JP2004506902A - Test unit for stable compound production and production method - Google Patents

Abstract

The present invention comprises the following components:
-In the dispersion medium, at least one active ingredient, poorly soluble or insoluble,
A test unit for finding and / or confirming a stable formulation containing at least one formulation aid-dispersion medium, and, suitably, at least one solvent, wherein the test The invention relates to a test unit in which the unit has a robot with at least one robot arm for addressing a matrix of positions on a support, wherein the mixing chamber is incorporated in the robot arm. The invention further provides that each of the n formulations is present at some known position of the m positions on the support, wherein n and m are both greater than 2, or Identify a method of making an array containing n formulations where equal natural numbers and m is greater than or equal to n, and an array containing n formulations and a stable formulation. And / or use of the array to find out and a test unit device for producing the array.

Description

ユビヌル Ｔ１５０
化学名：
２，４，６−トリアニリノ−ｐ−（カルボ−２’−エチルヘキシル−１’−オキシ）−１，３，５−トリアジン
【００８２】
下記の表１は、試験した配合助剤と相当する配合物中の有効成分の粒度を示す。
【００８３】
【表１】

【表２】

【表３】

【００８４】
実施例２：多種の有効成分に対する１種の配合助剤（ゼラチンＢ１００）の試験に関し、沈殿による懸濁液の製造
−７ｇ／ｌの濃度でのゼラチンＢ１００水溶液の製造；及び
−１０ｇ／ｌの濃度での有効成分のアセトン溶液の製造；
−０．９ｍｌのゼラチン溶液をハミルトンシリンジに取り；
−有効成分溶液０．１ｍｌをハミルトンシリンジに取り；
−両溶液を廃棄物容器に排出し（濯ぎ工程）、次いで、同量のゼラ
チン溶液と有効成分溶液をシリンジに取り；
−両溶液を同時に９：１容量比（ゼラチン溶液：有効成分溶液）で
混合室に供給し、その中で混合し；
−得た混合物を標準微小滴定受皿の溜め（区画）に通し；
−有効成分を含むシリンジを１０ｍｌのアセトンで３度濯ぎ、アセ
トンを全体の装置に通すことによって、供給路と排出路及び混合
室を濯ぎ洗い、それによって、同じ配合助剤、ゼラチン、及び他
の有効成分での、他の配合物を製造し、他の微小滴定受皿の溜め
に供給することができる；
−約１時間後、配合物中の有効成分の粒径をファイバーオプチック
準弾性光散乱（ＦＯＱＥＬＳ）によって測定した、−有効成分が
沈降している可能性があるため、測定前５分間に、配合物の典型
的な粒度分布を得るため、サンプルをマグネチックスターラーで
注意深く攪拌した。
−各測定後毎に、ＦＯＱＥＬＳ検出器を水で、次いでアセトンで、 続
いてもう１度水で濯ぎ洗いした。
並列化、かつ自動化された１８個の得られた配合物の粒度測定及び並列化、かつ自動化された配合物の製造は平行して、即ち、先の粒度の測定の前でも次の沈殿が起っているように行われる。
【００８５】
実施例２として製造した配合物における各種の有効成分とその測定粒度を、下表に示す。
【００８６】
【表４】

【表５】

【表６】

【００８７】
実施例３：１種の有効成分（ビタミンＡパルミテート）に対する多数配合助剤の試験に関し、エマルションの製造
−１５ｇ／ｌの濃度を有する選択した配合助剤（乳化剤）水溶液の
製造；
−１０ｇ／ｌの濃度を有する有効成分ビタミンＡパルミテートの
オリーブ油溶液の製造
−９ｍｌの乳化剤溶液をハミルトンシリンジに取り；そして
−ビタミンＡパルミテート溶液１ｍｌをハミルトンシリンジに取
り；
−シリンジ中の両溶液を廃棄物容器に排出し（濯ぎ工程）、次いで、
同量の乳化剤溶液とビタミンＡパルミテート溶液を再びシリン
ジに取り、
−両溶液を同時に９：１容量比（乳化剤溶液：ビタミンＡパルミ
テート溶液）で混合室に供給し、その中で混合し；
−得た混合物（エマルション）を１５ｍｌのガラス反応管中に通し；
−乳化剤溶液を含むシリンジを１０ｍｌの水で３度濯ぎ、水を全体
の装置に通すことによって、供給路と排出路及び混合室を濯ぎ洗
い、それによって、同じ有効成分及び他の乳化剤との、他の配合
物を製造し、他の反応管に供給することができる；
−約１５分後、巨視的相分離を観察できるかどうか、ＣＣＤカメラ
の補助によって検査する。デジタル画像操作プログラムによって、
自動的にデジタル画像の解析を行う。
【００８８】
並列化、かつ自動化された１５個の得られた配合物の相特性の測定及び並列化、かつ自動化された配合物の製造は平行して、即ち、先の相特性の測定の前でも次の乳化が起っているように行われる。
【００８９】
下表に、使用した配合助剤による有効成分ビタミンＡパルミテート含有エマルションの相分離の詳細を示す。
【００９０】
【表７】

