailability**
(ng.h/ml)/(mg/kg) Micronized drug suspension29.5 8.3 3.85 Exam le 1 Wet milled drug suspension86.1 13.7 11.2 Exam le 2 Pluronic F68 532 152 69.5 Solid Dispersion***
Exam le 3 Compound (/Polymer Complex529 189 69.1 Exam le 4 Compound (/Polymer Complex560 72 73.1 Exam le 5 Compound (/Polymer Complex588 3gg 76.8 Exam le 6 Compound (/Polymer Complex604 124 78.9 Exam le 7 Compound (/Polymer Complex768 387 100.3 Exam le 8 Compound (/Polymer Complex415 152 54.2 Exam le 9 Compound (/Polymer Complex264 152 34.5 Exam le 10 s * Results are mean values (with standard deviations) for four animals (2 males and 2 females).
** Compared to Single Dose Intravenous Administration.
*** Converts to crystalline form after exposure to 40°C, 75%RH, 1 wk, open io condition.
Figure 3 shows plasma concentration-time profile of different batches of the compound/polymer complex produced in accordance to Example 4. The results of these tests (summarized in Figure 3), show batch to batch reproducibility and is consistency. Batch to batch reproducibility and consistency is an important aspect of any formulation that is intended for administration to human patients.
Figures 4-7 show that Compounds II, III, IV and V also can be converted into amorphous form using this invention.
In summary, as is shown by the data in Tables 1 and 2 above and in Figures s 1, 2, and 4-7, the powder x-ray diffraction patterns of the compound/polymer(s) complexes obtained in Examples 4-16 shows that molecularly dispersing a poorly soluble compound in an ionic polymers) according to the present invention converts the compounds into amorphous form and maintains excellent stability of the amorphous compound upon long-term storage.
io
Claims (46)
1. A pharmaceutical composition comprising a water-insoluble complex of a therapeutically active, stable amorphous compound and a water-insoluble ionic polymer that has a molecular weight greater than about 80,000 D and a glass transition temperature equal to or greater than about 50°C, and a carrier.
2. The pharmaceutical composition of claim 1 wherein the therapeutically active compound is a compound that is poorly soluble when in crystalline form.
3. The pharmaceutical composition of claim 2 wherein the poorly soluble therapeutically active compound in its crystalline form has a solubility of less than 1 mg/mL in aqueous solution.
4. The pharmaceutical composition of claim 1 wherein the ionic polymer is a cationic polymer.
5. The pharmaceutical composition of claim 4 wherein the cationic polymer is a copolymer of dimethylaminoethylmethacrylate and neutral methacrylic ester.
6. The pharmaceutical composition of claim 5 wherein the cationic polymer is Eudragit E R.
7. The pharmaceutical composition of claim 1 wherein the ionic polymer is an anionic polymer.
8. The pharmaceutical composition of claim 7 wherein the anionic polymer is a copolymer of methacrylic acid and ethyl acrylate or methacrylic acid and methyl methacrylate.
9. The pharmaceutical composition of claim 8 wherein the anionic polymer is selected from the group consisting of Eudragit L 100-55R , Eudragit L-100R
and Eudragit S-100R.
and Eudragit S-100R.
10. The pharmaceutical composition of claim 7 wherein the anionic polymer is selected from the group consisting of polyvinyl acetate phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, cellulose acetate terphthalate, polycyanoacrylate and hydroxypropyl methyl cellulose acetyl succinate, carboxy methyl cellulose, and low substituted hydroxypropylcellulose.
11. The pharmaceutical composition of claim 1 wherein the solubility of the ionic polymer is pH dependent.
12. The pharmaceutical composition of claim 11 wherein the ionic polymer is insoluble at pH above about 4.
13. The pharmaceutical composition of claim 1 wherein the ionic polymer and the therapeutically active compound in its crystalline form are both relatively insoluble above pH of about 4.
14. The pharmaceutical composition of claim 11 wherein the ionic polymer is insoluble at pH below about 4.
15. The pharmaceutical composition of claim 1 wherein the ionic polymer and the therapeutically active compound in its crystalline form are both relatively insoluble at pH below about 4.
16. The pharmaceutical composition of claim 1 wherein the therapeutically active compound is selected from the group consisting of Compounds I, II, III, IV, V, VI, VII and VIII.
17. A pharmaceutical composition comprising a water-insoluble complex of Compound I in stable amorphous form and a water-insoluble ionic polymer that has a molecular weight greater than about 80,000 D and a glass transition temperature equal to or greater than about 50°C, and a carrier.
18. The pharmaceutical composition of claim 1 wherein the ionic polymer is.
present in the water-insoluble complex at not less than about 20%, by weight.
present in the water-insoluble complex at not less than about 20%, by weight.
19. The pharmaceutical composition of claim 18 wherein the therapeutically active compound is present in the water-insoluble complex at about 0.1% to about 80%, by weight of said complex.
