Pharmaceutical composition containing 1-{2-[(3s, 4r)-1-{[(3r, 4r)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl) pyrrolidin-3-yl] carbonyl}-4-(methoxymethyl) pyrrolidin-3-yl]-5-(trifluoromethyl) phenyl} piperidine-4-carboxylic acid or pharmaceutically acceptable salt or co-crystal thereof

Abstract

The present invention relates to a pharmaceutical composition containing, as an active ingredient, 1-{2-[(3S, 4R)-1-{[(3R, 4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl) pyrrolidin-3-yl] carbonyl}-4-(methoxymethyl) pyrrolidin-3-yl]-5-(trifluoromethyl) phenyl} piperidine-4-carboxylic acid (compound A), or a pharmaceutically acceptable salt or co-crystal thereof, and more specifically, to a pharmaceutical composition containing, as an active ingredient, 1-{2-[(3S, 4R)-1-{[(3R, 4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl) pyrrolidin-3-yl]-5-(trifluoromethyl) phenyl} piperidine-4-carboxylic acid (compound A). The content of the compound A is 30% by weight or more based on the total weight of the pharmaceutical composition, and preferably, the pharmaceutical composition is obtained by a production method which comprises a step of granulating the compound A in a fluidized bed granulator, and a granulation step for obtaining a granulated material by spraying a binder solution containing the compound A or the pharmaceutically acceptable salt or co-crystal thereof and a binder onto a powder containing the compound A or the pharmaceutically acceptable salt or co-crystal thereof.

Description

Technical Field

[0001] The present invention relates to a novel pharmaceutical composition comprising 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid (hereinafter referred to as Compound A) or a pharmaceutically acceptable salt or cocrystal thereof (hereinafter Compound A or a pharmaceutically acceptable salt or cocrystal thereof is referred to as Compound A, etc.) as an effective ingredient and a method for preparing the same. Background Art

[0002] Patent Document 1 discloses that various pyrrolidine compounds including Compound A or pharmaceutically acceptable salts thereof, or co-crystals thereof, etc. have excellent melanocortin receptor (MCR) activation effects. In addition, Patent Document 2 discloses co-crystals of Compound A.

[0003] Prior art literature

[0004] Patent Literature

[0005] Patent Document 1: WO2015 / 182723

[0006] Patent Document 2: WO2020 / 138481 Summary of the invention

[0007] Problems to be solved by the invention

[0008] As described in Patent Document 1, compound A and the like show excellent MCR activation action and are therefore expected to be active ingredients of drugs. However, the powder of the compound has chemical properties such as high adhesion and hydrophobicity, and there is room for improvement in its formulation.

[0009] Specifically, the inventors of the present application have found the following problems through their research: when compound A etc. is formulated, it is difficult to granulate due to poor powder flowability and adhesion to the can body during granulation; when tableting, sticking occurs during tablet compression, etc. It is also known that solving these problems becomes more important if the content of compound A etc. in one tablet is increased for miniaturization.

[0010] Therefore, the object of the present invention is to provide a novel pharmaceutical composition containing compound A etc. as an active ingredient, and in particular, to overcome the problems encountered during the manufacture of fluidized bed granulation, or the problems of sticking during tableting when the pharmaceutical composition is manufactured, and to provide a formulation technology with a good yield and / or a low defective rate. In addition, a pharmaceutical composition with a high content of compound A etc. which overcomes the problems encountered during the manufacture is provided.

[0011] Means for solving problems

[0012] The inventors of the present application have conducted in-depth research to solve the above-mentioned problems. As a result, it is known that in a fluidized bed granulator, by reducing the amount of compound A, etc. fed into the fluidized bed as a powder, the fluidity of the powder can be improved. In addition, it is found that by spraying a binding liquid containing compound A, etc. and a binder on the powder in the fluidized bed to perform granulation, sticking can be reduced when the obtained granules are compressed into tablets, and the defective rate is reduced, thereby completing the present invention. Furthermore, especially when manufacturing a preparation containing compound A, etc. at a high content, granulation is performed by spraying a binding liquid containing a binder and compound A, etc. on the powder containing compound A, etc., thereby completely solving the problems of adhesion to the tank body on the basis of solving the above two problems, and successfully achieving a high content of compound A, etc.

[0013] The gist of the present invention is as follows.

[0014] [1] A pharmaceutical composition comprising 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid (Compound A) or a pharmaceutically acceptable salt or cocrystal thereof as an active ingredient, wherein the content of Compound A or a pharmaceutically acceptable salt or cocrystal thereof is 30% by weight or more, calculated as Compound A, based on the total weight of the pharmaceutical composition.

[0015] [2] The pharmaceutical composition according to [1], further comprising one or more selected from the group consisting of a disintegrant, a binder and an excipient.

[0016] [3] The pharmaceutical composition according to [2], wherein the content of the disintegrant is 0.1 wt% to 30 wt% based on the total weight of the pharmaceutical composition.

[0017] [4] The pharmaceutical composition according to [2] or [3], wherein the disintegrant is carboxymethylcellulose calcium or low-substituted hydroxypropyl cellulose.

[0018] [5] The pharmaceutical composition according to any one of [2] to [4], wherein the content of the binder is 1% to 15% by weight based on the total weight of the pharmaceutical composition.

[0019] [6] The pharmaceutical composition according to any one of [2] to [5], wherein the binder is a water-soluble polymer.

[0020] [7] The pharmaceutical composition according to [6], wherein the water-soluble polymer is hydroxypropyl cellulose.

[0021] [8] The pharmaceutical composition according to any one of [2] to [7], wherein the content of the excipient is 10% to 50% by weight based on the total weight of the pharmaceutical composition.

[0022] [9] The pharmaceutical composition according to any one of [2] to [8], wherein the excipient is lactose hydrate.

[0023]

[10] The pharmaceutical composition according to any one of [1] to [9], further comprising a lubricant.

[0024]

[11] The pharmaceutical composition according to

[10] , wherein the content of the lubricant is 0.1 wt% to 5 wt% based on the total weight of the pharmaceutical composition.

[0025]

[12] The pharmaceutical composition according to

[10] or

[11] , wherein the lubricant is magnesium stearate.

[0026]

[13] The pharmaceutical composition as described in any one of [1] to

[12] , wherein the content of Compound A or its pharmaceutically acceptable salt or cocrystal is 50% by weight or more, calculated as Compound A, based on the total weight of the pharmaceutical composition.

[0027]

[14] The pharmaceutical composition according to any one of [1] to

[13] , which is a granulated product of Compound A or a pharmaceutically acceptable salt or co-crystal thereof, a capsule comprising the granulated product, or a tablet obtained by compressing the granulated product.

[0028]

[15] The solid dosage pharmaceutical composition according to

[14] , wherein the granulated material is a granulated material obtained by granulating a powder containing Compound A or a pharmaceutically acceptable salt or co-crystal thereof by fluidized bed granulation.

[0029]

[16] A pharmaceutical composition as described in any one of [1] to

[15] , wherein the granulated material is composed of a portion containing compound A or a pharmaceutically acceptable salt or co-crystal thereof and substantially free of a binder, and a portion containing compound A or a pharmaceutically acceptable salt or co-crystal thereof and a binder.

[0030]

[17] A pharmaceutical composition as described in any one of [1] to

[16] , wherein the granulated material is a granulated material obtained by spraying a powder that may contain compound A or a pharmaceutically acceptable salt or co-crystal thereof with a binding liquid containing compound A or a pharmaceutically acceptable salt or co-crystal and a binder.

[0031]

[18] A pharmaceutical composition as described in any one of [1] to

[17] , wherein the granulated material is obtained by spraying a powder containing compound A or its pharmaceutically acceptable salt or co-crystal with a binding liquid containing compound A or its pharmaceutically acceptable salt or co-crystal and a binder.

[0032]

[19] The pharmaceutical composition as described in any one of

[17] or

[18] , wherein the ratio of the total weight of Compound A or its pharmaceutically acceptable salt or co-crystal in the aforementioned powder to the total weight of Compound A or its pharmaceutically acceptable salt or co-crystal in the aforementioned binding liquid is 70:30 to 0:100.

[0033]

[20] The pharmaceutical composition according to any one of

[14] to

[19] , wherein the median particle size of the granulated material is 90 μm to 400 μm.

[0034]

[21] The pharmaceutical composition according to any one of

[14] to

[20] , wherein the angle of repose of the granulated material is 50 degrees or less.

[0035]

[22] The pharmaceutical composition according to any one of

[14] to

[21] , which is a tablet obtained by compressing the granulated material.

[0036]

[23] The pharmaceutical composition as described in

[22] , wherein the hardness of the tablet is 30N or more.

[0037]

[24] A pharmaceutical composition as described in

[22] or

[23] , wherein 6.5 g of the aforementioned tablet is tested at a cylinder speed of 25 rpm for 4 minutes using a cylinder described in the tablet abrasion test method of the Japanese Pharmacopoeia, and the abrasion degree after correction for moisture absorption is less than 1%.

[0038]

[25] The pharmaceutical composition according to any one of

[22] to

[24] , wherein the amount of each decomposition product of the tablet is less than 1% when subjected to a stability test for 6 months at a temperature of 40°C and a relative humidity of 75%.

[0039]

[26] The pharmaceutical composition as described in any one of [1] to

[25] , wherein Compound A or a pharmaceutically acceptable salt or cocrystal thereof is a phosphate cocrystal of Compound A.

[0040]

[27] The method for producing a pharmaceutical composition according to any one of [1] to

[26] , comprising a granulation step of obtaining a granulated material by fluidized bed granulation.

