Solid dispersion containing substance to be dispersed, pharmaceutical composition containing same, and production methods therefor

Abstract

The present invention pertains to a solid dispersion comprising: (1) an amorphous substance to be dispersed having a molecular weight of 1,000-5,000 g / mol; and (2) a polymer, wherein the ratio of the total mass of the polymer to the total mass of the substance to be dispersed is less than 1.0, and the following (I) or (II) is satisfied.　(I) The glass transition temperature of the substance to be dispersed is different by at least 1ºC from the glass transition temperature of the solid dispersion. (II) The glass transition temperature of the solid dispersion is 94.5-105.5% of the value of Tga expressed by expression (A). [In expression (A), Tgc represents the glass transition temperature of the substance to be dispersed, Tgp represents the glass transition temperature of the polymer, Wa represents the total mass of the solid dispersion, Wc represents the total mass of the substance to be dispersed contained in the solid dispersion, and Wp represents the total mass of the polymer contained in the solid dispersion.]

Description

Solid dispersion containing a substance to be dispersed, pharmaceutical composition containing the same, and methods for producing the same

[0001] The present invention relates to a solid dispersion containing a substance to be dispersed, a pharmaceutical composition containing the same, and methods for producing the same.

[0002] In order to improve the solubility of drugs, solid dispersions containing poorly soluble compounds and polymers have been prepared (Patent Documents 1 to 5, Non-Patent Document 1).

[0003] International Publication No. WO 2010 / 126030 International Publication No. WO 2014 / 092061 International Publication No. WO 2015 / 189901 International Publication No. WO 2008 / 047201 U.S. Pat. No. 10,004,719

[0004] International Journal of Pharmaceutics, 2010, Vol. 399, pp. 94-101

[0005] Conventionally, when preparing a solid dispersion containing a poorly soluble compound (active ingredient), a certain amount of polymer has been blended into the solid dispersion to ensure sufficient amorphous stability of the poorly soluble compound. However, there has been a problem in that the greater the amount of polymer, the longer the disintegration time of the solid dispersion and the pharmaceutical composition containing the solid dispersion.

[0006] An object of the present invention is to provide a solid dispersion that has excellent amorphous stability while reducing the amount of polymer, and a pharmaceutical composition containing the solid dispersion.

[0007] The present invention relates to, for example, the following inventions: [1] A solid dispersion comprising (1) a substance to be dispersed, which has a molecular weight of 1000 g / mol to 5000 g / mol and is amorphous, and (2) a polymer, wherein the ratio of the total mass of the polymer to the total mass of the substance to be dispersed is less than 1.0, and which satisfies the following (I) or (II): (I) the glass transition temperature of the substance to be dispersed differs from the glass transition temperature of the solid dispersion by 1°C or more; (II) the glass transition temperature of the solid dispersion is 94.5% to 105.5% of the value of Tga represented by the following formula (A); [In formula (A), Tgc represents the glass transition temperature of the substance to be dispersed, Tgp represents the glass transition temperature of the polymer, Wa represents the total mass of the solid dispersion, Wc represents the total mass of the substance to be dispersed contained in the solid dispersion, and Wp represents the total mass of the polymer contained in the solid dispersion.] [2] The solid dispersion according to [1], which satisfies (I). [3] The solid dispersion according to [1], which satisfies (II). [4] The solid dispersion according to [1], which satisfies (I) and (II). [5] The solid dispersion according to [1], wherein the glass transition temperature of the solid dispersion is 100°C or higher and 200°C or lower. [6] The solid dispersion according to any one of [1] to [5], wherein the glass transition temperature of the substance to be dispersed is higher than the glass transition temperature of the polymer. [7] The solid dispersion according to [6], wherein the glass transition temperature of the substance to be dispersed is higher by 1°C or more than the glass transition temperature of the polymer. [8] The solid dispersion according to any one of [1] to [7], wherein the glass transition temperature of the substance to be dispersed is higher by 1°C or more than the glass transition temperature of the solid dispersion. [9] The solid dispersion according to any one of [1] to [8], wherein the glass transition temperature of the substance to be dispersed is 90°C or more and 180°C or less.

[10] The solid dispersion according to any one of [1] to [9], wherein the substance to be dispersed is a peptide compound.

[11] The solid dispersion according to

[10] , wherein the number of amino acid residues constituting the peptide compound is 5 to 30.

[12] The solid dispersion according to

[10] or

[11] , wherein the number of unnatural amino acid residues contained in the peptide compound is 1 or more.

[13] The solid dispersion according to any one of

[10] to

[12] , wherein the number of N-substituted amino acid residues contained in the peptide compound is 1 or more.

[14] The solid dispersion according to any one of

[10] to

[13] , wherein the number of N-substituted amino acid residues contained in the peptide compound is 5 or more. [15 ... substituent on the nitrogen atom of the N-substituted amino acid is C １ -C ６The solid dispersion according to

[13] or

[14] , wherein the polymer is an alkyl group.

[16] The solid dispersion according to any of

[10] to

[15] , wherein the ClogP of the peptide compound is 4 or more and 25 or less.

[17] The solid dispersion according to any of

[10] to

[16] , wherein the ClogP / number of amino acid residues of the peptide compound is 1.0 or more.

[18] The solid dispersion according to any of

[10] to

[17] , wherein the peptide compound has a cyclic portion.

[19] The solid dispersion according to

[18] , wherein the number of amino acid residues contained in the cyclic portion is 5 or more and 15 or less.

[20] The solid dispersion according to any of [1] to

[19] , wherein the glass transition temperature of the polymer is 30°C or more and 170°C or less.

[21] The solid dispersion according to any of [1] to

[20] , wherein the polymer is a pharmaceutically acceptable polymer.

[22] The solid dispersion according to any of [1] to

[21] , wherein the weight-average molecular weight of the polymer is 3,000 or more and 400,000 or less.

[23] The solid dispersion according to any one of [1] to

[22] , wherein the polymer is at least one selected from the group consisting of a nonionic polymer and an ionic polymer.

[24] The solid dispersion according to any one of [1] to

[23] , wherein the polymer is an ionic polymer.

[25] The solid dispersion according to any one of [1] to

[24] , wherein the polymer is an acidic polymer.

[26] The solid dispersion according to any one of [1] to

[24] , wherein the polymer is a basic polymer.

[27] The solid dispersion according to any one of [1] to

[23] , wherein the polymer is a nonionic polymer.

[28] The solid dispersion according to

[27] , wherein the nonionic polymer is a neutral non-cellulosic polymer.

[29] The solid dispersion of

[28] , wherein the neutral non-cellulosic polymer is at least one selected from the group consisting of (i), (ii), (iii), and (iv): (i) vinyl polymers and copolymers having at least one substituent selected from the group consisting of hydroxyl, alkylacyloxy, and cyclic amide-containing groups; (ii) vinyl copolymers of at least one hydrophilic hydroxyl-containing repeating unit and at least one hydrophobic alkyl- or aryl-containing repeating unit, polyvinyl alcohol; (iii) polyvinyl alcohol, polyvinyl alcohol-polyvinyl acetate copolymer, polyvinylpyrrolidone, copovidone, acrylate and methacrylic acid copolymer, polyethylene-polyvinyl alcohol copolymer, and (iv) polyoxyethylene-polyoxypropylene block copolymer.

[30] The solid dispersion of

[27] , wherein the nonionic polymer is a neutral cellulosic polymer.

[31] The solid dispersion according to

[30] , wherein the neutral cellulose polymer is at least one selected from the group consisting of hydroxypropyl methylcellulose acetate (HPMCA), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethyl cellulose.

[32] The solid dispersion according to

[27] , wherein the nonionic polymer is a neutralized acidic polymer.

[33] The solid dispersion according to

[32] , wherein the neutralized acidic polymer is at least one selected from the group consisting of cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, methylcellulose phthalate, hydroxymethylcellulose ethyl phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate: HPMCAS), hydroxypropyl methyl acetate maleate, hydroxypropyl methyl trimellitate, carboxymethyl ethyl cellulose, polyvinyl butyrate phthalate, polyvinyl alcohol acetate phthalate, methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl methacrylate copolymer, and methacrylic acid copolymer.

[34] The solid dispersion according to

[24] , wherein the ionic polymer is at least one selected from the group consisting of acidic polymers and basic polymers.

[35] The solid dispersion according to

[25] or

[34] , wherein the acidic polymer is at least one selected from the group consisting of cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, methylcellulose phthalate, hydroxymethylcellulose ethyl phthalate, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methyl acetate maleate, hydroxypropyl methyl trimellitate, carboxymethyl ethyl cellulose, polyvinyl butyrate phthalate, polyvinyl alcohol acetate phthalate, methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl methacrylate copolymer, and methacrylic acid copolymer.

[36] The solid dispersion according to

[26] or

[34] , wherein the basic polymer is at least one selected from the group consisting of aminoalkyl methacrylic acid copolymer E and polyvinyl acetal diethylaminoacetate.

[37] The solid dispersion according to any one of [1] to

[22] , wherein the polymer is at least one selected from the group consisting of a polymer having a hydroxypropyl cellulose skeleton, a polymer having a povidone skeleton, and a block copolymer.

[38] The solid dispersion according to

[37] , wherein the polymer is at least one selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymer, methacrylic acid / methyl methacrylate copolymer, and methacrylic acid / ethyl acrylate copolymer.

[39] The solid dispersion according to any one of [1] to

[38] , wherein the bulk density calculated from the volume of powder obtained by gently filling 0.5 g of the solid dispersion into a 5 mL graduated cylinder is 0.15 g / mL or more.

[40] The solid dispersion according to any one of [1] to

[39] , wherein in a physical stability test under conditions of 40°C and 75% RH, no crystals are observed up to one month after the start of the test.

[41] The solid dispersion according to any one of [1] to

[40] , wherein in a physical stability test under conditions of 80°C and 75% RH, no crystals are observed up to one month after the start of the test.

[42] The solid dispersion according to any one of [1] to

[41] , wherein the disintegration time in a disintegration test using a second dissolution test fluid as the test fluid at a test fluid temperature of 37.0°C and an oscillation frequency of 30 times / minute is 1,000 seconds or less.

[43] The solid dispersion according to any one of [1] to

[42] , wherein the content of the substance to be dispersed in the solid dispersion is more than 50% by mass and less than 100% by mass, based on the total amount of the solid dispersion.

[44] A pharmaceutical composition comprising the solid dispersion according to any one of [1] to

[43] .

[45] The pharmaceutical composition according to

[44] , which is a molded solid.

[46] The pharmaceutical composition according to

[44] or

[45] , wherein the content of the solid dispersion is 99% by mass or less based on the total amount of the pharmaceutical composition.

[47] The pharmaceutical composition according to any one of

[44] to

[46] , wherein the solubility in water at pH 6.5, pressure 1 atm, and temperature 25°C is 10 mg / mL or less.

[48] ​​The pharmaceutical composition according to any one of

[44] to

[47] , wherein in a physical stability test under conditions of 40°C and 75% RH, no crystals are observed up to one month after the start of the test.

[49] The pharmaceutical composition according to any one of

[44] to

[48] , wherein in a physical stability test under conditions of 80°C and 75% RH, no crystals are observed up to one month after the start of the test.

[50] The pharmaceutical composition according to any one of

[44] to

[49] , wherein the disintegration time in a disintegration test using the second dissolution test fluid as the test fluid at a test fluid temperature of 37.0°C and an oscillation frequency of 30 times / minute is 1,000 seconds or less.

[51] The pharmaceutical composition according to any one of

[44] to

[50] , further comprising a surfactant.

[52] The pharmaceutical composition according to

[51] , wherein the surfactant is a pharmaceutically acceptable surfactant.

[53] The pharmaceutical composition according to

[51] or

[52] , wherein the surfactant has a linear hydrocarbon group.

[54] The pharmaceutical composition according to any one of

[51] to

[53] , wherein the number of carbon atoms contained in the linear hydrocarbon group is from 5 to 17.