20. The pharmaceutical composition of claim 19 wherein the therapeutically active compound is present in the water-insoluble complex at about 30% to about 70%, by weight of said complex.
21. The pharmaceutical composition of claim 20 wherein the ionic polymer is present in the water-insoluble complex at about 50%, by weight, and the therapeutically active compound is present at about 50%, by weight of said complex.
22. A method for preparing a pharmaceutical formulation comprising a water-insoluble complex of a stable, amorphous therapeutically active compound and an ionic polymer comprising:
(a) dissolving the therapeutically active compound and ionic polymer in a suitable solvent;
(b) contacting the solution of step (a) with an aqueous solution at a pH in which the ionic polymer is poorly soluble thereby microprecipitation the therapeutically active compound and ionic polymer as a compound/polymer complex;
(c) preparing a pharmaceutical formulation that includes the compound/ polymer complex of step (b) above.
(a) dissolving the therapeutically active compound and ionic polymer in a suitable solvent;
(b) contacting the solution of step (a) with an aqueous solution at a pH in which the ionic polymer is poorly soluble thereby microprecipitation the therapeutically active compound and ionic polymer as a compound/polymer complex;
(c) preparing a pharmaceutical formulation that includes the compound/ polymer complex of step (b) above.
23. The method of claim 22, wherein in step (a), the therapeutically active compound and the ionic polymer are dissolved in a solvent selected from the group consisting of ethyl alcohol, methyl alcohol, dimethylsulfoxide, dimethylacetamide, dimethyl formamide, N-methylpyrrolidone, Transcutol R (diethylene glycol monoethyl ether, Gattefosse), glycofural, propylene carbonate, tetrahydrofuran, polyethylene glycol and propylene glycol.
24. The method in claim 22 wherein in step (b), microprecipitation is carried out by removing the solvent by spray drying or lyophilizing.
25. The method of claim 22 wherein in step (a), the insoluble therapeutically active and the ionic compound polymer are dissolved by adjusting the pH.
26. The method of claim 22 wherein after step (b), residual solvent is removed.
27. The method of claim 26 wherein the residual solvent is removed by washing the compound/polymer complex.
28. The method of claim 26 wherein the residual solvent is removed by evaporation or drying.
29. The method of claim 28 wherein the residual solvent is removed by spray drying.
30. A method for preparing a pharmaceutical formulation comprising a water-insoluble complex of a stable, amorphous therapeutically active compound and an ionic polymer comprising:
(a) dissolving the therapeutically active compound, in its crystalline form, and ionic polymer in an organic solvent;
(b) contacting the product of step (a) with an aqueous solution at a pH at which the ionic polymer and the therapeutically active compound will precipitate as a compound/polymer matrix;
(c) washing the compound/polymer matrix;
(d) drying the compound/polymer matrix; and (e) preparing a pharmaceutical formulation that incorporates the washed and dried compound/polymer matrix of step (d) above.
(a) dissolving the therapeutically active compound, in its crystalline form, and ionic polymer in an organic solvent;
(b) contacting the product of step (a) with an aqueous solution at a pH at which the ionic polymer and the therapeutically active compound will precipitate as a compound/polymer matrix;
(c) washing the compound/polymer matrix;
(d) drying the compound/polymer matrix; and (e) preparing a pharmaceutical formulation that incorporates the washed and dried compound/polymer matrix of step (d) above.
31. The method of claim 30 wherein the therapeutically active compound that is incorporated in the compound/polymer matrix is predominantly in amorphous form.
32. The method of claim 31 wherein the ionic polymer is selected from the group consisting of Eudragit R E100, Eudragit R L100, Eudragit R L100-55 and Eudragit R S100.
33. A method for preparing a water-insoluble complex of a stable amorphous compound and an ionic polymer comprising:
(a) melting together the therapeutically active compound and the ionic polymer; and (b) cooling the mixture resulting from step (a).
(a) melting together the therapeutically active compound and the ionic polymer; and (b) cooling the mixture resulting from step (a).
34. A method for preparing a pharmaceutical formulation comprising a water-insoluble complex of a stable amorphous compound and an ionic polymer comprising:
(a) dissolving the therapeutically active compound and the ionic polymer in a supercritical fluid;
(b) removing the supercritical fluid resulting in the microprecipitation of the therapeutically active compound in the polymer matrix; and (c) preparing a pharmaceutically formulation that includes the product of step (b) above.
(a) dissolving the therapeutically active compound and the ionic polymer in a supercritical fluid;
(b) removing the supercritical fluid resulting in the microprecipitation of the therapeutically active compound in the polymer matrix; and (c) preparing a pharmaceutically formulation that includes the product of step (b) above.
35. The method of claim 34 wherein the supercritical fluid used in step (a) is selected from the group consisting of liquid nitrogen and liquid carbon dioxide.