[0001]
The present invention relates to a test unit for finding and / or confirming a stable formulation, a method for producing an array of n formulations and an array comprising n formulations, The use of a test unit to produce an array of formulations of the present invention.
[0002]
Many active ingredients show low solubility or insolubility in both aqueous and organic phases. Such limited solubility of the active ingredient renders practically no direct use possible due to its low availability, e.g. low bioavailability for pharmaceuticals, food additives or crop protection agents. ing. Formulations of these active ingredients are used to increase the availability of the poorly soluble active ingredients.
[0003]
U.S. Pat. No. 4,973,352 relates to an aqueous microemulsion-based herbicide containing, as active ingredients, a combination of a phenoxyphenoxy or heteroarylphenoxycarboxylic acid ester and a salt of bentazone. The system consists of the active ingredient, one or more emulsifiers and one or more organic solvents, with water as a dispersion medium. According to U.S. Pat. No. 4,973,352, the difficulty there is to produce a stable formulation which is stable and does not show heterogeneity on storage. In order to do this, it is necessary to find a suitable component from many possibilities and a mixing ratio of the component.
[0004]
Patent WO 97/07787 relates to the preparation of a cyclosporin formulation suitable for oral administration. This formulation contains the active ingredient, at least one alcohol having 2 to 3 carbon atoms as solvent and at least one nonionic surfactant. Dilution of this formulation with an aqueous medium gives amorphous, bioavailable cyclosporin nanoparticles with a particle size of <1 μm and with 50% by weight of nanoparticles. Here too, the problem is to find a suitable formulation with suitable stability and good bioavailability.
[0005]
U.S. Pat. No. 4,522,743 relates to the preparation of a finely dispersed carotenoid or retinoid composition having a particle size <0.5 [mu] m. The preparation is carried out by dissolving the active substance at an elevated temperature in a water-miscible organic solvent. This is followed by rapid mixing of the solution with water or an aqueous solution of the formulation aid in a mixing chamber, where the active substance precipitates in a finely dispersed form. The problem again is to find a suitable formulation aid to obtain a stable formulation.
[0006]
Complex interactions between the active ingredients, formulation aids, dispersion media and, where appropriate, other ingredients, such as other solvents, may result in suitable ingredients, mixing ratios and methods for obtaining a stable formulation. Making it impossible to predict.
[0007]
It is an object of the present invention to provide an experimental strategy that solves the problem of poorly soluble active ingredient formulation with a minimum of time and cost. The desired active ingredient is often more expensive or less available, especially in the early stages of its development. Therefore, another object of the present invention is to start with the minimum amount of the desired active ingredient in the study of a suitable formulation.
[0008]
The purpose of this is to
-At least one active ingredient which is poorly soluble or insoluble in the dispersion medium;
Minutes,
-At least one compounding aid
A dispersion medium, and
-Suitably at least one solvent
A test unit for finding and / or confirming a stable formulation, comprising at least an address for addressing a matrix of positions on a support. Starting from a test unit having a robot with one robot arm, it has been found to be achieved.
[0009]
In this case, the test unit according to the invention has a mixing chamber built into the robot arm.
[0010]
The object is a method of manufacturing an array further comprising n formulations, wherein each of the n formulations is present at some known position of the m positions on the support. Wherein n and m are both natural numbers greater than or equal to 2; m is greater than or equal to n;
-At least one type of poorly soluble or insoluble dispersion medium;
Active ingredient,
-At least one compounding aid;
A dispersion medium, and
-Suitably at least one solvent,
Containing, of which
In each case, at least in at least one solvent,
Is also one kind of active ingredient, and in any case, at least in the dispersion medium
A solution of one compounding aid is also mixed vigorously in a mixing chamber and n
Obtaining n compounds in the mixing step,
In this case, at least one parameter selected from the components used, the concentration of the components used, the temperature or the mixing time, suitably at least one solvent or dispersant used, and The other components used are achieved by an array containing n formulations, with each formulation being different.
[0011]
In the following description, the terms used in the singular, "active ingredient", "compounding aid" and "solvent" are all well read as "at least one active ingredient", "at least one blending aid" and It means "at least one solvent".
[0012]
Conventional methods of the prior art make it possible to produce about two formulations for each person in the laboratory, but with the aid of the test unit according to the invention and the method of the invention, one day It is possible to produce more than 1000 formulations. The probability of finding a stable formulation for the various active ingredients is therefore much higher with the aid of the process according to the invention than with conventional processes. Moreover, the time during which such stable formulations can be found is much shorter than using conventional methods.
[0013]
Furthermore, the amounts of the components, especially the active ingredients, are very small. The active ingredient content for each formulation produced is generally <10 mg, preferably 1 mg, particularly preferably <0.1 mg. This is an important criterion because the active ingredients used are often costly or difficult to use.
[0014]
The test unit device according to the invention, the method according to the invention and the array according to the invention thus make it possible to find the active ingredient formulation in a fast and cost-effective manner.
[0015]
For the purposes of the present invention, a formulation is a system having at least one continuous phase, which is generally liquid and at least one dispersed phase (dispersion). This dispersed phase can be solid, liquid or gaseous. Thus, the formulation is preferably a suspension or a nanosuspension, an emulsion or a microemulsion, a solubiliser or a foam. Preferred microdispersions and nanodispersions are generally between 1 nm and 50 μm, preferably between 5 nm and 5 μm, particularly preferably between 10 nm and 500 nm (hydrodynamic radius (r _H )) Has an average particle size of the dispersed phase. Average particle size can be measured, for example, by light scattering or using an analytical ultracentrifuge.
[0016]
The stable formulations for the purposes of the present invention are distinguished by having a dispersed phase which is essentially finely and evenly dispersed in the dispersion medium. This generally means that, over a period of time, depending on the application range in which the stable formulation is used, there is no particle size growth of the dispersed phase (eg, due to agglomeration) and sedimentation or creaming in the stable formulation Means not to occur.