[0041]

[28] A method for producing a pharmaceutical composition as described in any one of [1] to

[26] , which comprises a granulation step of spraying a powder that may contain compound A or its pharmaceutically acceptable salt or co-crystal with a binding liquid containing compound A or its pharmaceutically acceptable salt or co-crystal and a binder in a fluidized bed granulator to obtain a granulated material.

[0042]

[29] A method for producing a pharmaceutical composition, the pharmaceutical composition comprising 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid (Compound A) or a pharmaceutically acceptable salt or cocrystal thereof as an active ingredient,

[0043] The production method includes a granulation step of spraying a powder containing compound A or its pharmaceutically acceptable salt or co-crystal with a binding liquid containing compound A or its pharmaceutically acceptable salt or co-crystal and a binder in a fluidized bed granulator to obtain a granulated product.

[0044]

[30] A method for producing a pharmaceutical composition according to any one of [1] to

[26] , comprising a granulation step of spraying a powder containing compound A or its pharmaceutically acceptable salt or co-crystal with a binding liquid containing compound A or its pharmaceutically acceptable salt or co-crystal and a binder in a fluidized bed granulator to obtain a granulated material.

[0045]

[31] A method as described in any one of

[27] to

[30] , which includes a first mixing step of mixing compound A or a pharmaceutically acceptable salt thereof or cocrystal with an excipient and / or a disintegrant to obtain a mixture, or a first mixing step of mixing only an excipient and a disintegrant to obtain a mixture, before the granulation step.

[0046]

[32] The method according to

[31] , which comprises a first mixing step of mixing Compound A or a pharmaceutically acceptable salt thereof or co-crystal with an excipient and / or a disintegrant to obtain a mixture before the granulation step.

[0047]

[33] The method according to any one of

[27] to

[32] , comprising a second mixing step of further mixing a disintegrant and / or a lubricant into the granulated material obtained in the granulation step.

[0048]

[34] The method as described in any one of

[27] to

[33] , wherein the ratio of the total weight of Compound A or its pharmaceutically acceptable salt or co-crystal in the aforementioned powder used in the aforementioned granulation step to the total weight of Compound A or its pharmaceutically acceptable salt or co-crystal in the aforementioned binding liquid is 70:30 to 0:100.

[0049]

[35] The method as described in any one of

[27] to

[34] , wherein the ratio of the total weight of Compound A or its pharmaceutically acceptable salt or co-crystal in the aforementioned powder used in the aforementioned granulation step to the total weight of Compound A or its pharmaceutically acceptable salt or co-crystal in the aforementioned binding liquid is 65:35 to 0:100.

[0050]

[36] The method as described in any one of

[27] to

[35] , wherein the ratio of the total weight of Compound A or its pharmaceutically acceptable salt or co-crystal in the aforementioned powder used in the aforementioned granulation step to the total weight of Compound A or its pharmaceutically acceptable salt or co-crystal in the aforementioned binding liquid is 50:50 to 30:70.

[0051]

[37] The method as described in

[36] , wherein, in the aforementioned granulation step, the content of Compound A or its pharmaceutically acceptable salt or co-crystal contained in the obtained solid dosage pharmaceutical composition, calculated as Compound A, is 50% by weight or more based on the total weight of the pharmaceutical composition.

[0052]

[38] The method as described in

[37] , wherein in the aforementioned granulation step, the content of Compound A or its pharmaceutically acceptable salt or co-crystal contained in the obtained pharmaceutical composition is 50% by weight, calculated as Compound A, based on the total weight of the pharmaceutical composition, and the ratio of the total weight of Compound A or its pharmaceutically acceptable salt or co-crystal in the aforementioned powder to the total weight of Compound A or its pharmaceutically acceptable salt or co-crystal in the aforementioned binding liquid is 50:50.

[0053]

[39] The method as described in

[37] , wherein in the aforementioned granulation step, the content of Compound A or its pharmaceutically acceptable salt or co-crystal contained in the obtained pharmaceutical composition, calculated as Compound A, is 50% by weight based on the total weight of the pharmaceutical composition, and the ratio of the total weight of Compound A or its pharmaceutically acceptable salt or co-crystal in the aforementioned powder to the total weight of Compound A or its pharmaceutically acceptable salt or co-crystal in the aforementioned binding liquid is 30:70.

[0054]

[40] The method according to any one of

[27] to

[39] , further comprising a drying step of drying the granulated material.

[0055]

[41] The method according to any one of

[27] to

[40] , further comprising a tableting step of tableting the granulated material obtained in the second mixing step.

[0056]

[42] The method as described in

[41] , which also includes a coating step of coating the tablets obtained in the tableting step.

[0057]

[43] A pharmaceutical composition characterized in that it is a pharmaceutical composition containing 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid (Compound A) or a pharmaceutically acceptable salt or cocrystal thereof as an active ingredient, wherein the pharmaceutical composition is produced by the following method, which includes a granulation step of spraying a binding liquid containing Compound A or a pharmaceutically acceptable salt or cocrystal thereof and a binder onto a powder containing Compound A or a pharmaceutically acceptable salt or cocrystal thereof in a fluidized bed granulator to obtain a granulated material.

[0058] Effects of the Invention

[0059] The pharmaceutical composition of the present invention has the advantage that a granulated product containing compound A and the like and a tablet containing the granulated product can be obtained efficiently without problems during production. In addition, since the pharmaceutical composition of the present invention can contain compound A and the like at a high ratio, it also has the advantage that a pharmaceutical composition having appropriate drug release properties and exhibiting the expected drug effect can be provided in a more compact form. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] [ Figure 1 ] is a graph showing the time-dependent change in color difference (ΔE) of the colorants measured by a colorimeter in the process of performing fluidized bed granulation by changing the weight ratio of the compound A etc. fed as powder to the fluidized bed granulator and the compound A etc. added to the binding liquid in Example 2, and tableting the obtained granulated material to obtain tablets. 7117-190201-J (0%) represents condition 2-1, 7117-190202-J (30%) represents condition 2-2, 7117-190203-J (50%) represents condition 2-3, and 7117-181001-M2 (70%) represents condition 2-4.

[0061] [ Figure 2 ] is a graph showing the time-dependent change in color difference (ΔE) of the colorimeter measured in Example 6 in the process of fluidized bed granulation by setting the weight ratio of compound A etc. fed as powder to compound A etc. added to the binding liquid to 7:3, and tableting the obtained granules to obtain tablets. Condition 6-1 is shown.

[0062] [ Figure 3] is a graph showing the time-dependent change in color difference (ΔE) of the colorimeter measured in Example 7 in the process of fluidized bed granulation by setting the weight ratio of compound A etc. fed as powder to compound A etc. added to the binding liquid to 3:7, and tableting the obtained granules to obtain tablets. Condition 7-1 is shown. DETAILED DESCRIPTION

[0063] <Pharmaceutical Composition>

[0064] As a feature of the present invention, the pharmaceutical composition is characterized in that, based on the total weight of the pharmaceutical composition, the content of compound A when converted is 30% by weight or more. Preferably, based on the total weight of the pharmaceutical composition, the content of compound A when converted is 30% by weight or more and 90% by weight or less, more preferably 30% by weight to 80% by weight, further preferably 30% by weight to 70% by weight, and particularly preferably 30% by weight to 60% by weight. As another embodiment, based on the total weight of the pharmaceutical composition, the content of compound A when converted can be 30% by weight to 40% by weight. In addition, as another preferred embodiment, based on the total weight of the pharmaceutical composition, the content of compound A when converted can be 40% by weight or more, preferably 40% by weight or more and 90% by weight or less, more preferably 40% by weight to 80% by weight, further preferably 40% by weight to 70% by weight, and particularly preferably 40% by weight to 60% by weight. In addition, preferably, an example in which the content of Compound A is 50% by weight or more based on the total weight of the pharmaceutical composition is given, preferably 50% by weight or more and 90% by weight or less, more preferably 50% by weight to 80% by weight, further preferably 50% by weight to 70% by weight, and particularly preferably 50% by weight to 60% by weight can be given. As a pharmaceutical composition containing Compound A or the like as an active ingredient at a high ratio, an example in which the content of Compound A is 50% by weight or more based on the total weight of the pharmaceutical composition is given, and a pharmaceutical composition in which the content of Compound A is 50% by weight when converted is particularly preferred.

[0065] In the present specification, the term "compound A conversion" means conversion based on compound A itself, that is, conversion based on the free form of compound A, for example, conversion based on the amount of compound A itself.

[0066] Another embodiment of the pharmaceutical composition of the present invention is a pharmaceutical composition comprising a granulated material obtained by fluidized bed granulation, wherein the weight ratio of the compound A etc. in the powder during granulation to the compound A etc. in the binding liquid is preferably between 70:30 and 0:100, and more preferably between 65:35 and 0:100. Particularly preferably, the weight ratio of the compound A etc. in the powder during granulation to the compound A etc. in the binding liquid is between 50:50 and 0:100.

[0067] In addition, as a pharmaceutical composition containing compound A etc. as an active ingredient at a high ratio, it is characterized in that the content of compound A is 30% by weight or more based on the total weight of the pharmaceutical composition, and the weight ratio of compound A etc. in the powder during granulation to the weight ratio of compound A etc. in the binding liquid is within 1:1.

[0068] (1) Between 65:35 and 0:100,

[0069] (2) Between 60:40 and 0:100,

[0070] (3) Between 50:50 and 0:100,

[0071] (4) Between 65:35 and 30:70,

[0072] (5) Between 60:40 and 30:70, or

[0073] (6) Between 50:50 and 30:70.

