MXPA01009971A

MXPA01009971A - Formulation arrays and use thereof.

Info

Publication number: MXPA01009971A
Application number: MXPA01009971A
Authority: MX
Inventors: Nicholas Galakatos
Original assignee: Millennium Pharm Inc
Priority date: 1999-04-05
Filing date: 2000-03-31
Publication date: 2002-07-30
Also published as: JP2002541442A; BR0009588A; EP1171231A1; AU775665B2; AU4056600A; NZ514592A; CZ20013606A3; WO2000059627A1; SK14062001A3; KR20020021783A; HK1045274A1; CA2365851A1; IL145715A0

Abstract

Methods have been developed which use high throughput combinatorial formulation technologies, preferably in combination with nanotechnology and microarrays, to improve one or more properties of materials used as components of, or in the manufacture or use of, health care products, consumer products, agricultural products, nutraceutical products, veterinary products, products for use in manufacturing or processing industries, military applications, and research reagents. In a preferred application, the bioavailability and pharmacokinetics of the drugs, especially small molecule pharmaceuticals, are optimized by making many new formulations and selecting those formulations based on one or more physical or chemical properties such as solubility in an aqueous solution, without compromising selectivity or potency. Systems employing these technologies have been designed to rapidly, systematically and cheap identify optimal compositions for a desired purpose. In one preferred embodiment, new formulations are prepared and tested for bioequivalence to a formulation that is approved or commercially available. In another embodiment, 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.

Description

they are initially selected based on their general characteristics, then the tests are carried out using the particular drug that has to be supplied, with minor changes, until an acceptable formulation is produced. Currently, even the definition of the best dosage is more a matter of selecting some representative values within an interval, testing these doses, then selecting the best of the few that have been tested. In most cases, only 10 to 20 formulation alternatives are available. It is evident that 20% of the 50 best-selling drugs benefit from the best pharmacokinetics (absorption, distribution, metabolism and / or excretion). Pharmacokinetics mathematically describes the amount of medication present in the bloodstream over time and significantly influences the efficacy and safety profile of the drug. Improved pharmacokinetics could increase compliance and reduce costs in health care. It is possible to develop optimal formulations taking into account the solubility and stability of the drug to be delivered, the biological properties of the drug, the requirements for release or supply, the ease of manufacture, the avoidance of systemic toxicity due to the components of the drug. formulation, and ^ "? I? MA ^^^ k ^^ ¡^ Ai? many other factors, such as manufacturing costs and even packaging requirements. Some products only require freeze drying for the formulation, but packaging is crucial to keep the final product anhydrous or prevent light or other factors from adversely affecting stability. Even formulations for cosmetics or fragrances are a fortuitous matter, with the random design of a variety of blends and performing the tests in a messy way. This random process usually results in a formulation that achieves the desired result. However, this is rarely the best result, since it would be too expensive and time consuming to formulate a medication, to test the supply characteristics as well as the preservation of the biological characteristics, to reformulate the medication, to re-test the supply characteristics and the biological properties, and repeat the process until the best formulation is reached, instead of just an acceptable formulation. Therefore, an object of the present invention is to offer a process and system for the automatic, systematic processing of materials or formulations to improve one or more properties of the materials that they are used as components of, or in the manufacture or use of, health care products, consumer products, agricultural products, nutraceutical products, veterinary products, products for use in the manufacturing or processing industries, military applications and reagents for research.

SUMMARY OF THE INVENTION Methods have been developed using high performance combinatorial formulation techniques, preferably in combination with nanotechnology and microassays, to improve one or more properties of the materials used as components of, or in the manufacture or use of, health care products, consumer products, agricultural products, nutraceutical products, veterinary products, products for use in the manufacturing or processing industries, military applications and reagents for research. In a preferred embodiment, the bioavailability and pharmacokinetics of drugs, especially small molecule pharmaceuticals, are optimized by making many new formulations and selecting those formulations based on one or more physical or chemical properties such as solubility in an aqueous solution, without compromising the selectivity or power. The systems that employ these technologies have been designed to identify quickly, systematic and economical optimal compositions for a desired purpose. In a preferred embodiment, new formulations are prepared and tested for bioequivalence for a formulation that is approved or sold commercially. In another modality, in vi tro formulations are initially optimized for their pharmacokinetics, such as absorption through the intestine (for an oral preparation), skin (for transdermal application) or mucosa (for nasal, buccal, vaginal or rectal), solubility, degradation or clearance by uptake into the reticular endothelial system ("RES"), metabolism or elimination, then tested in vivo. In another preferred embodiment, the formulation is optimized based on the microstructure of the drug, the carrier or the combination of the components. The microstructure includes crystalline or amorphous structures, or combinations of these, polymorphs, solvates, hydrates, isomorphic desolvates, glasses, solid solutions and specific unit cells such as hexagonal packaging orders, ionic crystals, holes or interstitial spaces and reticles. Other microstructures may include, or be influenced by the presence of, structures such as i. *? enantiomers or racemic forms or mixtures of the active agents.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a schematic of the method for optimizing formulations. Figure 2a and 2b is a more detailed scheme of a process to formulate and analyze multiple samples, for parameters such as solubility (UV-Vis-HPLC) and oral absorbance, where Figure 2a is a schematic of the process where the solids are deposit in the settlement, then reconstitute and scrutinize; and Figure 2b is a schematic of the process where liquids are deposited in an array, dried, reconstituted and then separated into liquids and solids and scrutinized. Figure 3a is a graph of the solubility (absorbance) of 3500 unique formulations containing antibiotic-antifungal with different excipients in water. Figure 3b is a graph of the data in Figure 3a plotted to show the standard deviations for each of the unique formulations. Figure 4 is a graph comparing the solubility (absorbance) of the commercial drug with five main or leader formulations (TPI-1 to TPI-5). Figure 5 is a graph of the relationship of the solubility of different reformulations of one of the main formulations, TPI-3, reformulated with only one or two of the three excipients shown in the relative relationships in the "pastel" that accompanies it. Figure ß is a graph of the solubility relation of different reformulations of a main formulation, TPI-1, comparing the effect of reformulation of the formulation with one or two of the three excipients in the main formulation, demonstrating that some excipients actually decrease the solubility. Figure 7 is a graph of the solubility relationship of different reformulations of a main formulation, TPI-2, showing the effect of reformulating the formulation with one or two of the three excipients in the main formulation, demonstrating that some of the the excipients have a synergistic effect on solubility. Figure 8 is a graph comparing the dissolution rates and equilibrium solubilities of TPI-2 and the antibiotic-antimycotic, showing TPI-2 with a higher dissolution rate as well as a greater equilibrium solubility compared to the antibiotic- antifungal « DETAILED DESCRIPTION OF THE INVENTION Methods have been developed to optimize formulations to improve one or more properties of the materials that are used as components of, or in the manufacture or use of, pharmaceutical or veterinary products, nutraceuticals, health care products , consumer products, agricultural products, industrial applications, military applications and reagents for research. In a preferred application, the bioavailability and pharmacokinetics of the drugs are improved by reformulating the medicament with one or more excipients. 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 library of formulations within an array or matrix and perform a scrutiny for bioactivity, physical, chemical or other desired properties. These methods lead to formulations with better oral bioavailability, expanded therapeutic indices, fewer side effects or less time of discovery or development, and it is possible to use them to obtain additional patent protection and achieve compliance with the regulations for compounds known using bioequivalent formulations. In general terms, the methods include the steps of: identifying one or more active compounds that are going to be formulated (or reformulated); select at least one criterion for optimization such as poor bioavailability (due to low solubility, absorption or metabolism); detect a large number of different combinations of active compounds (based on different dosages, carriers, packaging, combinations with other active ingredients) and / or excipients preferably using microarray technology or micro order in vi tro to select a small number of better formulations candidate; then perform the scrutiny of these candidates using animal and human models in vivo. It is possible to perform the scrutiny with very high entries - for example, more than 100,000 formulations per day. When used herein, "compositions" refers to combinations of two or more components. The compositions, not the components, are screened to determine the optimum formulations. This is not a screening or detection technique to identify compounds that have a particular activity, rather it is to detect novel formulations of known compounds to identify those 10 *: * J'i formulations with the most desirable properties. When used herein, nanoscale refers to formulations or components thereof being present in the individual formulations in amounts of nanograms; "microscale" refers to the formulations or components thereof being present in the individual formulations in microgram amounts. "microarray" refers to plates, deposits or other means of retention on matrix or arrays for very, very small amounts at separate sites on or in support medium. The sample formulations usually consist of less than one gram (1000 mg). In a preferred embodiment, the samples consist of less than. 100 micrograms (any of the 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 scanned as described herein, usually at least 10, more commonly at least 50 to 100, and preferably more than 1000 samples. "Automated" refers to high performance in the range of 100 or more samples being generated or by generation using software to formulate the samples. As described in more detail below, the ttt > fc j¿¿.?? áj-Í --- ÉÉüt. ll l ijjt'iiifi components can be molecules with biological activity such as nucleotide molecules, proteins or peptides, polysaccharides or sugars, or combinations of these, foods, nutrients, cosmetics, or fragrances, dyes. The components can also be carriers for the delivery of the drugs, stabilization reagents or excipients that alter the release, or even reagents for packaging or processing or variables. For industrial applications, the components can be catalysts, surfactants, optical enhancers, dyes and other common ingredients of materials such as detergents, coatings, paints and lubricants. For agricultural applications, the components can be herbicides, pesticides, fertilizers or growth enhancers, as well as oils, stabilizers and surfactants that are important for application, stability and function of the active ingredients. When used herein, "compositions" refers to mixtures of two or more components or to a library in which one or more variables are modified such as the concentration of one or more components. In the preferred embodiment, libraries are constructed using systemic combinations of two or more components, for example, varying concentrations ? g ^ m > m of the medicament and the selection and concentration of one or more excipients, as demonstrated in the following examples, in a grid or array (i.e., an ordered array of components) such as a 96-well, nano- or microarray plate . Preferably, the system is automated to control the mixing or combination of the components. Otherwise, the compositions can be prepared prior to insertion into the grid for testing, for example, microspheres containing the drug can be tested by modifying the concentration of the drug in an aerosol which is spray dried in each well, producing microspheres of the drug within a carrier matrix, each having a different concentration of the drug. Once constructed, the libraries are screened using automated screens, for example, by initially testing the solubility (for example by optical absorbance), then testing the main candidates for oral absorption and then bioavailability using additional in vitro screening tests or animal tests. . The tests can be done simultaneously or in sequence. Usually multiple formulations have been identified in each step of the tests, then they will be subjected to additional tests. These compositions are also analyzed for ^ A ^^^ á ^ jta? Í determine the optimal formulations or the combinations of the components in the formulations.