[55] The pharmaceutical composition according to

[51] or

[52] , wherein the surfactant is represented by any one of the following general formulas (a1) to (a3): [In general formulas (a1) to (a3), R １ represents a saturated or unsaturated, linear hydrocarbon group having from 5 to 17 carbon atoms, which may have a substituent; X represents sodium or potassium; and Y represents a group represented by the following formula (a4) or a stereoisomer thereof. [In formula (a4), represents a bond.]

[56] The pharmaceutical composition according to

[51] or

[52] , wherein the surfactant is represented by the following general formula (a3): [In general formula (a3), R １represents an optionally substituted, saturated or unsaturated, straight-chain hydrocarbon group having from 5 to 17 carbon atoms, and X represents sodium or potassium.

[57] The pharmaceutical composition according to

[51] or

[52] , wherein the surfactant is sodium dodecyl sulfate.

[58] The pharmaceutical composition according to any of

[44] to

[57] , further comprising an excipient.

[59] The pharmaceutical composition according to any of

[44] to

[58] , further comprising a disintegrant.

[60] A method for producing a solid dispersion, comprising a step of evaporating by spray drying a solvent in a mixture containing (1) a substance to be dispersed, which is amorphous and has a molecular weight of from 1000 g / mol to 5000 g / mol, and (2) a polymer, in an amount such that the ratio of the total mass of the polymer to the total mass of the substance to be dispersed is less than 1.0.

[61] The production method according to

[60] , wherein the solvent is capable of dissolving the substance to be dispersed and the polymer.

[62] The production method according to

[60] or

[61] , wherein the solvent is one or more selected from the group consisting of water, alcohols, ketones, esters, acetonitrile, methylene chloride, toluene, 1,1,1-trichloroethane, and tetrahydrofuran.

[63] The production method according to any one of

[60] to

[62] , wherein the solvent is an alcohol.

[64] The production method according to any one of

[60] to

[62] , wherein the solvent is a ketone.

[65] The production method according to any one of

[60] to

[62] , wherein the solvent is an ester.

[66] The production method according to any one of

[62] or

[63] , wherein the alcohol is one or more selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, and butanol.

[67] The production method according to

[62] or

[64] , wherein the ketone is one or more selected from the group consisting of acetone, methyl ethyl ketone, and methyl isobutyl ketone.

[68] The production method according to

[62] or

[65] , wherein the ester is one or more selected from the group consisting of ethyl acetate and propyl acetate.

[69] The production method according to any one of

[60] to

[68] , wherein the solvent is one kind.

[70] The production method according to any one of

[60] to

[69] , wherein the solvent is ethanol, acetone, or tetrahydrofuran.

[71] The method according to any one of

[60] to

[70] , wherein spray drying is carried out under conditions of an air volume of 100 L / h to 800 L / h, a temperature of 40°C to 120°C, and 1 atm.

[72] The method according to any one of

[10] to

[71] , wherein the peptide compound is represented by the following structural formula (1):

[0008] According to the present invention, it is possible to provide a solid dispersion having excellent amorphous stability while reducing the amount of polymer, and a pharmaceutical composition containing the solid dispersion.

[0009] Graph showing the results of XRD measurement of the solid dispersion of Example I-A-1. Graph showing the results of XRD measurement of the solid dispersion of Example I-A-4. Graph showing the results of XRD measurement of the solid dispersion of Comparative Example I-A-ii. Graph showing the results of XRD measurement of the solid dispersion of Example V-G-4. Graph showing the results of XRD measurement of the solid dispersion of Example V-J-4. Graph showing the results of XRD measurement of the solid dispersion of Comparative Example V-G-4. Graph showing the results of XRD measurement of the solid dispersion of Comparative Example V-J-4. Graph showing the results of DSC measurement of the solid dispersion of Example I-A-1. Graph showing the results of DSC measurement of the solid dispersion of Example I-A-2. Graph showing the results of DSC measurement of the solid dispersion of Example I-A-3. Graph showing the results of DSC measurement of the solid dispersion of Example I-A-4. Graph showing the results of DSC measurement of the solid dispersion of Example I-A-5. Graph showing the DSC measurement results of the solid dispersion of Example I-A-6. Graph showing the DSC measurement results of the solid dispersion of Comparative Example I-A-i. Graph showing the DSC measurement results of the solid dispersion of Comparative Example I-A-ii. Graph showing the DSC measurement results of the solid dispersion of Example I-B-4. Graph showing the DSC measurement results of the solid dispersion of Example I-C-4. Graph showing the DSC measurement results of the solid dispersion of Example I-D-4. Graph showing the DSC measurement results of the solid dispersion of Example I-E-4. Graph showing the DSC measurement results of the solid dispersion of Example I-F-4. Graph showing the DSC measurement results of the solid dispersion of Example I-G-4. Graph showing the DSC measurement results of the solid dispersion of Example I-H-4. Graph showing the DSC measurement results of the solid dispersion of Example I-I-4. Graph showing the DSC measurement results of the solid dispersion of Example I-J-4. Graph showing the DSC measurement results of the solid dispersion of Example I-L-4. Graph showing the DSC measurement results of the solid dispersion of Example V-G-4. Graph showing the DSC measurement results of the solid dispersion of Example V-J-4. Graph showing the DSC measurement results of the solid dispersion of Comparative Example V-G-4. Graph showing the DSC measurement results of the solid dispersion of Comparative Example V-J-4. Graph showing the DSC measurement results of the solid dispersion of Example I-K-4. Graph showing the DSC measurement results of the solid dispersion of Example V-A-4.1 is a graph showing the results of DSC measurement of the solid dispersion of Example VI-A-4.

[0010] Hereinafter, embodiments of the present invention will be described in detail, but the present invention is not limited to the following embodiments.

[0011] 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.

[0012] 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.

[0013] As used herein, the term "about" when used in conjunction with a numerical value means a range of values ​​of plus and minus 10% of that numerical value.

[0014] In the present invention, 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.

[0015] The solid dispersion according to this embodiment comprises (1) a substance to be dispersed, which has a molecular weight of 1000 g / mol or more and 5000 g / mol or less and is amorphous, and (2) a polymer, in which the ratio of the total mass of the polymer to the total mass of the substance to be dispersed is less than 1.0, and satisfies the following (I) or (II): (I) the glass transition temperature of the substance to be dispersed is different from that of the solid dispersion; (II) the glass transition temperature of the solid dispersion is 94.5% or more and 105.5% or less of the value of Tga represented by the following formula (A); In formula (A), Tgc represents the glass transition temperature of the substance to be dispersed, Tgp represents the glass transition temperature of the polymer, Wa represents the total mass of the solid dispersion, Wc represents the total mass of the substance to be dispersed contained in the solid dispersion, and Wp represents the total mass of the polymer contained in the solid dispersion.

[0016] (Substance to be Dispersed) The molecular weight of the substance to be dispersed according to this embodiment may be 1000 g / mol or more and 5000 g / mol or less. The molecular weight in this specification refers to the sum of the atomic weights of the atoms constituting the compound molecule (unit: "g / mol"), and is obtained by calculating the sum of the atomic weights of the atoms included in the molecular structure (unit: "g / mol"). In this specification, the unit of molecular weight may be omitted. The molecular weight can be measured, for example, by liquid chromatography mass spectrometry (LC / MS).

[0017] The molecular weight of the dispersion target substance according to this embodiment may be, for example, 1100 g / mol or more, 1200 g / mol or more, 1300 g / mol or more, or 1400 g / mol or more. The molecular weight of the dispersion target substance according to this embodiment may be, for example, 4000 g / mol or less, 3000 g / mol or less, 2500 g / mol or less, 2000 g / mol or less, 1800 g / mol or less, 1600 g / mol or less, or 1500 g / mol or less. Examples of the molecular weight range of the dispersion target substance according to this embodiment include 1000 g / mol to 4000 g / mol, 1000 g / mol to 3000 g / mol, 1100 g / mol to 2500 g / mol, 1200 g / mol to 2000 g / mol, 1300 g / mol to 1800 g / mol, 1400 g / mol to 1600 g / mol, and 1400 g / mol to 1500 g / mol. The molecular weight of the dispersion target substance according to this embodiment is, for example, 1000 g / mol to 5000 g / mol, preferably 1200 g / mol to 2000 g / mol, more preferably 1300 g / mol to 1800 g / mol, and most preferably 1400 g / mol to 1600 g / mol. When the molecular weight is within the above range, the substance to be dispersed is less likely to crystallize and has excellent amorphous stability.

[0018] The dispersion target substance according to this embodiment exists as an amorphous substance in the solid dispersion according to this embodiment. In this specification, "amorphous" refers to a substance that does not have long-range order. The amorphous nature of the dispersion target substance can be confirmed, for example, by performing X-ray diffraction (XRD) measurement on the solid dispersion as described in the Examples below, and checking that the XRD spectrum shows a broad diffraction pattern or a halo pattern with no diffraction peaks, in other words, that it does not show a sharp diffraction pattern.

[0019] As used herein, amorphous stability refers to the length of time that the substance to be dispersed in a solid dispersion can remain amorphous. Amorphous stability can be measured by storing a solid dispersion under certain conditions, such as 40°C and 75% RH, 80°C and 75% RH, or 40°C and 85% RH, and then examining whether the substance to be dispersed in the solid dispersion remains amorphous. Specifically, it can be measured by the physical stability test described in the Examples. Furthermore, since the physical stability of a pharmaceutical composition is governed by the physical stability of the solid dispersion contained in the pharmaceutical composition, the physical stability of the solid dispersion contained in the pharmaceutical composition can be measured by subjecting the pharmaceutical composition to the above physical stability test. Conversely, measuring the physical stability of a solid dispersion can reveal the physical stability of a pharmaceutical composition containing the solid dispersion.

[0020] The glass transition temperature (Tgc) of the dispersion target substance according to this embodiment may be, for example, 90°C or higher, 100°C or higher, 110°C or higher, 120°C or higher, 130°C or higher, 135°C or higher, or 140°C or higher. The glass transition temperature (Tgc) of the dispersion target substance according to this embodiment may be, for example, 180°C or lower, 175°C or lower, 170°C or lower, 165°C or lower, or 160°C or lower. Examples of the range of the glass transition temperature (Tgc) of the dispersion target substance according to this embodiment include 90°C or higher and 180°C or lower, 100°C or higher and 175°C or lower, 110°C or higher and 170°C or lower, 120°C or higher and 165°C or lower, 130°C or higher and 160°C or lower, 135°C or higher and 160°C or lower, or 140°C or higher and 160°C or lower. The glass transition temperature (Tgc) of the dispersion target material according to this embodiment is, for example, 90°C to 180°C, preferably 100°C to 175°C, more preferably 120°C to 170°C, and most preferably 130°C to 165°C. When the glass transition temperature is within the above range, the dispersion target material is less likely to crystallize and has excellent amorphous stability. In this specification, the glass transition temperature (°C) refers to the value measured by differential scanning calorimetry (DSC) described in the Examples below. Specifically, the glass transition temperature is the temperature corresponding to the point at which the value is smallest among the values ​​obtained by first differentiating the Rev Heat Flow [mW] curve obtained by differential scanning calorimetry with respect to temperature [°C]. Note that, when determining the point at which the value is smallest among the values ​​obtained by first differentiation, noise near the start of the DSC measurement is excluded and the point at which the value is smallest is determined.

[0021] The dispersion target substance according to this embodiment may have a solubility in 50 mM phosphate buffer (pH 6.5) at 25°C and 1 atm of 10 mg / mL or less, or may be greater than 0 mg / mL. The solubility of the dispersion target substance according to this embodiment in 50 mM phosphate buffer (pH 6.5) at 25°C and 1 atm may be, for example, 5 mg / mL or less, 2.5 mg / mL or less, 2 mg / mL or less, 1 mg / mL or less, 0.5 mg / mL or less, 0.25 mg / mL or less, 0.1 mg / mL or less, 0.05 mg / mL or less, 0.025 mg / mL or less, 0.01 mg / mL or less, 0.005 mg / mL or less, 0.0025 mg / mL or less, or 0.001 mg / mL or less. Alternatively, the solubility may be 0.0001 mg / mL or more, 0.0005 mg / mL or more, or 0.001 mg / mL or more. The solubility of the dispersion target substance in 50 mM phosphate buffer (pH 6.5) at 25°C and 1 atm is, for example, greater than 0 mg / mL and 10 mg / mL or less, preferably greater than 0 mg / mL and 1 mg / mL or less, more preferably greater than 0 mg / mL and 0.1 mg / mL or less, and most preferably greater than 0 mg / mL and 0.05 mg / mL or less. The solubility of the dispersion target substance in 50 mM phosphate buffer (pH 6.5) at 25°C and 1 atm can be measured, for example, by the method described in the Examples below.

[0022] The dispersion target substance according to this embodiment may be a compound classified as Class II or Class IV in the Biopharmaceutics Classification System (BCS). The BCS is a guideline for predicting the gastrointestinal absorption characteristics of pharmaceuticals by classifying them into four classes (Class I to Class IV) based on their solubility and absorption rate.

[0023] Solubility in BCS (D ０ : Dose Number) is D ０ = 1 as the boundary, D ０ When D is less than 1, the solubility is judged to be high (high solubility), and ０ When the value is ≧1, the solubility is judged to be low (low solubility). ａF: the rate of absorption from the digestive tract) is measured with a 90% absorption rate as the boundary. ａ When the absorption rate is ≦0.9, it is determined that the absorption rate is low (low absorption rate), and F ａ When the D solubility is ≥ 0.9, the absorption rate is judged to be high (high absorption rate). BCS Classes I to IV are defined as follows: Class I: High solubility (D ０ ≦1) and high absorption rate (F ａ ≧0.9) Class II: Low solubility (D ０ ≧1) and high absorption rate (F ａ ≧0.9) Class III: High solubility (D ０ ≦1) and low absorption rate (F ａ ≦0.9) Class IV: Low solubility (D ０ ≧1) and low absorption rate (F ａ ≦0.9)

[0024] The dispersion target substance according to this embodiment may be a peptide compound. In this specification, the term "peptide compound" is not particularly limited as long as it refers to a peptide compound in which amino acid residues are linked by amide bonds or ester bonds. The number of amino acid residues constituting the peptide compound may be, for example, 5 or more, 7 or more, 8 or more, 9 or more, or 10 or more. The number of amino acid residues constituting the peptide compound may also be 30 or less, 25 or less, 20 or less, 15 or less, 14 or less, 13 or less, or 12 or less. The number of amino acid residues constituting the peptide compound may be, for example, 5 to 30 or less, 7 to 25 or less, 8 to 15 or less, 9 to 14 or less, 9 to 13 or less, or 11. The number of amino acid residues constituting the peptide compound is, for example, 5 to 30, preferably 9 to 15, more preferably 10 to 14, and most preferably 11 to 13. The peptide compound may have a branched structure.

[0025] As used herein, the term "amino acid" includes natural amino acids and unnatural amino acids. Also, as used herein, the term "amino acid residue" includes natural amino acid residues and unnatural amino acid residues.

[0026] Naturally occurring amino acids refer to glycine (Gly), alanine (Ala), serine (Ser), threonine (Thr), valine (Val), leucine (Leu), isoleucine (Ile), phenylalanine (Phe), tyrosine (Tyr), tryptophan (Trp), histidine (His), glutamic acid (Glu), aspartic acid (Asp), glutamine (Gln), asparagine (Asn), cysteine ​​(Cys), methionine (Met), lysine (Lys), arginine (Arg), and proline (Pro).

[0027] Examples of unnatural amino acids include, but are not limited to, β-amino acids, D-amino acids, N-substituted amino acids (excluding Pro), α,α-disubstituted amino acids, amino acids whose side chains differ from those of natural amino acids, hydroxycarboxylic acids, etc. As used herein, unnatural N-substituted amino acids refer to N-substituted amino acids other than Pro.

[0028] As used herein, amino acids are allowed to have any steric configuration. The side chain of an amino acid is not particularly limited, and can be freely selected from, in addition to a hydrogen atom, for example, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, a heteroaralkyl group, a cycloalkyl group, or a spiro-linked cycloalkyl group. Each of these groups may be substituted, and the substituents are not limited. For example, one or more groups may be independently selected from any substituent containing a halogen atom, an O atom, a S atom, a N atom, a B atom, a Si atom, or a P atom. Examples of such groups include optionally substituted alkyl groups, alkoxy groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, aralkyl groups, cycloalkyl groups, etc., or oxo, aminocarbonyl, halogen atoms, etc. An amino acid according to one embodiment may be a compound having a carboxy group and an amino group in the same molecule (even in this case, imino acids such as proline and hydroxyproline are also included in the amino acid).

[0029] As used herein, "alkyl" refers to a monovalent group derived from an aliphatic hydrocarbon by removing any one hydrogen atom, and does not contain heteroatoms (atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds in the skeleton, but has a subset of hydrocarbyl or hydrocarbon group structures containing hydrogen and carbon atoms. Alkyl includes not only linear but also branched chain alkyls. Alkyl preferably has 1 to 20 carbon atoms (C １ -C ２０ , hereinafter referred to as “C ｐ -C ｑ " means that the number of carbon atoms is p to q), and preferably C １ -C １０ Alkyl, more preferably C １ -C ６ Specific examples of the alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, isobutyl (2-methylpropyl), n-pentyl, s-pentyl (1-methylbutyl), t-pentyl (1,1-dimethylpropyl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), 3-pentyl (1-ethylpropyl), 1,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1,2,2-tetramethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, and 2-ethylbutyl.

[0030] Halogen-derived substituents include fluoro (-F), chloro (-Cl), bromo (-Br), iodo (-I), and the like.

[0031] Substituents derived from O atoms include hydroxy (-OH), oxy (-OR), carbonyl (-C(=O)-R), carboxy (-CO ２H), oxycarbonyl (-C(=O)-OR), carbonyloxy (-O-C(=O)-R), thiocarbonyl (-C(=O)-SR), carbonylthio group (-S-C(=O)-R), aminocarbonyl (-C(=O)-NHR), carbonylamino (-NH-C(=O)-R), oxycarbonylamino (-NH-C(=O)-OR), sulfonylamino (-NH-SO ２ -R), aminosulfonyl (-SO ２ -NHR), sulfamoylamino (-NH-SO ２ -NHR), thiocarboxy (-C(=O)-SH), carboxycarbonyl (-C(=O)-CO ２ H).

[0032] Examples of oxy (—OR) include alkoxy, cycloalkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, aralkyloxy, and the like.

[0033] Examples of carbonyl (-C(=O)-R) include formyl (-C(=O)-H), alkylcarbonyl, cycloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, and the like.

[0034] Examples of oxycarbonyl (-C(=O)-OR) include alkyloxycarbonyl, cycloalkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl, and the like.

[0035] Examples of carbonyloxy (—O—C(═O)—R) include alkylcarbonyloxy, cycloalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, aralkylcarbonyloxy, and the like.

[0036] Examples of thiocarbonyl (-C(=O)-SR) include alkylthiocarbonyl, cycloalkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, aralkylthiocarbonyl, and the like.

[0037] Examples of carbonylthio (-S-C(=O)-R) include alkylcarbonylthio, cycloalkylcarbonylthio, alkenylcarbonylthio, alkynylcarbonylthio, arylcarbonylthio, heteroarylcarbonylthio, aralkylcarbonylthio, and the like.

[0038] Examples of aminocarbonyl (-C(=O)-NHR) include alkylaminocarbonyl, cycloalkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, etc. In addition to these, compounds in which the H atom bonded to the N atom in -C(=O)-NHR is further substituted with an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl are also included.

[0039] Examples of carbonylamino (-NH-C(=O)-R) include alkylcarbonylamino, cycloalkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylcarbonylamino, etc. In addition to these, compounds in which the H atom bonded to the N atom in -NH-C(=O)-R is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl are also included.

[0040] Examples of oxycarbonylamino (-NH-C(=O)-OR) include alkoxycarbonylamino, cycloalkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, aralkyloxycarbonylamino, etc. In addition to these, examples include compounds in which the H atom bonded to the N atom in -NH-C(=O)-OR is further substituted with an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.

[0041] Sulfonylamino (-NH-SO ２ Examples of —R) include alkylsulfonylamino, cycloalkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, etc. In addition to these, —NH—SO ２ Examples include compounds in which the H atom bonded to the N atom in —R is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.

[0042] Aminosulfonyl (-SO ２ Examples of —NHR) include alkylaminosulfonyl, cycloalkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, and the like. ２ Examples include compounds in which the H atom bonded to the N atom in —NHR is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.

[0043] Sulfamoylamino (-NH-SO ２Examples of —NHR) include alkylsulfamoylamino, cycloalkylsulfamoylamino, alkenylsulfamoylamino, alkynylsulfamoylamino, arylsulfamoylamino, heteroarylsulfamoylamino, and aralkylsulfamoylamino. ２ The two H atoms bonded to the N atom in —NHR may be substituted with substituents independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, and these two substituents may form a ring.

[0044] Substituents derived from S atoms include thiol (-SH), thio (-S-R), sulfinyl (-S(=O)-R), sulfonyl (-S(O) ２ -R), sulfo (-SO ３ H), pentafluorosulfanyl (-SF ５ ) etc.

[0045] Examples of thio (-S-R) include alkylthio, cycloalkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, aralkylthio, and the like.

[0046] Examples of sulfinyl (-S(=O)-R) include alkylsulfinyl, cycloalkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heteroarylsulfinyl, aralkylsulfinyl, and the like.

[0047] Sulfonyl (-S(O) ２ Examples of —R) include alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, and the like.

[0048] As a substituent derived from the N atom, azide (-N ３ , also called "azido group"), cyano (-CN), primary amino (-NH ２ ), secondary amino (—NH—R), tertiary amino (—NR(R′)), amidino (—C(═NH)—NH２ ), substituted amidino (—C(═NR)—NR′R″), guanidino (—NH—C(═NH)—NH ２ ), substituted guanidino (—NR—C(═NR′″)—NR′R″), aminocarbonylamino (—NR—CO—NR′R″), and the like.

[0049] Examples of secondary amino (-NH-R) include alkylamino, cycloalkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, and aralkylamino.

[0050] Examples of tertiary amino (—NR(R′)) include an amino group having any two substituents independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, etc., such as alkyl(aralkyl)amino, and these two substituents may form a ring.

[0051] Examples of substituted amidino (-C(=NR)-NR'R'') include groups in which the three substituents R, R', and R'' on the N atom are each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, such as alkyl(aralkyl)(aryl)amidino.

[0052] Examples of substituted guanidino (-NR-C(=NR'")-NR'R") include groups in which R, R', R", and R'" are each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, and groups in which these groups form a ring.

[0053] Examples of aminocarbonylamino (—NR—CO—NR′R″) include groups in which R, R′, and R″ are each independently selected from a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, and groups in which these groups form a ring.

[0054] Examples of the substituent derived from the B atom include boryl (-BR(R')) and dioxyboryl (-B(OR)(OR')). These two substituents R and R' may be groups independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, etc., or may be a group in which these groups form a ring. Specific examples include cyclic boryl groups, and more specific examples include pinacolatoboryl groups, neopentanediolateboryl groups, and catecholateboryl groups.

[0055] The main chain amino group of the amino acid is unsubstituted (-NH ２ ) or may be substituted (i.e., —NHR, where R represents, for example, an alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, aralkyl group, cycloalkyl group, or the like, which may have a substituent, and the carbon chain bonded to the N atom and the carbon atom at the α-position may form a ring, as in proline).

[0056] In the present specification, an amino acid in which the main chain amino group is substituted is referred to as an "N-substituted amino acid." As used herein, the "N-substituted amino acid" is preferably an N-alkyl amino acid, an N-C １ -C ６ Alkyl amino acids, N-C １ -C ５ Alkyl amino acids, N-C １ -C ４ Alkyl amino acids, N-C １ -C ３ Alkyl amino acids, N-ethyl amino acids, N-methyl amino acids, N-C ７ -C １４ Examples include, but are not limited to, aralkyl amino acids, N-benzyl amino acids, and N-phenethyl amino acids.

[0057] Specific examples of the substituent on the nitrogen atom of the N-substituted amino acid in this specification (R in the above-mentioned —NHR) include alkyl groups (preferably C １ -C ６ alkyl group, more preferably C １ -C ４ alkyl group, more preferably C １ -C３ an alkyl group, more preferably an ethyl group or a methyl group), C ７ -C １４ Examples include an aralkyl group, a benzyl group, a phenethyl group, etc. As the substituent on the nitrogen atom of the N-substituted amino acid, an ethyl group or a methyl group is more preferred, and a methyl group is particularly preferred (i.e., an N-methyl amino acid is particularly preferred as the N-substituted amino acid).

[0058] As used herein, the term "hydrocarbon group" refers to a structure made up of carbon atoms and hydrogen atoms.

[0059] As used herein, "amino acid" includes all corresponding isotopes. An isotope of an "amino acid" is one in which at least one atom has been replaced with an atom having the same atomic number (number of protons) but a different mass number (sum of the number of protons and neutrons). Examples of isotopes included in "amino acids" as used herein include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, each of which is ２ H. ３ H. １３ C. １４ C. １５ N. １７ O. １８ O. ３２ P. ３５ S. １８ F. ３６ Cl, etc. Compounds herein containing all proportions of radioactive or non-radioactive isotopes are within the scope of the present invention.

[0060] The number of unnatural amino acid residues contained in the peptide compound of this embodiment may be, for example, 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, or 10 or more. The number of unnatural amino acid residues contained in the peptide compound of this embodiment may be, for example, 30 or less, 25 or less, 20 or less, 15 or less, 14 or less, 13 or less, or 12 or less. The number of unnatural amino acid residues contained in the peptide compound of this embodiment can be, for example, 1 to 30, 2 to 25, 3 to 20, 4 to 15, 5 to 14, 6 to 13, 7 to 12, or 11. The number of unnatural amino acid residues contained in the peptide compound of this embodiment is, for example, 1 to 30, preferably 3 to 15, more preferably 5 to 12, and most preferably 7 to 10.

[0061] The number of N-substituted amino acid residues contained in the peptide compound according to this embodiment may be, for example, 1 or more, 2 or more, 3 or more, 4 or more, or 5 or more. The number of N-substituted amino acid residues contained in the peptide compound according to this embodiment is, for example, 1 or more, preferably 2 or more, more preferably 3 or more, and most preferably 5 or more.

[0062] The peptide compound according to this embodiment may be a peptide compound having a cyclic portion (sometimes referred to herein as a "cyclic peptide compound"). As used herein, the "cyclic portion" of a peptide compound refers to a cyclic portion formed by linking four or more amino acid residues. The number of amino acid residues constituting the cyclic portion of a cyclic peptide compound may be, for example, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, or 10 or more. The number of amino acid residues constituting the cyclic portion of a cyclic peptide compound may be, for example, 15 or less, 14 or less, 13 or less, or 12 or less. Examples of the number of amino acid residues constituting the cyclic portion of the cyclic peptide compound include 5 to 15, 6 to 15, 7 to 15, 8 to 15, 9 to 15, 10 to 15, 5 to 14, 6 to 14, 7 to 14, 8 to 14, 9 to 14, 10 to 14, 5 to 13, 6 to 13, 7 to 13, 8 to 13, 9 to 13, 10 to 13, 5 to 12, 6 to 12, 7 to 12, 8 to 12, 9 to 12, 10 to 12, 5 to 11, 6 to 11, 7 to 11, 8 to 11, 9 to 11, 10 to 11, or 11. The number of amino acid residues constituting the cyclic portion of the cyclic peptide compound is, for example, 5 to 15, preferably 9 to 15, more preferably 10 to 14, and most preferably 11 to 13. The cyclic portion is preferably formed via a covalent bond such as an amide bond, a carbon-carbon bond-forming reaction, an S—S bond, a thioether bond, or a triazole bond, and can be formed by bonding a group on the N-terminus and a group on the C-terminus of a linear peptide compound to which amino acid residues are linked. Specifically, for example, the cyclic portion can be formed by bonding an amino group on the N-terminus and a carboxy group on the C-terminus of a linear peptide compound to which amino acid residues are linked. The cyclization may be in any form, such as cyclization via a carbon-nitrogen bond such as an amide bond, cyclization via a carbon-oxygen bond such as an ester bond or an ether bond, cyclization via a carbon-sulfur bond such as a thioether bond, cyclization via a carbon-carbon bond, cyclization via a sulfur-sulfur bond, or cyclization via a heterocyclic ring structure.Among these, cyclization via a covalent bond such as an amide bond or a carbon-carbon bond is preferred, and cyclization via an amide bond between a carboxy group in a side chain and an amino group in the main chain is more preferred. The positions of the carboxy group and amino group used for cyclization may be on the main chain or on the side chain, and are not particularly limited as long as they are in positions that allow cyclization.

[0063] Specific examples of the peptide compound according to this embodiment include compounds I to V described in the Examples below. The structural formulae of compounds I to V are as follows:

[0064] The peptide compound according to this embodiment is most preferably Compound I.

[0065] The peptide compound according to this embodiment preferably has a ClogP of 4 or more and 25 or less. ClogP is a partition coefficient calculated by a computer and can be determined in accordance with the principles described in "CLOGP Reference Manual Daylight Version 4.9 (Release date: August 1, 2011, https: / / www.daylight.com / dayhtml / doc / clogp / )." As an example of a method for calculating ClogP, the ClogP may be calculated using the ClogP Reference Manual published by Daylight Chemical Information Systems, Inc. One example is calculation using Daylight Version 4.95 (release date: August 1, 2011, ClogP algorithm version 5.4, database version 28, https: / / www.daylight.com / dayhtml / doc / release_notes / index.html) by Yahoo! Japan.

[0066] The ClogP of the peptide compound according to this embodiment is more preferably 24 or less, even more preferably 23 or less, even more preferably 22 or less, even more preferably 21 or less, and particularly preferably 20 or less. The lower limit of the ClogP of the peptide compound according to this embodiment is more preferably 5 or more, even more preferably 6 or more, even more preferably 7 or more, even more preferably 8 or more, and particularly preferably 10 or more. Examples of the ClogP range of the peptide compound according to this embodiment include 5 or more and 24 or less, 6 or more and 23 or less, 7 or more and 22 or less, 8 or more and 21 or less, 9 or more and 20 or less, 10 or more and 20 or less, 11 or more and 18 or less, and 11.2 or more and 16.1 or less. The ClogP range of the peptide compound according to this embodiment is, for example, 4 to 25, preferably 6 to 23, more preferably 8 to 21, and most preferably 9 to 20.

[0067] The peptide compound according to this embodiment preferably has a ClogP / amino acid residue ratio of 1.0 or greater. Here, "number of amino acid residues" refers to the total number of amino acid residues constituting the peptide compound. For example, a cyclic peptide compound having a cyclic portion consisting of 10 amino acid residues and a linear portion consisting of 1 amino acid residue has 11 amino acid residues. The ClogP / amino acid residue ratio is a value calculated by dividing the ClogP of a peptide compound by the number of amino acid residues contained in the peptide compound. For example, when the ClogP of a peptide compound is 14.0 and the number of amino acid residues contained in the peptide compound is 7, the ClogP / amino acid residue ratio of the peptide compound is calculated to be 2.0.

[0068] The Clog P / number of amino acid residues of the peptide compound according to this embodiment is more preferably 1.1 or more, and even more preferably 1.2 or more. The upper limit of the Clog P / number of amino acid residues of the peptide compound according to this embodiment is preferably 1.8 or less, more preferably 1.7 or less, even more preferably 1.6 or less, and even more preferably 1.5 or less. Examples of ranges of the Clog P / number of amino acid residues of the peptide compound according to this embodiment include 1.0 or more and 1.8 or less, 1.0 or more and 1.7 or less, 1.1 or more and 1.6 or less, and 1.1 or more and 1.5 or less. The Clog P / number of amino acid residues of the peptide compound according to this embodiment is, for example, 1.0 to 1.8, preferably 1.0 to 1.7, more preferably 1.1 to 1.6, and most preferably 1.1 to 1.5.

[0069] (Polymer) The polymer according to this embodiment may be any pharmaceutically acceptable polymer.

[0070] The glass transition temperature (Tgp) of the polymer according to this embodiment may be, for example, 30°C or higher, 50°C or higher, 90°C or higher, 95°C or higher, 100°C or higher, 105°C or higher, 110°C or higher, or 115°C or higher. The glass transition temperature (Tgp) of the polymer according to this embodiment may be, for example, 170°C or lower, 160°C or lower, 150°C or lower, 140°C or lower, 135°C or lower, 130°C or lower, 125°C or lower, or 120°C or lower. Examples of the range of the glass transition temperature (Tgp) of the polymer according to this embodiment include 30°C or higher and 170°C or lower, 90°C or higher and 140°C or lower, 100°C or higher and 135°C or lower, or 105°C or higher and 130°C or lower. The glass transition temperature (Tgp) of the polymer according to this embodiment is, for example, in the range of 30°C to 170°C, preferably 90°C to 140°C, more preferably 100°C to 135°C, and most preferably 105°C to 130°C.

[0071] The weight-average molecular weight of the polymer according to this embodiment may be, for example, 3,000 or more, 5,000 or more, 10,000 or more, 15,000 or more, or 20,000 or more. Furthermore, the weight-average molecular weight of the polymer according to this embodiment may be, for example, 400,000 or less, 200,000 or less, 150,000 or less, 100,000 or less, 80,000 or less, 70,000 or less, 60,000 or less, or 50,000 or less. Examples of the range of the weight-average molecular weight of the polymer according to this embodiment include 3,000 to 400,000 or less, 5,000 to 200,000 or less, 10,000 to 150,000 or less, 15,000 to 80,000 or less, or 20,000 to 50,000 or less. The weight-average molecular weight of the polymer according to this embodiment is, for example, 3,000 to 400,000, preferably 5,000 to 200,000 or less, more preferably 10,000 to 80,000 or less, and most preferably 15,000 to 50,000 or less. In this specification, "weight-average molecular weight" refers to a value measured by size exclusion chromatography.

[0072] Polymers that can be used in the solid dispersions of the present invention should be pharmaceutically acceptable and preferably have at least some solubility in aqueous solution at physiologically relevant pH (e.g., 1 to 8). Almost any polymer that has an aqueous solubility of at least about 0.1 mg / mL over at least a portion of the pH range of 1 to 8 may be suitable.

[0073] Polymers according to this embodiment include, for example, nonionic polymers and ionic polymers. A nonionic polymer is a polymer that is substantially free of ionic functional groups. "Substantially free of ionic functional groups" means that the number of ionic groups covalently attached to the polymer is less than about 0.05 milliequivalents per gram of polymer. Preferably, the number is less than about 0.02 milliequivalents per gram of neutral polymer. "Ionic functional groups" means functional groups that are at least about 10% ionized over at least a portion of the physiologically relevant pH range of 1 to 8. Such groups have pKa values ​​of about 0 to 9.

[0074] Nonionic polymers include, for example, neutral non-cellulosic polymers, neutral cellulosic polymers, and neutralized acidic polymers.

[0075] Neutral non-cellulosic polymers can include, for example, (i) vinyl polymers and copolymers having at least one substituent selected from the group consisting of hydroxyl, alkylacyloxy, and cyclic amide containing groups; (ii) vinyl copolymers of at least one hydrophilic hydroxyl-containing repeating unit and at least one hydrophobic alkyl- or aryl-containing repeating unit, polyvinyl alcohol; (iii) polyvinyl alcohol having at least a portion of the repeating units in the unhydrolyzed (vinyl acetate) form, polyvinyl alcohol-polyvinyl acetate copolymers, polyvinylpyrrolidone, copovidone, acrylate and methacrylic acid copolymers, polyethylene-polyvinyl alcohol copolymers; and (iv) polyoxyethylene-polyoxypropylene block copolymers.

[0076] Neutral cellulosic polymers can include, for example, hydroxypropyl methylcellulose acetate (HPMCA), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethyl cellulose.

[0077] In another aspect, polymers that can be used in the present invention include neutralized acidic polymers. Neutralized acidic polymers are described in more detail in U.S. Patent Application Publication No. 2003-0054038, filed June 17, 2002, entitled "Pharmaceutical Compositions of Drugs and Neutralized Acidic Polymers." The relevant disclosures of said patent application are incorporated herein by reference. "Acidic polymer" refers to any polymer having a substantial number of acidic moieties. Generally, a substantial number of acidic moieties would be about 0.05 milliequivalents or more of acidic moieties per gram of polymer. "Acidic moieties" include any functional group that is sufficiently acidic to be capable of at least partially donating hydrogen cations to water when contacted with or dissolved in water, thereby increasing the hydrogen ion concentration. This definition includes any functional group or "substituent" (as the functional group is so called when it is covalently attached to the polymer) that has a pKa of less than about 10.

[0078] By "neutralized acidic polymer" is meant any acidic polymer in which a substantial portion of the "acidic moieties" or "acidic substituents" are "neutralized," i.e., present in deprotonated form. The "degree of neutralization," α, of a polymer substituted with a monoprotic acid (e.g., carboxylic acid) is defined as the fraction of acidic moieties on the polymer that are neutralized, i.e., deprotonated by base. Typically, for an acidic polymer to be considered a "neutralized acidic polymer," α must be at least about 0.01 (or 1%), more preferably at least about 0.1 (10%), even more preferably at least about 0.5 (50%), and most preferably at least 0.9 (90%) (meaning that at least 90% of the acidic moieties are neutralized).

[0079] Examples of neutralized acidic polymers include cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, methylcellulose phthalate, hydroxymethylcellulose ethyl phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate: HPMCAS), hydroxypropyl methyl acetate maleate, hydroxypropyl methyl trimellitate, carboxymethyl ethyl cellulose, polyvinyl butyrate phthalate, polyvinyl alcohol acetate phthalate, methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl methacrylate copolymer, and methacrylic acid copolymer.

[0080] Ionic polymers include, for example, acidic polymers and basic polymers. Ionic polymers have substantially ionic functional groups and are at least about 10% ionized over at least a portion of the physiologically relevant pH range of 1 to 8. Ionic polymers are generally classified into acidic polymers and basic polymers based on the pH range in which they are ionized. Acidic polymers (or enteric polymers) are soluble in neutral or alkaline solutions, while basic polymers are soluble in acidic or neutral solutions.

[0081] Examples of acidic polymers include cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, methylcellulose phthalate, hydroxymethylcellulose ethyl phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methyl acetate maleate, hydroxypropyl methyl trimellitate, carboxymethyl ethyl cellulose, polyvinyl butyrate phthalate, polyvinyl alcohol acetate phthalate, methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl methacrylate copolymer, and methacrylic acid copolymer.

[0082] Examples of basic polymers include aminoalkyl methacrylic acid copolymer E and polyvinyl acetal diethylaminoacetate.

[0083] The polymers according to this embodiment may be used alone or in combination of two or more.

[0084] As the polymer according to this embodiment, at least one selected from the group consisting of a polymer having a hydroxypropyl cellulose skeleton, a polymer having a povidone skeleton, and a block copolymer polymer may be used, and at least one selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymer, methacrylic acid / methyl methacrylate copolymer, and methacrylic acid / ethyl acrylate copolymer may be used.

[0085] (Excipient) The excipient according to this embodiment should be pharmaceutically acceptable within a range that does not impair the effects of the present invention, and examples thereof include starches such as cornstarch, lactose, glucose, mannitol, etc.

[0086] (Disintegrant) The disintegrant according to the present embodiment should be pharmaceutically acceptable within a range that does not impair the effects of the present invention, and examples thereof include low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, croscarmellose sodium, carboxymethyl starch sodium, crospovidone, polyvinylpyrrolidone, etc.

[0087] (Solid Dispersion) The solid dispersion according to this embodiment is composed of a substance to be dispersed and a polymer, and the substance to be dispersed is dispersed in the polymer. The substance to be dispersed is preferably uniformly dispersed in the polymer. Furthermore, the substance to be dispersed is preferably dispersed in the polymer in minute units, and more preferably dispersed at the molecular level.

[0088] The solid dispersion according to this embodiment satisfies the following (I) or (II): (I) the glass transition temperature (Tgc) of the substance to be dispersed is different from the glass transition temperature of the solid dispersion; (II) the glass transition temperature of the solid dispersion is 94.5% or more and 105.5% or less of the value of Tga represented by the following formula (A); In formula (A), Tgc represents the glass transition temperature of the substance to be dispersed, Tgp represents the glass transition temperature of the polymer, Wa represents the total mass of the solid dispersion, Wc represents the total mass of the substance to be dispersed contained in the solid dispersion, and Wp represents the total mass of the polymer contained in the solid dispersion.

[0089] The glass transition temperature (Tgc) of the substance to be dispersed and the glass transition temperature of the solid dispersion usually differ, and may differ by 1°C or more, 2°C or more, 3°C or more, 4°C or more, 5°C or more, 8°C or more, 10°C or more, 15°C or more, 20°C or more, 25°C or more, or 30°C or more. The glass transition temperature (Tgc) of the substance to be dispersed and the glass transition temperature of the solid dispersion differ, for example, by 1°C or more, preferably by 2°C or more, more preferably by 3°C or more, and most preferably by 5°C or more. If the glass transition temperature (Tgc) of the substance to be dispersed and the glass transition temperature of the solid dispersion differ, it can be inferred that the substance to be dispersed is dispersed uniformly and in fine units in the solid dispersion.

[0090] The glass transition temperature (Tgc) of the substance to be dispersed may be higher than the glass transition temperature of the solid dispersion, and may be 1° C. or more higher, 2° C. or more higher, 3° C. or more higher, 4° C. or more higher, 5° C. or more higher, 10° C. or more higher, 8° C. or more higher, 15° C. or more higher, 20° C. or more higher, 25° C. or more higher, or 30° C. or more higher. The glass transition temperature (Tgc) of the substance to be dispersed is, for example, 1° C. or more higher, preferably 2° C. or more higher, more preferably 3° C. or more higher, and most preferably 5° C. or more higher than the glass transition temperature of the solid dispersion.

[0091] The glass transition temperature of the solid dispersion may be, for example, 94.5% to 105.5% of the value of Tga represented by the above formula (A), 95% to 105%, 96% to 104%, 97% to 103%, 98% to 102%, 99% to 101%, or 100%. The glass transition temperature of the solid dispersion is, for example, 94.5% to 105.5%, preferably 95% to 105%, more preferably 96% to 104%, and most preferably 97% to 103% of the value of Tga represented by the above formula (A). The glass transition temperature of the solid dispersion may be, for example, 94.5% to 105.5% of the value of Tga represented by the formula (A), 95.0% to 105.0%, 96.0% to 104.0%, 97.0% to 103.0%, 98.0% to 102.0%, 99.0% to 101.0%, or 100.0%. The glass transition temperature of the solid dispersion is, for example, 94.5% to 105.5%, preferably 95.0% to 105.0%, more preferably 96.0% to 104.0%, and most preferably 97.0% to 103.0% of the value of Tga represented by the formula (A).

[0092] The glass transition temperature of the solid dispersion according to this embodiment may be, for example, 100°C or higher, 110°C or higher, 120°C or higher, 125°C or higher, 130°C or higher, 135°C or higher, or 140°C or higher. The glass transition temperature of the solid dispersion according to this embodiment may be, for example, 200°C or lower, 190°C or lower, 180°C or lower, 170°C or lower, or 165°C or lower. Examples of the glass transition temperature range of the solid dispersion according to this embodiment include 100°C or higher and 200°C or lower, 120°C or higher and 180°C or lower, 130°C or higher and 170°C or lower, or 140°C or higher and 165°C or lower. The glass transition temperature of the solid dispersion according to this embodiment is, for example, 100°C to 200°C, preferably 120°C to 180°C, more preferably 130°C to 170°C, and most preferably 140°C to 165°C.

[0093] In the solid dispersion according to this embodiment, the glass transition temperature (Tgc) of the substance to be dispersed may be higher than the glass transition temperature (Tgp) of the polymer. Specifically, for example, the glass transition temperature (Tgc) of the substance to be dispersed may be higher than the glass transition temperature (Tgp) of the polymer by 1°C or more, 3°C or more, 10°C or more, 15°C or more, 20°C or more, 25°C or more, 30°C or more, 35°C or more, 40°C or more, 45°C or more, 50°C or more, 80°C or more, or 100°C or more. The glass transition temperature (Tgc) of the substance to be dispersed is higher than the glass transition temperature (Tgp) of the polymer by, for example, 10°C or more, preferably 20°C or more, more preferably 30°C or more, and most preferably 40°C or more. In this embodiment, it is preferred that the Tgc is higher than the glass transition temperature of the solid dispersion, and the glass transition temperature of the solid dispersion is higher than the Tgp. Furthermore, for example, Tgc may be 110°C to 180°C, the glass transition temperature of the solid dispersion may be 100°C to 170°C, and Tgp may be 30°C to 170°C, preferably Tgc may be 120°C to 175°C, the glass transition temperature of the solid dispersion may be 110°C to 170°C, and Tgp may be 90°C to 140°C, more preferably Tgc may be 130°C to 170°C, the glass transition temperature of the solid dispersion may be 120°C to 165°C, and Tgp may be 100°C to 135°C, and most preferably Tgc may be 140°C to 165°C, the glass transition temperature of the solid dispersion may be 130°C to 165°C, and Tgp may be 105°C to 130°C.

[0094] In the solid dispersion according to this embodiment, the ratio of the total mass of polymer to the total mass of the substance to be dispersed is less than 1.0. This ratio may be, for example, 0.90 or less, 0.80 or less, 0.70 or less, 0.60 or less, 0.50 or less, 0.40 or less, 0.30 or less, 0.20 or less, 0.10 or less, 0.010 or less, or 0.0010 or less. There is no particular restriction on the lower limit of this ratio, and it may be, for example, 0.00010 or more. The ratio of the total mass of polymer to the total mass of the substance to be dispersed is, for example, less than 1.0, preferably 0.8 or less, more preferably 0.5 or less, and most preferably 0.4 or less. This ratio is, for example, greater than 0. The ratio of the total mass of polymer to the total mass of the substance to be dispersed is, for example, greater than 0 but less than 1.0, preferably greater than 0 but 0.8 or less, more preferably greater than 0 but 0.5 or less, and most preferably greater than 0 but 0.4 or less.

[0095] The content of the substance to be dispersed 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 the substance to be dispersed 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 range of the content of the dispersion target substance in the solid dispersion according to this embodiment can be, for example, greater than 50% by mass and less than 100% by mass, 60% by mass to 99% by mass, 65% by mass to 95% by mass, 70% by mass to 90% by mass, or 75% by mass to 85% by mass, based on the total amount of the solid dispersion. The content of the dispersion target substance in the solid dispersion according to this embodiment can be, for example, greater than 50% by mass and less than 100% by mass, preferably 60% by mass to 99% by mass, more preferably 65% ​​by mass to 90% by mass, and most preferably 70% by mass to 85% by mass. The content of the dispersion target substance in the solid dispersion can be measured, for example, by a method using high-performance liquid chromatography (HPLC) as described in the Examples below.

[0096] The polymer content 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 polymer content 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. Examples of the range of the polymer content in the solid dispersion according to this embodiment include, for example, more than 0% by mass, less than 50% by mass, 1% by mass or more to 40% by mass or less, 5% by mass or more to 35% by mass or less, 10% by mass or more to 30% by mass or less, or 15% by mass or more to 25% by mass or less, based on the total amount of the solid dispersion. The polymer content in the solid dispersion according to this embodiment is, for example, more than 0% by mass and less than 50% by mass, preferably 1% by mass or more and 40% by mass or less, more preferably 10% by mass or more and 35% by mass or less, and most preferably 15% by mass or more and 30% by mass or less, based on the total amount of the solid dispersion. The polymer content in the solid dispersion can be determined 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.

[0097] The solid dispersion according to this embodiment may have a bulk density of 0.15 g / mL or more, calculated from the volume of powder obtained by gently filling 0.5 g of the solid dispersion into a 5 mL measuring cylinder.

[0098] The solid dispersion according to this embodiment may be one in which no crystals are observed up to one month after the start of a physical stability test under conditions of 40°C and 75% RH. The physical stability test is a test carried out by the method described in the Examples below. Specifically, the solid dispersion is stored for a predetermined period of time in an environment maintained at a specific temperature and humidity, and after the predetermined period has elapsed, the presence or absence of a halo pattern is confirmed by, for example, XRD measurement. The solid dispersion according to this embodiment has excellent amorphous stability, and can maintain an amorphous state up to one month after the start of the test under conditions of 40°C and 75% RH.

[0099] Similarly, the solid dispersion according to this embodiment may be one in which no crystals are observed up to one month after the start of a physical stability test under conditions of 80°C and 75% RH.

[0100] The solid dispersion according to this embodiment may have a disintegration time of 1000 seconds or less in a disintegration test using a second dissolution test fluid (a liquid obtained by adding 118 mL of 0.2 M sodium hydroxide solution and water to 250 mL of 0.2 M potassium dihydrogen phosphate solution to make 1000 mL, and having a pH of 6.7 to 6.9) at a test fluid temperature of 37.0°C and an oscillation frequency of 30 times / minute. The disintegration time may be, for example, 950 seconds or less, 900 seconds or less, 850 seconds or less, or 800 seconds or less. The solid dispersion to be subjected to the disintegration test is preferably in the dosage form of a tablet.

[0101] (Method for Producing Solid Dispersion) The solid dispersion according to this embodiment can be produced, for example, by a production method including a step of mixing a substance to be dispersed and a polymer in a solvent to prepare a mixed solution (mixing step), and a step of removing the solvent from the mixed solution obtained in the mixing step to obtain a solid dispersion containing the substance to be dispersed and the polymer (obtaining step).

[0102] The substance to be dispersed and the polymer may be the same as the substance to be dispersed and the polymer described above.

[0103] The solvent used in the mixing step may be any solvent that can dissolve the dispersion target substance and the polymer, 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 may be used as a mixed solvent of two or more types.

[0104] The obtaining step may be carried out, for example, by a spray drying method using a spray drying apparatus (e.g., a small spray dryer B-290, manufactured by BUCHI). Examples of spray drying conditions include those described in the Examples below. Specifically, for example, a solution containing the substance to be dispersed and a polymer is spray-dried in a spray dryer at an inlet temperature of 50-90°C (outlet temperature of 45-55°C), an aspirator output of 100%, a peristaltic pump output of 20-25%, and a spray air flow meter height of 25-30 mm, and the resulting powder is dried overnight in a vacuum dryer at 60°C and 0 Pa, thereby obtaining a powder of a solid dispersion.

[0105] The term "spray drying" is conventionally used and broadly refers to a process that involves breaking up a liquid mixture into small droplets (atomization) in a spray drying apparatus and rapidly removing the solvent from the mixture. A strong driving force acts within the spray drying apparatus to evaporate the solvent from the droplets. Spray drying processes and spray drying apparatus are generally described in Perry's Chemical Engineers' Handbook, pp. 20-54 to 20-57 (6th ed., 1984). Further details regarding spray drying processes and apparatus are reviewed in Marshall, "Atomization and Spray-Drying," 50 Chem. Eng. Prog. Monogr. Series 2 (1954) and Masters, Spray Drying Handbook (4th ed., 1985). A strong driving force for solvent evaporation is generally provided by maintaining a partial pressure of the solvent within the spray-drying apparatus that is much lower than the vapor pressure of the solvent at the temperature of the droplets being dried. This can be accomplished by (1) maintaining a partial vacuum (e.g., 0.01-0.50 atm) within the spray-drying apparatus; (2) mixing the droplets with a warm drying gas; or (3) both (1) and (2). Additionally, at least a portion of the heat required for solvent evaporation can be provided by heating the spray solution.

[0106] Solvent-containing feedstocks can be spray-dried under a wide variety of conditions and still yield solid dispersions with acceptable properties. For example, various types of nozzles can be used to atomize the spray solution, thereby introducing it into the spray-drying chamber as a collection of small droplets. Essentially any type of nozzle can be used to spray the solution, as long as the droplets formed are small enough and dry enough (due to evaporation of the solvent) so as not to adhere to or coat the spray-drying chamber walls.

[0107] The maximum droplet size varies widely depending on the size, shape, and flow pattern within the spray dryer, but generally the droplets should be less than about 500 μm in diameter when discharged from the nozzle. Examples of types of nozzles that can be used to form solid dispersions include two-fluid nozzles, fountain-type nozzles, flat fan-type nozzles, pressure nozzles, and rotary atomizers. In a preferred embodiment, a pressure nozzle is used. Details are disclosed in U.S. Published Patent Application No. 2003-0185893, filed January 24, 2003, which is incorporated herein by reference.

[0108] The spray solution can be delivered to the spray nozzle(s) at a wide range of temperatures and flow rates. Generally, the temperature of the spray solution can range anywhere from just above the freezing point of the solvent to about 20°C above its ambient pressure boiling point (due to pressurization of the solution). In some cases, it can be higher. The flow rate of the spray solution to the spray nozzle can vary widely depending on the type of nozzle, the size of the spray dryer, and the spray drying conditions (e.g., the inlet temperature and flow rate of the drying gas). Generally, the energy for evaporating the solvent from the spray solution in a spray drying process comes primarily from the drying gas.

[0109] The drying gas can in principle be essentially any gas, but for safety reasons and to minimize undesired oxidation of the drug or other substances in the solid dispersion, an inert gas such as nitrogen, nitrogen-enriched air, or argon is utilized. The drying gas is typically introduced into the drying chamber at a temperature of about 60°C to about 240°C.

[0110] The large surface area to volume ratio of the droplets and the large driving force for solvent evaporation result in a rapid solidification time for the droplets. Solidification times should be less than about 20 seconds, preferably less than about 10 seconds, and more preferably less than 1 second. This rapid solidification is often important to ensure that the particles maintain a uniform, homogeneous dispersion instead of separating into drug-rich and polymer-rich phases.

[0111] After solidification, the solid powder typically remains in the spray-drying chamber for about 5-60 seconds to allow further evaporation of the solvent from the solid powder. The final solvent content of the solid dispersion upon exiting the dryer should be low because this reduces the mobility of the drug molecules within the solid dispersion and improves its stability. Generally, the solvent content of the solid dispersion upon exiting the spray-drying chamber should be less than 10% by weight, preferably less than 2% by weight, and more preferably less than 1% by weight.

[0112] After formation, the solid dispersion can be dried using any suitable drying method to remove residual solvent, such as tray drying, vacuum drying, fluidized bed drying, microwave drying, belt drying, rotary drying, and other drying methods known in the art. Suitable secondary drying methods include vacuum drying or tray drying. To minimize chemical decomposition during drying, drying may be carried out under an inert gas such as nitrogen or under vacuum.

[0113] 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.

[0114] One embodiment of the method for producing a solid dispersion using spray drying includes a production method comprising a step of evaporating, by spray drying, a solvent in a mixture containing (1) a substance to be dispersed that has a molecular weight of 1000 g / mol or more and 5000 g / mol or less and is amorphous, and (2) a polymer, in an amount such that the ratio of the total mass of the polymer to the total mass of the substance to be dispersed is less than 1.0 (corresponding to a removing step). The production method according to this embodiment may further comprise a step of mixing the substance to be dispersed and the polymer in a solvent to obtain a mixture containing the substance to be dispersed and the polymer (corresponding to a mixing step) prior to the step of evaporating the solvent by spray drying.

[0115] [Pharmaceutical Composition] The pharmaceutical composition according to this embodiment contains the solid dispersion described above. The pharmaceutical composition according to this embodiment may contain only the solid dispersion described above, or may contain other pharmaceutically acceptable ingredients in addition to the solid dispersion described above. The pharmaceutical composition may use the solid dispersion described above as it is, or may be composed of the solid dispersion itself or a mixture of the solid dispersion and other pharmaceutically acceptable ingredients. The pharmaceutical composition may also take the form of a powder, granules, tablets, or capsules filled with these.

[0116] The content of the solid dispersion contained in the pharmaceutical composition according to this embodiment may be, for example, 100% by mass based on the total amount of the pharmaceutical composition, or may be 99% by mass or less, 90% by mass or less, 80% by mass or less, 70% by mass or less, 60% by mass or less, 50% by mass or less, 40% by mass or less, or 30% by mass or less.

[0117] The other components 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, surfactants, etc.

[0118] 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, and sodium hydrogen phosphate. Examples of preservatives include ethyl parahydroxybenzoate and propyl parahydroxybenzoate. Examples of antioxidants include butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, and propyl gallate.

[0119] The pharmaceutical composition according to this embodiment may further contain a surfactant. The surfactant is not particularly limited as long as it is pharmaceutically acceptable.

[0120] In the present invention, the term "surfactant" refers to a substance having both a hydrophilic group and a hydrophobic group in the molecule, and includes ionic surfactants and nonionic surfactants.

[0121] Ionic surfactants are those that dissociate into ions (charged atoms or atomic groups) when dissolved in water. Ionic surfactants are further classified into anionic surfactants, cationic surfactants, and amphoteric surfactants depending on the charge of the ions produced.

[0122] Examples of nonionic surfactants include sugar ester surfactants such as sorbitan fatty acid esters (C12-18), polyoxyethylene (POE) sorbitan fatty acid esters (C12-18), and sucrose fatty acid esters; fatty acid ester surfactants such as POE fatty acid esters (C12-18), POE resin acid esters, and POE fatty acid diesters (C12-18); alcohol surfactants such as POE alkyl ethers (C12-18); alkylphenol surfactants such as POE alkyl (C8-12) phenyl ether, POE dialkyl (C8-12) phenyl ether, and POE alkyl (C8-12) phenyl ether formalin condensates; and polyoxyethylene-polyoxypropylene block polymers. alkyl (C12-18) polyoxyethylene-polyoxypropylene block polymer surfactants such as polyoxyethylene-polyoxypropylene block polymer ether; alkylamine surfactants such as POE alkylamine (C12-18) and POE fatty acid amide (C12-18); bisphenol surfactants such as POE fatty acid bisphenyl ether; polyaromatic ring surfactants such as polyoxyalkylene (POA) benzylphenyl (or phenylphenyl) ether and POA styrylphenyl (or phenylphenyl) ether; POE ether and ester type silicone and fluorine-based surfactants; and vegetable oil surfactants such as POE castor oil and POE hydrogenated castor oil.

[0123] Preferred examples of nonionic surfactants include polyoxyl 40 stearate, sorbitan trioleate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyl 35 castor oil, lauromacrogol, and tocopherol polyethylene glycol succinate (TPGS).

[0124] Examples of anionic surfactants include sulfate surfactants such as alkyl sulfate (C12-18), POE alkyl ether sulfate (C12-18), POE alkylphenyl ether sulfate (C12-18), POE benzyl (or styryl)phenyl (or phenylphenyl) ether sulfate, polyoxyethylene, and polyoxypropylene block polymer sulfate; paraffin (alkane) sulfonate (C12-22), alpha olefin sulfonate (C14-16), dialkyl sulfosuccinate (C8-12), alkylbenzene sulfonate (C12), mono- or dialkyl (C3-6) naphthalene sulfonate, naphthalene sulfonate-formalin condensate, alkyl (C8- 12) Sulfonate surfactants such as diphenyl ether disulfonate, lignin sulfonate, POE alkyl (C8-12) phenyl ether sulfonate, and POE alkyl (C12-18) ether sulfosuccinic acid half ester; carboxylate surfactants such as fatty acid salts (C12-18), N-acylamino acid salts (C12-18), and resin acid salts; and phosphate surfactants such as POE alkyl (C12-18) ether phosphate, POE mono- or dialkyl (C8-12) phenyl ether phosphate, POE benzyl (or styryl) phenyl (or phenylphenyl) ether phosphate, polyoxyethylene-polyoxypropylene block polymer, and alkyl (C8-12) phosphate.

[0125] In the present invention, the surfactant may be used alone or in combination of two or more kinds in an appropriate ratio.

[0126] A surfactant according to one embodiment may be a surfactant having a linear hydrocarbon group. The number of carbon atoms contained in the linear hydrocarbon group may be 5 or more, 6 or more, 8 or more, 10 or more, or 12. Examples of the range of the number of carbon atoms contained in the linear hydrocarbon group include 5 or more and 17 or less, 6 or more and 15 or less, 8 or more and 13 or less, 10 or more and 12 or less, and 12.

[0127] Moreover, the surfactant according to one embodiment is preferably a compound represented by any one of the following general formulas (a1) to (a3).

[0128] In general formulas (a1) to (a3), R １ represents a saturated or unsaturated, linear hydrocarbon group having from 5 to 17 carbon atoms, which may have a substituent; X represents sodium or potassium; and Y represents a group represented by the following formula (a4) or a stereoisomer thereof:

[0129]

[0130] In general formulas (a1) to (a3), R １ is preferably an alkyl group having 5 to 17 carbon atoms, more preferably an alkyl group having 7 to 12 carbon atoms, even more preferably an alkyl group having 8 to 12 carbon atoms, even more preferably an alkyl group having 10 to 12 carbon atoms, and particularly preferably an alkyl group having 11 carbon atoms. Also, it is preferably a linear alkyl group. Also, it is preferably a saturated alkyl group. Also, it is preferably an alkyl group having no substituent. In addition, in formula (a4), indicates a bond.

[0131] Moreover, the surfactant according to one embodiment is more preferably a compound represented by the following general formula (a3). [In general formula (a3), R １ represents a saturated or unsaturated, linear hydrocarbon group having 5 to 17 carbon atoms, which may have a substituent, and X represents sodium or potassium.

[0132] In addition, in the surfactant according to one embodiment, R １ is preferably a saturated, linear hydrocarbon group having 5 to 17 carbon atoms.

[0133] The surfactant according to one embodiment may be an anionic surfactant, a cationic surfactant, an amphoteric surfactant, or a nonionic surfactant. Anionic surfactants or cationic surfactants are preferred, and cationic surfactants are more preferred. Examples of anionic surfactants include carboxylates, sulfonates, and sulfate ester salts, with sulfonates being preferred and sodium lauryl sulfate (sodium dodecyl sulfate) being more preferred.

[0134] The form of the pharmaceutical composition according to this embodiment is not particularly limited, but is typically solid. The pharmaceutical composition according to this embodiment is used by being formed into dosage forms such as powders, fine granules, granules, tablets, coated tablets, capsules, etc.

[0135] The pharmaceutical composition according to this embodiment may be administered orally or parenterally, but is preferably administered orally since the solubility of the substance to be dispersed (active ingredient) is improved.

[0136] The subject to which the pharmaceutical composition of this embodiment 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.

[0137] The dosage of the pharmaceutical composition according to this embodiment is not particularly limited, and may be administered so that the dosage of the dispersion target substance (active ingredient) per kg of subject body weight (kg) is 0.1 mg / kg to 1000 mg / kg. The dosage of the dispersion target substance (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.

[0138] The pharmaceutical composition according to this embodiment can be produced by molding into any dosage form using a conventional method.

[0139] The solubility of the pharmaceutical composition according to this embodiment in 50 mM phosphate buffer (pH 6.5) at 25°C and 1 atm may be 10 mg / mL or less, or may be greater than 0 mg / mL. The solubility of the pharmaceutical composition according to this embodiment in 50 mM phosphate buffer (pH 6.5) at 25°C and 1 atm may be, for example, 5 mg / mL or less, 2.5 mg / mL or less, 2 mg / mL or less, 1 mg / mL or less, 0.5 mg / mL or less, 0.25 mg / mL or less, 0.1 mg / mL or less, 0.05 mg / mL or less, 0.025 mg / mL or less, 0.01 mg / mL or less, 0.005 mg / mL or less, 0.0025 mg / mL or less, or 0.001 mg / mL or less. Alternatively, it may be 0.0001 mg / mL or more, 0.0005 mg / mL or more, or 0.001 mg / mL or more. The solubility of the pharmaceutical composition according to this embodiment in 50 mM phosphate buffer (pH 6.5) at 25°C and 1 atm is, for example, greater than 0 mg / mL and 10 mg / mL or less, preferably greater than 0 mg / mL and 1 mg / mL or less, more preferably greater than 0 mg / mL and 0.1 mg / mL or less, and most preferably greater than 0 mg / mL and 0.05 mg / mL or less. The solubility of the pharmaceutical composition in 50 mM phosphate buffer (pH 6.5) at 25°C and 1 atm can be measured, for example, by the method described in the Examples below.

[0140] The pharmaceutical composition according to this embodiment may be one in which no crystals are observed up to one month after the start of a physical stability test under conditions of 40°C and 75% RH. The physical stability test is a test carried out by the method described in the Examples below. Specifically, the pharmaceutical composition is stored for a predetermined period of time under an environment maintained at a specific temperature and humidity, and after the predetermined period of time, the presence or absence of a halo pattern is confirmed by, for example, XRD measurement. The pharmaceutical composition according to this embodiment contains the solid dispersion according to the present invention, which has excellent amorphous stability, and therefore can maintain an amorphous state up to one month after the start of the test under conditions of 40°C and 75% RH.

[0141] Similarly, the pharmaceutical composition according to this embodiment may be one in which no crystals are observed up to one month after the start of the physical stability test under conditions of 80°C and 75% RH.

[0142] The pharmaceutical composition according to this embodiment may have a disintegration time of 1000 seconds or less in a disintegration test using the second dissolution test fluid (a liquid obtained by adding 118 mL of 0.2 M sodium hydroxide solution and water to 250 mL of 0.2 M potassium dihydrogen phosphate solution to make 1000 mL, and having a pH of 6.7 to 6.9) at a test fluid temperature of 37.0°C and an oscillation frequency of 30 times / minute. The disintegration time may be, for example, 950 seconds or less, 900 seconds or less, 850 seconds or less, or 800 seconds or less. The pharmaceutical composition to be subjected to the disintegration test is preferably in tablet form.

[0143] Preferred specific embodiments of the present invention will be described below as examples, but the present invention is not limited thereto.

[0144] [Synthesis Example] Synthesis of Cyclic Peptide Compounds Cyclic peptide compounds I to V used in this example are shown in Tables 4, 5, and 6. These compounds were synthesized according to the method described in WO 2021 / 090855.

[0145]

[0146]

[0147]

[0148] The reagents used in this example are summarized in Table 7.

[0149] The molecular weights (unit: g / mol) of Compounds I to V and Cyclosporin A are as follows: Compound I: 1437.7 Compound II: 1451.1 Compound III: 1436.1 Compound IV: 1410.1 Compound V: 1463.7 Cyclosporin A: 1202.6

[0150] The Tgc (unit: °C) of Compounds I to V and Cyclosporin A is as follows: Compound I: 164 Compound II: 140 Compound III: 157 Compound IV: 156 Compound V: 161 Cyclosporin A: 125

[0151] The ClogP values ​​of Compounds I to V and Cyclosporin A are as follows: Compound I: 14.5 Compound II: 15.1 Compound III: 14.6 Compound IV: 14.2 Compound V: 15.1 Cyclosporin A: 14.4

[0152] The solubilities (unit: mg / mL) of Compounds I to V and cyclosporine A in 50 mM phosphate buffer (pH 6.5) at 25°C and 1 atm were measured by the following method. 50 mM phosphate buffer (PB, pH 6.5) was added to the compound powder, and the mixture was shaken under normal pressure (25°C, 2000 rpm, 16 to 24 hours), filtered, and the compound concentration in the filtrate was measured by HPLC. The solubility (unit: mg / mL) was calculated from the measured compound concentration. The HPLC conditions were as follows. Detector: ultraviolet absorption photometer (measurement wavelength: 230 nm) Column: stainless steel tube with an inner diameter of 2.1 mm and a length of 5 cm packed with 1.7 μm ethylene-bridged hybrid particles for liquid chromatography Column temperature: constant temperature around 70° C. Mobile phase A: water / trifluoroacetic acid mixture (2000 / 1) Mobile phase B: acetonitrile / trifluoroacetic acid mixture (2000 / 1) Mobile phase delivery: concentration gradient control by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 8 below Injection volume: 10 μL Sample temperature: constant temperature around 25° C. The solubilities (unit: mg / mL) of Compounds I to V and Cyclosporin A in 50 mM phosphate buffer (pH 6.5) at 25° C. and 1 atm are as follows: Compound I: less than 0.001 Compound II: 0.001 Compound III: 0.010 Compound IV: 0.020 Compound V: less than 0.001 Cyclosporin A: 0.011

[0153] The weight average molecular weights of the polymers are as follows: HPMCAS: 21,000-26,000 HPMC: 16,000-60,000 HPMCP55S: 37,500-60,500 Eudragit L100: 125,000 Eudragit L100-55: 320,000 Eudragit EPO: 47,000 PVP K30: 44,000-54,000 PVP VA64: 45,000-70,000 HPC-L: 140,000 HPC-SSL: 40,000 Soluplus: 90,000-140,000 PVAP: 45,000-68,000

[0154] The Tgp (unit: °C) of each polymer is as follows: HPMCAS: 118 HPMC: 128 HPMCP55S: 129 Eudragit L100: NON AVAILABLE Eudragit L100-55: 123 Eudragit EPO: 49 PVP K30: 161 PVP VA64: 108 HPC-L: NON AVAILABLE HPC-SSL: NON AVAILABLE Soluplus: 79 PVAP: 128

[0155] Example I-A-4 5.0 g of Compound I was added to 108 mL of acetone at 25°C and 1 atm with stirring to dissolve the compound I to a solids concentration of 6 wt / vol% (4.6 wt / vol% as Compound I concentration). Next, 1.5 g of HPMCAS was added with stirring, and the resulting solution was spray-dried using a small spray dryer B-290 (manufactured by BUCHI) at an inlet temperature of 50-90°C (outlet temperature of 45-55°C), an aspirator output of 100%, a peristaltic pump output of 20-25%, and a spray air flow meter height of 25-30 mm. The powder recovered after spray drying was dried overnight in a vacuum dryer at 60°C and 0 Pa to obtain 6.5 g of a solid dispersion.

[0156] (Comparative Example V-J-4) 30 mg of HPC-SSL was dissolved as a polymer in 10 mL of purified water at 25°C and 1 atm to a solids concentration of 0.3 wt / vol%. Next, 100 mg of amorphous cyclosporine A was weighed and placed in a mixer vessel (150 mL volume, ARE-310, Thinky) together with 30 g of zirconia beads (ZIRCONIA OXIDE, 0.5 mm, Nikkato). 0.3 mL of the polymer solution obtained above was added, and the mixture was mixed at 1000 RPM for 2 minutes to obtain a suspension. Subsequently, 9.7 mL of the polymer solution was added to the mixer vessel, and the mixture was mixed at 2000 RPM for 2 minutes. Finally, the mixture was mixed at 400 RPM for 1 minute to obtain a suspension. The resulting suspension was freeze-dried to obtain a solid dispersion.

[0157] Comparative Example VG-4 A comparative example was produced in the same manner as in Comparative Example VJ-4, except that PVP K30 was used as the polymer instead of HPC-SSL.

[0158] The other examples, reference examples, and comparative examples were produced in the same manner as in Example IA-4, except that the conditions were changed to obtain the results shown in Tables 9 and 10 below (however, the dispersion target substance content and polymer content for the reference examples are set values).

[0159]

[0160]

[0161] (Preparation Example I-A-4) 34.24 wt. % of the solid dispersion obtained in Example I-A-4 was used as the active ingredient, 26.34 wt. % of SLS as a surfactant, 27.29 wt. % of mannitol as an excipient, 10.54 wt. % of croscarmellose sodium as a disintegrant, 1 wt. % of silicon dioxide as a fluidizer, and 0.6 wt. % of magnesium stearate as a lubricant were mixed. The resulting mixed powder was then dry granulated using a compression simulator HB100 (manufactured by Huxley Bertram), dry granulated using a small-scale hand mill (manufactured by Gerteis), and compressed using a compression simulator HB100 (manufactured by Huxley Bertram) to obtain tablets.

[0162] Specifically, to prepare a 2.67 g batch, 0.91 g of the solid dispersion obtained in Example I-A-4, 0.7 g of sodium lauryl sulfate, 0.73 g of mannitol, 0.28 g of croscarmellose sodium, 0.03 g of silicon dioxide, and 0.02 g of magnesium stearate were mixed. The resulting mixed powder was dry granulated using a compression simulator HB100 at a punch initial height of -2.0 mm, an upper punch descent depth of 3.0 mm, a compression speed of 2.0 RPM, and a compression pressure of 4.0 kN. The granules obtained by dry granulation were dry sized using a small-scale hand mill (mesh size 1.00). 0.002 g of magnesium stearate was added to the sized powder obtained by dry granulation and mixed, and then the mixture was compressed into tablets using a compression simulator HB100 with an initial punch height of -2.0 mm, an upper punch descent depth of 3.0 mm, a compression speed of 30.0 RPM, a pre-compression pressure of 9.0 kN, and a main compression pressure of 10.0 kN.

[0163] Tablets containing other examples and comparative examples as the main ingredient were molded in the same manner as in Production Example IA-4, except that the conditions were changed as shown in Tables 11 to 13 below.

[0164]

[0165]

[0166]

[0167] (Measurement Example 1: Measurement of Crystalline State Using X-ray Diffraction (XRD) Measurement Apparatus) The crystalline state of the solid dispersions obtained in the above Examples and Comparative Examples was measured by XRD under the following conditions: Measurement apparatus (model): Empyrean (manufactured by Malvern Panalytical) Anticathode: Cu Tube voltage: 45 kV Tube current: 40 mA Step width: 0.026° Scan axis: 2θ Scan rate: 1.313° / sec Scan range: 3-25°

[0168] The results are shown in Table 14 and Figures 1 to 7. Figures 1 to 7 are graphs showing examples of XRD measurement results. From the XRD results, each of these solid dispersions exhibited a halo pattern specific to amorphous materials, indicating that the substance to be dispersed was present in the solid dispersion as an amorphous substance.

[0169]

[0170] (Measurement Example 2: Measurement of content of substance to be dispersed by high performance liquid chromatography (HPLC)) The content of substance to be dispersed in the solid dispersions obtained in the above Examples and Comparative Examples was measured by HPLC under the following conditions. Detector: ultraviolet absorption spectrophotometer (measurement wavelength: 230 nm) Column: stainless steel tube with an inner diameter of 2.1 mm and a length of 5 cm packed with 1.7 μm ethylene-bridged hybrid particles for liquid chromatography Column temperature: constant temperature around 70° C. Mobile phase A: water / trifluoroacetic acid mixture (2000 / 1) Mobile phase B: acetonitrile / trifluoroacetic acid mixture (2000 / 1) Mobile phase delivery: concentration gradient control by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 15 below Injection volume: 1-3 μL Sample temperature: constant temperature around 25°C

[0171] The results are shown in Table 16. The HPLC results confirmed that the solid dispersion contained the substances to be dispersed at the respective ratios.

[0172]

[0173] (Measurement Example 3: Measurement of Glass Transition Point by Differential Scanning Calorimetry (DSC) Apparatus) The glass transition points of the solid dispersions obtained in the above Examples, Reference Examples, and Comparative Examples were measured by mDSC under the following conditions. Measuring apparatus (model): Q200 (manufactured by TA Instruments) Heating rate: 5°C / min Measurement temperature range: 35 to 200°C (220°C for Examples I-D-4, I-D-5, and I-D-6) Ambient gas: dry nitrogen Flow rate of ambient gas: 50 mL / min Cell: aluminum pan Sample amount: 2 to 10 mg Reference: empty container

[0174] The results are shown in Tables 17 and 18 and Figures 8 to 32. Figures 8 to 32 are graphs showing example DSC measurement results. The mDSC results showed that the solid dispersions obtained by spray drying in each of the Examples, Reference Examples, and Comparative Examples each exhibited a unique and single glass transition point. Furthermore, in the solid dispersions obtained by spray drying in the Examples, the glass transition temperatures of Compounds I to V and cyclosporine A differed from the glass transition temperature of the obtained solid dispersion by 1°C or more, or the glass transition temperature of the obtained solid dispersion was 94.5% to 105.5% of the Tga value. From this, it was inferred that Compounds I to V and cyclosporine A were mixed with the polymer and dispersed uniformly and in fine units in the solid dispersion. On the other hand, in the solid dispersions obtained by freeze-drying in the Comparative Examples, the glass transition temperature of cyclosporine A differed from the glass transition temperature of the obtained solid dispersion by no more than 1°C, and the glass transition temperature of the obtained solid dispersion was not 94.5% to 105.5% of the Tga value. From this, it was inferred that cyclosporine A was not present in the solid dispersion in a uniform and finely dispersed state.

[0175]

[0176]

[0177] (Measurement Example 4: Measurement of water content using thermogravimetry (TG-DTA) apparatus) The water contents of the solid dispersions obtained in the above examples were measured by TG-DTA, and the results are shown in Table 19. The TG-DTA results showed that the solid dispersions obtained in each example contained 1 to 2 wt. % water.

[0178]

[0179] (Evaluation Example 1: Physical Stability Test) The results of a physical stability test performed on the solid dispersions prepared in the above Examples and Comparative Examples are shown in Table 20. Physical stability was evaluated by XRD measurement after storage for one month at 40°C and 75% RH for the solid dispersions obtained in Examples V-G-4 and V-J-4, and Comparative Examples V-G-4 and V-J-4, and after storage for one month at 80°C and 75% RH for the solid dispersions obtained in Examples V-G-4 and V-J-4, and Comparative Examples V-G-4 and V-J-4. As a result of XRD measurement after the physical stability test, all solid dispersions exhibited a halo pattern characteristic of amorphous materials, and even solid dispersions with extremely low polymer ratios were found to have sufficient physical stability. These examples demonstrate that for the substance to be dispersed in the present invention, a solid dispersion that is sufficiently stable physically can be obtained even when the polymer ratio is significantly reduced.

[0180]

[0181] (Evaluation Example 2: Disintegration Test) The evaluation results of a disintegration test conducted on the tablets prepared in the above Production Example are shown in Table 21. The test conditions were: dissolution test fluid 2; test fluid temperature 37.0°C; oscillation frequency 30 times / min; n = 3 tablets per sample; and the measurement endpoint was the time when the tablets disappeared from the basket. As a result of the disintegration test, it was observed that the lower the proportion of polymer contained in the solid dispersion, the shorter the disintegration time of the tablets. These examples show that the disintegration property of tablets can be significantly improved by reducing the proportion of polymer contained in the solid dispersion.

[0182]

[0183] (Evaluation Example 3: Bulk Density) The bulk density of the solid dispersions prepared in the above Examples and Comparative Examples was measured, and the results are shown in Table 22. In the test, 0.5 g of a measurement sample was gently filled into a 5 mL measuring cylinder, the volume of the obtained powder was measured, and the bulk density was calculated from the obtained volume. As a result of measuring the bulk density, it was found that the solid dispersions prepared by spray drying had a higher bulk density than the solid dispersions prepared by freeze-drying. This result indicates that the handleability of the solid dispersions as powders is improved by obtaining them by spray drying.

[0184]

Claims

1. (1) A dispersion target substance having a molecular weight of 1000 g / mol or more and 5000 g / mol or less and being amorphous, and (2) a polymer, A solid dispersion having a ratio of the total mass of the polymer to the total mass of the dispersed substance to less than 1.0, and satisfying either (I) or (II) below: (i) The glass transition temperature of the substance to be dispersed and the glass transition temperature of the solid dispersion differ by 1°C or more; (II) The glass transition temperature of the solid dispersion is 94.5% or more and 105.5% or less of the value of Tga represented by the following formula (A); [Math 1] [In formula (A), Tgc represents the glass transition temperature of the dispersion target substance, Tgp represents the glass transition temperature of the polymer, Wa represents the total mass of the solid dispersion, Wc represents the total mass of the dispersion target substance contained in the solid dispersion, and Wp represents the total mass of the polymer contained in the solid dispersion.]

2. The solid dispersion according to claim 1, wherein the glass transition temperature of the solid dispersion is 100°C or higher and 200°C or lower.

3. The solid dispersion according to claim 1, wherein the content of the substance to be dispersed in the solid dispersion is more than 50% by mass and less than 100% by mass, based on the total amount of the solid dispersion.

4. The solid dispersion according to claim 1, wherein the glass transition temperature of the dispersed substance exceeds the glass transition temperature of the polymer.

5. The solid dispersion according to claim 1, wherein the glass transition temperature of the dispersed substance is 90°C or higher and 180°C or lower.

6. The solid dispersion according to claim 1, wherein the substance to be dispersed is a peptide compound.

7. The solid dispersion according to claim 6, wherein the number of amino acid residues constituting the peptide compound is 5 or more and 30 or less.

8. The solid dispersion according to claim 6, wherein the number of N-substituted amino acid residues contained in the peptide compound is 1 or more.

9. The solid dispersion according to claim 1, wherein the glass transition temperature of the polymer is 30°C or higher and 170°C or lower.

10. The solid dispersion according to claim 1, wherein the weight-average molecular weight of the polymer is 3,000 or more and 400,000 or less.

11. The solid dispersion according to claim 1, wherein the bulk density calculated from the volume of powder obtained by gently filling a 5 mL graduated cylinder with 0.5 g of the solid dispersion is 0.15 g / mL or more.

12. The solid dispersion comprises the solid dispersion described in any one of claims 1 to 11, A pharmaceutical composition in which the content of the solid dispersion is 99% by mass or less, based on the total amount of the pharmaceutical composition.

13. The pharmaceutical composition according to claim 12, wherein no crystals are observed in a physical stability test conducted under 40°C and 75% RH conditions until one month has elapsed since the start of the test.

14. The pharmaceutical composition according to claim 12, wherein the second dissolution test solution is used as the test solution, and the disintegration time in the disintegration test under the conditions of a test solution temperature of 37.0°C and an amplitude frequency of 30 times / minute is 1000 seconds or less.

15. A method for producing a solid dispersion, comprising the step of evaporating a solvent in a mixture containing (1) a dispersion target substance having a molecular weight of 1,000 g / mol or more and 5,000 g / mol or less and being amorphous, and (2) a polymer in an amount such that the ratio of the total mass of the polymer to the total mass of the dispersion target substance is less than 1.0, by spray drying.

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