[0074] In addition, preferably, the following pharmaceutical composition can be cited, characterized in that:

[0075] The content of the free form of compound A is 30% by weight or more and 90% by weight or less based on the total weight of the pharmaceutical composition, and the weight ratio of the compound A, etc. in the powder during granulation to the weight ratio of the compound A, etc. in the binding liquid is within 1:10% to 2:10%;

[0076] (1) Between 65:35 and 0:100,

[0077] (2) Between 60:40 and 0:100,

[0078] (3) Between 50:50 and 0:100,

[0079] (4) Between 65:35 and 30:70,

[0080] (5) Between 60:40 and 30:70, or

[0081] (6) Between 50:50 and 30:70;

[0082] Alternatively, the content of compound A is 30% by weight or more and 80% by weight or less based on the total weight of the pharmaceutical composition, and the weight ratio of compound A, etc. in the powder during granulation to the weight ratio of compound A, etc. in the binding liquid is within 1:10% to 1:10%;

[0083] (1) Between 65:35 and 0:100,

[0084] (2) Between 60:40 and 0:100,

[0085] (3) Between 50:50 and 0:100,

[0086] (4) Between 65:35 and 30:70,

[0087] (5) Between 60:40 and 30:70, or

[0088] (6) Between 50:50 and 30:70;

[0089] Alternatively, the content of compound A is 30% by weight or more and 70% by weight or less based on the total weight of the pharmaceutical composition, and the weight ratio of compound A, etc. in the powder during granulation to the weight ratio of compound A, etc. in the binding liquid is within 1:10% to 1:10%;

[0090] (1) Between 65:35 and 0:100,

[0091] (2) Between 60:40 and 0:100,

[0092] (3) Between 50:50 and 0:100,

[0093] (4) Between 65:35 and 30:70,

[0094] (5) Between 60:40 and 30:70, or

[0095] (6) Between 50:50 and 30:70;

[0096] Alternatively, the content of compound A is 30% by weight or more and 60% by weight or less based on the total weight of the pharmaceutical composition, and the weight ratio of compound A, etc. in the powder during granulation to the weight ratio of compound A, etc. in the binding liquid is within 1:10% to 1:10%;

[0097] (1) Between 65:35 and 0:100,

[0098] (2) Between 60:40 and 0:100,

[0099] (3) Between 50:50 and 0:100,

[0100] (4) Between 65:35 and 30:70,

[0101] (5) Between 60:40 and 30:70, or

[0102] (6) Between 50:50 and 30:70;

[0103] Alternatively, the content of compound A is 30% by weight or more and 50% by weight or less based on the total weight of the pharmaceutical composition, and the weight ratio of compound A, etc. in the powder during granulation to the weight ratio of compound A, etc. in the binding liquid is within 1:10% to 1:10%;

[0104] (1) Between 65:35 and 0:100,

[0105] (2) Between 60:40 and 0:100,

[0106] (3) Between 50:50 and 0:100,

[0107] (4) Between 65:35 and 30:70,

[0108] (5) Between 60:40 and 30:70, or

[0109] (6) Between 50:50 and 30:70;

[0110] Alternatively, the content of compound A is 30% by weight or more and 40% by weight or less based on the total weight of the pharmaceutical composition, and the weight ratio of compound A, etc. in the powder during granulation to the weight ratio of compound A, etc. in the binding liquid is within 1:10% to 2:10%;

[0111] (1) Between 70:30 and 0:100,

[0112] (2) Between 65:35 and 0:100,

[0113] (3) Between 60:40 and 0:100,

[0114] (4) Between 50:50 and 0:100,

[0115] (5) Between 70:30 and 30:70,

[0116] (6) Between 65:35 and 30:70,

[0117] (7) Between 60:40 and 30:70, or

[0118] (8) Between 50:50 and 30:70.

[0119] Particularly preferably, the content of compound A is 30% to 60% by weight based on the total weight of the pharmaceutical composition, and the weight ratio of compound A, etc. in the powder during granulation to compound A, etc. in the binding liquid is between 50:50 and 30:70. Alternatively, the content of compound A is 30% to 50% by weight based on the total weight of the pharmaceutical composition, and the weight ratio of compound A, etc. in the powder during granulation to compound A, etc. in the binding liquid is between 50:50 and 30:70. It is also preferred that any of the above pharmaceutical compositions is a granule comprising a granulation obtained by fluidized bed granulation, a capsule comprising the granulation, or a tablet obtained by compressing the granulation.

[0120] In addition, as a pharmaceutical composition containing compound A etc. as an active ingredient at a high ratio, the following example can be cited: based on the total weight of the pharmaceutical composition, the content of compound A converted is 50% by weight or more, and the weight ratio of compound A etc. in the powder during granulation to compound A etc. in the binding liquid is between 50:50 and 30:70. The following example is particularly preferred: based on the total weight of the pharmaceutical composition, the content of compound A converted is 50% by weight or more, and the weight ratio of compound A etc. in the powder during granulation to compound A etc. in the binding liquid is 50:50. In addition, the following example is also particularly preferred: based on the total weight of the pharmaceutical composition, the content of compound A converted is 50% by weight or more, and the weight ratio of compound A etc. in the powder during granulation to compound A etc. in the binding liquid is 30:70. It is also preferred that any of the above-mentioned pharmaceutical compositions is a granule comprising a granulation obtained by fluidized bed granulation, or a capsule comprising the granulation, or a tablet obtained by compressing the granulation. In addition, the surface of the pharmaceutical composition may be further coated.

[0121] More preferably, as a pharmaceutical composition containing compound A etc. as an active ingredient at a high ratio, the following example can be cited: based on the total weight of the pharmaceutical composition, the content of compound A is 50% by weight when converted, and the weight ratio of compound A etc. in the powder during granulation to compound A etc. in the binding liquid is between 50:50 and 30:70. The following example is particularly preferred: based on the total weight of the pharmaceutical composition, the content of compound A is 50% by weight when converted, and the weight ratio of compound A etc. in the powder during granulation to compound A etc. in the binding liquid is 50:50. In addition, the following example is also particularly preferred: based on the total weight of the pharmaceutical composition, the content of compound A is 50% by weight when converted, and the weight ratio of compound A etc. in the powder during granulation to compound A etc. in the binding liquid is 30:70. It is also preferred that any of the above-mentioned pharmaceutical compositions is a granule comprising a granulation obtained by fluidized bed granulation, or a capsule comprising the granulation, or a tablet obtained by compressing the granulation, and the surface of the pharmaceutical composition may be further coated.

[0122] In addition, as a pharmaceutical composition containing compound A etc. as an active ingredient at a high ratio, the following examples can be cited: based on the total weight of the pharmaceutical composition, the content of compound A converted is 30% by weight or more, preferably 50% by weight or more, and when the content of compound A etc. converted is set to X% by weight based on the total weight of the pharmaceutical composition, the weight ratio of compound A etc. in the powder during granulation to compound A etc. in the binding liquid is less than (100-(1.23X-15.79)) and is 1.23X-15.79 or more. It is also preferred that any of the above pharmaceutical compositions is an example of a granule comprising a granulation obtained by fluidized bed granulation, a capsule comprising the granulation, or a tablet obtained by tabletting the granulation, and the surface of the pharmaceutical composition may be further coated.

[0123] Compound A, i.e., 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof, which is an active ingredient of the pharmaceutical composition of the present invention, is described in Patent Documents 1 and 2 and can be produced by the methods described in these documents, etc.

[0124] In the present invention, compound A may be in the form of a pharmaceutically acceptable salt or co-crystal. As a preferred embodiment, a co-crystal of compound A may be mentioned, preferably a co-crystal with phosphoric acid, especially 1 equivalent of phosphoric acid. The co-crystal of compound A and phosphoric acid may be obtained by conventional methods, for example, by the method described in Patent Document 2.

[0125] In the present invention, the phosphoric acid eutectic of Compound A may also be referred to as a compound having a contact angle of 48 to 57°, preferably 50 to 55°. The contact angle is a value obtained by the method described in Examples below.

[0126] The pharmaceutical composition of the present invention may contain other components in addition to Compound A or a pharmaceutically acceptable salt or co-crystal thereof (hereinafter, sometimes referred to as Compound A, etc.).

[0127] As other components, there may be mentioned additives acceptable for pharmaceutical preparations.

[0128] Examples of "adjuvants acceptable for formulation" include excipients, disintegrants, binders, lubricants commonly used in the art, and coating agents, coating aids, colorants, masking agents, plasticizers, stabilizers, sweeteners, flavoring agents, antioxidants, glossing agents, flavoring agents, fragrances, defoaming agents, chewing agents, cooling agents, sugar-coating agents, foaming agents, disintegration aids, fluidizing agents, etc., as needed.

[0129] As the disintegrant, a common disintegrant added to medicines can be used, and the type thereof is not particularly limited. For example, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, cross-linked carboxymethyl cellulose sodium, cross-linked polyvinylpyrrolidone, starch, microcrystalline cellulose, hydroxypropyl starch, carboxymethyl starch sodium, partially alpha-starched starch, etc., and more than one of them can be used, preferably carboxymethyl cellulose calcium, carboxymethyl starch sodium, partially alpha-starched starch, low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium, and more preferably carboxymethyl cellulose calcium and low-substituted hydroxypropyl cellulose.

[0130] In addition, as a disintegrant, the water absorption capacity is preferably 4 mL / g or more, and more preferably 6 mL / g or more. Specifically, carboxymethylcellulose calcium and low-substituted hydroxypropyl cellulose are preferred.

