KR20020034168A - Sample arrays and high-throughput testing thereof to detect interactions - Google Patents

Abstract

The present invention provides a highly data processing method for producing an array comprising a plurality of said samples, each sample consisting of a combination of components in varying concentrations and identities, and testing each sample for one or more properties. To an advanced data processing method. Non-active ingredients and active ingredients by the same method as described above; Multiple non-active ingredients; Or detect or measure an interaction between a plurality of active ingredients or detect a lack of interaction. The present invention is particularly suitable for preparing multiple drug-excipient samples simultaneously, and then quickly testing each sample for detection or measurement of interaction. Once such interactions are detected or measured, they can be used to develop formulations optimized for drug administration.

Description

Sample Arrays for Interaction Detection and Their Highly Data Processing Trial {SAMPLE ARRAYS AND HIGH-THROUGHPUT TESTING THEREOF TO DETECT INTERACTIONS}

This application is part of application No. 09 / 540,462, filed Mar. 31, 2000, filed Jul. 28, 1999, US Provisional Application No. 60 / 146,019, and Applied Apr. 5, 1999, Claims the benefit of application 60 / 127,755, the entire contents of some of these continuing and provisional applications, which are incorporated herein by reference. It also claims priority to US Provisional Application No. 60 / 146,019, filed July 28, 1999.

The discovery of pharmaceutical formulations that optimize bioavailability and duration of action of drugs and minimize undesirable properties is an important part of drug development and research. Drugs are rarely dispensed as pure compounds, especially due to issues of stability, solubility and bioavailability. In most cases, agents are administered in pharmaceutical formulations containing the active ingredient and excipients. It has been widely demonstrated that the physical and chemical properties of most drugs, such as their stability, solubility, dissolution, permeability and distribution, are directly related to the medium in which they are administered. This is because the medium affects the physical, chemical and chemical environment of the active ingredient, for example the medicament. The physical and chemical properties of the drug mixture in the formulation are directly related to pharmacological and pharmacokinetic properties such as absorbency, bioavailability, metabolic profile, toxicity and efficacy. Such effects are caused by physical and chemical interactions between the excipient and the drug and / or physical and chemical interactions between the excipients themselves. Other properties affected by the formulation to which the medicament is administered include mechanical properties such as compressibility, compressibility, and flow properties and sensory properties such as taste, odor and color.

Therefore, the goal of formulation development is to find formulations that optimize the desired properties of the medicament under the conditions of administration, such as the stability, solubility and bioavailability of the medicament. This is typically a tedious process in which each variable is evaluated separately at various points over a wide range of conditions or combinations. For example, if the formulation contains a medicament characterized by poor solubility, the solubility of the medicament in the salt concentration range to find an interaction between the medicament and the excipient or excipients that affect the solubility of the medicament; pH; Excipients; And drug concentrations should be prepared and tested. While some general rules exist, the effects of excipients and excipient combinations on the physical and chemical properties of the medicament are not readily foreseen. Furthermore, there are more than 3,000 excipients when conceiving pharmaceutical formulations, which vary in degree and type of interaction with each other and with the medicament, respectively. Because of the large number of variables involved, there is no industrially time and resources to identify, measure and develop interactions between excipients and drugs, and therefore cannot provide an optimized pharmaceutical formulation for a particular drug. Such an operation may require testing hundreds to thousands of samples per day. Assuming three hundred substances are tested for efficacy as excipients in pharmaceutical formulations, even if there is no change in concentration and physical or chemical properties, the number of possible combinations is enormous, i.e. when selecting two substances, 44,850 There are four possible combinations, 4,455,100 combinations for the three components, and 330,791,175 combinations for the four components. The complexity is increased when considering the relative proportions of each component. Unfortunately, there is no known technique that can simultaneously make multiple drug-excipient combinations and then automatically supply each combination to a system for identifying combinations with optimized properties. Today, for more cost effective reasons, most drugs are dispensed and administered in standard, unoptimized formulations (Allen's Compounded Formulations: U.S. Pharmacists Collection 1995 to 1998, ed. Loyd Allen).

Unfortunately, current pharmaceutical formulation research and development still relies on a few selected excipients and counteracts the active ingredients to well known oral or parenteral formulation systems. The present invention rejects the traditional approach.

The need to provide an optimized formulation is not limited to formulations in which the active ingredient is a medicament. Similar problems face the administration of dietary supplements, alternative medicines, nutritional drugs, sensory compounds, pesticides, and consumer and industrial product formulations. For example, vitamin formulations similar to pharmaceutical formulations may be characterized by poor stability, solubility, bioavailability, taste or odor. In another example, industrial product formulations, such as paper bleach, may benefit from re-formulation for higher stability so that activity is not reduced during shipment.

Summary of the Invention

The present invention relates to a highly data processing method for creating and simultaneously identifying multiple component combinations at varying concentrations and to a highly data processing method for testing each combination. Active and non-active ingredients in the same manner as described above; Multiple inactive ingredients; Or detect or measure interactions between multiple active ingredients. The present invention particularly provides a number of drug-excipient combinations, which are then rapidly tested for each of the excipients and agents; Excipients; Or suitable for detecting or measuring the interaction between multiple agents or for detecting the lack of such interaction. Once such interactions or lack of interactions have been identified, they can be used to develop formulations optimized for drug administration.

Thus, the present invention is directed to determining the overall optimal formulation for any particular ingredient, or for optimizing any particular desired property or result, such as bioavailability, efficacy, release, stability, and the like; Or advanced data processing tests of pharmaceutical formulations for all of them. To the best of our knowledge, a systematic and highly operational method of preparation, selection, testing and analysis of formulations has not been published prior to the present invention. Moreover, automated systems for the generation, selection and testing of such formulations are included in the present invention. Finally, computer analysis of such data is included in the present invention. Specific embodiments of the present invention are described in detail below.

In one embodiment, the invention relates to an arrangement of samples, wherein each sample comprises a common component and one or more additional components, where each sample differs from any other sample for one or more of the following:

(i) identity of additional components,

(ii) the ratio of common components to additional components, or

(iii) physical state of common components.

Common component means that the component is present in all samples. Preferably, the common ingredient is an active ingredient, more preferably an active ingredient of a pharmaceutical, dietary supplement, alternative medicine, nutraceutical, sensory compound, pesticide, consumer product formulation, or industrial product formulation. . The samples and components may be in the form of solids, liquids, gels, foams, pastes, ointments, powders, suspensions or emulsions.

In another embodiment, the present invention

(a) each sample comprises a common component and one or more additional components, wherein each sample produces an array of samples different from any other sample for one or more of the following:

(i) identity of additional components,

(ii) the ratio of common components to additional components, or

(iii) the physical state of the common components;

(b) Each sample is tested for one or more properties.

It relates to a method for measuring or detecting the interaction between the components, including.

In yet another embodiment, the present invention

(a) each sample comprises two or more components, wherein each sample is different from any other sample with respect to the identity of the components, and the samples may also be different with respect to the ratio of components or the physical state of the components; Preparing an array of samples that can be made;

(b) Each sample is tested for one or more properties.

It relates to a method for measuring or detecting the interaction between the components, including.

In this embodiment, the samples do not have a common component. The method is useful for testing mixtures of components, for example chemical fragrances, each component having a different identity or formula.

Preferably, the samples are prepared by a computer, tested, automatically analyzed and data stored and / or analyzed. Preferably, the common ingredients are active ingredients, more preferably pharmaceuticals, dietary supplements, alternative medicines, nutraceuticals, sensory compounds, pesticides, active ingredients of consumer product formulations, or active ingredients of industrial product formulations. The samples and components may be in the form of solids, liquids, gels, foams, pastes, ointments, powders, suspensions or emulsions.

In another embodiment, the present invention

(a) each sample comprises a common component and one or more additional components, wherein each sample produces an array of samples different from any other sample for one or more of the following:

(i) identity of additional components,

(ii) the ratio of common components to additional components, or

(iii) the physical state of the common components;

(b) testing each sample for one or more properties to produce a property-result for each sample;

(c) comparing the property-result produced for each sample with a baseline or a control standard for the property to produce a comparison result for the sample

It relates to a method of testing or optimizing one or more properties of an active ingredient formulation, comprising.

Preferably, the samples are prepared by a computer, tested, automatically analyzed and data stored and / or analyzed. Preferably, the active ingredient is an active ingredient of a medicament, dietary supplement, alternative drug, nutraceutical, sensory compound, pesticide, consumer product formulation, or industrial product formulation. Most preferably, the active ingredient is a medicament. The samples and components may be in the form of solids, liquids, gels, foams, pastes, ointments, powders, suspensions or emulsions.

In yet another embodiment, the present invention

(a) each sample comprises a common component and one or more additional components, wherein each sample is an arrangement of samples different from any other sample for one or more of the following:

(i) identity of additional components,

(ii) the ratio of common components to additional components, or

(iii) the physical state of the common components; And

(b) a sample tester for testing each sample for one or more properties

It relates to a system for measuring or detecting the interaction between the components, including.

Preferably, the common ingredient is an active ingredient of a pharmaceutical, dietary supplement, alternative medicine, nutraceutical, sensory compound, pesticide, consumer product formulation, or industrial product formulation. Most preferably, the common ingredient is a medicament. The samples and components may be in the form of solids, liquids, gels, foams, pastes, ointments, powders, suspensions or emulsions.

These and other features, aspects, and advantages of the present invention will be better understood with reference to the following detailed description, examples, and appended claims.

The present invention relates to the generation and analysis of data for multicomponent chemical compositions, in particular pharmaceutical formulations or other formulations. More specifically, the present invention relates to highly data processing methods, systems and apparatus for measuring and testing samples for optimization of sample properties and discovery of new compositions.

1 illustrates an arrangement of samples, processing samples, analyzing the samples for one or more properties, collecting and storing data, analyzing the data, detecting or measuring interaction, or Schematic of how to detect lack.

2A and 2B are more detailed schematic diagrams of the process of formulating a plurality of samples and analyzing them for properties such as solubility (UV-VIS HPLC) and estimated oral absorbency, wherein FIG. 2A shows solids as samples of the above arrangement. A schematic of the process of putting in a well, then reconstituting and testing; 2B is a schematic diagram of the process of putting a liquid into an array, drying, reconstituting, then separating and testing the liquid into a solid.

FIG. 3A is a graph of the solubility (absorbance) of 3,500 unique formulations containing griseofulvin with various excipients in water, and FIG. 3B is in the data of FIG. 3A prepared to show the standard deviation for each of these unique formulations. For the graph.

4 is a graph of solubility (absorbance) comparison of five leading formulations (TPI-1 to TPI5) with commercially available agents.

FIG. 5 is a graph of the solubility ratios of various re-formulations of TPI-3, one of the leading formulations, re-formulated with only one or two of three excipients showing a ratio relative to the attached “pie”.

FIG. 6 is a graph of the solubility ratios of various reformulations of the formulation, comparing the effect of re-formulating the lead formulation, TPI-1, with one or two of the three excipients in the lead formulation. Demonstrates reduced solubility.

FIG. 7 is a graph of the solubility ratios of various reformulations of the formulation, showing the effect of re-formulating one of the leading formulations, TPI-2, with one or two of the three excipients in the leading formulation. Demonstrates a synergistic effect on solubility.

FIG. 8 is a graph comparing the dissolution rate and equilibrium solubility of TPI-2 with Griseofulvin, indicating that TPI-2 has a higher equilibrium solubility as well as a higher dissolution rate compared to Griseofulvin.

As used herein, the term "array" refers to a number of samples that participate in a conventional experiment, where each sample comprises two or more components, one of which is a common component. The term "common component" simply refers to a specific compound present in all samples of the configuration, with the exception of the negative control standard. The arrangement is designed to provide a data set, and analysis of the set enables detection or measurement of interactions (including lack of interaction) between common components and other components. Each sample in the array is different from any other sample in the array for one or more of the following:

(i) identity of additional components,

(ii) the ratio of common components to additional components, or

(iii) physical state of common components.

The arrangement may comprise 24, 36, 48, 96 or more samples, preferably at least 1000, more preferably at least 10,000 samples. An array typically includes one or more sub-arrays. For example, the sub-array may be a 96-well plate of sample wells.

As used herein, the term "sample" refers to a mixture of common components and one or more additional samples. Preferably the sample comprises two or more additional ingredients, more preferably three or more additional ingredients. In general, a sample contains one common component but may comprise a plurality of components in common. The sample may be present in any container or holder or in or on any material or surface, but the only requirement is that the sample is placed in a separate location. Preferably, the sample is contained in a sample well, such as a 250 μl volume of 24, 36, 48 or 96 well plates (or filter plates) available from Millipore (Bedford, Mass.). The sample may comprise less than about 100 mg of common components, preferably less than about 1 mg, more preferably less than about 100 μg, even more preferably less than 100 ng. Preferably the total volume of the sample is 150 to 200 μl. Preferably, the sample comprises at least two, more preferably at least three additional components.