[0017]
The preparation of the formulation depends on the nature of the dispersion.
[0018]
Suspensions and nanosuspensions
Suspensions and nanosuspensions can be obtained by various methods.
a) By dispersion:
It is obtained by vigorously mixing the active ingredient with the formulation aid solution in suspension. In this case, a suspension or nanosuspension will spontaneously form if suitable components and mixing ratios are selected. When a suspension or nanosuspension is produced by dispersion, a medium for suspending the active ingredient and a solution of the mixing aid (dispersion medium) are used in order to avoid formation of various liquid phases. It is necessary that they can be mixed with each other at the ratio used.
b) by precipitation:
This is obtained by vigorously mixing a solution of the active ingredient in a suitable solvent with a solution of the formulation aid. In this case, a suspension or nanosuspension is produced, if the active ingredient precipitates and a suitable ingredient and mixing ratio are selected. When a suspension or nanosuspension is produced by precipitation, a solvent for dissolving the active ingredient and a solvent (dispersion medium) for the compounding aid are used in order to avoid generation of various liquid phases. It is necessary that they can be mixed with each other in the proportions used.
[0019]
The precipitation of the active ingredient in the dispersion medium can take place in various ways, of which two suitable methods are described in detail below.
Precipitation by changing the performance of the solvent / dispersant composition
The solution of the active ingredient in a suitable solvent is mixed in a mixing chamber with the formulation aid dissolved in the dispersion medium, whereby the active ingredient in the solvent / dispersion medium mixture is mixed as a result of the mixing of the solvent and the dispersion medium. Is exceeded, and the active ingredient precipitates. By this method, it is possible to achieve the spontaneous generation of stable formulations. In this method, the aggregation state of the active ingredient changes, but the chemical identity does not change. This can be achieved by using chemically different dissolution / dispersion media or by using the same dissolution / dispersion media, for example, by changing the pH, ionic concentration or temperature.
-Reactive precipitation by using suitable precursors of the active ingredient
A solution of the active ingredient in one or more suitable reactive precursors in a suitable solvent, which may be the same compound or a mixture of compounds as the dispersion medium, is dissolved in the dispersion medium in a mixing chamber. Mix with the formulation aid. The actual active ingredient is formed by the reaction of the precursor (s) and precipitates from the reaction mixture to form a stable formulation. The reaction of the precursor (s) is, for example, a chemical reaction, a salt formation or a complex formation reaction.
[0020]
Suitable formulation auxiliaries (dispersants) are generally high and low molecular weight surfactants.
[0021]
Emulsions and microemulsions
Emulsions and microemulsions are obtained by emulsification. This results from vigorous mixing of the active ingredient, either in liquid or in solution, with a solution of the formulation aid in a mixing cell. In this case, a spontaneous emulsion or microemulsion is formed by selecting suitable components and mixing ratios.
[0022]
Solubilized material
The solubilized product is obtained by solubilization, that is, by dissolving a substance insoluble in a specific liquid by adding a compounding aid. For this purpose, the active ingredient is dissolved in a minimum amount of solvent capable of dissolving the active ingredient and mixed vigorously with the emulsifier solution in a mixing cell.
[0023]
The solvent and the amount of solvent used here depend on the active ingredient used and / or the desired field of reaction.
[0024]
Preferably used formulation auxiliaries (emulsifiers) are active ingredients used and dispersants used, for example hydrophilic substances, for example monohydric and polyhydric alcohols, esters, ethers, nonionic and ionic surfactants, It depends on the salt, amide and other nitrogen-containing compound of the particular organic acid of the alkali metal or alkaline earth metal.
[0025]
The dispersion medium is a medium in which the active ingredient is blended and administered according to the present invention. The dispersing medium forms the continuous phase of the formulation. Generally, the active ingredient is poorly soluble or insoluble in the dispersion medium. The dispersion medium can consist of different chemical compounds. In a preferred embodiment of the present invention, the dispersion medium is an aqueous system. However, it is also possible that the dispersion medium is a hydrophobic system.
[0026]
According to the invention, the active ingredient is a substance which is poorly soluble or insoluble in the dispersion medium. Active ingredients preferably used are vitamins, retinoids, coloring agents, especially carotenoids, pharmaceuticals, crop protection agents, fine chemicals, catalysts, enzymes, flame retardants, lime-deposition, inhibitors, cosmetics and UV. (UV) stabilizers.
[0027]
Suitable solvents which can be used according to the invention, in particular for suspensions and nanosuspensions, are those which are at least partially miscible with the dispersion medium. The solvents used preferably are at least 10% by weight, particularly preferably at least 25% by weight, miscible with the dispersion medium. Solvents which are preferably used have a boiling point below 200 ° C. in order not to overheat the active ingredient to remove such solvents from the reaction mixture. Solvents having less than 10 carbon atoms are particularly preferably used. Suitable solvents for use in aqueous systems as dispersion media are selected from alcohols, ethers, esters, ketones and acetals. Particularly preferred are ethanol, n-propanol, isopropanol, butane-1,2-diol-1-methyl ether, propane-1,2-diol-1-n-propyl ether or acetone.
[0028]
Particularly suitable solvents for the emulsion are those which are essentially immiscible or only slightly miscible with the dispersion medium. Examples are halogenated solvents such as chloroform or methylene chloride, non-halogenated solvents such as ethers such as t-butyl methyl ether or dimethyl ether, esters such as ethyl acetate or butyl acetate, hydrocarbons such as cyclohexane or n-hexane. And oils, such as vegetable oils, such as sunflower, peanut and malt oils, animal oils or synthetic oils.
[0029]
The support according to the invention is a material with a hard surface or a parallel reactor. This surface has physically separated regions (positions). In a preferred embodiment of the invention, the support is a microtiter plate or a parallel reactor and the position is a well of a microtiter dish or a reaction tube in a parallel reactor.
[0030]