[0131] The content of the disintegrant can be appropriately changed according to the dosage form, etc., and is preferably 0.1% to 30% by weight based on the total weight of the pharmaceutical composition, more preferably 1% to 15% by weight, 3% to 15% by weight, and particularly preferably 5% to 10% by weight.

[0132] As excipients, common excipients added to medicines can be used, and their types are not particularly limited. For example, mannitol, xylitol, sorbitol, erythritol, maltitol, glucose, sucrose, lactose, microcrystalline cellulose, calcium hydrogen phosphate, calcium phosphate, wheat starch, rice starch, corn starch, potato starch, sodium carboxymethyl starch, dextrin, α-dextrin, β-dextrin, carboxyvinyl polymer, light anhydrous silicic acid, magnesium oxide, magnesium hydroxide, sodium bicarbonate, magnesium aluminum silicate, polyethylene glycol, medium-chain fatty acid triglycerides, etc., and more than one of them can be used, preferably lactose (hydrate or anhydrous), D-mannitol, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, corn starch, more preferably lactose, and further preferably lactose hydrate.

[0133] The content of the excipient can be appropriately changed according to the dosage form, and is preferably 10% to 50% by weight based on the total weight of the pharmaceutical composition, more preferably 20% to 50% by weight, 20% to 40% by weight, and particularly preferably 20% to 30% by weight.

[0134] As the binder, a common binder added to medicines can be used, and the type thereof is not particularly limited. Preferably, a water-soluble polymer can be used, for example, carboxymethyl cellulose, sodium carboxymethyl cellulose, copovidone, α-starch, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (hydroxypropyl methylcellulose), pullulan, polyvinyl pyrrolidone (povidone), polyvinyl alcohol, gelatin, gum arabic, agar, tragacanth gum, sodium alginate, propylene glycol alginate, etc., and more than one of them can be used, preferably HPC, hydroxypropyl methylcellulose, povidone, polyvinyl alcohol, and more preferably HPC.

[0135] The content of the binder can be appropriately changed according to the dosage form, and is preferably 1% to 15% by weight based on the total weight of the pharmaceutical composition, more preferably 1% to 10% by weight, 2% to 10% by weight, and particularly preferably 2% to 5% by weight.

[0136] As lubricants, common lubricants added to medicines can be used, and their types are not particularly limited. For example, stearic acid, magnesium stearate, calcium stearate, polyoxyethylene stearate, sodium stearyl fumarate, magnesium aluminum silicate, cetyl alcohol, talc, hardened oil, sucrose fatty acid ester, glyceryl behenate, light anhydrous silicic acid, hydrated silica, dimethyl polysiloxane, microcrystalline wax, beeswax, white beeswax, etc., and more than one of them can be used, preferably magnesium stearate, calcium stearate, sodium fumarate stearate, sucrose fatty acid ester, talc, light anhydrous silicic acid, hydrated silica, and more preferably magnesium stearate.

[0137] The content of the lubricant can be appropriately changed according to the dosage form, and is preferably 0.1% to 5% by weight based on the total weight of the pharmaceutical composition, more preferably 0.5% to 4% by weight, 1% to 4% by weight, and particularly preferably 1% to 3% by weight.

[0138] The dosage form of the pharmaceutical composition of the present invention is preferably a solid preparation. As long as it is a solid preparation, there is no particular limitation, and examples thereof include granules, tablets, capsules, powders, fine granules, and lozenges. Granules, capsules, and tablets are preferred, and granules containing granules containing compound A, etc., capsules containing the granules, or tablets obtained by tableting the granules are preferred. Among them, tablets are preferred, and tablets obtained by tableting granules obtained by fluidized bed granulation are particularly preferred.

[0139] The pharmaceutical composition containing compound A etc. is more preferably a granulated product consisting of a portion containing compound A etc. and substantially free of binder and a portion containing compound A etc. and a binder, a capsule containing the granulated product, or a tablet obtained by compressing the granulated product. Furthermore, the pharmaceutical composition containing compound A etc. is more preferably a granulated product consisting of a portion containing compound A etc. and substantially free of binder and a portion containing compound A etc. and a binder, a capsule containing the granulated product, or a tablet obtained by compressing the granulated product, and contains compound A etc. at a high content rate.

[0140] In addition, a pharmaceutical composition containing compound A etc. is also preferred, such as a granulated product in which the chemical properties such as adhesion and hydrophobicity of compound A etc. are substantially masked by a binder, a capsule containing the granulated product, or a tablet obtained by compressing the granulated product. Furthermore, the pharmaceutical composition containing compound A etc. is more preferably a granulated product in which the chemical properties such as adhesion and hydrophobicity of compound A etc. are substantially masked by a binder, a capsule containing the granulated product, or a tablet obtained by compressing the granulated product, and contains compound A etc. at a high content rate.

[0141] In addition, a pharmaceutical composition containing Compound A etc. is also preferred, such as a granulated product suitable for tableting in which Compound A etc. is not exposed in the form of powder on the surface of the granulated product, a capsule containing the granulated product, or a tablet obtained by tableting the granulated product. Furthermore, a solid preparation containing Compound A etc. is more preferably a pharmaceutical composition containing Compound A etc. at a high content rate, such as a granulated product suitable for tableting in which Compound A etc. is not exposed in the form of powder on the surface of the granulated product, a capsule containing the granulated product, or a tablet obtained by tableting the granulated product.

[0142] When the pharmaceutical composition of the present invention is a pharmaceutical preparation composition comprising a granulated material containing compound A and the like, the shape and properties of the granulated material are not particularly limited, but preferably have the following shapes and properties.

[0143] The particle size of the granulated material containing compound A etc. is not particularly limited, and the median value (D 50 ), preferably 1000 μm or less, more preferably in the range of 90 μm to 500 μm, and particularly preferably in the range of 90 μm to 400 μm. It should be noted that the particle size of the granulated material can be measured, for example, by the sieving method shown below.

[0144] Weigh the tare weight of each sieve (mesh size is 710μm, 500μm, 355μm, 250μm, 180μm, 150μm, 106μm, 75μm and bottom plate) to the nearest 0.1g. Stack sieves with coarser mesh sizes on the sieves with smaller mesh sizes, place a sample weighing 5g accurately on the top sieve, and cover it with a lid. Oscillate the sieve for 5 minutes. Carefully remove the sieves of each layer from the sieve combination to avoid sample loss. Weigh the mass of each sieve again and determine the mass of the sample on the sieve. Calculate the proportion of the sample remaining on each sieve based on the total amount of sample and the mass on each sieve.

[0145] The angle of repose of the granulated material containing the compound A and the like is preferably 50 degrees or less.

[0146] The "angle of repose" refers to the angle between the generatrix of the cone formed when the drug particles fall gently on the horizontal plane and the horizontal plane. For example, it can be measured by the following steps.

[0147] The angle of repose is formed on a fixed circular plate with a retaining edge for retaining the powder layer. Make sure that the circular plate does not vibrate. In order to carefully form a symmetrical cone, it is best to change the height of the funnel according to the height of the cone. In this case, since the funnel will move, care must be taken to avoid vibration. In order to minimize the impact of the powder falling on the front end of the cone, the height of the lower end of the funnel foot is maintained at a distance of about 2 to 4 cm from the top of the deposit. By measuring the height of the cone, the angle of repose α is calculated according to the following formula.

[0148] tanα=height / (0.5×diameter of the disk)

[0149] The granulated material containing the compound A and the like preferably has a flowability with a minimum pore size (orifice) of 3.15 to 8 mm, more preferably 3.15 to 4 mm.

[0150] The bulk density refers to the ratio of the mass of the powder sample in the uncompacted (loose) state to the volume of the powder including the void volume factor between the particles.

[0151] The tap density refers to the increased bulk density obtained by mechanically tapping a container containing a powder sample.

[0152] In the granulated material containing compound A, the Hausner ratio is preferably 1.00 to 1.45. The Hausner ratio is a measure of the compressibility and flowability of the powder. When the Hausner ratio is 1.00 to 1.11, 1.12 to 1.18, 1.19 to 1.25, 1.26 to 1.34, 1.35 to 1.45, 1.46 to 1.59, or 1.60 or more, the degree of flow accuracy is very good, good, slightly good, fair, slightly poor, poor, and very poor, respectively.

[0153] The Hausner ratio can be obtained by measuring the bulk density (V0) or the tap density (V f ), according to the formula Hausner ratio = V0 / V f Figure it out.

[0154] The pharmaceutical composition of the present invention may also be a pharmaceutical composition comprising coated granules obtained by coating a granulated product with a coating agent. As the coating agent used for coating the granulated product, a common coating agent used in medicine can be used, and its type is not particularly limited. For example, one or more of water-soluble cellulose derivatives, water-soluble vinyl derivatives, water-soluble acrylic acid derivatives, water-insoluble cellulose derivatives, water-insoluble vinyl derivatives, water-insoluble acrylic acid polymers, gastric-soluble vinyl derivatives, gastric-soluble acrylic acid polymers, enteric cellulose derivatives, enteric vinyl derivatives, enteric acrylic acid polymers, corn protein, shellac, and wax can be used.

[0155] The pharmaceutical composition of the present invention may be a capsule comprising the above-mentioned granulated material in a capsule.

[0156] As capsules, common materials used for encapsulation of drugs can be used, for example, capsules formed of materials such as gelatin, hypromellose, pullulan, etc. The amount of compound A in one capsule can be appropriately adjusted according to the type of disease, for example, it can be 10 mg to 500 mg in terms of compound A.

[0157] The pharmaceutical composition of the present invention may be a tablet obtained by compressing the above-mentioned granulated material.