According to the invention, the "physical state" of a component is initially defined by whether the component is liquid or solid. When the component is a solid, the physical state is further defined by the particle size and whether the component is crystalline or amorphous. If the component is crystalline, the physical state is determined by (1) whether the crystal matrix comprises a co-adduct or the crystal matrix originally contained a co-adduct, but the co-adduct was removed to create a gap. Whether or not; (2) crystal habits; (3) shape, ie crystal habit and size distribution; And (4) further subdivided into internal structure (polymorphism). In co-adducts, the crystal matrix may comprise stoichiometric or non-stoichiometric amounts of adducts, for example crystallization solvents or water, ie solvates or hydroxides. Non-stoichiometric solvates and hydroxides include inclusions or inclusion compounds, ie where the solvent or water is trapped inside the crystal matrix, for example at random intervals in the channel. Stoichiometric solvates or hydroxides are when the crystalline matrix comprises solvents or water in specific proportions at certain places. That is, the solvent or water molecule is part of the crystal matrix in a finite arrangement. In addition, the physical state of the crystal matrix can be changed by removing the cavity adduct originally present in the crystal matrix. For example, when the solvent or water is removed from the solvate or hydroxide, pores will form inside the crystal matrix to form a new physical state. Crystal behavior is a description of the appearance of individual crystals. For example, the crystals may have the shape of a cube, tetragonal, tetragonal, monoclinic, triclinic, oblong, or hexagonal. Processing properties are influenced by the crystal behavior. The internal structure of the crystal is related to the crystal form or polymorphism. A given compound may exist in different polymorphs, ie unique crystal species. In general, different polymorphs of a given compound differ in structure and properties as crystals of two different compounds. Solubility, melting point, density, hardness, crystal shape, optical and electrical properties, vapor pressure and stability all vary depending on the shape of the polymorph.

When referring to the interaction between components, "interaction" refers to the nature of the components (such as the ability to dissolve a particular agent) that the components as a mixture have a different size or value than the properties of each component alone. The interaction between the components will affect the nature of the sample. By way of example only, certain combinations and ratios of excipients may interact such that the combination has a high stabilizing power for a particular agent. Once such interactions are detected, they can be used to develop improved formulations for the medicament.

As used herein, "component" means any substance. The component may be active or inactive. As used herein, “active ingredient” means a substance that confers primary utility to a formulation when the formulation is used for its intended purpose. Examples of active ingredients are pharmaceuticals, dietary supplements, alternative medicines, nutraceuticals, sensory compounds, pesticides, active ingredients in consumer product formulations, or active ingredients in industrial product formulations. As used herein, "non-active ingredient" refers to an ingredient that is useful or potentially useful in formulations for the administration of the active ingredient, but which does not significantly affect the active nature of the active ingredient. Examples of suitable non-active ingredients include, but are not limited to, excipients, solvents, diluents, stabilizers and combinations thereof.

Preferably, the samples in the array contain common active ingredients and non-active ingredients. Those skilled in the art can use a number of permutations. In one example, where the active ingredient is a medicament, dietary supplement, alternative drug or nutraceutical, the preferred non-active ingredient is an excipient. If the active ingredient is a sensory compound, for example a flavoring or flavoring agent, the non-active ingredient is preferably a non-active (non-sensory) substance or ingredient known in the art for administration of the sensory compound. Where the active ingredient is a pesticide, the non-active ingredient is preferably inactive substances commonly used in the art for administration of pesticides. If the active ingredient relates to a consumer or industrial product formulation, the non-active ingredient is preferably an inactive substance known in the art for the delivery of such an active ingredient.

As used herein, the term "analytical factor" refers to a method, biological material or reagent, eg, enzyme or cell line, useful for measuring the properties of a sample.

As used herein, the term "formulation" means a composition comprising one or more active ingredients and one or more non-active ingredients in a predetermined ratio. The formulations are used as directed for the administration of the active ingredient.

As used herein, the term "administration" refers to the action of delivering or applying the active ingredient through the dosage form to the intended use. For example, administration of medicaments, dietary supplements, alternatives, and nutraceuticals include, but are not limited to, oral consumption, intravenous injection, and topical application. Administration of pesticides includes, but is not limited to, spraying and spraying crops. Administration of the sensory compound includes, but is not limited to, applying perfume and deodorant to the human body, or eating food or candy supplemented with flavor substances. Administration of consumer and industrial product formulations includes applying or simply using the product as directed. For example, administration of a paint means applying the paint to a surface with a paint brush, administration of a lubricant includes applying the lubricant to a surface in need thereof.

The ratio of common components to certain additional components according to the present invention will vary from sample to sample when the ratio is intentionally changed to change the properties of the sample to be measurable.

As used herein, the term "property" refers to the physical or chemical properties of a sample. Preferred properties are those that relate to the efficacy, safety, stability or utility of the formulation before or after administration. For example, properties for medicaments, dietary supplements, alternatives, and nutraceutical formulations include physical properties such as fluidity, softness, stability, solubility, dissolution, permeability, and distribution; Mechanical properties such as compressibility, compressibility and flow properties; Sensory properties such as feeling in the mouth, appearance, tissue, color, taste and smell; And properties that affect utility, such as absorbency, bioavailability, toxicity, metabolic profile, potency, release rate, and rate of dispersion. Optimizing the physical, sensory and usability properties can potentially lower the required dose for the same therapeutic effect while reducing side effects, thereby improving patient acceptance.

The arrangement comprises at least two samples, preferably at least 24, 36, 48, 72 or more samples, more preferably at least 96, even more preferably at least 1000 and most preferably at least 10,000 samples. The samples may be placed in separate locations and defined in any container or holder, absorbed in a suitable material, or placed in a separate location on a flat surface. Preferably, the sample is received in the sample well. The sample well may have any dimension or volume. Preferably, the sample wells have a volume in the range of 200-300 μl, more preferably 250 μl. Arrangements can be made by adding common components and additional component (s) to the sample wells. The common component is selected by the skilled person depending on the interaction to be measured or identified. Preferably, the common ingredient is an active ingredient (ie, a common active ingredient), more preferably a medicament (ie a common drug). However, in some cases the common ingredient is an inactive ingredient, for example when the arrangement is envisioned to detect or measure the interaction between a particular excipient (common excipient) and other excipients. The active and non-active ingredients are selected from a list of known substances published in the literature, or the ingredient can be a recently discovered substance. Preferably, the non-active ingredient is already known in the art for the administration of the active ingredient group under study. For example, if the common ingredient is a medicament, an inactive ingredient can be selected from a list of known excipients.

For each sample in the array, a common component and each component is present in a specific ratio. The ratio of the common component to the additional component is easily varied from sample to sample by the skilled person depending on the information the identity and arrangement of the common component is to provide.

Preferably, the sample components are mixed to obtain a homogeneous solution or suspension. Those skilled in the art will know how to add and mix the components of each sample based on the particular study. The ingredients can be added and mixed manually or automatically.

Preferably, the components are automatically added to the sample wells and mixed. "Automated" refers to a sample made using software and robotics for the addition and mixing of the ingredients. After the components have been added to the sample wells and mixed, the samples can be processed by well known techniques such as heating, filtration and freeze drying. One skilled in the art will know how to handle the sample depending on the nature of the test being tested. The samples can be treated individually or as a group, preferably as a group.

In accordance with the method of the present invention, each sample in the array is tested or analyzed for specific properties to provide a data set. The sample can be tested by various known methods depending on the components and the nature of the problem. A property can be detected or measured immediately to provide a value or magnitude for that property. The value or size of the property may be compared with a control standard or standard to assess whether the components of the sample interact or whether the sample has the potential to act as a formulation for administration of the active ingredient. For example, when an array of samples, each sample having the same known drug but different excipients, is tested to find a combination of excipients in which the drug exhibits the highest solubility, the solubility of the drug in each formulation is determined by the solubility. It can be compared with a control standard or standard for. For example, the solubility of the drug in each sample can be compared with the solubility of the drug in a commercial formulation or the solubility of an isolated drug.

Medications, Dietary Supplements, Alternative Medicines, and Nutraceuticals

The present invention is useful for the development of formulations with optimal properties by detecting or measuring pharmaceuticals, dietary supplements, alternative pharmaceuticals or the interactions between Neutrastical and excipients.

In one embodiment, the invention relates to an arrangement of samples comprising a common ingredient and one or more additional ingredients, wherein each sample is a medicament, dietary supplement, alternative medicine or nutraceutical. The sample is different from any other sample for one or more of the following:

(i) identity of additional components,

(ii) the ratio of common components to additional components, or

(iii) physical state of common components.

As used herein, the term "pharmaceutical" means any substance that has a therapeutic, disease preventing, diagnostic or prophylactic effect when administered to a human or animal. The term medicament includes prescription drugs and over-the-counter drugs. Agents suitable for use in the present invention include all known or developed agents.

Examples of suitable agents include, but are not limited to, cardiovascular agents such as amlodipine besylate, losartan potassium, irbesartan, ditilazem hydrochloride, clopidogrel bisulfate, digoxin, abysimab, purosemide, amidodarone Hydrochloride, veraprost, tocopheryl nicotinate; Infection inhibiting components such as amoxicillin, clavulanate potassium, azithromycin, itacazole, acyclovir, fluconazole, terbinafine hydrochloride, erythromycin ethylsuccinate and acetyl sulfisoxazole; Psychotherapeutic ingredients such as sertalin hydrochloride, vanlafaxine, bupropion, hydrochloride, olanzapine, buspirone hydrochloride, alprazolam, methylphenidate hydrochloride, fluvoxamine maleate and ergoloid mesylate; Gastrointestinal products such as lansoprazole, ranitidine hydrochloride, pamotidine, ondansetron hydrochloride, granitone hydrochloride, sulfasalazine and infliximab; Respiratory therapeutics such as loratadine, fexofindadine hydrochloride, cetirizine hydrochloride, fluticazone propionate, salmeterol xinapoate and budesonide; Cholesterol reducing agents such as atorvastatin calcium, lovastatin, bezafibrate, cipropibrate and gemfibrozil; Cancer and cancer related therapies such as paclitaxel, carboplatin, tamoxifen citrate, docetaxel, iperubicin hydrochloride, leuprolide acetate, bicarutamid, goserelin acetate grafts; Irinotecan hydrochloride, gemcitabine hydrochloride and sagramostim; Blood modifiers such as epoetin alfa, enoxaparin sodium and hemophilia inhibitors; Arthritis therapeutic ingredients such as celecoxib, nabumetone, misoprostol and rofecoxib; AIDS and AIDS-related agents such as lamivudine, indinavir sulfate, stavudine and lamivudine; Diabetes and diabetes related therapies such as metformin hydrochloride, troglitazone and acarbose; Biopharmaceuticals such as hepatitis B vaccine and hepatitis A vaccine; Hormones such as estradiol, mycophenolate mofetil and methylprednisolone; Analgesics such as tramadol hydrochloride, fentanyl, metamizol, ketoprofen, morphine sulfate, lysine acetylsalicylate, ketoralak tromethamine, morphine, roxofene sodium and ibuprofen; Skin products such as isotretinoin and clindamycin phosphate; Anesthetics such as propofol, midazolam hydrochloride and lidocaine hydrochloride; Migraine treatments such as sumatriptan succinate, zolmitrippan and rizatrippan benzoate; Sedatives and hypnotics such as zolpidem, zolpidem tartrate, triazolam and hycosin butylbromide; Imaging components such as iohexol, technetium, TC99M, cestamibi, iomeprol, gadodiamide, ioversol and iopromide; And diagnostic and contrast ingredients such as alsaktide, americium, betazole, histamine, mannitol, methyrapone, petagastrin, pentolamine, radioactive B ₁₂ , gadodiamide, gadopentetic acid, gadoteridol and There is purple flubron. Other agents for use in the present invention include those shown in Table 1 below, which have problems that can be alleviated by the development of new dosage forms according to the arrangement and method of the present invention.

Further examples of suitable medicaments are disclosed in 2000 Med Ad News 19: 56-60 and The Physicians Desk Reference, 53rd edition, 792-796, Medical Economics Company (1999).

Examples of suitable veterinary medicaments include, but are not limited to, vaccines, antibiotics, growth promoting ingredients, and antiparasitic agents. Other examples of suitable veterinary agents are described in The Merck Veterinary Manual, 8th ed., Merck and Co., Inc., Rahway, NJ, 1998; (1997); The Encyclopedia of Chemical Technology, 24 Kirk-Othomer (4th ed., P. 826); And Veterinary Drugs in ECT 2nd ed., Vol 21, A.L. Shore and R.J. Magee, American Cyanamid Co.

