Solid dispersions of poorly soluble drugs

Abstract

By providing a solid dispersion containing (2E)-3-{2,6-dichloro-4-[(4-{3-[(1S)-1-(hexyloxy)ethyl]-2-methoxyphenyl}-1,3-thiazolyl)carbamoyl]phenyl}-2-methyl-2-acrylic acid or a pharmaceutically acceptable salt thereof and a water-soluble polymer, the water solubility of the compound is increased, and the absorption of the compound when administered orally is increased.

Description

Technical Field

[0001] This invention relates to solid dispersions for improving the solubility and oral absorption of poorly soluble drugs. Background Technology

[0002] When oral administration of poorly soluble drugs with polar groups in their molecules, oral absorption is sometimes reduced due to low solubility under pH conditions in the digestive tract. In particular, compounds with acidic groups in their molecules tend to become poorly soluble as the pH decreases. Therefore, when administered orally, they cannot dissolve efficiently from the formulation in the stomach, and even if they temporarily dissolve, they will immediately precipitate out, resulting in low oral absorption. As an example of such a compound, there is (2E)-3-{2,6-dichloro-4-[(4-{3-[(1S)-1-(hexyloxy)ethyl]-2-methoxyphenyl}-1,3-thiazolyl)carbamoyl]phenyl}-2-methyl-2-acrylic acid or a pharmaceutically acceptable salt thereof (hereinafter, sometimes referred to as "Compound I") (Patent Documents 1-3).

[0003] Various studies are being conducted on methods to improve the oral absorption of poorly soluble drugs. For example, when the poorly soluble drug is a compound with an acidic group in its molecule, preparations have been reported that (1) improve the solubility of the poorly soluble drug by forming it into a salt (Patent Document 4), and (2) improve the solubility of the poorly soluble drug by combining it with an alkaline reagent to create an alkaline environment around the poorly soluble drug if the solubility is reduced at low pH (Patent Documents 5-7, Non-Patent Document 1).

[0004] Patent document 4 describes how the solubility of poorly soluble drugs in water at pH 7 is improved by salting them, but oral administration can cause drug precipitation under the acidic pH conditions of the stomach.

[0005] The formulation in Patent Document 5 is manufactured by adding an alkaline reagent to granules containing a poorly soluble drug from the outside. In addition, the formulation in Non-Patent Document 1 is made by directly compressing a mixture containing a poorly soluble drug and an alkaline reagent into tablets. Although the drug dissolution is improved in each formulation, a large amount of alkaline reagent is required when preparing formulations of drugs with particularly high poor solubility, which is not suitable as a formulation.

[0006] In addition, the formulations in Patent Documents 6 and 7 granulate the poorly soluble drug, the alkaline reagent, and the disintegrant together. Therefore, during disintegration, the granules themselves disintegrate, causing the alkaline reagent to disperse from the vicinity of the poorly soluble drug, which may result in the loss of an environment suitable for the dissolution of the poorly soluble drug.

[0007] As one method to improve the oral absorption of poorly soluble drugs, methods for forming solid dispersions are known. Since solid dispersions are manufactured by loading finely micronized poorly soluble drugs onto a base, the poorly soluble drugs exist in an amorphous state within the solid dispersion (Non-Patent Document 2). Patent Documents 8-15 disclose solid dispersions. However, the compounds in the solid dispersions disclosed in Patent Documents 8-15 have significantly different chemical structures from Compound I of this application, and these documents do not disclose that Compound I exists in an amorphous state within the solid dispersion.

[0008] Based on the above, as a method to improve the solubility and oral absorption of compound I, it is hoped that a solid dispersion of compound I can be developed.

[0009] Existing technical documents

[0010] Patent documents

[0011] Patent Document 1: International Publication No. 2005 / 014561

[0012] Patent Document 2: International Publication No. 2009 / 017098

[0013] Patent Document 3: International Publication No. 2012 / 043709

[0014] Patent Document 4: International Publication No. 2006 / 100281

[0015] Patent Document 5: International Publication No. 2009 / 048940

[0016] Patent Document 6: International Publication No. 2007 / 061415

[0017] Patent Document 7: Japanese Application Publication No. Hei 3-240729

[0018] Patent Document 8: Japanese Application Publication No. Hei 7-118154

[0019] Patent Document 9: International Publication No. 98 / 01122

[0020] Patent Document 10: International Publication No. 2009 / 123169

[0021] Patent Document 11: Japanese Patent Application No. 2012-522791

[0022] Patent Document 12: Japanese Patent Application No. 2012-527491

[0023] Patent Document 13: Japanese Application Publication No. 2014-58584

[0024] Patent Document 14: Japanese Application Publication No. 2018-20982

[0025] Patent Document 15: International Publication No. 2010 / 107040

[0026] Non-patent literature

[0027] Non-patent literature 1: "Design and evaluation of oral drug delivery formulations", page 178, (1995)

[0028] Non-patent literature 2: Pharmaceutics, Vol. 69, No. 5, pp. 329-335 (2009). Summary of the Invention

[0029] The problem that the invention aims to solve

[0030] The object of the present invention is to provide formulations, particularly solid dispersions, in which the solubility of poorly soluble drugs, especially compound I, is improved, resulting in improved oral absorption.

[0031] Solution for solving the problem

[0032] The inventors discovered that a solid dispersion containing compound I could be obtained, thereby completing the following invention (hereinafter, sometimes referred to as "the formulation of the present invention").

[0033] That is, the present invention relates to:

[0034] (1) A solid dispersion containing (2E)-3-{2,6-dichloro-4-[(4-{3-[(1S)-1-(hexyloxy)ethyl]-2-methoxyphenyl}-1,3-thiazolyl)carbamoyl]phenyl}-2-methyl-2-acrylic acid or a pharmaceutically acceptable salt thereof, and a water-soluble polymer;

[0035] (2) The solid dispersion described in (1) above, wherein the water-soluble polymer is selected from one or more of cellulose polymers, vinyl polymers, acrylic polymers and polyether polymers;

[0036] (3) The solid dispersion described in (2) above, wherein the water-soluble polymer is a cellulose-based polymer, which is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methylcellulose, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxyethyl methylcellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose and cellulose acetate;

[0037] (4) The solid dispersion described in (3) above, wherein the cellulose polymer is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, methyl cellulose, carboxymethyl ethyl cellulose and hydroxypropyl methyl cellulose acetate succinate;

[0038] (5) The solid dispersion described in (4) above, wherein the cellulose polymer is selected from one or more of methylcellulose, carboxymethyl ethyl cellulose and hydroxypropyl methylcellulose acetate succinate;

[0039] (6) The solid dispersion described in (2) above, wherein the water-soluble polymer is a vinyl polymer, and the vinyl polymer is selected from one or more of the following: polyvinylpyrrolidone, polyvinyl polypyrrolidone, polyvinyl alcohol, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyvinyl alcohol-polyethylene glycol-graft copolymer, polyvinyl acetal diethylaminoacetate, fumaric acid-stearic acid-polyvinyl acetal diethylaminoacetate-hydroxypropyl methylcellulose mixture and polyvinyl acetal diethylaminoacetate;

[0040] (7) The solid dispersion described in (6) above, wherein the vinyl polymer is selected from one or more of polyvinylpyrrolidone, polyvinyl polypyrrolidone, polyvinyl alcohol and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer;

[0041] (8) The solid dispersion described in (7) above, wherein the vinyl polymer is polyvinylpyrrolidone and / or polyvinyl polypyrrolidone;

[0042] (9) The solid dispersion described in (2) above, wherein the water-soluble polymer is an acrylic polymer, and the acrylic polymer is selected from one or more of the following: aminoalkyl methacrylate copolymer E, methacrylate copolymer L, methacrylate copolymer LD, methacrylate copolymer S, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer, aminoalkyl methacrylate copolymer, methyl acrylate-methacrylate-methyl methacrylate copolymer, and 2-methyl-5-vinylpyridine acrylate-methyl methacrylate copolymer;

[0043] (10) The solid dispersion described in (2) above, wherein the water-soluble polymer is a polyether polymer, which is polyethylene glycol and / or propylene oxide-ethylene oxide block copolymer;

[0044] (11) The solid dispersion of any one of (1) to (10) above, comprising (2E)-3-{2,6-dichloro-4-[(4-{3-[(1S)-1-(hexyloxy)ethyl]-2-methoxyphenyl}-1,3-thiazolyl)carbamoyl]phenyl}-2-methyl-2-acrylic acid or a pharmaceutically acceptable salt thereof, and a water-soluble polymer thereof, wherein the weight ratio of the compound or a pharmaceutically acceptable salt thereof to the water-soluble polymer is 1:0.1 to 1:50;

[0045] (12) The solid dispersion described in (11) above, wherein the weight ratio of the aforementioned compound or its pharmaceutically acceptable salt to the water-soluble polymer is 1:0.5 to 1:25;

[0046] (13) The solid dispersion described in (12) above, wherein the weight ratio of the aforementioned compound or its pharmaceutically acceptable salt to the water-soluble polymer is 1:1 to 1:10;

[0047] (14) A solid dosage form selected from powders, granules and tablets, which contains any one of the solid dispersions described in (1) to (13) above;

[0048] (15) The solid dispersion or solid dosage form of any one of (1) to (14) above, wherein the dissolution rate of (2E)-3-{2,6-dichloro-4-[(4-{3-[(1S)-1-(hexyloxy)ethyl]-2-methoxyphenyl}-1,3-thiazolyl)carbamoyl]phenyl}-2-methyl-2-acrylic acid or a pharmaceutically acceptable salt thereof is 1% or more after 60 minutes from the start of the dissolution test in the dissolution test method (paddle method) specified in the Japanese Pharmacopoeia;

[0049] (16) The solid dispersion or solid preparation of any one of (1) to (15) above, wherein (2E)-3-{2,6-dichloro-4-[(4-{3-[(1S)-1-(hexyloxy)ethyl]-2-methoxyphenyl}-1,3-thiazolyl)carbamoyl]phenyl}-2-methyl-2-acrylic acid is in an amorphous state;

[0050] (17) (2E)-3-{2,6-dichloro-4-[(4-{3-[(1S)-1-(hexyloxy)ethyl]-2-methoxyphenyl}-1,3-thiazolyl)carbamoyl]phenyl}-2-methyl-2-acrylic acid, which is in an amorphous state.

[0051] Invention Effects

[0052] The formulation of the present invention is a solid dispersion that exhibits high solubility for poorly soluble drugs, particularly compound I, and is therefore expected to exhibit high oral absorption over a broad range from the stomach to the upper small intestine. Attached Figure Description

[0053] Figure 1 The diagram illustrates the dissolution behavior of capsules containing the solid dispersion of compound I obtained in Examples 1-4 and Reference Examples 1-2 at the start of a time-lapse test and after a certain period of time since the start of the time-lapse test. The vertical axis represents the dissolution rate (%), and the horizontal axis represents the time (minutes) since the start of the dissolution test.

[0054] Figure 2 The diagram shows the dissolution behavior of the compound I suspension obtained in Comparative Example 1 at the start of the time-delayed storage test and after a certain period of time since the start of the time-delayed storage test. The vertical axis represents the dissolution rate (%), and the horizontal axis represents the time (minutes) after the start of the dissolution test.

[0055] Figure 3 The graph shows the changes in plasma concentration of compound I resulting from oral administration of the solid dispersion capsules obtained in Examples 1, 2, and 4. The vertical axis represents plasma concentration (ng / mL), and the horizontal axis represents time (hours) after the start of the test.

[0056] Figure 4 : Shows the powder X-ray diffraction pattern of compound I crystals. The vertical axis represents intensity (cps), and the horizontal axis represents 2θ (degrees).

[0057] Figure 5 The image shows the powder X-ray diffraction pattern of the solid dispersion powder containing compound I and hydroxypropyl methylcellulose acetate succinate obtained in Example 5. The vertical axis represents intensity (cps), and the horizontal axis represents 2θ (degrees).

[0058] Figure 6 The image shows the powder X-ray diffraction pattern of the solid dispersion powder containing compound I and methylcellulose obtained in Example 6. The vertical axis represents intensity (cps), and the horizontal axis represents 2θ (degrees).

[0059] Figure 7 The image shows the powder X-ray diffraction pattern of the solid dispersion powder containing the compound and hydroxypropyl methylcellulose obtained in Example 7. The vertical axis represents intensity (cps), and the horizontal axis represents 2θ (degrees).

[0060] Figure 8 The image shows the powder X-ray diffraction pattern of the solid dispersion powder containing compound I and povidone obtained in Example 8. The vertical axis represents intensity (cps), and the horizontal axis represents 2θ (degrees).

[0061] Figure 9 : This shows the powder X-ray diffraction pattern of the solid dispersion powder containing compound I and polyvinyl alcohol obtained in Reference Example 3. The vertical axis represents intensity (cps), and the horizontal axis represents 2θ (degrees).

[0062] Figure 10 : This shows the powder X-ray diffraction pattern of the solid dispersion powder containing compound I and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer obtained in Reference Example 4. The vertical axis represents intensity (cps), and the horizontal axis represents 2θ (degrees).

[0063] Figure 11 : This shows the powder X-ray diffraction pattern of the solid dispersion powder containing compound I and the methacrylic acid copolymer L-SD obtained in Reference Example 5. The vertical axis represents intensity (cps), and the horizontal axis represents 2θ (degrees). Detailed Implementation

[0064] The terminology used in this specification is explained.

[0065] "Poorly soluble" means that the solubility in a solvent, particularly water, buffer solution, or digestive tract fluid, is less than 1 mg / ml, more preferably less than 100 μg / ml, further preferably less than 10 μg / ml, particularly preferably less than 1 μg / ml, and most preferably less than 0.1 μg / ml. It is preferable to be poorly soluble in any solvent with a pH of 7 or lower, more preferably in any solvent with a pH of 4 to 7, and even more preferably in solvents with a pH of 4 and / or 7. In the case of compounds having a basic group within the molecule, it is preferable to be poorly soluble in any solvent with a pH of 7 or higher, more preferably in any solvent with a pH of 7 to 9, and even more preferably in solvents with a pH of 7 and / or 9. The solvent used to determine the solubility is not particularly limited. Examples of solvents for pH 4 include acetate buffer and citrate buffer. Examples of solvents for pH 5 include acetate buffer, citrate buffer, and phosphate buffer. Examples of solvents for pH 7 include water and phosphate buffer. Examples of solvents for pH 9 include carbonate buffer. The temperature for measuring solubility is preferably 20–40°C, more preferably 37°C, in any case.

[0066] As a poorly soluble drug for the formulation of the present invention, examples include the following formula described in International Publication No. 2005 / 014561 and International Publication No. 2009 / 017098, namely (2E)-3-{2,6-dichloro-4-[(4-{3-[(1S)-1-(hexyloxy)ethyl]-2-methoxyphenyl}-1,3-thiazolyl)carbamoyl]phenyl}-2-methyl-2-acrylic acid or a pharmaceutically acceptable salt thereof (compound I).

[0067] [Chemistry 1]

[0068]

[0069] In addition, compound I is manufactured using the method described in International Publication No. 2015 / 093586.

[0070] The formulation of this invention is a solid dispersion, essentially containing a drug and a polymer. A solid dispersion refers to a matrix formed by mixing a drug with a polymer and then solidifying the mixture, resulting in a stable dispersion of the amorphous drug molecules within the polymer. More specifically, a solid dispersion refers to a matrix formed by dissolving and mixing a drug with a water-soluble polymer in a co-solvent in a single step, followed by solidification, resulting in a stable dispersion of the amorphous drug molecules within the polymer. This formulation technology improves solubility and dissolution rate by solidifying crystalline, poorly soluble drugs, thereby making the drugs amorphous.

[0071] In this specification, "amorphous" means substantially amorphous. For example, it means that 80% or more, preferably 90% or more, more preferably 95% or more, and most preferably 99% or more of the compounds present in the composition are in an amorphous state. Furthermore, regarding crystallinity, it means, for example, having a crystallinity of about 20% or less, preferably about 10% or less, more preferably about 5% or less, and most preferably about 1% or less.

[0072] In this specification, "improved solubility" means increasing the solubility of compound I in water or buffer solutions, etc. Specifically, it is specified that, for example, when evaluating a solid dispersion or a pharmaceutical composition containing a solid dispersion by dissolution testing, the solubility of the solid dispersion containing compound I (or, compound I in a solid dispersion of compound I) is at least 1.5 times the solubility of compound I itself, or at least 2 times, or even more preferably 5 times, or even more preferably 10 times.

[0073] In this specification, "stable" means that the solid dispersion inhibits the crystallization of the amorphous compound in a time-dependent stability test.

[0074] To ensure high quality, including stability during storage, the pharmaceutical compositions of the present invention are preferably in an amorphous state.

[0075] As used in this specification, "amorphous state" refers to a state that does not have a regular three-dimensional crystalline structure. Whether a compound or preparation is amorphous can be determined by several techniques, including powder X-ray diffraction, Raman spectroscopy, infrared spectroscopy, differential scanning calorimetry, solid-state NMR, and electron microscopy.

[0076] The polymer used in the solid dispersion of the formulation of this invention can be any pharmaceutically acceptable polymer, and can be a mixture of two or more. Specifically, the polymer used in the solid dispersion is a water-soluble polymer. As a water-soluble polymer, any pharmaceutically acceptable polymer can be used, specifically including cellulose-based polymers, vinyl-based polymers, acrylic polymers, and polyether-based polymers. Cellulose-based polymers, vinyl-based polymers, and acrylic polymers are preferred.

[0077] Examples of cellulose-based polymers include hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methylcellulose, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxyethyl methylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, and cellulose acetate phthalate. Preferably, these are hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methylcellulose, carboxymethyl ethyl cellulose, and hydroxypropyl methylcellulose acetate succinate. More preferably, they are methylcellulose, carboxymethyl ethyl cellulose, and hydroxypropyl methylcellulose acetate succinate.

[0078] Examples of vinyl-based polymers include polyvinylpyrrolidone, polyvinyl polypyrrolidone, polyvinyl alcohol, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer. Polyvinylpyrrolidone and polyvinyl polypyrrolidone are preferred.

[0079] As acrylic polymers, specific examples include aminoalkyl methacrylate copolymer E, methacrylate copolymer L, methacrylate copolymer LD, methacrylate copolymer S, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer, aminoalkyl methacrylate copolymer, methyl acrylate-methacrylate-methyl methacrylate copolymer, and 2-methyl-5-vinylpyridine acrylate-methacrylate copolymer.

[0080] Examples of polyether-based polymers include polyethylene glycol and propylene oxide-ethylene oxide block copolymers.

[0081] In order to manufacture the solid dispersion of the formulation of the present invention, the weight ratio of (2E)-3-{2,6-dichloro-4-[(4-{3-[(1S)-1-(hexyloxy)ethyl]-2-methoxyphenyl}-1,3-thiazolyl)carbamoyl]phenyl}-2-methyl-2-acrylic acid or a pharmaceutically acceptable salt thereof as compound I to the polymer is 1:0.05 to 1:100, preferably 1:0.1 to 1:50, more preferably 1:0.5 to 1:25, and particularly preferably 1:1 to 1:10.

[0082] The following describes in detail the solid dispersion comprising compound I and a water-soluble polymer, and the method for manufacturing a pharmaceutical composition comprising the solid dispersion of the present invention.

[0083] The solid dispersion of the present invention is typically manufactured by dissolving and / or suspending compound I and a water-soluble polymer in a pharmaceutically acceptable solvent, followed by distillation of the solvent.

[0084] As a pharmaceutically acceptable solvent used in this invention, there are no particular limitations on any substance that can maintain Compound I in an amorphous state in the presence of a water-soluble polymer. Examples include ketones such as acetone, methanol, ethanol, propanol and other alcohols, dichloromethane, or mixtures thereof and mixtures with water. One or more pharmaceutically acceptable solvents can be used, preferably in combination. A mixture of ethanol and acetone is particularly suitable. Regarding the proportion of water, in a pharmaceutically acceptable solvent amount, it is suitable to contain more than 0% by weight and less than 50% by weight. For example, the ratio of ethanol to acetone is 9.9:0.1 to 0.1:9.9, another is 9.5:0.5 to 5.0:5.0, and yet another is 9.5:0.5 to 8.5:1.5. Alternatively, the ratio of ethanol to acetone may be, for example, 10.0:0.0 to 0.1:9.9, another option is 10.0:0.0 to 5.0:5.0, yet another option is 10.0:0.0 to 6.0:4.0, and yet another option is 9.5:0.5 to 8.5:1.5.

[0085] The amount of solvent acceptable in pharmaceuticals is not particularly limited as long as it is the amount required for compound I to be in an amorphous state, and is 1 to 100 times (w / w) relative to the weight of the compound and the water-soluble polymer, or 5 to 20 times (w / w) in other cases.

[0086] As a method for distilling off pharmaceutically acceptable solvents used in this invention, there is no particular limitation as long as the solvent is distilled off from a liquid in which compound I and a water-soluble polymer are dissolved and / or suspended. Examples include spray drying, vacuum drying, and ventilation drying. Spray drying is another example.

[0087] The method for manufacturing the solid dispersion of the present invention involves dissolving and / or suspending compound I and a water-soluble polymer in a pharmaceutically acceptable solvent, and then distilling off the solvent to produce the solid dispersion.

[0088] The manufacturing method itself can employ well-known methods. Examples include, for instance, the pulverization process of compound I, water-soluble polymers, or additives, the mixing process, or the dissolution / suspension process in pharmaceutically acceptable solvents, the spray drying process, the depressurization drying process, the mixing process, the sieving process, etc.

[0089] The solid dispersion comprising compound I and a water-soluble polymer of the present invention is further formulated with pharmaceutically acceptable additives to form a pharmaceutical composition. Examples of dosage forms for this formulation include solid dosage forms, specifically tablets, capsules, powders, granules, and pills as described in the General Principles of Pharmaceutical Preparations in the Japanese Pharmacopoeia. Tablets, granules, or capsules are preferred, and tablets are more preferred.

[0090] As an additive incorporated into a pharmaceutical composition, there are no particular restrictions as long as it is pharmaceutically acceptable. Specific uses include excipients, disintegrants, binders, lubricants, coating agents, etc.

[0091] As an excipient, any pharmaceutically acceptable excipient is acceptable, and a mixture of two or more can be used. Specifically, either water-soluble or water-insoluble excipients can be used. More specifically, examples of water-soluble excipients include glucose, fructose, lactose, sucrose, D-mannitol, erythritol, maltitol, trehalose, and sorbitol; examples of water-insoluble excipients include corn starch, potato starch, wheat starch, rice starch, crystalline cellulose, anhydrous silica, and hydrated silica.

[0092] The content of excipients relative to the formulation of the present invention is preferably 9-99% by weight, more preferably 15-98% by weight, further preferably 35-97% by weight, particularly preferably 50-95% by weight, and most preferably 50-90% by weight.

[0093] As a disintegrant, any pharmaceutically acceptable disintegrant is acceptable, and a mixture of two or more can be used. Specific examples include cellulose derivatives, corn starch, α-starch, starch derivatives, polyvinylpyrrolidone derivatives, and agar powder. Cellulose derivatives, polyvinylpyrrolidone derivatives, or starch derivatives are preferred. Examples of cellulose derivatives include low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, and croscarmellose sodium, with low-substituted hydroxypropyl cellulose or calcium carboxymethyl cellulose being preferred. Examples of polyvinylpyrrolidone derivatives include croscarmellose, with croscarmellose being preferred. Examples of starch derivatives include sodium carboxymethyl starch, with sodium carboxymethyl starch being preferred.

[0094] The content of the disintegrant relative to the formulation of the present invention is 0.2 to 30% by weight, preferably 0.5 to 20% by weight, more preferably 1 to 10% by weight.

[0095] As an adhesive, any pharmaceutically acceptable material is acceptable, and a mixture of two or more types may be used. Specific examples include cellulose derivatives, polyvinylpyrrolidone, hydroxypropyl starch, sodium carboxymethyl starch, etc., with cellulose derivatives and / or polyvinylpyrrolidone being preferred. Examples of cellulose derivatives include hydroxypropyl methylcellulose, a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose, etc., with hydroxypropyl cellulose being preferred.

[0096] The content of the adhesive relative to the formulation of the present invention is 0.1 to 20% by weight, preferably 0.25 to 15% by weight, and more preferably 0.5 to 10% by weight.

[0097] As a lubricant, any substance that is pharmaceutically acceptable can be used, and a mixture of two or more substances is also acceptable. Specific examples include sucrose fatty acid esters, talc, hydrated silica, and metal stearate salts. Magnesium stearate and talc are preferred.

[0098] The lubricant content is 0.1 to 10% by weight, preferably 0.25 to 5.0% by weight, and more preferably 0.5 to 3.0% by weight, relative to the formulation of the present invention.

[0099] As a coating agent, any pharmaceutically acceptable material can be used. Specific examples include polyvinyl alcohol, ethyl cellulose, carboxymethyl ethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, PVA copolymers, ethyl acrylate-methyl methacrylate copolymer dispersions, aminoalkyl methacrylate copolymers, opadryl, carnauba wax, carboxyvinyl polymers, dried methacrylic acid copolymers, dimethylaminoethyl methacrylate-methyl methacrylate copolymers, stearyl alcohol, shellac, cetyl alcohol, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methyl cellulose, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, methacrylic acid copolymers, and 2-methyl-5-vinylpyridine acrylate-methacrylic acid copolymers. Hydroxypropyl methyl cellulose is preferred. Coating can be performed using known methods.

[0100] The coating agent described above may contain one or more colorants. Examples of colorants include food colorings such as Edible Red No. 3, Edible Yellow No. 5, and Edible Blue No. 1, titanium dioxide, ferric oxide, brown ferric oxide, black ferric oxide, copper chlorophyllin, sodium copper chlorophyllin, riboflavin, and matcha powder. Titanium dioxide and / or ferric oxide are preferred. The coloring sometimes also has a light-blocking effect. Some poorly soluble drugs sometimes decompose by reacting with an alkaline reagent (e.g., magnesium oxide) in a specific wavelength region, such as 300–500 nm, but this decomposition is inhibited by pre-mixing with a colorant, preferably ferric oxide.

[0101] Other additives include acidulants, foaming agents, artificial sweeteners, flavorings, colorings, stabilizers, buffers, and antioxidants.

[0102] As a formulation containing the solid dispersion of the present invention, particularly a solid formulation, it can specifically be granules, fine granules, tablets, powders, capsules, pills, etc., and can be manufactured by known means.

[0103] There are no particular limitations on the manufacturing method of granules containing the solid dispersion of the present invention. Specifically, it is a method of mixing the solid dispersion of the present invention, disintegrants, excipients, and other additives to prepare a mixed powder, and then granulating the mixed powder. Preferably, it is a wet granulation method by adding water or water containing a binder and solvent for granulation, or a dry granulation method or melt granulation method by compression molding without using water. As machinery for mixing the active ingredients, additives, etc., a V-type mixer or a container mixer can be used. In addition, as granulation machinery, a wet extrusion granulator, a fluidized bed granulator, a stirred granulator, a dry crushing granulator, or a melt extrusion granulator can be used.

[0104] There are no particular limitations on the method for manufacturing tablets containing the solid dispersion of the present invention. Specifically, granules are manufactured by the above method, and then excipients, disintegrants, and lubricants are mixed with the granules. The mixed granules are then compressed into tablets using a tableting machine. Alternatively, the solid dispersion of the present invention, excipients, disintegrants, and lubricants are mixed, and the mixture is compressed into tablets using a tableting machine. A V-type mixer or a container mixer can be used as the machinery for mixing the active ingredients, additives, etc. Furthermore, a single-punch tableting machine or a rotary tableting machine can be used as the tableting machine.

[0105] Granules and tablets containing the solid dispersion of the present invention are sometimes coated with pigments and polymers after manufacturing to form a coating layer. For forming a coating layer on granules, fluidized bed granulation coating machines, fluidized bed rotary coating machines, etc., can be used. For forming a coating layer on tablets, pot-type coating machines, aerated coating machines, etc., can be used. When forming a coating layer on the surface of a formulation using light-stabilizing substances and polymers, the light-stabilizing substances and polymers are dissolved or suspended in solvents such as water and ethanol to prepare a coating solution. The coating solution is sprayed onto the granules or tablets while they are flowing in a coating machine, and then dried to form a coating layer.

[0106] The tablet shape can be any shape, specifically round, oval, spherical, stick-shaped, or donut-shaped. It can also be a laminated tablet, a tablet with a core, etc., but a single-layer tablet, which is easy to manufacture, is preferred. Furthermore, markings, text, and dividing lines for improved legibility can be applied.

[0107] The determination of powder X-ray diffraction patterns was performed in accordance with the powder X-ray diffraction determination method described in the General Test Methods section of the Japanese Pharmacopoeia.

[0108] Typically, the diffraction angle (2θ) in powder X-ray diffraction may have an error within the range of ±0.2°, therefore the value of the diffraction angle also includes values ​​within the range of approximately ±0.2°. Therefore, crystals with peaks exhibiting completely uniform diffraction angles in powder X-ray diffraction, as well as crystals with peaks exhibiting uniform diffraction angles with an error of approximately ±0.2°, can also be used in the formulations of this invention.

[0109] Whether compound I or its formulations are amorphous can be confirmed by the absence of specific diffraction peaks and the presence of a broad diffraction curve (halo pattern) in powder X-ray diffraction. It is known to those skilled in the art that "displaying a halo pattern" is substantially synonymous with "absence of specific powder X-ray diffraction peaks" herein.

[0110] Hereinafter, preferred embodiments of the solid dispersion of the present invention will be described.

[0111] A solid dispersion comprising (2E)-3-{2,6-dichloro-4-[(4-{3-[(1S)-1-(hexyloxy)ethyl]-2-methoxyphenyl}-1,3-thiazolyl)carbamoyl]phenyl}-2-methyl-2-acrylic acid or a pharmaceutically acceptable salt thereof as compound I, and a water-soluble polymer.

[0112] Other methods include: solid dispersions containing compound I and cellulose-based polymers, solid dispersions containing compound I and vinyl-based polymers, solid dispersions containing compound I and acrylic-based polymers, and solid dispersions containing compound I and polyether-based polymers.

[0113] Other methods include: solid dispersions containing compound I and hydroxypropyl cellulose, solid dispersions containing compound I and hydroxypropyl methylcellulose, solid dispersions containing compound I and hydroxypropyl methylcellulose phthalate, solid dispersions containing compound I and methylcellulose, solid dispersions containing compound I and carboxymethyl ethyl cellulose, solid dispersions containing compound I and hydroxypropyl methylcellulose acetate succinate, solid dispersions containing compound I and hydroxyethyl methylcellulose, solid dispersions containing compound I and hydroxyethyl cellulose, solid dispersions containing compound I and sodium carboxymethyl cellulose, solid dispersions containing compound I and calcium carboxymethyl cellulose, and solid dispersions containing compound I and cellulose acetate phthalate. Preferably, it comprises: a solid dispersion containing compound I and hydroxypropyl cellulose, a solid dispersion containing compound I and hydroxypropyl methylcellulose, a solid dispersion containing compound I and hydroxypropyl methylcellulose phthalate, a solid dispersion containing compound I and methylcellulose, a solid dispersion containing compound I and carboxymethyl ethyl cellulose, and a solid dispersion containing compound I and hydroxypropyl methylcellulose acetate succinate. More preferably, it comprises: a solid dispersion containing compound I and methylcellulose, a solid dispersion containing compound I and carboxymethyl ethyl cellulose, and a solid dispersion containing compound I and hydroxypropyl methylcellulose acetate succinate.

[0114] Other methods include: solid dispersions containing compound I and polyvinylpyrrolidone; solid dispersions containing compound I and polyvinylpyrrolidone; solid dispersions containing compound I and polyvinyl alcohol; solid dispersions containing compound I and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer; solid dispersions containing compound I and polyvinyl alcohol-polyethylene glycol-graft copolymer; solid dispersions containing compound I and polyvinyl acetal diethylaminoacetate; solid dispersions containing compound I and a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose; and solid dispersions containing compound I and polyvinyl acetal diethylaminoacetate. Preferably, it is a solid dispersion containing compound I and polyvinylpyrrolidone, a solid dispersion containing compound I and polyvinylpyrrolidone, a solid dispersion containing compound I and polyvinyl alcohol, or a solid dispersion containing compound I and a polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer; more preferably, it is a solid dispersion containing compound I and polyvinylpyrrolidone, or a solid dispersion containing compound I and polyvinylpyrrolidone.

[0115] Other methods include: solid dispersions containing compound I and aminoalkyl methacrylate copolymer E, solid dispersions containing compound I and methacrylate copolymer L, solid dispersions containing compound I and methacrylate copolymer LD, solid dispersions containing compound I and methacrylate copolymer S, solid dispersions containing compound I and aminoalkyl methacrylate copolymer RS, solid dispersions containing compound I and ethyl acrylate-methyl methacrylate copolymer, solid dispersions containing compound I and aminoalkyl methacrylate copolymer, solid dispersions containing methyl acrylate-methacrylate-methyl methacrylate copolymer, and solid dispersions containing compound I and 2-methyl-5-vinylpyridine acrylate-methacrylate copolymer.

[0116] Other methods include: solid dispersions containing compound I and polyethylene glycol, and solid dispersions containing compound I and propylene oxide-ethylene oxide block copolymers.

[0117] Other methods include: solid dispersions containing compound I and cellulose polymers, with a weight ratio of compound I to cellulose polymers of 1:0.1 to 1:50; solid dispersions containing compound I and vinyl polymers, with a weight ratio of compound I to vinyl polymers of 1:0.1 to 1:50; solid dispersions containing compound I and acrylic polymers, with a weight ratio of compound I to acrylic polymers of 1:0.1 to 1:50; and solid dispersions containing compound I and polyether polymers, with a weight ratio of compound I to polyether polymers of 1:0.1 to 1:50. Preferably, it is a solid dispersion containing compound I and a cellulose-based polymer, wherein the weight ratio of compound I to the cellulose-based polymer is 1:0.5 to 1:25; a solid dispersion containing compound I and a vinyl-based polymer, wherein the weight ratio of compound I to the vinyl-based polymer is 1:0.5 to 1:25; a solid dispersion containing compound I and an acrylic-based polymer, wherein the weight ratio of compound I to the acrylic-based polymer is 1:0.5 to 1:25; or a solid dispersion containing compound I and a polyether-based polymer, wherein the weight ratio of compound I to the polyether-based polymer is 1:0.5 to 1:25. More preferably, it is a solid dispersion containing compound I and a cellulose polymer, wherein the weight ratio of compound I to the cellulose polymer is 1:1 to 1:10; a solid dispersion containing compound I and a vinyl polymer, wherein the weight ratio of compound I to the vinyl polymer is 1:1 to 1:10; a solid dispersion containing compound I and an acrylic polymer, wherein the weight ratio of compound I to the acrylic polymer is 1:1 to 1:10; or a solid dispersion containing compound I and a polyether polymer, wherein the weight ratio of compound I to the polyether polymer is 1:1 to 1:10.

[0118] Other formulations include: solid dispersions containing compound I and hydroxypropyl cellulose, with a weight ratio of compound I to hydroxypropyl cellulose of 1:0.1 to 1:50; solid dispersions containing compound I and hydroxypropyl methylcellulose, with a weight ratio of compound I to hydroxypropyl methylcellulose of 1:0.1 to 1:50; solid dispersions containing compound I and hydroxypropyl methylcellulose phthalate, with a weight ratio of compound I to hydroxypropyl methylcellulose phthalate of 1:0.1 to 1:50; solid dispersions containing compound I and methylcellulose, with a weight ratio of compound I to methylcellulose of 1:0.1 to 1:50; solid dispersions containing compound I and carboxymethyl ethyl cellulose, with a weight ratio of compound I to carboxymethyl ethyl cellulose of 1:0.1 to 1:50; and solid dispersions containing compound I and hydroxypropyl methylcellulose acetate succinate, with a weight ratio of compound I to hydroxypropyl methylcellulose succinate of 1:0.1 to 1:50. Solid dispersions containing hydroxypropyl methylcellulose acetate succinate in a weight ratio of 1:0.1 to 1:50; solid dispersions containing compound I and hydroxyethyl methylcellulose in a weight ratio of 1:0.1 to 1:50; solid dispersions containing compound I and hydroxyethyl cellulose in a weight ratio of 1:0.1 to 1:50; solid dispersions containing compound I and sodium carboxymethyl cellulose in a weight ratio of 1:0.1 to 1:50; solid dispersions containing compound I and calcium carboxymethyl cellulose in a weight ratio of 1:0.1 to 1:50; and solid dispersions containing compound I and cellulose acetate in a weight ratio of 1:0.1 to 1:50. Preferably, it is a solid dispersion containing compound I and hydroxypropyl cellulose, wherein the weight ratio of compound I to hydroxypropyl cellulose is 1:0.5 to 1:25; a solid dispersion containing compound I and hydroxypropyl methylcellulose, wherein the weight ratio of compound I to hydroxypropyl methylcellulose is 1:0.5 to 1:25; a solid dispersion containing compound I and hydroxypropyl methylcellulose phthalate, wherein the weight ratio of compound I to hydroxypropyl methylcellulose phthalate is 1:0.5 to 1:25; a solid dispersion containing compound I and methylcellulose, wherein the weight ratio of compound I to methylcellulose is 1:0.5 to 1:25; a solid dispersion containing compound I and carboxymethyl ethyl cellulose, wherein the weight ratio of compound I to carboxymethyl ethyl cellulose is 1:0.5 to 1:25; a solid dispersion containing compound I and hydroxypropyl methylcellulose acetate succinate, wherein the weight ratio of compound I to hydroxypropyl methylcellulose acetate succinate is 1:0.5 to 1:25.More preferably, it is a solid dispersion containing compound I and methylcellulose, wherein the weight ratio of compound I to methylcellulose is 1:1 to 1:10; a solid dispersion containing compound I and carboxymethyl ethyl cellulose, wherein the weight ratio of compound I to carboxymethyl ethyl cellulose is 1:1 to 1:10; or a solid dispersion containing compound I and hydroxypropyl methylcellulose acetate succinate, wherein the weight ratio of compound I to hydroxypropyl methylcellulose acetate succinate is 1:1 to 1:10.

[0119] Other formulations include: solid dispersions containing compound I and polyvinylpyrrolidone, with a weight ratio of compound I to polyvinylpyrrolidone of 1:0.1 to 1:50; solid dispersions containing compound I and polyvinylpyrrolidone, with a weight ratio of compound I to polyvinylpyrrolidone of 1:0.1 to 1:50; solid dispersions containing compound I and polyvinyl alcohol, with a weight ratio of compound I to polyvinylpyrrolidone of 1:0.1 to 1:50; solid dispersions containing compound I and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, with a weight ratio of compound I to polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer of 1:0.1 to 1:50; and solid dispersions containing compound I and polyvinyl alcohol-polyethylene glycol-graft copolymer, with a weight ratio of compound I to polyvinyl alcohol-polyethylene glycol-graft copolymer of 1:0.1 to 1:50. Solid dispersions containing ethylene glycol-graft copolymers in a weight ratio of 1:0.1 to 1:50; solid dispersions containing compound I and polyvinyl acetal diethylaminoacetate in a weight ratio of 1:0.1 to 1:50; solid dispersions containing compound I and a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose in a weight ratio of 1:0.1 to 1:50; solid dispersions containing compound I and polyvinyl acetal diethylaminoacetate in a weight ratio of 1:0.1 to 1:50. Preferably, it is a solid dispersion containing compound I and polyvinylpyrrolidone, wherein the weight ratio of compound I to polyvinylpyrrolidone is 1:0.5 to 1:25; a solid dispersion containing compound I and polyvinylpyrrolidone, wherein the weight ratio of compound I to polyvinylpyrrolidone is 1:0.5 to 1:25; a solid dispersion containing compound I and polyvinyl alcohol, wherein the weight ratio of compound I to polyvinyl alcohol, polyvinyl acrylic acid, and polymethyl methacrylate copolymer is 1:0.5 to 1:25. More preferably, it is a solid dispersion containing compound I and polyvinylpyrrolidone, wherein the weight ratio of compound I to polyvinylpyrrolidone is 1:1 to 1:10; or a solid dispersion containing compound I and polyvinylpyrrolidone, wherein the weight ratio of compound I to polyvinylpyrrolidone is 1:1 to 1:10.

[0120] The other methods are: solid dispersions containing compound I and aminoalkyl methacrylate copolymer E, wherein the weight ratio of compound I to aminoalkyl methacrylate copolymer E is 1:0.1 to 1:50; solid dispersions containing compound I and methacrylic acid copolymer L, wherein the weight ratio of compound I to methacrylic acid copolymer L is 1:0.1 to 1:50; solid dispersions containing compound I and methacrylic acid copolymer LD, wherein the weight ratio of compound I to methacrylic acid copolymer LD is 1:0.1 to 1:50; solid dispersions containing compound I and methacrylic acid copolymer S, wherein the weight ratio of compound I to methacrylic acid copolymer S is 1:0.1 to 1:50; and solid dispersions containing compound I and aminoalkyl methacrylate copolymer RS, wherein the weight ratio of compound I to aminoalkyl methacrylate copolymer RS ​​is 1:0.1 to 1:50. Solid dispersions with a weight ratio of 1:0.1 to 1:50; solid dispersions containing compound I and ethyl acrylate-methyl methacrylate copolymer, wherein the weight ratio of compound I to ethyl acrylate-methyl methacrylate copolymer is 1:0.1 to 1:50; solid dispersions containing compound I and aminoalkyl methacrylate copolymer, methyl acrylate-methyl methacrylate-methyl methacrylate copolymer, wherein the weight ratio of compound I to aminoalkyl methacrylate copolymer, methyl acrylate-methyl methacrylate-methyl methacrylate copolymer is 1:0.1 to 1:50; solid dispersions containing compound I and 2-methyl-5-vinylpyridine acrylate-methyl methacrylate copolymer, wherein the weight ratio of compound I to 2-methyl-5-vinylpyridine acrylate-methyl methacrylate copolymer is 1:0.1 to 1:50.Preferably, it comprises: a solid dispersion containing compound I and aminoalkyl methacrylate copolymer E, wherein the weight ratio of compound I to aminoalkyl methacrylate copolymer E is 1:0.5 to 1:25; a solid dispersion containing compound I and methacrylic acid copolymer L, wherein the weight ratio of compound I to methacrylic acid copolymer L is 1:0.5 to 1:25; a solid dispersion containing compound I and methacrylic acid copolymer LD, wherein the weight ratio of compound I to methacrylic acid copolymer LD is 1:0.5 to 1:25; a solid dispersion containing compound I and methacrylic acid copolymer S, wherein the weight ratio of compound I to methacrylic acid copolymer S is 1:0.5 to 1:25; and a solid dispersion containing compound I and aminoalkyl methacrylate copolymer RS, wherein the weight ratio of compound I to aminoalkyl methacrylate copolymer RS ​​is... A solid dispersion with a weight ratio of 1:0.5 to 1:25; a solid dispersion containing compound I and ethyl acrylate-methyl methacrylate copolymer, wherein the weight ratio of compound I to ethyl acrylate-methyl methacrylate copolymer is 1:0.5 to 1:25; a solid dispersion containing compound I and aminoalkyl methacrylate copolymer, methyl acrylate-methyl methacrylate-methyl methacrylate copolymer, wherein the weight ratio of compound I to aminoalkyl methacrylate copolymer, methyl acrylate-methyl methacrylate-methyl methacrylate copolymer is 1:0.5 to 1:25; a solid dispersion containing compound I and 2-methyl-5-vinylpyridine acrylate-methyl methacrylate copolymer, wherein the weight ratio of compound I to 2-methyl-5-vinylpyridine acrylate-methyl methacrylate copolymer is 1:0.5 to 1:25.More preferably, it comprises: a solid dispersion containing compound I and aminoalkyl methacrylate copolymer E, wherein the weight ratio of compound I to aminoalkyl methacrylate copolymer E is 1:1 to 1:10; a solid dispersion containing compound I and methacrylate copolymer L, wherein the weight ratio of compound I to methacrylate copolymer L is 1:0.5 to 1:25; a solid dispersion containing compound I and methacrylate copolymer LD, wherein the weight ratio of compound I to methacrylate copolymer LD is 1:1 to 1:10; a solid dispersion containing compound I and methacrylate copolymer S, wherein the weight ratio of compound I to methacrylate copolymer S is 1:1 to 1:10; and a solid dispersion containing compound I and aminoalkyl methacrylate copolymer RS, wherein the weight ratio of compound I to aminoalkyl methacrylate copolymer RS ​​is 1:1 to 1:10. Solid dispersions with a weight ratio of 1:1 to 1:10; solid dispersions containing compound I and ethyl acrylate-methyl methacrylate copolymer, wherein the weight ratio of compound I to ethyl acrylate-methyl methacrylate copolymer is 1:1 to 1:10; solid dispersions containing compound I and aminoalkyl methacrylate copolymer, methyl acrylate-methyl methacrylate-methyl methacrylate copolymer, wherein the weight ratio of compound I to aminoalkyl methacrylate copolymer, methyl acrylate-methyl methacrylate-methyl methacrylate copolymer is 1:1 to 1:10; solid dispersions containing compound I and 2-methyl-5-vinylpyridine acrylate-methyl methacrylate copolymer, wherein the weight ratio of compound I to 2-methyl-5-vinylpyridine acrylate-methyl methacrylate copolymer is 1:1 to 1:10.

[0121] Another option is a solid dispersion containing compound I and polyethylene glycol, wherein the weight ratio of compound I to polyethylene glycol is 1:0.1 to 1:50; or a solid dispersion containing compound I and a propylene oxide-ethylene oxide block copolymer, wherein the weight ratio of compound I to the propylene oxide-ethylene oxide block copolymer is 1:0.1 to 1:50. Preferably, it is a solid dispersion containing compound I and polyethylene glycol, wherein the weight ratio of compound I to polyethylene glycol is 1:0.5 to 1:25; or a solid dispersion containing compound I and a propylene oxide-ethylene oxide block copolymer, wherein the weight ratio of compound I to the propylene oxide-ethylene oxide block copolymer is 1:0.5 to 1:25. More preferably, it is a solid dispersion containing compound I and polyethylene glycol, wherein the weight ratio of compound I to polyethylene glycol is 1:1 to 1:10; or a solid dispersion containing compound I and propylene oxide-ethylene oxide block copolymer, wherein the weight ratio of compound I to propylene oxide-ethylene oxide block copolymer is 1:1 to 1:10. Example

[0122] The present invention will be further described in detail below with examples of manufacturing, embodiments and comparative examples, but these examples do not limit the present invention. Compound I was manufactured by the method described in International Publication No. 2015 / 093586 (in which compound I is referred to as “compound (XI')”).

[0123] Experimental Example 1: Evaluation of the solubility of Compound I

[0124] According to Method 2 (paddle method) of the Dissolution Test Method in the 14th revised edition of the Japanese Pharmacopoeia, the following solvents were added to Compound I, followed by ultrasonic irradiation and stirring at 37°C and 50 rpm for 3 hours. After 3 hours, the sample was filtered through a 0.45 μm filter, and the drug concentration in the filtrate was determined by HPLC. It should be noted that 100 mM citrate buffer (pH 4), 100 mM phosphate buffer (pH 7), and 100 mM carbonate buffer (pH 9) were used as solvents.

[0125] The results are shown in Table 1. Compound I was confirmed to be poorly soluble in both acidic and neutral solvents.

[0126] [Table 1]

[0127]

[0128] Test Example 2: Dissolution Test of Capsules Containing Solid Dispersion Powder

[0129] Capsules are made from a solid dispersion powder of compound I with a water-soluble polymer weight ratio of 1:9, as described below.

[0130] As shown in Table 2, compound I and the water-soluble polymer were dissolved in an ethanol / acetone (1 / 1) mixture, and the solvent was removed under reduced pressure at 40°C. The resulting solid was pulverized using a KC-HUK type tablet pulverizer (manufactured by KONISHI Corporation) to form a solid dispersion. D-mannitol (ROQUETTE), hydrated silica (Carplex 67, DSL Japan), and calcium carboxymethyl cellulose (FMC BioPolymer) were mixed in a specific ratio to produce a solid dispersion powder. The prepared solid dispersion powder was then filled into gelatin No. 2 capsules (Qualicaps). Table 2 shows the composition of the solid dispersion powder and the capsules.

[0131] [Table 2]

[0132]

[0133] As water-soluble polymers, as shown in Table 3, polyvinylpyrrolidone (Kollidone 25, BASF Japan), methylcellulose (SM-4, Shin-Etsu Chemical Industry), hydroxypropyl methylcellulose (TC-5, Shin-Etsu Chemical Industry), hydroxypropyl cellulose (HPC-SSL, Nippon Soda), polyethylene glycol 6000 (PEG6000, Wako Pure Chemical Industries), and polyoxyethylene (160)polyoxypropylene (30) glycol (Poloxamer 188, BASF) were used.

[0134] [Table 3]

[0135]

[0136] (Comparative Example 1: Preparation of Suspension)

[0137] A suspension was obtained by mixing 5 mg of compound I and 25 mg of hydroxypropyl cellulose and suspending them in 10 ml of water.

[0138] (Dissolution test method)

[0139] The following dissolution tests were conducted on the capsules obtained in Examples 1-4 and Reference Examples 1-2, and the suspension obtained in Comparative Example 1 (Dissolution Test 1: Examples 1-4 and Reference Examples 1-2, Dissolution Test 2: Comparative Example 1).

[0140] Dissolution test 1

[0141] Dissolution testing was performed according to Method 2 (paddle method) of the Dissolution Test Method in the 14th revised edition of the Japanese Pharmacopoeia, using the Japanese Pharmacopoeia.

[0142] The disintegration test was performed using 900 ml of the second solution at 37°C and 50 rpm. Samples of the disintegration test solution were taken from the disintegration test apparatus at arbitrary intervals. The sampled test solution was diluted twice with THF and the UV absorbance was measured using a spectrophotometer (DU7500 SPECTROPHOTOMETER, BECKMAN).

[0143] It should be noted that only in the dissolution test of Example 4 was the rotation speed increased from 50 rpm to 100 rpm after 20 minutes, and from 100 rpm to 200 rpm after 40 minutes.

[0144] UV absorbance: 250nm

[0145] Pool length: 1cm

[0146] Dissolution test 2

[0147] Dissolution tests were conducted according to Method 2 (paddle method) of the 14th revised edition of the Japanese Pharmacopoeia Dissolution Test Method, using 900 ml of the solution specified in Method 2 of the Japanese Pharmacopoeia Disintegration Test Method, at 37°C and 50 revolutions per minute. An Optical Fiber dissolution monitor (DM-3100, manufactured by Otsuka Electronics Co., Ltd.) was installed in the dissolution test apparatus for online measurement.

[0148] UV absorbance: 250nm

[0149] Optical path length: 0.5cm

[0150] (Results of the dissolution test)

[0151] The results of dissolution tests of the capsules obtained in Examples 1-4 and Reference Examples 1-2 are shown in Figure 1 The results of the dissolution test of the suspension obtained in Comparative Example 1 are shown in... Figure 2 The dissolution rates 60 minutes after the start of the aforementioned dissolution test showed very high dissolution rates for any solid dispersion capsule compared to the suspension of Comparative Example 1. Based on these results, it is confirmed that although compound I is poorly soluble, its solubility can be improved by preparing it as the solid dispersion of the present invention.

[0152] Experimental Example 3: Evaluation of oral absorption in dogs

[0153] The following evaluation of oral absorption in dogs was conducted on the capsules obtained in Examples 1, 2, and 4, and the suspension obtained in Comparative Example 1.

[0154] Male beagle dogs were fasted for 24 hours before being orally administered one sample capsule. Blood samples were collected from the forelimb veins before and at certain times after administration. Blood drug concentrations were measured using LC / MS / MS to determine the maximum blood drug concentration (Cmax) and the time to reach the highest blood drug concentration (Tmax). The area under the blood drug concentration-time curve (AUC) from the time of administration to infinity was calculated using the trapezoidal method.

[0155] (Results of oral absorption evaluation in dogs)

[0156] The results of blood concentration changes in Examples 1, 2, and 4, which contained 3 mg of compound I, are shown in... Figure 3 The Tmax, Cmax, and AUC of the capsules obtained in Examples 1, 2, and 4, and the suspension obtained in Comparative Example 1. inf The results are shown in Table 4. As a result, the capsules containing solid dispersion powder obtained in Examples 1, 2 and 4 showed significantly improved absorption compared to the suspension of Comparative Example 1.

[0157] [Table 4]

[0158]

[0159] Experimental Example 4: Stability of freshly manufactured solid dispersion

[0160] (Method for manufacturing solid dispersions)

[0161] The following describes the preparation of a solid dispersion of compound I: a water-soluble polymer in a weight ratio of 1:9.

[0162] As shown in Table 5, after dissolving compound I and water-soluble polymer in ethanol in a certain proportion, the solvent was removed under reduced pressure at 40°C. The resulting solid was then pulverized using a KC-HUK type tablet pulverizer (manufactured by KONISHI Corporation) to produce a solid dispersion.

[0163] [Table 5]

[0164]

[0165] As water-soluble polymers, as shown in Table 6, hydroxypropyl methylcellulose acetate succinate (AQOAT, Shin-Etsu Chemical Industry), methylcellulose (SM-4, Shin-Etsu Chemical Industry), hydroxypropyl methylcellulose (TC-5, Shin-Etsu Chemical Industry), povidone (Kollidone 25, BASF Japan), polyvinyl alcohol (PVA IV-88, Merck), polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (POVACOAT, Daido Chemical), and methacrylic acid copolymer (Eudragit L-SD, EVONIK Japan) were used.

[0166] [Table 6]

[0167]

[0168] Powder X-ray diffraction was performed on the solid dispersions obtained in Examples 5-8 and Reference Examples 3-5 to confirm the amorphization process by observing the presence or absence of crystallization peaks. It should be noted that, for example... Figure 4 As shown, the powder X-ray diffraction pattern of compound I exhibits sharp diffraction peaks.

[0169] For the solid dispersion powder manufactured as described above, powder X-ray diffraction determination was performed according to the powder X-ray diffraction determination method described in the General Test Methods of the Japanese Pharmacopoeia. The determination conditions are as follows.

[0170] (Apparatus)

[0171] RINT Ultima manufactured by Rigaku Corporation

[0172] (Operating Instructions)

[0173] For the sample, the determination was carried out under the following conditions.

[0174] Measurement method: Reflectance method

[0175] Wavelength used: CuKα rays

[0176] Tube current: 30mA

[0177] Tube voltage: 40kV

[0178] The incident angle (2θ) of the X-rays: 4°~35°

[0179] Sampling width: 0.02°

[0180] Scanning speed: 5° / min

[0181] Diverging slit: 1 / 2°

[0182] Diverging longitudinal slit: 5 mm

[0183] Scattering slit: 0.73 mm

[0184] Light-entry slit: 0.3 mm

[0185] Monochromatic light receiving slit: 0.8 mm.

[0186] (result)

[0187] The results of powder X-ray diffraction measurements of the solid dispersions of Examples 5-8 and Reference Examples 3-5 are shown in Table 7 and... Figures 5-11 Immediately after manufacturing, any solid dispersion powder exhibits a halo pattern without specific diffraction peaks in powder X-ray diffraction, confirming that compound I in the formulation is in an amorphous state.

[0188] [Table 7]

[0189]

[0190] Experimental Example 5: Stability of solid dispersions after time-lapse stability test

[0191] The solid dispersions obtained in Examples 5-8 and Reference Examples 3-5 were placed in sealed glass bottles and stored under the following conditions. After storage for a period of time, powder X-ray diffraction was performed under the conditions described above, and the stability of the formulation was evaluated by the presence or absence of crystallization peaks.

[0192] Storage conditions: 40℃, store for 1 month

[0193] (Results of time-dependent stability tests on solid dispersions)

[0194] Regarding the stability of the solid dispersion powders obtained in Examples 5-8 and Reference Examples 3-5 after storage, the results of powder X-ray diffraction measurements are shown in Table 8 and... Figures 5-11.

[0195] [Table 8]

[0196]

[0197] For the solid dispersion containing polyvinyl alcohol obtained in Reference Example 3, the solid dispersion containing polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer obtained in Reference Example 4, and the solid dispersion containing methacrylic acid copolymer L-SD obtained in Reference Example 5, after storage for a period of time, diffraction peaks were confirmed by powder X-ray diffraction.

[0198] On the other hand, the solid dispersions containing hydroxypropyl methylcellulose acetate succinate obtained in Example 5, the solid dispersions containing methylcellulose obtained in Example 6, the solid dispersions containing hydroxypropyl methylcellulose obtained in Example 7, and the solid dispersions containing povidone obtained in Example 8 all showed halo patterns without specific diffraction peaks in powder X-ray diffraction. Therefore, they maintained an amorphous state even after being stored at 40°C for one month, demonstrating formulation stability.

[0199] Experimental Example 6: Effect of the content of water-soluble polymers on the stability over time

[0200] (Method for manufacturing solid dispersions)

[0201] Following the methods for manufacturing solid dispersions described in Examples 5-8 and Reference Examples 3-5 above, a solid dispersion with a weight ratio of compound I to water-soluble polymer of 1:3 was manufactured. Compound I and the water-soluble polymer were dissolved in an ethanol / acetone (1 / 1) mixture at a specific ratio. The solvent was removed under reduced pressure at 40°C. The resulting solid was then pulverized using a KC-HUK type tablet pulverizer (manufactured by KONISHI Corporation) to prepare a solid dispersion powder.

[0202] Compound I: The weight ratio and types of water-soluble polymers are shown in Table 9. Hydroxypropyl cellulose-SL (HPC-SL, Nippon Soda), hydroxypropyl methylcellulose (TC-5, Shin-Etsu Chemical), methylcellulose (SM-4, Shin-Etsu Chemical), hydroxypropyl methylcellulose acetate succinate (AQOAT, Shin-Etsu Chemical), carboxymethyl ethyl cellulose (CMEC, FREUND), hydroxypropyl methylcellulose phthalate (HPMCP, Shin-Etsu Chemical), and povidone (Kollidone 25, BASF Japan) were used as water-soluble polymers.

[0203] [Table 9]

[0204]

[0205] The solid dispersions obtained in Examples 9-21 were placed in sealed glass bottles and stored under the following conditions. Powder X-ray diffraction (PXRD) was then performed on the stored samples under these conditions. The stability of the formulation was evaluated by the presence or absence of crystallization peaks determined by PXRD. Storage conditions: 40°C, 1-3 months.

[0206] (Results of stability testing of the formulation)

[0207] Regarding the storage stability of the solid dispersions obtained in Examples 9-21, the results of powder X-ray diffraction measurements are shown in Table 10. It should be noted that cases where no specific diffraction peak was observed are marked as "0", and cases where a diffraction peak was observed are marked as "×".

[0208] [Table 10]

[0209]

[0210] As a result, in the solid dispersion of compound I at a weight ratio of 1:3 to the water-soluble polymer, halo patterns without specific diffraction peaks were confirmed in all solid dispersions. Therefore, it maintained an amorphous state at 40°C for 1–3 months, demonstrating formulation stability.

[0211] It should be noted that when the solid dispersion of compound I with a water-soluble polymer weight ratio of 1:2 is stored at 40°C for 1 to 3 months, the solid dispersions with water-soluble polymers of methylcellulose, hydroxypropyl methylcellulose acetate succinate, and carboxymethyl ethyl cellulose all exhibit halo patterns without specific diffraction peaks, thus maintaining an amorphous state and demonstrating the stability of the formulation.

[0212] Industrial practicality

[0213] The water solubility of compound I is increased by preparing a solid dispersion containing (2E)-3-{2,6-dichloro-4-[(4-{3-[(1S)-1-(hexyloxy)ethyl]-2-methoxyphenyl}-1,3-thiazolyl)carbamoyl]phenyl}-2-methyl-2-acrylic acid or a pharmaceutically acceptable salt thereof (compound I) and a water-soluble polymer. Furthermore, the absorption of compound I is increased by oral administration of this solid dispersion.

Claims

1. A solid dispersion comprising (2E)-3-{2,6-dichloro-4-[(4-{3-[(1S)-1-(hexyloxy)ethyl]-2-methoxyphenyl}-1,3-thiazolyl)carbamoyl]phenyl}-2-methyl-2-acrylic acid or a pharmaceutically acceptable salt thereof, and a water-soluble polymer; This water-soluble polymer is a cellulose-based polymer or a vinyl-based polymer. The cellulose polymer is selected from one or more of hydroxypropyl cellulose, methyl cellulose, carboxymethyl ethyl cellulose, and hydroxypropyl methyl cellulose acetate succinate. The vinyl polymer is polyvinylpyrrolidone. in, The weight ratio of the compound or its pharmaceutically acceptable salt to the water-soluble polymer is 1:2 to 1:10, and Among them, (2E)-3-{2,6-dichloro-4-[(4-{3-[(1S)-1-(hexyloxy)ethyl]-2-methoxyphenyl}-1,3-thiazolyl)carbamoyl]phenyl}-2-methyl-2-acrylic acid is in an amorphous state.

2. The solid dispersion according to claim 1, wherein, Water-soluble polymers are cellulose-based polymers.

3. The solid dispersion according to claim 2, wherein, Cellulose polymers are selected from one or more of methylcellulose, carboxymethyl ethyl cellulose, and hydroxypropyl methylcellulose acetate succinate.

4. The solid dispersion according to claim 2, wherein, Water-soluble polymers are vinyl-based polymers.

5. A solid dosage form selected from powders, granules and tablets, comprising the solid dispersion according to any one of claims 1 to 4.

6. The solid dispersion or solid dosage form according to any one of claims 1 to 4, wherein, The dissolution rate of (2E)-3-{2,6-dichloro-4-[(4-{3-[(1S)-1-(hexyloxy)ethyl]-2-methoxyphenyl}-1,3-thiazolyl)carbamoyl]phenyl}-2-methyl-2-acrylic acid or a pharmaceutically acceptable salt thereof shall be 1% or more after 60 minutes from the start of the dissolution test (paddle method) as specified in the Japanese Pharmacopoeia.

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