[0158] Tableting can be performed using known methods. The amount of compound A in one tablet can be appropriately adjusted according to the type of disease, for example, as compound A, the range of 0.1 to 1000 mg, preferably the range of 0.1 to 500 mg, more preferably the range of 50 mg to 300 mg, particularly preferably 50 mg, 100 mg, 200 mg or 300 mg.

[0159] When the pharmaceutical composition of the present invention is in the form of a tablet, the tablet is excellent in stability and solubility and preferably has one or more of the following properties.

[0160] 1) The hardness of the tablet is 30N or more.

[0161] 2) Using a cylinder described in the tablet abrasion test method of the Japanese Pharmacopoeia, a 6.5 g tablet was tested at a cylinder rotation speed of 25 rpm for 4 minutes, and the abrasion after correction for moisture absorption was 1% or less.

[0162] 3) When the stability test was conducted for 6 months under the conditions of a temperature of 40°C and a relative humidity of 75%, the amount of each decomposition product was less than 1%.

[0163] The surface of the obtained tablet may be subjected to coating treatment.

[0164] As the coating agent, coating agents commonly used in medicines can be used, and can be appropriately selected according to the purpose of rapid solubility, sustained release, enteric solubility, gastric solubility, etc. For example, one or more selected from water-soluble cellulose derivatives, water-soluble vinyl derivatives, water-soluble acrylic acid derivatives, water-insoluble cellulose derivatives, water-insoluble vinyl derivatives, water-insoluble acrylic acid polymers, gastric-soluble vinyl derivatives, gastric-soluble acrylic acid polymers, enteric cellulose derivatives, enteric vinyl derivatives, enteric acrylic acid polymers, zein, shellac, wax, etc. can be used.

[0165] In the coating solution, in addition to the coating agent, various additives can also be coordinated. As such additives, coating aids, colorants, screening agents, plasticizers, lubricants, etc. can be enumerated. As coating aids, for example, higher alcohols such as hardened oil, stearic acid and its salt, monostearate glycerin, talcum, kaolin, sucrose fatty acid esters, cetyl alcohol, etc. can be enumerated. As colorants, in addition to food coloring, lake pigments, etc., all colored substances that can be used in medicine can also be enumerated. As screening agents, titanium dioxide, precipitated calcium carbonate, calcium hydrogen phosphate, calcium sulfate, etc. can be enumerated. As plasticizers, in addition to phthalic acid derivatives such as diethyl phthalate, polyethylene glycol, propylene glycol, triacetin, triethyl citrate, glycerol, glycerol fatty acid esters, silicone oils, etc. can also be enumerated.

[0166] As a specific example of a coating liquid, there can be mentioned a substance prepared in the following manner: a base material such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, polyvinyl pyrrolidone, pullulan, etc. is combined with a plasticizer such as polyethylene glycol, propylene glycol, triacetin, triethyl citrate, glycerol, glycerol fatty acid ester, and additives such as titanium dioxide, talc, iron oxide, precipitated calcium carbonate, calcium hydrogen phosphate, calcium sulfate, etc. are added thereto as needed.

[0167] The use of the pharmaceutical composition of the present invention is not particularly limited as long as it is a disease for which compound A etc. can be used as an active ingredient to exert a therapeutic or preventive effect. Examples include diseases that can be treated or prevented by activation of MCR, especially MC1R, as described in Patent Document 1. Specifically, examples include autoimmune diseases, diseases related to inflammation, and diseases related to fibrosis.

[0168] Examples of such diseases include rheumatoid arthritis, gouty arthritis, osteoarthritis, inflammatory bowel disease, systemic sclerosis, psoriasis, fibrosis, protoporphyria (e.g., erythropoietic protoporphyria, etc.), systemic lupus erythematosus, melanoma, skin cancer, vitiligo, hair loss, pain, ischemia / reperfusion injury, inflammatory brain diseases, hepatitis, sepsis / septic shock, nephritis, transplantation, HIV disease progression, vasculitis, uveitis, retinitis pigmentosa, age-related macular degeneration, microbial infection, celiac disease, nephrotic syndrome, melanoma infiltration, and the like.

[0169] In addition, the pharmaceutical composition of the present invention is also useful for treating or preventing photodermatosis (also called photosensitivity), hypopigmentation, side effects of phototherapy, and the like.

[0170] Examples of photodermatoses include photoallergic dermatitis, vesiculovirus vacciniformis, DNA repair abnormalities, and porphyria.

[0171] Examples of photoallergic dermatitis include solar urticaria, polymorphic light eruption, chronic photodermatitis, photosensitivity contact dermatitis, and photosensitivity photosensitized drug eruption.

[0172] Examples of DNA repair abnormalities include xeroderma pigmentosum, Bloom's syndrome, Werner's syndrome, Rothmund-Thomson syndrome, trichotillomannia, and ultraviolet hypersensitivity syndrome.

[0173] Examples of porphyria include congenital myeloid porphyria, variant porphyria, acute intermittent porphyria, porphyria cutanea tarda, and hereditary coproporphyria.

[0174] Examples of hypopigmentation diseases include congenital hypopigmentation diseases such as oculocutaneous albinism, mottled disease, depigmented birthmarks, hypopigmentation (Ito leukoplakia), phenylketonuria, tuberous sclerosis, hereditary symmetrical dyschromatosis, Waardenburg syndrome, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, glycerol kinase deficiency, and Dietz syndrome, and acquired hypopigmentation diseases such as Sutton leukoplakia, Vogt-Koyanagi-Harada disease, senile leukoplakia, leukoplakia after sea bathing, and syphilitic leukoplakia.

[0175] On the other hand, phototherapy is used for the purpose of treating inflammatory skin diseases, vitiligo, alopecia areata, etc., and known treatments include narrow-spectrum UVB therapy, excimer phototherapy, PUVA therapy, etc., but side effects include, in the short term, photoallergic symptoms and phototoxic symptoms such as redness, sunburn, and burning sensation of the irradiated part, and in the long term, cancers such as skin cancer, photoaging of spots and wrinkles, etc. Compound A, etc., can also protect the skin and exert preventive and therapeutic effects against such side effects of phototherapy.

[0176] In addition, the pharmaceutical composition of the present invention is also useful for treating or preventing interstitial lung disease and diseases and symptoms associated with scleroderma, and is particularly useful for treating or preventing interstitial lung disease, fibrosis of skin and visceral tissues, vascular dysfunction, etc. in scleroderma patients.

[0177] As interstitial lung disease, interstitial pneumonia can be mentioned, as interstitial pneumonia, idiopathic interstitial pneumonia can be mentioned, and idiopathic interstitial pneumonia accompanied by idiopathic pulmonary fibrosis can be mentioned. In addition, as interstitial lung disease, interstitial lung disease associated with collagen disease and interstitial lung disease associated with scleroderma can also be mentioned. Here, scleroderma is preferably systemic scleroderma, and systemic scleroderma includes localized cutaneous sclerosis type systemic scleroderma and diffuse cutaneous sclerosis type systemic scleroderma.

[0178] Examples of diseases and symptoms associated with scleroderma include those selected from the group consisting of skin fibrosis, flexion contracture, gastroesophageal reflux disease, dysphagia, Raynaud's phenomenon, digital ulcers, pulmonary hypertension, and renal crisis.

[0179] Here, flexion contracture is a symptom caused by skin fibrosis in scleroderma, which can be improved by inhibiting skin fibrosis. Gastroesophageal reflux and dysphagia are symptoms caused by esophageal fibrosis in scleroderma, which can be improved by inhibiting esophageal fibrosis. Raynaud's phenomenon, finger ulcers, pulmonary hypertension and renal crisis are symptoms caused by vascular dysfunction in scleroderma, which can be improved by inhibiting vascular dysfunction. As pulmonary hypertension, there is no particular limitation, for example, arterial pulmonary hypertension can be cited.

[0180] The pharmaceutical composition obtained in the present invention is particularly useful as an oral agent. The dosage varies according to the patient's symptoms, age, sex, target duration, etc. Specifically, the dosage per administration can be 0.1 to 1000 mg in terms of compound A, preferably 0.1 to 500 mg. More preferably, 10 mg to 300 mg or 100 mg to 300 mg can be cited. For example, specifically, 50 mg, 100 mg, 200 mg or 300 mg is preferred.

[0181] <Manufacturing method>

[0182] Hereinafter, as one feature of the present invention, a pharmaceutical composition containing compound A, etc., preferably a method for producing the pharmaceutical composition of the present invention will be described. However, the pharmaceutical composition of the present invention is not limited to those produced by the following production method.

[0183] The production method of the present invention includes the following granulation step.

[0184] A granulation step of spraying a binding liquid containing Compound A or a pharmaceutically acceptable salt thereof or a cocrystal (Compound A, etc.) and a binder onto a powder substantially containing no binder in a fluidized bed granulator to obtain a granulated product.

[0185] The powder substantially containing no binder may contain compound A and the like.

[0186] One embodiment of the production method of the present invention includes the following granulation step.

[0187] The granulation step is to obtain granules by spraying a binding liquid containing Compound A or a pharmaceutically acceptable salt thereof or cocrystal (Compound A etc.) onto a powder containing Compound A etc. and substantially no binder in a fluidized bed granulator.

[0188] The production method of the present invention according to this embodiment is characterized in that the compound A and the like are contained in both the powder and the binding liquid used for fluidized bed granulation.