36. The method of claim 34 wherein removal of the supercritical fluid in step (b) is accomplished by evaporation.
37. The method of claim 22, 30, 33, 34 or 35 wherein the therapeutically active compound is selected from the group consisting of Compounds I, II, III, IV, V, VI, VII and VIII.
38. A stable, water-insoluble complex prepared by (a) dissolving Compound I and a water-insoluble ionic polymer having a molecular weight greater than 80,000D and a glass transition temperature equal to or greater than 50°C in a suitable solvent; and (b) co-precipitating Compound I and the ionic polymer as a compound/polymer complex.
39. The complex of claim 38 wherein precipitation in step (b) in effected by contacting the solution of step (a) with an aqueous solution at a pH in which the ionic polymer is poorly soluble.
40. A water-insoluble complex comprising a stable, amorphous compound and a water-insoluble ionic polymer that has a molecular weight greater than 80,000 D and a glass transition temperature equal to or greater than 50°C.
41. The complex of claim 40 wherein the amorphous compound is poorly soluble in crystalline form.
42. A water-insoluble complex comprising Compound I in stable amorphous form and a water-insoluble ionic polymer that has a molecular weight greater than 80,000 D and a glass transition temperature equal to or greater than 50°C.
43. A method for stabilizing an amorphous compound comprising molecularly dispersing the compound in a water-insoluble ionic polymer that has a molecular weight greater than 80,000 D and a glass transition temperature equal to or greater than 50°C.
44. A method for converting a poorly soluble, crystalline compound to a stable amorphous form of said compound comprising molecularly dispersing said compound in a water-insoluble ionic polymer that has a molecular weight greater than 80,000 D and a glass transition temperature equal to or greater than 50°C.
45. A therapeutically active compound in stable amorphous form molecularly dispersed in a water-insoluble ionic polymer that has a molecular weight greater than 80,000 D and a glass transition temperature equal to or greater than 50°C.
46. The invention as herein before described.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10133698P | 1998-09-22 | 1998-09-22 | |
| US60/101,336 | 1998-09-22 | ||
| US13653199P | 1999-05-28 | 1999-05-28 | |
| US60/136,531 | 1999-05-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2282906A1 CA2282906A1 (en) | 2000-03-22 |
| CA2282906C true CA2282906C (en) | 2010-07-20 |
Family
ID=26798138
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2282906A Expired - Lifetime CA2282906C (en) | 1998-09-22 | 1999-09-20 | Stable complexes of poorly soluble compounds |
Country Status (33)
| Country | Link |
|---|---|
| US (1) | US6350786B1 (en) |
| EP (1) | EP0988863B2 (en) |
| JP (5) | JP2000095708A (en) |
| KR (1) | KR100362019B1 (en) |
| CN (1) | CN1201821C (en) |
| AR (2) | AR022096A1 (en) |
| AT (1) | ATE265232T1 (en) |
| AU (1) | AU770745B2 (en) |
| BR (1) | BR9904283A (en) |
| CA (1) | CA2282906C (en) |
| CO (1) | CO5140077A1 (en) |
| CZ (1) | CZ300215B6 (en) |
| DE (1) | DE69916733T3 (en) |
| DK (1) | DK0988863T4 (en) |
| ES (1) | ES2218918T5 (en) |
| HK (1) | HK1026632A1 (en) |
| HR (1) | HRP990287B1 (en) |
| HU (1) | HU228341B1 (en) |
| ID (1) | ID24034A (en) |
| IL (1) | IL131957A (en) |
| MA (1) | MA26692A1 (en) |
| MY (1) | MY124377A (en) |
| NO (1) | NO326928B1 (en) |
| NZ (1) | NZ337884A (en) |
| PE (1) | PE20001049A1 (en) |
| PL (1) | PL202757B1 (en) |
| PT (1) | PT988863E (en) |
| RS (1) | RS50193B (en) |
| RU (1) | RU2240827C2 (en) |
| SG (1) | SG97131A1 (en) |
| SI (1) | SI0988863T2 (en) |
| TR (1) | TR199902324A2 (en) |
| TW (1) | TWI234465B (en) |
Families Citing this family (85)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1027886B1 (en) | 1999-02-10 | 2008-07-09 | Pfizer Products Inc. | Pharmaceutical solid dispersions |
| US6440959B1 (en) * | 1999-04-21 | 2002-08-27 | Hoffman-La Roche Inc. | Pyrazolobenzodiazepines |
| AR033651A1 (en) * | 1999-10-01 | 2004-01-07 | Hoffmann La Roche | DERIVATIVES OF PYRIMIDINE-2,4,6-TRIONA, PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS AND THE USE OF THEM FOR THE MANUFACTURE OF A MEDICINAL PRODUCT |
| US6313143B1 (en) * | 1999-12-16 | 2001-11-06 | Hoffmann-La Roche Inc. | Substituted pyrroles |
| AU5543801A (en) * | 2000-05-16 | 2001-11-26 | Ortho Mcneil Pharm Inc | Process for coating medical devices using super-critical carbon dioxide |
| US6469179B1 (en) | 2000-10-03 | 2002-10-22 | Hoffmann-La Roche Inc. | Amorphous form of cell cycle inhibitor having improved solubility and bioavailability |
| US6482847B2 (en) * | 2000-10-03 | 2002-11-19 | Hoffmann-La Roche Inc. | Amorphous form of cell cycle inhibitor having improved solubility and bioavailability |
| US20050048126A1 (en) | 2000-12-22 | 2005-03-03 | Barrett Rabinow | Formulation to render an antimicrobial drug potent against organisms normally considered to be resistant to the drug |
| US9700866B2 (en) | 2000-12-22 | 2017-07-11 | Baxter International Inc. | Surfactant systems for delivery of organic compounds |
| US8067032B2 (en) | 2000-12-22 | 2011-11-29 | Baxter International Inc. | Method for preparing submicron particles of antineoplastic agents |
| US6548531B2 (en) | 2001-02-09 | 2003-04-15 | Hoffmann-La Roche Inc. | Method for cancer therapy |
| US6716845B2 (en) | 2001-03-30 | 2004-04-06 | Hoffmann-La Roche Inc. | Barbituric acid derivatives |
| DE10296849T5 (en) * | 2001-05-30 | 2004-04-29 | Csir Corporate Building Scientia | Process for encapsulating an active substance |
| US20030044514A1 (en) * | 2001-06-13 | 2003-03-06 | Richard Robert E. | Using supercritical fluids to infuse therapeutic on a medical device |
| WO2002102373A1 (en) * | 2001-06-15 | 2002-12-27 | F. Hoffmann-La Roche Ag | Method for administration of cancer therapeutic |
| ES2333645T3 (en) | 2001-06-22 | 2010-02-25 | Bend Research, Inc. | PHARMACEUTICAL COMPOSITIONS OF DISPERSIONS OF MEDICINES AND NEUTRAL POLYMERS. |
| KR20040011549A (en) | 2001-06-22 | 2004-02-05 | 화이자 프로덕츠 인크. | Pharmaceutical Compositions Comprising Low-Solubility and/or Acid-Sensitive Drugs and Neutralized Acidic Polymers |
| US20060003012A9 (en) | 2001-09-26 | 2006-01-05 | Sean Brynjelsen | Preparation of submicron solid particle suspensions by sonication of multiphase systems |
| BR0212833A (en) | 2001-09-26 | 2004-10-13 | Baxter Int | Preparation of submicron sized nanoparticles by dispersion and solvent or liquid phase removal |
| US20030139373A1 (en) * | 2001-11-20 | 2003-07-24 | Breimer Lars Holger | Method for cancer therapy |
| KR100664822B1 (en) | 2002-02-01 | 2007-01-04 | 화이자 프로덕츠 인코포레이티드 | Method for making homogeneous spray-dried solid amorphous drug dispersions utilizing modified spray-drying apparatus |
| ES2333318T3 (en) | 2002-08-12 | 2010-02-19 | Bend Research, Inc. | PHARMACEUTICAL COMPOSITIONS OF MEDICINES WITH SEMIORDENATED STRUCTURE AND OF POLYMER. |
| DE10351087A1 (en) * | 2003-10-31 | 2005-05-25 | Bayer Technology Services Gmbh | Solid active ingredient formulation |
| WO2005046697A1 (en) * | 2003-11-14 | 2005-05-26 | Ajinomoto Co., Inc. | Sustained-release phenylalanine derivative preparation for oral administration |
| WO2005046696A1 (en) * | 2003-11-14 | 2005-05-26 | Ajinomoto Co., Inc. | Solid dispersion or medicinal solid dispersion preparation of phenylalanine derivative |
| KR100771411B1 (en) * | 2004-04-01 | 2007-10-30 | 에프. 호프만-라 로슈 아게 | Cyclodextrin inclusions complexes of pyrimidine-2,4,6-triones |
| AR049915A1 (en) * | 2004-06-14 | 2006-09-13 | Anacor Pharmaceuticals Inc | COMPOUNDS WITH BORO CONTENT AND METHODS OF USE OF THE SAME |
| WO2006062980A2 (en) * | 2004-12-07 | 2006-06-15 | Nektar Therapeutics | Stable non-crystalline formulation comprising tiagabine |
| JP5209876B2 (en) * | 2004-12-28 | 2013-06-12 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Quick disintegrating tablet and method for producing the same |
| US8604055B2 (en) | 2004-12-31 | 2013-12-10 | Dr. Reddy's Laboratories Ltd. | Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors |
| ES2644450T3 (en) | 2004-12-31 | 2017-11-29 | Dr. Reddy's Laboratories Ltd. | New benzylamine derivatives as CETP inhibitors |
| EP1690528A1 (en) * | 2005-02-11 | 2006-08-16 | Abbott GmbH & Co. KG | Process for the preparation of dosage forms comprising a solid dispersion of a microcrystalline active agent |
| US20080274192A1 (en) * | 2005-05-19 | 2008-11-06 | Pfizer Inc. | Pharmaceutical Compositions Comprising an Amorphous Form of a Vegf-R-Inhibitor |
| EP1767194A1 (en) * | 2005-06-09 | 2007-03-28 | Helm AG | Process for the preparation of adsorbates of drospirenone |
| DK1893612T3 (en) * | 2005-06-22 | 2011-11-21 | Plexxikon Inc | Pyrrole [2,3-B] pyridine derivatives as protein kinase inhibitors |
| US20080031944A1 (en) * | 2006-08-04 | 2008-02-07 | Cima Labs Inc. | Stabilization of lorazepam |
| UY30535A1 (en) * | 2006-08-10 | 2008-03-31 | Cipla Ltd | COMPOSITION UNDERSTANDING ANTIRRETROVIRAL PHARMACOS AND AT LEAST AN INSOLUBLE WATER POLYMER, PREPARATION PROCESS AND APPLICATIONS. |
| US20080107725A1 (en) * | 2006-10-13 | 2008-05-08 | Albano Antonio A | Pharmaceutical Solid Dosage Forms Comprising Amorphous Compounds Micro-Embedded in Ionic Water-Insoluble Polymers |
| WO2008063888A2 (en) | 2006-11-22 | 2008-05-29 | Plexxikon, Inc. | Compounds modulating c-fms and/or c-kit activity and uses therefor |
| PE20081581A1 (en) * | 2006-12-21 | 2008-11-12 | Plexxikon Inc | PIRROLO [2,3-b] PYRIDINES COMPOUNDS AS KINASE MODULATORS |
| WO2008079909A1 (en) * | 2006-12-21 | 2008-07-03 | Plexxikon, Inc. | Pyrrolo [2,3-b] pyridines as kinase modulators |
| WO2008081829A1 (en) | 2006-12-27 | 2008-07-10 | Astellas Pharma Inc. | Aminoalkylmethacrylate copolymer e for maintaining solubility of poorly water-soluble drug |
| EP2155166A2 (en) * | 2007-05-11 | 2010-02-24 | F. Hoffmann-Roche AG | Pharmaceutical compositions for poorly soluble drugs |
| US8426467B2 (en) | 2007-05-22 | 2013-04-23 | Baxter International Inc. | Colored esmolol concentrate |
| US8722736B2 (en) | 2007-05-22 | 2014-05-13 | Baxter International Inc. | Multi-dose concentrate esmolol with benzyl alcohol |
| EP1997479A1 (en) * | 2007-05-31 | 2008-12-03 | Helm AG | Stabilized amorphous candesartan cilexetil compositions for oral administration |
| MX2010000617A (en) | 2007-07-17 | 2010-05-17 | Plexxikon Inc | Compounds and methods for kinase modulation, and indications therefor. |
| BRPI0816513A2 (en) * | 2007-10-19 | 2015-03-24 | Purdue Research Foundation | Pharmaceutical composition and method for preparing the solid suspension |
| US8632805B2 (en) * | 2008-06-20 | 2014-01-21 | Mutual Pharmaceutical Company, Inc. | Controlled-release formulations, method of manufacture, and use thereof |
| US7794750B2 (en) * | 2008-06-20 | 2010-09-14 | Mutual Pharmaceutical Company, Inc. | Controlled-release formulations, method of manufacture, and use thereof |
| WO2010044842A1 (en) * | 2008-10-16 | 2010-04-22 | University Of Tennessee Research Foundation | Tamper resistant oral dosage forms containing an embolizing agent |
| KR20100073454A (en) * | 2008-12-23 | 2010-07-01 | 국립암센터 | Novel pyrazolodiazepine compound as an transglutaminase inhibitor, the preparation method thereof and a composition containing the same |
| WO2010114928A2 (en) * | 2009-04-03 | 2010-10-07 | F.Hoffmann-La Roche Ag | Compositions and uses thereof |
| US8329724B2 (en) | 2009-08-03 | 2012-12-11 | Hoffmann-La Roche Inc. | Process for the manufacture of pharmaceutically active compounds |
| NZ629615A (en) | 2009-11-06 | 2016-01-29 | Plexxikon Inc | Compounds and methods for kinase modulation, and indications therefor |
| EP2581084A4 (en) * | 2010-05-31 | 2014-06-25 | Astellas Pharma Inc | Solid dispersion comprising triazole compound |
| JP5941069B2 (en) | 2011-02-07 | 2016-06-29 | プレキシコン インコーポレーテッドＰｌｅｘｘｉｋｏｎ Ｉｎｃ． | Compounds and methods for kinase regulation and indications therefor |
| RU2013139701A (en) | 2011-02-17 | 2015-03-27 | Ф. Хоффманн-Ля Рош Аг | METHOD FOR CONTROLLED CRYSTALLIZATION OF AN ACTIVE PHARMACEUTICAL INGREDIENT FROM THE STATE OF A COOLED LIQUID BY EXTRUSION OF HOT DECAY |
| AR085279A1 (en) | 2011-02-21 | 2013-09-18 | Plexxikon Inc | SOLID FORMS OF {3- [5- (4-CHLORINE-PHENYL) -1H-PIRROLO [2,3-B] PIRIDINA-3-CARBONIL] -2,4-DIFLUOR-PHENIL} -AMIDE OF PROPANE ACID-1- SULFONIC |
| US9199967B2 (en) | 2011-08-18 | 2015-12-01 | Dr. Reddy's Laboratories Ltd. | Substituted heterocyclic amine compounds as cholestryl ester-transfer protein (CETP) inhibitors |
| WO2013037396A1 (en) * | 2011-09-12 | 2013-03-21 | Bioneer A/S | Solution of polymer in api for a solid dosage form |
| CN103958511A (en) | 2011-09-27 | 2014-07-30 | 雷迪博士实验室有限公司 | 5 - benzylaminomethyl - 6 - aminopyrazolo [3, 4 -b] pyridine derivatives as cholesteryl ester -transfer protein (cetp) inhibitors useful for the treatment of atherosclerosis |
| CA2852058C (en) | 2011-10-14 | 2021-06-01 | Array Biopharma Inc. | A solid dispersion of n4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-n6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine |
| EP2827900B1 (en) | 2012-03-23 | 2018-03-21 | Array Biopharma, Inc. | Amorphous solid dispersion for use in the treatment of brain cancer |
| US20140128431A1 (en) | 2012-04-03 | 2014-05-08 | Hoffmann-Laroche Inc. | Pharmaceutical composition with improved bioavailability, safety and tolerability |
| EP2649989B1 (en) | 2012-04-13 | 2017-10-18 | King Saud University | Method for preparing a solid dispersion, solid dispersion obtained thereby and use thereof |
| US9150570B2 (en) | 2012-05-31 | 2015-10-06 | Plexxikon Inc. | Synthesis of heterocyclic compounds |
| JO3339B1 (en) * | 2012-09-11 | 2019-03-13 | Shanghai Inst Pharmaceutical Ind | Stabilised amorphous form of agomelatine, a process for its preparation and pharmaceutical compositions containing it |
| US20170071930A1 (en) | 2012-11-19 | 2017-03-16 | Dr. Reddy's Laboratories Ltd. | Pharmaceutical compositions of cetp inhibitors |
| EP2934486A2 (en) * | 2012-12-20 | 2015-10-28 | Kashiv Pharma, LLC | Orally disintegrating tablet formulation for enhanced bioavailability |
| MY192032A (en) | 2013-01-22 | 2022-07-24 | Hoffmann La Roche | Pharmaceutical composition with improved bioavailability |
| TWI615157B (en) | 2013-02-06 | 2018-02-21 | 大塚製藥股份有限公司 | Solid dispersion comprising amorphous cilostazol |
| WO2015038376A1 (en) * | 2013-09-11 | 2015-03-19 | 3M Innovative Properties Company | Coating compositions, dental structures thereof and methods for generating contrast |
| WO2015082562A1 (en) * | 2013-12-05 | 2015-06-11 | Alrise Biosystems Gmbh | Process for the production of drug formulations for oral administration |
| PT107846B (en) * | 2014-08-01 | 2019-03-22 | Hovione Farm S A | Production of Amorphous Solid Dispersion Nanoparticles by Controlled Co-Precipitation |
| JP2018516262A (en) * | 2015-05-29 | 2018-06-21 | サン ファーマシューティカル インダストリーズ リミテッドＳｕｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｉｎｄｕｓｔｒｉｅｓ Ｌｔｄ． | Oral pharmaceutical composition of isotretinoin |
| CA3041155C (en) * | 2016-12-13 | 2021-12-14 | Nanjing Transthera Biosciences Co., Ltd. | Multi-kinase inhibitor compound, and crystal form and use thereof |
| MA49059A (en) | 2017-04-28 | 2021-03-24 | Seagen Inc | TREATMENT OF POSITIVE HER2 CANCERS |
| KR102082775B1 (en) * | 2017-05-02 | 2020-02-28 | 주식회사 삼양바이오팜 | Formulation with enhanced water solubility and bioavailability |
| RU2725879C2 (en) * | 2018-07-26 | 2020-07-07 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Казанский Государственный медицинский университет" Министерства здравоохранения Российской Федерации | Interpolymer carrier for oral systems of controlled delivery of active pharmaceutical ingredients |
| WO2020114853A1 (en) | 2018-12-03 | 2020-06-11 | H. Lundbeck A/S | Prodrugs of 4-((1r,3s)-6-chloro-3-phenyl-2,3-dihydro-1h-inden-1-yl)-1,2,2-trimethylpiperazine and 4-((1/r,3s)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1h-inden-1-yl)-2,2-dimethy-1-(methyl-d3)piperazine |
| AU2021210974A1 (en) | 2020-01-24 | 2022-09-22 | Nanocopoeia, Llc | Amorphous solid dispersions of dasatinib and uses thereof |
| AU2021212258A1 (en) | 2020-01-31 | 2022-09-29 | Nanocopoeia, Llc | Amorphous nilotinib microparticles and uses thereof |
| KR20220129628A (en) | 2020-03-03 | 2022-09-23 | 데쿠세리아루즈 가부시키가이샤 | Method for manufacturing an image display device |
| WO2021222739A1 (en) | 2020-04-30 | 2021-11-04 | Nanocopoeia, Llc | Orally disintegrating tablet comprising amorphous solid dispersion of nilotinib |
Family Cites Families (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS51118816A (en) * | 1975-04-08 | 1976-10-19 | Meiji Seika Kaisha Ltd | A process for stabilizing non-crystalloidal solid |
| US4344934A (en) * | 1978-11-20 | 1982-08-17 | American Home Products Corporation | Therapeutic compositions with enhanced bioavailability |
| EP0224249A1 (en) * | 1985-11-27 | 1987-06-03 | Syntex (U.S.A.) Inc. | Amorphous benzimidazole derivatives |
| CZ280738B6 (en) * | 1988-02-10 | 1996-04-17 | F. Hoffmann - La Roche And Co., Aktiengesellschaft | Substituted pyrroles, their use for preparing medicaments and medicaments based thereon |
| JP2528706B2 (en) † | 1988-05-30 | 1996-08-28 | ゼリア新薬工業株式会社 | Pharmaceutical composition of dihydropyridine compound |
| USRE36736E (en) | 1989-02-06 | 2000-06-13 | Hoffman-La Roche Inc. | Substituted pyrroles |
| JPH0729926B2 (en) † | 1989-07-25 | 1995-04-05 | 大塚製薬株式会社 | Composition for easily absorbable preparations |
| US5399363A (en) | 1991-01-25 | 1995-03-21 | Eastman Kodak Company | Surface modified anticancer nanoparticles |
| CA2108575C (en) † | 1991-04-16 | 2002-10-22 | Kouichi Nakamichi | Method of manufacturing solid dispersion |
| US5281420A (en) | 1992-05-19 | 1994-01-25 | The Procter & Gamble Company | Solid dispersion compositions of tebufelone |
| TW493991B (en) | 1995-05-08 | 2002-07-11 | Novartis Ag | Pharmaceutical composition for oral administration of active agent having low water solubility and process for preparation of the same |
| GB9511220D0 (en) † | 1995-06-02 | 1995-07-26 | Glaxo Group Ltd | Solid dispersions |
| ATE240734T1 (en) * | 1995-07-26 | 2003-06-15 | Kyowa Hakko Kogyo Kk | PREPARATION OF XANTHINDERIVATES AS A SOLID DISPERSION |
| JPH11514979A (en) † | 1995-09-07 | 1999-12-21 | フイズ テクノロジーズ リミテッド | Bioavailable system for virtually insoluble bioactive agents |
| DE19548624A1 (en) | 1995-12-23 | 1997-06-26 | Boehringer Mannheim Gmbh | New barbituric acid derivatives, processes for their preparation and medicaments containing these compounds |
| JPH09208459A (en) * | 1996-02-07 | 1997-08-12 | Eisai Co Ltd | Preparation improved in solubility |
| ATE314843T1 (en) | 1996-03-12 | 2006-02-15 | Pg Txl Co Lp | WATER SOLUBLE PACLITAXEL PRODRUGS |
| EP0954288B1 (en) * | 1996-06-28 | 2004-08-11 | Schering Corporation | Solid solution of an antifungal agent with enhanced bioavailability |
| PE91598A1 (en) | 1996-07-29 | 1998-12-24 | Hoffmann La Roche | SUBSTITUTED PYRROLES |
| US6229011B1 (en) | 1997-08-22 | 2001-05-08 | Hoffman-La Roche Inc. | N-aroylphenylalanine derivative VCAM-1 inhibitors |
| DE69909068T2 (en) | 1998-03-17 | 2004-05-06 | F. Hoffmann-La Roche Ag | SUBSTITUTED BISINDOLYLMALEIMIDES FOR INHIBITING CELL PROLIFERATION |
-
1999
- 1999-09-07 US US09/391,060 patent/US6350786B1/en not_active Expired - Lifetime
- 1999-09-13 AT AT99117908T patent/ATE265232T1/en active
- 1999-09-13 SI SI9930573T patent/SI0988863T2/en unknown
- 1999-09-13 ES ES99117908T patent/ES2218918T5/en not_active Expired - Lifetime
- 1999-09-13 EP EP99117908A patent/EP0988863B2/en not_active Expired - Lifetime
- 1999-09-13 PT PT99117908T patent/PT988863E/en unknown
- 1999-09-13 DK DK99117908T patent/DK0988863T4/en active
- 1999-09-13 DE DE69916733T patent/DE69916733T3/en not_active Expired - Lifetime
- 1999-09-16 IL IL13195799A patent/IL131957A/en not_active IP Right Cessation
- 1999-09-17 CZ CZ0330499A patent/CZ300215B6/en not_active IP Right Cessation
- 1999-09-17 PE PE1999000947A patent/PE20001049A1/en not_active IP Right Cessation
- 1999-09-17 NZ NZ337884A patent/NZ337884A/en not_active IP Right Cessation
- 1999-09-17 SG SG9904570A patent/SG97131A1/en unknown
- 1999-09-17 CO CO99059117A patent/CO5140077A1/en unknown
- 1999-09-20 AU AU48807/99A patent/AU770745B2/en not_active Expired
- 1999-09-20 HU HU9903189A patent/HU228341B1/en unknown
- 1999-09-20 CA CA2282906A patent/CA2282906C/en not_active Expired - Lifetime
- 1999-09-20 MY MYPI99004065A patent/MY124377A/en unknown
- 1999-09-20 HR HR990287 patent/HRP990287B1/en not_active IP Right Cessation
- 1999-09-20 ID IDP990878D patent/ID24034A/en unknown
- 1999-09-20 AR ARP990104725A patent/AR022096A1/en not_active Application Discontinuation
- 1999-09-20 TW TW088116184A patent/TWI234465B/en not_active IP Right Cessation
- 1999-09-21 JP JP11267142A patent/JP2000095708A/en not_active Withdrawn
- 1999-09-21 TR TR1999/02324A patent/TR199902324A2/en unknown
- 1999-09-21 RS YUP-473/99A patent/RS50193B/en unknown
- 1999-09-21 RU RU99120377/15A patent/RU2240827C2/en active
- 1999-09-21 MA MA25778A patent/MA26692A1/en unknown
- 1999-09-21 NO NO19994583A patent/NO326928B1/en not_active IP Right Cessation
- 1999-09-21 CN CNB991194063A patent/CN1201821C/en not_active Expired - Lifetime
- 1999-09-21 BR BR9904283-5A patent/BR9904283A/en not_active Application Discontinuation
- 1999-09-22 PL PL335592A patent/PL202757B1/en unknown
- 1999-09-22 KR KR1019990041130A patent/KR100362019B1/en active IP Right Grant
-
2000
- 2000-09-19 HK HK00105891A patent/HK1026632A1/en not_active IP Right Cessation
-
2007
- 2007-06-06 JP JP2007150911A patent/JP2007224048A/en active Pending
-
2011
- 2011-04-13 AR ARP110101253A patent/AR080892A2/en not_active Application Discontinuation
-
2012
- 2012-10-18 JP JP2012230446A patent/JP6253135B2/en not_active Expired - Lifetime
-
2015
- 2015-07-16 JP JP2015141952A patent/JP2015187170A/en active Pending
-
2016
- 2016-08-31 JP JP2016169245A patent/JP6534979B2/en not_active Expired - Lifetime
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2282906C (en) | Stable complexes of poorly soluble compounds | |
| US5573783A (en) | Redispersible nanoparticulate film matrices with protective overcoats | |
| EP1039909B1 (en) | Method of production and composition of an oral preparation of itraconazole | |
| EP0955041B1 (en) | Aqueous dispersion useful for the production of coating and binding means for oral solid medicament | |
| CN104159574A (en) | A method for producing stable, amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one polymeric stabilizing and matrix- forming component | |
| JPS63165318A (en) | Light-stable nifedipin concentrate and manufacture | |
| CA2393737A1 (en) | Compositions containing itraconazole with improved bioavailability and narrow intra- and inter-individual variation of its absorption | |
| Wang et al. | Ginkgolides-loaded soybean phospholipid-stabilized nanosuspension with improved storage stability and in vivo bioavailability | |
| WO2021156223A1 (en) | Nanoformulations of methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate | |
| JP2005515224A (en) | Drug nanoparticles from template emulsion | |
| MXPA04008137A (en) | Sustained release preparations and process for producing the same. | |
| Tripathy et al. | Solid dispersion: A technology for improving aqueous solubility of drug | |
| CN114533735A (en) | Lurasidone hydrochloride pharmaceutical composition and preparation method thereof | |
| MXPA99008648A (en) | Stable compounds of low solub compounds | |
| KR20230025062A (en) | Long-acting injectable suspension of crystalline montelukast and preparation method thereof | |
| CA2388614A1 (en) | Pharmaceutical agent preparations |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20190920 |