Solid dispersion and composition containing same

Abstract

This solid dispersion comprises: a component (1) which is one or more selected from the group consisting of a compound represented by formula (I), a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable solvate thereof; and a component (2) which is one or more polymers selected from the group consisting of hydroxypropyl methylcellulose and a derivative thereof, wherein the total content of the component (2) per 1 part by mass of the total content of the component (1) is more than 0.1 parts by mass and less than 1.0 part by mass. This composition comprises said solid dispersion and an alkyl sulfate.

Description

Solid dispersion and composition containing same

[0001] The present invention relates to a solid dispersion and a composition containing the same. More specifically, the present invention relates to a solid dispersion containing a cyclic peptide compound and hydroxypropyl methylcellulose or a derivative thereof, and a composition containing the solid dispersion and an alkyl sulfate.

[0002] RAS is a protein belonging to the small GTPase family, and KRAS, NRAS, and HRAS are known. RAS is activated or inactivated depending on its binding state with GDP or GTP. It is activated by the exchange reaction of GDP to GTP by GEF (guanine nucleotide exchange factor) and inactivated by the hydrolysis reaction of GTP by GAP (GTPase-activating protein) (Non-Patent Document 1). Activated RAS induces cell proliferation, survival, and differentiation by activating various downstream signals such as the MAPK pathway, PI3K / Akt pathway, and RAL pathway, and constitutive activation of RAS plays an important role in the development and progression of cancer. It is known that in cancer, the RAS-RAF-MEK-ERK pathway is activated by activation of upstream RAS signals, constitutive activation of RAS, and / or activating mutations of RAS (Non-Patent Document 2). These activating RAS mutations have been observed in numerous types of cancer. G12, G13, and Q61 are known as hotspots for RAS mutations, with frequent mutations observed at G12 in KRAS and at Q61 in NRAS. It is also known that these mutations are associated with patient prognosis (Non-Patent Document 3). Patent Document 1 discloses cyclic compounds that have selective KRAS inhibitory activity against HRAS and NRAS.

[0003] In order to improve the solubility of drugs, solid dispersions containing poorly soluble compounds and polymers have been prepared. For example, Patent Documents 2 and 3 describe the preparation of a solid dispersion containing a specific cyclic peptide compound and hydroxypropyl methylcellulose acetate succinate (HPMCAS), and the preparation of a composition containing this solid dispersion and sodium lauryl sulfate (SLS).

[0004] International Publication No. WO 2023 / 214576 International Publication No. WO 2023 / 063376 International Publication No. WO 2024 / 080308

[0005] Nat. Rev. Drug Discov. , 2014, 13(11), pp. 828-851 Nat. Rev. Drug Discov. , 2014, 13(12), pp. 928-942 Nat. Rev. Drug Discov. , 2016, 15(11), pp. 771-785

[0006] The present inventors, while studying pharmaceutical formulations of the compound represented by formula (I), have found that in a formulation containing a solid dispersion of the compound represented by formula (I) and hydroxypropyl methylcellulose acetate succinate (HPMCAS) and sodium lauryl sulfate (SLS), the weight of the formulation required to achieve a certain level of solubility in artificial small intestinal fluid (FaSSIF: Fasted State Simulated Intestinal Fluid) (hereinafter, solubility in FaSSIF may be simply referred to as "solubility") can be reduced by setting the content of HPMCAS in the solid dispersion to less than 1 part by mass per part by mass of the compound represented by formula (I) in the solid dispersion.

[0007] Patent Documents 2 and 3 do not disclose specific examples of solid dispersions in which the polymer content per 1 part by mass of a specific cyclic peptide compound is less than 1 part by mass, nor do they disclose or suggest that such a composition can reduce the weight of the formulation required to achieve a certain level of solubility.

[0008] An object of the present invention is to provide a solid dispersion that can reduce the weight of a formulation required to achieve a certain level of solubility, and a composition containing the solid dispersion.

[0009] The present invention includes, for example, the following inventions: [A-1] A solid dispersion comprising component (1), which is one or more selected from the group consisting of a compound represented by formula (I), a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable solvate thereof, and component (2), which is one or more polymers selected from the group consisting of hydroxypropyl methylcellulose and derivatives thereof, wherein the total content of component (2) per part by mass of the total content of component (1) is more than 0.1 part by mass and less than 1.0 part by mass. [A-2] The solid dispersion according to [A-1], wherein the component (1) is a compound represented by formula (I) or a solvate thereof. [A-3] The solid dispersion according to [A-1] or [A-2], wherein the component (1) is a compound represented by formula (I) or a hydrate thereof. [A-4] The solid dispersion according to any of [A-1] to [A-3], wherein the component (1) is a compound represented by formula (I). [A-5] The solid dispersion according to any of [A-1] to [A-3], wherein the component (1) is a hydrate of the compound represented by formula (I). [A-6] The solid dispersion according to any of [A-1] to [A-5], wherein the component (2) is one or more polymers selected from the group consisting of hydroxypropyl methylcellulose and esters thereof. [A-7] The solid dispersion according to any one of [A-1] to [A-6], wherein component (2) is one or more polymers selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methyl acetate maleate, and hydroxypropyl methyl trimellitate. [A-8] The solid dispersion according to any one of [A-1] to [A-7], wherein component (2) is one polymer selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methyl acetate maleate, and hydroxypropyl methyl trimellitate. [A-9] The solid dispersion according to any one of [A-1] to [A-8], wherein component (2) is hydroxypropyl methylcellulose acetate succinate (HPMCAS). [A-10] The solid dispersion according to any one of [A-1] to [A-9], wherein the total content of the component (2) per 1 part by mass of the total content of the component (1) is 0.2 parts by mass or more and 0.7 parts by mass or less. [A-11] The solid dispersion according to any one of [A-1] to [A-9], wherein the total content of the component (2) per 1 part by mass of the total content of the component (1) is 0.25 parts by mass or more and 0.6 parts by mass or less.[A-12] The solid dispersion according to any one of [A-1] to [A-9], wherein the total content of component (2) per part by mass of the total content of component (1) is 0.3 parts by mass or more and 0.5 parts by mass or less. [A-13] The solid dispersion according to [A-1] to [A-12], wherein the solid dispersion is used in combination with an alkyl sulfate. [A-14] The solid dispersion according to [A-13], wherein the amount of the alkyl sulfate used in combination is 1.37 parts by mass or more and 6.66 parts by mass or less per part by mass of the total content of component (1). [A-15] The solid dispersion according to [A-13], wherein the amount of the alkyl sulfate used in combination is 1.5 parts by mass or more and 5.0 parts by mass or less per part by mass of the total content of component (1). [A-16] The solid dispersion according to [A-13], wherein the amount of the alkyl sulfate used in combination is 1.8 parts by mass or more and 4.0 parts by mass or less per part by mass of the total content of component (1). [A-17] The solid dispersion according to [A-13], wherein the amount of the alkyl sulfate used in combination is 2.0 parts by mass or more and 3.0 parts by mass or less per part by mass of the total content of the component (1). [A-18] A composition comprising the solid dispersion according to any one of [A-1] to [A-17] and an alkyl sulfate. [A-19] The composition according to [A-18], wherein the total content of the alkyl sulfate per part by mass of the total content of the component (1) is 1.37 parts by mass or more and 6.66 parts by mass or less. [A-20] The composition according to [A-18], wherein the total content of the alkyl sulfate per part by mass of the total content of the component (1) is 1.5 parts by mass or more and 5.0 parts by mass or less per part by mass of the total content of the component (1). [A-21] The composition according to [A-18], wherein the total content of the alkyl sulfate salts per part by mass of the total content of the component (1) is 1.8 parts by mass or more and 4.0 parts by mass or less per part by mass of the total content of the component (1). [A-22] The composition according to [A-18], wherein the total content of the alkyl sulfate salts per part by mass of the total content of the component (1) is 2.0 parts by mass or more and 3.0 parts by mass or less per part by mass of the total content of the component (1). [A-23] The composition according to any of [A-20] to [A-22], which is a composition for enhancing absorption of the component (1).[A-24] The composition described in any one of [A-20] to [A-23], which is a pharmaceutical composition. [A-25] The composition described in [A-24], which is a pharmaceutical composition for administration. [A-26] The composition described in [A-25], which is a pharmaceutical composition for oral administration. [A-27] The composition described in any one of [A-18] to [A-26], which is in the form of a tablet. [A-28] The composition described in any one of [A-24] to [A-27], in which the component (1) is an active ingredient. [A-29] The composition described in any one of [A-24] to [A-27], which is a pharmaceutical composition for treating or preventing cancer. [A-30] The composition described in any one of [A-18] to [A-29], in which the alkyl sulfate is lauryl sulfate. [A-31] The composition described in any one of [A-18] to [A-30], in which the alkyl sulfate is sodium lauryl sulfate. [B-1] A method for producing a solid dispersion, comprising: a component (1) which is one or more selected from the group consisting of a compound represented by formula (I), a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable solvate thereof; a component (2) which is one or more polymers selected from the group consisting of hydroxypropyl methylcellulose and derivatives thereof; and a solvent, wherein the total content of component (2) per part by mass of the total content of component (1) is more than 0.1 part by mass and less than 1.0 part by mass, the method comprising the step of removing the solvent from a mixture. [B-2] The manufacturing method according to [B-1], wherein the solvent is removed by spray drying. [B-3] The manufacturing method according to [B-1] or [B-2], wherein the component (1) is a compound represented by formula (I) or a solvate thereof. [B-4] The manufacturing method according to any one of [B-1] to [B-3], wherein the component (1) is a compound represented by formula (I) or a hydrate thereof. [B-5] The manufacturing method according to any one of [B-1] to [B-4], wherein the component (1) is a compound represented by formula (I). [B-6] The manufacturing method according to any one of [B-1] to [B-5], wherein the component (1) is a hydrate of the compound represented by formula (I). [B-7] The manufacturing method according to [B-1] or [B-2], wherein the component (1) is a salt of the compound represented by formula (I). [B-8] The manufacturing method according to any one of [B-1] to [B-7], wherein component (2) is one or more polymers selected from the group consisting of hydroxypropyl methylcellulose and esters thereof. [B-9] The manufacturing method according to any one of [B-1] to [B-8], wherein component (2) is one or more polymers selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methyl acetate maleate, and hydroxypropyl methyl trimellitate. [B-10] The manufacturing method according to any one of [B-1] to [B-9], wherein component (2) is one polymer selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methyl acetate maleate, and hydroxypropyl methyl trimellitate. [B-11] The method according to any one of [B-1] to [B-10], wherein the component (2) is hydroxypropyl methylcellulose acetate succinate (HPMCAS). [B-12] The method according to any one of [B-1] to [B-11], wherein the total content of the component (2) per 1 part by mass of the total content of the component (1) in the mixture is 0.2 parts by mass or more and 0.7 parts by mass or less.[B-13] The manufacturing method according to any one of [B-1] to [B-11], wherein the total content of component (2) per part by mass of the total content of component (1) in the mixture is 0.25 parts by mass or more and 0.6 parts by mass or less. [B-14] The manufacturing method according to any one of [B-1] to [B-11], wherein the total content of component (2) per part by mass of the total content of component (1) in the mixture is 0.3 parts by mass or more and 0.5 parts by mass or less. [B-15] A manufacturing method for a composition, comprising a step (mixing step) of mixing the solid dispersion obtained by the manufacturing method according to any one of [B-1] to [B-14] and an alkyl sulfate. [B-16] The manufacturing method according to [B-15], wherein in the mixing step, 1.37 parts by mass or more and 6.66 parts by mass or less of the alkyl sulfate is mixed per part by mass of the total content of component (1). [B-17] The manufacturing method according to [B-15], wherein the alkyl sulfate is mixed in an amount of 1.5 parts by mass or more and 5.0 parts by mass or less per part by mass of the total content of component (1) in the mixing step. [B-18] The manufacturing method according to [B-15], wherein the alkyl sulfate is mixed in an amount of 1.8 parts by mass or more and 4.0 parts by mass or less per part by mass of the total content of component (1) in the mixing step. [B-19] The manufacturing method according to [B-15], wherein the alkyl sulfate is mixed in an amount of 2.0 parts by mass or more and 3.0 parts by mass or less per part by mass of the total content of component (1) in the mixing step. [B-20] The manufacturing method according to any one of [B-16] to [B-19], wherein the alkyl sulfate is lauryl sulfate. [B-21] The manufacturing method according to any one of [B-16] to [B-20], wherein the alkyl sulfate is sodium lauryl sulfate.

[0010] According to the present invention, it is possible to provide a solid dispersion that can reduce the weight of a formulation required to achieve a certain level of solubility, and a composition containing the solid dispersion.

[0011] 1 shows the results of powder X-ray diffraction measurement of the solid dispersion obtained in Reference Example 1. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°).

[0034] FIG. 1 shows the results of powder X-ray diffraction measurement of the solid dispersion obtained in Comparative Example 1a. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°).

[0035] FIG. 1 shows the results of powder X-ray diffraction measurement of the solid dispersion obtained in Comparative Example 2. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°).

[0036] FIG. 1 shows the results of powder X-ray diffraction measurement of the solid dispersion obtained in Example 1. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°).

[0037] FIG. 1 shows the results of powder X-ray diffraction measurement of the solid dispersion obtained in Example 1b. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°).

[0038] FIG. 1 shows the results of powder X-ray diffraction measurement of the solid dispersion obtained in Example 1-1. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°).

[0039] 4 shows the results of powder X-ray diffraction measurement of the solid dispersion obtained in Comparative Example 3. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). This figure shows the results of powder X-ray diffraction measurement of the solid dispersion obtained in Comparative Example 4. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). This figure shows the results of powder X-ray diffraction measurement of the solid dispersion obtained in Comparative Example 5. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). This figure shows the results of powder X-ray diffraction measurement of the solid dispersion obtained in Comparative Example 6. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). This figure shows the results of powder X-ray diffraction measurement of the solid dispersion obtained in Comparative Example 1b. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). This figure shows the results of the solubility test of Test Formulations 3-1 and 3-2 in Measurement Example 3. The vertical axis is the soluble concentration of peptide 1, and the horizontal axis is the shaking time.

[0033] Figure 1 shows the results of the solubility test for each evaluation formulation in Evaluation Example 1. The vertical axis represents the dissolved concentration of peptide 1, and the horizontal axis represents the shaking time.

[0034] Figure 1 shows the results of the solubility test for each evaluation formulation in Evaluation Example 1. The vertical axis represents the dissolved concentration of peptide 1, and the horizontal axis represents the shaking time.

[0035] Figure 1 shows the results of the solubility test for Evaluation Formulation 1 in Evaluation Examples 2-3. The vertical axis represents the dissolved concentration of peptide 1, and the horizontal axis represents the shaking time.

[0036] Figure 1 shows the results of the solubility test for Evaluation Formulation 3 in Evaluation Example 2-3. The vertical axis represents the dissolved concentration of peptide 1, and the horizontal axis represents the shaking time.1 shows the results of the solubility test of Evaluation Formulation 5 in Evaluation Example 2-3. The vertical axis represents the dissolved concentration of Peptide 1, and the horizontal axis represents the shaking time.

[0012] Hereinafter, embodiments of the present invention will be described in detail, but the present invention is not limited to the following embodiments.

[0013] As used herein, "one or more" means one or more than one. When "one or more" is used in the context of substituents on a group, the term means a number from one to the maximum number of substituents permitted by that group. Specific examples of "one or more" include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and / or more.

[0014] In this specification, the term "to" indicating a range includes both ends of the range. For example, "A to B" means a range equal to or greater than A and equal to or less than B.

[0015] In this specification, the meaning of the term "and / or" includes any combination of "and" and "or" appropriately combined. Specifically, for example, "A, B and / or C" includes the following seven variations: (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, and (vii) A, B and C.

[0016] The solid dispersion according to this embodiment comprises (1) one or more components selected from the group consisting of a compound represented by formula (I), a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable solvate thereof (also referred to herein as “component (1)”), and (2) one or more polymers selected from the group consisting of hydroxypropyl methylcellulose and derivatives thereof (also referred to herein as “component (2)”), wherein the total content of component (2) per part by mass of the total content of component (1) is more than 0.1 part by mass and less than 1.0 part by mass.

[0017] The compound represented by formula (I), its pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates can be produced, for example, by the method disclosed in Patent Document 1. In this specification, the compound represented by formula (I) is also referred to as "peptide 1." The IUPAC name of peptide 1 is (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaoxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0] ４，８ .0 ２６，３０ ]pentatetracont-42-ene-23,1'-cyclobutane]-17-carboxamide.

[0018] The salt of the compound represented by formula (I) may be any pharmaceutically acceptable salt, and specific examples thereof include hydrochlorides, hydrobromides, hydroiodides, phosphates, phosphonates, sulfates, sulfonates such as methanesulfonate and p-toluenesulfonate, carboxylates such as acetate, citrate, malate, tartrate, succinate, and salicylate, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, and ammonium salts such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt, and tetraalkylammonium salt. These salts are produced, for example, by contacting the compound represented by formula (I) with an acid or base that can be used in the production of pharmaceuticals.

[0019] As used herein, the term "solvate" refers to a molecular group formed by the compound represented by formula (I) or a pharmaceutically acceptable salt thereof together with a solvent. A solvate in which the solvent is water is also called a hydrate. Solvates include not only solvates with a single solvent but also solvates with multiple solvents. Examples of solvates of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof include solvates with solvents such as water, alcohols (e.g., methanol, ethanol, 1-propanol, 2-propanol, etc.), and dimethylformamide. As the solvate of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a hydrate is preferred, and specific examples of such hydrates include mono- to decahydrates, preferably mono- to pentahydrates, and more preferably mono- to trihydrates.

[0020] The solid dispersion according to this embodiment may contain, as component (1), one or more of the compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

[0021] Hydroxypropyl methylcellulose is also known as hypromellose. In this specification, the term "hydroxypropyl methylcellulose derivative" refers to a polymer obtained by reacting (modifying) the hydroxyl groups of hydroxypropyl methylcellulose, and examples thereof include esters, ethers, carbamates, and carbonates of hydroxypropyl methylcellulose. In the hydroxypropyl methylcellulose derivative according to this embodiment, the proportion of modified hydroxyl groups of hydroxypropyl methylcellulose is not particularly limited, but may be, for example, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, or 80% or more.

[0022] The hydroxypropyl methylcellulose or derivative thereof according to this embodiment is not particularly limited, but is preferably hydroxypropyl methylcellulose or an ester thereof, more preferably hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methyl acetate maleate, or hydroxypropyl methyl trimellitate, and most preferably hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0023] The solid dispersion according to this embodiment may contain, as component (2), one type of hydroxypropyl methylcellulose or a derivative thereof, or two or more types thereof.

[0024] In the solid dispersion according to this embodiment, the total content of component (2) per part by mass of component (1) is more than 0.1 parts by mass and less than 1.0 parts by mass. The total content of component (2) per part by mass of component (1) may be, for example, 0.15 parts by mass or more, 0.2 parts by mass or more, 0.25 parts by mass or more, or 0.3 parts by mass or more, or may be 0.95 parts by mass or less, 0.9 parts by mass or less, 0.85 parts by mass or less, 0.8 parts by mass or less, 0.75 parts by mass or less, 0.7 parts by mass or less, 0.65 parts by mass or less, 0.6 parts by mass or less, 0.55 parts by mass or less, or 0.5 parts by mass or less. The range of the total content of component (2) per 1 part by mass of the total content of component (1) may be, for example, more than 0.1 part by mass and less than 1.0 part by mass, preferably 0.2 parts by mass or more and 0.7 parts by mass or less, more preferably 0.25 parts by mass or more and 0.6 parts by mass or less, and most preferably 0.3 parts by mass or more and 0.5 parts by mass or less.

[0025] The content of component (1) in the solid dispersion according to this embodiment may be, for example, more than 50% by mass, 55% by mass or more, 60% by mass or more, 62.5% by mass or more, 65% by mass or more, 70% by mass or more, or 75% by mass or more, based on the total amount of the solid dispersion. The content of component (1) in the solid dispersion according to this embodiment may be, for example, less than 100% by mass, 99% by mass or less, 97.5% by mass or less, 95% by mass or less, 92.5% by mass or less, 90% by mass or less, 87.5% by mass or less, 85% by mass or less, 82.5% by mass or less, or 80% by mass or less, based on the total amount of the solid dispersion. The content of component (1) in the solid dispersion according to this embodiment may be, for example, more than 50% by mass and less than 100% by mass, or may be 60% by mass or more and 99% by mass or less, preferably 65% ​​by mass or more and 95% by mass or less, more preferably 70% by mass or more and 90% by mass or less, and most preferably 75% by mass or more and 85% by mass or less, based on the total amount of the solid dispersion. The content of component (1) in the solid dispersion can be measured, for example, by a method using high performance liquid chromatography (HPLC) as described in the Examples below.

[0026] The content of component (2) in the solid dispersion according to this embodiment may be, for example, less than 50% by mass, 45% by mass or less, 40% by mass or less, 38.5% by mass or less, 35% by mass or less, 30% by mass or less, or 25% by mass or less, based on the total amount of the solid dispersion. The content of component (2) in the solid dispersion according to this embodiment may be, for example, more than 0% by mass, 1% by mass or more, 2.5% by mass or more, 5% by mass or more, 7.5% by mass or more, 10% by mass or more, 12.5% ​​by mass or more, 15% by mass or more, 17.5% by mass or more, or 20% by mass or more, based on the total amount of the solid dispersion. The range of the content of component (2) in the solid dispersion according to this embodiment may be, for example, more than 0% by mass and less than 50% by mass, 1% by mass or more and 40% by mass or less, preferably 5% by mass or more and 35% by mass or less, more preferably 10% by mass or more and 30% by mass or less, and most preferably 15% by mass or more and 25% by mass or less, based on the total amount of the solid dispersion. The content of component (2) in the solid dispersion can be determined, for example, by subtracting the content (% by mass) of the substance to be dispersed contained in the solid dispersion, measured by a method using high performance liquid chromatography (HPLC), from 100% by mass.

[0027] The solid dispersion according to this embodiment refers to a semi-solid or solid substance in which component (1) and component (2) are dispersed together. From the viewpoint of improving solubility, component (1) and component (2) are usually uniformly dispersed in the solid dispersion, preferably uniformly dispersed at a fine level, and most preferably uniformly dispersed at a molecular level.

[0028] The method for forming the solid dispersion is not particularly limited, and examples thereof include a method of forming the solid dispersion by removing a certain amount or all of the solvent from a solution in which component (1) and component (2) are dissolved, and a method of mixing solid components (1) and (2) while adding a certain amount of solvent. Specific examples include spray drying, freeze drying, precipitation, melt extrusion, and mixed grinding. Spray drying or freeze drying is preferred, spray drying or freeze drying is more preferred, and spray drying is most preferred. By using the spray drying method, component (1) and component (2) can be more uniformly dispersed in the solid dispersion, and the solubility of a substance (e.g., component (1)) contained in the solid dispersion can be further improved. The solvent may be any solvent capable of dissolving component (1) and component (2), and examples thereof include water, alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, and butanol), ketones (e.g., acetone, methyl ethyl ketone, and methyl isobutyl ketone), esters (e.g., ethyl acetate and propyl acetate), acetonitrile, methylene chloride, toluene, 1,1,1-trichloroethane, and tetrahydrofuran. The solvent may be used alone or as a mixed solvent of two or more kinds.

[0029] Solid dispersions are typically in the form of small particles. The particles may have a volume average diameter of less than 500 μm, or less than 100 μm in diameter, or less than 50 μm in diameter, or less than 25 μm in diameter. When solid dispersions are formed by spray drying, the resulting dispersion is in the form of such small particles.

[0030] The solid dispersion according to this embodiment can be obtained, for example, by a production method comprising: component (1), which is one or more selected from the group consisting of the compound represented by formula (I), a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable solvate thereof; component (2), which is one or more polymers selected from the group consisting of hydroxypropyl methylcellulose and derivatives thereof; and a solvent, wherein the total content of component (2) per part by mass of the total content of component (1) is more than 0.1 part by mass and less than 1.0 part by mass (removal step).

[0031] The production method according to this embodiment may include, in addition to the removal step, a step of preparing a mixture (preparation step) containing component (1) which is one or more selected from the group consisting of the compound represented by formula (I), a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable solvate thereof, component (2) which is one or more polymers selected from the group consisting of hydroxypropyl methylcellulose and derivatives thereof, and a solvent, wherein the total content of component (2) per 1 part by mass of the total content of component (1) is more than 0.1 part by mass and less than 1.0 part by mass.

[0032] The solvent used in the production method according to this embodiment is not particularly limited as long as it can dissolve component (1) and component (2), and examples thereof include water, alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, and butanol), ketones (e.g., acetone, methyl ethyl ketone, and methyl isobutyl ketone), esters (e.g., ethyl acetate and propyl acetate), acetonitrile, methylene chloride, toluene, 1,1,1-trichloroethane, and tetrahydrofuran. The solvent may be used alone or as a mixed solvent of two or more types.

[0033] The total content of component (2) per part by mass of the total content of component (1) in the mixture may be, for example, 0.15 parts by mass or more, 0.2 parts by mass or more, 0.25 parts by mass or more, or 0.3 parts by mass or more, and may be 0.95 parts by mass or less, 0.9 parts by mass or less, 0.85 parts by mass or less, 0.8 parts by mass or less, 0.75 parts by mass or less, 0.7 parts by mass or less, 0.65 parts by mass or less, 0.6 parts by mass or less, 0.55 parts by mass or less, or 0.5 parts by mass or less. The range of the total content of component (2) per part by mass of the total content of component (1) in the mixture may be, for example, more than 0.1 parts by mass but less than 1.0 parts by mass, preferably 0.2 parts by mass or more and 0.7 parts by mass or less, more preferably 0.25 parts by mass or more and 0.6 parts by mass or less, and most preferably 0.3 parts by mass or more and 0.5 parts by mass or less.

[0034] In the production method according to this embodiment, the specific aspects of the components (1) and (2) are the same as those described above.

[0035] Examples of methods for removing the solvent in the removal step include spray drying, freeze drying, precipitation, melt extrusion, and mixed grinding. Spray drying or freeze drying is preferred, spray drying or freeze drying is more preferred, and spray drying is most preferred.

[0036] The conditions for removing the solvent in the removal step can be appropriately set depending on the types of component (1), component (2) and solvent, the type of method for removing the solvent, and the like.

[0037] The composition according to this embodiment contains the above-described solid dispersion and an alkyl sulfate.

[0038] The alkyl sulfate may be, for example, an alkyl sulfate having 6 to 18 carbon atoms (C6-C18; hereinafter, "Cp-Cq" means that the number of carbon atoms is p to q), with C8-C16 alkyl sulfate being preferred, C10-C14 alkyl sulfate being more preferred, and C12 alkyl sulfate (lauryl sulfate) being most preferred. The alkyl sulfate may be any pharmaceutically acceptable salt, including, for example, alkali metal salts such as sodium salt and potassium salt; and alkaline earth metal salts such as magnesium salt and calcium salt. These salts are produced, for example, by contacting (neutralizing) alkyl sulfate with a base that can be used in the production of pharmaceuticals. The alkyl sulfate is more preferably lauryl sulfate, and most preferably sodium lauryl sulfate.

[0039] The composition according to the present embodiment may contain one type of alkyl sulfate alone, or may contain two or more types of alkyl sulfates.

[0040] In the composition according to this embodiment, the total content of alkyl sulfates per part by mass of the total content of component (1) is 1.37 parts by mass or more and 6.66 parts by mass or less. The total content of alkyl sulfates per part by mass of the total content of component (1) may be, for example, 1.37 parts by mass or more, 1.4 parts by mass or more, 1.5 parts by mass or more, 1.6 parts by mass or more, 1.7 parts by mass or more, 1.8 parts by mass or more, 1.9 parts by mass or more, or 2.0 parts by mass or more, or 6.66 parts by mass or less, 6.5 parts by mass or less, 6.0 parts by mass or less, 5.5 parts by mass or less, 5.0 parts by mass or less, 4.5 parts by mass or less, 4.5 parts by mass or less, 4.0 parts by mass or less, 3.5 parts by mass or less, or 3.0 parts by mass or less. The range of the total content of alkyl sulfates per part by mass of the total content of component (1) may be, for example, 1.37 parts by mass or more and 6.66 parts by mass or less, preferably 1.5 parts by mass or more and 5.0 parts by mass or less, more preferably 1.8 parts by mass or more and 4.0 parts by mass or less, and most preferably 2.0 parts by mass or more and 3.0 parts by mass or less.

[0041] The content of the solid dispersion contained in the composition according to this embodiment may be, for example, more than 0% by mass and not more than 90% by mass, more than 0% by mass and not more than 80% by mass, more than 0% by mass and not more than 70% by mass, more than 0% by mass and not more than 60% by mass, more than 0% by mass and not more than 50% by mass, more than 0% by mass and not more than 40% by mass, or more than 0% by mass and not more than 30% by mass, based on the total amount of the composition.

[0042] The composition according to this embodiment can be obtained by a production method including a step of mixing the solid dispersion and an alkyl sulfate (mixing step). The production method may include, in addition to the mixing step, a step of producing the solid dispersion (production step). The production step may be, for example, the same as that described in the method for producing the solid dispersion according to this embodiment.

[0043] In the mixing step, 1.37 to 6.66 parts by mass of alkyl sulfate may be mixed per 1 part by mass of the total content of component (1). In the mixing step, the amount of alkyl sulfate mixed per 1 part by mass of the total content of component (1) may be, for example, 1.37 parts by mass or more, 1.4 parts by mass or more, 1.5 parts by mass or more, 1.6 parts by mass or more, 1.7 parts by mass or more, 1.8 parts by mass or more, 1.9 parts by mass or more, or 2.0 parts by mass or more, or 6.66 parts by mass or less, 6.5 parts by mass or less, 6.0 parts by mass or less, 5.5 parts by mass or less, 5.0 parts by mass or less, 4.5 parts by mass or less, 4.5 parts by mass or less, 4.0 parts by mass or less, 3.5 parts by mass or less, or 3.0 parts by mass or less. In the mixing step, the range of the amount of alkyl sulfate mixed per part by mass of the total content of component (1) may be, for example, 1.37 parts by mass or more and 6.66 parts by mass or less, preferably 1.5 parts by mass or more and 5.0 parts by mass or less, more preferably 1.8 parts by mass or more and 4.0 parts by mass or less, and most preferably 2.0 parts by mass or more and 3.0 parts by mass or less, as the total amount of alkyl sulfate.

[0044] The specific embodiment of the alkyl sulfate in the production method according to this embodiment is the same as that described above.

[0045] In the mixing step, in addition to the solid dispersion and alkyl sulfate, other components may also be mixed together. The other components can be appropriately selected depending on the intended use of the resulting composition. Specific examples of other components include the pharmaceutically acceptable other components described below.

[0046] When the composition according to this embodiment is a pharmaceutical composition, the pharmaceutical composition may contain, in addition to the solid dispersion and alkyl sulfate described above, other pharmaceutically acceptable ingredients, provided that the effects of the present invention are not impaired. The other ingredients are not particularly limited as long as they are pharmaceutically acceptable, and examples thereof include excipients, disintegrants, fluidizing agents / lubricants, flavoring agents, stabilizers, pH adjusters, preservatives, antioxidants, etc.

[0047] Examples of excipients include lactose, corn starch, sucrose, glucose, mannitol, sorbitol, starch, crystalline cellulose, silicon dioxide, and magnesium aluminometasilicate. Examples of disintegrants include starch, pregelatinized starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium chloride, sodium bicarbonate, calcium citrate, anhydrous silicic acid, dextrin, pectin, carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, and sodium starch glycolate. Examples of flow agents and lubricants include light anhydrous silicic acid, hydrous silicic acid dioxide, magnesium stearate, and talc. Examples of flavoring agents include cocoa powder, peppermint, aromatic powder, peppermint oil, borneol, and cinnamon powder. Examples of stabilizers include phosphatidic acid, ascorbic acid, glycerin, and cetanol. Examples of pH adjusters include lactic acid, succinic acid, gluconic acid, citric acid, citric acid hydrate, trisodium citrate, phosphoric acid, potassium carbonate, sodium bicarbonate, tartaric acid, malic acid, ascorbic acid, fumaric acid, aspartic acid, glutamic acid, glutamic acid hydrochloride, malonic acid, maleic acid, meglumine, arginine, lysine, glycine, sodium carbonate, sodium hydrogen phosphate, etc. Examples of preservatives include ethyl parahydroxybenzoate, propyl parahydroxybenzoate, etc. Examples of antioxidants include butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, propyl gallate, etc.

[0048] When the composition according to the present embodiment is a pharmaceutical composition, the form of the pharmaceutical composition is not particularly limited, but is typically solid. The pharmaceutical composition according to the present embodiment is used by being formed into dosage forms such as powders, fine granules, granules, tablets, coated tablets, capsules, etc.

[0049] When the composition according to this embodiment is a pharmaceutical composition, the pharmaceutical composition may be administered orally or parenterally, and is preferably administered orally because the solubility of component (1) (the active ingredient) is enhanced.

[0050] When the composition according to this embodiment is a pharmaceutical composition, the subject to which the pharmaceutical composition is administered is not particularly limited and may be a human or a non-human animal, such as a dog, monkey, miniature pig, rabbit, rat, or mouse.

[0051] When the composition according to this embodiment is a pharmaceutical composition, the dosage of the pharmaceutical composition is not particularly limited, and may be administered so that the dosage of component (1) (active ingredient) per kg of subject body weight (kg) is 0.1 mg / kg to 1000 mg / kg. The dosage of component (1) (active ingredient) may be, for example, 1 mg / kg to 500 mg / kg, 1 mg / kg to 100 mg / kg, 1 mg / kg to 50 mg / kg, 3 mg / kg to 30 mg / kg, 10 mg / kg to 30 mg / kg, 0.1 mg / kg to 10 mg / kg, 1 mg / kg to 5 mg / kg, 10 mg / kg to 100 mg / kg, 15 mg / kg to 50 mg / kg, 20 mg / kg to 40 mg / kg, 25 mg / kg to 35 mg / kg, 3 mg / kg, or 30 mg / kg.

[0052] The composition according to this embodiment can be produced by molding into any dosage form using a conventional method.

[0053] The composition (pharmaceutical composition) according to this embodiment has enhanced solubility of component (1), and therefore can be used as a composition for enhancing absorption of component (1).

[0054] The composition (pharmaceutical composition) according to this embodiment contains component (1) that has a selective KRAS inhibitory activity against HRAS and NRAS, and therefore can be used as a pharmaceutical composition for treating or preventing cancer.

[0055] Preferred specific embodiments of the present invention will be described below as examples, but the present invention is not limited thereto.

[0056] Synthesis Example 1: Method for synthesizing peptide 1 Peptide 1 represented by the following formula (I) and name was synthesized by a method similar to that described in WO 2022 / 234853, and the final product was obtained as a dry product. Specifically, compound PP2320 in WO 2022 / 234853 corresponds to peptide 1. (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaoxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 ４，８ .0 ２６，３０ ]pentatetracont-42-ene-23,1'-cyclobutane]-17-carboxamide

[0057] Experimental Example 1: Preparation of solid dispersions containing peptides and surfactants and measurement of dissolution concentrations. A fixed amount of peptide 1 and each of the surfactants listed in Table 1 were each dissolved in dimethyl sulfoxide (DMSO) to prepare a peptide 1 solution and each surfactant solution. Next, 50 μL of the resulting peptide 1 solution and each surfactant solution were mixed together so that the peptide 1 concentration was 0.25 mg / mL and the peptide 1 / surfactant ratio was 1 / 2 (w / w), yielding each mixture. After lyophilization, each mixture was mixed with 50 μL of FaSSIF solution and shaken at 37°C at 1000 rpm for 10 or 240 minutes. The resulting suspensions were filtered and diluted with DMSO containing 4-hydroxyquinoline, an internal standard (IS). The FaSSIF solution was prepared by dissolving taurocholic acid and lecithin in a phosphate buffer containing sodium and chloride to a concentration of 3 mmol / L and 0.75 mmol / L, respectively, using 3F Powder (FFF02) and FaSSIF buffer concentrate (FASBUF) obtained from Biorelevant, and adjusting the pH to 6.5. (FaSSIF solutions were prepared in the same manner in all subsequent experimental procedures.) The soluble concentration of peptide 1 in the FaSSIF solution in the presence of each surfactant was quantified by HPLC / UV under the conditions listed in Tables 2 and 3. The results are shown in Table 4.

[0058]

[0059]

[0060]

[0061]

[0062] Experimental Example 2: Preparation of Solid Dispersions Containing Peptides and Polymers and Measurement of Dissolution Concentration Peptide 1 and each of the polymers listed in Table 5 were dissolved in DMSO in a predetermined amount to prepare a Peptide 1 solution and each of the polymer solutions. Next, 50 μL of the resulting Peptide 1 solution and each of the polymer solutions were mixed together so that the Peptide 1 concentration was 0.25 mg / mL and the Peptide 1 / polymer ratio was 1 / 2 (w / w), yielding each mixed solution. After lyophilization, each mixed solution was added with 50 μL of FaSSIF solution and shaken at 37°C and 1000 rpm for 10 or 240 minutes. The resulting suspensions were filtered and diluted with DMSO containing 4-hydroxyquinoline, an internal standard (IS). The dissolution concentration of Peptide 1 in FaSSIF solution in the presence of each polymer was then quantified by HPLC / UV under the conditions listed in Tables 2 and 3. The results are shown in Table 6.

[0063]

[0064]

[0065] [Reference Example 1, Comparative Examples 1a, 1b, and 2 to 6, Examples 1, 1b, 1-1, and 2: Preparation of Solid Dispersions] (Reference Example 1) Peptide 1 and Eudragit L100 were added to ethanol so that the weight ratio of Peptide 1 to Eudragit L100 was 1:2 and the solid concentration was 8 wt / vol % to prepare a solution. This solution was spray-dried to obtain a solid dispersion.

[0066] (Comparative Examples 1a and 1b) Peptide 1 and HPMC AS-L were added to acetone at a weight ratio of 1:2 and at a solid concentration of 12 wt / vol % to prepare a suspension. This suspension was spray-dried to obtain a solid dispersion.

[0067] Comparative Example 2 Peptide 1 and HPMC AS-L were added to acetone at a weight ratio of 1:1 and a solid concentration of 8 wt / vol % to prepare a suspension. This suspension was spray-dried to obtain a solid dispersion.

[0068] Example 1 Peptide 1 and HPMC AS-L were added to acetone at a weight ratio of 1:0.5 and a solid concentration of 6 wt / vol % to prepare a suspension. This suspension was spray-dried to obtain a solid dispersion.

[0069] Example 1b: Peptide 1 and HPMC AS-L were added to acetone at a weight ratio of 1:0.5 and a solid concentration of 6 wt / vol % to prepare a suspension. This suspension was spray-dried to obtain a solid dispersion.

[0070] Example 1-1 A suspension was prepared by adding Peptide 1 and HPMC(TC5)E to a solution of methanol and water at a volume ratio of 9:1 so that the weight ratio of Peptide 1 and HPMC(TC5)E was 1:0.5 and the solid concentration was 6 wt / vol %. This suspension was spray-dried to obtain a solid dispersion.

[0071] Example 2 Peptide 1 and HPMC AS-L were added to acetone at a weight ratio of 1:0.3 and a solid concentration of 5.2 wt / vol % to prepare a suspension. This suspension was spray-dried to obtain a solid dispersion.

[0072] Comparative Example 3 Peptide 1 and HPMC AS-L were added to acetone at a weight ratio of 1:0.1 and a solid concentration of 4.4 wt / vol % to prepare a suspension. This suspension was spray-dried to obtain a solid dispersion.

[0073] Comparative Example 4 Peptide 1 was added to acetone to give a concentration of 4 wt / vol % to prepare a solution, which was then spray-dried to obtain a solid dispersion.

[0074] Comparative Example 5 Peptide 1 and PVP VA64 were added to ethanol at a weight ratio of 1:0.5 and a solid concentration of 6 wt / vol % to prepare a solution, which was then spray-dried to obtain a solid dispersion.

[0075] Comparative Example 6 Peptide 1 and Eudragit L100 were added to ethanol at a weight ratio of 1:0.5 and a solid concentration of 6 wt / vol % to prepare a solution, which was then spray-dried to obtain a solid dispersion.

[0076] Measurement Example 1: Powder X-ray diffraction measurement of solid dispersions containing peptide and polymer The solid dispersions obtained in Reference Example 1, Comparative Examples 1a, 1b, and 2 to 6, and Examples 1, 1b, 1-1, and 2 were each subjected to powder X-ray diffraction measurement by the following measurement method. Measurement device: D8 Discover, 2D VANTEC-500 solid state detector (manufactured by Bruker) Radiation source: CuKα Tube voltage / tube current: 40 kV / 40 mA or 50 kV / 1000 μA Measurement range: 5 to 31° Exposure time: 40 to 80 seconds

[0077] The results are shown in Figures 1 to 12. As a result of the measurement, a halo pattern was confirmed in all solid dispersions.

[0078] Measurement Example 2: Peptide 1 Content The content of Peptide 1 in the solid dispersions obtained in Reference Example 1, Comparative Examples 1a, 1b, and 2 to 6, and Examples 1, 1b, 1-1, and 2 was measured under the following conditions.

[0079] <Content Measurement: Solid Dispersions of Reference Example 1 and Comparative Example 1a> The solid dispersions obtained in Reference Example 1 and Comparative Example 1a were weighed into glass vials so that each formulation amounted to 1 mg, and dissolved in dimethyl acetamide. The sample was diluted with dimethyl acetamide containing 2-(1-Naphthyl)ethanol as an internal standard, and analyzed by LC / UV under the conditions described in Table 7. The results are shown in Table 10.

[0080]

[0081] <Content Measurement: Solid Dispersions of Comparative Examples 1b and 2 to 6 and Examples 1, 1b, 1-1 and 2> The solid dispersions obtained in Comparative Examples 1b and 2 to 6 and Examples 1, 1b, 1-1 and 2 were weighed into glass vials so that the formulation amounted to 1 mg, diluted with dimethyl acetamide containing 2-(1-Naphthalyl)ethanol as an internal standard, and analyzed by LC / UV under the conditions described in Table 8 for Comparative Examples 1b and 2 to 4 and Examples 1 and 2, and under the conditions described in Table 9 for Comparative Examples 5 and 6 and Examples 1b and 1-1. The results are shown in Table 10.

[0082]

[0083]

[0084] Measurement Example 3: Solubility Test The solid dispersion obtained in Reference Example 1 or Comparative Example 1a, lactose (Pharmatose 200M, manufactured by DFE Pharma), and SLS were weighed out in the amounts shown in Table 11 and mixed together to prepare Measurement Preparations 3-1 and 3-2, which are lactose mixtures.

[0085]

[0086] The dissolved concentrations of Test Formulation 3-1 and Test Formulation 3-2 were measured using an Agilent Technologies 708-DS solubility tester. The amount of test formulation used was 75 mg (containing 12.5 mg of peptide 1). The solubility test was performed at a rotation speed of 50 rpm using 50 mL of FaSSIF solution. Sampling was performed using an Agilent Technologies 850-DS sampling station, and sample filtration was performed using a Whatman 850-DS 8-channel filter plate. The obtained samples were diluted with a dimethyl acetamide / ethylene glycol mixture containing the internal standard 2-(1-naphthalene)ethanol and analyzed by LC / UV under the conditions listed in Table 12.

[0087]

[0088] The results of the solubility test are shown in Figure 13. The results of the solubility test confirmed that Measurement Formulation 3-1 had higher solubility than Measurement Formulation 3-2. These results confirmed that HPMC AS-L is suitable as a polymer for preparing a solid dispersion containing Peptide 1.

[0089] Evaluation Example 1: Dissolution concentration and formulation weight The solid dispersions obtained in Comparative Examples 1b and 2 to 6 and Examples 1, 1b, 1-1 and 2, SLS and lactose (Pharmatose 200M, manufactured by DFE Pharma) were weighed and mixed in the amounts shown in Table 13 to prepare evaluation formulations 1 to 10.

[0090]

[0091] The solubility of evaluation formulations 1 to 10 was evaluated using an Agilent Technologies 708-DS solubility tester. The amount of evaluation formulation was the amount listed in "Total (mg)" in Table 13 (containing 7.5 mg of peptide 1), and the solubility test conditions were a rotation speed of 50 rpm and 50 ml of FaSSIF solution as the test solution. Sampling was performed using an Agilent Technologies 850-DS sampling station, and sample filtration was performed using a Whatman 850-DS 8-channel filter plate. The obtained sample was diluted with a dimethyl acetamide / ethylene glycol mixture containing the internal standard 2-(1-naphthalene)ethanol and analyzed by LC / UV under the conditions listed in Table 14.

[0092]

[0093] The results of the solubility test are shown in Table 15 and Figures 14 and 15.

[0094] The results of the solubility test showed that all evaluation formulations 1 to 6 had equivalent solubility at 240 minutes after the start of the solubility test. Furthermore, evaluation formulations 5, 4, and 3 had higher dissolution concentrations at 5 and 10 minutes compared to evaluation formulations 2 and 1. These results indicated that formulations with a peptide 1:polymer ratio of 1:0.5 or less had excellent initial dissolution rates. Furthermore, the dissolution concentrations at 120 and 240 minutes for evaluation formulations 9 and 10 were higher than those for evaluation formulations 7 and 8. Evaluation formulations 3 and 4 were lighter in weight (mg) than the other evaluation formulations, demonstrating that they had good solubility with a small amount of additives. Among these, evaluation formulation 3 was the lightest of all evaluation formulations 1 to 6, demonstrating good solubility with the smallest amount of additives. Furthermore, the solid dispersions obtained in Examples 1 and 2 are also considered to have excellent tablet disintegration properties because the weight ratio of HPMC AS-L to Peptide 1 was as low as less than 1. These results confirmed that hydroxypropyl methylcellulose or a derivative thereof is suitable as a polymer for preparing solid dispersions containing Peptide 1.

[0095] [Evaluation Example 2: Stability Evaluation] (Evaluation Example 2-1: Chemical Stability) For Evaluation Formulation 11 and Evaluation Formulation 12, each reagent was weighed out as shown in Table 16 so that the amount of peptide 1 was 1 mg, and the mixture was placed in a glass vial and mixed. The mixture was then placed in an aluminum pouch containing an oxygen scavenger and moisture absorber, sealed, and stored in a constant temperature bath at 40°C for 6 months. To evaluate chemical stability, samples before and after storage were dissolved in N,N-dimethylacetamide containing hexyl benzoate as an internal standard, and the peak intensity of peptide 1 (the peak intensity of peptide 1 in a fixed amount of evaluation formulation) was analyzed by LC / UV under the conditions shown in Table 17.

[0096]

[0097]

[0098] The residual rate was calculated using the following formula: Residual rate (%) = {(Peptide 1 peak intensity after storage / Internal standard peak intensity) / (Peptide 1 peak intensity before storage / Internal standard peak intensity)} × 100 The results are shown in Table 18.

[0099] As shown in Table 18, in all of the evaluation formulations, Peptide 1 exhibited a high retention rate of 98% or more when stored at 40°C for 6 months in the presence of a moisture-absorbing oxygen scavenger, demonstrating its chemical stability. These results demonstrate that Peptide 1 is chemically stable at least when the weight ratio of Peptide 1 to HPMC AS-L is in the range of 1:2 to 1:0.

[0100] (Evaluation Example 2-2: Physical Stability) A spatula-sized amount of each of Evaluation Formulation 11 and Evaluation Formulation 12 was scooped into a glass vial. The vial was then placed in a glass desiccator containing a sufficient amount of saturated aqueous sodium chloride solution to maintain a constant humidity throughout the storage period, sealed, and stored in a constant temperature bath at 40°C for 6 months. According to JOURNAL OF RESEARCH of the National Bureau of Standards-A. Physics and Chemistry, Vol. 81A, No. 1, January-February 1977, it is believed that the humidity inside the desiccator was maintained at approximately 75% RH during the storage period. To evaluate physical stability, Peptide 1 was analyzed before and after storage using the following measurement method. Measuring device: D8 Discover, 2D VANTEC-500 solid state detector (manufactured by Bruker) Radiation source: CuKα Tube voltage / tube current: 50 kV / 1000 μA Measurement range: 5 to 31° Exposure time: 120 seconds The results are shown in Table 19.

[0101]

[0102] As shown in Table 19, it was revealed that Peptide 1 remained amorphous and physically stable in all evaluation formulations when stored in the presence of a saturated aqueous sodium chloride solution at 40°C for 6 months. These results demonstrate that amorphous Peptide 1 is physically stable at least when the weight ratio of Peptide 1 to HPMC AS-L is in the range of 1:2 to 1:0.

[0103] (Evaluation Example 2-3: Dissolution Concentration Stability) For each of Evaluation Formulations 1, 3, and 5, 33.8 mg of Peptide 1 was weighed into a glass vial. The vial was then sealed in a glass desiccator containing a sufficient amount of saturated sodium chloride solution to maintain a constant humidity throughout the storage period, and then stored in a 40°C thermostatic chamber for one or three months. According to JOURNAL OF RESEARCH of the National Bureau of Standards-A. Physics and Chemistry, Vol. 81A, No. 1, January-February 1977, it is believed that the humidity inside the desiccator was maintained at approximately 75% RH throughout the storage period. To evaluate physical stability, a Peptide 1 solubility test was subsequently performed using each Evaluation Formulation before and after storage. The results are shown in Table 20.

[0104]

[0105] The solubility of Evaluation Formulations 1, 3, and 5 was evaluated using an Agilent Technologies 708-DS solubility tester. The amount of Evaluation Formulation used for the evaluation was the amount listed in "Total (mg)" in Table 13 (containing 7.5 mg of Peptide 1). The solubility test was performed at a rotation speed of 50 rpm and using 50 ml of FaSSIF solution as the test solution. Sampling was performed using an Agilent Technologies 850-DS sampling station, and sample filtration was performed using a Whatman 850-DS 8-channel filter plate. The obtained sample was diluted with a dimethyl acetamide / ethylene glycol mixture containing the internal standard 2-(1-naphthalenyl)ethanol and analyzed by LC / UV under the conditions listed in Table 21. The results are shown in Figures 16 to 18.

[0106]

[0107] Figure 16 shows the results of the solubility test for Evaluation Formulation 1. Figure 17 shows the results of the solubility test for Evaluation Formulation 3. Figure 18 shows the results of the solubility test for Evaluation Formulation 5. As shown in Table 20 and Figures 16 to 18, it was revealed that the peptide maintained its solubility and was physically stable in all solid dispersion-containing formulations when stored at 40°C for 1 month or 3 months in the presence of a saturated aqueous sodium chloride solution. These results demonstrate that amorphous Peptide 1 is physically stable at least when the weight ratio of Peptide 1 to HPMC AS-L is in the range of 1:2 to 1:0.

[0108] (Evaluation Example 2-4: Monkey PK test) In order to evaluate the absorbability of Peptide 1 in the solid dispersion obtained in Example 1, an evaluation formulation 13 was prepared by mixing SLS and lactose (Pharmatose 200M, manufactured by DFE Pharma) with the composition shown in Table 22. A PK test was carried out by administering this evaluation formulation to monkeys so that the dose of Peptide 1 was 3 mg / kg. As a result of the test, it was confirmed that the exposure of Peptide 1 was sufficiently high, with an AUC (0-48 h) of 4750 (ng·h / mL) and a Cmax of 510 (ng / mL).

[0109]

Claims

1. A solid dispersion comprising component (1), which is one or more selected from the group consisting of a compound represented by formula (I), a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable solvate thereof, and component (2), which is one or more polymers selected from the group consisting of hydroxypropyl methylcellulose and derivatives thereof, wherein the total content of component (2) per part by mass of the total content of component (1) is more than 0.1 part by mass and less than 1.0 part by mass.

2. The solid dispersion according to claim 1, wherein the component (1) is a compound represented by formula (I).

3. The solid dispersion according to claim 1 or 2, wherein component (2) is one or more polymers selected from the group consisting of hydroxypropylmethylcellulose and esters thereof.

4. The solid dispersion according to any one of claims 1 to 3, wherein component (2) is one or more polymers selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methyl acetate maleate, and hydroxypropyl methyl trimellitate.

5. The solid dispersion according to any one of claims 1 to 4, wherein component (2) is a polymer selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methyl acetate maleate, and hydroxypropyl methyl trimellitate.

6. The solid dispersion according to any one of claims 1 to 5, wherein component (2) is hydroxypropyl methylcellulose acetate succinate (HPMCAS).

7. A composition comprising the solid dispersion according to any one of claims 1 to 6 and an alkyl sulfate.

8. The composition according to claim 7, wherein the total content of the alkyl sulfates per 1 part by mass of the total content of the component (1) is 1.37 parts by mass or more and 6.66 parts by mass or less.

9. The composition according to claim 7 or 8, which is a pharmaceutical composition.

10. The composition of claim 9, which is a pharmaceutical composition for oral administration.

11. The composition according to claim 9 or 10, in the form of a tablet.

12. The composition according to any one of claims 9 to 11, wherein the component (1) is an active ingredient.

13. The composition of any one of claims 7 to 12, wherein the alkyl sulfate is lauryl sulfate.

14. The composition of any one of claims 7 to 13, wherein the alkyl sulfate is sodium lauryl sulfate.

15. A method for producing a solid dispersion, comprising: component (1), which is one or more selected from the group consisting of a compound represented by formula (I), a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable solvate thereof; component (2), which is one or more polymers selected from the group consisting of hydroxypropyl methylcellulose and derivatives thereof; and a solvent, wherein the total content of component (2) per 1 part by mass of the total content of component (1) is more than 0.1 part by mass and less than 1.0 part by mass, the method comprising a step of removing the solvent from a mixture.

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