As used herein, a "dietary supplement" means a non-caloric or non-caloric substance administered to a human or animal to provide said nutritional benefit or non-caloric or minor-caloric substance administered as a food that is endowed with aesthetic, tissue, stability or nutritional benefit. -Means calorie or insignificant calorie material. Dietary supplements include, but are not limited to, fat binders such as cardiac; Fish oil; Plant extracts, for example garlic and pepper extracts; Vitamins and minerals; Food additives such as preservatives, sour flavoring agents, caking inhibitors, antifoaming ingredients, antioxidants, swelling ingredients, coloring ingredients, curing ingredients, dietary fibers, emulsifiers, enzymes, stable ingredients, wetting agents, fermentation ingredients, lubricants, b Nutritional sweeteners, edible solvents, thickeners; Fatty substitutes and flavor enhancers; And dietary supplements, such as appetite suppressants. Examples of suitable dietary supplements are disclosed in 1994, The Encyclopedia of Chemical Technology, 11 Kirk-Othomer (4th ed., P. 805-833). Examples of suitable vitamins are described in 1998, The Encyclopedia of Chemical Technology, 25 Kirk-Othomer (4th ed., P. 1) and Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 9th Edition, eds. Joel G. Harman and Lee E. Limbird, McGraw-Hill, 1996 p. 1547, which is incorporated herein by reference. Examples of suitable minerals are described in The Encyclopedia of Chemical Technology, 16 Kirk-Othomer (4th ed., P. 746) and "Mineral Nutrients", ECT 3rd ed., Vol 15, pp. 570-603, C.L. Rollinson and M.G. Enig, University of Maryland, which is incorporated herein by reference.

As used herein, the term "alternative medicine" means a substance, preferably a natural substance, such as a medicinal herb or herbal extract or concentrate, which is administered to a subject or patient for the treatment of a disease or for general health and happiness, The material does not require FDA approval. Examples of suitable alternative medicines include, but are not limited to, ginkgo biloba, ginseng root, gilcho root, oak bark, caba cava, echinacea, harpagofiti roots, and others are described in the Complete German Commission E. Monographs: Therapeutic Guide to Herbal Medicine, Mark Blumenthal et al. eds., Integrative Medicine Communications 1998.

As used herein, the term "nutraceutical" refers to a food having both calorie values and pharmaceutical or therapeutic properties. Examples of nutraceuticals are garlic, pepper, bran and fiber, and health drinks. Examples of suitable nutraceuticals are described in M.C. Linder, ed. Nutritional Biochemistry and Metabolism with Clinical Applications, Elwevier, New York, 1985; Pszczola et al., 1998 Food technology 52: 30-37 and Shukla et al., 1992 Cereal Foods World 37: 665-666.

Preferably, if the common ingredient is a medicament, dietary supplement, alternative drug or nutraceutical, the additional ingredient (s) is an excipient. As used herein, the term “excipient” is processed or manufactured to formulate a medicament, dietary supplement, alternative medicament and nutraceutical for administration to an animal or human, or used by those skilled in the art. By non-active substance used in the formulation of a medicament. Preferably the excipient is one that is approved or considered safe for human and animal administration. Examples of suitable excipients include, but are not limited to, sour flavoring agents such as lactic acid, hydrochloric acid and tartaric acid; Dissolution components such as nonionic, cationic and anionic surfactants; Absorbents such as kaolin, cellulose and kaolin; Alkalizing components such as diethanolamine, potassium citrate and sodium bicarbonate; Caking inhibitors such as tribasic calcium phosphate, magnesium trisilicate and talc; Antimicrobial components such as benzoic acid, sorbic acid, benzyl alcohol, benzethonium chloride, bronopol, alkyl parabens, cerimide, phenol, phenylmercury acetate, thimerazole and phenoxyethanol; Antioxidants such as ascorbic acid, alpha tocopherol, propyl gallate and sodium metabisulfite; Binders such as gum arabic, alginic acid, carboxymethyl cellulose, hydroxyethyl cellulose; Dextrin, gelatin, rubber, magnesium aluminum silicate, maltodextrin, povidone, starch, vegetable oils and zein; Buffering components such as sodium phosphate, malic acid, and potassium citrate; Chelating components such as EDTA, malic acid and maltol; Coating components such as auxiliary sugars, cetyl alcohol, polyvinyl alcohol, carnauba wax, lactose maltitol, titanium dioxide; Controlled release vehicles such as microcrystalline waxes, white waxes and yellow waxes; Desiccants such as calcium sulfate; Detergents such as sodium lauryl sulfate; Diluents such as calcium phosphate, sorbitol, starch, talc, lactitol, polymethacrylate, sodium chloride, and glyceryl palmitostearate; Disintegrants such as colloidal silicon dioxide, croscarmellose sodium, magnesium aluminum silicate, sodium polyacryline and sodium starch glycolate; Dispersion components such as poloxamer 386, and polyoxyethylene fatty esters (polysorbates); Emollients such as cetearyl alcohol, lanolin, mineral oil, petrolatum, cholesterol, isopropyl myristate and lecithin; Emulsifying components such as anionic emulsifying waxes, monoethanolamines and medium chain triglycerides; Flavor components such as ethyl maltol, ethyl vanillin, fumaric acid, malic acid, maltol and menthol; Humectants such as glycerin, propylene glycol, sorbitol and triacetin; Lubricants such as calcium stearate, canola oil, glyceryl palmitostearate, magnesium oxide, poloxamers, sodium benzoate, stearic acid and zinc stearate; Solvents such as benzyl phenylformate, vegetable oils, diethyl phthalate, ethyl oleate, glycerol, glycofurol, indigo carmine, polyethylene glycol, sunset yellow, tartazine, triacetin; Stabilizing components such as cyclodextrin, albumin, xanthan gum; And tonic components such as glycerol, dextrose, potassium chloride and sodium chloride; And mixtures thereof. Excipients include those that alter the rate of absorption, bioavailability, or other pharmacokinetic properties of the medicament, dietary supplement, replacement medicament, or neutral. Other examples of suitable excipients, such as binders and fillers, are described in Remington's Pharmaceutical Sciences, 18th Edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, PA, 1995 and Handbook of Pharmaceutical Excipients, 3rd Edition, ed. Arthur H. Kibbe, American Pharmaceutical Association, Washington D.C. 2000.

As used herein, the definition of “excipient” also includes a solvent. Aqueous solvents can be used to prepare mixtures, suspensions and matrices made from water soluble polymers. Organic solvents will typically be used to dissolve the hydrophobic and some hydrophilic polymers. Preferred organic solvents are solvents which are volatile or have a relatively low boiling point, can be removed under vacuum, are acceptable for human administration in trace amounts and are non-toxic, for example methylene chloride. Other solvents may also be used, such as ethyl acetate, ethanol, methanol, dimethyl formamide, acetone, acetonitrile, tetrahydrofuran, acetic acid, dimethyl sulfoxide and chloroform, and mixtures thereof. Preferred solvents are described in Federal Register vol. 62, No. 85, pp. 24301-24309 (May 1997), as grade 3 residual solvents by the Food and Drug Administration. Drug solvents administered parenterally or administered as a solution or suspension are more typically distilled water, buffered saline, lactated Ringer's solution or some other pharmaceutically acceptable carrier.

In one aspect of the embodiment related to the arrangement of the sample, the common ingredient is selected from the group of drugs, dietary supplements, alternative medicines and nutraceuticals, and the additional ingredients also include drugs, dietary supplements, alternative medicines and It is selected from the group of Nutraceutical. That is, each sample may include a plurality of active ingredients, where a particular active ingredient is present in all samples (ie, it is a common ingredient). Advantageous or Synergistic Interactions Between Drugs, Dietary Supplements, Alternative Drugs, and Neutrauticals and Other Drugs, Dietary Supplements, Alternative Drugs, and Nutrasticals Using Such an Arrangement Can be detected. For example, each sample contains the same common medicament and is particularly advantageous for the active ingredients using a sample that includes a different additional ingredient selected from the group of drugs, dietary supplements, alternatives, and neutraticals. Combinations can be identified. Such advantageous combinations cannot be expected based on the nature of the isolated components. Such arrays of multiple active ingredient samples may also be used to formulate two or more active ingredients together, for example to find excipient combinations suitable for formulating two or more agents in multiple dosage forms. These multiple dosage forms eliminate the need for a patient to take multiple medications because the prescribed medication is conveniently contained in one formulation.

In another embodiment, the present invention

(a) each sample comprises a common ingredient that is a medicament, dietary supplement, replacement drug, or nutraceutical and one or more additional ingredients, wherein each sample is different from any other sample for one or more of the following: Manufacture an array of:

(i) identity of additional components,

(ii) the ratio of common components to additional components, or

(iii) the physical state of the common components;

(b) each sample is tested for properties to generate a data set;

(c) analyze the data set to measure or detect interactions

It relates to a method for measuring or detecting the interaction between the components, including.

Preferably, the samples are tested for properties associated with the administration and pharmacokinetics of the medicament, dietary supplement, alternative medicament or nutraceutical. Preferred properties include physical properties such as fluidity, crumbness, stability, solubility, dissolution, permeability and distribution; Mechanical properties such as compressibility, compressibility and flow properties; Sensory properties such as feeling in the mouth, appearance, texture, color, taste and smell; And properties that affect utility, such as absorbency, bioavailability, toxicity, metabolic profile, potency, release rate, and rate of dispersion. Although some biological properties are related to the in vivo performance of the active ingredient, eg, pharmaceutical formulations, the properties can be measured by in vitro tests that can estimate the in vivo performance.

Toxicity is the tendency of pharmaceutical formulations to cause adverse side effects when administered to a subject or patient. Toxicity includes hypersensitivity and allergic reactions. Efficacy is the activity the formulation has for its intended purpose. All of these biological properties can be measured by in vitro techniques such as microbial analysis. A discussion of in vitro biological test methods is described in Remington's Pharmaceutical Sciences, 18th Edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, PA 1995, pp. 499-500.

Absorbency is such that the active ingredient, eg, a medicament, passes from the site of application through the physiological barrier layer, for example across the gastrointestinal tract in the case of oral administration; Into the bloodstream across the skin in the case of transdermal administration; Or in the case of intradermal administration, the process of migration into the dermis across the corneal layer. Many factors measure the ease with which a drug is absorbed, such as the concentration, solubility and permeability of the drug. There are techniques for testing each of these properties, but some general tests are used to directly assess absorbency, for example, Lennernas, H. 1998 J. Pharm. Sci. 87: 403-410 can be used a Ussing chamber containing HT Caco-2 / MS processed cells as reported. A detailed discussion of the theory and method of determining absorbency of a drug is described in Remington's Pharmaceutical Sciences, 18th Edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, PA 1995, pp. 710-714.

Solubility refers to equilibrium solubility or steady state and is measured as component weight / solvent volume. Potential bioavailability issues exist when the active ingredient, eg, a pharmaceutical substance, has a water solubility of less than about 1 mg / ml at a physiological pH of 1-7. Descriptive terms used to refer to solubility provided in parts of solvent per part of solvent are highly soluble (<1 part); Freely soluble (1 to 10 parts); Solubility (10 to 30 parts); Insufficiently soluble (30 to 100 parts); Slightly soluble (100 to 1,000 parts); Very slightly soluble (1,000 to 10,000 parts); And insoluble (> 10,000 parts). Remington's Pharmaceutical Sciences, 18th Edition, ed., Incorporated herein by reference for solution and phase equilibrium. Alfonso Gennaro, Mack Publishing Co. Easton, PA 1995, Ch. 16].

Solubility can be tested by mixing a sample with a test solvent and stirring the sample at constant temperature until equilibrium is reached. Equilibrium is usually achieved by stirring the sample for 6 to 24 hours. If the component is acidic or basic, its solubility can be influenced by pH, and those skilled in the art will consider such factors when testing the solubility properties of the sample. Once equilibrated, the sample can be used to determine the amount of dissolved component by standard techniques such as mass spectrometry, HPLC, UV spectroscopy, fluorescence spectroscopy, gas chromatography, optical density or colorimetry. . For discussion of the theory and method of measurement of solubility see Streng et al., 1984 J. Pharm. Sci. 63: 605; Kaplan 1972 Drug Metab. Rev. 1:15; And Remington's Pharmaceutical Sciences, 18th Edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, PA 1995, pp. 1456-1457. For a discussion of heat of dissolution, pKa and pH solubility profile effects, and measurement techniques thereof, see Fiese et al., The Theory and Practice of Industrial Pharmacy, 3rd ed., Lachman L .; Lieberman, H. A .; And Kanig, J.L. Eds., Lea and Febiger, Philadelphia, 1986 pp. 185-188.