A fundamental factor in the formulation of active ingredients that are poorly soluble or insoluble in the dispersion medium is an efficient and powerful mixing of the individual components. The mixing chamber is used according to the invention for this purpose. This results in a vigorous agitation of the components, which allows the production of a stable formulation.
[0031]
This mixing chamber is integrated into the robot arm according to the invention. This means that in a miniaturized, automated and / or parallelized process, the active ingredient, suitably dissolved in a solvent, and the compounding aid, dissolved in a dispersion medium, are mixed vigorously in a mixing chamber, and then the support It can be placed on the position as defined above, and subsequently screened for specific performance.
[0032]
In this case, parallel or serial screening can be performed. In the first screening (parallel screening), the resulting formulation is visually inspected. It is also possible to inspect the resulting formulation by parallel measurement of light transmission at selected wavelengths. In a second screening, the resulting formulation can be screened by dynamic light scattering to determine the average particle size. Examples of suitable methods for characterizing the resulting formulation are FOQELS (fiberoptic quasi-elastic light scattering) and FODLS (fiberoptic dynamic light scattering).
[0033]
In a preferred embodiment, the characterization of the formulation is performed in such a way as to incorporate the optical measuring cell into a robot arm, the arm being, for example, on a support or in another robot arm. Has a micropipette device for applying. This is particularly preferably an optical fiber for particle size measurement by dynamic light scattering. A fiber optic sensor for particle size measurement by quasi-elastic light scattering (FOQELS) is disclosed, for example, in European Patent Application Publication No. 0295564.
[0034]
With the aid of this test unit, it is possible to produce a large number of different formulations in a reproducible manner, so that a large number of formulations can be used in a short time and their stability and other properties tested. it can.
[0035]
Using the test unit according to the invention, it is possible to find suitable formulation auxiliaries for stabilizing specific active ingredients, for example in nanodispersions or microdispersions in dispersion media. For this purpose, in certain solvents or suspending agents, solutions or suspensions of the active ingredient which are poorly soluble or insoluble in the dispersion medium or, if it is, for example, liquid, the pure active ingredient The suspension is mixed vigorously in a mixing chamber according to the invention with various solutions of the compounding aids at various concentrations in various mixing steps, or with various compounding aids in the required dispersion medium, It is then applied to a defined position on the support.
[0036]
It is also possible to find a variety of active ingredients that can be formulated as stable formulations with certain formulation aids. For this purpose, various solutions or suspensions at various concentrations of the active ingredient, which are poorly soluble or insoluble in the dispersion medium, or various active agents in a particular solvent or suspending agent. Various solutions or suspensions of the ingredients or, if it is, for example, a liquid, its pure active ingredient are mixed in a mixing chamber with the desired dispersing medium in the various mixing steps in a particular formulation aid solution. Mix vigorously and then apply to the defined position on the support.
[0037]
The mixing chamber is designed in a preferred embodiment of the invention to have two supply channels and one outlet, the supply channels being arranged at an angle of> 0 ° to 180 ° with respect to each other. I have. This angle is particularly preferably between 80 and 100 ° or between 160 and 180 °.
[0038]
The material of the mixing chamber, and the materials of the supply path introduced into the mixing chamber and the discharge path derived from the mixing chamber are arbitrary materials that are inert to the components used. Suitable materials, especially for the mixing chamber, are steel or glass. Particularly suitable for the supply and discharge channels are Teflon tubes or steel capillaries.
[0039]
The mixing chamber generally has a volume of 10-5000 μL, preferably 50-1000 μL. Therefore, a small amount of each component can be mixed with a small loss.
[0040]
The diameter of the supply path and the discharge path is generally 0.1 to 5 mm, preferably 0.1 to 1 mm, particularly preferably 0.2 to 0.9 mm, and each supply and discharge path has a different diameter. It is possible.
[0041]
If a suitable solution of the compounding aid and the active ingredient is introduced into the mixing chamber by means of a computer controlled Hamilton syringe, the compression rate of the syringe is 0.01-0.1 ml / s for the active ingredient supply, The supply of the compounding aid is 0.1 to 5 ml / s. If such feeds are filled with each other, rapid mixing is obtained. In a preferred embodiment of the invention, the feed rates of the two feeds are such that the total amount of the components to be mixed in each case is supplied to the mixing chamber within the same time, irrespective of the total amount of the two feed solutions. Adjust to. This means that, for example, when the supply path has the same diameter and the volume of the solution of the compounding aid in the dispersion medium is twice the volume of the active ingredient solution in the solvent, the feeding rate of the compounding aid is , Twice the active ingredient.
[0042]
For each mix, the mixing process can be precisely adjusted, ensuring very good reproducibility of the resulting mix. Furthermore, it is possible that the volumetric flows of both the active ingredient feed and the formulation aid feed are kept constant or provided with a gradient.
[0043]
Following mixing, the resulting various formulations are placed at defined positions on a support and screened for specific performance.
[0044]
A preferred embodiment of the mixing chamber is shown in FIG. The meaning in this is as follows.
1. Mixing room
2. Active ingredient supply port
3. Compounding agent supply port
4. Vent
5. Sealing place
6. > Angle between 0 ° and 180 °
[0045]
In a preferred embodiment, the mixing chamber is designed in one T shape as shown in FIG. The angle 6 between the active ingredient feed and the formulation aid feed is generally between> 0 ° and 180 °. The angle is preferably from 80 ° to 100 °, particularly preferably about 90 ° or 160 ° to 180 °, particularly preferably about 180 °. At an angle of about 180 °, the active ingredient feed and the formulation aid feed are countercurrent to each other. In this arrangement, the outlet is at an angle of about 90 ° to the supply.
[0046]
Depending on the solvent, the storage tank, syringe, supply port and mixing chamber can be heated below the boiling point of the solvent used.
[0047]
Another embodiment of the mixing chamber is shown in FIG. The meaning in this is as follows.
[0048]
1, 2 Supply port of active ingredient and compounding aid
3 outlet
4 Sealing place
[0049]
