JP7569181B2 - Method for producing a solid composition containing amorphous poorly water-soluble material - Google Patents

Description

The present disclosure relates to a method for producing a solid composition containing an amorphous poorly water-soluble material, and a solid composition containing an amorphous poorly water-soluble material.

Conventionally, techniques for amorphizing water-insoluble polyphenols have been known for the purpose of increasing the water solubility and bioabsorbability of the water-insoluble polyphenols.
For example, there have been proposed a method of forming a complex of curcumin and/or its analogues with a water-soluble cellulose derivative using an organic solvent method (Patent Document 1), a method of mixing (A) poorly soluble polyphenols, (B) at least one selected from plant-derived polysaccharides, seaweed-derived polysaccharides, microbial-derived polysaccharides, plant-derived polypeptides, and microbial-derived polypeptides, and (C) at least one selected from monosaccharides and disaccharides, followed by heating and melting the mixture and cooling and solidifying the melt (Patent Document 2), a method of heating and kneading a crystalline poorly water-soluble polyphenol, a hydrophilic polymer, and a nonionic surfactant (Patent Documents 3 and 4), and a method of melting crystalline curcumin alone to make it amorphous, followed by adding a water-soluble polymer such as dextrin (Patent Document 5).

WO2015/174475 Brochure JP 2016-049105 A WO2017/061627 Brochure JP 2019-123700 A WO2019/160146 Brochure

However, there is a further need to provide a method for producing a solid composition containing an amorphous poorly water-soluble material, and a solid composition containing an amorphous poorly water-soluble material.
An object of the present disclosure is to provide a new method for producing a solid composition containing an amorphous poorly water-soluble material, and a solid composition containing an amorphous poorly water-soluble material, etc.

This disclosure includes the following aspects:

[1] A method for producing a solid composition containing an amorphous poorly water-soluble material, which essentially consists of (1a) an amorphous poorly water-soluble material, and (2) one or more hydrophilic polymers selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), and polyvinylpyrrolidone (PVP), comprising:
(1b) a crystalline poorly water-soluble material, and (2) one or more hydrophilic polymers selected from the group consisting of HPMC, HPC, and PVP;
A manufacturing method comprising:
[2] The method for producing the present invention described in [1], wherein the poorly water-soluble material is at least one selected from the group consisting of polyphenols, polyphenol derivatives, carotenoids, coenzyme Q10, vitamins, and sesamin.
[3] The method for producing a pharmaceutical composition according to [2], wherein the polyphenol is one or more selected from the group consisting of curcumin, luteolin, silymarin, rutin, quercetin, myricitrin, quercitrin, isoquercitrin, naringenin, resveratrol, and hesperetin; the polyphenol derivative is a polymethoxyflavonoid; the carotenoid is at least one selected from the group consisting of xanthophylls, carotenes, and apocarotenoids; and the vitamin is at least one selected from the group consisting of vitamin A, vitamin D, vitamin E, and vitamin K.
[4] The method according to any one of [1] to [3] above, wherein the mass ratio of the (1b) crystalline poorly water-soluble material and the (2) hydrophilic polymer is within the range of 1:99 to 60:40.
[5] The method for producing a water-insoluble material according to any one of [1] to [4], wherein the heating temperature in the step A is a temperature equal to or higher than the glass transition temperature of the water-insoluble material.
[6] The manufacturing method described in [5] above, wherein the heating temperature in step A is a temperature below the melting point of the poorly water-soluble material.
[7] The method according to any one of [1] to [6] above, further comprising step B of granulating the kneaded mixture obtained in step A.
[8] A solid composition containing an amorphous poorly water-soluble material, produced by the production method according to any one of [1] to [7] above.
[9] The solid composition containing an amorphous poorly water-soluble material according to [8] above, which is an oral composition.

According to the present disclosure, a new method for producing a solid composition containing an amorphous poorly water-soluble material, and a solid composition containing an amorphous poorly water-soluble material are provided. In particular, according to the present disclosure, it is possible to prepare a formulation that has a high content of poorly water-soluble material, has excellent long-term stability, and has a high proportion of amorphous material.

1 is a table showing the results of Example 1, Comparative Examples 1 and 2. Specifically, the table shows the content residual rate (%) of the poorly water-soluble material (curcumin), the evaluation results of the amorphous nature of the poorly water-soluble material (X-ray powder diffraction (XRD) analysis chart, degree of amorphousness [XRD analysis value/evaluation]), and the evaluation results of the change in appearance after storage. In the figure, the X-axis of the XRD analysis chart shows 2θ (°), and since the measurement was performed at 2θ = 5° to 60°, but no peak was observed in the range of 2θ = 40° to 60°, only the range of 2θ = 5° to 40° is shown (same for Figures 2 and 3). In addition, the Y-axis of the XRD analysis is the signal intensity, and shows 0 to 5000 counts (same for Figures 2 and 3). In the figure, the XRD analysis value means a value calculated by the formula: {(S2)/((S1) + (S2))} × 100 (same for Figures 2 to 6). 1 is a table showing XRD charts of Example 2 and Comparative Example 3. 1 is a table showing the results of Example 1 and Comparative Example 4. 1 is a diagram showing the results of Examples 3 to 6. In the diagram, y ₀ = 0 counts, y ₁ = 5000 counts, y ₂ = 6000 counts, and y ₃ = 7000 counts (the same applies to FIGS. 5 and 6). 1 is a table showing the results of Examples 7 to 9. 1 is a table showing the results of Examples 10 to 12. 1 is a table showing the results of Comparative Examples 5 and 6.

The terms , symbols and abbreviations used herein may be understood as meanings commonly used in the technical field to which the present invention belongs, in accordance with the context of the present specification, unless otherwise limited. In the present specification, the term "comprise" is used with the intention of including the meaning of the term "consisting essentially of" and the meaning of the term "consisting of". Unless otherwise limited, the steps, treatments or operations described herein may be carried out at room temperature. In the present specification, room temperature may mean a temperature in the range of 10 to 40° C.

<Method of producing a solid composition containing a poorly water-soluble material>
A manufacturing method according to one aspect of the present disclosure includes:
A method for producing a solid composition containing an amorphous poorly water-soluble material, the solid composition essentially consisting of (1a) an amorphous poorly water-soluble material, and (2) one or more hydrophilic polymers selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), and polyvinylpyrrolidone (PVP), comprising:
The method includes a step A of heating and kneading (1b) a crystalline poorly water-soluble material, and (2) one or more hydrophilic polymers selected from the group consisting of HPMC, HPC, and PVP.

The solid composition containing an amorphous poorly water-soluble material (hereinafter also referred to as the present solid composition), which is the object of the manufacturing method of the present disclosure, is
The composition essentially consists of (1a) an amorphous, poorly water-soluble material, and (2) one or more hydrophilic polymers selected from the group consisting of HPMC, HPC, and PVP.

The total content of components (1a) and (2) in the solid composition can be, for example, 95% by mass or more, 96% by mass or more, 97% by mass or more, 98% by mass or more, 99% by mass or more, or 100% by mass.