I. Components of the formulations In general, the components can be divided into active components such as drugs, foods, nutrients, cosmetics or fragrances, and other components that can affect the stability, solubility or rate of dissolution, release or pharmacokinetics. Other components can be physical or chemical components that are used to modify the final composition. For example, the components may be materials that are used as carriers of drugs, hygroscopic compounds to reduce the water content of the materials in the formulation such as packaging or packaging that maintains a particular water content, reagents that are inert in the composition when formulated initially but that are proposed to alter the composition at its site of application or end use, such as pore formers and pH modifying compounds, stabilizers, components that increase adhesion at the application site, surfactants that improve the solubility, dispersion or dissolution, etc. When used herein, "solubility" refers to the solubility in equilibrium or steady state (and is usually measured as solvent amount / volume) and the solution refers to the rate of dissolution (which is usually measured as the unit quantity / volume / time).

A. Pharmaceutical and veterinary formulations As described herein, the objective is to obtain formulations that are optimized for a suggested purpose. Representative purposes include chemical and / or physical stability of the medicament and / or the formulation during manufacture, packaging, distribution, storage and administration (as it relates to the active component (s) as well as the formulation). as a whole, and the components of these), the uptake of the drug, half-life of the drug after administration to a patient, pharmaceutical properties, supply kinetics and other factors that determine the efficacy and economy of a drug. In some cases 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. Accordingly, the screening or screening process will usually vary at least one component of the formulation, and more commonly, multiple components of the formulation, and will select based on one or more properties of the formulation as a whole.

Therapeutic, prophylactic and diagnostic materials When used herein, bioactive molecules include therapeutic, prophylactic and diagnostic molecules can be proteins or peptides, nucleosides or nucleotide molecules, polysaccharides or sugars or synthetic chemical entities, or combinations thereof. In a preferred embodiment, the bioactives are drugs. In the most preferred mode, medications are small molecule drugs. Preferred medications are those that have already been approved for at least one indication. The most preferred drugs are those that can be administered orally, and which have undesirable characteristics of stability, processing, bioavailability or taste (due to problems with dissolution, absorption, duration or others) that can be modified by reformulation. Examples include ZOCAR® or simvastatin, a statin that is administered orally in the form of tablets to reduce cholesterol, which is characterized by very low solubility in water, and undergoes extensive metabolism of the first step in the liver. Another example is I? í M? I I II go I H-Élill-ÜI ril-fa llllUl LOSEC® or omeprazole, which is distributed as enteric-coated granules in capsules, with malabsorption due to presystemic metabolism. Other medications of particular interest are PROZAC® or fluoxetine hydrochloride and VASOTEC® or enalapril meleate [sic]. Prozac is a well-known antidepressant with a slow dissolution rate, limited solubility and slow absorption. VASOTEC® is an antihypertensive characterized by degradation during storage, perhaps due to hydrolysis, with only approximately 60% absorption. PRILOSEC® or omeprazole are absorbed slowly and undergo extensive metabolism in the liver. CLARITIN® or laratadine, an antihistamine, is insoluble in water and therefore formulated as a micronized medication, which is rapidly absorbed then undergoes extensive first-pass metabolism. PAXIL® or paroxetine hydrochloride is extensively metabolized after oral administration. CIPRO® or ciprofloxacin is practically insoluble in water, absorption 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. Other medications characterized by extreme variability include VOLTAREN-XR® and ADALAT CC® others with poor properties of t, t'iL ^ - "- at-" tiíftf 'J "firttfí-iliin ir -l; ^ < a ~~ -« i »Jfo-ri-M ^ dissolution are NORVASC® and SANDIMMUNE® (cyclosporin). Cycloophorin exhibits extremely variable absorption, no matter what its formulation. Other medications with malabsorption include ZOVIRAX® and ZESTRIL®. TAXOL® or paclitaxel is another drug in which the formulation plays an important role due to its lack of water solubility and highly lipophilic properties. Still other medications are the "natural", complex formulations like PREMARIN®, a mixture of conjugated estrogens similar to that found in the urine of loaded mares. Other drugs that can be reformulated advantageously are those that have properties such as a noxious taste, for example BIAXIN® or clarithromycin, a crystalline macrolide antibiotic that is practically insoluble in water. Representative veterinary pharmacists include vaccines, antibiotics, growth-enhancing agents, worming agents such as IVERMECTIN® and STRONGID®, 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. The formulation of these materials is usually crucial for the supply ,, 18 effective, detection sensitivity, choice of a proposed site and to improve comfort for the patient.

Reagents for research Many of the same types of materials used as pharmaceuticals and diagnostics can also be used as reagents for research. These materials do not need to include components approved by the GRAS or FDA, and usually will not have problems related to pharmacokinetics. Examples include antibodies, labels for proteins or oligonucleotides, buffer solutions, enzymes and other reagents that are used in laboratory studies.

Acceptable carriers for pharmaceutical use or food grade Bioactive materials such as medicines, diagnostics and nutraceuticals can be formulated as tablets, powders, particles, solutions, suspensions, patches, capsules, with coatings, excipients, or packaging that also affect the supply properties, the biological properties and stability during storage.