In this embodiment, the mixing chamber is designed to have two feed channels and one outlet, the first feed channel being located inside the second. In this case, the angle between the feed channels is 0 °, ie the active ingredient feed and the formulation aid feed are in the form of a cylindrical channel.
[0050]
A solution of the active ingredient in the solvent, which is poorly soluble or insoluble in the dispersion medium, or a suspension of the active ingredient in a pure active ingredient or a suspending agent, and a solution of the formulation aid in the dispersion medium, Generally obtained from a storage tank.
[0051]
Delivery of a solution or suspension of the active ingredient, which is poorly soluble or insoluble in the dispersion medium, in a solvent or dispersant, or delivery of the pure active ingredient to the mixing chamber, and of a solution of the formulation aid in the dispersion medium. The dispensing of the mixing chamber and the disposition of the various formulations obtained in each case after the mixing step in known positions on the support are carried out by means of a dispenser in a preferred embodiment.
[0052]
Other possible ways of introducing the reaction components into the mixing chamber or onto the support include a feed line through which the appropriate components can be precisely pumped into the mixing chamber or onto the support via a pump, in particular an HPLC pump. Is included.
[0053]
In a preferred embodiment of the method according to the invention, a solution of the active ingredient which is poorly soluble or insoluble in the dispersion medium or of the pure active ingredient in a solvent and a solution of the formulation aid in the dispersion medium are mixed in a mixing chamber. Pump to the mixing chamber, or by a supply line that can deliver the appropriate components via a control system with a syringe, eg, a Hamilton μl syringe. In this case, an appropriate solution is obtained from the storage tank.
[0054]
The test unit device according to the invention is preferably a precision actuatable micropipette device which contains a mixing chamber therein and is activated with the aid of a robot. Thus, it is possible to deliver the resulting formulation directly from the mixing chamber onto a support by means of a micropipette device.
[0055]
A further aspect of the present invention relates to a method of making an array containing n formulations, wherein each of the n formulations has some known position of m positions on the support. N and m are both natural numbers greater than or equal to 2 and m is greater than or equal to n;
-At least one active ingredient which is poorly soluble or insoluble in the dispersion medium;
Minutes,
-At least one compounding aid;
A dispersion medium, and
-Suitably at least one solvent,
Containing, of which
In each case, at least in at least one solvent,
Is also one kind of active ingredient, and in any case, at least in the dispersion medium
A solution of one compounding aid is also mixed vigorously in a mixing chamber and n
Obtaining n compounds in the mixing step,
In this case, at least one parameter selected from the components used, the concentration of the components used, the temperature or the mixing time, suitably at least one solvent or dispersion medium used, and Are different in the manufacture of each formulation.
[0056]
In the following description, the terms “active ingredient”, “compounding aid”, and “solvent” used in the singular form all refer to “at least one active ingredient” and “at least one blending aid”. "And" at least one solvent ".
[0057]
With the aid of the method according to the invention, it is possible to find both suitable formulation auxiliaries for a particular active ingredient and various active ingredients which can be formulated with the particular formulation auxiliaries.
[0058]
The variables n and m in the method according to the invention are both natural numbers greater than or equal to 2, preferably greater than or equal to 10, particularly preferably greater than or equal to 70, very preferably 100 or more. Greater or equal number. Furthermore, independently of n and m, m is at least equal to or greater than n. Preferably, m is equal to n.
[0059]
The active ingredients, formulation aids, dispersion media and solvents suitable according to the invention and the formulations obtained with the aid of the method according to the invention, such as suspensions, nanosuspensions, emulsions, microemulsions and solubilisates, , Already listed above.
[0060]
Suitable supports and positions on the supports and preferred embodiments of the mixing chamber according to the invention have likewise already been described above.
[0061]
In the method of the present invention, in each case, a solution of an active ingredient in a solvent having low solubility or insolubility in a dispersion medium, or a pure active ingredient and a solution of a compounding aid in a dispersion medium in each case, Mix vigorously in the mixing chamber to obtain n mixtures containing the active ingredient in precipitation, the formulation aid, suitably a solvent and a dispersion medium, in n mixing steps.
[0062]
Each method of preparing the n resulting blends depends on the parameters selected from the components used, the concentrations of the components used, the temperature or mixing time, the solvent or dispersion medium used, and, where appropriate, the other components used. At least one is different.
[0063]
In a preferred embodiment, the mixing step is performed in an automated and / or parallel manner. Delivery of a suitable solution of the active ingredient, which is poorly soluble or insoluble in the dispersion medium, in a solvent and of, for example, the pure active ingredient when in liquid form, and the delivery of the formulation aids in the dispersion medium itself. It is particularly preferred that it is performed in an automated and / or parallel way. With the help of such automated and / or parallelized methods, it is possible to produce a large number of different formulations in a reproducible manner, so that a large number of formulations can be used in a short time and their Performance, eg, their stability, can be tested.
[0064]
Automated delivery of the appropriate solution in a solvent of the active ingredient, which is poorly soluble or insoluble in the dispersion medium, or of the pure active ingredient, and the formulation aid in the dispersion medium to the mixing chamber and the resulting blending The delivery of an object to a defined position on a support has already been described above.
[0065]
In a preferred embodiment, the n resulting formulations are present in a reservoir on a microtiter dish or in a reaction tube of a parallel reactor.
[0066]
The process according to the invention gives formulations in which the dispersed phase is present (in hydrodynamic radius) in a particle size of generally from 1 nm to 50 μm, preferably from 5 nm to 5 μm, particularly preferably from 10 nm to 500 μm. Such a small particle size makes it possible to produce a stable formulation.
[0067]
With the aid of the method according to the invention, it is possible to obtain an array containing n formulations, wherein each of the n formulations is one of m positions on the support. Where n and m are both natural numbers greater than or equal to 2 and m is greater than or equal to n, and the formulation comprises:
-At least one active ingredient which is poorly soluble or insoluble in the dispersion medium;
Minutes,
-At least one compounding aid;
A dispersion medium, and
-Suitably at least one solvent,
It contains.
[0068]
The variables n and m in the array according to the invention are both natural numbers greater than or equal to 2, preferably greater than or equal to 10, particularly preferably greater than or equal to 70, even more preferably greater than 100 Or equal. Further, while n and m are independent of each other, m is at least equal to or greater than n. Preferably, m is equal to n.
[0069]
The active ingredients, formulation aids, dispersion media and solvents suitable according to the invention and the formulations obtained with the aid of the method according to the invention, such as suspensions, nanosuspensions, emulsions, microemulsions and solubilisates, , Already listed above.
[0070]
Suitable supports and positions on the supports according to the invention have also been described above.
[0071]
The array can be screened for specific performance, eg, physicochemical stability and / or particle size of the formulation. In addition, parallel or rapid serial screening can be performed. In the first screening (parallel screening), the resulting formulation is subjected to physicochemical stability (eg, sedimentation, creaming, macroscopic phase), for example, visually, for example, with the naked eye, or with the aid of a camera. (For the formation of the boundaries of It is also possible to examine the resulting formulation by parallel measurement of light transmission at selected wavelengths. In a second screening, the resulting formulation can be screened by dynamic light scattering to determine the average particle size. Suitable methods for characterizing the resulting formulation are, for example, FOQELS (quasi-elastic light scattering of fiber optics) and FODLS (fiber optic dynamic light scattering). Thus, arrays according to the present invention can find a large number of stable formulations in a rapid and cost-effective manner.
[0072]
The array is preferably manufactured using a test unit according to the method of the invention. The array is preferably manufactured with the aid of the method according to the invention.
[0073]
Another aspect of the invention is a method of producing n solid compositions, which comprises, following the production of the formulation, by spray drying, vacuum drying, lyophilization or with a solvent and suitably at least By distilling off a part of the dispersion medium, followed by drying by one of the above-mentioned drying methods, by removing the dispersion medium and, if appropriate, the solvent, of the n formulations obtained by the process according to the invention. can get. In a preferred embodiment of the method according to the invention, the solvent and the dispersion medium are removed, and the n formulations are subsequently delivered to defined positions on the support.
[0074]
By this method, an array containing n solid compositions is obtained, wherein each of the n solid compositions is present at some known position of the m positions on the support; Here, n and m are both natural numbers greater than or equal to 2, preferably greater than or equal to 10, particularly preferably greater than or equal to 70, even more preferably greater than 100 or Equally, and the solid composition comprises:
-At least one active ingredient, poorly soluble or insoluble in the dispersion medium,
as well as
-At least one compounding aid
It contains.
[0075]
Suitable supports and positions on the support, active ingredients and preferably used formulation auxiliaries have already been mentioned.
[0076]
The particle size of the dispersed phase in the solid composition is preferably from 1 nm to 50 μm, particularly preferably from 5 nm to 5 μm, more preferably from 10 nm to 500 nm. These solid compositions are suitable for producing stable formulations by the addition of a dispersion medium, preferably by the addition of an aqueous system. However, it is also possible to use a hydrophobic system as dispersion medium.
[0077]
Another aspect of the present invention is the use of an array containing n formulations, wherein each of the n formulations has some known position of m positions on the support. Wherein n and m are both natural numbers greater than or equal to 2, preferably greater than or equal to 10, particularly preferably greater than or equal to 70, and even more preferably greater than 100. Or equivalently, and the composition comprises the following components:
-Dispersion medium
-Suitably at least one solvent,
-At least one active ingredient that is sparingly soluble or insoluble in the dispersion medium, and
And
-At least one compounding aid
Is included to find and / or confirm a stable formulation. Suitable active ingredients, formulation auxiliaries, dispersion media and solvents and suitable supports and positions on the supports have already been described in detail above.
[0078]
The formulation is confirmed by screening performed in parallel and / or in series. Various screening methods are already listed above. With conventional methods, a very large amount of time and therefore also a cost is required, whereas the use described above makes it possible to quickly find stable formulations.
[0079]
The following examples further illustrate the invention.
Example
Example 1: Preparation of a suspension by precipitation for the testing of a number of formulation aids against one active ingredient (UVINUL T150)
Preparation of an aqueous solution of the selected formulation aid having a concentration of -15 g / l;
A active ingredient having a concentration of -10 g / l, Uvinul T150,
Production of seton solution;
Taking -9 ml of the formulation aid solution into a Hamilton syringe; and
-1 ml of an acetone solution of Uvinul T150 into a Hamilton syringe
take;
Draining both solutions in the syringe into a waste container (rinse step);
Take the same amount of formulation aid and Ubinul T150 into the syringe again;
9% volume ratio of both solutions simultaneously (mixing aid solution: Uvinul T150)
Solution) into the mixing chamber and mix therein;
Passing the resulting mixture through a 15 ml glass reaction tube;
-Rinse the syringe containing the formulation aid three times with 10 ml of water and allow the water to
Rinsing the supply and discharge channels and the mixing chamber by passing through the device,
Thereby, the same active ingredient Ubinul T150 and other compounding aids
Other formulations can be prepared and supplied to other reaction tubes;
After about 1 hour, the particle size of the active ingredient in the formulation is
Measured by quasi-elastic light scattering (FOQELS),
5 minutes before the measurement, the typical
The sample with a magnetic stirrer to obtain an optimal particle size distribution.
Stir carefully.
-After each measurement, continue the FOQELS detector with water and then with acetone.
And rinsed again with water.
[0080]
The parallelized and automated measurement of the particle size of the n = 29 resulting formulations and the parallelized and automated production of the formulation are performed in parallel, i.e. before the previous particle size measurement, the following Performed as if precipitation had occurred.
[0081]
Embedded image