[0189] (1) The total weight of compound A and the like in the aforementioned powder, and

[0190] (2) The total weight ratio of Compound A and the like in the aforementioned adhesive solution is preferably between 70:30 and 0:100, more preferably between 65:35 and 0:100, and particularly preferably between 50:50 and 30:70. The preferred range of the weight ratio may be any of the ranges described in the above section of the pharmaceutical composition of the present invention.

[0191] By adjusting the content within the above range, problems occurring during granulation and tableting can be avoided, and granules suitable for pharmaceutical compositions containing a high content of compound A and the like can be obtained.

[0192] It should be noted that, in order to avoid problems occurring during granulation, it is preferred to mix an excipient and / or a disintegrant with Compound A, or to mix only an excipient and a disintegrant, and use the resulting mixture as a powder for granulation, or to use an excipient or a disintegrant alone as a powder. It is particularly preferred to mix an excipient and / or a disintegrant with Compound A, and use the resulting mixture as a powder for granulation.

[0193] Therefore, the production method of the present invention preferably includes the following mixing step (first mixing step) before the granulation step.

[0194] A mixing step of mixing compound A and the like with an excipient and / or a disintegrant to obtain a mixture.

[0195] In addition, components other than the excipient and / or disintegrant may be further mixed. As a more preferred example, the granulated powder contains the compound A and the excipient and / or disintegrant and contains substantially no binder.

[0196] Furthermore, in the production method of the present invention, it is preferred that a drying step of drying the granulated material is included after the granulation step.

[0197] The obtained granules can be used as granules directly or after being coated.

[0198] The obtained granulated material may be contained in a capsule as it is, or may be contained in a capsule after being coated, and then used as a capsule.

[0199] On the other hand, the production method of the present invention may include a tabletting step of compressing the obtained granulated material into tablets in order to obtain tablets.

[0200] Here, when disintegrants and lubricants are mixed and used during tableting, a mixing step (second mixing step) of further mixing disintegrants and lubricants in the granules may be included. In this way, additives such as those required for tableting are added and mixed to the granules obtained by the granulation step, and the obtained particles are sometimes referred to as mixed particles in this specification. In this specification, since the mixed particles and the granules differ little in the formulation ingredients, the preferred ranges of the median value of the particle size of the above-mentioned granules, the angle of repose, the minimum pore size, the Hausner ratio and other indicators are also applicable to the case of mixed particles.

[0201] The production method of the present invention may further include a step of coating the tablets obtained in the tableting step.

[0202] The following is a detailed description of a production method in which a binding liquid containing compound A etc. is sprinkled on a powder that may contain compound A etc., drug particles are granulated, the granulated product is compressed into tablets, and the tablets are coated.

[0203] <First Mixing Step>

[0204] First, compound A etc. is mixed with excipient and / or disintegrant, or only excipient and disintegrant are mixed to prepare powder for granulation, or excipient or disintegrant is used alone to prepare powder for granulation. Preferably, compound A etc. is mixed with excipient and / or disintegrant to prepare powder for granulation. It should be noted that other ingredients other than excipient and / or disintegrant may also be mixed. However, as other ingredients other than excipient and / or disintegrant, it is substantially free of binder.

[0205] The shape of the compound A etc. used in the granulation is not particularly limited, and various shapes can be used, preferably crystals. Crystals include eutectics. Crystals can be single crystals or polycrystalline. The size of the powder of the compound A etc. used is not particularly limited as long as it is a granulable size. For example, the median of the particle size measured by actual measurement based on microscopic observation, using an electrical or optical particle size measuring device, etc. is preferably 0.1 μm to 100 μm, and more preferably 1 μm to 10 μm.

[0206] The types of excipients and disintegrants used are not particularly limited, and the above-mentioned excipients and / or disintegrants can be appropriately selected and used. In the case where compound A or its pharmaceutically acceptable salt or co-crystal is mixed with an excipient in the first mixing step, compound A or its pharmaceutically acceptable salt or co-crystal is mixed with the excipient in a weight ratio of 0:100 to 50:50. More preferably, in the first mixing step, compound A or its pharmaceutically acceptable salt or co-crystal is mixed with the excipient in a weight ratio of 25:75 to 50:50. In addition, in the case where compound A or its pharmaceutically acceptable salt or co-crystal is mixed with a disintegrant in the first mixing step, compound A or its pharmaceutically acceptable salt or co-crystal is mixed with a disintegrant in a weight ratio of 0:100 to 50:50. More preferably, in the first mixing step, compound A or its pharmaceutically acceptable salt or co-crystal is mixed with a disintegrant in a weight ratio of 25:75 to 50:50. In the first mixing step, when compound A or its pharmaceutically acceptable salt or cocrystal, an excipient and a disintegrant are mixed and used, the weight ratio of compound A or its pharmaceutically acceptable salt or cocrystal to the total weight of the excipient and the disintegrant is 0:100 to 50:50. More preferably, the weight ratio of compound A or its pharmaceutically acceptable salt or cocrystal to the total weight of the excipient and the disintegrant is 25:75 to 50:50. The case where an excipient and a disintegrant are used together is more preferred. Particularly preferably, compound A or its pharmaceutically acceptable salt or cocrystal, an excipient and a disintegrant are mixed in a weight ratio of 47:45:8 or 35:55:10.

[0207] As a mixing device, for example, a container rotating mixer can be used for mixing. Examples of container rotating mixers include tumble blenders, V blenders, double cone blenders, and bin tumblers.

[0208] <Granulation process>

[0209] In the granulation step, first, a binder liquid for granulation is prepared.

[0210] Examples of the solvent for the adhesive solution include water, alcohol solvents such as methanol, ethanol, and 2-propanol, and mixed solvents thereof. Among them, water, particularly purified water, is a preferred solvent.

[0211] A binder solution containing the compound A etc. can be obtained by dissolving the binder in such a solvent to prepare a solution and dispersing the compound A etc. in the solution.

[0212] As the binder, a substance such as the above-mentioned water-soluble polymer can be appropriately selected and used. The concentration of the binder in the binder liquid is preferably set to 1 to 10% by weight, for example.

[0213] The concentration of the compound A etc. in the binding liquid (spray liquid) is not particularly limited, but is preferably 5% by weight or more, more preferably 10% to 60% by weight, and particularly preferably 30% to 50% by weight, based on the weight of the compound A etc. It should be noted that in order to uniformly disperse the drug in the preparation, the compound A etc. to be dispersed is preferably finely pulverized by dry or wet pulverization.

[0214] In the granulation step, the total weight of the sprayed binding liquid is preferably equal to or more than the total amount of the powder used in the granulation, more preferably 1 to 3 times, and even more preferably 1 to 2 times. The amount of compound A, etc. in the powder used in the granulation and the amount of compound A, etc. in the sprayed binding liquid are preferably adjusted to a weight ratio of 70:30 to 0:100, more preferably 65:35 to 0:100. In particular, in a pharmaceutical composition containing a high amount of compound A, etc., the amount of compound A, etc. in the powder used in the granulation and the amount of compound A, etc. in the sprayed binding liquid are particularly preferably adjusted to a weight ratio of 65:35 to 30:70, more preferably 50:50 to 30:70. In addition, a pharmaceutical composition produced by such a method is also preferred.

[0215] Granulation can be carried out according to the conventional fluidized bed granulation procedure.

[0216] The granulating apparatus used is not particularly limited as long as it is a fluidized bed granulating apparatus. The spraying method may be any of a top spray type, a bottom spray type, and a tangential spray type.

[0217] The fluidized bed granulation device is usually composed of a fluidized bed body, a rectifying plate, a blower, an air intake filter, a heat exchanger, a spray device, a dust collector, an exhaust fan, etc. The air supplied by the blower is purified by the air intake filter, heated by the heat exchanger, passed through the rectifying plate and fed into the device body. The hot air keeps the mixture of compound A etc. and excipients and / or disintegrants put into the device in a fluid state, and a liquid obtained by suspending compound A etc. in a binder solution is sprayed as a binder liquid, whereby droplets adhere to the surface of the powder, and through the binder droplets, the powder particles repeatedly adhere and aggregate, and the particles gradually grow (granulation and coating).

[0218] The inlet air temperature during granulation can be selected from the range of 50°C to 90°C, preferably from the range of 60°C to 80°C. The liquid velocity during granulation depends on the scale of the granulation apparatus used, the feed amount of the mixture of compound A and excipients and / or disintegrants, and the desired particle size of the granules. For example, when 10 kg of feed is added, the amount of solution can be selected from the range of 100 g / min to 300 g / min. The air volume during granulation depends on the scale of the granulation apparatus used, the feed amount of the mixture of compound A and excipients and / or disintegrants, and the desired particle size of the granules. For example, when 10 kg of feed is added, it can be selected from the range of 1 m / min to 300 g / min. 3 / min~10m 3 The spray air volume during granulation depends on the scale of the granulation device used, the liquid velocity, and the spray nozzle position. For example, when the feed is 10 kg, it can be selected from the range of 100 L / min to 500 L / min. The spray nozzle diameter during granulation depends on the scale of the granulation device used. For example, when the feed is 10 kg and the flow rate is 200 g / min, it can be selected from the range of 0.5 mm to 2.0 mm.

[0219] <First Drying Step>

[0220] Next, the granules obtained in the granulation step are dried. Drying can be performed under reduced pressure or normal pressure in such a manner that the drying loss value measured by an infrared moisture meter is, for example, 3% by weight or less. Drying can be performed in a granulating device, or the drying operation can be performed after the granules are taken out of the granulating device.

[0221] <Second Mixing Step>

[0222] Next, in order to provide for tableting, a disintegrant, a lubricant, etc. are mixed with the granulated material obtained in the drying step. As a mixing device, for example, a container rotary mixer can be used for mixing. Examples of container rotary mixers include tumble blenders, V blenders, double cone mixers, bin tumblers, etc.