1. Poorly Water-Soluble Material In this specification, an amorphous poorly water-soluble material may be referred to as "amorphous (1a)" or "poorly water-soluble material (1a)," a crystalline poorly water-soluble material may be referred to as "crystalline (1b)" or "poorly water-soluble material (1b)," and when both are referred to collectively without distinction, they may be referred to as "poorly water-soluble material (1)."

The poorly water-soluble material (1) to which the present disclosure relates is a poorly water-soluble substance that does not dissolve in water or dissolves only in small amounts. The poorly water-soluble material before undergoing the amorphization step contains a large amount of poorly water-soluble material (1b) in a crystalline state.
The poorly water-soluble material (1b) can have at least one of the following characteristics:
(i) The solubility in pure water at 25° C. is 0.1 mass % or less.
The solubility can be evaluated and judged in accordance with the provisions of the Japanese Pharmacopoeia as follows.
The substance is added to pure water at 25°C at a concentration of 0.1% by mass, and is shaken vigorously for 30 seconds every 5 minutes. The degree to which the substance dissolves within 30 minutes is evaluated. If insoluble matter is found when the aqueous solution is visually observed after 30 minutes, the solubility in pure water at 25°C can be determined to be 0.1% by mass or less.
(ii) The octanol/water partition coefficient (logP) is in the range of more than 1 and not more than 21.
Preferably, the logP value is in the range of more than 1 and not more than 9. For compounds whose molecular structures have been elucidated, the logP value can be determined in silico using calculation software such as ALOGPS (URL: http://www.vcclab.org/lab/alogps/).
On the other hand, for compounds whose molecular structure is unknown, it can be experimentally determined using the following formula by high performance liquid chromatography in accordance with JIS Z 7260-117 (2006).
[formula]
logP = log(Coc/Cwa)
Coc: test substance concentration in 1-octanol layer
Cwa: Concentration of the test substance in the aqueous layer. (iii) The solubility in the second liquid of the 16th Edition of the Japanese Pharmacopoeia, measured using a method in accordance with the Japanese Pharmacopoeia dissolution test (paddle method), is 3 mg/100 mL or less.

The poorly water-soluble material (1) can be, for example, a poorly water-soluble bioactive substance. In this specification, a bioactive substance can mean a compound that acts on a living body, preferably the human body, to cause some biological reaction or control an adult reaction.

The poorly water-soluble material (1) is preferably a compound that contains one or more (preferably two or more) conjugated dienes and may optionally contain one or more oxygen atoms. The conjugated diene structure may be part of a ring (e.g., benzene, cyclohexadiene).

The poorly water-soluble material (1) may preferably be one or more selected from the group consisting of polyphenols, polyphenol derivatives, carotenoids, coenzyme Q10, vitamins, and sesamin. The poorly water-soluble material (1) may more preferably be polyphenols.

1-1. Polyphenols and polyphenol derivatives The polyphenols may be one type or a combination of two or more types.
Polyphenols are plant components having two or more phenolic hydroxy groups (hydroxy groups bonded to aromatic rings such as benzene rings and naphthalene rings) in the molecule, examples of which include the following. The following examples may be compounds or compositions.
1. Curcuminoids [e.g., curcumin (including keto and enol forms), dimethoxycurcumin, bisdimethoxycurcumin], and tetrahydrocurcumin,
2. Flavonoids [flavones (e.g., luteolin, apigenin, diosmin), flavanones (e.g., hesperetin, naringenin, hesperidin, eriodictyol), flavonols (e.g., quercetin, myricetin, silibinin, silymarin [a mixture of flavonolignans such as silibinin, isosilibinin, silychristin, and silydianin], similarin, rutin, isoquercitrin, quercitrin, myricetin, myricitrin, enzymatically modified isoquercitrin, kaempferol), flavanols (e.g., catechin (E), gallocatechin , epicatechin (EC), epicatechin gallate (ECg), epigallocatechin (EGC), epigallocatechin gallate (EGCg), theaflavin, theaflavin 3-gallate, theaflavin 3'-gallate, theaflavin 3,3'-gallate), isoflavones (e.g., genistein, daidzein, glycitein), anthocyanidins (e.g., cyanidin, delphinidin, malvidin, pelargonidin, peonidin, aurantidin, eurobinidin, luteolinidin, petunidin, rosinidin), procyanidins, polycyanidins],
3. Stilbenoids [e.g., resveratrol, piceatannol],
4. Tannins [e.g., condensed tannins (proanthocyanidins, oligomeric proanthocyanidins (OPCs)), hydrolyzable tannins],
5. Monophenols [e.g., hydroxytyrosol, p-tyrosol],
6. Capsaicinoids (e.g., capsaicin, dihydrocapsaicin),
7. Phenolic acids [e.g., hydroxycinnamic acids (e.g., p-coumaric acid, caffeic acid, ferulic acid), hydroxybenzoic acids (e.g., p-hydroxybenzoic acid, gallic acid, ellagic acid), rosmarinic acid],
8. The aglycone of the compound.
9. Compounds in which the hydrogen atom of at least one phenolic hydroxy group of the above-mentioned compounds has been substituted with another group (e.g., acetylated products, malonylated products, methylated products, glycosides, etc.).

The polyphenol may be, for example, a synthetic product, or may be a product isolated and purified from a natural source. Furthermore, it may be a crude product, for example, in the form of an extract derived from a natural product.
Examples of such extracts include turmeric extract, bayberry extract, sophora japonica extract, milk thistle extract, coffee extract, licorice extract, cucumber extract, scutellaria extract, gentian (or gentian) extract, geranium extract, cholesterol and its derivatives, hawthorn extract, peony extract, ginkgo extract, scutellaria (or scutellaria) extract, carrot extract, rosa baicalensis (or rosa rubra, or rosehip) extract, sampanzu (or scutellaria) extract, tormentilla extract, parsley extract, peony extract, mocha extract, melissa extract, yarrow extract, saxifrage extract, rosemary extract, lettuce extract, tea extract (e.g., oolong tea extract, black tea extract, green tea extract), microbial fermentation metabolites, and monk fruit extract.

A polyphenol derivative refers to a compound in which the hydrogen atom of at least one phenolic hydroxyl group of the polyphenol described above is replaced with another group (e.g., acyl group, malonyl group, alkyl group, glycosyl group, etc.), resulting in zero or one phenolic hydroxyl group. Examples of polyphenol derivatives include, but are not limited to, polymethoxyflavonoids (hereinafter referred to as PMF). PMF refers to flavonoids having four or more methoxy groups ( _-OCH3 ). Preferred examples include flavones having four or more methoxy groups. PMF can be one type or a combination of two or more types.
Examples of PMFs include the following:
PMF with four _-OCH3 groups: 5,6,7,4'-tetramethoxyflavone
PMFs with five -OCH3 _groups : tangeretin, sinensetin
PMF with six -OCH ₃ groups: nobiletin, 3,5,6,7,3',4'-hexamethoxyflavone
PMF with seven -OCH ₃ groups: 3,5,6,7,8,3',4'-heptamethoxyflavone

The PMF may be, for example, a synthetic product or a product isolated and purified from a natural source. Furthermore, it may be a crude product, for example, in the form of an extract derived from a natural product.

Preferred examples of polyphenols include curcuminoids, flavonoids, stilbenoids, and their aglycones. Of these, preferred examples of curcuminoids include curcumin. Preferred examples of flavonoids include flavones (e.g., luteolin), flavanones (e.g., hesperetin, naringenin), and flavonols (e.g., silibinin, silymarin, rutin, quercetin, myricitrin, quercitrin, and isoquercitrin). Preferred examples of stilbenoids include resveratrol.
Further, suitable examples of the polyphenol derivatives include nobiletin, which is a methylated product of flavone, and tangeretin.

1-2. Carotenoid The carotenoid may be one type or a combination of two or more types.
Examples of carotenoids include the following: The following examples may be compounds or compositions.
Xanthophylls [e.g., lutein, zeaxanthin, canthaxanthin, fucoxanthin, astaxanthin, antheraxanthin, violaxanthin, cryptoxanthin], carotenes [e.g., α-carotene, β-carotene, γ-carotene, δ-carotene, lycopene], and apocarotenoids [e.g., apocarotenal, bixin, crocetin].
Preferred examples thereof include xanthophylls and carotenes. Preferred examples of xanthophylls include lutein and astaxanthin. Preferred examples of carotenes include β-carotene and lycopene.

The carotenoid may be, for example, a synthetic product, or may be isolated and purified from natural sources. Furthermore, it may be a crude product, for example, in the form of an extract derived from a natural product.

1-3. Coenzyme Q10
Coenzyme Q10 can be one type or a combination of two or more types.
Examples of coenzyme Q10 include ubiquinone (oxidized CoQ), ubiquinol (reduced CoQ: CoQH ₂ ), and semiquinone radical intermediate (CoQH.). In the present disclosure, a preferred example of coenzyme Q10 includes ubiquinol. Ubiquinol is also known as reduced coenzyme Q10, reduced coenzyme Q, reduced CoQ, or reduced UQ, and is a fat-soluble component known as an effective fat-soluble antioxidant.

The coenzyme Q10 may be, for example, a synthetic product, or may be isolated and purified from natural sources. Furthermore, it may be a crude product, for example, in the form of an extract derived from a natural product.

1-4. Vitamins The vitamins can be one type or a combination of two or more types.
Examples of vitamins include the following: The following examples may be compounds or compositions.
Vitamin A [e.g., retinol], vitamin D [e.g., ergosterol, ergocalciferol, cholecalciferol], vitamin E [e.g., tocopherol, tocotrienol], and vitamin K [e.g., phylloquinone].

The vitamins may be, for example, synthetic, or may be isolated and purified from natural sources. Furthermore, they may be crudely purified, for example, in the form of an extract derived from a natural product.

1-5. Sesamin Sesamin is a type of lignan found in, for example, sesame, Japanese pepper, and ginkgo.

The sesamin may be, for example, synthetic or isolated and purified from natural sources. It may also be a crude product, for example, in the form of an extract derived from a natural product.

2. Materials for making poorly water-soluble materials amorphous (hydrophilic polymers )
In the present invention, a hydrophilic polymer (hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), and/or polyvinylpyrrolidone (PVP)) is used to make the poorly water-soluble material (1b) amorphous. Suitable examples of the hydrophilic polymer include HPMC.
The HPMC to be used is not particularly limited, but may have a degree of substitution with a methoxy group of, for example, 20 to 40%, 25 to 35%, or 27 to 30%. Also, may have a degree of substitution with a hydroxypropoxy group of, for example, 3 to 20%, 5 to 15%, or 7 to 12%.
The HPC to be used is not particularly limited, but may have a degree of substitution with hydroxypropoxy groups of, for example, 7 to 12%, or 4 to 7.5%.
The PVP used is not particularly limited, but can have a K value (viscosity characteristic value correlated with molecular weight) in the range of 15 to 130, preferably 27 to 96, and more preferably 27 to 60. The K value is calculated by applying the relative viscosity value (25°C) measured by a capillary viscometer to the following Fikentscher formula.

HPMC, HPC, and PVP can be used alone or in combination of two or more types.

The mass ratio of the poorly water-soluble material (1a) and the hydrophilic polymer in this solid composition is preferably within the range of 1:99 to 60:40, more preferably within the range of 5:95 to 50:50, and even more preferably within the range of 10:90 to 40:60.

3. Process for producing a solid composition containing an amorphous poorly water-soluble material
3-1. Process A
In step A,
(1b) A crystalline poorly water-soluble material, and (2) one or more hydrophilic polymers selected from the group consisting of HPMC, HPC, and PVP are heated and kneaded.
The heating and kneading step (step A) makes it possible to change the crystalline poorly water-soluble material (1b) into an amorphous material.

The heating and kneading step is not particularly limited as long as the poorly water-soluble material (1b) can be melted, and can be carried out according to a standard method in the industry (heating and melting and kneading). For example, a method for making the poorly water-soluble material (1b) amorphous can be a method in which the poorly water-soluble material (1b) is heated until it melts. On the other hand, the organic solvent method in which the poorly water-soluble material (1b) or the like is dissolved in an organic solvent (which may involve heating or stirring to increase solubility) is not included in the manufacturing method of the present invention, since the composition of this solid composition makes it impossible to prepare an amorphous preparation of high purity.

In the manufacturing method of the present invention, the heating and kneading step can be suitably carried out by using a kneading machine such as a kneader or mixer that can control the temperature; or an extruder such as a single screw extruder, an intermeshing screw extruder, or a multi-screw extruder (e.g., a twin screw extruder). The kneading machine can perform multiple operations (kneading operations) such as mixing, crushing, kneading, and pounding in parallel to create a state in which the materials are uniformly mixed and to change the crystalline poorly water-soluble material (1b) to an amorphous state. The extruder is a machine that can perform the kneading operation and extrusion simultaneously or continuously. As with the kneading machine, the extruder can mix the materials uniformly and change the poorly water-soluble material (1b) to an amorphous state, and then extrude the solid composition containing the obtained amorphous poorly water-soluble material (1a).

The extruder may be a commercially available device. Examples of extruders include a single screw extruder and a twin screw extruder. A preferred device is a twin screw extruder. Examples of the extruder include (1) a type in which the diameter of the screw shaft is constant, (2) a type in which the diameter of the screw shaft increases, and (3) a type in which the pitch of the screw decreases along the extrusion direction.
Twin screw extruders may be used with non-perfect, partial, or perfect intermeshing screws.

The kneading conditions are preferably set so that the crystalline poorly water-soluble material (1b) is highly amorphous (preferably almost completely, more preferably substantially completely, and even more preferably completely). The kneading conditions preferably include temperature conditions.

In the step A, for example, the poorly water-soluble material (1b) and the cellulose derivative (2) are preferably kneaded under a temperature condition of the glass transition temperature (Tg) (°C) of the poorly water-soluble material (1b) or higher. When two or more poorly water-soluble materials (1b) are used, a temperature higher than the glass transition temperature (°C) of the poorly water-soluble material (1b) having the highest glass transition temperature can be used. For example, when the poorly water-soluble material (1b) is curcuminoid, its glass transition temperature is 72°C, so that the heating and kneading temperature can be 80°C or higher, preferably higher than 80°C. Therefore, for example, the temperature can be 100°C or higher, 110°C or higher, 120°C or higher, 130°C or higher, 140°C or higher, 150°C or higher, or 160°C or higher.
The glass transition temperature (Tg) can be determined in accordance with JIS K 7121:2012.

The upper limit of the temperature in the step A is not particularly limited, but may be, for example, the melting point (Tm) of the poorly water-soluble material (1b) + 80 (°C), or the melting point + 30 (°C), preferably the melting point + 20 (°C), more preferably the melting point + 10 (°C), even more preferably the melting point (°C), and even more preferably the melting point - 10 (°C). Specifically, for example, it may be 240°C or less, preferably 230°C or less, more preferably 220°C or less, even more preferably 200°C or less, even more preferably 190°C or less, and particularly preferably 180°C or less. In addition, when a plurality of poorly water-soluble materials (1b) are used, the melting point (°C) means the melting point (°C) of the material with the highest melting point.
The temperature can be, for example, in the range of 100°C to 240°C, in the range of 120°C to 230°C, in the range of 130°C to 220°C, in the range of 140°C to 210°C, in the range of 150°C to 200°C, in the range of 100°C to 200°C, in the range of 100°C to 180°C, in the range of 120°C to 200°C, or in the range of 120°C to 180°C.
The melting point (Tm) can be determined in accordance with JIS K 7121:1987.
The heating and kneading temperature in the step A can usually be adjusted by setting the internal temperature of equipment such as a kneader or an extruder, or by setting the operating conditions thereof.

The lower limit of the time for step A can be, for example, 1 second, 10 seconds, or 30 seconds. The upper limit of the time for step A can be, for example, 10 minutes, 5 minutes, or 3 minutes. The time for step A can be within the range of 1 second to 10 minutes, 10 seconds to 5 minutes, or 30 seconds to 3 minutes.
The time can usually be adjusted by setting the operating conditions of the equipment such as the kneader or extruder.

In one embodiment, the production method of the present disclosure can include a step of preparing the present solid composition containing the amorphous poorly water-soluble material (1a) by heating and kneading the poorly water-soluble material (1b) and the cellulose derivative (2), and then cooling the present solid composition to a desired temperature such as room temperature. Furthermore, the production method can also include a step of disintegrating or pulverizing the solid composition thus obtained with a disintegrator, a grinder, or the like.
In addition to the kneading step, or the cooling step, or the crushing/pulverizing step, the production method of the present disclosure can also be produced by a method having a solid-liquid separation step (e.g., solvent precipitation), a drying step (e.g., spray drying, freeze drying, reduced pressure drying, etc.), a sizing step (sieving, etc.), and/or a granulation step. These methods can be carried out according to standard methods in the industry.

3-2. Process B
The manufacturing method of the present disclosure may include a step B of granulating the kneaded mixture obtained in the step A.
The granulation may be carried out by a method using a commercially available pulverizer, etc. The granulation conditions may be set according to the desired particle size, for example.

The particle size of the present solid composition obtained in step B can be appropriately selected depending on the form of the preparation.
The lower limit of the particle size (median size; hereinafter the same) of the solid composition can be, for example, 0.1 μm, 0.5 μm, 1 μm, 5 μm, or 10 μm. The upper limit of the particle size of the solid composition can be, for example, 50 μm, 100 μm, 200 μm, or 500 μm. The particle size can be, for example, within the range of 0.1 to 500 μm, 0.5 to 500 μm, 0.5 to 200 μm, 1 to 100 μm, 5 to 100 μm, or 10 to 100 μm. The particle size (median size) can be measured according to the description of the examples described later.

The amorphous state of the poorly water-soluble material contained in the solid composition can be confirmed by powder X-ray diffraction. Powder X-ray diffraction is a method commonly used to detect crystalline materials contained in a sample. In the chart obtained by this method, scattered light due to amorphous materials is detected as a broad peak (referred to as a "halo peak" in the present invention), and diffracted light due to crystalline materials is detected as a sharp peak (referred to as a "sharp peak" in the present invention).
The amorphous state of the poorly water-soluble material (1) contained in the present solid composition can be simply evaluated based on a numerical value (also referred to as the "XRD analysis value" in the present invention) obtained by analyzing the present solid composition with a powder X-ray diffraction apparatus, in which the area of the halo peak in the range of 2θ = 5° to 60° is (S1) and the area of the sharp peak (the part beyond the halo peak) derived from the poorly water-soluble material (1b) in a crystalline state in the same range is (S2) from the formula: {(S2)/((S1)+(S2))}×100(%).
The smaller this value (XRD analysis value) is, the more the poorly water-soluble material (1a) in the amorphous state is contained in the poorly water-soluble material contained in the solid composition. However, it cannot be quantified with high accuracy, and does not indicate the specific proportion of the poorly water-soluble material (1a) in the amorphous state contained in the sample.

In the present solid composition, the XRD analysis value is, for example, 4.0% or less, 3.0% or less, 2.0% or less, 1.0% or less, 0.8% or less, 0.5% or less, or 0%. The present solid composition preferably has an XRD analysis value of 1.0% or less. More preferably, the present solid composition has an XRD analysis value of 0%, and such a solid composition is substantially or completely free of the crystalline poorly water-soluble material (1b).

The manufacturing method of the present invention is capable of amorphizing the material at a relatively low temperature range, so it is possible to maintain a high residual content (%) of the poorly water-soluble material. Examples of the residual content (%) of the poorly water-soluble material include 70% or more, 75% or more, 80% or more, 85% or more, and 90% or more.

<Solid composition containing poorly water-soluble material>
The composition of the present disclosure is a solid composition containing an amorphous poorly water-soluble material (1a) produced by the production method of the present disclosure described above.
For example, the quantitative ratio of the poorly water-soluble material (1a) to the hydrophilic polymer (2) in the present solid composition can be understood from the explanation of the production method.
The content of the poorly water-soluble material (1a) in the solid composition can be usually 1% by mass or more, preferably 5% by mass or more, more preferably 10% by mass or more, and even more preferably 15% by mass or more. The content of the poorly water-soluble material (1a) in the solid composition can be usually 60% by mass or less, preferably 50% by mass or less, more preferably 40% by mass or less, and even more preferably 35% by mass or less.
The content of the poorly water-soluble material (1a) in the present solid composition can be within the range of usually 1 to 60 mass%, preferably 5 to 50 mass%, more preferably 10 to 40 mass%, and even more preferably 15 to 35 mass%.

The content of hydrophilic polymer (2) in the solid composition can be usually 40% by mass or more, preferably 50% by mass or more, more preferably 60% by mass or more, and even more preferably 65% by mass or more. The content of hydrophilic polymer (2) in the solid composition can be usually 99% by mass or less, preferably 95% by mass or less, more preferably 90% by mass or less, and even more preferably 85% by mass or less. The content of hydrophilic polymer (2) in the solid composition can be usually in the range of 40 to 99% by mass, preferably 50 to 95% by mass, more preferably 60 to 90% by mass, and even more preferably 65 to 85% by mass.

The present solid composition is characterized by having a solid shape. Such solid shapes include powder, granule, block, and rod shapes. As described below, the present solid composition is used to prepare a product having a desired form (e.g., a formulation form) by mixing it with any other additive that does not affect the crystal state (ratio of crystalline and amorphous) of the poorly water-soluble material (1). In this case, the present solid composition is preferably prepared in a powder or granule form. The particle size of the powder or granule in this case can be appropriately selected depending on the form, and can include, for example, the particle size (median size) described above.

This solid composition can be used as it is as medicines, quasi-drugs, food and drink (including, for example, health foods, functional foods, dietary supplements (or supplements), nutritional functional foods, nutritional supplements, special dietary foods, foods for specified health uses, etc.), oral care products, cosmetics (including, for example, functional cosmetics, skin care products, hair care products, etc.), etc., or as a raw material thereof. Since this solid composition contains a very high proportion of poorly water-soluble material (1a) in an amorphous state, it may be used by adding the same poorly water-soluble material (1b) raw material as before amorphization. In this way, the advantages of adding the raw material powder before amorphization include the fact that the amount of absorption can be easily adjusted when the body absorbability of the amorphous preparation is too high, and the fact that the physical properties such as the hygroscopicity of the powder can be easily adjusted. In this case, the poorly water-soluble material (1) contained in the preparation may be adjusted, for example, to a range of amorphous:crystalline = 1:0.1 to 1:5 (mass ratio), preferably amorphous:crystalline = 1:2.

Furthermore, the solid composition can be mixed with other ingredients (e.g., ingredients of medicines, quasi-drugs, food and beverages, oral care products, or cosmetic products or additives thereto) as necessary so as not to affect the amorphous state of the poorly water-soluble material (1a) contained therein, and used to prepare the desired medicines, quasi-drugs, food and beverages, oral care products, or cosmetic products.

Examples of other additives include, but are not limited to, binders, disintegrants, lubricants, excipients, colorants, flavorings, fragrances, perfume oils, surfactants, preservatives, antioxidants, UV absorbers, moisturizers, and pH adjusters. These ingredients include those that are specified as additives in the fields of pharmaceuticals, quasi-drugs, and foods.

More specifically, these include sucrose, fructose, starches, cellulose, dextrin, powdered gum arabic, powdered ghad gum, methylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, polyethylene glycol, talc, silicon dioxide, magnesium stearate, stearic acid, stearyl alcohol, hydroxypropyl starch, sodium carboxymethyl starch, powdered agar, carboxymethylcellulose (calcium), ester oil, wax, higher fatty acids, higher alcohols, anionic surfactants, cationic surfactants, nonionic surfactants, amphoteric surfactants, and polyhydric alcohols.

The aforementioned foods and beverages include, without limitation, general foods and beverages, as well as health foods, functional foods, dietary supplements (or supplements), nutritional functional foods, nutritional supplements, special purpose foods, and foods for specified health uses. Oral care products include, without limitation, toothpastes (powders, pastes), oral odor prevention and deodorants (gum, tablets, etc.), periodontal disease prevention and improvement agents, etc. Cosmetics include, without limitation, functional cosmetics, skin care products, makeup products, cosmetics, and hair care products. The solid composition itself or a final product containing the solid composition can be a composition that is orally administered or orally ingested (e.g., oral medicines, foods and beverages), a composition that is applied to the oral cavity (e.g., oral care products), a composition that is applied to the bronchi and lungs, a composition that is administered to the eyes, a composition that is administered to the ears, a composition that is applied to the nose, a composition that is applied to the rectum, a composition that is applied to the vagina, or a composition that is applied to the skin.

Examples of product forms containing the present solid composition include tablets (e.g., uncoated tablets, sugar-coated tablets, multi-layer tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.), capsules, granules (e.g., effervescent granules), powders, oral jellies, oral tablets (e.g., troches, sublingual tablets, buccal tablets, adhesive tablets, gums, etc.), oral sprays, oral semisolids, mouthwashes, dialysis agents (e.g., peritoneal dialysis agents, hemodialysis agents), inhalants (e.g., inhalation powders, inhalation aerosols), suppositories, rectal semisolids, enemas, eye ointments, ear drops, nasal drops (nasal powders), vaginal tablets, vaginal suppositories, external solids (e.g., external powders), and sprays (e.g., external aerosols, pump sprays). The present solid composition can also be mixed with a liquid when used to prepare a liquid formulation. Such dosage forms include oral liquids (e.g., elixirs, suspensions, emulsions, and lemonades), syrups (e.g., syrup preparations), oral sprays, inhalation solutions, enemas, nasal solutions, external solutions (e.g., liniments and lotions), and sprays (e.g., external aerosols and pump sprays).
In particular, the present solid composition can be preferably an oral composition.

The content of the poorly water-soluble material (1a) in the oral composition can be usually 0.01% by mass or more, preferably 1% by mass or more, more preferably 3% by mass or more, and even more preferably 5% by mass or more. The content of the poorly water-soluble material (1a) in the composition can be usually 60% by mass or less, preferably 50% by mass or less, more preferably 40% by mass or less, and even more preferably 30% by mass or less. The content of the poorly water-soluble material (1a) in the composition can be usually within the range of 0.01 to 60% by mass, preferably 1 to 50% by mass, more preferably 3 to 40% by mass, and even more preferably 5 to 30% by mass.

Since the crystallinity of the poorly water-soluble material contained in the solid composition is reduced or lost, the solid composition has excellent disintegration, dispersibility, solubility, and/or non-aggregation properties when in contact with an aqueous medium (e.g., water, body fluids). Therefore, when the solid composition is administered to the body of an organism, it is expected to have an effect of increasing the maximum blood concentration (Cmax) of the poorly water-soluble material (1a) contained in the composition and an effect of increasing the total absorption amount of the material into the blood.
Due to this property, the function (e.g., biological activity) of the poorly water-soluble material (1a) contained in the present solid composition can be exhibited to a high degree.

In addition, this solid composition has the advantage of being excellent in storage stability, as it is less susceptible to caking and color changes even during storage.

Other embodiments disclosed herein include those in which, instead of (2) above, the hydrophilic polymer is one or more hydrophilic polymers selected from the group consisting of gum arabic, gum ghatti, low molecular weight gum ghatti, modified starch, locust bean gum, guar gum, alginic acid or a salt thereof, carrageenan (including ι-carrageenan, λ-carrageenan, and κ-carrageenan), pectin (including HM pectin and LH pectin), xanthan gum, pullulan, microcrystalline cellulose, fermented cellulose, methylcellulose, carboxymethylcellulose (CMC), dextrin (including resistant dextrin), cyclodextrin (including α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin), soybean polysaccharides, agar, tamarind seed gum, guar gum hydrolyzate, karaya gum, tara gum, welan gum, and gellan gum (including native gellan gum and acetylated gellan gum). Here, gum ghatti includes gum ghatti with a molecular weight of 800,000 or more, and low molecular weight gum ghatti includes gum ghatti with a molecular weight of less than 800,000, preferably around 100,000 to 200,000 in terms of emulsifying power.

The present invention will be described in more detail below with reference to examples. However, the present invention is not limited to these examples, and many modifications within the technical concept of the present invention are possible for those skilled in the art. Unless otherwise specified, the following tests were carried out at room temperature (25±5°C) and atmospheric pressure. Furthermore, unless otherwise specified, "%" means "% by mass" and "parts" means "parts by mass."

<Ingredients>
The materials used in the following test examples and their details are as follows:

<Test Method>
The test methods employed in the following tests are as follows:
(1) Content and residual content rate (%) of poorly water-soluble materials contained in the solid composition
The content of the poorly water-soluble material contained in the produced solid composition was measured, and the content ratio (measured value (%)) in 100% of the solid composition was calculated. The content of the poorly water-soluble material was measured by absorbance method for astaxanthin, and by HPLC method for the other poorly water-soluble materials.
As shown in the formula below, the obtained measured value (%) was divided by the ratio blended during production (theoretical value (%)), and the percentage of the obtained value was taken as the "residual content rate (%) of poorly water-soluble material."
[formula]
Residual content rate of poorly water-soluble materials (%) = "Measured value (%) / Theoretical value (%)" x 100

(a) Measurement of curcumin content (i) Preparation of measurement samples and standard samples
Curcumin 1 (Nagara Science Co., Ltd.) was dissolved in methanol, diluted with 50% acetonitrile water to 0.4 to 40 μg/ml, and filtered through a 0.45 μm membrane filter to prepare a standard sample.
The produced solid composition was diluted about 1000 to 1250 times with 50% acetonitrile water, and filtered through a 0.45 μm membrane filter to prepare a measurement sample.

The standard sample and the measurement sample were subjected to HPLC analysis under the following conditions.
(ii) Measurement conditions HPLC device: Agilent 1220 Infinity II LC system (Agilent Technologies Japan, Ltd., hereinafter the same)
Stationary phase: Atlantis T3 column (silica-based reversed phase _C18 ) (2.1 x 150 mm, 3 μm) (Waters, the same applies below)
Mobile phase: 50% (v/v) acetonitrile aqueous solution containing 0.1% (v/v) phosphoric acid Flow rate: 0.5 ml/min
Column temperature: 40℃

(b) Measurement of luteolin content (i) Preparation of measurement samples and standard samples
3',4',5,7-Tetrahydroxyflavone (Tokyo Chemical Industry Co., Ltd.) was dissolved in ethanol, diluted with 40% acetonitrile water to 0.4-40 μg/ml, and filtered through a 0.45 μm membrane filter to prepare a standard sample.
In addition, the produced solid composition was dissolved in 50% ethanol in water, then diluted 1000-fold with 40% acetonitrile in water, and filtered through a 0.45 μm membrane filter to prepare a measurement sample.
The standard sample and the measurement sample were subjected to HPLC analysis under the following conditions.

(ii) Measurement conditions HPLC device: Agilent 1220 Infinity II LC system Stationary phase: Atlantis T3 column (2.1 x 150 mm, 3 μm)
Mobile phase: 40% (v/v) acetonitrile aqueous solution containing 0.1% (v/v) phosphoric acid Flow rate: 0.3 ml/min
Column temperature: 40℃

(c) Measurement of silymarin content (i) Preparation of measurement samples and standard samples
Silybin (mixture of Silybin A and Silybin B) (Tokyo Chemical Industry Co., Ltd.) was dissolved in methanol, then diluted with 35% methanol water to 0.4-40 μg/ml (total amount of silybin), and filtered through a 0.45 μm membrane filter to prepare a standard sample.
In addition, the produced solid composition was dissolved in 65% aqueous methanol, then diluted 1000-fold with 35% aqueous methanol, and filtered through a 0.45 μm membrane filter to prepare a measurement sample.
The standard sample and the measurement sample were subjected to HPLC analysis under the following conditions.
The silymarin content was calculated using a calibration curve of a silybin standard sample containing 98.7% silybin (as the total amount of silybin A and silybin B).

(ii) Measurement conditions HPLC device: Agilent 1220 Infinity II LC system Stationary phase: Atlantis T3 column (2.1 x 150 mm, 3 μm)
Mobile phase: A: 0.2% (v/v) phosphoric acid aqueous solution, B: methanol Flow rate: 0.6 ml/min
Column temperature: 40℃
Mobile phase gradient conditions: Table 3

(d) Measurement of polymethoxyflavonoid (PMF) content (i) Preparation of measurement samples and standard samples
Nobiletin (Fujifilm Wako Pure Chemical Industries, Ltd.) was dissolved in acetonitrile, then diluted with 50% acetonitrile water to 0.4-40 μg/ml, and filtered through a 0.45 μm membrane filter to prepare a standard sample.
In addition, the produced solid composition was dissolved in acetonitrile, then diluted 1250-fold with 50% acetonitrile water, and filtered through a 0.45 μm membrane filter to prepare a measurement sample.
The standard sample and the measurement sample were subjected to HPLC analysis under the following conditions.
The PMF content was calculated using a calibration curve of a nobiletin standard sample.

(ii) Measurement conditions HPLC device: Agilent 1220 Infinity II LC system Stationary phase: Atlantis T3 column (2.1 x 150 mm, 3 μm)
Mobile phase: 50% (v/v) acetonitrile aqueous solution containing 0.1% (v/v) phosphoric acid Flow rate: 0.5 ml/min
Column temperature: 40℃

(e) Measurement of hesperetin content (i) Preparation of measurement samples and standard samples
Hesperetin (Tokyo Chemical Industry Co., Ltd.) was dissolved in methanol, diluted with 20% acetonitrile water to 0.4 to 40 μg/ml, and filtered through a 0.45 μm membrane filter to prepare standard samples.
In addition, the produced solid composition was dissolved in 50% acetonitrile water, then diluted 1000-fold with 20% acetonitrile water, and filtered through a 0.45 μm membrane filter to prepare a measurement sample.
The standard sample and the measurement sample were subjected to HPLC analysis under the following conditions.

(ii) Measurement conditions HPLC device: Agilent 1220 Infinity II LC system Stationary phase: Atlantis T3 column (2.1 x 150 mm, 3 μm)
Mobile phase: A: 0.2% (v/v) phosphoric acid aqueous solution, B: acetonitrile Flow rate: 0.6 ml/min
Column temperature: 40℃
Mobile phase gradient conditions: Table 4

(f) Measurement of resveratrol content (i) Preparation of measurement samples and standard samples
Resveratrol (Fujifilm Wako Pure Chemical Industries, Ltd.) was dissolved in methanol, diluted with 25% acetonitrile water to 0.4-40 μg/ml, and filtered through a 0.45 μm membrane filter to prepare a standard sample.
In addition, the produced solid composition was dissolved in 50% aqueous methanol, then diluted 1000-fold with 50% aqueous acetonitrile, and filtered through a 0.45 μm membrane filter to prepare a measurement sample.
The standard sample and the measurement sample were subjected to HPLC analysis under the following conditions.

(ii) Measurement conditions HPLC device: Agilent 1220 Infinity II LC system Stationary phase: Atlantis T3 column (2.1 x 150 mm, 3 μm)
Mobile phase: 0.15% (v/v) phosphoric acid in 25% (v/v) acetonitrile aqueous solution Flow rate: 0.6 ml/min
Column temperature: 40℃

(g) Measurement of sesamin content (i) Preparation of measurement samples and standard samples
(+)-Sesamin and (+)-Episesamin (both from Nagara Science Co., Ltd.) were each dissolved in methanol, then diluted with 70% methanol in water to approximately 0.4 to 40 μg/ml, and filtered through a 0.45 μm membrane filter to prepare standard samples.
In addition, the produced solid composition was dissolved in 50% methanol in water, then diluted 1000-fold with 70% methanol in water, and filtered through a 0.45 μm membrane filter to prepare a measurement sample.
The standard sample and the measurement sample were subjected to HPLC analysis under the following conditions.
The (+)-Sesamin content and (+)-Episesamin content were calculated separately, and the sum of these values was regarded as the sesamin content.

(ii) Measurement conditions HPLC device: JASCO LC-2000Plus series system (JASCO Corporation)
Stationary phase: L-column2 ODS column (4.6 x 250 mm, 5 μm) (Chemicals Evaluation and Research Institute, Japan)
Mobile phase: 70% (v/v) methanol aqueous solution Flow rate: 1.0 ml/min
Column temperature: 30℃

(h) Measurement of Astaxanthin Content The total carotenoid content in the solid composition after production was measured by absorbance method.
(i) Preparation of Measurement Sample A specific amount of the produced solid composition was weighed out (sample weighed amount), which was then diluted 2500 to 5000 times with acetone containing 1.2 mM BHT (dibutylhydroxytoluene), and filtered through a 0.2 μm membrane filter to obtain a measurement sample.
(ii) Measurement Conditions The absorbance of the measurement sample was measured using a spectrophotometer JASCO V-660DS (manufactured by JASCO Corporation). Specifically, the absorbance A at the maximum absorption wavelength near 474 nm was measured using 1.2 mM BHT-containing acetone as a control solution, and the percentage (%) of the total carotenoids contained in the measurement sample was calculated using the following formula.

(2) Evaluation of amorphousness of solid composition <X-ray powder diffraction (XRD) analysis>
The crystallinity of the solid composition was evaluated by XRD analysis of each of the samples immediately after production (initial) and after storage for a certain period of time after production (after storage). The storage was performed by placing the solid composition immediately after production in a low-density polyethylene bag (product name "Unipack A-8", manufactured by Nippon Seisakusho Co., Ltd.) and leaving it in a dark place at 40°C or 60°C and a relative humidity of 75% or in an aluminum bag (product name "Lamizip PET/AL/PE Stand Type", manufactured by Nippon Seisakusho Co., Ltd.) for one week to six months.
(i) Measurement Conditions The solid composition immediately after production and the solid composition after storage were subjected to the following powder X-ray diffraction apparatus.
Powder X-ray diffraction equipment: Smart Lab (Rigaku)
Conditions: Focusing method X-ray output: 3kW Range: 5-60°
Step width: 0.05°
Detector: D/teX Ultra 250
Optical system: CBO-E (for concentration method)
Analysis software: Smart Lab Studio II

From the obtained XRD analysis results, the area (S2) of the sharp peak (peak derived from the poorly water-soluble material (1b) in a crystalline state) in the range of 2θ = 5 to 60°, and the total area ((S1) + (S2)) of said area (S2) and the area of the halo peak (S1) were calculated using software PDXLII (Rigaku Corporation) according to the manual. Based on the XRD analysis values calculated by applying these values to the formula below, the degree of amorphization was evaluated according to the following criteria.

[XRD analysis value]
{(S2)/((S1)+(S2))}×100(%)
[Evaluation Criteria for Amorphous Degree]
⊚: XRD analysis value is 1.0% or less.
◯: The XRD analysis value is greater than 1.0% and equal to or less than 4.0%.
×: XRD analysis value is more than 4.0%.

(2-3) Appearance Evaluation of Solid Composition The appearance of the solid composition was evaluated (color change, presence or absence of caking, presence or absence of solidification). The evaluation was performed visually for each sample immediately after production (initial stage) and after storage for 1 week to 6 months after production (post-storage). Here, "caking" refers to a state in which the powder is solidified but returns to a powdery state when loosened, and "solidification" refers to a state in which the powder remains solidified and does not return to a powder state even if an attempt is made to loosen it. The storage conditions were the same as those for the crystallinity evaluation.

Test Example 1
Hydroxypropylmethylcellulose (HPMC) was used as a hydrophilic polymer, and a powder-shaped amorphous formulation was produced by a heat kneading method using an extruder and a pulverizer, and its properties were evaluated.

<Production of amorphous preparations: Heat kneading method>
The raw materials shown in Table 5 were uniformly mixed and heated and kneaded in a twin-screw extruder (product: Process 11; Thermo Fisher Scientific) (conditions: maximum heating temperature 200°C, screw rotation speed 200 rpm, kneading time approximately 2 minutes).

After the heating and kneading, the composition extruded and discharged in a rod state was pulverized using a pulverizer to obtain a powdered solid composition (median diameter: about 100 μm to 400 μm). The particle diameter of the pulverized material was measured using a Microtrac MT3300EX II (manufactured by Microtrac Bell) under the following measurement conditions.
<Particle size measurement conditions>
Measurement mode: Dry Dry feeder: Turbotrac One-Shot Dry
Set Zero Time: 5 seconds Measurement Time: 5 seconds Particle Refractive Index: 1.81
Particle shape: non-spherical

<Tests and their results>
The produced amorphous preparations (solid compositions) were evaluated for the content (residual content) of the poorly water-soluble material (1), the degree of amorphousness, and the appearance by the methods described above.
The test results are summarized in Figure 1. In the figure, the X-axis of the XRD analysis chart indicates 2θ (°) and ranges from 5 to 40°.
The preparation of Example 1 had a good residual content immediately after preparation, and the results of XRD analysis showed that it was highly amorphous, and furthermore, it was confirmed that the amorphous state was stably maintained even after storage.
On the other hand, the preparation of Comparative Example 1, which contained reduced palatinose as the third component, had good amorphousness immediately after preparation, but after 2 weeks of storage, a crystalline peak was observed in the XRD analysis and caking was observed. Also, the preparation of Comparative Example 2, which used a surfactant (polysorbate 80) as the third component, showed a crystalline peak in the XRD analysis immediately after preparation, and after 2 weeks of storage, the peak became even more prominent and yellowing was observed.

Test Example 2
In the same manner as in Example 1, amorphization tests were carried out under various temperature conditions using curcumin as the poorly water-soluble material and HPMC as the hydrophilic polymer.

<Production of amorphous preparations: Heat kneading method>
22.5% by mass of curcumin raw material and 77.5% by mass of HPMC1 (Example 2), and 22.5% by mass of curcumin raw material, 52.5% by mass of HPMC1, and 25% by mass of sucrose stearate (Comparative Example 3) were uniformly mixed and heated and kneaded in a twin-screw extruder (product: Process11; Thermo Fisher) (screw rotation speed: 200 rpm; temperature: 160°C, 180°C, 200°C, 220°C, and 240°C). After the hot kneading, the composition extruded and discharged in a rod state was pulverized using a pulverizer to obtain a powdery solid composition (median diameter: about 100 μm to 400 μm).

<Tests and their results>
After preparation, each formulation was subjected to XRD analysis to evaluate its amorphous nature, and the results are shown in FIG.
As shown in Figure 2, when curcumin is used in combination with HPMC, a highly amorphous preparation can be prepared even at a relatively low temperature of 160°C, which is below the melting point (183°C), as long as the heating and kneading temperature is equal to or higher than the glass transition temperature of curcumin (69°C) (Example 2). On the other hand, when a preparation containing a sucrose fatty acid ester as a third component in addition to HPMC was heated and kneaded at 160°C, a peak derived from crystals was observed, suggesting that the amorphousization was incomplete (Comparative Example 3).
These results suggest that when amorphization is performed by a heat kneading method at 200° C. or lower, particularly in a relatively low temperature range between the glass transition temperature and the melting point of the poorly water-soluble material to be amorphized, it is advisable to use HPMC and perform the amorphization in a two-component system that does not contain a third component such as a sucrose fatty acid ester.

Test Example 3
Preparation of Formulations by Solvent Spray Method
25 parts by mass of the curcumin raw material and 75 parts by mass of HPMC2 were mixed, and 16.7 times the amount of 70% ethanol water was added after heating to 80° C. and stirring. The mixture was stored at 80° C. and spray-dried using a spray device MDL-015 (Fujisaki Electric) (Inlet temperature 140° C., Outlet temperature 90° C., flow rate 16 g/min).

<Tests and their results>
A comparison test (XRD analysis and appearance evaluation) was carried out between the powder preparation prepared above (Comparative Example 4) and the preparation of the present invention prepared in the above Test Example 1 (Example 1). The results are shown in FIG.

The preparation (Example 1) produced by the heat kneading method of the present invention had a good curcumin retention rate and was less likely to caking after storage, and thus had excellent storage stability, compared to the preparation (Comparative Example 4) produced by the solvent spraying method. According to the XRD analysis chart, the peak shapes were different between the two preparations, suggesting that although the curcumin in both preparations was amorphous, the molecular state (molecular arrangement and intermolecular distance) of the curcumin and HPMC was different due to the difference in manufacturing method.

Test Example 4
As shown in Table 6, each material was mixed in each ratio to produce amorphous preparations (solid compositions) (Examples 3 to 6) in the same manner as in Example 1. The content (residual content rate) of the poorly water-soluble material (1), the degree of amorphousness, and the appearance were evaluated by the methods described above. The heating and kneading temperature and time are shown in Table 6.

The results are shown in Figure 4. As shown in Figure 4, it was confirmed that highly amorphous preparations could be produced by using curcumin in combination with not only HPMC but also hydrophilic polymers such as HPC and PVP (Examples 3 to 5). In addition, highly amorphous preparations could be produced using luteolin, a type of polyphenol like curcumin, as a poorly water-soluble material (Example 6). All of these amorphized preparations maintained a stable amorphous state even after storage. In addition, the storage stability of amorphous preparations using only HPMC, HPC, or PVP was higher than that of amorphous preparations containing other polymers (data not shown), confirming the usefulness of using HPMC, HPC, or PVP as the only hydrophilic polymer when amorphizing poorly water-soluble materials by the heat-kneading method.

Test Example 5
As shown in Table 7, each material was mixed in each ratio to produce amorphous preparations (solid compositions) (Examples 7 to 12) in the same manner as in Example 1. The content (residual content rate) of the poorly water-soluble material (1), the degree of amorphousness, and the appearance were evaluated by the methods described above. The heating and kneading temperature and time are shown in Table 7.

The results are shown in Figures 5-1 and 5-2. As shown in Figures 5-1 and 5-2, it was confirmed that highly amorphous formulations can be produced by combining many types of poorly water-soluble materials with hydrophilic polymers such as HPMC during heating and kneading. Furthermore, the amorphous state of all of these amorphous formulations was stably maintained even after storage.

Test Example 6
Only the curcumin raw material was heated and kneaded using an extruder until it melted, and the melt was kept at room temperature to cool and solidify, and then pulverized to prepare a solid composition (Comparative Example 5). In addition, HPMC and dextrin were powder-mixed with this in the ratios shown in Figure 6 to prepare a solid composition (Comparative Example 6).
The solid compositions thus prepared (Comparative Examples 5 and 6) were evaluated for degree of amorphization by the method described above.

The results are shown in Figure 6.
As shown in Fig. 6, when curcumin was melted by heating alone, the amorphization was insufficient. It was also confirmed that the desired amorphization could not be achieved even when HPMC and dextrin were subsequently added thereto.

Conventionally, in the heat kneading method using a kneader or the like, the viscosity of the base material (polymer) used to stabilize the amorphous substance could be a problem. Specifically, when a polymer with high viscosity is used for heat kneading, it is necessary to knead with a stronger torque or at a higher temperature to reduce the viscosity, which causes a problem of a decrease in the content of poorly water-soluble materials in the amorphous formulation. According to the present disclosure, it has been confirmed that heat kneading at a temperature of melting point + 10°C or lower, preferably below the melting point, can stably amorphize the formulation without significantly decreasing the content of poorly water-soluble materials.

Claims (6)

A method for producing a solid composition containing an amorphous poorly water-soluble material, which essentially consists of (1a) an amorphous poorly water-soluble material, and (2) one or more hydrophilic polymers selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, and polyvinylpyrrolidone, comprising:
(1b) a crystalline poorly water-soluble material, and (2) one or more hydrophilic polymers selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, and polyvinylpyrrolidone ,
A production method comprising a step A of heating and kneading the component (1b) at a temperature of not less than the glass transition temperature of the component (1b) and not more than 230° C. in the absence of a surfactant,
The above-mentioned method for producing a pharmaceutical composition, wherein the poorly water-soluble material is at least one selected from the group consisting of polyphenols, polymethoxyflavonoids, carotenoids, coenzyme Q10, vitamins, and sesamin . The method according to claim 1 , wherein the polyphenol is one or more selected from the group consisting of curcumin, luteolin, silymarin, rutin, quercetin, myricitrin, quercitrin, isoquercitrin, nobiletin, tangeretin, naringenin, and resveratrol. The method according to claim 1 or 2 , wherein a mass ratio of the (1b) crystalline poorly water-soluble material and the (2) hydrophilic polymer is within a range of 1:99 to 60:40. The method according to any one of claims 1 to 3 , further comprising a step B of granulating the kneaded mixture obtained in the step A. A solid composition containing an amorphous poorly water-soluble material, produced by the production method according to any one of claims 1 to 4 . The solid composition containing an amorphous poorly water-soluble material according to claim 5 , which is an oral composition.

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