Ubinul T150
Chemical name:
2,4,6-trianilino-p- (carbo-2'-ethylhexyl-1'-oxy) -1,3,5-triazine
[0082]
Table 1 below shows the particle size of the active ingredients in the formulation corresponding to the formulation aids tested.
[0083]
[Table 1]

[Table 2]

[Table 3]

[0084]
Example 2: Preparation of a suspension by precipitation, for testing one formulation aid (gelatin B100) against various active ingredients
Preparation of an aqueous solution of gelatin B100 at a concentration of -7 g / l; and
Preparation of an acetone solution of the active ingredient at a concentration of -10 g / l;
Taking -0.9 ml of gelatin solution into a Hamilton syringe;
Taking 0.1 ml of the active ingredient solution into a Hamilton syringe;
-Drain both solutions into a waste container (rinse step) and then add an equal amount of
Taking the tin solution and the active ingredient solution into a syringe;
-Both solutions at the same time in a 9: 1 volume ratio (gelatin solution: active ingredient solution)
Feeding into a mixing chamber and mixing therein;
Passing the resulting mixture through a reservoir (compartment) of a standard microtiter dish;
-Rinse the syringe containing the active ingredient three times with 10 ml of acetone,
Feed and discharge channels and mixing
Rinse the chamber, so that the same formulation aids, gelatin, and other
Produce other formulations with other active ingredients and pool other microtiter pans
Can be supplied to
After about one hour, the particle size of the active ingredient in the formulation is
Measured by quasi-elastic light scattering (FOQELS),
5 minutes before the measurement, the typical
The sample with a magnetic stirrer to obtain an optimal particle size distribution.
Stir carefully.
-After each measurement, continue the FOQELS detector with water and then with acetone.
And rinsed again with water.
The parallelization and automation of the particle size measurement and parallelization of the 18 resulting formulations and the production of the automated formulation are parallel, i.e. the next precipitation occurs even before the previous particle size measurement. It is performed as if.
[0085]
The following table shows the various active ingredients and the measured particle size in the formulation produced as Example 2.
[0086]
[Table 4]

