WO2000059627A1 - Formulation arrays and use thereof - Google Patents
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- WO2000059627A1 WO2000059627A1 PCT/US2000/008589 US0008589W WO0059627A1 WO 2000059627 A1 WO2000059627 A1 WO 2000059627A1 US 0008589 W US0008589 W US 0008589W WO 0059627 A1 WO0059627 A1 WO 0059627A1
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Classifications
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- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
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- 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
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- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00277—Apparatus
- B01J2219/00279—Features relating to reactor vessels
- B01J2219/00306—Reactor vessels in a multiple arrangement
- B01J2219/00313—Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
- B01J2219/00315—Microtiter plates
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00277—Apparatus
- B01J2219/00279—Features relating to reactor vessels
- B01J2219/00306—Reactor vessels in a multiple arrangement
- B01J2219/00313—Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
- B01J2219/00315—Microtiter plates
- B01J2219/00317—Microwell devices, i.e. having large numbers of wells
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
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- B01J2219/00351—Means for dispensing and evacuation of reagents
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00277—Apparatus
- B01J2219/00351—Means for dispensing and evacuation of reagents
- B01J2219/00378—Piezo-electric or ink jet dispensers
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/00603—Making arrays on substantially continuous surfaces
- B01J2219/00659—Two-dimensional arrays
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/0068—Means for controlling the apparatus of the process
- B01J2219/00686—Automatic
- B01J2219/00689—Automatic using computers
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
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- B01J2219/0068—Means for controlling the apparatus of the process
- B01J2219/00702—Processes involving means for analysing and characterising the products
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00718—Type of compounds synthesised
- B01J2219/0072—Organic compounds
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
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- B01J2219/00718—Type of compounds synthesised
- B01J2219/00745—Inorganic compounds
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00718—Type of compounds synthesised
- B01J2219/00756—Compositions, e.g. coatings, crystals, formulations
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- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B40/00—Libraries per se, e.g. arrays, mixtures
- C40B40/18—Libraries containing only inorganic compounds or inorganic materials
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- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B60/00—Apparatus specially adapted for use in combinatorial chemistry or with libraries
- C40B60/14—Apparatus specially adapted for use in combinatorial chemistry or with libraries for creating libraries
Definitions
- This invention is generally in the field of methods and systems for developing optimized formulations for health care products, consumer products, agricultural products, nutraceutical products, pharmaceutical formulations, veterinary products, foods, research reagents, and industrial products, by simultaneous and sequential processing and assaying of formulations.
- Most drug formulations are developed by adaptation of existing formulations to new drugs to achieve the desired delivery characteristics.
- compounds that are to be delivered orally are usually packaged in a capsule or tablet, optionally including an enteric coating or controlled release formulation.
- Compounds that are to be delivered topically are formulated in a gel or transdermal patch, again using a carrier that has previously been developed for delivery of other drugs.
- pharmacokinetics mathematically describes the amount of drug present in the bloodstream over time and significantly impacts a drug's efficacy and safety profile. Improved pharmacokinetics could increase compliance and lower healthcare costs.
- Optimal formulations can be developed by taking into consideration the solubility and stability of the drug to be delivered, the biological properties of the drug, the release or delivery requirements, the ease of manufacturing, the avoidance of systemic toxicity due to the components of the formulation, and many other factors, such as cost of manufacture, and even packaging requirements. Some products require only freeze drying for the formulation, but the packaging is critical to keeping the final product dry or to avoid light or other factors negatively impacting stability.
- new formulations are prepared and tested for bioequivalence to a formulation that is approved or commercially available.
- the formulations are initially optimized in vitro for their pharmacokinetics, such as absorption through the gut (for an oral preparation), skin (for transdermal application), or mucosa (for nasal, buccal, vaginal or rectal formulation), solubility, degradation or clearance by uptake into the reticuloendothelial system ("RES"), metabolism or elimination, then tested in vivo.
- the formulation is optimized based on microstructure of the drug, the carrier, or the combination of the two components.
- Microstructure includes crystalline or amorphous structures, or combinations thereof, polymorphs, solvates, hydrates, isomorphic desolvates, glasses, solid solutions, and specific unit cells such as hexagonal packing orders, ionic crystals, holes or interstitial spaces, and lattices.
- Other microstructures can include, or be influenced by the presence of, structures such as enantiomers or racemic forms or mixtures, of the active agents.
- Figure 1 is a schematic of the method to optimize formulations.
- Figures 2a and 2b is a more detailed schematic of a process to formulate and analyze multiple samples, for parameters such as solubility (UV-Vis HPLC) and oral absorbance, wherein Figure 2a is a schematic of the process wherein solids are deposited in the array, then reconstituted and screened; and Figure 2b is a schematic of the process wherein liquids are deposited into an array, dried, reconstituted and then separated into liquids and solids and screened.
- Figure 3a is a graph of the solubility (absorbance) of 3,500 unique formulations containing antibiotic-antifungal with various excipients in water.