Dissolution refers to the process by which solids with only significant solubility enter the solution. Many factors, such as solubility, particle size, crystal state and presence of diluents, disintegrants or other excipients, affect solubility. For a discussion of the theory and method of measurement of dissolution, see Remington's Pharmaceutical Sciences, 18th Edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, PA 1995, Ch. 34.

Stability refers to the chemical and physical stability of the ingredient as a whole or for its components during the preparation, packaging, dispensing, storage and administration of the active ingredient (s).

Chemical stability refers to the resistance of a formulation to chemical reactions caused by, for example, heat, ultraviolet light, moisture, chemical reactions between components or oxygen. Chemical stability also refers to the ability of a compound to maintain a particular stereoisomeric form, eg, optical activity, without conversion to another stereoisomeric form. Well known measurement methods for chemical stability include mass spectrometry, UV-VIS spectroscopy, polarimetry, chiral and non-chiral HPLC, chiral and non-chiral gas chromatography, and liquid chromatography-mass spectrometry (LC-MS) It includes. In the case of surface bleaching due to oxidation or reaction of the active ingredient with excipients or itself, the surface reflectance measurements may have greater sensitivity than other assays. A discussion of the theory and methods of measuring chemical stability is described in Xu et al., Stability-Indicating HPLC Methods for Drug Analysis American Pharmaceutical Association, Washington D.C. 1999 and Remington's Pharmaceutical Sciences, 18th Edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, PA 1995, pp. 1458-1460.

Physical stability is the ability of a formulation to maintain its physical form; For example maintain particle size; Maintain crystalline or amorphous forms; Maintaining complexed forms such as hydrates and solvates; Absorbency to ambient moisture, ie resistance to hygroscopicity; And the ability to maintain mechanical properties such as compressibility and flow properties. Methods of measuring molar stability include spectrometry, sieving or testing, microscopy, sedimentation, stream scanning, and light scattering. Polymorphic changes are detected by, for example, differential scanning calorimetry or quantitative infrared analysis. A discussion of the theory and method of measuring physical stability is described in Fiese et al., The Theory and Practice of Industrial Pharmacy, 3rd ed., Lachman L .; Lieberman, H. A .; And Kanig, J.L. Eds., Lea and Febiger, Philadelphia, 1986 pp. 193-194 and Remington's Pharmaceutical Sciences, 18th Edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, PA 1995, pp. 1448-1451.

Permeability refers to the tendency of components to cross biological membranes. Biological membranes act as lipid blocking layers for most drugs and allow absorption of lipid-soluble substances by passive diffusion. Lipid-insoluble materials can pass through the barrier layer quite difficult. The ex vivo procedure for measuring permeation properties consists of an aqueous / organic-lipid layer / aqueous system. Another in vitro procedure is an inverted vesicle technique using segments of the rat small intestine. For a discussion of the theory and method of measuring permeability, see Remington's Pharmaceutical Sciences, 18th Edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, PA 1995, pp. 1460-1461.

Dispensing refers to the way in which the component itself is distributed between two phases such that each phase is saturated. If the ingredients are added in an amount that is insufficient to saturate the solution in an incompatible solvent system, the ingredients will be dispensed in a defined proportion between the solvents. Understanding the partitioning effect makes it possible to estimate whether the absorption site, for example the component, is absorbed in the stomach or small intestine. For a discussion of the theory and method of measurement of partitioning, see Hansch et al., 1972 J. Pharm. Sci. 61: 1; Dressman et al., 1984 J. Pharm. Sci. 73: 1274; Suzuki et al., 1970 J. Pharm. Sci. 59: 644; And Remington's Pharmaceutical Sciences, 18th Edition, ed. AlfonsoGennaro, Mack Publishing Co. Easton, PA 1995, Ch. 34.

Metabolic profile or metabolism refers to the conversion of a medicament, dietary supplement, replacement medicament, or other chemical in humans or animals following administration of a nutraceutical. As soon as the medicament enters the body, it becomes sensitive to various enzymes or chemical metabolic processes in the stomach, intestines and liver as well as other areas of the body. Metabolism takes place in different parts of the body, and formulation is particularly important for optimizing for example transdermal, skin and gastric metabolism. Metabolism occurs by changes in functional groups such as ring or branched chain hydroxylation, nitro-group reduction, aldehyde oxidation, dealkylation, deamination, or by conjugated bonds, wherein the agent is a flexible group, for example It combines with glucuronic acid or glycine to form secretory compounds. Metabolism of the active ingredient, eg, a medicament, may be accelerated or delayed depending on the dosage form in which the active ingredient is administered. Although metabolism occurs in the body, it can be measured using various in vitro assays. For example, certain oral medications, such as penicillin, are undesirably metabolized via acid hydrolysis in the digestive tract. In order to mitigate such metabolism and to evaluate the efficacy of formulations that allow the medicament to enter the bloodstream, a formulation comprising the medicament in question is placed in a medium close to the digestive medium and the rate or degree of hydrolysis may be appropriately analyzed, eg For example, it can measure by HPLC. Similarly, for a drug known to be metabolized by a particular enzyme, the efficacy of the formulation to promote or delay metabolism can be tested by exposing the drug formulation to the enzyme or similar enzyme under suitable conditions and measuring the rate of degradation. For a discussion of the theory and method of measurement of metabolism, see Remington's Pharmaceutical Sciences, 18th Edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, PA 1995, pp. 431, 742, 1665, 1753 and 1831.

Compressibility refers to the ability of a powder to reduce its volume under pressure, while compressibility refers to the ability to compact into tablets of a certain strength or hardness. When the powder is compacted, the powder particles adopt a more efficient packing arrangement which further undergoes elastic or reversible deformation upon pressurization. If the force is removed during the step, the powder will be restored to the efficiently charged state. Further application of pressure results in compression of the powder, ie irreversible deformation. The compression step is very important in the manufacture of tablets. For tableting, the medicament in the formulation mixture must be irreversibly deformed (compressed) into tablets that have sufficient hardness to resist corrosion and disintegration upon pressurization and strength sufficient to resist brittle cracks. Remington's Pharmaceutical Sciences, 18th Edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, PA 1995, pp. 1457-1458, and Ch. 92 and Jones et al., 1977 Pharmazeutische Industrie, 39: 469. Many techniques for assessing compressibility and compressibility have been published (Rees et al., 1987 J. Pharm. Pharmacol. 30: 601 and Jones in Polermand ed: Formulation and Preparation of Dosage Forms, Elsevier, North Holland, 29 , 1977).

Powder flow characteristics refer to the ability of the bulk powder to flow. Powders can be broadly classified as free flowing and cohesive. Flow characteristics can be affected by particle size, shape and shape as well as other factors such as density, electrostatic charge, absorbed air or the presence of moisture. Free flowing powder can be characterized by a simple flow device consisting of a grounded metal tube through which an agent flows through an orifice onto an electronic balance. A discussion of the measurement of properties affecting flow properties is described in Kaye Chemical Analysis: Direct Characterization of Fine Particles, Vol. 61, John Wiley and Sons, New York 1981; Sutton et al., Characterization of Powder Surfaces, Academic Press, London, 1976, pp. 1,7 and 158; Hiestand et al., 1973 J. Pharm. Sci. 62: 1513; And Hiestand, et al., 1974 J. Pharm. Sci. 63: 605.

Softness is an indicator of the cohesiveness and hardness of pharmaceuticals, dietary supplements, alternative medicines, and powdered solid dosage forms of nutraceuticals such as tablets. The softness can be measured by well known methods, for example Roche softness meter. A discussion of softness and methods of measurement thereof is described in Remington's Pharmaceutical Sciences, 18th Edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, PA 1995, pp. 1639-1640.

Fluidity is about deformation and flow of matter. For medicaments, dietary supplements, alternative medicines, nutraceuticals, consumer product formulations and industrial formulations, fluidity relates to mechanical properties such as adhesive strength, tack and viscosity. Flowability is particularly important in the pharmaceutical use of biopolymers and mucoadhesives. For example, it is important in transdermal and dermal applications in which bioadhesives are adhered to the skin and later removed painlessly. Fluidity is also important in industrial and consumer product formulations such as polymers, adhesives, pastes, gels, rubbers, inks, and It is important in plastics. The fluidity can be measured by well known methods, and Remington's Pharmaceutical Sciences, 18th Edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, PA 1995, Ch. 22.

Dispersion is related to the mechanical disintegration of solids and liquids into small particles and their distribution and dissolution in fluid vehicles. Dispersibility is particularly important in pharmaceuticals, dietary supplements, alternative medicines, and nutraceutical formulations. Dispersibility of the formulation can be improved by additives such as disintegrants and lubricants. Remington's Pharmaceutical Sciences, 18th Edition, ed., Incorporated herein by reference, for a discussion of dispersion and its association with dissolution and disintegration. Alfonso Gennaro, Mack Publishing Co. Easton, PA 1995, pp. 595-596.

The rate of release relates to the release of the medicament from the pharmaceutical formulation, thus providing the drug with absorbency. Control of the release rate allows for timely delivery over an extended period of time or immediate delivery of the entire dosage form. The release rate is closely correlated with the nature of the formulation, such as crumbness, dispersion, disintegration, drug concentration, drug-carrier interaction, particle size and type, pH, polarity, surface tension and fluidity. For a discussion of release rates and their assay analysis, see Chemical Aspects of Drug Delivery Systems, eds. D.R. Karsa and R.A. Stephenson, The Royal Society of Chemistry, Cambridge, UK, 1996.

Sensory substance

In another embodiment, the invention relates to an arrangement of samples, each sample comprising a common sensory substance and one or more additional components, wherein each sample is different from any other sample for one or more of the following: :

(i) identity of additional components,

(ii) the ratio of common sensory substances to additional components, or

(iii) the physical state of common sensory substances.

As used herein, the term "sensory material" means any known or intended chemical, preferably aromatic, flavoring or spice, used to provide an olfactory or taste effect in humans or animals. Sensory substances also include any chemicals used to mask odors and tastes. Examples of suitable fragrance materials include, but are not limited to, musk materials, such as cibetone, ambritolide, ethylene brasylate, musk xylene, Tonalide® and Glaxolide®. ; Amber materials such as Ambrox, Ambraynolide and Ambrinol; Sandalwood materials such as α-anthalol, β-anthalol, Sandalor® and Bacandanol®; Patchouli and wood materials such as patchouli oil, patchouli alcohol, Timberol® and Polywood®; Floral odorous materials such as Givescone®, damascone, irons, linal wool, Lilial® and dehydrozasmonate. Other examples of fragrance materials suitable for use in the present invention are described in Perfumes: Art, Science, Technology, P.M. Muller ed. Elsevier, New York, 1991. Examples of suitable flavoring agents include, but are not limited to, benzaldehyde, anetol, dimethyl sulfide, vanillin, methyl anthranilate, nutkaton and cinnamil acetate. Examples of suitable spices include, but are not limited to, pimento, tarragon, cloves, pepper, sage, thyme and coriander. Other examples of suitable flavoring materials and spices are described in Flavor and Fragrance Materials-1989, Allured Publishing Corp. Wheaton, IL, 1989; Bauer and Garbe Common Flavor and Fragrance Materials, VCH Verlagsgesellschaft, Weinheim, 1985; And (1994) The Encyclopedia of Chemical Technology, 11 Kirk-Othomer (4th ed. P. 1-61).

Preferred ingredients for use with sensory substances are those known in the art of flavoring and flavoring formulations, for example ingredients used in the manufacture of functional products, for example colognes and spices, skin cleansers, shower products, skin Protective products, gels, sunscreens, deodorants and antiperspirants, hair protectants and shampoos, and those used in the formulation of cosmetics. Another example of suitable ingredients are the excipients indicated above for use with a medicament, which may also be used in the formulation of formulations comprising sensory substances. Other examples of suitable components for a sample comprising a sensory substance are described in Perfumes: Art, Science, Technology, P.M. Muller ed. Elsevier, New York, 1991 p. 338-345, 347-362, 40-42 and (1996) The Encyclopedia of Chemical Technology, 11 Kirk-Othomer (4th ed. P. 171-201).

In one aspect of the embodiment with respect to the arrangement of the samples, the common component is the sensory substance and the additional component (s) are the other sensory substance. That is, each sample may comprise a plurality of sensory materials, where a particular sensory material is present in all samples (common sensory material). Such an array of samples can be used to detect advantageous or synergistic interactions between sensory materials. For example, interactions with one another can identify particularly advantageous sensory combinations. Such advantageous combinations cannot be anticipated based on the nature of the isolated sensory materials.

In another embodiment, the present invention

(a) each sample comprises a common sensory substance and one or more additional components, each sample producing an array of samples different from any other sample for one or more of the following:

(i) identity of additional components,

(ii) the ratio of common sensory substances to additional components, or

(iii) the physical state of common sensory substances;

(b) each sample is tested for properties to generate a data set;

(c) analyze the data set to measure or detect interactions

It relates to a method for measuring or detecting the interaction between the sensory substance and another component.

Preferably, the sample comprising the sensory substance is tested for properties associated with its use in functional products, such as perfumes, air fresheners, deodorants, colognes, foods, candy, or medicaments with aroma or flavor. Desirable properties of the sensory substance are: strength and quality of the smell, stall (how long the smell lasts), evaporation rate, solubility, distribution, biodegradability, odor, taste, feeling in the mouth, appearance, lack of smell, taste Lack, toxicity, efficacy, tissue, color, appearance or distribution, and physical and chemical stability. One skilled in the art can easily develop an assay to measure such properties, for example the methods discussed above for measuring the properties of pharmaceutical formulations. For example, the intensity and quality of an odor can be measured by smelling a sample or by sensory nerve techniques such as an electronic nose. See, for example, Matzger et al., 2000 J. Comb. Chem. 2: 301-304; Gibson et al., 2000 Chem. Ind. (London) 8: 287-289; Ormancey et al., 1998 Semin. Food Anal. 3: 77-84; Bain, H., Measurement of Consumer Perceptions and Evaluation of odor as an Aid to Perfume Selection, In ESOMAR Seminar on Research for Flavors and Fragrances, Lyon 1989, Esomar, Amsterdam, 1989. Properties such as stall, evaporation rate, solubility, partitioning, and physical and chemical stability can be measured by applying the methods discussed for such agents.

pesticide

In yet another embodiment, the invention relates to an arrangement of samples, each sample comprising a common pesticide and one or more additional ingredients, where each sample is different from any other sample for one or more of the following: :

(i) identity of additional components,

(ii) the ratio of common pesticides to additional ingredients, or

(iii) the common state of pesticides.

As used herein, the term “pesticide” is any known or intended to be used in farms, yards or gardens, crops, decorative foods, homes or residential areas favorable to shrubs or vegetables, or used to kill pests, plants or fungi. Means the substance. Examples of pesticides suitable for use in the present invention include insecticides, herbicides, fungicides, pest repellents, fertilizers and growth promoters. For a discussion of pesticides, see The Agrochemicals Handbook (1987) 2nd Ed., Hartley and Kidd, editiors: The Royal Society of Chemistry, Nottingham, England.

Pesticides include chemicals, compounds, and substances administered to kill pests, such as insects, mice, and mice, and to drive out garden pests such as deer and marmots. Examples of suitable pesticides that can be used according to the present invention include, but are not limited to, abamectin (anicide), bifenthrin (an insecticide), cyphenotrin (insecticide), imidacloprid (insecticide) and praletrin ( Pesticides). Other examples of pesticides suitable for use in the present invention are described in Crop Protection Chemicals Reference, 6th ed., Chemical and Pharmaceutical Press, John Wiely & Sons Inc., New York, 1990; (1996) The Encyclopedia of Chemical Technology, 18 Kirk-Othomer (4th ed., P. 311-341); And Hayes et al., Handbook of Pesticide Toxicology, Academic Press, Inc., San Diego, CA, 1990.

Herbicides include selective and non-selective chemicals, compounds, and substances administered to kill plants or inhibit plant growth. Examples of suitable herbicides include, but are not limited to, photosystem I inhibitors such as activophene; Photosystem II inhibitors such as atrazine; Bleach herbicides such as flulidone and difunon; Chlorophyll biosynthesis inhibitors, such as DTP, cletodim, cetoxydim, methyl haloxope, tralcoxysid and alacolore; Damage causing agents for the antioxidant system, for example paraquat; Amino acid and nucleotide biosynthesis inhibitors such as paseolotoxin and imazapyr; Cell division inhibitors such as prolonamide; And plant growth regulator synthesis and function inhibitors such as dicamba, chlorambene, diclofo and ansimidol. Other examples of suitable herbicides are described in Herbicide Handbook, 6th ed., Weed Science Society of America, Champaign, II 1989; (1995) The Encyclopedia of Chemical Technology, 13 Kirk-Othomer (4th ed., P. 73-136); And Duke, Handbook of Biologically Active Phytochemicals and Their Activities, CRC Press, Boca Raton, FL, 1992.

Fungicides include chemicals, compounds, and substances administered to plants and crops that selectively or non-selectively kill fungi. For use in the present invention, fungicides may be systemic or non-systemic. Examples of suitable non-systemic fungicides include, but are not limited to, thiocarbamates and thiuram derivatives such as ferbam, giram, tiram and nabam; Imides such as captan, polpet, captapol and diclofloanide; Aromatic hydrocarbons such as quintogens, dinocap and chloronep; Dicarboximides such as vinclozoline, clozolinate and ifprodione. Examples of systemic fungicides include, but are not limited to, mitochondrial respiratory inhibitors such as carboxycin, oxycarboxycin, flutoranyl, fenfuram, mepronil and metfuroxam; Microtubule polymerization inhibitors such as thiabendazole, fuberidazole, carbendazim and benomil; Sterol biosynthesis inhibitors such as tripolin, phenarimol, nuarimol, imazaryl, triadimefon, propiconazole, flusilazole, dodemorph, tridemorph and fenpropidine; And RNA biosynthesis inhibitors, for example etirimole and dimethirimol; Popolipic biosynthesis inhibitors, such as efenfenfoss and ifprobenfoss. Other examples of suitable fungicides are disclosed in Torgeson, ed., Fungicides: An Advanced Treatise, Vols. 1 and 2, Academic Press, Inc., New York, 1967 and (1994) The Encyclopedia of Chemical Technology, 12 Kirk-Othomer (4th ed., P. 73-227).

Ingredients that combine with the pesticide to form a sample include materials known in the art of pesticide formulation, for example inert ingredients such as solvents, emulsifiers, surfactants, dispersants, stabilizers, preservatives, sequestrants, colorants, flavors And flavors. Examples of suitable ingredients for samples comprising pesticides are described in Stevens et al., 1993 Pesticide Science 38: 103-122 and Adjuvants for Agrochemicals, ed. C.L. Foy, CRC Press, Boca Raton, Florida, 1992.

In one aspect of the embodiment of the arrangement of the samples, the common component is a pesticide and the additional component (s) is another pesticide. That is, each sample may comprise a plurality of pesticides, where a particular pesticide is present in all samples (common pesticides). Such an array of samples can be used to detect advantageous or synergistic interactions between pesticides. For example, interactions with one another can identify particularly advantageous pesticide combinations. Such advantageous combinations cannot be anticipated based on the nature of the isolated pesticides.

In another embodiment, the present invention

(a) each sample comprises a common pesticide and one or more additional ingredients, each sample producing an array of samples different from any other sample for one or more of the following:

(i) identity of additional components,

(ii) the ratio of common pesticides to additional ingredients, or

(iii) the common state of pesticides;

(b) each sample is tested for properties to generate a data set;

(c) analyze the data set to measure or detect interactions

It relates to a method for measuring or detecting the interaction between the components, including.

Preferably, the sample comprising the pesticide is tested for properties related to the use and administration of the pesticide. Preferred properties for pesticides include biodegradability (eg, rate of degradation due to chemical instability and microbial metabolism), rate of soil uptake, efficacy, toxicity, duration of effect, and rate of evaporation. Such properties are directly related to solubility (particularly water solubility), distribution and physical and chemical stability, and can be measured by the methods discussed above for the determination of drug formulation properties. One skilled in the art can easily develop an assay to measure such properties. For references that aid in the development of assays related to the determination of pesticide properties, see Sunsundaram et al., Pesticide Transformation Products: Fate and Significance in the Environment, ACS Symposium Series No. 459, American Chemical Society 1991. Tweedy et al., Pesticide Residues and Food Safety: A Harvest of Viewpoints, ACS Symposium Series No. 459, American Chemical Society 1991; Van Emon et al., Immunochemical Methods For Environmental Analysis, ACS Symposium Series No. 442, American Chemical Society 1990; And Cairns et al., Emerging Stratagies for Pesticide Analysis, CRC Press, Boca Raton, FL 1992; From the series Modern Methods of Pesticide Analysis.

Consumer and Industrial Product Formulations

In another embodiment, the invention relates to an arrangement of samples, each sample comprising a common ingredient and one or more additional ingredients that are active ingredients of a consumer product formulation or an active ingredient of an industrial product formulation, wherein each sample Is different from any other sample for one or more of the following:

(i) identity of additional components,

(ii) the ratio of common components to additional components, or

(iii) physical state of common components.

As used herein, "consumer product formulation" means a consumer formulation that does not aim to be absorbed or taken into the human or animal body, including the active ingredient. Consumer product formulations include, but are not limited to, cosmetics such as lotions, facial cosmetics; Antiperspirants and deodorants, shaving products, and nail care products; Hair products such as shampoos, colorants, conditioners; Hand and body soap; varnish; slush; glue; And detergents and cleaners.

As used herein, "industrial product formulation" means an industrial formulation that is not intended to be absorbed or ingested by the human or animal body. Industrial product formulations include, but are not limited to, polymers; Rubber; plastic; Industrial chemicals such as solvents, bleaches, inks, dyes, fire retardants, antifreezes, and formulations for road, automobile, truck, jet and airplane deicing; Industrial lubricants; Industrial adhesives; Construction materials such as cement.

Those skilled in the art will readily select active and non-active ingredients for use in consumer and industrial product formulations and will readily configure the arrangements according to the invention for detecting or measuring interactions between the active ingredient and additional ingredients. Data on such interactions can help optimize consumer and industrial product formulations. Such active and non-active ingredients are well known in the literature and the following references are provided by way of example only. Active and non-active ingredients for use in cosmetic formulations are described in (1993) The Encyclopedia of Chemical Technology, 7 Kirk-Othomer (4th ed., P.572-619); M.G. de Navarre, The Chemical and Manufacture of Cosmetics, D. Van Nostrand Company, Inc., New York, 1941; CTFA International Cosmetic Ingredient Dictionary and Handbook, 8th Ed., CTFA, Washington, D.C., 2000; and A. Nowak, Cosmetic Preparations, Micelle Press, London, 1991. Active and non-active ingredients for use in hair care products are described in (1994) The Encyclopedia of Chemical Technology, 12 Kirk-Othomer (4th ed., P.881-890) and Shampoos and Hair Preparations in ECT 1st ed., Vol. 12, pp. 221-243, F.E. Wall. Active and non-active ingredients for use in hand and body soaps are disclosed in (1997) The Encyclopedia of Chemical Technology, 22 Kirk-Othomer (4th ed., P. 297-396), incorporated herein by reference. Active and non-active ingredients for use in paints are described in (1996) The Encyclopedia of Chemical Technology, 17 Kirk-Othomer (4th ed., P. 1049-1069), and "Paint" in ECT 1st ed., Vol. 9, pp. 770-803, HEHillman, Eagle Paint and Varnish Corp. Active and non-active ingredients for use in consumer and industrial lubricants are described herein. (1995) The Encyclopedia of Chemical Technology, 15 Kirk-Othomer (4th ed., P.463-517); DD Fuller, Theory and practice of Lubrication for Engineers, 2nd ed., John Wiley & Sons, Inc., 1984; and A. Raimondi and AZ Szeri, in ER Booster, eds., Handbook of Lubrication, Vol. 2, CRC Press Inc., Boca Raton , FL, 1983. Active and non-active ingredients for use in consumer and industrial adhesives are described in (1991) The Encyclopedia of Chemical Technology, 1 Kirk-Othomer (4th ed). , p. 445-465) and IM Skeist, ed., Handbook of Adhesives, 3rd ed. Van Nostrand-Reinhold, New York, 1990. Active and non-active ingredients for use in polymers are disclosed in (1996) The Encyclopedia of Chemical Technology, 19 Kirk-Othomer (4th ed., P. 881-904). . Active and non-active ingredients for use in rubber are disclosed in (1997) The Encyclopedia of Chemical Technology, 21 Kirk-Othomer (4th ed., P. 460-591). . Active and non-active ingredients for use in plastics are disclosed in (1996) The Encyclopedia of Chemical Technology, 19 Kirk-Othomer (4th ed., P.290-316). . Active and non-active ingredients for use in industrial chemicals are disclosed in Ash et al., Handbook of Industrial Chemical Additives, VCH Publisher, New York 1991, incorporated herein by reference. Active and non-active ingredients for use in bleaching ingredients are disclosed in (1992) The Encyclopedia of Chemical Technology, 4 Kirk-Othomer (4th ed., P.271-311), which is incorporated herein by reference. have. Active and non-active ingredients for use in inks are disclosed in (1995) The Encyclopedia of Chemical Technology, 14 Kirk-Othomer (4th ed., P.482-503). . Active and non-active ingredients for use in dyes are disclosed in (1993) The Encyclopedia of Chemical Technology, 8 Kirk-Othomer (4th ed., P.533-860). . Active and non-active ingredients for use in fire retardants are disclosed in (1993) The Encyclopedia of Chemical Technology, 10 Kirk-Othomer (4th ed., P.930-1022). have. Active and non-active ingredients for use in antifreeze and ice making agents are described in (1992) The Encyclopedia of Chemical Technology, 3 Kirk-Othomer (4th ed., P.347-367). Is disclosed. Active and non-active ingredients for use in cement are disclosed in (1993) The Encyclopedia of Chemical Technology, 5 Kirk-Othomer (4th ed., P.564).

In another embodiment, the present invention

(a) each sample comprises a common ingredient that is an active ingredient of a consumer product formulation or an active ingredient of an industrial product formulation and one or more additional ingredients, wherein each sample is different from any other sample for one or more of the following: Manufacture an array of:

(i) identity of additional components,

(ii) the ratio of common components to additional components, or

(iii) the physical state of the common components;

(b) each sample is tested for properties to generate a data set;

(c) analyze the data set to measure or detect interactions

It relates to a method for measuring or detecting the interaction between the components, including.

Preferably, samples comprising active and additional ingredients of a consumer or industrial product formulation are tested for properties related to the use and administration of the consumer or industrial product formulation. Preferred properties for testing of samples comprising active ingredients of industrial or consumer product formulations include solubility (particularly water solubility), biodegradability, distribution, and physical and chemical stability. Such properties can be measured by applying the methods discussed above for the determination of drug formulation properties.

In accordance with the present invention, once an ideal formulation has been identified, it can be prepared on a large scale for use as a formulation for the delivery of the active ingredients using standard scale-up procedures well known in the art. For example, promising samples can be scaled up as pharmaceutical formulations for the delivery of a medicament.

Sample preparation and test system

The basic requirements for sample preparation, processing and testing are as follows: (1) Dispensing mechanism of adding components to separate locations on the array plate, eg, sample wells. Preferably the dispensing mechanism is automatically controlled by computer software and can change one or more additional variables, for example the identity and / or component concentration of the ingredient (s), more preferably two or more variables. For example, adding common pharmaceutical ingredients and excipients to sample wells involves material handling techniques and robotics well known to those skilled in the pharmaceutical manufacturing arts. Of course, if desired, individual components may be manually placed in a suitable well in the arrangement. Such picking techniques are also known to those skilled in the art. (2) There is also a test mechanism to test each sample for one or more properties. Preferably, the test mechanism is automatically driven by a computer. Preferably, the system further comprises a processing mechanism for processing the sample after the addition of the component. For example, after the addition of the components, the samples can be processed by stirring, milling, filtration, centrifugation, emulsifying or removing solvents (eg lyophilization) and reconstituting by methods and apparatus well known in the art. . Preferably the samples are automatically processed simultaneously.

1 is a flow diagram illustrating preparation of a sample arrangement, processing of a sample, sample analysis for one or more properties, data collection and storage, and analysis of such data, and detection or measurement of interaction, or detection of lack of interaction. The first step involves selecting a source of the component 2, ie a common component and one or more additional components in one or more concentrations. The common and additional ingredients are then added to a plurality of sample sites, for example sample wells on a sample plate, to provide a sample, and then the sample is stirred, milled, filtered, centrifuged, emulsified or concentrated and The sample array 4 is prepared by treatment by the recomposition. Each sample of the array (4) is tested for one or more properties and the data collected and stored (6) for subsequent data analysis (8) to measure or identify the interaction (s) between components or to interact Detect lack of (s) (9). For example, separate sample sites in different amounts, different pH, common components in different physical states, such as medicaments and additional components, such as excipients or other agents, in liquid or solid form, or a combination thereof, For example, sample arrays can be prepared by dispensing into sample wells. Different samples comprising different combinations can be processed and tested for properties. Test data is stored and preferably analyzed by computer to measure or identify interactions between common agents and excipients or other agents. Such interactions can be used to develop formulations that are optimal for the administration of the medicament.

Automated dispensing mechanisms can dispense or add ingredients in the form of liquids, gels, foams, pastes, ointments, powders, suspensions or emulsions or solids such as powders, tablets or pellets. Preferably the solid is in the form of fine pellets or fine tablets prepared by fine pelletization or micro tableting. The micro pellets can be prepared using standard pharmaceutical tablet presses with appropriate modifications. Such machines are well known in the art. See, eg, Remington's Pharmaceutical Sciences, 18th Edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, PA, 1995, Ch. 92]. Preferably the tableting machine comprises a small mold of about 1/16 "to about 3/16" in diameter. Any necessary modifications are readily made by those skilled in the art. The fine tablet press can be suitably modified to produce fine tablets of most arbitrary solid components. If the ingredient is an active ingredient, for example a medicament, it is preferably dispersed in a matrix of compressible inert carrier material, for example potassium chloride. Preferably, the ratio of active ingredient to carrier is from about 0.5 to about 10 parts of active ingredient to about 90 to about 99.5 parts of carrier, more preferably about 1 part of active ingredient to about 99 parts of carrier. Preferably, the weight of the finished fine tablet is about 0.1 to about 50 mg, more preferably about 1 to about 10 mg, most preferably about 5 mg. In addition, the finished fine tablet contains about 1 to about 100 mg of the active ingredient, more preferably about 10 to about 75 mg, most preferably about 50 mg of the active ingredient. If the ingredient is an inactive ingredient, for example an excipient, it can be dispersed in an inert matrix as disclosed immediately above or pelletized in the absence of an inert carrier.

Another non-limiting method of making fine pellets involves forcing a paste comprising a component and an inert carrier into the mold, drying the paste, and then ejecting the pellet. In this method, the components to be pelletized are first homogenized with an inert carrier and a solvent. Preferably, the inert carrier is lactose or mannitol. Any solvent is suitable and is easily selected by those skilled in the art depending on the component. Preferably, the solvent is relatively volatile, more preferably has a boiling point of about 100 ° C. or more, for example an alcohol such as methanol or ethanol. Preferably, the ratio of solvent to active ingredient / inert carrier mixture is from about 10: 1 to about 1:10, more preferably from about 6: 1 to about 1: 1, even more preferably from about 5: 1 to about 3: 1. The components, solvent and inert carrier are homogenized with a paste and then the solvent is removed under reduced pressure to give a dry powder. The powder is then mixed with another solvent, for example water, to produce a homogeneous paste, which is forced into an individual tubular mold. Preferably, the dimensions of the mold are from about 1/16 "to about 3/16", preferably about 1/8 ", and the inner diameter is about 1/32" to about 1/8 ", preferably Is about 5/64 ". The paste for about 1 minute to about 5 hours, preferably about 5 minutes to about 1 hour, more preferably about 10 minutes; A temperature of about 15 to about 100 ° C., more preferably about 20 to about 30 ° C .; Dry at a pressure of about 10 to about 100 mmHg, preferably about 20 mm / Hg. Preferably, the mold paste is dried for about 10 minutes at approximately room temperature and approximately atmospheric pressure. The dried paste is then ejected from the mold in the form of fine pellets, preferably by inserting a flat head pin through the mold, wherein the pin is approximately the same diameter, preferably slightly smaller than the inner diameter of the mold. Have a diameter. The molded fine pellets are then subjected to reduced pressure preferably for about 6 to about 24 hours, more preferably for about 12 hours; At about 15 to about 100 ° C., preferably at about room temperature; Drying at a pressure of about 10 to about 1000 mm / Hg, preferably about 20 mm / Hg.

Preferred automated mechanisms for adding solid components, preferably fine pellets, to the sample wells include containers or boxes for each component. The outlet of the box is adjusted so that individual fine tablets can be "unified" and distributed to specific sample wells in the array. Once the components common to the components are placed in the sample wells of the array, the array process is continued as outlined below.

2A and 2B illustrate the arrangement of samples by placing components into a sample well, processing the samples, testing the samples for one or more properties to generate data, and collecting, storing, and analyzing the data to correlate them. Detailed schematic diagram illustrating a system of the present invention for measuring or detecting an action or detecting a lack of interaction. Figures 2A and 2B relate to low water solubility agents as common ingredients and excipients as additional ingredients, but the systems and methods shown in Figures 2A and 2B apply equally to all active and non-active ingredients discussed herein. do.

2A shows a common component source 10 of solids, such as a solid-pharmaceutical source and a solid-component source 12, such as a solid-excipient source, preferably in the form of fine pellets, e.g. For example, a system is automatically dispensed into sample wells in a 96 well filter plate (for example commercially available from Millipore) to provide a plurality of dry samples 14. Common components of the various combinations and combinations of the various components are generated using standard software (e.g., Matlab software commercially available from Mathworks, Natick, Mass.). The combinations generated as above can be downloaded to a recording sheet, for example Microsoft EXCEL. From the recording sheet, a work list can be generated that indicates an automated dispensing mechanism to produce an array of samples according to various combinations generated by the formulation software. The task list can be generated using standard programming methods depending on the automated distribution mechanism used. The use of so-called worklists allows the file to be used as process control rather than as a separate programmed step. The task list also serves as the formulation output of the formulation program which is suitably controlled in a file format readable directly by an automatic dispensing mechanism. The automated dispensing mechanism delivers one or more common ingredients, such as medicaments, as well as various additional ingredients, such as excipients, to each sample well. Preferably, the automated dispensing mechanism can deliver several amounts of each component. Automated liquid dispensing mechanisms are well known and commercially available as, for example, Tecan Genesis from Tecan-US, RTP, North Carolina. Automated solid distribution mechanisms are readily obtained by modifying commercially available robotics systems. Multiple dry samples 14 prepared as described above are mixed with one or more solvents using the Tecan automated liquid pipetting system to provide an array 20 of samples, each sample containing a solution or suspension. Include. During or after the solvent addition, the samples can be mixed or stirred, but preferably the force of adding the liquid provides suitable mixing. If desired, an arrangement 22 of filtrates can be made by filtering the suspension to separate the solid and liquid phases. To perform filtration, a filter poolate comprising the suspension is placed on top of a receiving plate containing the same number of sample wells, wherein each well corresponds to a sample well on the filter plate. By applying centrifugal or vacuum force to the filter plate above the receiving plate combination, the liquid phase of the filter plate is forced through the filter on each sample well base to the corresponding sample well of the receiving plate. Suitable centrifuges are commercially available, for example, from DuPont (Wilmington, DE). The receiving plate is envisioned for analysis of individual filtrate samples.

Analysis of the filtrate is performed on a device 24, for example UV-Vis spectroscopy (plate-based readers known to those skilled in the art, such as Spectramax Plus from Molecular Devices, Sunnyvale, CA). (SpectraMax Plus)], GC, HPLC and LC-MS can be used to provide data on component solubility. In the case of GC, HPLC and LC-MS, any of a number of devices sold by automated pipetting stations such as Genesis or Gilson from Tecan (Gilson, Middleton, WI) are used for sample introduction. Analytical devices used to measure stability 26 include, but are not limited to, UV-Vis spectroscopy, MS, GC, HPLC or LC-MS. These devices are also modified for use with the arrangement as previously discussed. Assay devices for measuring absorbance 28 include Caco-2 cell lines or using chambers. The Caco-2 cell line is known to those of skill in the art to be a surrogate for intestinal permeability measurements. There are especially commercially available analytical devices for absorption analysis, ie those sold by Tecan-US (cell proliferation and cell supply platform). Useing chambers are widely used by those skilled in the art to measure the field permeability of a compound. There are commercially available devices for measurement of absorbency, such as those sold by World Precision Instruments, Sarasota, Florida. Systems for measuring metabolism (30) include, for example, P-450, microsomes and lysosomes (Trouet A et al., Available from companies such as In Vitro Technologies, 1450 South Rolling Road, Baltimore, MD 21227). , Methods in Enzymology, Vol. 31, Academic Press, Inc., New York, 1987, pp. 287-313 and 323-329) and in vivo analysis. Other analytical devices that may be used with the methods and arrangements of the present invention include pH sensors, ion intensity sensors, optical spectrometers, turbidity measuring devices, calorimeters, infrared spectrometers, polarimeters, radioactivity counters, conductivity meters, and heat dissociation meters. The property-test data is collected and stored (32), followed by analysis (34) to detect or measure interaction (36).

The collection and storage of data 32 is preferably performed by a computer using suitable software. Such computers and software for data collection and storage are readily selected by those skilled in the art. The samples are first analyzed for the properties under study using a suitable device as discussed immediately above to generate a data set. For example, UV spectrophotometric analysis for each sample can be obtained using a Spectramax Plus ^™ spectrophotometer available from Molecular Devices. The data is typically collected and stored using software provided by the device manufacturer. For example, data collected by SpectraMax is collected and stored using Softpro ^™ from Molecular Devices. The data set can then be downloaded to a database for analysis.

Data analysis 34 may be performed using visualization software, such as SPOTFIRE (commercially available from Spotfire, Inc., Cambridge, MA). The visualized data can be analyzed directly to arrive at optimized formulations and interactions 36. Alternatively, the data can be processed through data mining operations to optimize scientific personnel's ability to detect complex multidimensional interactions or lack of interactions between components or to perform future experiments to optimize formulation. have. Examples of suitable data mining software include, but are not limited to, SPOTFIRE; MATLAB (Mathworks, Natick, Mass.); STATISTICA (Statsoft, Tulsa, Oklahoma). All generated analysis files are stored on a central file server, ie a database, where the files can be accessed by traditional means known to those skilled in the art.

2B shows essentially the same process except for a common liquid component 38, such as a liquid medicament and liquid component (s) 40, for example a liquid excipient. Such liquid components can be dispensed using an automated liquid dispensing mechanism to produce the same arrangement 42. The solvent is then removed under reduced pressure or by evaporation to provide an array 44 of dried samples. Lyophilization or other solvent removal procedures are readily applied to the arrangement 42 by those skilled in the art. Commercially available lyophilizers can be used without modification. The array of dried samples 44 may be reconstituted into an array 46 of reconstituted samples by adding one or more component solvents using an automated liquid pipetting apparatus as described above. The array 46 of reconstituted samples can then be analyzed as discussed above with respect to FIG. 2A.

Although the present invention has been described in considerable detail with reference to some preferred embodiments, other embodiments are possible. Accordingly, the spirit and scope of the appended claims should not be limited to the description of the preferred embodiments contained herein.

The invention will be further understood by reference to the non-limiting examples of the arrangements and methods described herein below. The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.

A commercial antibiotic, griseofulvin, with a complex derivatized benzofuran cyclohexane structure, was selected as a common component for use in the arrangement to identify excipient combinations that dissolve the drug in an aqueous medium more efficiently than the commercial griseofulvin formulation. . Such compounds are commercially available for oral administration. A dose of 3.3 mg / lb body weight is administered per day for 50 lbs children and 330 mg / day is typical for adults. The selected compounds are practically water insoluble, slightly soluble in polar organic solvents such as ethanol, methanol, acetone and acetic acid and soluble in dimethylformamide and dioxane. The low water solubility limits the bioavailability. The commercially available formulations used as standard are partially dissolved in a carrier comprising polyethylene glycol 8000 and partially dispersed in other inert excipients (corn starch, lactose, magnesium stearate and sodium lauryl sulfate). It consists of a compound of ultra-fine crystals.

Using the method of the present invention, an excipient which rapidly prepares and systematically analyzes an array of samples each containing a mixture of griseofulvin and various excipients to interact with each other and with the compound to provide improved water solubility over the commercial formulation. The combination was identified.

The GRAS (“generally considered safe”) excipients shown in Table 2 below (all obtainable from Sigma-Aldrich Fine Chemicals or BASF) were used as excipients in the following examples.

Samples were prepared, processed and analyzed as described in the Examples below.

Example 1: Preparation and Identification of Griseofulvin Formulations with Improved Solubility

Preparation of Formulations with Improved Solubility

Three aqueous mother liquors of different concentrations, 0.015 mg / ml, 0.15 mg / ml and 1.5 mg / ml, for each of the 18 excipients were prepared to give a total of 54 mother liquors. Three different excipients were added to each sample well, with each excipient selected from one of each of its three mother liquors. Thus, each sample well (Millipore 96 well filter plate, 250 μl volume, Tecan® liquid handling device using a Genesis liquid handling device (Tecan) in an array of 20 of 3 of the 18 excipients shown above -US, RTP, NC), including a 1 micropore size polytetrafluoroethylene membrane at the base of each well). The number of possible unique combinations of three different excipients each selected from three different concentrations of mother liquor is calculated as follows:

{18! / [3! X (18-3)!]} X3 ³

A total of 22,032 unique samples (66,096 samples for n = 3) were generated, with 32 unique samples per assay plate and a total of 689 assay plates. Excipients, concentrations and all permutations of griseofulvin according to the above formula were generated using Matlab program formulation software. The permutations generated above were downloaded to the Microsoft EXCEL record sheet and the work list was prepared according to standard programming methods well known to those skilled in the art. The task list was then used to adjust the automated dispensing mechanism to produce various permutations of excipients and griseofulvin produced by Matlab. The Genesis liquid treatment device was used as an automated dispensing mechanism. The task list combines Genesis-compliant control (as found in the Genesis Operating Manual) with the formulation output of the Matlab program in a file format readable directly by the Genesis device. Thus, the Genesis liquid handling device delivered 20 μl of griseofulvin / dioxane solution (0.15 mg of griseofulvin / ml dioxane) and the concentration of various combinations and excipients produced by the matlab program to each sample well. . The force provided by the addition of excipients was sufficient to properly mix the components.

Sample trial

All solvents were removed by lyophilization and water (200 μl) was then added back to each dried well of the filter plate using the Genesis liquid handling device. The plates were incubated at 37 ° C. for 1 hour in an Innova 4200 incubator (New Brunswick Scientific, Edison, NJ). The plates were then centrifuged as described above to separate any undissolved solids. The centrifuge was Sorvall RT6000B (DuPont, Wilmington, DE). Filtrates from each well were collected in UV clear 96 well receiving plates (Corning, Corning, NY) to measure on a UV plate reader at 290 nm (SpectraMax Plus, Molecular Devices, Sunnyvale, Calif.).

Griseofulvin without any excipients was tested alone to establish base solubility.

result

The solubility measured by absorbance of the filtrate at 290 nm for 3,500 unique samples is shown in FIG. 3A. Commercial Griseofulvin formulation FULVICIN (Schering-Plough) alone provided a reference absorbance (solubility) of 0.3 absorbance units. Most of the samples showed improved solubility compared to the commercial griseofulvin formulations. Approximately 1,200 samples shown in FIG. 3A showed significantly higher solubility compared to the remaining samples.

Samples (measured by absorbance) that showed a 100% increase in solubility relative to griseofulvin alone were identified as the leading formulation. Five samples were identified and shown in boxes in FIG. 3A. The composition of the five leading formulations (TP1 to TP5) is shown in Table 3 below.

3B provides standard deviation for each of the 3,500 unique samples (each tested with n = 3). The majority of the samples tested could be reproduced with less than 10% standard deviation.

The samples can be further optimized using the same techniques described above by further varying the concentration of each component in the sample.

Example 2: Identification of Lead Formulations on Larger Scales

Five leading formulations identified from the above examples were identified on a 10,000-fold laboratory scale of the fine array of 96 well plates by weighing each component and mixing them in a solid state in a scintillation vial. Griseofulvin (30 mg) was metered into each formulation. Each formulation was formulated three times.

Formulations

TPI-1: PEG 1000 300 mg, Beta-cyclodextrin 30 mg, Polyoxyethylene 40 stearate 30 mg

TPI-2: PEG 1000 300 mg, SDS 30 mg, Polyoxyethylene 40 Stearate 3 mg

TPI-3: PEG 1000 300 mg, polyoxyethylene 40 stearate 30 mg, gum arabic 3 mg

TPI-4: PEG 1000 300 mg, gum arabic 30 mg, cetrimide 30 mg

TPI-5: 300 mg polyvinyl alcohol, 30 mg benzethonium chloride, PEG 1000 3 mg

15 ml of water were added to each vial and the formulations were incubated at 37 ° C. for 1 hour and then filtered through a 0.2 μ filter to remove any undissolved solids. The filtrate was measured using a UV spectrometer at 290 nm in a 1 cm path-length quartz cuvette.

Commercially available FULVICIN (containing 165 mg of gliofulvin) in tablet form was ground into powder and tested in the same manner as the leading formulations in an amount containing 30 mg of greeopoolbin for comparison.

result

The laboratory scale dissolution analysis results were plotted in FIG. 4 as absorbance at 290 nm, representing the mean and standard deviation from three measurements. Up to 300% increase in solubility (measured by UV) was achieved compared to commercial formulations. The five leading formulations identified in the microarray test have all been found to have increased solubility in solid form compared to commercially available drugs in laboratory scale (10,000 ×) dissolution assays, which are from the microarray analysis format. The results can now be transferred to conventional laboratory scale analysis.

Example 3: Evaluation of the Individual Effects of Each Formulation

In order to test the effect of each excipient on the solubility of griseofulvin, the first three leading formulations (TPI-1 to TPI-3) identified above in the microanalysis described above were (1) one of only three excipients, Or (2) "solved" on a laboratory scale with a Griseofulvin formulation containing two of three excipients in different combinations (eg, components 1 and 2, 2 and 3, 1 and 3). The solubility of each sample was then measured using the same laboratory procedure as described above for head identification using the absorbance at 290 nm for measurement of the solubility.

The solubility for the "unpacked" formulations is shown in Figures 5, 6 and 7 as the ratio for their respective lead formulations (some re-formulations have solubility greater or less than the lead formulations identified in Example 1, It is important that the results relate to the starting lead formulation, not absolute absorbance).

In FIG. 5, excipient 14 (polyoxyethylene 40 stearate) (present as a small percentage in TPI-3, as indicated by the area of the pie chart) has a significant increase in solubility and the solubility is excipient 10 (PEG 1000). Slightly improved. Thus, a positive solubility interaction was identified between excipient 14 and griseofulvin.

As shown in FIG. 5, 14 (polyoxyethylene 40 stearate) was the only important excipient in TPI-3 and the addition of 10 (PEG 1000) and 1 (Arabic rubber) did not affect the overall solubility. The addition of excipient 2 (β-cyclodextrin) actually reduced the total solubility of griseopulin at TPI-1 as shown in FIG. 6, demonstrating antagonistic solubility interactions between excipients.

In contrast, as shown in FIG. 7, excipients 3 (SDS), 10 (PEG 1000) and 14 (polyoxyethylene 40 stearate) show synergistic solubility interactions with increasing solubility of griseofulvin.

Example 4: Comparison of Dissolution Rates Under Simulated USP Conditions

The dissolution rate of TPI-2 and the commercial griseofulvin formulation (165 mg) was compared on a laboratory scale using 1000 ml of deionized water at 37 ° C. in a 1000 ml Erlenmeyer flask stirred at 300 RPM using a 1.5 in magnetic stirring rod. . Dissolution rates for each formulation were measured separately. Each formulation was added to stirring deionized water and 1 ml aliquots were recovered 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 1.5 ml Eppendorf vials, centrifuged at 14,000 RPM for 10 seconds at room temperature to remove undissolved solids and UV absorbance was measured in a quartz cuvette of 1 cm path length at 290 nm.

result

The dissolution rate is shown in FIG. 8. TPI-2 exhibited a faster dissolution rate as well as higher equilibrium solubility compared to commercial formulation FULVICIN, further demonstrating the effectiveness of the leading formulations selected from these microanalysiss.

These results demonstrate the efficacy of advanced data processing formulations and test methods, and demonstrate how the results can be scaled up to highly reproducible.

The foregoing outlines rather broadly the more suitable and important features of the present invention. While it will be appreciated that the invention disclosed herein satisfies the aforementioned objects, it will be appreciated that many modifications and embodiments can be devised by those skilled in the art. Accordingly, the appended claims are intended to cover all such modifications.

Claims (125)

Each sample comprises a common component and one or more additional components, wherein each sample is an array of samples different from any other sample for one or more of the following: (i) identity of additional components, (ii) the ratio of common components to additional components, or (iii) physical state of common components. The arrangement of claim 1, wherein the common ingredient is a medicament, a dietary supplement, a replacement medicament, or a nutraceutical. The arrangement of claim 1, wherein the amount of common components is less than about 100 mg. The arrangement of claim 1, wherein the amount of common components is less than about 1 mg. The arrangement of claim 1, wherein the amount of common components is less than about 100 μg. The arrangement of claim 1, wherein the amount of common components is less than about 100 ng. The arrangement of claim 1, wherein the components enhance the solubility or dissolution of the components in common. 3. The arrangement according to claim 2, wherein the medicament, dietary supplement, alternative medicament or nutraceutical is effective for topical, transdermal, intradermal, pulmonary, mucosal or ocular administration. The arrangement of claim 2, wherein the component is effective to alter the absorption, bioavailability, metabolism, or other pharmacokinetic or pharmacological properties of the medicament, dietary supplement, replacement medicament, or nutraceutical. 10. The arrangement of claim 9 wherein the component is a bioadhesive excipient, a bioadhesive coating agent, an excipient effective to enhance solubility or dissolution of common components, or an encapsulant. The arrangement of claim 1, wherein at least 24 samples are present. The arrangement of claim 1, wherein at least 48 samples are present. The arrangement of claim 1, wherein at least 96 samples are present. (a) each sample comprises a common component and one or more additional components, wherein each sample produces an array of samples different from any other sample for one or more of the following: (i) identity of additional components, (ii) the ratio of common components to additional components, or (iii) the physical state of the common components; (b) Each sample is tested for one or more properties. Comprising, the method of measuring or detecting the interaction between the components. 15. The method of claim 14, wherein the common ingredient is a medicament, a dietary supplement, an alternative drug, or a nutraceutical. 15. The method of claim 14, wherein the property is absorptive, bioavailability, toxicity, metabolic profile, efficacy, stability, solubility, dissolution, distribution, softness, appearance, feeling in the mouth, release rate, dispersion rate, flowability, permeability, compressibility, Method that is compressive, flow characteristic, color, taste or smell. The method of claim 14, wherein testing the properties of each sample produces a data set. 18. The method of claim 17, further comprising analyzing the data set for detection or measurement of interaction. 18. The method of claim 17, further comprising analyzing the data set to detect lack of interaction. The method of claim 14, wherein the preparation of the array and the testing of the sample are performed by an automated sample preparation and test system. 20. The method of claim 19, wherein the data set is analyzed by a computer. The method of claim 14, wherein the amount of common components is less than about 100 mg. The method of claim 14, wherein the amount of common ingredients is less than about 1 mg. The method of claim 14, wherein the amount of common components is less than about 100 μg. The method of claim 14, wherein the amount of common components is less than about 100 ng. The method of claim 14, wherein the arrangement comprises at least 24 samples. The method of claim 14, wherein the arrangement comprises 48 or more samples. The method of claim 14, wherein the arrangement comprises at least 96 samples. The method of claim 14, wherein at least 1000 samples are tested per day. (a) each sample comprises an active ingredient and one or more additional ingredients, wherein each sample produces an array of samples different from any other sample for one or more of the following: (i) identity of additional components, (ii) the ratio of active ingredient to additional ingredient, or (iii) the physical state of the active ingredient; (b) testing each sample for one or more properties to produce a property-result for each sample; (c) comparing the property-result produced for each sample with a baseline or a control standard for the property to produce a comparison result for the sample A method of testing or optimizing one or more properties of an active ingredient formulation, comprising. 31. The method of claim 30, wherein the active ingredient is a medicament, a dietary supplement, an alternative drug, or a nutraceutical. 31. The method according to claim 30, wherein the property is absorptive, bioavailability, toxicity, metabolic profile, efficacy, stability, solubility, dissolution, distribution, softness, appearance, feeling in the mouth, release rate, dispersion rate, flowability, permeability, compressibility, Method that is compressive, flow characteristic, color, taste or smell. 31. The method of claim 30, wherein the data set is generated by testing a property of each sample and comparing the property results to a baseline or a control standard. 31. The method of claim 30, wherein preparation of the array and testing of the sample is performed by an automated sample preparation and test system. 34. The method of claim 33, further comprising analyzing the data set by a computer. 31. The method of claim 30, wherein the amount of active ingredient is less than about 100 mg. 31. The method of claim 30, wherein the amount of active ingredient is less than about 1 mg. The method of claim 30, wherein the amount of active ingredient is less than about 100 μg. 31. The method of claim 30, wherein the amount of active ingredient is less than about 100 ng. The method of claim 30, wherein the arrangement comprises at least 24 samples. The method of claim 30, wherein the arrangement comprises at least 48 samples. The method of claim 30, wherein the arrangement comprises at least 96 samples. The method of claim 30, wherein at least 1000 samples are tested per day. (a) each sample comprises a common component and one or more additional components, wherein each sample is an array of samples different from any other sample for one or more of the following: (i) identity of additional components, (ii) the ratio of common components to additional components, or (iii) the physical state of the common components; And (b) a sample tester for testing each sample for one or more properties A system for measuring or detecting interactions between components, including. 45. The system of claim 44, further comprising a mechanism for directing each sample separately from the array to a sample tester. 45. The system of claim 44, wherein the common ingredient is a medicament, a dietary supplement, a replacement medicament, or a nutraceutical. 45. The method according to claim 44, wherein the sample tester has absorbency, bioavailability, toxicity, metabolic profile, efficacy, stability, solubility, dissolution, distribution, softness, appearance, feeling in the mouth, release rate, dispersion rate, flowability, permeability, compressibility. System suitable for testing for compressibility, flow properties, color, taste or smell. 45. The system of claim 44, further comprising an automated manufacturing and testing system for preparing and testing the sample. 48. The system of claim 47, further comprising a computer for analyzing the data set. 45. The system of claim 44, wherein the amount of common component is less than about 100 mg. 45. The system of claim 44, wherein the amount of common component is less than about 1 mg. The system of claim 44, wherein the amount of common components is less than about 100 μg. 45. The system of claim 44, wherein the amount of common components is less than about 100 ng. 45. The system of claim 44, wherein the arrangement comprises at least 24 samples. 45. The system of claim 44, wherein the arrangement comprises at least 48 samples. 45. The system of claim 44, wherein the arrangement comprises at least 96 samples. Each sample comprises a common sensory substance and one or more additional components, wherein each sample is an array of samples different from any other sample for one or more of the following: (i) identity of additional components, (ii) the ratio of common sensory substances to additional components, or (iii) the physical state of common sensory substances. 59. The arrangement of claim 57, wherein the amount of common sensory substance is less than about 100 mg. 59. The arrangement of claim 57, wherein the amount of common sensory substance is less than about 1 mg. The arrangement of claim 57, wherein the amount of common sensory substance is less than about 100 μg. The arrangement of claim 57, wherein the amount of common sensory substance is less than about 100 ng. 58. The arrangement of claim 57, wherein at least 24 samples. 58. The arrangement of claim 57, wherein at least 48 samples. 58. The arrangement of claim 57, wherein at least 96 samples. (a) each sample comprises a common sensory substance and one or more additional components, wherein each sample produces an array of samples different from any other sample for one or more of the following: (i) identity of additional components, (ii) the ratio of common sensory substances to additional components, or (iii) the physical state of common sensory substances; (b) Each sample is tested for properties A method for measuring or detecting the interaction of the sensory substance with another component, comprising. 67. The method of claim 65, wherein the property is of odor quality, stall, evaporation rate, solubility, distribution, biodegradability, odor, taste, lack of odor, lack of taste, toxicity, efficacy, tissue, color, appearance, distribution, or physical And chemical stability. 66. The method of claim 65, wherein testing of the properties of each sample produces a data set. 68. The method of claim 67, further comprising analyzing the data set for detection or measurement of interaction. 68. The method of claim 67, further comprising analyzing the data set to detect lack of interaction. 66. The method of claim 65, wherein the preparation of the sample and the testing of the sample are performed by an automated sample preparation and test system. 70. The method of claim 69, wherein the data set is analyzed by a computer. 66. The method of claim 65, wherein the amount of common sensory substance is less than about 100 mg. 66. The method of claim 65, wherein the amount of common sensory substance is less than about 1 mg. 66. The method of claim 65, wherein the amount of common sensory substance is less than about 100 μg. 66. The method of claim 65, wherein the amount of common sensory substance is less than about 100 ng. 66. The method of claim 65, wherein the arrangement comprises at least 24 samples. 66. The method of claim 65, wherein the arrangement comprises at least 48 samples. 66. The method of claim 65, wherein the arrangement comprises at least 96 samples. 66. The method of claim 65, wherein at least 1000 samples are tested per day. Each sample comprises a common pesticide and one or more additional ingredients, wherein each sample is an array of samples different from any other sample for one or more of the following: (i) identity of additional components, (ii) the ratio of common pesticides to additional ingredients, or (iii) the common state of pesticides. 81. The arrangement of claim 80, wherein the amount of common pesticide is less than about 100 mg. 81. The arrangement of claim 80, wherein the amount of common pesticide is less than about 1 mg. 81. The arrangement of claim 80, wherein the amount of common pesticide is less than about 100 μg. 81. The arrangement of claim 80, wherein the amount of common pesticide is less than about 100 ng. 81. The arrangement of claim 80, wherein at least 24 samples. 81. The arrangement of claim 80, wherein at least 48 samples. 81. The arrangement of claim 80, wherein at least 96 samples. (a) each sample comprises a common pesticide and one or more additional ingredients, wherein each sample produces an array of samples different from any other sample for one or more of the following: (i) identity of additional components, (ii) the ratio of common pesticides to additional ingredients, or (iii) the common state of pesticides; (b) Each sample is tested for properties Comprising, the method of measuring or detecting the interaction between the components. 89. The method of claim 88, wherein the property is biodegradability, efficacy, solubility, stability or partitioning. 89. The method of claim 88, wherein testing the nature of each sample produces a data set. 93. The method of claim 90, further comprising analyzing the data set for detection or measurement of interaction. 93. The method of claim 90, further comprising analyzing the data set to detect lack of interaction. 89. The method of claim 88, wherein the preparation and testing of the sample is performed by an automated sample preparation and test system. 92. The method of claim 91, wherein the data set is analyzed by a computer. 89. The method of claim 88, wherein the amount of common pesticide is less than about 100 mg. 89. The method of claim 88, wherein the amount of common pesticide is less than about 1 mg. 89. The method of claim 88, wherein the amount of common pesticide is less than about 100 μg. 89. The method of claim 88, wherein the amount of common pesticide is less than about 100 ng. 89. The method of claim 88, wherein the arrangement comprises at least 24 samples. 89. The method of claim 88, wherein the arrangement comprises at least 48 samples. 89. The method of claim 88, wherein the arrangement comprises at least 96 samples. 89. The method of claim 88, wherein at least 1000 samples are tested per day. Each sample comprises a common ingredient which is an active ingredient of a consumer product formulation or an active ingredient of an industrial product formulation and one or more additional ingredients, wherein each sample is an arrangement of samples different from any other sample for one or more of the following: : (i) identity of additional components, (ii) the ratio of common components to additional components, or (iii) physical state of common components. 103. The arrangement of claim 103, wherein the amount of common components is less than about 100 mg. 103. The arrangement of claim 103, wherein the amount of common components is less than about 1 mg. 103. The arrangement of claim 103, wherein the amount of common components is less than about 100 μg. 103. The arrangement of claim 103, wherein the amount of common pesticide is less than about 100 ng. 107. The arrangement of claim 103, wherein twenty four or more samples. 107. The arrangement of claim 103, wherein at least 48 samples. 107. The arrangement of claim 103, wherein 96 or more samples. (a) each sample comprises a common ingredient that is an active ingredient of a consumer product formulation or an active ingredient of an industrial product formulation and one or more additional ingredients, wherein each sample differs from any other sample for one or more of the following: Prepare an array of samples: (i) identity of additional components, (ii) the ratio of common components to additional components, or (iii) the physical state of the common components; (b) Each sample is tested for properties Comprising, the method of measuring or detecting the interaction between the components. 112. The method of claim 111, wherein the property is biodegradable, toxic, potency, solubility, stability, partitioning, compressibility, compressibility, odor, lack of odor or flow characteristic. 112. The method of claim 111, wherein testing of the properties of each sample produces a data set. 116. The method of claim 113, further comprising analyzing the data set for detection or measurement of interaction. 115. The method of claim 113, further comprising analyzing the data set to detect lack of interaction. 112. The method of claim 111, wherein the preparation of the sample and the testing of the sample are performed by an automated sample preparation and test system. 116. The method of claim 114, wherein the data set is analyzed by a computer. 112. The method of claim 111, wherein the amount of common ingredients is less than about 100 mg. 112. The method of claim 111, wherein the amount of common component is less than about 1 mg. 112. The method of claim 111, wherein the amount of common components is less than about 100 μg. 112. The method of claim 111, wherein the amount of common components is less than about 100 ng. 112. The method of claim 111, wherein the arrangement comprises at least 24 samples. 112. The method of claim 111, wherein the arrangement comprises 48 or more samples. 112. The method of claim 111, wherein the arrangement comprises at least 96 samples. 112. The method of claim 111, wherein at least 1000 samples are tested per day.