[Table 5]

[Table 6]

[0087]
Example 3: Production of an emulsion for testing multiple formulation auxiliaries against one active ingredient (vitamin A palmitate)
-15 g / l of a selected compounding aid (emulsifier) aqueous solution having a concentration of
Manufacturing;
Of active ingredient Vitamin A palmitate having a concentration of -10 g / l
Production of olive oil solution
Taking 9 ml of the emulsifier solution into a Hamilton syringe; and
-Take 1 ml of vitamin A palmitate solution into a Hamilton syringe
R;
Draining both solutions in the syringe into a waste container (rinse step);
Add the same amount of emulsifier solution and vitamin A palmitate solution to
Take it
-9: 1 volume ratio of both solutions simultaneously (emulsifier solution: Vitamin A palmi)
Tate solution) into the mixing chamber and mix therein;
Passing the resulting mixture (emulsion) through a 15 ml glass reaction tube;
-Rinse the syringe containing the emulsifier solution three times with 10 ml of water,
Rinse the supply and discharge channels and the mixing chamber by passing
And therefore other formulations with the same active ingredients and other emulsifiers
Can be manufactured and supplied to other reaction tubes;
After about 15 minutes, check if you can observe the macroscopic phase separation by using a CCD camera.
Inspect with the aid of By digital image manipulation program,
Analyze digital images automatically.
[0088]
The parallelization and automation of the measurement of the phase properties of the 15 resulting formulations and the parallelization and the production of the automated formulations are parallel, i.e. before the previous phase properties measurement, the following It is done as if emulsification had occurred.
[0089]
The following table shows details of the phase separation of the emulsion containing the active ingredient Vitamin A palmitate by the blending aid used.
[0090]
[Table 7]

Claims (14)

The following ingredients,
-In the dispersion medium, at least one active ingredient, poorly soluble or insoluble,
-At least one compounding aid;
A test unit for finding and / or confirming a stable formulation, comprising a dispersion medium and, suitably, at least one solvent, wherein the test unit is located on a support. A test unit, comprising: a robot having at least one robot arm for addressing the matrix, wherein the mixing chamber is incorporated in the robot arm. 2. The test unit according to claim 1, wherein an optical measuring cell is incorporated in the robot arm or, if appropriate, another robot arm. 3. The method according to claim 1, wherein the mixing chamber has at least two supply channels and at least one outlet, and the supply channels are arranged at an angle of more than 0 ° and not more than 180 ° with respect to each other. Test unit equipment. The test unit according to claim 3, wherein the angle is 80 to 100 ° or 160 to 180 °. The mixing chamber has at least two supply paths and at least one discharge port, and at least one supply path is disposed inside another supply path (cylindrical flow path shape). 3. The test unit device according to 1 or 2. The test unit device according to any one of claims 1 to 5, wherein the support is a microtiter dish or a parallel reactor, and the position is a reservoir of the microtiter dish or a reaction vessel of the parallel reactor. A method of making an array comprising n formulations, wherein each of the n formulations is present at some known position of the m positions on the support, where n and m are both Is also a natural number greater than or equal to 2; m is greater than or equal to n;
-In the dispersion medium, at least one active ingredient, poorly soluble or insoluble,
-At least one compounding aid;
-A dispersion medium, and-suitably at least one solvent,
Containing, of which
In each case suitably a solution of at least one active ingredient in at least one solvent, and in each case at least one compounding aid in a dispersion medium, in a mixing chamber Vigorous mixing, n blending steps to obtain n blends,
In this case, at least one parameter selected from the components used, the concentration of the components used, the temperature or the mixing time, suitably at least one solvent or dispersant used, and A method for producing an array containing n formulations, wherein the other components used are different for each formulation. The method according to claim 7, wherein the mixing is performed in the mixing chamber according to any one of claims 3 to 5. The method according to claim 7 or 8, wherein each step is performed rapidly, in series or in parallel. Each of the n formulations is present at some known position of the m positions on the support, where n and m are both natural numbers greater than or equal to 2 and m is greater than n Large or equal, the formulation has the following ingredients:
-In the dispersion medium, at least one active ingredient, poorly soluble or insoluble,
-At least one compounding aid;
-A dispersion medium, and-suitably at least one solvent,
An array comprising n formulations, comprising: The array according to claim 10, wherein the active ingredient content for each formulation prepared is <10 mg, preferably <1 mg, particularly preferably <0.1 mg. Use of the array according to claim 10 for identifying and / or finding a stable formulation. An application of the test unit according to any one of claims 1 to 6 for producing an array according to claim 10. any of the n solid compositions is present at some known position of the m positions on the support, where n and m are both natural numbers greater than or equal to 2; The following ingredients,
-In the dispersion medium, at least one active ingredient, which is poorly soluble or insoluble, and-at least one formulation aid,
An array comprising n solid compositions, comprising: