CZ2002334A3 - Assembly of samples - Google Patents

Abstract

The invention relates to high-throughput methods to prepare an array comprising a large number of samples, each sample consisting of a combination of components, at varying concentrations and identities, and high-throughput methods to test each sample for one or more properties. Such methods allow detection or measurement of interactions or detection of lack of interactions between inactive components and active components; between multiple inactive components; or between multiple active components. The invention is particularly suited for making a large number of pharmaceutical-excipient samples at the same time, then rapidly testing each sample to detect or measure an interaction. Once such interaction is detected or measured, it can be exploited to develop optimized formulations for pharmaceutical administration.

Description

Sample set

Technical field

The invention relates to sample assembly and analysis. It concerns chemical samples with a plurality of components, especially pharmaceutical compositions and similar mixtures of various substances. The invention specifically relates to methods, systems and devices for efficient sample measurement and for creating new compositions with various components.

State of the art

The discovery that it is possible to optimize the bioavailability of active ingredients and the duration of action while minimizing undesirable properties of the formulation is an important part of pharmaceutical drug development and research. Pharmaceutically active ingredients are rarely supplied as pure compounds due to problems with their stability, solubility and bioavailability. In most cases, pharmaceutical active ingredients are administered in the form of pharmaceutical formulations that contain the active ingredient and excipients. It is well documented that the physical and chemical properties, such as stability, solubility, dissolution, permeability and other properties of most pharmaceutical agents are directly dependent on the environment in which they are administered. This environment affects the physical and chemical properties of the active ingredient. The physical and chemical properties of the substances in the resulting mixture are directly related to the pharmacological and pharmacokinetic properties, such as absorption, bioavailability, metabolic profile, toxicity and efficacy. The resulting effects are caused by physical and chemical interactions between excipients and also by physical and chemical interactions between the active substance and excipients. Other properties that are influenced in this way are, for example, mechanical properties such as compressibility, flow properties and sensory properties such as taste, smell and colour.

The aim of developing such formulations is to find a formulation that optimises the desired properties of the pharmaceuticals, such as stability, solubility and bioavailability of the pharmaceutical under the conditions of administration. These are usually laborious procedures in which the effect of each component must be determined separately in several amounts under different conditions and in different combinations. For example, if the formulation contains a pharmaceutical that is poorly soluble, the solubility at different salt concentrations, pH, excipients must be determined, and different concentrations of the pharmaceutical must be prepared and tested to determine the interactions between the pharmaceutical and excipients or between excipients alone in influencing the solubility of the pharmaceutical. Although there are some general rules, it is not easy to predict the effect of excipients and their combinations on the physical and chemical properties of the pharmaceuticals. In addition, there are more than 3,000 excipients available for the formulation of pharmaceuticals, and each of these has different degrees and types of interactions with other excipients and with the pharmaceuticals. Since there may be a number of variables, there is usually not enough time and other resources in industrial conditions to identify, measure or exploit interactions between excipients and pharmaceutical substances and thus it is not possible to design the optimal composition of a pharmaceutical preparation with respect to a particular pharmaceutical substance. The work requires testing hundreds to thousands of samples per day. If it is necessary to test 300 different substances as excipients for a pharmaceutical preparation with almost no changes in concentrations and physical or chemical properties, the number of possible combinations is already enormous. In the case of a choice of two substances, there are 44,850 possible combinations, in the case of a choice of three components from the above number, there are 4,455,100 combinations and in the case of 4 components, there are already 330,791,175 possible combinations. The complexity of the tests increases if the mutual ratio of the components is to be taken into account. Unfortunately, there are no known technologies that can simultaneously create a large number of combinations of a pharmaceutical substance with an excipient and then automatically feed these combinations into a system for identifying these combinations and their properties. Currently, for reasons of economy, most pharmaceutical substances are supplied in the form of standard, non-optimized formulations, such as those listed in Allen's Compounded Formulations: U.S.

Pharmacists Collection 1995 to 1998, ed. Lloyd Allen.

Unfortunately, current research and development of pharmaceutical compositions is still based on the selection of a small number of excipients and their processing with pharmaceutically active substances into known dosage forms for oral or parenteral administration. The invention aims to overcome this traditional approach.

However, the need to design optimized formulations is not limited to formulations in which the basic ingredient is a pharmaceutical substance. Similar problems also arise in the case of dietary supplements, alternative medicine products, food products, sensory substances, agrochemicals and other consumer and industrial products. For example, similar to the case of pharmaceuticals, vitamin formulations may also be characterized by low stability, solubility, bioavailability or an inappropriate taste or odor. Another example can be industrial products, such as bleaches in the production of paper pulp, which should be modified so that there is no decrease in effectiveness during transportation.

The essence of the invention

The invention relates to efficient methods for preparing a large number of combinations of different components at varying concentrations simultaneously and also to efficient methods for testing these combinations. These methods should allow the detection or measurement of interactions between inactive and active components, between a number of inactive components or between a number of active components. These methods should also demonstrate the absence of interaction between inactive and active components, between a number of inactive components or between a number of active components. The method according to the invention is particularly suitable for generating a large number of combinations of pharmaceutical excipients and then for rapid testing of each combination to detect or measure interactions or to demonstrate the absence of such interactions between the excipients and the pharmaceutical substance, between the excipients and each other or between the pharmaceutical substances. Once the interaction or absence of interaction is demonstrated, this knowledge can be used to develop • 0

ΒΒ » « • 0 optimized means, especially optimized pharmaceutical means.

The invention thus relates to the rapid testing of pharmaceutical compositions to determine the overall optimum composition for any particular ingredient or to optimize any desired property of the composition, for example bioavailability, efficacy, release rate, stability, and the like. Such a method has not been described or published to date. The invention also relates to an automated system for the creation and serial testing of such compositions. Finally, computer analysis of the data obtained in the above manner is envisaged. Specific embodiments of the invention will be described in more detail below.

According to one possible embodiment, the invention comprises a set of samples, each sample containing one component common to all samples and at least one other component, each of said samples differing from any other sample by at least one of the following properties:

(i) the identity of the additional component, (ii) the ratio of the common component to the additional component, or (iii) the physical state of the common component.

A common component is a component that is present in each sample. Preferably, such a component is an active substance, in particular a pharmaceutical substance, a food supplement, a substance for use in alternative medicine, a nutrient, a sensory substance, an agrochemical substance, an active ingredient of a consumer product or an active ingredient of an industrial product. The samples and their individual components may be solids, liquids, gels, foams, pastes, suspensions, emulsions or various mixtures in the liquid state or solids, dispersed with a solvent.

According to another possible embodiment, the invention provides a method for measuring or detecting interactions between components, the method comprising:

(a) a set of samples shall be prepared, each sample containing a component common to all samples and at least one additional component, each of the samples differing from any other sample in at least one of the following properties: (i) the identity of the additional component, (ii) the ratio of the common component to the additional component, or (iii) the physical state of the common component; (b) each of the samples shall be tested for one or more properties.

According to yet another embodiment, the invention relates to a method of measuring or detecting an interaction between components, the method comprising:

(a) a set of samples shall be prepared in which each sample contains at least 2 components and differs from any other sample in the identity of its components, in addition, the samples may further differ in the ratio of the components or the physical state of the components, and (b) each of the samples shall be tested for one or more properties.

In this embodiment, the samples do not contain a component common to all samples. The procedure is suitable for testing mixtures of components, such as chemical fragrances, in which each component has a different identity or chemical formula.

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The samples are preferably prepared, tested and analyzed automatically and the data obtained are stored and/or analyzed by computer. Preferably, such a component is an active substance, in particular a pharmaceutical substance, a food supplement, a substance for use in alternative medicine, a nutrient, a sensory substance, an agrochemical substance, an active ingredient of a consumer product or an active ingredient of an industrial product. In a very preferred embodiment, the common component is a pharmaceutical substance. The samples and their individual components can be solids, liquids, gels, foams, pastes, suspensions, emulsions or various mixtures in the liquid state or solids, triturated with a solvent.

According to another possible embodiment, the invention relates to a method for testing or optimizing one or more properties of a composition containing an active substance, the method comprising (a) preparing a set of samples, in which each sample contains a component common to all samples and at least one additional component, each of the samples differing from any other sample in at least one of the following properties (i) the identity of the additional component, (ii) the ratio of the active substance to the additional component, or (iii) the physical state of the active substance, (b) testing each of the samples for at least one property to obtain results for each sample, (c) comparing the result obtained for each sample, either with a baseline value or with a control sample for said property, to obtain a final result for each sample.

• · ·· ·· ·

The samples are preferably prepared, tested and analyzed automatically and the data obtained are stored and/or analyzed by computer. Preferably, such a component is an active substance, in particular a pharmaceutical substance, a food supplement, a substance for use in alternative medicine, a nutrient, a sensory substance, an agrochemical substance, an active ingredient of a consumer product or an active ingredient of an industrial product. In a very preferred embodiment, the common component is a pharmaceutical substance. The samples and their individual components can be solids, liquids, gels, foams, pastes, suspensions, emulsions or various mixtures in the liquid state or solids, dispersed with a solvent.

In yet another embodiment, the invention relates to a system for measuring or detecting interaction between components, the system comprising:

(a) a set of samples, each sample containing a common component and at least one additional component, each sample differing from any other sample in at least one of the following characteristics:

(i) the identity of the additive component, (ii) the ratio of the common component to the additive component, or (iii) the physical state of the common component, and (b) equipment for testing samples for one or more properties.

Preferably, the common ingredient is a pharmaceutical substance, a food supplement, a substance for use in alternative medicine, a nutrient, a sensory substance, an agrochemical substance, an active ingredient of a consumer product or an active ingredient of an industrial product. In a very preferred embodiment, the common ingredient is a pharmaceutical substance. Samples and their •

* 4 ♦ · · • · ·· components can be solids, liquids, gels, foams, pastes, suspensions, emulsions, and the like.

The invention will be described in more detail below in connection with the accompanying drawings.

Overview of images in drawings

Fig. 1 schematically illustrates a method for preparing a sample set, processing these samples, analyzing the samples for one or more properties, collecting and storing the obtained data, and detecting or measuring the interaction or absence of interaction between the individual components of the samples.

Figures 2A and 2B schematically illustrate the process in which a series of samples are generated and analyzed for various properties such as solubility (UV-VIS HPLC) and oral absorption is determined. Figure 2A schematically illustrates the process in which solids are placed in sample wells in a sample assembly and then reconstituted and tested. Figure 2B schematically illustrates the process in which liquids are placed in a sample assembly, samples are reconstituted, liquid and solid are separated, and samples are processed.

Fig. 3A graphically shows the solubility (absorbance) of 3500 different formulations containing griseofulvin and various excipients in water.

Figure 3B graphically depicts the data from Figure 3A, adjusted to show the standard deviation for each individual sample.

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Figure 4 shows a graph comparing the solubility (absorbance) of a commonly supplied pharmaceutical composition with five preferred compositions TPI-1 to TPI-5.

Figure 5 shows a graph of the solubility ratio of various formulations of one of the preferred formulations, TPI-3, which was modified with only one or two of the three excipients, in terms of their relative ratios, which are shown on the disc below the graph. Figure 6 shows a graph of the solubility ratio of various formulations of the preferred formulation, TPI-1, comparing the effect of changing one or two of the three excipients in this formulation, thereby demonstrating that some excipients actually reduce solubility.

Figure 7 shows a graph of the solubility ratio in various formulations of one of the preferred TPI-2 formulations. The effect of varying one or two of the three excipients in this formulation is illustrated and it is apparent that some excipients have a synergistic effect on solubility.

Figure 8 shows a graph comparing the dissolution rate and equilibrium solubility for TPI-2 and griseofulvin. It is clear that TPI-2 has a higher dissolution rate and also a higher equilibrium solubility compared to griseofulvin.

The term "set" in the application means a larger number of samples in a single experiment, each of which consists of at least two components, one of which is a component common to all samples. This means that this component is present in every sample of the set of samples, with the exception of negative control samples. The set is • · Φ · · · Φ « « * • · · · · ·»♦·»»· · φ • Φ Φ φφφ φ φ φ • ·· ♦· * Φ·ΦΦΦΦΦ adjusted so that it is possible to obtain data from it, the analysis of which allows to detect or measure the interaction or absence of interaction between the common component and other components. Each sample in the set of samples differs from any other sample in the same set by at least one of the following properties:

(i) the identity of the additional component, (ii) the ratio of the common component to the additional component, or (iii) the physical state of the common component.

The array may contain 24, 36, 48, 96 or more samples, preferably 1000 or more samples, especially 10,000 or more samples. The array is typically formed by one or more sub-assemblies. Such a sub-assemblie may be, for example, a 96-well plate containing the samples.

The term "sample" refers to a mixture of a component common to all samples and one or more additional components. Preferably, the sample contains at least two additional components and in particular three or more additional components. Typically, the sample will contain one component common to all samples, but the samples may contain a plurality of common components. The sample may be placed in any container or holder or on any material or surface, the only requirement being that the samples be placed separately. Preferably, the samples are placed in sample wells, for example in 24, 36, 48 or 96 well 250 μΐ plates (Millipore, Bedford, MA). The sample may contain less than about 100 mg of the common component, preferably less than 1 mg and particularly preferably less than 100 μg, particularly preferably the sample contains less than 100 ng of the common component. The sample has s ·· 99

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9999 • t 9 9 9 9 9 • · · 9 9 9 9 9 • · 99 9 999 • · · » · · · · · · » · · · · » ₉ ·· 99 99 9 preferably a total volume of 150 to 200 μΐ. Preferably, the sample contains at least two additional components, and in particular three or more additional components.