Ji? Já * ku ± ?? l? M i ~ a **. And * tÉ * »-. ^ t ^^, ... y.- > ^ .. * and & * - m ^, »** ~ ^. ^. ¿m ^ < * f * J ?? ^? A variety of materials for use in tablets are known as diluents or binders, wet binders, lubricants, disintegrating agents, glidants, stabilizers, wetting agents and other ingredients. Representative diluents / binders include lactose, microcrystalline cellulose, calcium phosphate, dibasic and tribasic phosphate, sucrose, pregelatinized starch, mannitol, sorbitol, calcium sulfate, dihydrate [sic], ethyl cellulose and polyethylene glycols. Representative wet binders include acacia, gelatin, starch, pregelatinized starch, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose. The lubricants include magnesium stearate, stearic acid, hydrogenated vegetable oils, sodium stearyl fumarate, mineral oil, talc, stearate, calcium, polyethylene glycol and propylene glycol. The disintegrating agents include starch, sodium starch glycolate, cross-linked sodium carboxymethylcellulose, modified starch (EXPLO ®, PRIMOGEL®) and cross-linked polyvinylpyrrolidone. The glidants include talc and silicas (silica gel, CABOSIL®). The stabilizers include butylated hydroxyanisole, butylated hydroxytoluene, EDTA, ascorbic acid, sodium bisulfite, sodium metabisulfite and propyl gallate. Wetting agents include dioctyl sodium sulfosuccinate, ÉJÉilli mi ilil-MlÜrrr - * - • * - "• -» * - * - sodium lauryl sulfate, polyoxyethylene sorbitan esters (eg, polysorbate 80), and lecithin Other ingredients include enteric coatings, materials for prolonged release, etc., which usually dissolve at specific pH levels or after prolonged exposure to GA contents. The materials usually consist of natural polymers such as derivatives of synthetic cellulose polymers, waxes, glycerol esters of long-chain fatty acids and synthetic polymers such as polyvinyl acetate. Materials used in hard gelatin capsules as diluents include lactose and anhydrous lactose [sic], starches such as microcrystalline cellulose, disintegrants such as pregelatinized starch, sodium starch glycolate, cross-linked sodium carboxymethylcellulose and cross-linked polyvinylpyrrolidone, and wetting agents such as esters of polyoxyethylene sorbitan, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, polyoexethylene / propylene copolymers (PLURONICS®, BASF), and polyethylene glycols. Sustained or controlled release formulations usually incorporate a polymer, polysaccharide or sugar matrix, as already described, or other material that can be used to encapsulate or ká léi? á? átí ^ k iJ á il ^? éí? U ^ ißmálU? * ^. ^. ^ .- tu- ...? ^ * M * .tJ.t¿Ü? *? ? máá », catch the drug or another bioactive to be released. The matrix may be in the form of granules, tablets, thick slices, bars, disks, hemispheres, or microparticles, or have an undefined shape, when used herein, the term microparticle includes microspheres and microcapsules, as well as microparticles, a unless otherwise specified. The matrix may be formulated from non-biodegradable or biodegradable matrices, although biodegradable matrices are preferred, in particular for parenteral administration. For oral administration it is possible to use polymers that can not erode. It is possible to form matrices of simple sugars or polysaccharides, as described above, or the polymers can have defined release characteristics employed. In general, synthetic polymers are preferred due to more reproducible synthesis and degradation, although it is possible to use natural polymers with equivalent or even better properties, especially some of the natural biopolymers that are degraded by hydrolysis, such as polyhydroxybutyrate. The polymer is selected based on the time required for in vivo stability, i.e., the time necessary for distribution to the site where the supply is desired, and the desired time. ? 22 for the supply. 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-acid) glycolide), polyanhydrides, polyorthoesters, polyamides, polycarbonates or polyalkenes 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 polyvinyl chloride, polyvinylpyrrolidone, polysiloxanes, polyvinyl alcohols, polyvinyl acetate, polystyrene, polyurethanes and copolymers thereof, celluloses derived as alkylcellulose, hydroxyalkyl celluloses , cellulose ethers, cellulose esters, nitro celluloses, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose , cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxylethyl cellulose, cellulose triacetate and the sodium salt of cellulose sulfate (together referred to herein as "synthetic celluloses" ), ....... -. ^ .. ^ -? * - J ^ - ^ - > t -? - á- > , -..-. ^ - A-a- > -to ? ?? polymers of acrylic acid, methacrylic acid or copolymers or derivatives thereof including esters, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate) and poly (octadecyl acrylate) (collectively referred to herein as "polyacrylic acids"), poly (butyric acid), poly (valeric acid) and poly (lactide-co-caprolactones), copolymers and combinations thereof. When used herein, "derivatives" include polymers with substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications made in a manner customary to those skilled in the art. Examples of the preferred biodegradable polymers 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), mixtures and copolymers thereof. Examples of the preferred natural polymers include proteins such as albumin and prolamines [sic], for example zein and polysaccharides such as alginate, cellulose, and polyhydroxyalkanoates, for example polyhydroxybutyrate. Examples of the 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 the choice of mucosal surfaces, such as in the gastrointestinal tract, include polyanhydrides, polyacrylic acid, poly (methyl methacrylates), poly (ethyl methacrylates), poly (butyl methacrylate), poly (isobutyl methacrylate), poly (hexyl methacrylate), 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, the interaction with the agent to be delivered. For example, the ease with which the agent dissolves in the solvent or the absence of harmful effects of the solvent on the agent to be supplied are factors to be considered in the selection of the solvent. It is possible to use aqueous solvents to prepare matrices formed of water soluble polymers. Organic solvents will usually be used to dissolve hydrophobic polymers and some hydrophilic ones. The preferred organic solvents are volatile or have a relatively low boiling point or can be removed in vacuo and which are acceptable for administration to humans in trace quantities, such as methylene chloride. Other solvents, such as ethyl acetate, ethanol, methanol, dimethylformamide (DMF), acetone, acetonitrile, tetrahydrofuran (THF), acetic acid, dimethyl sulfoxide (DMSO) and chloroform, and combinations of these, can also be used. Preferred solvents are those classified as residual solvents class 3 by the Food and Drug Administration, as published in Federal Register volume 62, number 85, pages 24301-24309 (May 1997). Solvents for medications that are administered parenterally or as a solution or suspension will usually be distilled water, buffered saline, lactated Ringer's solution [sic] or some other JH ril k * lbí? MM ^ * - ^ - 'u ^ < ** * t? > ? -., -. ^ .- t, ¿^ - ^. j ..- .. ^. ^ - l faith .. ». J. & - ^. ^ a? A ^ .... Yes. ^. r-t «a *. Mli < carrier acceptable for pharmaceutical use. It is possible to use many other types of formulations, including polymers and other materials such as mineral oil or petrolatum, to form coatings, ointments, ointments, "jellies" or even transdermal patches, in particular for application to the skin, mucosal surfaces (vaginal, rectal, nasal, pulmonary) or where controlled release is desired. Other components include pH modifiers, viscosity modifying agents, solubility enhancers, antioxidants, dyes and dyes.

B. Nutrient, nutraceutical and food products Nutrient and food products that can be formulated include vitamins, herbal remedies, spices, dyes, antioxidants and other preservatives, and materials that modify aggregation, improve storage, improve flavors, or solve issues of the processing. The nutrients can be vitamin formulations, fertilizers or growth enhancers for plants or tissue cultures, or media for cell cultures or bacterial fermentation. Carriers and excipients include many of those that are useful in pharmaceutical preparations, so -4 27 X? M > . such as starches, sugars such as lactose, and emollients, as well as stabilizers, antioxidants and pH modifying agents.

C. Health care products, cosmetics and perfumes Health care products include items such as deodorants, cleansers, cosmetics, feminine products, lotions, shampoos and hair care items. Representative components of the 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 [sic]. Cleaners 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 cetyldimethicone, polyglyceryl-4-isostearate, dehydrogenated castor oil, cetearyl methicone, and antioxidants, sunscreens such as propilparaben [sic]. The shampoos may include materials such as alcohol, surfactants such as cyclopentacyl oxane, and dimethicone, protein such as collagen hydrolyzate, fragrances and chelating agents such as ethylenediamine tetraacetic acid (EDTA). Cosmetics and perfumes are usually complex mixtures that can be as simple as mixtures of dyes or essences, but usually include multiple components that affect the skin, such as hydroxy acids, absorption, prevent bacterial growth, and stability of the skin. "active" components such as antioxidants, as well as colors or pigments and compounds that modify the viscosity or rheological properties (including compounds that prevent aggregation, increases fluidity or fluid flow). Many of the same components present in the pharmaceutical compositions can be included in cosmetics or perfumes as carriers.

D. Consumer and industrial products Industrial products cover a wide range of materials from products for household cleaning such as detergents for dishwashers and cleaners to oils and other lubricants for cars and other machinery, to reagents for manufacturing and cleaning silicon wafers for use in computers and coatings for computer monitors and car windshields to block the brightness, paints, ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ --------- * - »- -.- J (-> - ^ .. i - J > - ^ ~ - - = ^.-.--«. - ^ .. t ^ A ^ ll. 29? * &K¡ * dyes, adhesives and lubricants, and materials used in the construction industry as concretes and ingredients for loading, etc. The specific applications are in those industries involved in the manufacture and / or processing of equipment, optical devices, electronic devices, devices, computers, and related equipment, as well as materials used in their operation. Other applications include batteries, matches (ie fuels), and chemiluminescent light emitting materials, as well as any of the many applications of the fibers. Other applications include catalysts and enzymes that are used in industrial processing. It is also possible to formulate new ceramic and polymeric materials.

E. Military applications Military applications include materials for military biological operations (biological gases and enervating gases), defenses against biological military operations, coatings that protect or improve visibility (such as coatings in glasses for night vision or in the field of weapons), and weapons (such as better ammunition formulations, including fuels, ammunition and explosives).

F. Packaging and processing conditions Although this is mainly described with reference to formulations containing one or more active compounds, high-throughput formulation techniques and detection 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 to prepare the formulation used or store the formulation. The tests can also be used to compare the packaging. It is well known that these factors may be crucial for the utility and economy of drug formulation, but these factors are usually not evaluated, or they are evaluated using a random sampling process, not a systematic, rapid comparison that allows the determination of the optimal conditions for the manufacturing, packaging and storage process. The variables involved in the packaging include water permeability, water content, light transfer, oxygen permeability or permeability to solvents. The exemplary variables involved in the processing conditions include the selection of the formulation process (freeze drying, dialysis, agitation rate of the drug or the t l? trtr rt ^ "a - carrier in the solvent, selection of pH or salt concentrations, etc.) The exemplary variables in stability for storage may be the inclusion of stabilizers as antioxidants, materials that prevent light from reaching the components of the formulation, coatings on the inside walls of the containers that prevent adhesion or diffusion, and the addition of desiccants.

II. Detection of multiple variables A. System design Assuming three hundred substances, even without variations in concentrations and without variations in physical parameters, the number of possible combinations is enormous: for two components there are 44,850 possible combinations, for three components there are 4,455,100 combinations , and for four components there are 330,791,175 possible combinations. The complexity increases when the relative abundance of each component is considered and varied. It is well established that combinations of two or more components can be very beneficial. For example, the combination of cyclosporin A and vitamin E doubles blood levels when oral clearance is cut in half. l f »? * k ?? i? j? .. ^^?. ?? i., ^ J - ^ »-., J ^ -L - .. & * ^ ti-i. ..ytyaatí ». * l-J ti -__: As described herein, the objective is not to identify the activity of a known compound, but to make combinations (ie, formulations) that optimize a desired characteristic of the formulation, such as the bioactivity of a drug under the conditions where it is going to be administered This is usually a tedious process, where each variable is evaluated separately, at different points on a range of conditions or combinations. As described in more detail below, the process includes: (1) selecting an active formulation or component of this (2) to determine which variables (ie, components and / or their concentrations) can be modified, and then (3) establish a "grid" that automatically prepares a large number of combinations that is automatically tested for one or more variables. For example, if the formulation contains a medicament characterized by poor oral uptake, the solubility of the drug in the range of salt concentrations; the pH values, carriers, and drug concentrations are prepared and tested simultaneously. The key to the process is the use of technologies that can make multiple combinations at the same time, then automatically feed each combination into a system to test which combinations have the most desirable properties, for example, stability of activity during storage time, stability during processing (manufacturing, packaging, or during application, and under physiological conditions); solubility; oral absorption (or whatever is appropriate); or function (metabolism, half-life, release characteristics-blood levels.) The mechanical properties of drug and food formulations to detect include flavor, size, texture form, odor , color and coatings (such as enteric coatings) Properties for non-medical applications such as household and industrial products include coatings that resist stains, have higher surfactant properties or better stability In a preferred embodiment to select the optimal drug formulations for oral delivery , a system nsaya formulations based on physical parameters, absorption and metabolism, all using simple, quick tests, in vi tro. In a simple embodiment, the different combinations are first tested for solubility, by measuring the rate of dissolution. Those candidates who look promising they can then be tested directly on animals or detected for other physical or chemical properties, for example, permeability - the passage through the gastrointestinal tract to the blood or lymphatic systems or to specialized tissues such as Peyer's patches - using a system such as a Ussing camera. It is also possible to test the metabolism of the compounds. The compounds that will be screened initially include compounds with poor solubility and permeability. The physical parameters include solubility, dissolution and microstructure, as well as stability with time, heat, ultraviolet radiation, oxygen, etc. The microstructures include crystalline or amorphous structures, or combinations of these, polymorphs, solvates, hydrates, isomorphic desolvates, glasses, solid solutions and specific unit cells such as hexagonal packaging orders, ionic crystals, holes or interstitial spaces and reticles. Glass facies can include rods, needles, spheres, plates, cubes and combinations of these. The crystalline forms of the active agents, or the formulations, can be used to produce pharmaceuticals with superior pharmaceutical properties. Other microstructures may include or be modified by the inclusion of, enantiomers or racemic forms or mixtures, of active agents. It is possible to use the modification of the microstructure to modify the uptake, solubility, dissolution, stability including shelf life, bioavailability, metabolism and manufacturing properties of the formulation such as compression parameters, bulk powder flow (such as it can be lubrication and dispersion), spatial orientation of the crystals in a bulk powder, and purity of the active agent. Variants of crystallinity can be produced by changing crystallization, desolvation, solvent vapor, freeze drying, heating, melting, trituration, precipitation, rapid cooling, slurry conversion, spray drying, solids dispersion and wet granulation. It is possible to obtain unique polymorphs of the crystalline forms of the drug with better pharmaceutical properties by chemical variations (i.e., co-solvents) or physical variation (i.e., temperature). The same aspects are also applicable to some non-pharmaceutical materials such as silicon wafers and photography. Solubility can be measured using common technology such as optical density or by colorimetry Absorption can be measured using an in vi tro assay such as an Ussing chamber containing HT Caco-engineered cells 2 / MS (Lennernas, H, J, Pharm. Sci. 87 (4), 403-410 (April 1998) As used in this context, permeability generally refers to the permeability of the intestinal wall with respect to the drug, that is, how much the drug passes through it.The metabolism can be measured using digestive enzymes and cell lines, such as lines. of hepatoma cells that are indicative of the effect of the liver on drug metabolism Variants of crystallinity can be detected using common techniques such as solid state spectroscopy, including infrared, Raman, NMR, in a microarray format, or crystallography, X-rays, neutron diffraction, powder X-ray diffraction, light microscopy, electron microscopy, differential scanning calorimetry, thermal gravimetric analysis and combinations of these. In another preferred embodiment to select optimal for oral delivery formulations, dosages high performance ( "AR") are mixed and lyophilised distributed, they are placed in different forms (powder against emulsion) then assayed. itiméái IAIE ^^^^^ i-tiiaia ^^ vi tro in Screening, when used herein, includes testing for any number of physiological or biological activities are known or recognized later. In the preferred method, 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 the metabolic function of eukaryotic cells, binding to specific receptors, modulation of inflammation and / or immunomodulation, modulation of angiogenesis, anticholinergic activity and modulation of levels or enzymatic activity. The physical and chemical properties that have to be explored include stability during the process, manufacturing, packaging, distribution and administration, especially of molecules such as proteins. Metabolic function tests include 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 of those currently known, and those that develop later. Usually, the initial screening test will be an average test that is used routinely in the field. The preferred assays will produce highly reliable and reproducible results, can be performed quickly and will produce predictive results of in vivo results. Numerous in vitro screening tests are known for drug formulations. After at least the initial exploration in vi tro, formulations that have been identified with one or more optimal characteristics may be tested in one or more animal or tissue models and ultimately in humans. Safety will be assessed through LD50 measurements and other toxicological evaluation methods (liver function tests, hematocrit, etc.). Efficacy will be evaluated in specific animal models for the type of problem for which treatment is sought. The techniques for counting are well known for specific domestic and industrial applications. For example, for coatings resistant to carpet stains, an aqueous solution of a red dye can be applied and the absorbance of the resulting stain can be measured. For laundry detergents, it is possible to measure the amount of grease that is emulsified with ** ** .- * M ~ .. *? KlU. M. and ^ ¿. ^^.? ^^^^^^^^ ^^ íaS ^ m ^ J ^ y ^^? ^^^. -JAl- -J-. , .. 39 the surfactant. For coatings, it is possible to measure the adhesion and resistance to scratches.

B. Microarray and nanotechnology systems Any system that can be automated to perform the tests can be used to explore different drug combinations. The basic requirements of the system are that it must have input means that provide variation of at least one factor (component (s) and / or concentration of the component (s)), most preferably two or more factors, in the wells test or in separate sites that allow automated scrutiny of each individual formulation for one or more selection criteria. Figure 1 is a flow chart of the process, beginning with the selection of the sources of the materials, that is, one or more components in one or more concentrations; mixing or depositing the components in sample wells or at separate sites to form an array of materials, testing one or more parameters, then collecting the data for further analysis. For example, the medicine component, and variations thereof (which may be the drug in different amounts, different pH values, different chemical forms such as salts or bases, different excipients, etc., are distributed in a liquid, gaseous or anhydrous phase , or combinations of these, in individual test pits or in separate sites in an array, it is possible to explore in the array the different combinations and / or they can be further processed, for example, by lyophilization in a lyophilizer, milling in a mill for produce a powder, or they can be emulsified by applying ultrasound to a mixture of solvents, then they can be detected in another test system, Figures 2A and 2B are more detailed schemes of the processes to formulate and test arrays of unique formulations. represents a system where the source of the drug 10 and the excipients 12 are provided in solid form, which are deposited in wells in a well a 96-well filter 14 under the control of formulation software 16. The anhydrous formulations are reconstituted with one or more solvents using an automated liquid pipetting system 18, producing an array of the reconstituted formulations. These are separated into liquids and solids (for example by centrifugation of the filtrate from the wells through the filter in collection tanks, as described in the following examples), then the liquids or solids, as You will be able to enter into one or more devices for analysis, for example, measuring devices. the solubility 24 such as UV-Vis spectroscopy, HPLC or LC-MS devices, devices for measuring stability 26 such as UV-Vis spectroscopy, HPLC or devices for liquid chromatography-mass spectroscopy (LC-MS), systems for measure absorption 28 such as a Caco-2 cell line or Ussing camera, and systems to measure metabolism such as P-450, microsomes, lysosomes, (available from companies such as in vi tro Technologies, 1450 South Rolling Road, Baltimore, MD 21227; see also; Trouet A, Methods Enzymol, vol.31, 323-329) and in vivo assays. The data 32 of the different tests are then collected and analyzed. Figure 2B shows practically the same process but for materials (drug 10) and excipient (s) 12) provided in liquid form that are dosed using an automated liquid pipetting system 34 to prepare the array of formulations 14. Then the solvent is removed 36 using a technique such as lyophilization. The dried formulations 38 are then reconstituted by the addition of one or more solvents using an automated liquid pipetting system 42, which is then treated in the same way 42 'i' yes as described with respect to the process for preparing anhydrous formulations. For analysis the formulations can be pumped by means of a peristaltic pump through individual optical irrigation windows in a manifold of sampling valves. From the multiple, the sample is processed using a UV-Vis HPLC to access the physical parameters and / or through Ussing cameras of parallel channels to assess the oral uptake / absorption, then they are discarded and / or passed through another multiple for subsequent analysis, for example by HPLC. Other media for analysis include pH detectors, ion concentration detectors, mass spectrometers, optical spectrometers, turbidity measuring devices, calorimeters, infrared and ultraviolet spectrometers, polarimeters, radioactivity counters, devices for measuring conductivity and heat of the dissolution. Some companies have developed microarray systems that can be adapted for use in the system described herein, although all are currently used for the sole purpose of screening to identify compounds having a particular defined activity, contrary to the screening of compounds having a known identity to identify the &jßui? »t? ? ií «ii m < M m ß? Siil? IUk optimal formulations. The most important modification will be the use of input means that modify one or more variables in each well, instead of introducing different compounds in each well. Examples of companies that have microarray systems include Beckman Instruments, Fullerton, CA, MicroFab Technologies, Plano, TX, Robbvins Scientific, Sunnyvale, CA; Zymark, Hoplinton, MA, Packard Instruments, Meriden, CT, Tomtec, Hamden, CT and Cartesian Technologies, Irvine, CA. These devices test samples based on a variety of different systems. All include hundreds of microscopic channels that direct samples to test wells, where reactions can occur. These include reactions with receptors, immobilized antibodies or fluorescent labels attached to the surfaces of the wells or immobilized on nanospheres or microparticles, which can be analyzed in situ or pumped to other receptacles for analysis. Luminex Corp. FlowMetrix TM systems pumps reagents to 96-well ELISA plates and then uses fluorescence and flow cytometry with latex microspheres for testing. These systems are connected to computers for the analysis of data using the appropriate software and data series. The Beckman Instruments system can supply samples in nanoliters of arrays of 96 or 384, and is particularly well suited for sequence hybridization analysis of nucleotide molecules. The MicroFab Technologies system supplies samples using injection printers to take small aliquots of samples into the wells. Other systems may also be adapted as required for use herein. There are basically two types of Informatics that can be used with these systems with the methods described here, as represented in Figures 2a and 2b, in the points referring to the automated solid or liquid dosing system and the data output, respectively. . One is the automation and system control software that allows a series of integrated manipulations to occur and to track the flow of the process, including the communication and the tracking of samples through the system, with high performance. A second is the scientific derivation that collects and stores data to allow another formulation development and design. Including the identification of complex interactions between assets and excipients, and the identification of main formulations. Then it is possible to process the data to optimize the capacity of the scientific staff to carry out future experiments for the optimization of the i ^? jtt & M | ^ AwU formulations, and develop future models of new formulations for other active components.

EXAMPLES The present invention will further be understood by reference to the following non-limiting examples of the process described herein for the high-throughput formulation and screening of drug formulations having the desirable properties. An antibiotic of approximate molecular weight 350 with a complex, benzofuran-cyclohexane structure, which is approved for use as an antibiotic and antifungal compound, was selected for reformulation with the purpose of producing more soluble compositions. This compound is soluble in DMF, but only slightly soluble in other organic solvents such as ethanol, methanol, acetone and acetic acid. The low solubility limits the antibiotic-antifungal applications due to its poor bioavailability. A commercial preparation consists of ultramicronized antibiotic-antifungal crystals partially dissolved in a carrier that includes polyethylene glycol 8000 and partially dispersed in other inert excipients (corn starch, lactose, magnesium stearate and sodium lauryl sulfate). A Í¿éá.? AAtÍ >; iuij? »tJí *. *? *? a * .i ...-,. ^ ü? tmaáí ....«? ^? Ü ?? ??? ^ - ^^ E ^ .-., ---.... ^ - M-Ü .- ^ mh, ^ - ^ J * - ^ - > At this dose of 3.3 mg / lb of body weight is administered per day for children of approximately 50 pounds. A different dose for adults of 330 mg / day is the common dose for treatment of fungal infections. This product is marketed for oral administration, but still has solubility and, therefore, limited bioavailability. Antibiotic-antibiotic-containing formulations have now been developed with greatly improved aqueous solubility. These contain the dispersed antibiotic-antifungal with different combinations of the following GRAS excipients ("generally regarded as safe, generally considered safe") (all can be obtained from Sigma Aldrich Fine Chemicals or BASF): (1) gum acacia tree gum (a branched polymer of galactose, rhamnose, arabinose and glucuronic acid, approximate molecular weight 25,000), (2) beta-cyclodextrin (cycloheptaamylose), (3) sodium dodecyl sulfate (SDS), (4) docusate (bis [2-ethyl] - hexyl ester] of sulfobutadiene or dioctyl sulfosuccinate), (5) sodium benzethonium chloride, (6) benzalkonium chloride (alkyldimethylbenzylammonium chloride), (7) cetrimide (dodecyltrimethylammonium bromide), (8) oleic acid (cis- 9- octadecenic), (9) sodium tartrate dihydrate, (10) polyethylene glycol 1000 (11) polyethylene glycol 10,000, (12) polyvinyl alcohol (13) Poloxamer 237 (block copolymer polyoxyalkylene oxide), (14) polyoxyethylene 40 stearate, (15) polyoxyethylene stearate 100 (16) T EEN 80® (polyoxyethylene sorbitan), (17) BRIJ 35® (23 lauryl ether), and (18) BRIJ 97® (10 oleyl ether). The formulations were developed and analyzed as demonstrated by the following examples.

EXAMPLE 1: Preparation and identification of antibiotic-antifungal formulations with better solubility Experimental procedure Preparation of formulations with better solubilities. 18 GRAS excipients (numbered 1-18, as indicated in the above) were selected. Three of the 18 excipients, 20 microliters each were added to each well in the microarray (filter plates 96-well Millipore, including polytetrafluoroethylene membranes with a pore size of one micron at the base of each well) using the system of liquid handling TECAN®. Each excipient was prepared in water in three concentrations (0.015 mg / ml, 0.15 mg / ml and 1.5 mg / ml), allowing the examination of the effects of the concentration of excipients. The number of possible unique formulations is calculated as: 18! x3 3! x (18-3)! 22,032 unique formulations were generated (a total of 66,096 samples for n = 3), with 32 unique formulations per assay plate and 689 total assay plates. The samples were generated using the MatLab program. 20 microliters of antibiotic-antimycotic dissolved in dioxane (0.15 mg antibiotic-antimycotic / ml of dioxane) were then added to each formulation in each sample well using the liquid handling system TECAN.

Scrutiny of the formulations All solvents were removed by lyophilization. 200 microliters of water was added to each dried formulation in each well of the filter plates. The plates were incubated at 37 ° C for one hour, then centrifuged to remove any of the undissolved solids. The filtrate from each well was collected in 96-well plates transparent to UV for measurements in a UV plate reader at 290 nm.

!? ^ S ^ í £ JÍUt &? IJM &?! MiS i * m ^ 8m TrrfteS To establish the baseline solubility antibiotic-antimycotic was tested alone without excipient.

Results Figure 3a shows the solubility measured as absorbance at 290 nm of the filtrates, for 3500 unique formulations. The antibiotic-antifungal only provides a base absorbance (solubility) of 0.3. Most of the formulations showed better solubility compared to the antibiotic-antifungal. Approximately 1200 formulations shown in Figure 3a showed significantly higher solubilities than the rest of the formulations. The formulations that demonstrated 100% increase in solubility compared to the antibiotic-antifungal alone (as measured by absorbance) were identified as primary formulations. Five formulations were identified that are marked in box in Figure 3a. Figure 3b provides the standard deviation for each of the 3,500 unique formulations (each tested at n = 3). Most of the formulations tested were reproducible, with standard deviations less than 10%. These formulations can be more optimized ^ -J «> -a ^ - ^ .. ^ - «- i-A .. ^ ... ^ .. J ^ a-3 ^^ J -. ^. A» .- fa- «jjJki? »Using the same scrutiny technique described above, making additional changes to the concentration of each component in the formulations.

EXAMPLE 2: Validation of the main formulations on a larger scale Experimental procedure identified five major formulations from the above screening were validated laboratory scale 10,000 x that Microarray in 96 weighing each component and mixing in the solid state in small vials for scintillation wells. 30 mg of the antibiotic-antifungal was weighed in the solid state and added to each formulation. Each formulation was made three times. These are: TPI-1: 300 mg PEG 1000, 30 mg beta-cyclodextrin, 30 mg polyoxyethylene 40 stearate. TPI-2: 300 mg of PEG 1000, 30 mg of SDS, 3 mg of polyoxyethylene 40 stearate. TPI-3: 300 mg of PEG 1000, 30 mg of polyoxyethylene 40 stearate, 3 mg of acacia. IPT-4: 300 mg of PEG 10,000 [sic] 30 mg acacia, 30 mg of cetrimide. - ^..-.- 1. ^^ - .. - Efe. . '- »* -' * ---" - riJi TPI-5: 300 mg of polyvinyl alcohol, 30 mg of benzethonium chloride, 3 mg of PEG 1000. 15 ml of water was added to each bottle and the formulations were incubated at 37 ° C for one hour before they were filtered through 0.2 micron filters to separate any of the undissolved solids The filtrates were measured using a UV spectrometer at 290 nm in a 1 cm long quartz cuvette The commercial drug (165 mg of antibiotic-antifungal) in tablet form was ground into powder and an amount containing 30 mg of antibiotic-antifungal was tested in the same way as the main formulations for comparison.

Results The results of the laboratory scale dissolution test are plotted in Figure 4 as absorbance at 290 nm, showing the averages and standard deviations from three measurements. An increase of up to 300% in the solubilities (as measured by UV) was obtained compared to the commercial formulation. All five major formulations identified in the microarray screening were validated in the solid form in the laboratory-scale dissolution test (10,000 x) to have an increased solubility compared to the commercial drug, providing the results of the assay format of the microarray can now be translated into normal laboratory scale assays.

EXAMPLE 3: Evaluation of the individual effect of each excipient Experimental procedure To examine the effect of each excipient on the antibiotic-antifungal solubility, the first three main formulations (TPI-1 to TPI-3) previously identified in the microarrays described above were "de-convoluted" at the laboratory scale in the antibiotic-antifungal formulations containing (1) one of the three excipients only, or (2) two of the three excipients in different combinations (eg, components one and two, two and three, one and three). The solubilities of each sample were then measured using the same laboratory procedures described above for the main validation, using the absorbance at 290 nm to determine solubility. The solubilities for the formulations "of He has*?. k.l ^ íA?, ^ My tMm. "convoluted" are shown in Figures 5, 6 and 7 as proportions for their respective main formulation (it is important to note that some reformulations have greater or lesser solubilities than the main formulations identified in Example 1, but that the results are relative to the formulation initial principal, no absolute absorbance.) In Figure 5, excipient 14 (polyoxyethylene 40 stearate) (which is present as a small percentage in TPI-3, as indicated by the area, on the pie chart) produces an agent substantial in solubility, which was slightly improved with excipient 10 (PEG 1000) As shown in Figure 5, 14 (polyoxyethylene 40 stearate) was the only important excipient in TPI-3 in addition to 10 (PEG 1000) and 1 (acacia) had no effect on total solubility The addition of excipient 2 (cyclodextrin B) actually decreased the total solubility of the antibiotic-antifungal in TPI-1, as shown in Figure 6, demonstrating an antagonistic effect between the excipients. On the contrary, as shown in Figure 7, the excipient 3 (SDS), 10 (PEG 1000) and 14 (polyoxyethylene 40 stearate) show synergy in the improvement of antibiotic-antifungal solubility.

EXAMPLE 4: Comparison of the rate of dissolution under USP conditions stimulated Experimental procedure The rates of dissolution of TPI-2 and the commercial, antibiotic-antifungal product (165 mg) were compared on a laboratory scale using 1000 ml of deionized water in 1000 ml Erlenmeyer flasks at 37 ° C with shaking at 300 rpm with a 1.5 inch magnetic stir bar The dissolution rate for each formulation was determined separately. Each formulation was added to deionized water under stirring 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. Each aliquot was added to a small 1.5 ml Eppendorf flask, centrifuged at room temperature at 14,000 RPM for 10 seconds to remove the undissolved solids and the ultraviolet absorbance at 290 nm was determined in a 1 cm long quartz cuvette.

Results Figure 8 shows the dissolution rates. TPI-2 showed a faster dissolution rate as well as a higher equilibrium solubility in 55 yr- * f. comparison with the antibiotic-antifungal, also confirming the validity of the selected main formulations of the microarrays. These results demonstrate the effectiveness of high performance formulation and screening methods and how it is possible to scale the results with a high degree of reproducibility.

Claims

1. An arrangement comprising at least 96 formulations, each of the formulations comprising a known active component and one more additional components, wherein each formulation differs from any other of the formulations with respect to at least one of the following: (i) identity of one or more of the additional components; or (ii) the proportion of the active component for one or more of the additional components.

2. The arrangement as claimed in claim 1, wherein the active component is present in each formulation in an amount of less than 100 micrograms.

3. The arrangement as claimed in claim 1, wherein the active component in each formulation is present in amounts of nanograms.

. The arrangement as claimed in any of the preceding claims, comprises more than 1000 formulations. -É-fi ------ ^ j -.---. L? - * MJJHá > ^^ li-al iiij lli

5. The arrangement as claimed in any of the preceding claims, wherein the active component is a food additive, a nutrient, a cosmetic, a fragrance, a pharmaceutical, a veterinary product, a nutraceutical, a health care product, a consumer product, an agricultural product, an industrial product, a diagnostic reagent or a research reagent.

6. The arrangement as claimed in any of the preceding claims, wherein the active component is a nucleotide, a protein, a peptide, a polysaccharide, a saccharide or a combination thereof.

7. The arrangement as claimed in claim 5, wherein the pharmacist is a small molecule.

8. The arrangement as claimed in any of the preceding claims, wherein the active component is a synthetic chemical entity.

9. The arrangement as claimed in any of the preceding claims, wherein one or more additional components improves the solubility or dissolution of the active component. .. ^. i SEQUENCE &: &&- ??, ¿yi.í. ..., ..., ».. at.-a-A-», ¿,., ".» .. ^ ". ^. U - * -» - AAl-tA 58

10. The arrangement as claimed in any of the preceding claims, wherein one or more additional components is effective to modify an absorption rate, bioavailability, metabolism or other pharmacokinetic property of the active component.

11. The arrangement as claimed in any of the preceding claims, wherein one or more of the formulations comprises a microstructural form of the active component.

12. The arrangement as claimed in claim 11, wherein the microstructural form of the active component is amorphous or crystalline.

13. The arrangement as claimed in any of the preceding claims, wherein one or more of the formulations comprises a salt, a co-crystal, a solvate or a clathrate of the active component.

14. The arrangement as claimed in claim 13 wherein the solvate is a hydrate.

15. The arrangement as claimed in claim 12, comprising two or more polymorphs of the active component. * ^ ¿..- i..i -. || g | i ||| t |.? FlfJ ...- ^ .._ », .- ,. ¡. ? A? YM.y .y *. ..yM *? a8 .- > - &, -? kJ

16. The arrangement as claimed in claim 12, comprising two or more crystalline forms, wherein at least two of the crystalline forms have a different crystal face.

17. The arrangement as claimed in any of the preceding claims, wherein the active component is a prior known pharmaceutical or currently used in humans.

18. The arrangement as claimed in any of the preceding claims, wherein one or more of the formulations comprises the active component in anhydrous form.

19. The arrangement as claimed in any of the preceding claims, wherein one or more of the formulations comprises the active component in solid form.

20. The arrangement as claimed in any of the preceding claims, wherein one or more of the formulations contains the active component in dissolved form.

21. A screening method for a plurality of formulations for the properties, each formulation comprises a combination of a known active component and one or more additional components, the method consists of: (a) preparing at least 96 formulations, each formulation containing the active component known and one or more additional components, wherein each formulation differs from any other of the formulations with respect to at least one of the following: (i) the identity of one or more additional components; or (ii) the ratio of the active component to one or more of the additional components; and (b) analyzing the formulations to detect one or more properties.

22. The method as claimed in claim 21, wherein more than 1000 formulations are prepared in a single array or multiple arrays.

23. The method as claimed in any of claims 21 or 22, wherein the amount of the active component in each formulation is less than 1000 you,. , & i iii, micrograms.

24. The method as claimed in any of claims 21-23, wherein the active component in each formulation is present in amounts of nanograms.

25. The method as claimed in any of claims 21-24, wherein the active component is a food additive, a nutrient, a cosmetic, a fragrance, a pharmaceutical, a veterinary product, a nutraceutical, a product for the care of the health, a consumer product, an agricultural product, an industrial product, a diagnostic or research reagent.

26. The method as claimed in any of claims 21-25, wherein the active component is a nucleotide, a protein, a peptide, a polysaccharide, a saccharide or a combination thereof.

27. The method as claimed in claim 25, wherein the pharmacist is a small molecule.

28. The method as claimed in any of the claims 21-27, wherein the active component is a synthetic chemical entity.

29. The method as claimed in any of claims 21-28, wherein one or more of the formulations differs with respect to at least one of the following: (a) the amount or concentration of the active component (b) the identity of one or more additional components (c) the amount or concentration of one or more of the additional components; or (d) the pH.

30. The method as claimed in any of claims 21-29, wherein the one or more properties explored are stability, solubility, rate of dissolution, release, pharmacokinetics, half-life, supply kinetics, hydrophobicity, absorption, metabolism, mechanical properties , taste, texture, smell, color or permeability.

31. A method for screening a plurality of formulations for the microstructural forms, each .... ^ ... ^. i ^ r-- - "^^" * "- ^" - ^^ formulation comprising a cobmianción of a known active component and one or more additional components, the method consists of: ( a) preparing at least 96 formulations, each formulation containing the known active component and one or more additional components, wherein each formulation differs from any other of the formulations with respect to at least one of the following: (i) the identity of one or more additional components, or (ii) the ratio of the active component to one or more of the additional components, (b) the processing of the arrangement, and (c) analyzing the processed formulations of the array to detect one or more microstructural forms, in wherein the processed array comprises at least two formulations having a different microstructural form of the active component.

32. The method as claimed in claim 31, wherein more than 1000 formulations are prepared in single or multiple arrays. rtiü-ririla ^ itr '^ -' ^ * '^ - ^ * - * 1' --'-- cJ ^ - ^ - ^ - ^ Jtt - ^ - a «M *»? jaaía

33. The method as it is claimed in any of claims 31 or 32, wherein the amount of the active component in each formulation is less than 100 micrograms.

34. The method as claimed in any of claims 31-32, wherein the active component in each formulation is present in amounts of nanograms.

35. The method as claimed in any of claims 31-34, wherein the active component is a food additive, a nutrient, a cosmetic, a fragrance, a pharmaceutical, a veterinary product, a nutraceutical, a product for the care of the health, a consumer product, an agricultural product, an industrial product, a diagnostic reagent or a reagent for research.

36. The method as claimed in any of claims 31-35, wherein the active component is a nucleotide, a protein, a peptide, a polysaccharide, a saccharide or a combination thereof.

37. The method as claimed in claim 35, ,.-.Y*.-. ...Y.. . ^^^^^^^^^^^^^^^^^^^^^ where the pharmacist is a small molecule.

38. The method as claimed in any of claims 31-37, wherein the active component is a synthetic chemical entity.

The method as claimed in any of claims 31-38, wherein one or more of the processed formulations differs with respect to at least one of the following: (a) the amount or concentration of the active component. (b) the identity of one or more additional components. (c) the amount or concentration of one or more of the additional components; or (d) the pH.

40. The method as claimed in any of claims 31-39, further comprises analyzing the microstructural form detected using one or more of the following: infrared spectroscopy, Raman spectroscopy, NMR, X-ray diffraction, neutron diffraction, ray diffraction X powder, light microscopy, electron microscopy, fi-wtfa? «.? ^ *« ^ fi "^^ -f -rrr ^. '? 66 differential scanning calorimetry or thermal gravimetric analysis.

41. The method as claimed in any of claims 31-40, wherein the processed formulations are analyzed to determine whether the microstructural form is amorphous or crystalline.

42. The method as claimed in any of claims 31-41, wherein one or more microstructural forms of the active component is amorphous or crystalline.

43. The method as claimed in any of claims 31-42, wherein one or more of the formulations comprises a salt, a co-crystal, a solvate, or a clathrate of the active component.

44. The method as claimed in claim 43, wherein the solvate is a hydrate.

45. The method as claimed in any of claims 31-44, wherein the array comprises two or more polymorphs of the active component. 67 t and ».s &,

46. The methods as claimed in any of claims 31-45, wherein the array comprises two or more crystalline forms of the active component, wherein at least two of the crystalline forms have a different crystal face.

47. The method as claimed in any of claims 31-46, wherein more than 100,000 formulations are screened per day.

48. The method as claimed in any of claims 31-47, wherein the component is a prior known pharmaceutical or currently used in humans.

49. The method as claimed in any of claims 31-48, wherein one or more of the formulations comprises the active component in anhydrous form.

50. The method as claimed in any of claims 31-49, wherein one or more of the formulations contains the active component in solid form. ? sÉ 68

51. The method as claimed in any of claims 31-50, wherein one or more of the formulations contains the active component in dissolved form.

52. A method for identifying optimal microstructural forms of an active component, consists of: (a) forming one or more structural forms of the active by processing an array comprising at least 96 formulations, each formulation consisting of a combination of a known active and one or more additional components, wherein each amount of the active in each formulation is less than one gram (b) selecting one or more of the microstructural forms; and (c) analyze the selected microstructural forms.

53. The method as claimed in claim 52, wherein the array comprises more than 1000 formulations.

54. The method as claimed in any of claims 52 or 53, wherein the amount of the Active component in each formulation is less than 100 micrograms.

55. The method as claimed in any of claims 52-54, wherein the active component in each formulation is present in amounts of nanograms.

The method as claimed in any of claims 52-55, wherein one or more of the processed formulations differs with respect to at least one of the following: (a) the amount or concentration of the active component (b) the identity of one or more of the additional components (c) the amount or concentration of one or more of the additional components; or (d) the pH.

57. The method as claimed in any of claims 52-56, wherein one or more of the microstructural forms of the active component is amorphous or crystalline.

58. The method as claimed in any of claims 52-57, wherein one or more of the formulations contain a salt, a co-crystal, a solvate or clathrate of the active component

59. The method as claimed in claim 58, wherein the solvate is a hydrate.

60. The method as claimed in any of claims 52-59, wherein the array comprises two or more polymorphs of the active component.

61. The method as claimed in any of claims 52-60, wherein the array comprises two or more crystalline forms of the active component, wherein at least two of the crystalline forms have a different crystal face.

62. The method as claimed in any of claims 52-61, wherein the active component is a food additive, a nutrient, a cosmetic, a fragrance, a pharmaceutical, a veterinary product, a nutraceutical, a product for the care of the health, a consumer product, an agricultural product, an industrial product, a diagnostic reagent or - '* -' "rtitihtff- i- .. * ^? * iu. * AíJ M? investigation.

63. The method as claimed in any of claims 52-62, wherein the active component is a nucleotide, a protein, a peptide, a polysaccharide, a saccharide or combination thereof.

64. The method as claimed in claim 62, wherein the pharmacist is a small molecule.

65. The arrangement as claimed in any of claims 52-64, wherein the active component is a synthetic chemical entity.

66. The method as claimed in any of claims 52-65, wherein the component is a prior known pharmaceutical or currently used in humans.

67. The method as claimed in any of claims 52-66, wherein one or more of the formulations comprises the active component in anhydrous form.

68. The method as claimed in any of the claims 52-67, wherein one or more of the formulations contains the active component in solid form.

69. The method as claimed in any of claims 52-68, wherein one or more of the formulations contains the active component in dissolved form.

A method for measuring or detecting one or more interactions between components, consists in: (a) preparing at least 96 formulations, each of the formulations containing a known active component and one or more additional components, wherein each formulation differs from any another of the formulations with respect to at least one of the following: (i) the identity of one or more additional components; or (ii) the ratio of the active component to one or more of the additional components (b) testing each formulation to detect an interaction by measuring one or more properties.

71. The method as claimed in claim 70, wherein the active component is a food additive, a nutrient, a cosmetic, a fragrance, a pharmaceutical, a veterinary product, a nutraceutical, a health care product, a product of consumption, an agricultural product, an industrial product, a diagnostic reagent or a reagent for research.

72. The method as claimed in claim 70 or 71, wherein the active component is a nucleotide, a protein, a peptide, a polysaccharide, a saccharide or a combination thereof.

73. The method as claimed in claim 71, wherein the pharmacist is a small molecule.

74. The arrangement as claimed in any of claims 70-73, wherein the active component is a synthetic chemical entity.

75. The method as claimed in any of claims 70-74, wherein the array comprises more than 1000 formulations.

76. The method as claimed in any of the References 70-75, wherein the amount of the active component in each formulation is less than 100 micrograms.

77. The method as claimed in any of claims 70-76, wherein the active component in each formulation is present in amounts of nanograms.

78. The method as claimed in any of claims 70-77, wherein the property is stability, solubility, dissolution rate, release, pharmacokinetics, half-life, supply kinetics, hydrophobicity, absorption, metabolism, mechanical properties, taste, texture, smell, color, or permeability.

79. The method as claimed in any of claims 70-78, further consists in generating a series of data.

80. The method as claimed in claim 79 further comprises analyzing the data series to detect or measure interactions between two or all of the components. ^^ ^^^ mm ^ A á ^^^^^^^ A ^^?

81. The method as claimed in claim 79, further comprises analyzing the data series to detect the absence of interactions between two or more components.

82. The method as claimed in any of claims 79-81, wherein the data series is analyzed by computer.

83. The method as claimed in any of claims 70-82, wherein the preparation of the arrangement and the performance of the testing of the formulations is carried out by an automated system.

84. The method as claimed in any of claims 70-83, wherein one or more of the formulations contains the active component in solid form.

85. The method as claimed in any of claims 70-84, wherein one or more of the formulations contains the active component in dissolved form.

86. A system for preparing and testing an array of formulations for one or more properties comprises: (a) an automated preparation and efficient distribution mechanism to prepare at least 96 formulations (b) an arrangement comprising at least 96 formulations, each of formulations containing a known active component and one or more additional components, wherein each formulation differs from any other of the formulations with respect to at least one of the following: (i) the identity of one or more of the additional components; or (ii) the ratio of the active component to one or more of the additional components; and (c) a mechanism to analyze each formulation for one or more properties.

87. The system as claimed in claim 86, wherein the amount of the active component in each formulation is less than 100 micrograms.

88. The system as claimed in claim 86, wherein the active component in each formulation is present in amounts of nanograms.

89. The system as claimed in any of claims 86-88, wherein the mechanism for analyzing consists of an in vi tro test.

90. The system as claimed in any of claims 86-89, further comprises a mechanism for directing each formulation separately from the array to the formulation tester.

91. The system as claimed in any of claims 86-90, wherein the active component is a food additive, a nutrient, a cosmetic, a fragrance, a pharmaceutical, a veterinary product, a nutraceutical, a product for the care of the health, a consumer product, an agricultural product, an industrial product, a diagnostic reagent or a reagent for research.

92. The system as claimed in any of claims 86-91, wherein the tester of the formulation is suitable for testing stability, solubility, rate of dissolution, release, pharmacokinetics, half-life, supply kinetics, hydrophobicity, absorption, metabolism, mechanical properties, taste, texture, smell, color, or permeability.

93. The system as claimed in any of claims 86-92, wherein the property is the microstructure.

94. The system as claimed in claim 93, wherein one or more of the formulations contains a microstructural form of the active component.

95. The system as claimed in any of claims 86-94, wherein the mechanism for analyzing comprises a detector for detecting the microstructural form. 1 Mil 1 - '• -i-i-. HMMIMÍÉM ^ MÉ TJÜtl-iiliHl t I SUMMARY OF THE INVENTION Methods have been developed that use technologies for high-performance combinatorial formulation, preferably in combination with nanotechnology and microarrays, to improve one or more properties of the materials that are used as components of, or in the manufacture or use of, the products for health care, consumer products, agricultural products, nutraceutical products, veterinary products, products for use in the manufacturing or processing industries, military applications and reagents for research. In a preferred application, the bioavailability and pharmacokinetics of drugs, especially small molecule pharmaceuticals, are optimized by making multiple new formulations and selecting these formulations based on one or more physical or chemical properties such as solubility in an aqueous solution, without compromise the selectivity or power. Systems that employ these technologies have been designed to quickly, systematically and economically identify optimal compositions for a specific purpose. In a preferred embodiment, new formulations for bioequivalence are prepared and tested with a formulation that is approved or u ^ Uá mavii for sale in the trade. In another embodiment, the formulations are initially optimized in vi tro for their pharmacokinetics, such as absorption through the intestine (for an oral preparation), through the skin (for transdermal application), or mucosa (for nasal formulations) , buccal, vaginal or rectal), solubility, degradation or clearance by uptake in the reticuloendothelial system ("RES"), metabolism or elimination, then tested in vivo. 9 < ?? - '"- -» • * • »* - ^^^ ¿^^« «^ 5 ^