- Figure 3b is a graph of the data in Figure 3a plotted to show standard deviations for each of the unique formulations.
- Figure 4 is a graph comparing solubility (absorbance) of the commercially available drug with five lead formulations (TPI-1 to TPI-5).
- Figure 5 is a graph of the ratio of the solubility of various reformulations of one of the lead formulations, TPI-3, reformulated with only one or two of the three excipients shown in relative ratios in the accompanying "pie”.
- Figure 6 is a graph of the ratio of the solubility of various reformulations of a lead formulation, TPI- 1 , comparing the effect of reformulating the formulation with one or two of the three excipients in the lead formulation, demonstrating that some excipients actually decrease solubility.
- Figure 7 is a graph of the ratio of the solubility of various reformulations of one lead formulation, TPI-2, showing the effect of reformulating the formulation with one or two of the three excipients in the lead formulation, demonstrating that some excipients have a synergistic effect on solubility.
- Figure 8 is a graph comparing rates of dissolution and equilibrium solubilities for TPI-2 and the antibiotic-antifungal, showing TPI-2 having a higher rate of dissolution as well as a higher equilibrium solubility compared to the antibiotic-antifungal.
- the method includes the initial step of selecting one or more variables of a drug formulation to be optimized, then formulating the drug using a large number of combinations of the variable(s) to create a formulation library within an array and screening for the desired bioactivity, physical, chemical or other properties.
- the methods include the steps of identifying one or more active compounds which are to be formulated (or reformulated); selecting at least one criteria for optimization such as poor bioavailability
- screening can be performed at very high inputs - for example, more than 100,000 formulations / day.
- compositions refer to combinations of two or more components.
- the compositions, not the components, are subjected to screening to determine the optimal formulations. This is not a screening technique to identify compounds having a particular activity, but rather screening of novel formulations of known compounds to identify those formulations with the most desirable properties.
- nanoscale refers to formulations or components thereof being present in individual formulations in nanogram quantities; microscale refers to formulations or components thereof being present in individual formulations in microgram quantities.
- “Microarrays” refer to array plates, reservoirs or other sample retaining means for many very small quantities at separate sites on or in a support means. Sample formulations typically consist of less than one gram (1000 mg).
- the samples consist of less than 100 micrograms (either of individual components or the formulation as a whole). In a more preferred embodiment, the samples consist of less than 25 micrograms.
- High throughput refers to the number of samples generated or screened as described herein, typically at least 10, more typically at least 50 to 100, and preferably more than 1000 samples.
- Automated refers to either high throughput in the range of 100 or more samples being generated or generation using software to formulate the samples.
- components can be biologically active molecules such as nucleotide molecules, proteins or peptides, polysaccharides or sugars, or combinations thereof, foods, nutrients, cosmetics or fragrances, dyes.
- Components can also be carriers for delivery of drugs, reagents for stabilization or excipients altering release, or even packaging or processing reagents or variables.
- components can be catalysts, surfactants, optical enhancers, dyes, and other common ingredients of materials such as detergents, coatings, paints, and lubricants.
- the components may be herbicides, pesticides, fertilizers or growth enhancers, as well as oils, stabilizers, and surfactants which are important to application, stability and function of the active ingredients.
- compositions refer to mixtures of two or more components or to a library in which one or more variable such as concentration of one or more component is varied.
- the libraries are constructed using systematic combinations of two or more components, for example, by varying concentrations of drug and selection and concentration of one or more excipients, as demonstrated in the following examples, in a grid or array (i.e., an ordered set of components) such as a 96 well plate, nano- or microarray.
- a grid or array i.e., an ordered set of components
- the system is automated to control mixing or blending of the components.
- compositions can be prepared prior to insertion into the grid for testing, for example, drug containing microspheres could be prepared by varying drug concentration in an aerosol which is spray dried into each well, yielding microspheres of drug within a carrier matrix, each having a different drug concentration.
- libraries are screened using automated screens, for example, testing initially for solubility (for example by optical absorbance), then testing lead candidates for oral absorption and then bioavailability using additional in vitro screening or animal testing. Testing can be done simultaneously or sequentially. Multiple formulations will typically be identified at each step of the testing, then subjected to additional testing. These compositions are further analyzed to determine the optimal formulations or combinations of components in the formulations.
- Components can be generally divided into active components, such as drugs, foods, nutrients, cosmetics or fragrances, and other components which may affect stability, solubility or rate of dissolution, release, or pharmacokinetics.
- Other components can be physical or chemical components that are used to alter the final composition.
- components may be materials used as drug carriers, hygroscopic compounds to lower water content of materials in the formulation as packaged or packaging which maintains a particular water content, reactants which are inert in the composition when initially formulated but which are intended to alter the composition at its ultimate site of application or use, such as pore forming agents and pH modifying compounds, stabilizers, components which increase adhesion at the site of application, surfactants which enhance solubility, dispersion, or dissolution, etc.
- solubility refers to the equilibrium solubility or steady state (and is usually measured as amount/volume solvent) and dissolution refers to the rate of dissolution (which is usually measured as amount/volume/unit time).
- the goal is to obtain formulations which are optimized for an intended purpose.
- Representative purposes include chemical and/or physical stability of the drug and/or formulation during manufacturing, packaging, distribution, storage and administration (as it relates to the active component(s) as well as to the formulation as a whole, and components thereof), drug uptake, drug half-life after administration to a patient, pharmaceutical properties, delivery kinetics, and other factors which determine the efficacy and economics of a drug.
- the drug may have a single property that negatively affects uptake, such as hydrophobicity or low solubility. In other cases, it may be a combination of properties.
- the screening process will typically vary at least one component of the formulation, and more typically, multiple components of the formulation, and select based on one or more properties of the formulation as a whole.
- bioactive molecules include therapeutic, prophylactic and diagnostic molecules, which can be proteins or peptides, nucleosides or nucleotide molecules, polysaccharides or sugars, or synthetic chemical entities, or combinations thereof.
- the bioactives are drugs.
- the drugs are small molecule drugs.
- Preferred drugs are those which are already approved for at least one indication.
- Most preferred drugs are those which can be administered orally, and which exhibit undesirable stability, processing, bioavailability or taste characteristics (due to problems with dissolution, absorption, duration, or other) that can be modified by reformulation.
- ZOCAR® or simvastatin examples include ZOCAR® or simvastatin, a statin administered orally in tablet form to lower cholesterol, which is characterized by very low solubility in water, and undergoes extensive first pass metabolism in the liver.
- Another example is LOSEC® or omeprazole, distributed as enteric coated granules in capsules, with poor absorption due to presystemic metabolism.
- Other drugs of particular interest are PROZAC® or fluoxetine hydrochloride and VASOTEC® or enalapril meleate.
- Prozac is a well known antidepressant with a slow rate of dissolution, limited solubility, and slow absorption.
- VASOTEC® is an antihypertensive characterized by degradation during storage, presumably due to hydrolysis, with only about 60% absorption.
- PRILOSEC® or omeprazole is slowly absorbed and undergoes extensive metabolism in the liver.
- CLARITIN® or loratidine an antihistamine, is insoluble in water and therefore formulated as micronized drug, which is rapidly absorbed then undergoes extensive first pass metabolism.
- PAXIL® or paroxetine hydrochloride is extensively metabolized following oral administration.
- CIPRO® or ciprofloxacin is practically insoluble in water, abso ⁇ tion is affected by ingestion of food, and it has a short half-life.
- PRAVACHOL® or pravastatin is another statin drug characterized by highly variable bioavailability due to extensive first pass metabolism by the liver.
- VOLTAREN- XR® and ADALAT CC® drugs characterized by extreme variability include VOLTAREN- XR® and ADALAT CC®. Others with poor dissolution properties are NORVASC® and SANDIMMUNE® (cyclosporin). Cyclosporin exhibits extremely variable absorption, regardless of its formulation. Other drugs with poor abso ⁇ tion include ZOVIRAX® and ZESTRIL®. TAXOL® or paclitaxel is another drug in which formulation plays an important role due to its lack of water solubility and highly lipophilic properties. S till other drugs are the complex "natural" formulations such as PREMARLN®, a mixture of conjugated estrogens similar to that in pregnant mare urine.
- PREMARLN® a mixture of conjugated estrogens similar to that in pregnant mare urine.
- drugs which can be advantageously reformulated are those which exhibit properties such as noxious taste, for example, BIAXTN® or clarithromycin, a crystalline macrolide antibiotic that is practically insoluble in water.
- veterinary pharmaceuticals include vaccines, antibiotics, growth enhancing agents, dewormers such as IVERMECTLN® and STRONGID®, and systemic and topical pesticides.
- Diagnostic agents include contrast agents for use with ultrasound, x- rays, fluorescence, MRI, CT, and other techniques known to those skilled in the art. Formulation of these materials is typically critical for effective delivery, detection sensitivity, targeting to an intended site, and for improved comfort to the patient.
- Bioactive materials such as drugs, diagnostics, and nutraceuticals can be formulated as tablets, powders, particles, solutions, suspensions, patches, capsules, with coatings, excipients, or packaging which further affects the delivery properties, the biological properties, and stability during storage.
- filler or binders A variety of materials are known for use in tablets as filler or binders, wet binders, lubricants, disintegrating agents, glidants, stabilizers, wetting agents, and other ingredients.
- Representative fillers/binders include lactose, micro-crystalline cellulose, calcium phosphate, dibasic and tribasic phosphate, sucrose, pregelatinized starch, mannitol, sorbitol, calcium sulfate, dihydrate, ethyl cellulose, and polyethylene glycols.
- Representative wet binders include acacia, gelatin, starch, pregelatinized starch, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose.
- Lubricants include magnesium stearate, stearic acid, hydrogenated vegetable oils, sodium stearyl fumarate, mineral oil, talc, calcium stearate, polyethylene glycol, and propylene glycol.
- Disintegrating agents include starch, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, modified starch (EXPLOTAB®, PRIMOGEL®) and cross-linked polyvinylpyrrolidone.
- Glidants include talc and silicas (silica gel, CABOSIL®).
- Stabilizers include butylated hydroxyanisole, butylated hydroxytoluene, EDTA, ascorbic acid, sodium bisulfite, sodium metabisulfite, and propyl gallate.
- Wetting agents include dioctyl sodiumsulfosuccinate, sodium lauryl sulfate, polyoxyethylene sorbitan esters (e.g., polysorbate 80), and lecithin.
- Other ingredients include enteric coatings, extended release materials, etc., which usually dissolve at specific pH levels or after extended exposure to GA contents.
- the materials typically consist of natural polymers such as synthetic cellulosic polymer derivatives, waxes, glycerol esters of long chain fatty acids, and synthetic polymers such as polyvinyl acetate.
- Materials used in hard gelatin capsules as fillers include lactose and anhydrose lactose, starches such as microcrystalline cellulose, disintigrants such as pregelatinzed starch, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinylpyrrolidone, and wetting agents such as polyoxyethylene sorbitan esters, sodium lauryl sulfate, dioctyl sodium, sulfosuccinate, polyoxyethylene/propylene copolymers (PLURONICS®, BASF), and polyethylene glycols.
- lactose and anhydrose lactose starches such as microcrystalline cellulose
- disintigrants such as pregelatinzed starch, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinylpyrrolidone
- wetting agents such as polyoxyethylene sorbitan esters, sodium lauryl sulfate, diocty
- Controlled or sustained release formulations typically inco ⁇ orate a matrix of polymer, polysaccharide or sugar, as described above, or other material which can be used to encapsulate or entrap the drug or other bioactive to be released.
- the matrix can be in the form of pellets, tablets, slabs, rods, disks, hemispheres, or microparticles, or be of an undefined shape.
- microparticle includes microspheres and microcapsules, as well as microparticles, unless otherwise specified.
- the matrix can be formed of non-biodegradable or biodegradable matrices, although biodegradable matrices are preferred, particularly for parenteral administration.
- Non-erodible polymers may be used for oral administration.
- Matrices may be formed of simple sugars or polysaccharides, as described before, or polymers have defined release characteristics employed.
- synthetic polymers are preferred due to more reproducible synthesis and degradation, although natural polymers may be used and have equivalent or even better properties, especially some of the natural biopolymers which degrade by hydrolysis, such as polyhydroxybutyrate.
- the polymer is selected based on the time required for in vivo stability, i. e. that time required for distribution to the site where delivery is desired, and the time desired for delivery.
- Representative synthetic polymers are: poly(hydroxy acids) such as poly(lactic acid), poly(glycolic acid), and poly(lactic acid-co-glycolic acid), poly(lactide), poly(glycolide), poly(lactide-co-glycolide), poly anhydrides, polyorthoesters, polyamides, polycarbonates, polyalkylenes such as polyethylene and polypropylene, polyalkylene glycols such as poly(ethylene glycol), polyalkylene oxides such as poly(ethylene oxide), polyalkylene terephthalates such as poly(ethylene terephthalate), polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides such as poly(vinyl chloride), polyvinylpyrrolidone, polysiloxanes, poly(vinyl alcohols), poly(vinyl acetate), polystyrene, polyurethanes and co-polymers thereof, derivativized celluloses such as alkyl
- biodegradable polymers examples include polymers of hydroxy acids such as lactic acid and glycolic acid, and copolymers with PEG, polyanhydrides, poly(ortho)esters, polyurethanes, poly(butyric acid), poly(valeric acid), poly(lactide-co-caprolactone), blends and copolymers thereof.
- preferred natural polymers include proteins such as albumin and prolamines, for example, zein, and polysaccharides such as alginate, cellulose and polyhydroxyalkanoates, for example, polyhydroxybutyrate.
- preferred non-biodegradable polymers include ethylene vinyl acetate, poly(meth)acrylic acid, polyamides, copolymers and mixtures thereof.
- Bioadhesive polymers of particular interest for use in targeting of mucosal surfaces, as in the gastrointestinal tract, include polyanhydrides, polyacrylic acid, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).
- Solvents A solvent for the polymer or other carrier, or in some cases for the bioactive component, is selected based on its biocompatibility as well as the solubility of the polymer and where appropriate, interaction with the agent to be delivered. For example, the ease with which the agent is dissolved in the solvent and the lack of detrimental effects of the solvent on the agent to be delivered are factors to consider in selecting the solvent.
- Aqueous solvents can be used to make matrices formed of water soluble polymers.
- Organic solvents will typically be used to dissolve hydrophobic and some hydrophilic polymers. Preferred organic solvents are volatile or have a relatively low boiling point or can be removed under vacuum and which are acceptable for administration to humans in trace amounts, such as methylene chloride.
- solvents such as ethyl acetate, ethanol, methanol, dimethyl formamide (DMF), acetone, acetonitrile, tetrahydrofuran (THF), acetic acid, dimethyl sulfoxide (DMSO) and chloroform, and combinations thereof, also may be utilized.
- Preferred solvents are those rated as class 3 residual solvents by the Food and Drug Administration, as published in the Federal Register vol. 62, number 85, pp. 24301-24309 (May 1997).
- Solvents for drugs that are administered parenterally or as a solution or suspension will more typically be distilled water, buffered saline, Lactated Ringer's or some other pharmaceutically acceptable carrier.
- Many other types of formulations can be used, including polymers and other materials such as mineral oil or petrolatum, to form coatings, ointments, salves, "jellies” or even transdermal patches, particularly for application to skin, mucosal surfaces (vaginal, rectal, nasal, pulmonary) or where controlled release is desired.
- Nutrients and food products which may be formulated include vitamins, herbal remedies, spices, colorings, antioxidants and other preservatives, and materials which modify aggregation, improve storage, enhance flavors, or address processing issues.
- Nutrients may be vitamin formulations, fertilizers or growth enhancers for plant or tissue culture, or media for cell culture or bacterial fermentation.
- Carriers and excipients include many of those useful in pharmaceutical preparations, as well as starches, sugars such as lactose, and emollients, as well as stabilizers, antioxidants, and pH modifying agents.
- Health care products include items such as deodorants, cleansers, cosmetics, feminine products, lotions, shampoos, and hair care items.
- deodorants include drying agents such as aluminum zirconium and carriers such as sodium bicarbonate, starches and polysaccharides such as corn starch, lubricants such as cyclomethicone, fragrances, propylene carbonate, silica and quaterium complexes.
- Cleansers include materials such as alcohol, water, glycerin, menthol, sodium borate, dyes such as d&c violet No. 2 or 33, and d&c No. 6.
- Hair care products include materials such as herbal extracts, surfactants such as cetyl dimethicone, polyglyceryl-4 isostearate, dydrogenated castor oil, cetearyl methicone, and antioxidants. sunscreens such as propylparaben.
- Shampoos may include materials such as alcohol, surfactants such as cyclopentasiloxane, and dimethicone, protein such as hydrolyzed collagen, fragrances, and chelating agents such as ethylenediaminotetraacetic acid (EDTA).
- Cosmetics and perfumes are usually complex mixtures that may be as simple as mixtures of tints or scents, but more commonly include multiple components that affect skin, such as hydroxy acids, abso ⁇ tion, prevent bacterial growth, and stability of the "active" components such as antioxidants, as well as colors or pigments and compounds altering the viscosity or rheological properties (including compounds which prevent aggregation, increase fluidity or fluid flow). Many of the same components present in pharmaceutical compositions can be included in cosmetics or perfumes as carriers.
- Industrial products cover a wide range of materials from household cleaning products such as dishwashing detergents and cleaners to oils and other lubricants for cars and other machinery, to reagents for making and cleaning silicon chips for use in computers and coatings for computer monitors and car windshields to block glare, paints, dyes, adhesives and lubricants, and materials used in the construction industry such as concretes and bulking agents, etc..
- Specific applications are in those industries involved in the manufacturing and/or processing of equipment, optical devices, electronic devices, appliances, computers and related hardware, as well as materials used in the operation of these. Further applications include batteries, matches (i.e., combustibles), and light-emitting chemiluminescent materials, as well as any of the multitude of applications of fibers.
- Other applications include catalysts and enzymes used in industrial processing. New ceramic and polymeric materials can also be formulated.
- Military applications include materials for biological warfare (biologicals and nerve gases), defenses against biological warfare, coatings that protect or enhance visibility (such as coatings on night vision glasses or gun scopes), and weapons (such as improved munitions formulations, including combustibles, ammunition and explosives).
- the high throughput formulating techniques and screening assays can also be used to compare the efficacy of various formulation conditions, for example, the effects of different solvents, pH, water content, excipients, and means for formulation used to prepare or store the formulation.
- the assays can also be used to compare packaging. It is well known that these factors can be critical to the usefulness and economics of a drug formulation, but these factors are usually not assessed, or they are assessed using a random sampling process, not a systematic, rapid comparison that allows for determination of the optimal manufacturing process, packaging, or storage conditions.
- Variables involved in packaging include water permeability, water content, light transfer, oxygen permeability or permeability to solvent.
- Exemplary variables involved in processing conditions include selection of the formulation process (freeze drying, dialysis, rate of stirring of drug or carrier in solvent, selection of pH or salt concentrations, etc.).
- Exemplary variables in stability to storage include inclusion of stabilizers such as antioxidants, materials which exclude light from reaching the formulation components, coatings on the interior walls of containers that prevent adhesion or diffusion, and addition of desiccants.
- the goal is not to identify the activity of a known compound, but to make combinations (i.e., formulations) which optimize a desired characteristic of the formulation, such as the bioactivity of a drug under the conditions where it is to be administered.
- a desired characteristic of the formulation such as the bioactivity of a drug under the conditions where it is to be administered.
- Mechanical properties of drug and food formulations to screen for include taste, size, shape, texture, smell, color, and coatings (such as enteric coatings).
- Properties for non-medical applications such as household and industrial products include coatings which resist stains, have increased surfactant properties, or better stability.
- the various combinations are first screened for solubility, by measuring the rate of dissolution. Those candidates which look promising can then be tested directly in animals or screened for other physical or chemical properties, for example, permeability - passage across the gastrointestinal tract into the blood or lymph systems or into specialized tissues such as the Peyer's patches - using a system such as an Ussing chamber. Metabolism of the compounds can also be tested.
- Compounds to be screened initially include both compounds with poor solubility and permeability.
- Microstructures includes crystalline or amo ⁇ hous structures, or combinations thereof, polymo ⁇ hs, solvates, hydrates, isomo ⁇ hic desolvates, glasses, solid solutions, and specific unit cells such as hexagonal packing orders, ionic crystals, holes or interstitial spaces, and lattices. Crystal habits can include rods, needles, spheres, plates, cubes, and combinations thereof. Crystal forms of the active agents, or formulations, can be used to produce pharmaceuticals with superior pharmaceutical properties. Other microstructures can include, or be influenced by the inclusion of, enantiomers or racemic forms or mixtures, of the active agents.
- Modifying the microstructure can be used to modify uptake, solubility, dissolution, stability including shelf life, bioavailability, metabolism, and formulation manufacturing properties such as compression parameters, bulk powder flow (such as lubrication and dispersion), spatial orientation of crystals in a bulk powder, and purity of the active agent.
- Crystallinity variants can be produced by changing crystallization, desolvation, solvent vapor, freeze drying, heating, melting, milling, precipitation, quench cooling, slurry conversion, spray drying, solid dispersion, and wet granulation.
- Unique polymo ⁇ hs of drug crystal forms with improved pharmaceutical properties can be obtained by chemical variations (i.e., co-solvents) or physical variation (i.e., temperature).
- Solubility can be measured using standard technology such as optical density or by colorimetry. Abso ⁇ tion can be measured using an in vitro assay such as an Ussing chamber containing HT Caco-2/MS engineered cells (Lennernas, H, J. Pharm. Sci. 87(4), 403-410 (April 1998).
- permeability generally refers to the permeability of the intestinal wall with respect to the drug, i.e., how much drug gets through.
- Metabolism can be measured using digestive enzymes and cell lines, such as hepatoma cell lines which are indicative of the effect of the liver on drug metabolism.
- Variants of crystallinity can be detected using standard techniques such as solid state spectroscopy, including infrared, Raman, NMR, in a microarray format, or crystallography, x-ray, neutron diffraction, powder x-ray diffraction, light microscopy, electron microscopy, differential scanning calorimetry, thermal gravimetric analysis, and combinations thereof.
- solid state spectroscopy including infrared, Raman, NMR, in a microarray format, or crystallography, x-ray, neutron diffraction, powder x-ray diffraction, light microscopy, electron microscopy, differential scanning calorimetry, thermal gravimetric analysis, and combinations thereof.
- HT high throughput
- In vitro screening includes testing for any number of physiological or biological activities, whether known or later recognized.
- each drug will be subjected to a battery of in vitro screening tests for a variety of activities, such as antibacterial activity, antiviral activity, antifungal activity, antiparasitic activity, cytotherapeutic activity especially against one or more types of cancer or tumor cells, alteration of metabolic function of eukaryotic cells, binding to specific receptors, modulation of inflammation and/or immunomodulation, modulation of angiogenesis, anticholinergic activity, and modulation of enzyme levels or activity.
- activities such as antibacterial activity, antiviral activity, antifungal activity, antiparasitic activity, cytotherapeutic activity especially against one or more types of cancer or tumor cells, alteration of metabolic function of eukaryotic cells, binding to specific receptors, modulation of inflammation and/or immunomodulation, modulation of angiogenesis, anticholinergic activity, and modulation of enzyme levels or activity.
- activities such as antibacterial activity, antiviral activity, antifungal activity, antiparasitic activity, cytotherapeutic activity especially against one or more types of cancer or tumor cells,
- Metabolic function testing includes sugar metabolism, cholesterol uptake, lipid metabolism, and blood pressure regulation, amino acid metabolism, nucleoside/nucleotide metabolism, amyloid formation, and dopamine regulation. These screening tests include any that are presently known, and those that are later developed. Typically the initial screening test will be an in vitro assay that is routinely used in the field. The preferred assays will yield highly reliable and reproducible results, can be performed quickly, and will give results predictive of in vivo results. Numerous in vitro screening tests for drug formulations are known. After at least one initial in vitro screen, the formulations that have been identified as having one or more optimal characteristics can undergo testing in one or more animal or tissue models and ultimately, in humans.
- Any automatable system for testing can be used to screen the various combinations of drugs.
- the basic system requirements are that they must have input means that provide for varying at least one factor (component(s) and/or concentration of component(s)), more preferably two or more factors, into test wells or at separate sites that allow for automated screening of each individual formulation for one or more selection criteria.
- Figure 1 is a flow chart of the process, beginning with selection of the material sources, i.e., one or more components at one or more concentrations; mixing or deposition of components into sample wells or at separate sites to form a material array, assaying for one or more parameters, then collection of data for subsequent analysis.
- component drug, and variations thereof which can be drug in different amounts, different pHs, different chemical forms such as salts or bases, different excipients, etc
- component drug are distributed in a liquid, gaseous, or dry phase, or combination thereof, into individual test wells or at separate sites in an array.
- the different combinations can be screened in the array, and/or further processed, for example, by lypophilization in a lyophilizer, milling in a mill to produce a powder, or emulsified by applying ultrasound to a solvent mixture, then screened in a further test system.
- Figures 2 A and 2B are more detailed schematics of processes for formulating and testing arrays of unique formulations.
- Figure 2A depicts a system where the drug source 10 and excipients 12 are provided in solid form, which is deposited in wells in a 96 well filter plate 14 under the control of formulating software 16.
- the dry formulations are reconstituted with one or more solvents using an automated liquid pipetting system 18, yield an array 20 of reconstituted formulations.
- liquids or solids are separated 22 into liquids and solids (for example, by centrifugation of the filtrate from the wells through the filter into collection reservoirs, as described in the following examples), then the liquids or solids, as appropriate, inputted into one or more devices for analysis, for example, devices for measuring solubility 24 such as UV- Vis spectroscopy, HPLC or LC-MS devices, devices for measuring stability 26 such as UV-Vis spectroscopy, HPLC, or liquid chromatograph-mass spectroscopy (LC-MS) devices, systems for measuring abso ⁇ tion 28 such as a Caco-2 cell line or Ussing Chamber, and systems for measuring metabolism 30 such as P-450, microsomes, lysosomes, (obtainable from companies such as In Vitro Technologies, 1450 South
- Figure 2B shows essentially the same process but for materials (drug 10 and excipient(s) 12) provided in liquid form which is dispensed using an automated liquid pipetting system 34 to make the formulation array 14.
- the solvent is then removed 36 using a technique such as lyophilization.
- the dried formulations 38 are then reconstituted 40 by addition of one or more solvents using an automated liquid pipetting system 42, which are then treated in the same manner as described with regard to the process for making dry formulations.
- the formulations can be pumped by a peristaltic pump through individual optical interrogation windows into a sample valve manifold .
- sample is processed using an UV-VIS HPLC to access physical parameters and/or through parallel channel Ussing chambers to assess uptake/oral absorbance, then disposed of into waste and/or passed through another manifold for further analysis for example by HPLC.
- Other means for analysis include pH sensors, ionic strength sensors, mass spectrometers, optical spectrometers, devices for measuring turbidity, calorimeters, infrared and ultraviolet spectrometers, polarimeters, radioactivity counters, devices measuring conductivity, and heat of dissolution.
- microarray systems that can be adapted for use in the system described herein, although all are currently used for the sole pu ⁇ ose of screening to identify compounds having a particular defined activity, as opposed to screening of compounds having a known identity to identify the optimal formulations.
- the most significant modification will be the use of input means that modify one or more variable in each well, rather than inputting different compounds into each well.
- Examples of companies having microarray systems include Beckman Instruments, Fullerton, CA, MicroFab Technologies, Piano, TX, Robbins Scientific, Sunnyvale, CA; Zymark, Hoplinton, MA, Packard Instruments,
- the Beckman Instruments system can deliver nanoliter samples of 96 or 384-arrays, and is particularly well suited for hybridization analysis of nucleotide molecule sequences.
- the MicroFab Technologies system delivers sample using inkjet printers to aliquot discrete samples into wells. Other systems can also be adapted as required for use herein.
- One is system automation and control software that enables the integrated set of manipulations to occur and track the process flow, including communication and sample tracking through the system, in high throughput.
- a second is scientific derivatization which collects and stores data to enable further development and design of formulations, including identification of complex interactions between the actives and excipients, and identification of lead formulations.
- the data can then be processed so as to optimize the ability of scientific personnel to conduct future experiments to optimize the formulations, and to develop future models of new formulations of other active components.
- EXAMPLES The present invention will be further understood by reference to the following non-limiting example of the process disclosed herein for high throughput formulation and screening of drug formulations having desirable properties.
- a commercially available preparation consists of ultramicrosized crystals of antibiotic-antifungal partially dissolved in a carrier including polyethylene glycol 8000 and partially dispersed in other inert excipients (corn starch, lactose, magnesium stearate, and sodium lauryl sulfate).
- a dosage of 3.3 mg/lb body weight is administered per day for children under 50 lbs..
- a different dose for adults of 330 mg/day is the typical dosage for treatment of fungal infections.
- This product is marketed for oral administration, but is still of limited solubility, and therefore bioavailability.
- Formulations containing antibiotic-antifungal have now been developed which have greatly enhanced aqueous solubility. These contain antibiotic-antifungal dispersed with various combinations of the following GRAS ("generally regarded as safe") excipients (all obtainable from Sigma- Aldrich Fine Chemicals or BASF): (1) gum arabic from acacia tree (a branched polymer of galactose, rhamnose, arabinose, and glucuronic acid, mw approximately 25000), (2) beta-cyclodextrin (cycloheptaamylose), (3) sodium dodecyl sulfate (SDS), (4) docusate (sulfobutanedioic acid bis[2- ethyl-hexl ester] or dioctyl sulfosuccinate), (5) sodium benzethonium chloride, (6) benzalkonium chloride (alkyldimethylbenzylammonium chloride), (7) cetrimide (dodecyl
- Formulations demonstrating 100% increase in solubility compared to antibiotic-antifungal alone were identified as lead formulations.
- Five formulations were identified and boxed in Figure 3a.
- EXAMPLE 2 Validation of lead formulations on a larger scale. Experimental Procedure
- the five lead formulations identified from the screen above were validated on a lab scale 10,000x that of the microarray in 96 well plates by weighing each component and mixing them in the solid state in scintillation vials. 30 mg of antibiotic-antifungal was weighed out in the solid state and added to each formulation. Each formulation was formulated three times. These are:
- TPI-1 300 mg PEG 1000, 30 mg beta-cyclodextrin, 30 mg polyoxyethylene 40 stearate
- TPI-2 300 mg PEG 1000, 30 mg SDS, 3 mg polyoxyethylene 40 stearate
- TPI-3 300 mg PEG 1000, 30 mg polyoxyethylene 40 stearate, 3 mg acacia
- TPI-4 300 mg PEG 10000, 30 mg acacia, 30 mg cetrimide
- TPI-5 300 mg polyvinylalcohol, 30 mg benzethonium chloride, 3 mg PEG 1000
- the first three lead formulations (TPI-1 to TPI-3) identified above in the microarrays described above were "de-convolved” on the lab scale into antibiotic-antifungal formulations that contain (1) one of the three excipients only, or (2) two of the three excipients in different combinations (example, components one and two, two and three, one and three). Solubilities of each sample were then measured using the same lab procedures described above for lead validation, using absorbance at 290 nm to determine solubility. The solubilites for the "de-convolved" formulations are shown in
- excipient 3 SDS
- 10 PEG 1000
- 14 polyoxyethylene 40 stearate
- TPI-2 and the commercial product, antibiotic-antifungal were compared at the lab scale using 1000 mL deionized water in 1000 mL Erlenmeyer flasks at 37°C stirred at 300 RPM with a 1.5 inch magnetic stir bar. The rate of dissolution for each formulation was determined separately. Each formulation was added to the stirring deionized water and 1 mL aliquots were removed at 0 seconds, 30 seconds, 1 minute, 3 minutes, 6 minutes, 10 minutes, 15 minutes 25 minutes, 40 minutes, and 50 minutes.
- TPI-2 showed a faster rate of dissolution as well as a higher equilibrium solubility compared to antibiotic-antifungal, further confirming the validity of the lead formulations selected from the microarrays.
Abstract
Description
Claims
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CA002365851A CA2365851A1 (en) | 1999-04-05 | 2000-03-31 | Formulation arrays and use thereof |
EP00919961A EP1171231A1 (en) | 1999-04-05 | 2000-03-31 | Formulation arrays and use thereof |
AU40566/00A AU775665B2 (en) | 1999-04-05 | 2000-03-31 | Formulation arrays and use thereof |
HK02105133.5A HK1045274A1 (en) | 1999-04-05 | 2002-07-10 | Formulation arrays and use thereof |
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EP1908513A1 (en) * | 2006-10-04 | 2008-04-09 | Universita'degli Studi Di Milano | Method for preparing and using chemical collections |
EP2167635A1 (en) * | 2007-06-15 | 2010-03-31 | GlaxoSmithKline LLC | Antibody formulations |
EP2167635A4 (en) * | 2007-06-15 | 2010-06-30 | Glaxosmithkline Llc | Antibody formulations |
WO2023131726A1 (en) * | 2022-01-10 | 2023-07-13 | The University Court Of The University Of Glasgow | Autonomous exploration for the synthesis of chemical libraries |
Also Published As
Publication number | Publication date |
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AU4056600A (en) | 2000-10-23 |
BR0009588A (en) | 2001-12-26 |
HK1045274A1 (en) | 2002-11-22 |
CA2365851A1 (en) | 2000-10-12 |
NZ514592A (en) | 2004-02-27 |
JP2002541442A (en) | 2002-12-03 |
IL145715A0 (en) | 2002-07-25 |
EP1171231A1 (en) | 2002-01-16 |
CZ20013606A3 (en) | 2002-04-17 |
MXPA01009971A (en) | 2002-07-30 |
AU775665B2 (en) | 2004-08-12 |
KR20020021783A (en) | 2002-03-22 |
SK14062001A3 (en) | 2002-12-03 |
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