Throughout the application of the invention, the term "physical state of a component" is understood to mean the fact that said component is liquid or solid. In the case that the component is a solid, its physical state will be further defined by the particle size and the fact that the component is crystalline or amorphous. In the case that the component is crystalline, the physical state may be varied depending on whether 1) the crystal matrix includes addition compounds or initially included addition substances, which, however, have been removed and left empty space, 2) depending on the type of crystal, 3) depending on the morphology of the crystal, that is, the type of crystal in connection with the particle size distribution, and 4) depending on the internal structure, or polymorphism. In the case that an addition substance is included, the crystal matrix may contain stoichiometric or non-stoichiometric amounts of this substance, for example, crystallization solvents or water in the case of solvates or hydrates. Non-stoichiometric solvates and hydrates include inclusions or clathrates, that is, This is a phenomenon in which solvent or water is trapped randomly in the crystal matrix at various intervals and, for example, in the form of channels. Stoichiometric solvates or hydrates have solvent or water at specific locations in the crystal matrix in specific ratios. This means that the solvent or water molecule is part of the crystal matrix in a defined arrangement. In addition, the physical state of the crystal matrix can change due to the removal of an additive originally present in the crystal matrix. For example, in the case of solvates or

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0 0 •00 hydrate, the solvent or water is removed, a cavity is formed in the crystal matrix, which creates a new physical state. Crystal type is a term describing the external appearance of individual crystals, for example, the fact that they are cubic, tetragonal, orthorhombic, monoclinic, triclinic, rhomboidal or hexagonal crystals. The processing properties are influenced by the type of crystals. The internal structure of crystals reflects the crystal form or polymorphism. A given compound can exist in various different polymorphic forms that crystallize in different ways. In general, different polymorphic forms of a given substance differ from each other in their structure and properties like crystals of two different compounds. The solubility, melting point, density, hardness, crystal shape, optical and electrical properties, vapor pressure, stability and other basic properties of each substance change with the polymorphic form.

When a possible interaction between components of the samples is reported, it means that the components in the form of a mixture have a certain property, for example, the ability to dissolve a specific pharmaceutical substance or varying degrees of such a property, which is different from the properties of the individual components separately. This means that the interaction between the components will affect the properties of the resulting samples. As an example, a certain combination of excipients may have a high solubilizing effect on a certain pharmaceutical substance. Once such an interaction is demonstrated, it can be used to develop advantageous pharmaceutical formulations for a certain pharmaceutical substance.

The term "ingredient" in the application process means any substance. It can be an active substance or ··· ·· ♦ · · · · · * * ♦· · ·♦·»»<

inactive. The term "active ingredient" means the substance that gives a particular composition its primary utility for a particular purpose. Examples of active ingredients include pharmaceuticals, food supplements, compositions for use in alternative medicine, nutrients, sensory substances, agrochemicals, active ingredients for consumer or industrial products, and the like. The term "inactive ingredient" means an ingredient that is useful or potentially useful in a composition for administering an active ingredient, but does not have the properties of an active ingredient. Examples of suitable inactive ingredients include common excipients, solvents, diluents, stabilizers, and combinations of such substances.

The sample in the sample set preferably contains a common active ingredient and inactive ingredients. Many variations are possible in the case where, for example, the active ingredient is a pharmaceutical ingredient, a food supplement, an alternative medicine ingredient or a nutrient, in this example the inactive ingredients are usually conventional excipients used in the pharmaceutical industry. In the case where the active ingredient is a sensory ingredient, for example a fragrance or a flavoring ingredient, the inactive ingredients are usually conventional inactive ingredients or ingredients commonly used in the use of sensory ingredients. In the case where the active ingredient is an agrochemical ingredient, the inactive ingredients are usually inactive ingredients commonly used in the application of agrochemical ingredients. In the case where the active ingredient is processed into a consumer or industrial product, the inactive ingredients are preferably inactive ingredients commonly used in the application of such active ingredients.

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The term "test agent" throughout the application means a biological material, process or reagent, such as an enzyme or cell line, that can be used to measure the properties of a particular sample.

The term "composition" throughout the application means a predefined mixture of one or more active substances and one or more inactive substances in a predefined ratio. The composition is intended for the administration or application of the active substance.

The term "administration or application" means the use of an active substance for an intended purpose in the form of a composition containing such a substance. For example, in the case of the administration of pharmaceutical substances, food supplements, active substances for alternative medicine and nutrients, oral administration, administration in the form of intravenous injection and topical administration can be envisaged. The application of agrochemical substances includes, for example, spraying or dusting plants. The application of sensory compounds includes, for example, applying perfumes and deodorants to the human body or consuming food or confectionery supplemented with a substance with a certain flavor.

Applying consumer and industrial products simply means using such products according to the manufacturer's recommendations. For example, applying varnish or paint means applying varnish to a surface with a brush, and applying lubricant means applying lubricant to the surface that needs to be lubricated.

According to the invention, the ratio of the common component and the additional component will vary from sample to sample so that it is possible to

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The term "property" refers to a physical or chemical property of a sample. Preferred properties will relate to the efficacy, safety, stability or usability of the compositions before or after administration. For example, in the case of pharmaceuticals, food supplements, active ingredients for alternative medicine and nutrients, such properties may include physical properties such as rheological properties, fragility, stability, solubility, dissolution rate, permeability, distributability, mechanical properties such as compressibility, flowability, sensory properties such as taste, appearance, texture, colour and odour, and other properties that may affect the usability of the composition such as absorption, bioavailability, toxicity, metabolic profile, efficacy, release rate of the active ingredient and dispersion rate of this substance. By optimizing the physical and sensory properties and properties that may affect usability, it is possible to reduce the dose of the active ingredient while maintaining the same therapeutic effect, thereby also reducing the number of side effects and improving patient compliance.

The assembly comprises at least two samples and preferably comprises 24, 36, 48, 72 or more samples, particularly 96 or more samples, more preferably 1000 or more samples, most preferably 10,000 or more samples. The samples are stored in separate locations in any container or holder, in a form absorbed onto a suitable material or the samples can be stored in separate locations • 0 00 • · · ♦

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0 0 0 • 0 0 0 ·· 00 • » « » · · » ♦· ♦··«··· « * • · · « · · ·« · ·» ··♦· flat surface. Preferably, the samples are placed in the sample wells. The sample wells can have any dimensions or volume. Preferably, the wells have a volume in the range of 200 to 300 μΐ and in particular about 250 μΐ. The assemblies can be prepared by placing a common component and an additional component or components in the individual sample wells. The common component is selected by the skilled person depending on the interaction to be measured or identified. Preferably, the common component is an active substance, and in particular a pharmaceutical substance. In some cases, however, the common component may also be an inactive substance, for example, if the sample set is to be used to detect or measure interactions between a certain excipient, which in this case is a common component, and other excipients, which in this case are additional components. The active substances and inactive substances can be selected from commonly known lists published in the literature, or it is also possible to use newly discovered compounds. The inactive substance is preferably a substance that is already known and is commonly used together with the active substance forming the common component in the set. For example, if the common component is a pharmaceutical substance, the inactive substance can be selected from a list of known excipients.

In each sample in the sample set, the common component and each additional component are present in certain proportions. The proportions of the common component to the additional components vary from sample to sample in such a way that the desired information about possible interactions can be obtained depending on the common component used.

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The components of the individual samples are preferably mixed to form a homogeneous solution or suspension. Any person skilled in the art will readily determine the addition and mixing of the components for each sample based on simple experiments. The components can be added and mixed manually or automatically.

Preferably, the individual components are added and mixed automatically into the sample wells. This means that computer programs and robots are used to prepare the samples.

After adding and mixing the components in the individual sample wells, the samples can then be processed by known methods, such as heating, filtration, and lyophilization.

Any person skilled in the art will readily determine how the sample should be processed based on the properties to be determined. Samples can be processed individually or in groups, with the samples preferably being processed in groups.

According to the invention, each sample in the array is tested for a specific property, thereby obtaining a data set. The samples can be tested by various known methods depending on the components of the sample and the properties of interest. The property of interest can only be demonstrated or measured to obtain a value that is a measure of this property. The values obtained can then be compared with control or standard values to determine whether there is an interaction between the components of the sample or whether the sample is suitable as the basis for a composition for administering the active substance. For example, if a set of samples is tested in which each sample contains the same known active substance but different excipients, it is possible to find a combination of excipients that gives the active substance the highest solubility, in these tests the solubility of the active substance is compared with • ♦ • 9 9 9

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control or standard values of its solubility. For example, the solubility of the active substance in each of the samples can be compared with the solubility of the same substance in commonly used and supplied preparations or with the solubility of the pure substance.

Pharmaceuticals, food supplements, active ingredients for alternative medicine and nutrients

As already mentioned, the invention can be used to detect or measure interactions between pharmaceuticals, dietary supplements, alternative medicine substances or nutrients and excipients, thereby leading to improved formulations that will have optimal properties.

According to one possible embodiment, the invention relates to a set of samples, in which each sample contains as a common component a pharmaceutical substance, a dietary supplement, a substance for alternative medicine or a nutrient and in addition contains at least one additional component, each of the samples differing from any other sample by at least one of the following properties:

(i) the identity of the additional component, (ii) the ratio of the common component to the additional component, or (iii) the physical state of the common component.

The term "pharmaceutical substance" throughout the application means any substance that has a therapeutic effect, can prevent the development of a disease, can be used for diagnostic purposes or has a prophylactic effect when administered to animals, including humans. Pharmaceutical preparations include both preparations linked to a medical

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4444 prescription, as well as over-the-counter pharmaceutical preparations. Pharmaceutical substances suitable for use according to the invention may be all known substances or substances yet to be developed.

Examples of suitable pharmaceutical agents include pharmaceutical agents for influencing the cardiovascular system, such as amlodipine besylate, losartan potassium, irbesartan, diltiazem hydrochloride, clopidogrel bisulfate, digoxin, abciximab, furosemide, amiodarone hydrochloride, beraprost or tocopheryl nicotinate, anti-infective agents such as amoxicillin, potassium clavulanate, azithromycin, itraconazole, acyclovir, fluconazole, terbinafine hydrochloride, erythromycin ethylsuccinate and acetylsulfisoxazole, psychotherapeutic agents such as sertaline hydrochloride, vanlafaxine, bupropion hydrochloride, olanzapine, buspirone hydrochloride, alprazolam, methylphenidate hydrochloride, fluvoxamine maleate and ergoloid mesylates, agents for use in diseases of the digestive system, such as lansoprazole, ranitidine hydrochloride, famotidine, ondansetron hydrochloride, granisetron hydrochloride, sulfasalazine and infiximab, respiratory drugs such as loratadine, fexofenadine hydrochloride, cetirizine hydrochloride, fluticasone propionate, salmeterol xinafoate and budesonide, cholesterol-lowering agents such as atorvastatin calcium, lovastatin, bezafibrate, ciprofibrate and gemfibrozil, agents for the treatment of cancer and related diseases such as paclitaxel, carboplatin, tamoxifen citrate, docetaxel, epirubicin hydrochloride, leuprolide acetate, bicalutamide, goserelin acetate in the form of • 4 · • 4 4

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4« 4444 implants, irinotecan hydrochloride, gemcitabine hydrochloride and sargramostim, substances affecting blood composition, such as epietin alfa, enoxaparin sodium and antihemophilic factor, substances used to treat joint inflammation, such as celecoxib, nabumetone, misoprostol and rofecoxib, pharmaceutical substances for the treatment of AIDS and related conditions, such as lamivudine, indinavir sulphate, stavudine and lamivudine, antidiabetic substances and substances for the treatment of related diseases, such as metformin hydrochloride, troglitazone, acarbose, vaccines, such as hepatitis B and hepatitis A vaccines, hormones, such as estradiol, mycophenolate mofetil and methylprednisolone, analgesics, such as tramadol hydrochloride, fentanyl, metamizole, ketoprofen, morphine sulphate, lysine acetylsalicylate, ketoralac tromethamine, morphine, loxoprofen sodium and ibuprofen, preparations for use in dermatology, such as isotretinoin and clindamycin phosphate, anesthetics such as propofol, midazolam hydrochloride and lidocaine hydrochloride, migraine treatment agents such as sumatriptan succinate, zolmitriptan and rizatriptan benzoate, sedatives and hypnotics such as zolpidem, zolpidem tartrate, triazolam and hycosine butyl bromide, contrast agents such as iohexol, technetium, TC99M, sestamibi, iomeprol, gadodiamide, ioversol and iopromide, and other diagnostic and contrast agents such as alsactide, americium, betazole, histamine, mannitol, metyrapone, petagastrin, phentolamine, radioactive B12, gadodiamide, gadopentenoic acid, gadoteridol and perflubron. Other pharmaceutical agents for use in the invention may be those listed below in Table Ia, the administration of which presents difficulties that could be alleviated by developing new agents when using the sample assembly of the invention.

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Table 1. Examples of pharmaceuticals Means Composition Features Sandimmune cyclosporine poor absorption due to low solubility in water Taxol paclitaxel poor absorption due to low solubility in water Viagra sildenafil poor absorption due to citrate to low solubility in water Norvir ritonavir Polymorphic shift may occur during transport and storage Fulvicin griseofulvin poor absorption due to low solubility in water Fortovas saquinavir poor absorption due to

to low solubility in water

Additional examples of pharmaceutical compositions are provided in 2000 Med Ad News 19, 56-60 and The Physicians Desk Reference, 53rd Edition, 792-796, Medical Economics Company (1999).

Examples of veterinary pharmaceutical compositions include, for example, vaccines, antibiotics, growth promoters and anthelmintics. Further examples of suitable veterinary pharmaceutical compositions can be found in The Merck Publication No.

Veterinary Manual, 8th edition, 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.

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The term "food supplement" means a non-caloric substance or a substance with a low energy content, which is administered to animals, including humans, to increase the nutritional value or it may be a non-energy or low-energy substance administered together with food to achieve an aesthetic, structural, stabilizing or nutritional effect. It may be, for example, substances capable of binding fats, such as caducean, fish oils, plant extracts, for example from garlic and pepper, vitamins and minerals, or also preservatives, acidulants, anti-caking agents, anti-foaming agents, antioxidants, bulking agents, colouring agents, dietary fibre, emulsifiers, stiffening agents, enzymes, humectants, leavening agents, glidants, artificial sweeteners, food solvents and thickeners, as well as fat substitutes and substances, flavour enhancers and other auxiliary ingredients, for example substances, appetite suppressants. Examples of suitable food supplements are given in The Encyclopedia of Chemical Technology, 11 Kirk-Othomer, 4th edition, pp. 805-833.

Examples of suitable vitamins are given in 1998 The Encyclopedia of Chemical Technology, 25 Kirk-Othomer,

4th edition p. 1 and Goodman & Gilman: The Pharmacological Basis of Therapeutics, 9th edition, ed. Joel G. Harman and Lee E. Límbírd, McGraw-Hill, 1996 p. 1547. Examples of suitable minerals can be found in The Encyclopedia of Chemical Technology, 16 Kirk-Othomer,

4th edition p. 746 and Mineral Nutrients in ET, 3rd edition, vol. 15, pp. 570-603, C. L. Rollinson and M. G. Enig,

University of Maryland.

The term "substances for alternative medicine" refers to substances, preferably natural, such _as plants, their extracts or concentrates of these extracts, intended for administration to patients to treat certain diseases or to ensure good health, and the materials used do not require FDA approval. Examples of such substances include ginkgo biloba, ginseng root, valerian root, oak bark, kava kava, milk thistle, harpagophyti root, and other substances are listed in The Complete German Commission E. Monographs: Therapeutic Guide to Herbal Medicine, Mark Blumenthal et al., Integrative Medicine Communications 1998.

The term "nutrients" refers to foods or food products that have both energy value and pharmaceutical or medicinal properties. Examples of such substances include garlic, pepper and paprika, bran and fiber, and various beverages. Examples of such substances can be found in M. C. Linder, Nutritional Biochemistry and Metabolism with Clinical Applications, Elsevier, New York, 1985, Pszczola et al., 1998, Food Technology 52, 30-37 and Shukla et al., 1992 Cereal Foods World 37, 665-666.

In the case where the common ingredient is a pharmaceutical substance, a food supplement, a substance for use in alternative medicine or a nutrient, the additional ingredients are usually excipients. The term "excipient" means inactive substances used in the manufacture of pharmaceutical preparations so that it is possible to prepare suitable pharmaceutical preparations, food supplements, alternative medicine preparations and nutrients for administration to animals including humans. Excipients must be safe for administration to humans and other animals.

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Examples of suitable excipients include acids such as lactic, hydrochloric and tartaric acid, solubilizers such as nonionic, cationic and anionic surfactants, absorbents such as bentonite, cellulose and kaolin, alkalizing agents such as diethanolamine, potassium citrate or sodium bicarbonate, anti-caking agents such as calcium phosphate, calcium silicate and talc, antimicrobials such as benzoic acid, sorbic acid, benzyl alcohol, benzethonium chloride, bronopol, alkylparabens, cetrimide, phenol, phenylmercuric acetate, thimerosol and phenoxyethanol, antioxidants such as ascorbic acid, α-tocopherol, propyl gallate and sodium metabisulfite, binders such as acacia, alginic acid, carboxymethylcellulose, hydroxyethylcellulose, dextrin, gelatin, guar gum, magnesium aluminum silicate, maltodextrin, polyvinylpyrrolidone, starch, vegetable oil and zein, buffers such as sodium phosphate, malic acid and potassium citrate, chelating agents such as EDTA, malic acid and maltol, coating agents such as sugars, cetyl alcohol, polyvinyl alcohol, carnauba wax, titanium dioxide and the like, controlled release media such as microcrystalline wax, white wax and yellow wax, water-removing agents such as calcium sulfate, detergents such as sodium lauryl sulfate, diluents such as calcium phosphate, sorbitol, starch, talc, lactitol, polymethacrylates, sodium chloride and glyceryl palmitostearate, disintegrants such as colloidal silicon dioxide, croscarmellose sodium, magnesium aluminum silicate, polacrilin potassium and sodium starch glycolate, dispersing agents such as poloxamer 386 and polyoxyethylene esters with fatty

• · · · ··· • · · · · · * • · · • ···· · • ·

acids (polysorbates), emollients such as cetearyl alcohol, lanolin, mineral oils, petrolatum, cholesterol, isopropyl myristate and lecithin, emulsifying agents such as anionic emulsifying wax, monoethanolamine and medium chain triglycerides, flavouring agents such as ethyl maltol, ethyl vanillin, fumaric acid, malic acid, maltol and menthol, water retaining agents such as glycerol, propylene glycol, sorbitol and triacetin, lubricants such as calcium stearate, canola oil, glyceryl palmitostearate, magnesium oxide, polyoxymer, sodium benzoate, stearic acid and zinc stearate, solvents such as alcohols, benzylphenyl formate, vegetable oils, diethyl phthalate, ethyl oleate, glycerol, glycofurol, indigo carmine, polyethylene glycol, tartrazine, triacetin, stabilising agents such as cyclodextrins, albumin and xanthan gum and osmotic pressure adjusting agents such as glycerol, dextrose, potassium chloride and sodium chloride and mixtures thereof. These may be substances which alter the rate of absorption, bioavailability or other pharmacokinetic properties of pharmaceuticals, dietary supplements, alternative medicine substances or nutrients. Other examples of suitable excipients, such as binders or fillers, can be found in Remington's Pharmaceutical Sciences, 18th edition, Alfonso Gennaro,

Mack Publishing Co. Easton, PA, 1995 and also in Handbook of Pharmaceutical Excipients, 3rd edition, Arthur H. Kibbe, American Pharmaceutical Association, Washington D. C. 2000.

The term "excipient" may also include solvents throughout the application. Aqueous solvents may be used to prepare mixtures, suspensions and matrices formed from

·· · polymers, soluble in water. Organic solvents are typically used to dissolve hydrophobic and some hydrophilic polymers. Preferred organic solvents are volatile or have a relatively low boiling point or can be removed under vacuum, are non-toxic, and in trace amounts are acceptable for human administration, such as methylene chloride. Other solvents such as ethyl acetate, ethanol, methanol, dimethylformamide, acetone, acetonitrile, tetrahydrofuran, acetic acid, dimethylsulfoxide, chloroform, and mixtures thereof may also be used. Preferred solvents are solvents classified as Group 3 according to the Food and Drug Administration, Federal Register, Vol. 62, No. 85, pp. 24301-24309 (May 1997). Solvents for substances to be administered parenterally, or in solution or suspension, are typically distilled water, buffered saline, lactic acid Ringer's solution, or some other pharmaceutically acceptable vehicle.

According to one embodiment of the sample set, in which the common component is selected from the group of pharmaceuticals, food supplements, active ingredients for alternative medicine and nutrients, the additional component can also be selected from the group of pharmaceuticals, food supplements, active ingredients for alternative medicine and nutrients. This means that each sample can contain a plurality of active components, with a certain active component being present in all samples and thus being a common component. The set of such samples can be used to detect beneficial or synergistic interactions between pharmaceuticals, food supplements, active ingredients for alternative medicine and nutrients • · For example, in a sample set in which each sample contains the same common pharmaceutical substance and each sample also contains a different additional component selected from the group of pharmaceutical substances, food supplements, active substances for alternative medicine or nutrients, it is possible to identify particularly advantageous combinations of the above-mentioned active substances. Such advantageous combinations may be completely unexpected based on the properties of the individual components separately. An assembly of such samples containing a plurality of active substances may also be used to determine a suitable combination of excipients for processing two or more active substances into a composition, for example for processing two or more pharmaceutical substances into a dosage form. Such dosage forms may, for example, eliminate the need for multiple administration of compositions with individual components, since the prescribed active substances can be processed into a single pharmaceutical composition.

According to another embodiment, the invention relates to a method for measuring or detecting an interaction between components, the method comprising (a) preparing a set of samples, each sample comprising a common component, which may be a pharmaceutical substance, a food supplement, an active ingredient for alternative medicine or a nutrient, and at least one additional component, each sample differing from any other sample by at least one of the following properties:

(i) the identity of the additional component, (ii) the ratio of the common component to the additional component, or (iii) the physical state of the common component, * · • » • ·

(b) each of the samples is tested for a specific property to produce a data set; and (c) this data is analyzed to measure or detect the interaction of the components.

Preferably, the samples are tested for properties that are relevant to the administration and pharmacokinetic properties of pharmaceuticals, food supplements, active ingredients for alternative medicine or nutrients. Preferred properties include physical properties such as rheological properties, fragility, stability, solubility, dissolution rate and permeability, mechanical properties such as compressibility and flow properties, sensory properties such as taste, appearance, texture, colour and odour, and properties that may affect the usability of the active ingredients such as absorption, bioavailability, toxicity, metabolic profile, efficacy, release rate and dispersion rate. Some of the biological properties relate to in vivo conditions, but they can be measured by in vitro tests, from which in vivo properties can be well estimated.

Toxicity is the property of a pharmaceutical agent to cause harm to the organism after administration. Toxicity also includes hypersensitivity and allergic reactions. In contrast, efficacy is the performance of a pharmaceutical or other agent for its intended purpose. Both of these biological properties can be measured in vitro, for example, using microorganisms. More detailed information on in vitro testing can be found in Remington's Pharmaceutical Sciences, 18th edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, PA, 1995, pp. 499-500.

• · · · ♦ · · • · · * · · · · · · •fl flflfl flflfl···· · ·

Absorption is the passage of an active ingredient, such as a pharmaceutical agent, from the site of administration across a physiological barrier, such as the passage across the gastrointestinal tract in the case of oral administration, passage through the skin into the bloodstream in the case of transdermal administration, or passage through the stratum corneum into the dermis in the case of intradermal administration. The success of absorption is determined by a number of factors, such as the concentration of the pharmaceutical agent, its solubility, and its ability to cross the barrier. Various procedures are available to determine these properties, some of which are general procedures designed for direct determination of absorption, such as the Ussing chamber containing recombinant HT Caco-2/MS cells, the chamber being described in Lennernas, H. 1988 J. Pharm. Sci. 87, 403-410. A more detailed discussion of the theoretical background and methods for measuring the absorption of pharmaceutical agents can be found in the comprehensive publication Remington's Pharmaceutical Sciences,

18th edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, PA, 1995, pp. 710-714.

Solubility refers to the equilibrium state and can be measured as the mass of a particular component in a certain volume of solvent. In the case where an active substance, for example a pharmaceutical substance, has an aqueous solubility of less than 1 mg/ml in the physiological pH range of 1 to 7, significant problems arise regarding the bioavailability of such a substance. The terms used to quickly estimate or describe solubility in parts of active substance per part of solvent are as follows: the substance is very soluble (less than 1 part), freely soluble (1 to 10 parts), soluble (10 to 30 parts), sparingly soluble (30 to 100 parts), poorly soluble (100 to 1000 parts) • · · · · ·

parts), very poorly soluble (1000 to 10000 parts), and insoluble (more than 10000 parts). A detailed discussion of solubility and equilibrium can be found in Remington's Pharmaceutical Sciences, 18th edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, PA, 1995, chap. 16.

Solubility can be measured by mixing a sample of a substance with the solvent of interest and stirring the mixture at a constant temperature until equilibrium is reached. Equilibrium is usually reached after stirring the sample for 6 to 24 hours. If the substance is acidic or basic in nature, its solubility may be affected by pH, and one skilled in the art will take this into account when determining the solubility of such a substance. Once equilibrium is reached, the sample can be tested for the amount of solute dissolved by standard methods, such as spectroscopy, mass spectroscopy, HPLC, fluorescence spectroscopy, gas chromatography, optical density determination, or colorimetry. A detailed discussion of such procedures can be found in 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 more detailed information on heat of solution, pKa, and solubility at various pH values, see 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.

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Dissolution is the process by which a solid substance passes into solution. Dissolution can be affected by a variety of factors, including solubility, particle size, crystalline form, and the presence of diluents, disintegrants, or other excipients. A more detailed discussion of dissolution and how to determine dissolution rates can be found in Remington's Pharmaceutical Sciences, 18th edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, PA, 1995, Chapter 34.

Stability refers to the chemical and physical stability of the components during processing, packaging, distribution, storage and administration of the active substance(s), and may relate to the entire product or to individual components.

Chemical stability refers to the resistance of a product to chemical reactions that may be induced by heat, ultraviolet radiation or water, to chemical reactions between individual components or to the action of oxygen. Chemical stability also refers to the ability of a substance to retain a certain stereoisomeric form without conversion to another stereoisomeric form, for example optically active. Known methods for measuring chemical stability include mass spectroscopy, UV-VIS spectroscopy, polarimetry, chiral and non-chiral HPLC, chiral and non-chiral gas chromatography and liquid chromatography combined with mass spectroscopy, LC-MS. In the case of surface discoloration due to oxidation or due to the reaction of the active substance with excipients or due to the reaction of the active substance with another active substance, measuring the surface reflectance may be a more sensitive procedure than other tests. A more detailed analysis of the method for measuring chemical stability can be found in the publications Xu • · ♦ · ·« »·

9 9 · • · ·

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 to maintain a physical form, such as particle size, crystalline or amorphous form, a complex form, such as a hydrate or solvate form, it may also be the resistance to absorb moisture from the air and to maintain mechanical properties, such as compressibility or flowability. Methods by which physical stability can be determined include spectroscopy, sieving, microscopic observation, settling and light scattering. Polymorphic changes can be determined, for example, by differential scanning calorimetry or quantitative infrared analysis. A more detailed discussion of methods for measuring physical stability can be found 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 ed., ed. Alfonso Gennaro, Mack Publishing Co. Easton, PA, 1995, pp. 1448-1451.

Permeability refers to the ability of a component to pass through biological membranes. Biological membranes act as lipid barriers for most pharmaceuticals and allow the absorption of lipid-soluble substances by passive diffusion. Substances that are insoluble in fats can only pass through such a barrier with great difficulty. An in vitro procedure for measuring permeability consists of an aqueous layer, followed by an organic lipid layer and then an aqueous system. Another in vitro procedure uses sections of rat small intestine.

A more detailed discussion of permeability measurement methods can be found in Remington's Pharmaceutical Sciences, 18th edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, PA, 1995, pp. 1460-1461.

The ability of a component to partition between two phases so that each phase is saturated is a possible property of active substances. If a component is added to a system of two immiscible solvents in an amount that is not sufficient to saturate both solutions, such a component will partition between the two solvents in a certain ratio. Knowledge of such ratios can make it possible to determine the site of absorption, for example, whether such a substance will be absorbed in the stomach or only in the small intestine. A detailed analysis of the method for determining this property can be found in the publications 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 ed., ed. Alfonso Gennaro, Mack Publishing Co. Easton, PA, 1995, pp. 1451-1452.

Metabolic profile or metabolism refers to the conversion of pharmaceuticals, dietary supplements, alternative medicine active ingredients or nutrients into other chemical substances after administration in the human or animal body. Once a pharmaceutical substance enters the body, it may undergo a number of enzymatic or chemical metabolic processes in the stomach, intestine, liver and other areas of the body. Depending on the type of metabolism that may occur at different sites • ·

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• · · · organism, it is possible to modify the compositions so that their transdermal, dermal or gastric metabolism is optimal. Metabolic changes may involve changes in functional groups, for example, hydroxylation of the ring or side chain, reduction of the nitro group, oxidation of the aldehyde, dealkylation, deamination and the like, or may involve conjugation, in which the pharmaceutical substance is combined with another group, for example, with glucuronic acid or glycine, to form a compound that can be eliminated from the organism. The metabolism of an active substance, for example, a pharmaceutical substance, can be accelerated or slowed down depending on the composition of the composition in which the active substance is administered. Although metabolism occurs in the organism, it can be measured using various in vitro tests. For example, some pharmaceutical substances, usually administered orally, such as penicillins, are undesirably metabolized by hydrolysis in the acidic environment of the digestive system. In order to determine the effectiveness of a composition of a particular composition in retarding such metabolism and allowing the passage of the pharmaceutical agent into the bloodstream, the composition containing such pharmaceutical agent can be placed in an environment that mimics the environment of the digestive system and the rate or extent of hydrolysis can be measured by an appropriate technique, such as HPLC. Similarly, in the case of pharmaceutical agents known to be metabolized by certain enzymes, the effectiveness of a composition of a particular composition in accelerating or retarding metabolism can be determined by placing the composition in an environment containing the enzyme under appropriate conditions and measuring the rate of degradation of the active agent. A detailed discussion of such procedures can be found in Remington's Pharmaceutical Sciences, 18th edition, ed. Alfonso Gennaro, • · » · · » ····«· ► · « φ· ·

Mack Publishing Co. Easton, PA, 1995, p. 431, 742, 1665, 1753 and 1831.

Compressibility refers to the ability to reduce volume when pressure is applied, while compressibility refers to the ability of a mixture to form a tablet of a certain strength or hardness. When a powder mixture is compressed, the powder particles assume a more favorable position and undergo elastic or reversible deformation. If the applied force is removed during this phase, the mixture will again disintegrate into a powder. However, when the pressure is further increased, compression occurs, which means irreversible deformation of the powder material. This compressibility is very important in the manufacture of tablets. In order for a certain mixture to be processed into tablets, the mixture must undergo irreversible deformation under pressure to form a tablet that is sufficiently hard and resistant to disintegration and sufficiently hard to prevent breakage. A more detailed description of the manufacture of tablets can be found in Remington's Pharmaceutical Sciences, 18th edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, PA, 1995, pp. 1457-1458 and Chapter 92 and also Jones et al., 1977 Pharmazeutische Industrie, 39, 469. There are also a number of publications available that describe methods for measuring compressibility and compressibility, for example Rees et al., 1987, J. Pharm. Pharmacol. 30, 601 and Jones, Polermand ed: Formulation and Preparation of Dosage Forms, Elsevier, North Holland, 29, 1977.

Powder flowability refers to the ability of a powder to flow. Powder materials can be classified as free-flowing or cohesive. Flowability can be influenced by particle size, shape, morphology, and other factors. • » ♦ · • · 9 9

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9 999 9 factors such as density, electrostatic charge and the presence of absorbed air or water. Free-flowing powders can be detected by passing through a simple device consisting of a metal tube through which the pharmaceutical substance passes onto an electronic balance. A more detailed discussion of methods for measuring free-flow can be found in Kaye's publications Chemical analysis: Direct

Characterization of Fine Particles. St. 61, John Wiley and Sons, New York 1981, Sutton et al., Characterization of Powder Surfaces, Academie Press, London, 1976, p. 1,

7, and 158, Hiestand et al., 1973, J. Pharm. Sci. 62,

1513, and Hiestand et al. 1974, J. Pharm. Sci. 63, 605.

Friability is an indicator of the cohesion and hardness of solid dosage forms formed from powdered materials, such as tablets containing pharmaceuticals, dietary supplements, active ingredients for alternative medicine, and nutrients. Friability can be measured by known methods, such as the Roch apparatus. A more detailed discussion of the relevant methods can be found in Remington's Pharmaceutical Sciences, 18th edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, PA, 1995, pp. 1639-1640.

Rheology is concerned with the deformation and flow of materials. In the case of pharmaceuticals, food supplements, alternative medicine active ingredients, nutrients, consumer products and industrial products, rheology refers to mechanical properties such as adhesion, stickiness and viscosity. These properties are particularly important in the pharmaceutical use of biological polymers and mucilaginous and adhesive materials. For example, in the case of transdermal or dermal • * • «4 » · 9 · • 9 ·« · · ♦ · • · 9 9 9 · 9 «#·· · » 9 9 • ••9 · · · ··· •9 ·· ·9 9 ·9 «999 t 9 · « »4 · administration, the biological adhesive must adhere to the skin, but it must be possible to remove it later without causing pain. Rheology is also important in the case of consumer and industrial products, for example containing polymers, adhesives, gels, gums, inks and plastics. A summary of methods for measuring rheological properties can be found in Remington's Pharmaceutical Sciences, 18th edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, PA, 1995, Chapter 22.

Dispersibility refers to the mechanical properties of solids and liquids to disperse into small particles and their distribution and dissolution in a liquid carrier medium. These properties are particularly important in the case of pharmaceuticals, dietary supplements, alternative medicine active ingredients and nutrients. Dispersibility can be enhanced by various additives, such as disintegrants and glidants. A detailed description of dissolution, disintegration and dispersibility tests can be found in Remington's Pharmaceutical Sciences, 18th edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, PA, 1995, pp. 595-596.

Release rate refers to the release of pharmaceutical agents from a pharmaceutical formulation so that the active ingredient is available for absorption. Controlling the release rate allows the use of dosage forms from which the pharmaceutical agent can be released over a prolonged period. The release rate is closely related to other properties of the dosage form, such as refraction, dispersibility, disintegration, concentration of the drug, drug-carrier interactions, particle size and type, pH, polarity, surface tension, and rheology. A more detailed discussion of assays that can measure release rate can be found in Chemical Aspects of Drug Delivery Systems, eds. D. R. Karsa and R. A. Stephenson, The Royal Society of Chemistry, Cambridge, UK, 1996.

Sensory materials

According to another possible embodiment, the invention relates to a sample assembly, in which each sample comprises a sensory material as a common component and in addition comprises at least one additional component, each sample differing from any other sample by at least one of the following properties:

(i) the identity of the additional component, (ii) the ratio of the sensory material as a common component to the additional component, or (iii) the physical state of the sensory material as a common component.

The term "sensory material" means any chemical substance known to be used to produce a particular taste or odor in humans or other animals, such as a fragrance, flavoring, or spice. Sensory material also includes any substance useful for masking a taste or odor. Examples of suitable materials include musk-type materials such as civetone, ambrettolide, ethylene brassylate, xylene derivative of musk, Tonalide ^R and Glaxolide ^R , ambergris-type materials such as ambrox, ambreinolide, and ambrinol, sandalwood-derived materials such as «φ φφ φφφ φ φφφ · φ φ φ * φ

Φ Φ · φφφ φ φφφφ· « φ φφφφ α-santalol, β-santalol, Sandalore ^R a_Bacdanol ^R , patchouli-type and wood-derived materials such as patchouli oil and alcohol, Timberol ^R and Polywood ^R , floral-scented materials such as Givescone ^R damascone, irony, linalool, Lilial ^R , Liestralis ^R and dihydrojasmonate. Other examples of suitable materials of this type can be found in Perfumes: Art, Science, Technology, PM Muller ed. Elsevier, New York, 1991. Examples of suitable fragrance materials can further include benzaldehyde, anethole, dimethyl sulfide, vanillin, methyl anthranilate, nootkatone and cinnamyl acetate. Examples of suitable spices can be cloves, pepper, sago, thyme and coriander. Other examples of fragrances and spices can be found 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,

Kirk-Othomer (4th ed., pp. 1-61).

Preferred excipients that can be used with sensory materials are known substances used in cosmetic compositions, for example, ingredients used in the manufacture of colognes and perfumes, skin cleansers, shower gels, skin care compositions, deodorants and antiperspirants, hair care products, shampoos and the like. Other examples of suitable ingredients may be the excipients mentioned above for pharmaceutical compositions, since the same substances can also be used to manufacture compositions containing sensory materials. Another example of suitable ingredients containing these materials are the compositions listed in Perfumes: Art, Science, Technology, P. M. Muller ed. Elsevier, New York, 1991, • 4 44 · · 1 ·« tt

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pp. 338-345, 347-362, 40-42 and 1996 The Encyclopedia of Chemical Technology, 18 Kirk-Othomer (4th ed. 171-201). In one embodiment of the sample array, the common component may be a sensory material and the additional component or components may be other different sensory materials. That is, each sample contains a plurality of sensory materials, of which a certain sensory material is present in all samples as a common component. The array of such samples can be used to detect favorable or synergistic interactions between sensory materials, for example to identify a combination of sensory materials that is particularly advantageous with respect to the interaction of the components with each other. Such advantageous combinations may be completely unexpected with respect to the properties of the individual components.

According to another possible embodiment, the invention relates to a method for determining the interaction between a sensory material and another additional component, the method comprising (a) preparing a set of samples in which each sample contains the sensory material as a common component and in addition contains at least one other additional component, each sample differing from any other sample by at least one of the following properties:

(i) the identity of the additive component, (ii) the ratio of the sensory material as a common component to the additive component, or (iii) the physical state of the sensory material as a common component, (b) each sample is tested for a specific property to obtain a data set, (c) the data set is analyzed to measure or detect interactions between the components.

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Samples containing sensory materials are preferably tested depending on their use in the form of certain products, such as perfumes, air fresheners, deodorants, colognes, food products, confectionery or pharmaceutical preparations with a certain taste or smell. Preferred properties of sensory materials are the intensity and quality of the smell, the persistence of the smell, the rate of evaporation, solubility, the ability to partition between two environments, biological degradability, the absence of unpleasant taste, toxicity, efficacy, structure, color, appearance and physical or chemical stability. Any person skilled in the art will easily design tests for measuring the above-mentioned properties, for example, the tests described above for measuring pharmaceutical preparations. The intensity and quality of the smell can be measured, for example, using a so-called electronic nose, the relevant procedures are described in the publications 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 Elavors and Fragrances, Lyon 1989, Esomar, Amsterdam, 1989. Other properties, such as evaporation rate, solubility, partition between two environments and physical and chemical stability, can be measured by adapting the procedures outlined above for testing pharmaceuticals.

Agrochemicals

According to another possible embodiment of the invention, the invention relates to a set of samples, each of which contains as φφ φφ • φ · φ φ φφ φ φ

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4499994 Φ Φ • 99 ΦΦΦΦ common component agrochemical substance and in addition contains at least one other additional component, each of the samples differing from any other sample by any of the following properties:

(i) the identity of the additive, (ii) the ratio of the agrochemical as a common ingredient to the additive, or (iii) the physical state of the agrochemical as a common ingredient.

The term "agrochemical" means any substance used in agriculture, on a farm, in a field or in a residential area to improve the condition of a garden, crop, ornamental plant, shrub, vegetable or the like, or to control insects, weeds or fungi. Examples of suitable agrochemicals for this type of use include pesticides, herbicides, fungicides, insect repellents, fertilizers and growth promoters. A more detailed description of the various agrochemicals can be found in The Agrochemical Handbook (1987) 2nd edition, Hartley and Kidd, ed. The Royal Society of Chemistry, Nottingham, England.

Pesticides include chemical compounds and various substances intended to kill pests, such as mice and rats, and to repel wild animals, such as deer and marmots. They may include abamectin (acaricide), bifenthrin (acaricide), cyphenothrin (insecticide), imidacloprid (insecticide), and prallethrin (insecticide). Other examples of suitable pesticides for this use can be found in Crop Protection Chemicals Reference, 6th Edition, Chemical and Pharmaceutical Press, John Wiley & Sons Inc., New York, 1990, (1996) The Encyclopedia of Chemical

• »·4· » · * • « ·· ··· ·

Technology, 18 Kirk-Othomer (4th ed. 311-341, and Hayes et al., Handbook of Pesticide Toxicology, Academic Press, Inc., San Diego, CA, 1990.

Herbicides include selective and non-selective agents used to suppress plant growth or kill them. Examples of suitable herbicides include photosystem I inhibitors such as actifluorfen, photosystem II inhibitors such as atrazine, bleaching herbicides such as fluridone and difunone, chlorophyll biosynthesis inhibitors such as DTP, clethodim, sethoxydim, methylhaloxyfop, tralkoxydim and alachlor, antioxidative system disruptors such as paraquat, amino acid and nucleotide biosynthesis inhibitors such as phaseolotoxin and imazapyr, cell division inhibitors such as pronamide and plant growth regulator synthesis inhibitors such as dicamba, chloramben, dichlofop and ancymidol. Further examples of suitable herbicides can be found in the Herbicide Handbook, 6th edition, Weed Science Society of America, Champaign, II 1989, (1995) The

Encyclopedia of Chemical Technology, 13 Kirk-Othomer (4th ed. 73-136) and Duke, Handbook of Biologically Active Phytochemicals and Their Activities, CRC Press, Boča Raton, EL, 1992.

Fungicides include chemical substances that are applied to plants and crops and that selectively or non-selectively kill fungi. For use according to the invention, they may be systemic or non-systemic fungicides. Non-systemic fungicides include, for example, thiocarbamate and thiurane derivatives, such as ferbam, ziram, thiram and nabam, imides such as captan, folpet, captafol and dichlofluanid, aromatic hydrocarbons such as • * • » • 9 9 » · · · ·»·· • · ·» · · · · 9 9 9

9 9 9 9 9 9 9999 9 9 9 9 9

9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 9999 quintozene, dinocap and chloroneb, dicarboximides such as vinclozolin, chlozolinate and iprodione. Examples of systemic fungicides include, for example, inhibitors of mitochondrial respiration such as carboxin, oxycarboxin, flutolanil, fenfuram, mepronil and methfuroxam, inhibitors of microtubulin polymerization such as thiabendazole, fuberidazole, carbendazim and benomyl, inhibitors of sterol biosynthesis such as triforin, fenarimol, nuarimol, imazalil, triadimefon, propiconazole, flusilazole, dodemorph, tridemorph and fenpropidin and inhibitors of RNA biosynthesis such as ethirimol and dimethirimol, and inhibitors of phospholipid biosynthesis such as ediphenphos and iprobenphos. Further examples of suitable fungicides can be found in Torgeson, ed. Fungicides: An Advanced Treatise, vol. 1 and 2, Academie Press, lne., New York, 1967 and 1994 The Encyclopedia of Chemical Technology, 12 Kirk-Othomer (4th ed. 73-227).

Other components that can be processed into samples with agrochemicals include substances known to be useful with agrochemicals, such as inert components such as solvents, emulsifiers, wetting agents, dispersants, stabilizers, preservatives, sequestrants, colorants, flavors, or fragrances. Examples of suitable components for such compositions can be found in Stevens et al. 1993,

Pesticide Science 38, 103-122 and Adjuvants for Agrochemicals, ed. C. L. Foy, CRC Press, Boca Raton, Florida, 1992.

According to one embodiment, the sample assemblies, in which the common component is an agrochemical, can be ·· ·« ·♦ · 99 99

9 9 9 9 9 9 9 9 9 9

9 99 9 9 9 9 9 9 9

9 9 9 9 9 9 9999 9 9 9 9 9

9 9 9 9 9 9 9 9 9

99 99 9 99 9999 additional components of another agrochemical. This means that each sample may contain a larger number of agrochemicals, with a certain agrochemical being present in all samples as a common component. A set of such samples can be used to detect a beneficial or synergistic interaction between agrochemicals, for example to identify a combination of pesticides that is particularly advantageous due to the interaction between the components. Such advantageous combinations may be completely unexpected due to the properties of the individual components.

According to another possible embodiment, the invention relates to a method for measuring or detecting an interaction between components, the method comprising (a) preparing a set of samples, in which each sample contains an agrochemical as a common component and in addition contains at least one additional component, each sample differing from any other sample by at least one of the following properties:

(i) the identity of the additive, (ii) the ratio of the agrochemical as a common ingredient to the additive, or (iii) the physical state of the agrochemical as a common ingredient, (b) each of the samples is tested for a specific property to obtain a data set, (c) the data set is analyzed to measure or detect interactions between the ingredients.

Preferably, samples containing agrochemicals are tested for properties that are relevant to the use of these compositions as agrochemicals. A preferred property of agrochemicals is, for example,

Φ· φ« φφ · ·· <·· • · « · φφφ φφ·· ·Φ·Φ · · · · φφ φ • φ · φφφ φ φφφφ φφφφ φφφφ φφ · φφφφφφφφ their biodegradability, for example the rate of degradation due to chemical instability or microbial metabolism, and also the rate of penetration into the soil, efficacy, toxicity, duration of action or rate of evaporation. Such properties are directly related to solubility, especially solubility in water, partitioning of components between two volumes of the carrier medium and physical or chemical stability, which can be measured by the above-mentioned methods for measuring these properties in pharmaceutical compositions. The skilled person will easily design tests for measuring these properties. A summary description of such tests can be found in the publications of Somasundaram 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. 446, 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 Strategies for Pesticide Analysis, CRC Press, Boca Raton, FL 1992.

Consumer and industrial products

In another possible embodiment, the invention relates to a set of samples, in which each sample contains a common component, which is the active ingredient of the composition and at least one additional component, each sample differing from any other sample by at least one of the following properties:

(i) the identity of the additional component, (ii) the ratio of the common component to the additional component or ·* flfl flfl · fl flfl » · · · • · ·» «flflfl • flfl flflfl · flfl·· • flflfl · · fl • flflfl flfl · • fl • flfl · • fl fl • flfl • flfl • · flflfl · (iii) the physical state of the common component.

The term "consumer product" means a product that is not intended for absorption or ingestion by humans or other animals and yet contains a usable active ingredient. It can be cosmetic products, such as various emulsions or makeup, antiperspirants and deodorants, shaving and nail care products, hair care products, such as shampoos, hair dyes and conditioners, soaps, lubricants, adhesives, wetting agents and cleaning agents.

The term "industrial product" also includes a product that is not intended for absorption or ingestion by humans or other animals. It may include polymers, rubbers, plastics, industrial chemicals such as solvents, bleaches, inks, paints, flame retardants, antifreeze and de-icing agents for vehicles and aircraft, industrial lubricants, industrial adhesives, and construction materials such as cements and the like.

Any person skilled in the art can readily select active ingredients and inactive ingredients suitable for inclusion in consumer and industrial compositions so that the interaction between the active ingredient and the additional ingredients can be demonstrated or measured. Data relating to such interactions can assist in optimizing the composition of such compositions.

Active ingredients and inactive ingredients are well known in the literature. Active and inactive ingredients for cosmetic products are listed, for example, in (1993) The Encyclopedia of Chemical Technology, 7 Kirk-Othomer (4th ed. 572-619), M. G. de Navarre, The Chemistry and «» ·· 44 • * · 4 4 9

4 ·» 4 4

4 4 4 4 4 4

4 4 4 4 4

4« «« • 4

4« 4«

44

4 4 4

4 «44 4

4 4 4

44 4444

Manufacture of Cosmetics, D. Van Nostrand Company, Inc., New York, 1941, CTFA International Cosmetics Ingredient Dictionary and Handbook, 8th ed. CTFA, Washington, D. C., 2000, and A. Nowak, Cosmetic Preparations, Micelle Press, London, 1991. Active and inactive ingredients for use in hair care are listed in (1994) The Encyclopedia of Chemical Technology, 12 Kirk-Othomer (4th ed. 881-890), and Shampoos and Hair Preparations in ECT

1st ed., vol. 12, pp. 221-243, F. E. Wall. Active and inactive ingredients for soaps intended for hand and body washing are listed in (1997) The Encyclopedia of Chemical Technology, 22 Kirk-Othomer (4th ed. 297-396). Active and inactive ingredients for use in varnishes are listed in (1996) The Encyclopedia of Chemical Technology, 17 Kirk-Othomer (4th ed. 1049-1069) and Paint, ECT 1st ed., vol. 9, pp. 770-803, Η. E. Hillman, Eagle Paint and Varnish Corp. Active and inactive ingredients for use in consumer and industrial lubricants are listed in (1995) The Encyclopedia of Chemical Technology, 15 Kirk-Othomer (4th ed. 463-517), D. D. Fuller, Theory and practice of Lubrication for Engineers,

2nd ed., John Wiley & Sons, Inc., 1984, A. Raimondi and A. Z. Szeri, E. R. Booser, eds. Handbook of Lubrication, vol. 2, CRC Press Inc., Boca Raton, FL, 1983. Active and inactive ingredients for use in adhesives are listed in (1991) The Encyclopedia of Chemical

Technology, 1 Kirk-Othomer (4th ed. 445-465) and I. M. Skeist, ed. Handbook of Adhesive, 3rd ed. Van NostrandReinhold, New York, 1990. Active and inactive components in polymers are listed in (1996) The

Encyclopedia of Chemical Technology, 19 Kirk-Othomer (4th ed. 881-904). Active and inactive ingredients for use in rubber compositions are listed in (1997) • 4 · * · • · ·· 4 • 4 4 4 4 ·

4 4 · ·

The Encyclopedia of Chemical Technology, 21 Kirk-Othomer (4th ed. 460-591). Active and inactive ingredients for plastics are also listed in (1996) The Encyclopedia of Chemical Technology, 19 Kirk-Othomer (4th ed. 290-316). Active and inactive ingredients for use in the manufacture of industrial chemicals are listed in Ash et al., Handbook of Industrial Chemical Additives, VCH Publishers, New York 1991. Active and inactive ingredients for bleaches are listed in (1992) The Encyclopedia of Chemical Technology, 4 Kirk-Othomer (4th ed. 271-311). Active and inactive ingredients for use in inks are also listed in (1995) The Encyclopedia of Chemical Technology, 14 Kirk-Othomer (4th ed. 482-503). Active and inactive ingredients for dyes are listed in (1993) The Encyclopedia of Chemical Technology, 8 Kirk-Othomer (4th ed. 533-860). Active and inactive ingredients for use in flame retardants are listed in (1993) The Encyclopedia of Chemical Technology, 10 Kirk-Othomer (4th ed. 9301022). Active and inactive ingredients for antifreeze and deicing agents are listed in (1992) The Encyclopedia of Chemical Technology, 3 Kirk-Othomer (4th ed. 347-367). Active and inactive ingredients for use in cements are listed in (1993) The Encyclopedia of Chemical Technology, 5 Kirk-Othomer (4th ed. 564).

According to another embodiment, the invention relates to a method for measuring or detecting an interaction between components, the method comprising (a) preparing a sample array, each sample comprising a common component, which is an active ingredient of a consumer or industrial product, and at least

4· 44 4« 4 ·· *4 • 4 4 ) 4 4 4 4 4 4 4 • « ·» 4 · · 4 4 4 · • · · 4 4 4 4 4··4 4 · · 4 • · · 4 4 4 444

44 44 4 44 4444 one additional component, each sample differing from any other sample in at least one of the following characteristics:

(i) the identity of the additive component, (ii) the ratio of the common component to the additive component, or (iii) the physical state of the common component, (b) each of the samples is tested for a specific property to obtain a data set, (c) the data set is analyzed to measure or detect the interaction.

Sample preparation and test systems

The basic prerequisites for the preparation, processing and testing of samples are the following:

(1) a dispensing mechanism that allows the components to be added to separate locations in the sample assembly plate, such as wells in the plate. The dispensing mechanism is preferably automatic and computer-controlled so that at least one variable, such as the identity of the components and/or their concentration, can be varied, preferably two or more variables can be varied. For example, the addition of a common pharmaceutical agent and excipients to a sample well may involve the operation of a robot, as is generally known in the manufacture of pharmaceutical compositions. However, it is also possible to add the individual components to the respective wells manually, as desired. Such techniques are well known in the art.

(2) a testing mechanism for performing a test on each sample to determine one or more of its properties. This mechanism is also preferably automatic and computer controlled. The system preferably further comprises a mechanism for processing the samples after addition

9

9999 components. For example, after addition of the components, the samples may be mixed, ground, filtered, centrifuged, emulsified, or the solvent may be removed, for example by lyophilization, or the samples may be reconstituted, etc. The samples are preferably processed automatically and simultaneously.

Fig. 1 schematically illustrates the preparation of a sample array, its processing and its analysis for one or more properties, the storage of data and its analysis and the detection or measurement of the interaction or the demonstration that the interaction does not exist. The first stage involves the selection of sources of 2 components. That is, a common component and one or more additional components are selected in a certain concentration or in different concentrations. The common components or additional components are then added to a plurality of separate sample locations, for example, into the wells of plates, to form samples, intended for further processing, for example, by mixing, grinding, filtering, centrifuging, emulsifying or concentrating, evaporating or reconstituting to form a sample array 4_. Each sample in the assembly 4_ can be tested for one or more properties, in the next stage the data obtained is collected 6 for subsequent analysis 8. to measure or identify the interaction 9. or to demonstrate the absence of the interaction _9- For example, a common component is placed in the individual wells, which may be a pharmaceutical substance and additional components, for example excipients or other pharmaceutical substances in different amounts, at different pH, at different physical states and the like in solid or liquid form, thereby creating an assembly 4. of samples. Different samples containing different combinations of components can be processed and their properties demonstrated. Data obtained

4

4 • · · · • · · · ···· · · are stored and analyzed, preferably in a computer, whereby interactions between a common pharmaceutical ingredient and excipients or other pharmaceutical substances can be measured or demonstrated. The knowledge gained about the interactions can then be used to develop an optimal means for administering the pharmaceutical substance.

The automatic dispensing mechanism may dispense or add individual components in liquid, gel, foam, paste, emulsion, suspension, or solid form, such as powders, tablets, or pellets. Preferably, solids are added in the form of micropellets or microtablets prepared by micropelleting or microtabletting. Micropellets may be prepared using standard and pharmaceutical tabletting equipment with appropriate modification. Such equipment is known in the art and is described, for example, in Remington's Pharmaceutical Sciences, 18th Edition, Alfonso Gennaro, Mack Publishing Co. Easton, PA, 1995, chap. 92. The tabletting equipment preferably includes a small punch, for example, 0.156 cm to 0.469 cm in diameter. Any skilled person will readily make the appropriate modification. With the appropriate modification, the microtabletting equipment can prepare microtablets using almost any solid component. In the case where the component is an active ingredient, for example a pharmaceutical substance, it is advantageous to mix this substance with a compressible inert carrier, for example potassium chloride. The ratio of active ingredient to carrier is preferably 0.5 to 10 parts of active ingredient to 90 to 99.5 parts of carrier, the preferred ratio being 1 part of active ingredient to 99 parts of carrier. The weight of the microtablets is preferably in the range of 0.1 to 50 mg, in particular 1 to 10 mg and particularly preferably 5 mg. It is also advantageous for the finished microtablets to contain 1 to 100 μς of active ingredient, in particular 10 to 75 μρ and particularly preferably 50 μς. In the case where the component is an inactive ingredient, for example an excipient, it can be dispersed in an inert matrix as described above, or directly processed into pellets without the use of an inert carrier.

Another possible method for forming micropellets is a method in which a paste containing the test ingredient and an inert carrier is pressed into a mold, after which the paste is dried and the resulting pellet is removed. In this method, the pelletized ingredient is first homogenized with an inert carrier and a solvent. The inert carrier is preferably lactose or mannitol. The appropriate solvent can be easily selected by any person skilled in the art depending on the ingredient used. The solvent is preferably relatively volatile, in particular with a boiling point of 100 °C or lower, for example alcohols such as methanol or ethanol. The ratio of solvent to active ingredient and inert carrier in the mixture can range from 10:1 to 1:10, preferably 6:1 to 1:1 and especially 5:1 to 3:1. The test ingredient, solvent and inert carrier are homogenized to a paste and then the solvent is removed under reduced pressure, resulting in a dry powder. This powder is then mixed with another solvent, preferably water, to form a homogeneous paste, which is then pressed into molds. The mold dimensions range from 0.156 cm to 0.469 cm in depth, preferably 0.312 cm in depth, and from 0.078 to 0.312 cm in internal diameter, especially 0.195 cm. The pastes are allowed to dry for about 1 minute to 5 hours, preferably 5 minutes to 1 hour, usually 10 minutes, at a temperature in the range of 15 to 100 °C, preferably 20 to 30 °C, at a pressure of 1.3 to 130 kPa, preferably about 2.6 kPa. Preferably, the paste in the mold is allowed to dry for about • · · · · · · · · · minutes at room temperature under atmospheric pressure. The dry paste in the form of micropellets is then extruded from the mold, preferably using a tip with a diameter equal to or slightly smaller than the inner diameter of the mold. The finished micropellets can then be dried under reduced pressure, typically for 6 to 24 hours, preferably for about 12 hours at a temperature of 15 to 100°C, preferably at room temperature and at the above pressure.

A preferred automatic mechanism for adding the first components, preferably micropellets, to the sample wells typically includes containers for each component. The output from these containers is controlled so that each micropellet is delivered to a specific well in the sample assembly. Once the individual components are placed in the sample wells in the sample assembly, the sample can then be tested.

Fig. 2A and 2B describe in detail the system of the invention for preparing a sample array by depositing components in sample wells, processing the samples, performing tests on one or more properties to produce a data set that is collected, stored, and analyzed to measure or demonstrate an interaction or to demonstrate the absence of such an interaction. Fig. 2A and 2B relate to pharmaceutical agents with low water solubility as co-components and excipients as additional components, however, the systems shown in Fig. 2A and 2B are suitable for any of the active and inactive components listed above.

FIG. 2A shows a system by which a source of a common ingredient 10, for example a solid pharmaceutical • · is distributed.

substances and a source of additional solid component 12, for example an excipient, it is an automatic system for distributing said components to sample storage locations, in particular it is about storing micropellets in the wells of a 96-well plate, which is commonly available (Millipore, Bedford,

MA). In this way, a dry sample assembly 14 is created. The combination of the common component and the various additional components in various combinations is created using a standard computer program (for example, Matlab software, commonly available from Mathworks, Natick, Massachusetts). The combinations thus created can be stored, for example, in a Microsoft Excel program. In this program, a work program can be created to instruct the automatic distribution mechanism to prepare a sample assembly based on the various combinations created by the computer program. The work program can be created using a standard programming procedure to allow control of the automatic system. The work program combines the output from the computer program with a command for the automatic distribution mechanism. The automatic distribution mechanism then stores at least one common component, for example a pharmaceutical substance, and various additional components, for example excipients, in individual wells. The automatic distribution mechanism can store various amounts of individual components. Mechanisms of this type are known and commonly available (for example, Tecan Genesis, Tecan-US, RTP, North Carolina). Specific automated distribution mechanisms for solids can be easily obtained by modifying off-the-shelf robotic systems. The dry samples 14 thus obtained are then mixed with one or more solvents using a Tecan automated liquid pipetting system to obtain a set of 20 samples, each of which is a solution or

• ·

9 suspensions. The samples may be mixed during or after the solvent addition, but usually sufficient mixing is achieved by the addition of the liquid. If necessary, the suspensions may be filtered to separate the solid and liquid phases, thereby forming a filtrate set 22. To perform the filtration, the plate containing the suspension is placed on another plate containing the same number of wells, the positions of which correspond to the positions of the wells on the original plate. Centrifugation or vacuum is then used to force the liquid phase through the filter into the wells of the second filter plate. A suitable centrifuge is commercially available, for example from DuPont, Wilmington, DE. The individual filtrates can then be analyzed on the resulting plate.

Analysis of the filtrates can provide data on the solubility of the components, typically using equipment 24, which can be UV-Vis spectroscopy using readout devices such as the SpectraMax Plus (Molecular Devices, Sunnyvale, CA), GC, HPLC, and LC-MS. For GS, HPLC, and LC-MS, an automated pipetting station, such as the Genesis (Tecan) or any of the devices available from Gilson, Middleton, WI, is used to store the samples. Analytical devices for measuring stability 26 include, for example, UV-Vis spectroscopy, MS, GC, HPLC, or LC-MS. These devices are also modified for use for the purpose indicated. Analytical devices for measuring absorption 28 include the use of the Caco-2 cell line or Ussing chamber. It is known that the Caco-2 cell line is commonly used to measure absorption through the intestinal wall. Analytical devices are available that are specific to these assays, particularly the Tecan-US (cell growth). Ussing chambers are also widely used to measure intestinal wall permeability for

compounds. These are also commercially available devices, such as World Precision Instruments, Sarasota, Florida for absorption measurements. Metabolism measurement systems include P-450, microsomes, and lysosomes, which are available from various companies, such as In Vitro Technologies, 1450 South Rolling Road,

Baltimore, MD 21227, the devices are also described in Trouet A. et al., Methods in Enzymology, vol. 31, Academic Press, Inc., New York, 1987, pp. 287-313 and 323-329, in vivo assays can also be used to measure metabolism. Other analytical devices that can be used in this context are pH meters, ionic strength sensors, optical spectrometers, turbidity meters, calorimeters, infrared spectrometers, polarimeters, radioactive counters, conductivity meters, and heat of solution meters. The data 32 obtained is collected and stored, followed by analysis 34 to detect or measure interactions 36.

The data 32 is preferably stored in a computer using an appropriate program. Any skilled person can easily select the appropriate program. The samples are first analyzed using an appropriate device, as described above, to obtain a set of data relating to the property of interest in the sample. For example, a spectrophotometric analysis of each sample in ultraviolet light can be obtained using a Spectramax Plus™ device (Molecular Devices, Sunnyvale, CA). The data is typically stored according to the manufacturer's instructions. For example, data obtained with the Spectramax device described above is preferably collected and stored using the Softpro™ program (Molecular Devices). The stored data is then analyzed. Analysis 34 is • 0 • · 0 0 ·

0 0 00 0 0 can also be done using a computer program, such as Spotfire (Spotfire lne., Cambridge,

MA). The visualized data can be directly analyzed to obtain information about interactions 36, which can again be used to prepare optimized compositions. Otherwise, the data can be processed in any other way that can demonstrate complex interactions between a number of components or, conversely, demonstrate the absence of such interactions. Examples of suitable software include Spotfire, Matlab (Mathworks, Natick, Massachusetts), Statistica (StatSoft, Tulsa, Oklahoma). All resulting analytical files are saved in a conventional manner.

Fig. 2B shows essentially the same procedure for liquid co-components 38, such as liquid pharmaceuticals and liquid excipients 40. The liquid components can be stored using an automatic liquid dispensing mechanism to form a sample assembly 42. The solvent is then evaporated under reduced pressure to obtain dry samples 44. The dry samples 44 can also be obtained from the assembly 42 by lyophilization or other solvent removal methods. In particular, commercially available lyophilization equipment can be used. The dry samples 44 can be reconstituted into reconstituted samples 46 by adding one or more solvents using an automatic liquid pipetting device as described above. The reconstituted samples 46 can then be tested as described above for the scheme of Fig. 2A.

The invention has been described in connection with a number of possible embodiments, but it is quite obvious that a number of changes and modifications could be proposed, as well as • · ·· ·♦ · • · · · · · · · · · · »φ 4 9 9 4 • · · · · · 9 4 444

4 9 9 4 4 9

94 • 4 9 ·

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4444 falling within the scope of the invention. For this reason, the invention cannot be limited to the described embodiments.

The practical embodiment of the invention will be illustrated by the following examples, which are not intended to limit the scope of the invention.

Examples of embodiments of the invention

Griseofulvin is a commonly available antibiotic with a complex structure based on benzofuran and cyclohexane. This antibiotic was chosen as a common component for use in a sample set designed to investigate advantageous combinations of excipients that would allow the active substance to be solubilized in an aqueous environment more effectively than is currently the case in commonly available pharmaceutical compositions containing griseofulvin. The compound is commonly supplied for oral administration. Children are usually given a dose of 6.6 mg/kg for a body weight of up to 50 kg, and a typical dose for adults is 330 mg daily. The compound is practically insoluble in water, sparingly soluble in polar organic solvents such as ethanol, methanol, acetone and acetic acid, and soluble in dimethylformamide and dioxane. The low solubility in water limits bioavailability. The commonly supplied composition, used as a standard, consists of microcrystals of the said substance, partly dissolved in a carrier of the polyethylene glycol 8000 type and partly dispersed in other inert excipients such as corn starch, lactose, magnesium stearate and sodium lauryl sulfate.

4 •• 4 4 4 4 4

444 *444444 4 4 • 4 4 4 4 4 4 4 ·· · 44 4444

Using the sample set of the invention, samples were prepared, each containing griseofulvin and a mixture of various excipients, and these samples were then systematically analyzed to identify a combination of excipients that could be shown to interact with the active ingredient to increase its solubility in water compared to the solubility in conventionally supplied formulations.

Table 2 below lists GRAS (Generally Regarded as Safe) excipients, all of which were obtained from Sigma-Aldrich Fine Chemicals or BASF. These were used as excipients in the following examples.

Table 2. Excipients used in the examples (1) gum arabic (branched polymer of galactose, rhamnose, arabinose and glucuronic acid, molecular weight approximately 25,000) (2) β-cyclodextrin (cycloheptaamylose) (3) sodium dodecyl sulfate (SDS) (4) sodium docusate (bis[2-ethylhexyl ester] or dioctyl sulfosuccinate of sulfobutanedicarboxylic acid) (5) sodium benzethonium chloride (6) benzalkonium chloride (alkyldimethylbenzylammonium chloride) (7) cetrimide (dodecyltrimethylammonium bromide) (8) oleic acid (cis-9-octadecenecarboxylic acid) (9) sodium tartrate dihydrate (10) polyethylene glycol 1000 (11) polyethylene glycol 10000 (12) polyvinyl alcohol ·· · • ·

(13) Poloxamer ^R 237 (polyoxyalkylene oxide chain copolymer) (14) polyoxyethylene 40 stearate (15) polyoxyethylene 100 stearate (16) Tween 80 ^R (polyoxyethylene sorbitan) (17) Brij 35 ^r (23 lauryl ether) (18) Brij 97 ^R (10 oleyl ether)

Samples were prepared, processed and analyzed as described in the following examples.

Example 1. Preparation and identification of griseofulvin-containing formulations with increased solubility

Preparation of formulations with improved solubility

Each of the 18 excipients was prepared as 3 stock solutions in water at different concentrations, namely 0.015 mg/ml, 0.15 mg/ml and 1.5 mg/ml, thus 54 stock solutions were prepared in total. 3 different excipients were added to each sample well in the form of one of their three stock solutions. This means that 3 of the 18 excipients used were added to each well of a 250 μΐ Millipore 96 filter plate with a polytetrafluoroethylene membrane at the bottom of each well with a pore size of the membrane of 1 μη in an amount of 20 μΐ using a Tecan ^R liquid handling device, a Genesis liquid handling device (Tecan-US, RTP, NC). The number of possible combinations of 3 different excipients selected from the stock solutions with 3 different concentrations can be calculated as • · · fl flfl • fl flfl • flfl

• » • flfl · flflfl flfl · • tflflfl fl · · fl > · · · · • flfl ···· !

3! x (18-3) !

A total of 22,032 samples were prepared (out of a total of 66,096 samples for n = 3), 32 samples were stored per plate in a total of 689 plates. All changes and combinations of excipients, their concentrations and griseofulvin were created using the MatLab computer program. The combinations thus obtained were stored in Microsoft Excel, and a work program was created in this program, which controlled the automatic distribution mechanism in such a way as to store all possible combinations that were created by the MatLab program. The Genesis liquid handling device was used as the automatic distribution mechanism, as already mentioned above. The work program combines the output from the MatLab program with the relevant commands for the distribution mechanism according to the manufacturer's instructions to create a program that is directly readable by the Genesis device. In this way, this device stores 20 μΐ of a sample containing griseofulvin and dioxane at a concentration of 0.15 mg griseofulvin/ml dioxane together with various combinations and concentrations of excipients based on the MatLab program. When adding the individual components to the well, sufficient self-mixing of the individual samples occurred.

Sample tests

All solvents were removed by lyophilization, then 200 μΐ of water was added to each dry well of the plate using the same equipment. Plates

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44 *4 4 · 4 • 4 · 4 * · 4 4 444 »··

4 4 • 4 44

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4444 were incubated for 1 hour at 37°C in an Innova 4200 incubator (New Brunswick Scientific, Edison, NJ). The plates were then centrifuged to remove any undissolved solids as described above. A Sorvall RT6000B centrifuge (DuPont, Wilmington, DE) was used for this purpose. The filtrate from each well was collected in another 96-well ultraviolet-transparent plate (Corning, Corning, NY) for measurement with a reader at 290 nm (SpectraMax Plus, Molecular Devices, Sunnyvale, CA).

Griseofulvin as such, without any excipient, was subjected to tests to determine the basic solubility of this substance.

Results

The solubility, measured as the absorbance of the filtrates at 290 nm, is shown in Fig. 3A for 3500 distinct samples. The baseline absorbance of 0.3 units is for the commercially available griseofulvin formulation Fulvicin (Schering-Plough). Most of the samples had improved solubility compared to the commercially available formulation. Approximately 1200 samples in Fig. 3A had significantly higher solubility than the rest of the samples.

Samples that showed a 100% increase in solubility compared to griseofulvin alone as measured by absorbance were identified as the best samples. From Fig. 3A, 5 such samples were identified, the compositions of which are given in Table 3 below. The samples are designated TP1-TP5.

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Table 3. Top 5 griseofulvin-containing products

TP1 TP2 TP3 TP4 TP5 Exc. % wt. Exc. % wt. Exc. % wt. Exc. % wt. Exc. % wt. (10) 83.3 (10) 90 (10) 90 (11) 83.3 (12) 90 (2) 8.3 (3) 1 (14) 9 (1) 8.3 (5) 9 (14) 8.3 (14) 9 (1) 1 (7) 8.3 (10) 1

Exc. = excipient

Figure 3B shows the standard deviation for each of the 3500 samples, each sample was tested in triplicate. Most samples gave reproducible results, so the standard deviations were less than 10%.

The samples can be further optimized using a similar testing system as described above by making further changes in the concentration of each component in the individual samples.

Example 2. Testing and evaluation of the best compositions on a larger scale The compositions identified in Example 1 were evaluated on a laboratory scale in quantities 10,000 times larger than in the case of the 96-well microassay. Each of the components was weighed into a scintillation vial and mixed there with the other components in the solid state. In addition, 30 mg of griseofulvin was added each time. Each of the samples was prepared in triplicate.

• · · · · »11»

Samples

TPI-1: 300 mg PEG 1000, 30 mg beta-cyclodextrin, 30 mg polyoxyethylene 40 stearate

TPI-2: 300 mg PEG 1000, 30 mg SDS, 3 mg polyoxyethylene 40 stearate

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

TPI-4: 300 mg PEG 10000, 30 mg gum acacia, 30 mg cetrimide

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

15 ml of water was added to each well and the samples were incubated for 1 hour at 37°C and then filtered through a 0.2 μm filter to remove any undissolved solids. The filtrates were measured using a UV spectrometer at 290 nm in a 1 cm deep silicon cuvette.

The commonly available Fulvicin preparation containing 165 mg griseofulvin in tablet form was ground into a powder and a portion of 30 mg griseofulvin was tested in the same way as the other samples for comparison.

Results

The results of the above laboratory tests are shown in the form of a graph in Fig. 4 as absorbance at 290 nm, showing the average values and standard deviations for 3 measurements. It is clear that an increase in solubility of up to 300% was achieved, measured under ultraviolet light and compared to the commercially available formulation. For all 5 formulations from Example 1, which were identified by microplate assays, an increase in solubility was demonstrated in the laboratory tests compared to the commercially available formulation, demonstrating that the microtest results can be transferred to the laboratory scale.

Example 3. Evaluation of each excipient individually

In order to determine the effect of each excipient on the solubility of griseofulvin, 3 of the samples from Example 1, namely samples TPI-1 to TPI-3, were subjected to further tests on a laboratory scale such that the new samples contained (1) only one of the three excipients or (2) two of the three excipients in various combinations, for example excipient 1 and 2, 2 and 3 or 1 and 3. The solubility of each sample was then measured in the same manner as above when measuring the absorbance at 290 nm to determine solubility.

The solubilities for the modified samples are shown in Figures 5, 6 and 7 as ratios to the original samples. It is important to note that some of the derived samples have higher or lower solubilities than the original sample identified in Example 1, but the results refer to the relative absorbance of the composition from Example 1 and not the absolute absorbance.

In Fig. 5 it is clear that the excipient 14, which is polyoxyethylene 40 stearate and which is present in a small amount in the original TPI-3 composition as evident from the section of the disc on the left below the graph, can provide a substantial increase in solubility, which can be further increased by the excipient 10, which is PEG 1000. This means that in • · • *

In the case of solubility, a positive interaction between excipient 14 and griseofulvin was demonstrated.

As can be seen from Figure 5, excipient 14 was the only significant excipient in TPI-3 and the addition of excipient 10, PEG 1000, and excipient 1, gum acacia, had no further effect on overall solubility. The addition of excipient 2, beta-cyclodextrin, actually reduced the overall solubility of griseofulvin in TPI-1, as can be seen from Figure 6, thus demonstrating an antagonistic interaction between the excipients in terms of solubility.

In contrast, it is clear from Fig. 7 that in the case of excipient 3 SDS, excipient 10, PEG 1000 and excipient 14, which is polyoxyethylene 40 stearate, a synergistic interaction was achieved in the case of griseofulvin solubility, which was significantly increased.

Example 4. Comparison of dissolution rates under simulated conditions according to the US Pharmacopeia

The dissolution rate of the TPI-2 formulation of Example 1 and a commercially available pharmaceutical formulation containing 165 mg of griseofulvin were compared on a laboratory scale using 1000 ml of deionized water in a 1000 ml Erlenmeyer flask at 37°C with a stirring speed of 300 rpm using a 3.7 cm magnetic stirrer. The dissolution rate for each formulation was determined separately. Each formulation was added to the stirred deionized water and 1 ml aliquots were then withdrawn at 0 seconds, 30 seconds, 1 minute, 3 minutes, 6, 10, 15,

25, 40 and 50 minutes. Each aliquot was placed in a 1.5 ml Eppendorf tube, centrifuged at room temperature for 10 seconds at 14,000 rpm to remove undissolved solids, and then the absorbance in ultraviolet light was measured at 290 nm using a 1 cm deep silicon cuvette.

Results

The dissolution rate is shown in Fig. 8. It is clear that in the case of the TPI-2 formulation, a higher dissolution rate and higher solubility were found compared to the commonly supplied Fulvicin formulation, which further confirms that microtests can indeed find the best combinations for pharmaceutical formulations.

The results therefore demonstrate the effectiveness of assays with sample sets and provide guidance on how to evaluate results with a high degree of reproducibility.

The application generally describes the important features of the invention.

It is obvious that many modifications could be made or other embodiments could be devised, all of which fall within the scope of the invention. The invention should not, therefore, be limited to the embodiments described.

Claims (122)

PATENTED 1. A set of samples, each sample containing a common component and at least one additional component, characterized in that each sample differs from any other sample in at least one of the following properties: (i) the identity of the additional component, (ii) the ratio of the common component to the additional component, or (iii) the physical state of the common component. 2. A sample assembly according to claim 1, characterized in that it contains a pharmaceutical substance, a food supplement, an active substance for alternative medicine or a nutrient as a common component. 3. The sample assembly according to claim 1, characterized in that the amount of the common component contained is less than 100 mg. 4. The sample assembly according to claim 1, characterized in that the amount of the common component contained is less than 1 mg. 5. The sample assembly according to claim 1, characterized in that the amount of the common component contained is less than 100 μς. 6. The sample assembly of claim 1, wherein the amount of the common component contained is less than 100 ng. fcfc · 7. The sample assembly of claim 1, wherein the additional component improves the solubility or dissolution of the common component. 8. The sample set according to claim 2, characterized in that it contains, as a pharmaceutical substance, food supplement, active substance for alternative medicine or nutrient, a compound effective upon topical, transdermal or intradermal administration, administration into the lungs, via the mucous membranes or into the eye. 9. The sample assembly of claim 2, wherein the additional component alters the absorption rate, bioavailability, metabolism, or other pharmacokinetic or pharmacological property of the pharmaceutical substance, food supplement, alternative medicine active ingredient, or nutrient. 10. The sample assembly of claim 9, wherein the additional component is a bioadhesive excipient, a bioadhesive coating, an excipient for increasing the solubility or dissolution rate of the common component, or an encapsulating substance. 11. The sample assembly of claim 1, characterized in that it contains at least 24 samples. 12. The sample assembly of claim 1, characterized in that it contains at least 48 samples. 13. The sample assembly of claim 1, comprising at least 96 samples. 14. A method of measuring or demonstrating an interaction between components, comprising (a) preparing a set of samples, each sample comprising a common component and at least one additional component, each sample differing from any other sample by at least one of the following properties: (i) the identity of the additive component, (ii) the ratio of the common component to the additive component, or (iii) the physical state of the common component, and (b) each sample shall be tested for one or more properties. 15. The method of claim 14, wherein the common ingredient is a pharmaceutical substance, a food supplement, an active ingredient for alternative medicine, or a nutrient. 16. The method of claim 14, wherein the determined property is absorption, bioavailability, toxicity, metabolic profile, efficacy, stability, solubility, dissolution, partition between two environments, refractoriness, appearance, mouthfeel, release rate, dispersion rate, rheological properties, permeability, compressibility, compressibility, flowability, color, taste or odor. 17. The method according to claim 14, characterized in that testing all samples for a specified property produces a data set. 18. The method of claim 17, wherein the obtained data set is analyzed to detect or measure the interaction. 19. The method of claim 17, wherein the data set is analyzed to demonstrate the absence of interaction. 20. The method of claim 14, wherein the sample assembly is prepared and subjected to testing in an automated manner for preparing and performing the tests. 21. The method of claim 19, wherein the data set is analyzed by a computer. 22. The method of claim 14, wherein the amount of the common component is less than 100 mg. 23. The method of claim 14, wherein the amount of the common component is less than 1 mg. 24. The method of claim 14, wherein the amount of the common component is less than 100 µg. 25. The method of claim 14, wherein the amount of the common component is less than 100 ng. 26. The method of claim 14, wherein the sample set comprises at least 24 samples. 4 4 ·♦ 44 4 4 4 * 4 4 4 4 4 4 4444 27. The method of claim 14, wherein the sample set comprises at least 48 samples. 28. The method of claim 14, wherein the sample set comprises at least 96 samples. 29. The method of claim 14, characterized in that at least 1000 samples are tested daily. 30. A method of testing or optimizing one or more properties of a composition containing an active ingredient, characterized in that (a) a set of samples is prepared, in which each sample contains the active ingredient and at least one additional ingredient, each sample differing from any other sample by at least one of the following properties: (i) the identity of the additive, (ii) the ratio of the active ingredient to the additive, or (iii) the physical state of the active ingredient, (b) each sample is tested for at least one property to produce a result for each individual sample, and (c) the result for each sample is compared to the baseline or control for that property to produce a result for that sample. 31. The method according to claim 30, characterized in that the active ingredient is a pharmaceutical substance, a food supplement, an active substance for alternative medicine or a nutrient. • 9 • · 9· · · 9 · 9 · 9 • 9 9 9 9 9 9999999 « « ·*·· 99 9 999 ·· 9 9 9 9 · 999999 32. The method of claim 30, wherein the determined property is absorption, bioavailability, toxicity, metabolic profile, efficacy, stability, solubility, dissolution, partition between two environments, refractoriness, appearance, mouthfeel, release rate, dispersion rate, rheological properties, permeability, compressibility, compressibility, flowability, color, taste or odor. 33. The method of claim 30, wherein a data set is obtained by testing each sample for a particular property and comparing the result for that property with a baseline value or control sample. 34. The method according to claim 30, characterized in that the preparation of the sample set and the performance of the tests are carried out using automated devices for preparing samples and performing tests. 35. The method according to claim 33, characterized in that the resulting data set is analyzed by a computer. 36. The method of claim 30, wherein the amount of active ingredient is less than 100 mg. 37. The method of claim 30, wherein the amount of active ingredient is less than 1 mg. 38. The method of claim 30, wherein the amount of active ingredient is less than 100 μς. 0 0 • 0 0 0·· 00 0 0 0000000 0 0 • 0 0 0 0 0 00 0 00 0000 39. The method of claim 30, wherein the amount of active ingredient is less than 100 ng. 40. The method of claim 30, wherein the sample set comprises at least 24 samples. 41. The method of claim 30, wherein the sample set comprises at least 48 samples. 42. The method of claim 30, wherein the sample set comprises at least 96 samples. 43. The method of claim 30, wherein at least 1000 samples are tested daily. 44. A system for measuring or detecting interaction between components, comprising (a) a set of samples, each sample comprising a common component and at least one additional component, each sample differing from any other sample by at least one of the following properties: (i) the identity of the additive component, (ii) the ratio of the common component to the additive component, or (iii) the physical state of the common component, and (b) testing equipment to perform tests on each sample for one or more of its properties. 45. The system of claim 44, further comprising a mechanism for feeding each sample separately from the sample array to the testing device. 0 0 0 0 0 0 4 00 00 0 0 0 · 0 0 0 0 0 0 0 0 0 0 0 00 0000 46. The system of claim 44, wherein the common component is a pharmaceutical substance, a food supplement, an active ingredient for alternative medicine, or a nutrient. 47. The system of claim 44, wherein the test device is suitable for testing properties such as absorption, bioavailability, toxicity, metabolic profile, efficacy, stability, solubility, dissolution, partition between two environments, refraction, appearance, mouthfeel, release rate, dispersion rate, rheological properties, permeability, compressibility, compressibility, flowability, color, taste or odor. 48. The system of claim 44, further comprising an automated system for preparing samples and subjecting the samples to testing. 49. The system of claim 47, further comprising a computer for analyzing the obtained data set. 50. The system of claim 44, wherein the amount of the common component is less than 100 mg. 51. The system of claim 44, wherein the amount of the common component is less than 1 mg. 52. The system of claim 44, wherein the amount of the common component is less than 100 pg. 9 9 9999 99 9 9 99 9 9 9 · 99 9 9 99 99 9 9 9 9 9 9 9 9 9 9 9 9 9 99 99 99 9 9 9 · • · 9 9 9 · · • 9 9 9 • ·9 9999 53. The system of claim 44, wherein the amount of the common component is less than 100 ng. 54. The system of claim 44, wherein the sample array comprises at least 24 samples. 55. The system of claim 44, wherein the sample array comprises at least 48 samples. 56. The system of claim 44, wherein the sample array comprises at least 96 samples. 57. A set of samples, characterized in that each sample contains a sensory material as a common component and in addition contains at least one additional component, each sample differing from any other sample by at least one of the following properties: (i) the identity of the additional component, (ii) the ratio of the sensory material as a common component to the additional component, (iii) the physical state of the sensory material as a common component. 58. The sample assembly of claim 57, wherein the amount of sensory material as a common component is less than 100 mg. 59. The sample assembly of claim 57, wherein the amount of sensory material as a common component is less than 1 mg. Φ® ·» ΦΦ · 49 Φφ ΦΦΦΦΦ Φ Φ Φ 9 9 9 ΦΦΦΦ φφφφ 4 4 Φ Φ Φ Φ ΦΦΦ Φ ΦΦΦΦ ΦΦΦ φ ΦΦΦΦ ΦΦΦ Φ Φ ΦΦ ΦΦ Φ ΦΦΦΦΦΦ 60. The sample assembly of claim 57, wherein the amount of sensory material as a common component is less than 100 µg. 61. The sample assembly of claim 57, wherein the amount of sensory material as a common component is less than 100 ng. 62. Report samples according to claim 57, in y sign it is you too m, that contains at least 24 samples. 63. Report samples according to claim 57, in y sign it is it is 1 m, that contains at least 48 samples. 64 . Report samples according to claim 57, in y sign it is it's three m, that contains at least 96 samples. 65. A method of measuring or detecting an interaction between a sensory material and another component, comprising (a) preparing a sample array, each sample comprising a sensory material as a common component and further comprising at least one additional component, each sample differing from any other sample by at least one of the following properties: (i) the identity of the additive component, (ii) the ratio of the sensory material as a common component to the additive component or • · · flfl flfl fl flfl • fl flfl • · · fl flfl · • fl flfl fl · • flflfl • fl flfl fl flfl fl • · fl • flfl • flfl flfl · · · · (iii) the physical state of the sensory material as a common component and (b) each of the samples shall be tested for a specific property. 66. The method of claim 65, wherein the monitored property is odor quality, evaporation rate, solubility, partitioning between two environments, biodegradability, odor, taste, absence of odor or taste, toxicity, efficacy, structure, color, appearance, or physical and chemical stability. 67. The method of claim 65, wherein each sample is subjected to testing for a particular property to produce a data set. 68. The method of claim 67, wherein the data set is analyzed to detect or measure an interaction. 69. The method of claim 67, wherein the data set is analyzed to detect the absence of interaction. 70. The method according to claim 65, characterized in that the preparation of samples and the subjection of samples to tests are carried out by an automatic device for preparing samples and for performing tests. 71. The method of claim 69, wherein the data set is analyzed by a computer. 4 4 9 9 9 9 9999 * 9 • 4 9 ·· ·· Φ 4 9 9 9 9 4 ΦΦΦ • Φ · •Φ ΦΦΦΦ 72. The method of claim 65, wherein the amount of sensory material as a common component is less than 100 mg. 73. The method of claim 65, wherein the amount of sensory material as a common component is less than 1 mg. 74. The method of claim 65, wherein the amount of sensory material as a common component is less than 100 µg. 75. The method of claim 65, wherein the amount of sensory material as a common component is less than 100 ng. 76. The method of claim 65, wherein the array comprises at least 24 samples. 77. The method of claim 65, wherein the array comprises at least 48 samples. 78. The method of claim 65, wherein the array comprises at least 96 samples. 79. The method of claim 65, wherein at least 1000 samples are analyzed daily. 80. A set of samples, characterized in that each sample contains an agrochemical substance as a common component and in addition contains at least one additional component, each sample differing from 9 9 99 9 9 9 9 9 9 99999 9 » • · · 9 9 9 9 9 9 9 any other sample with at least one of the following properties: (i) the identity of the additive, (ii) the ratio of the agrochemical as a common ingredient to the additive, or (iii) the physical state of the agrochemical as a common ingredient. 81. The sample assembly of claim 80, wherein the amount of agrochemical as a common component is less than 100 mg. 82. The sample assembly of claim 80, wherein the amount of agrochemical as a common component is less than 1 mg. 83. The sample assembly of claim 80, wherein the amount of agrochemical as a common component is less than 100 μς. 84. The sample assembly of claim 80, wherein the amount of agrochemical as a common component is less than 100 ng. 85. The sample assembly of claim 80, wherein the assembly comprises at least 24 samples. • · • · 9 99 ··· ··· · « « • · · ···· ·· • · ··· ··«···· · · ► ·· · ·· ····< contains at least contains at least 86. The sample assembly of claim 80, wherein there are 48 samples. 87. The sample assembly of claim 80, wherein there are 96 samples. 88. A method of measuring or detecting an interaction between components, characterized in that (a) a set of samples is prepared, in which each sample contains as a common component an agrochemical substance and in addition contains at least one additional component, each sample differing from any other sample by at least one of the following properties: (i) the identity of the additive, (ii) the ratio of the agrochemical as a common ingredient to the additive, or (iii) the physical state of the agrochemical as a common ingredient, and (b) each sample shall be tested for a specific property. 89. The method of claim 88, wherein the property under investigation is biodegradability, efficacy, solubility, stability, or partitioning between two environments. 90. The method of claim 88, wherein testing each sample for a particular property produces a data set. • · §4 ·· 91. The method of claim 90, wherein the data set is analyzed to detect or measure an interaction. 92. The method of claim 90, wherein the data set is analyzed to demonstrate the absence of interaction. 93. The method according to claim 88, characterized in that the preparation of the sample set and the performance of the tests are carried out by an automatic device for preparing samples and for performing tests. 94. The method of claim 91, wherein the data set is analyzed by a computer. 95. The method of claim 88, wherein the amount of agrochemical as a common ingredient is less than 100 mg. 96. The method of claim 88, wherein the amount of agrochemical as a common ingredient is less than 1 mg. 97. The method of claim 88, wherein the amount of agrochemical as a common component is less than 100 μς. 98. The method of claim 88, wherein the amount of agrochemical as a common component is less than 100 ng. 99. The method of claim 88, wherein the sample set comprises at least 24 samples. 100. The method of claim 88, wherein the sample set comprises at least 48 samples. 101. The method of claim 88, wherein the sample set comprises at least 96 samples. 102. The method of claim 88, wherein at least 1000 samples are analyzed daily. 103. A set of samples, characterized in that each sample contains as a common component the active ingredient of a consumer product or industrial product and in addition contains at least one additional component, each sample differing from any other sample by at least one of the following properties: (i) the identity of the additional component, (ii) the ratio of the common component to the additional component, or (iii) the physical state of the common component. 104. The sample assembly of claim 103, wherein the amount of the common component is less than 100 mg. 105. The sample assembly of claim 103, wherein the amount of the common component is less than 1 mg. 106. The sample assembly of claim 103, wherein the amount of the common component is less than 100 µg. ·· · · ··· ·· ·· • · · β ·«· · · · · 107. The sample assembly of claim 103, wherein the amount of the common component is less than 100 ng. 108. The sample assembly of claim 103, comprising at least 24 samples. 109. The sample assembly of claim 103, comprising at least 48 samples. 110. The sample assembly of claim 103, comprising at least 96 samples. 111. A method of measuring or detecting an interaction between components, characterized in that (a) a set of samples is prepared, in which each sample contains a common component, which is an active ingredient of a consumer product or an active ingredient of an industrial product and in addition at least one additional component, each sample differing from any other sample by at least one of the following properties: (i) the identity of the additive component, (ii) the ratio of the common component to the additive component, or (iii) the physical state of the common component, and (b) each of the samples shall be tested for a specific property. 112. The method according to claim 111, characterized in that the monitored property is biological. 4» · • ·· · · • · 9 9 9 9 • 9 · 9 9 9 9999999 9 Λ degradability, toxicity, efficacy, solubility, stability, partition between two phases, compressibility, compressibility, odor, absence of odor or flowability. 113. The method of claim 111, wherein the tests for a certain property of the sample produce a data set. 114. The method of claim 113, wherein the data set is analyzed to detect or measure an interaction. 115. The method of claim 113, wherein the data set is analyzed to demonstrate the absence of interaction. 116. The method according to claim 111, characterized in that the preparation of the sample set and the performance of the tests are carried out by an automatic device for preparing the sample set and for performing the tests. 117. The method of claim 114, wherein the data set is analyzed by a computer. 118. The method of claim 111, wherein the amount of the common component is less than 100 mg. 119. The method of claim 111, wherein the amount of the common component is less than 1 mg. 120. The method of claim 111, wherein the amount of the common component is less than 100 μς. 121. The method of claim 111, wherein the amount of the common component is less than 100 ng. 122. The method of claim 111, wherein the array comprises at least 24 samples. 123. The method of claim 111, wherein the array comprises at least 48 samples. 124. The method of claim 111, wherein the array comprises at least 96 samples. 125. The method of claim 111, wherein at least 1000 samples are tested daily.