[0223] The blending ratio of the disintegrant can be, for example, in the range of 0.1 to 10% by weight relative to the total weight of the granulated material. The blending ratio of the lubricant can be, for example, in the range of 0.1 to 10% by weight relative to the total weight of the granulated material.

[0224] <Tableting process>

[0225] In this process, the mixture obtained in the second mixing process is tableted by a tableting device to form tablets. The tableting hardness can be selected from the range of 20 to 100N, for example. As the tableting device, a tableting machine classified as a rotary tableting machine can be used. Here, in this specification, the obtained tablets are referred to as plain tablets, and when expressed as "the total weight of the pharmaceutical composition", etc., it refers to the weight of the plain tablet. That is, the weight ratio of compound A, etc. in one tablet is based on the weight of the plain tablet.

[0226] <Coating process>

[0227] In this step, the tablets obtained in the tableting step are coated appropriately according to the purpose. As a coating apparatus, for example, an apparatus classified as a coating pan, for example, an apparatus classified as a perforated coating system can be used.

[0228] As the coating agent, the coating agents described above can be used, and they can be appropriately selected and used according to the purpose such as rapid solubility, sustained release, enteric solubility, gastric solubility, etc.

[0229] The amount of the coating agent relative to the tablet may be an amount sufficient to coat the surface of the tablet, and may be varied according to the desired release properties.

[0230] <Second Drying Step>

[0231] Drying can be performed under reduced pressure or normal pressure so that the loss on drying measured by an infrared moisture meter is, for example, 3% by weight or less. The drying can be performed in the coating apparatus or separately after the coated tablet is taken out of the coating apparatus.

[0232] Example

[0233] Hereinafter, the present invention will be specifically described with reference to Examples, but the present invention is not limited to the following Examples.

[0234] Hereinafter, various test items of Examples and Comparative Examples were measured in the following manner.

[0235] <Particle Size Distribution>

[0236] There are 9 kinds of sieves used: 710μm, 500μm, 355μm, 250μm, 180μm, 150μm, 106μm, 75μm and bottom plate

[0237] method:

[0238] Weigh the tare weight of each sieve, accurate to 0.1 g. Stack the sieves with coarser sieve pores on top of the sieve with smaller sieve pores in turn. Place a test sample with an accurately measured mass of 5 g on the topmost sieve, cover it, and shake the sieve for 5 minutes. Carefully remove each layer of the sieve from the sieve combination to avoid loss of the test sample, weigh the mass of each sieve again, and determine the mass of the test sample on the sieve. Calculate the proportion of the test sample remaining on each sieve based on the total amount of the test sample and the mass on each sieve.

[0239] <Bulk density>

[0240] Using a funnel, let the test sample flow freely into a 100 mL stainless steel cylindrical container until it overflows. Then, carefully scrape off the excess powder from the upper surface of the container. Subtract the mass of the empty measuring container measured in advance to determine the mass (m0) of the powder. Calculate the bulk density (g / mL) according to the formula m0 / 100.

[0241] <Tap density>

[0242] Install an auxiliary cylinder on the 100 mL stainless steel cylindrical container for which the bulk density has been measured. Using a funnel, let the test sample flow freely until it overflows. Then, vibrate the measuring container with the auxiliary cylinder a total of 200 times at a frequency of 50 - 60 times per minute. After the vibration operation, remove the auxiliary cylinder and carefully scrape off the excess powder from the upper surface of the measuring container. Use the formula m f / 100 (m f is the mass of the powder in the measuring container after vibration and scraping) to calculate the tap density (g / mL).

[0243] <Hausner ratio>

[0244] The Hausner ratio is calculated by the following formula. Hausner ratio = ρ t / ρ0 (ρ t : tap density, ρ0: bulk density)

[0245] <Minimum aperture>

[0246] Measurable apertures: 3.15 mm, 4 mm, 5 mm, 6.3 mm, 8 mm, 10 mm, 12.5 mm, 16 mm, 20 mm, 25 mm

[0247] Using a funnel, gently place the test sample into the cylindrical container for measuring the aperture, and measure the smallest aperture through which the test sample freely falls as the minimum aperture.

[0248] [Example 1]

[0249] Under the following conditions, fluidized bed granulation is carried out using the phosphoric acid eutectic of compound A to obtain tablets.

[0250] Condition 1-1: The ratio of the phosphoric acid eutectic of compound A fed as powder to the fluidized bed granulator to the phosphoric acid eutectic of compound A added to the binding liquid is 3:7 by weight

[0251] Condition 1-2: The ratio of the phosphoric acid eutectic of compound A fed as powder to the fluidized bed granulator to the phosphoric acid eutectic of compound A added to the binding liquid is 5:5 by weight

[0252] The step of preparing the adhesive solution was carried out in the following steps.

[0253] [1] 0.456 kg of hydroxypropyl cellulose was slowly added to 7.164 kg of purified water and stirred for more than 30 minutes to dissolve it.

[0254] [2] 8.702 kg of phosphoric acid eutectic of compound A in an arbitrary ratio is slowly added to the aqueous solution of [1] while stirring, and the mixture is stirred and dispersed for more than 20 minutes.

[0255] [3] The entire amount of the suspension prepared in [2] was sieved through a sieve, and the absence of undissolved hydroxypropyl cellulose and agglomerates of the phosphoric acid eutectic of Compound A was visually confirmed.

[0256] [4] Add 1.5 kg of purified water to the SUS container used in [3], wash the attached original drug into it, and sieve it with a sieve to prepare an adhesive liquid.

[0257] Granulation and drying were carried out according to the following procedure.

[0258] [1] 4.218 kg of lactose hydrate, 0.760 kg of carboxymethylcellulose calcium and the remaining phosphoric acid eutectic of Compound A were sequentially placed in a fluidized bed granulation dryer.

[0259] [2] Preheating and mixing are performed at an intake air temperature setting value of 70°C until the exhaust air temperature reaches 40°C, and then the binder liquid spraying rate is adjusted to reach the target liquid rate for granulation.

[0260] [3] After the entire amount of the binder liquid is sprayed, the mixture is dried at an inlet air temperature of 80°C until the product temperature reaches 45°C to obtain granules.

[0261] Mixing and tableting were carried out in the following steps.

[0262] [1] 0.760 kg of carboxymethylcellulose calcium and 0.304 kg of magnesium stearate were added to the granulated material into a mixer and the mixture was stirred at a speed of 25 min. -1 The mixed particles were mixed to obtain mixed granules. It should be noted that the amounts of carboxymethylcellulose calcium and magnesium stearate used in this step are theoretical values, and are adjusted according to the actual yield of the granulated product.

[0263] [2] The mixed granules of [1] are tableted to obtain plain tablets. It should be noted that, based on compound A, the weight ratio of the phosphoric acid eutectic of compound A in the plain tablets is 50%.

[0264] The coating solution and coating were carried out according to the following steps.

[0265] [1] While stirring purified water, the coating ingredients are slowly added to the mixture so that the solid content concentration becomes 10 w / w%, and the mixture is stirred for 45 minutes or more.

[0266] [2] Sieve with a sieve to obtain a coating liquid.

[0267] [3] The tablets are coated using a vented coating system.

[0268] Table 1 shows the results of the production.

[0269] [Table 1]

[0270]

[0271] In both conditions 1-1 and 1-2, the fluidity during granulation was good, no adhesion to the can body was observed, and no sticking was observed during tableting.

[0272] [Example 2]

[0273] The phosphoric acid cocrystal of Compound A was used for fluidized bed granulation under the following conditions to obtain tablets.

[0274] Condition 2-1: The weight ratio of the phosphoric acid eutectic of compound A fed as powder to the fluidized bed granulator to the phosphoric acid eutectic of compound A added to the binding liquid is 10:0

[0275] Condition 2-2: The ratio of the phosphoric acid eutectic of compound A fed as powder to the fluidized bed granulator to the phosphoric acid eutectic of compound A added to the binding liquid is 7:3 by weight

[0276] Condition 2-3: The ratio of the phosphoric acid eutectic of compound A fed as powder to the fluidized bed granulator to the phosphoric acid eutectic of compound A added to the binding liquid is 5:5 by weight

[0277] Condition 2-4: The ratio of the phosphoric acid eutectic of compound A fed as powder to the fluidized bed granulator to the phosphoric acid eutectic of compound A added to the binding liquid is 3:7 by weight

[0278] The step of preparing the adhesive solution was carried out in the following steps.

[0279] [1] 30 g of hydroxypropyl cellulose was slowly added to 470 g of purified water and stirred to dissolve.

[0280] [2] The entire amount of the suspension prepared in [1] was sieved through a sieve, and the absence of undissolved hydroxypropyl cellulose was visually confirmed to prepare a binding liquid.

[0281] [3] If necessary, 572.5 g of a phosphoric acid eutectic of compound A in any proportion is slowly added to the aqueous solution of [2] while stirring, and the mixture is stirred and dispersed for 20 minutes or more.

[0282] [4] The entire amount of the suspension prepared in [3] was sieved through a sieve, and the absence of undissolved hydroxypropyl cellulose and agglomerates of the phosphoric acid eutectic of Compound A added as needed was visually confirmed.

[0283] [5] Add 100 g of purified water to the SUS container used in [3], wash the attached original drug into it, and sieve it with a sieve to prepare an adhesive liquid.

[0284] Granulation and drying were carried out according to the following procedure.

[0285] [1] 277.5 g of lactose hydrate, 50 g of carboxymethylcellulose calcium and the remaining phosphoric acid eutectic of Compound A were placed in a fluidized bed granulation dryer in that order.

[0286] [2] After preheating and mixing at an inlet air temperature setting of 70°C, the binder liquid spraying rate is adjusted to a target liquid rate for granulation.

[0287] [3] After the entire amount of the binder liquid is sprayed, the mixture is dried at an inlet air temperature of 80°C until the product temperature reaches about 35°C or higher, thereby obtaining granules.

[0288] Mixing and tableting were carried out in the following steps.

[0289] [1] 50 g of carboxymethylcellulose calcium and 20 g of magnesium stearate were mixed with the granulated material 100 times by bag mixing to obtain mixed granules. It should be noted that the amounts of carboxymethylcellulose calcium and magnesium stearate used in this step are theoretical values ​​based on the above values ​​and are adjusted according to the actual yield of the granulated material.

[0290] [2] The mixture of [1] is tableted to obtain plain tablets. During tableting, in order to confirm the adhesion of the powder to the tablet over time, the tableting is stopped at 5 minutes, 10 minutes, and 20 minutes after the start of tableting, and the tablet is evaluated using a colorimeter. It should be noted that the weight ratio of the phosphoric acid eutectic of compound A in the plain tablet is 50% based on compound A.

[0291] Table 2 shows the results of the production.

[0292] [Table 2]

[0293]

[0294] In any of the conditions 2-1 to 2-4, the fluidity during granulation was good, and no adhesion to the can body was observed.

[0295] The time-dependent change of the colorimeter is shown in Figure 1 .

[0296] The color difference measured by a colorimeter is represented by ΔE. When the ΔE value of the punch color before tableting is set to 0, if powder adheres to the punch during tableting, the color changes from the initial color, so the ΔE value becomes larger.

[0297] As described above, the ratio of the amount of the phosphoric acid eutectic of compound A introduced into the fluidized bed granulator to the amount dispersed in the binding liquid was changed, and granulation was performed by fluidized bed granulation to obtain Figure 1 The results recorded. That is, regarding the formulation system of condition 2-3 or 2-4 in which the ratio of the weight of the phosphoric acid eutectic of compound A put into the fluidized bed granulator to the weight of the phosphoric acid eutectic of compound A dispersed in the binding liquid is set to 5:5 or 3:7, it can be confirmed that its ΔE value is smaller than the formulation system of condition 2-1 or 2-2 (ratio of 10:0, 7:3, etc.). That is, it can be confirmed that by dispersing a part of the phosphoric acid eutectic of compound A in the binding liquid for granulation as in condition 2-3 or 2-4, the adhesion of powder to the pulp can be reduced. This shows that by dispersing a part of the phosphoric acid eutectic of compound A in the binding liquid for granulation, the degree of sticking to the pulp is improved. It should be noted that the measurement conditions of the colorimeter are shown in Table 3.

[0298] [Table 3]

[0299]

[0300] [Example 3]

[0301] The phosphoric acid cocrystal of Compound A was used for fluidized bed granulation under the following conditions to obtain tablets.

[0302] Condition 3-1: The ratio of the phosphoric acid eutectic of compound A fed as powder into the fluidized bed granulator to the phosphoric acid eutectic of compound A added to the binding liquid is 0:10 by weight

[0303] The step of preparing the adhesive solution was carried out in the following steps.

[0304] [1] 27 g of hydroxypropyl cellulose was slowly added to 473 g of purified water and stirred to dissolve.

[0305] [2] The entire amount of the suspension prepared in [1] was sieved through a sieve, and the absence of undissolved hydroxypropyl cellulose was visually confirmed to prepare a binding liquid.

[0306] [3] 343.5 g of the phosphoric acid eutectic of compound A was slowly added to the aqueous solution of [2] while stirring, and the mixture was stirred and dispersed for more than 20 minutes.

[0307] [4] The entire amount of the suspension prepared in [3] was sieved through a sieve, and the absence of undissolved hydroxypropyl cellulose and agglomerates of the phosphoric acid eutectic of Compound A added as needed was visually confirmed.

[0308] [5] Add 100 g of purified water to the SUS container used in [3], wash the attached original drug into it, and sieve it with a sieve to prepare an adhesive liquid.

[0309] Granulation and drying were carried out according to the following procedure.

[0310] [1] About 421.5 g of lactose hydrate and 30 g of carboxymethylcellulose calcium were placed in a fluidized bed granulation dryer in sequence.

[0311] [2] After preheating and mixing at an inlet air temperature setting of 70°C, the binder liquid spraying rate is adjusted to a target liquid rate for granulation.

[0312] [3] After the entire amount of the binder liquid is sprayed, the mixture is dried at an inlet air temperature of 80°C until the product temperature reaches about 35°C or higher, thereby obtaining granules.

[0313] Mixing and tableting were carried out in the following steps.

[0314] [1] 45 g of carboxymethylcellulose calcium and 18 g of magnesium stearate were mixed with the granulated material by bag mixing 100 times to obtain mixed granules. It should be noted that the amounts of carboxymethylcellulose calcium and magnesium stearate used in this step are theoretical values ​​and are adjusted according to the actual yield of the granulated material.

[0315] [2] The mixture of [1] is tableted to obtain a plain tablet. It should be noted that, based on the conversion of compound A, the weight ratio of the phosphoric acid eutectic of compound A in the plain tablet is 33.3%.

[0316] Table 4 shows the results of the production.

[0317] [Table 4]

[0318]

[0319] The flowability during granulation was good, no adhesion to the can body was observed, and no sticking was observed during tableting.

[0320] [Example 4]

[0321] The phosphoric acid cocrystal of Compound A was used for fluidized bed granulation under the following conditions to obtain tablets.

[0322] Condition 4-1: The ratio of the phosphoric acid eutectic of compound A fed as powder to the fluidized bed granulator to the phosphoric acid eutectic of compound A added to the binding liquid is 0:10 by weight

[0323] The step of preparing the adhesive solution was carried out in the following steps.

[0324] [1] 18 g of hydroxypropyl cellulose was slowly added to 282 g of purified water and stirred to dissolve.

[0325] [2] The entire amount of the suspension prepared in [1] was sieved through a sieve, and the absence of undissolved hydroxypropyl cellulose was visually confirmed to prepare a binding liquid.

[0326] [3] 343.5 g of the phosphoric acid eutectic of compound A was slowly added to the aqueous solution of [2] while stirring, and the mixture was stirred and dispersed for more than 20 minutes.

[0327] [4] The entire amount of the suspension prepared in [3] was sieved through a sieve, and the absence of undissolved hydroxypropyl cellulose and agglomerates of the phosphoric acid eutectic of Compound A added as needed was visually confirmed.

[0328] [5] Add 100 g of purified water to the SUS container used in [3], wash the attached original drug into it, and sieve it with a sieve to prepare an adhesive liquid.

[0329] Granulation and drying were carried out according to the following procedure.

[0330] [1] About 166.5 g of lactose hydrate and 30 g of carboxymethylcellulose calcium were placed in a fluidized bed granulation dryer in sequence.

[0331] [2] After preheating and mixing at an inlet air temperature setting of 70°C, the binder liquid spraying rate is adjusted to a target liquid rate for granulation.

[0332] [3] After the entire amount of the binder liquid is sprayed, the mixture is dried at an inlet air temperature of 80°C until the product temperature reaches about 35°C or higher, thereby obtaining granules.

[0333] Mixing and tableting were carried out in the following steps.

[0334] [1] 30 g of carboxymethylcellulose calcium and 12 g of magnesium stearate were mixed with the granulated material by bag mixing 100 times to obtain mixed granules. It should be noted that the amounts of carboxymethylcellulose calcium and magnesium stearate used in this step are theoretical values ​​based on the above values ​​and are adjusted according to the actual yield of the granulated material.

[0335] [2] The mixture of [1] is tableted to obtain a plain tablet. It should be noted that, based on the conversion of compound A, the weight ratio of the phosphoric acid eutectic of compound A in the plain tablet is 50%.

[0336] The production results are shown in Table 5.

[0337] [Table 5]

[0338]

[0339] The flowability during granulation was good and no sticking was observed during tableting.

[0340] [Example 5]

[0341] Put all the phosphoric acid eutectic of compound A into a fluidized bed granulator, and perform fluidized bed granulation as follows to obtain tablets. It should be noted that the processing volume of the granulation process is defined as 1 batch, and the production is repeated 3 times. The obtained 3 batches are collected and mixed in the mixing process. In addition, the processing volume of the mixing process is defined as 1 lot, and the following tableting process and coating process are implemented. (1 batch = 3 batches)

[0342] The preparation process of the adhesive solution is carried out according to the following steps. (The amount recorded is for one small batch)

[0343] [1] 37.80 g of hydroxypropyl cellulose was slowly added to 434.7 g of purified water and stirred to dissolve. Taking into account the amount of loss during the process, the amount of material added was set to 150% of the theoretical amount of material added.

[0344] [2] The entire amount of the suspension prepared in [1] was sieved through a sieve, and visually confirmed that no undissolved hydroxypropyl cellulose was present.

[0345] Granulation and drying were carried out according to the following procedure. (The amount recorded is for one small batch)

[0346] [1] A portion of 401.8 g of lactose hydrate was added to a bag containing 320.6 g of phosphoric acid eutectic of compound A, mixed 50 times, sieved with a sieve, and added to a granulator. The remaining lactose hydrate was then added to the granulator.

[0347] [2] Granulation is performed by adjusting the binder liquid spraying speed to the target liquid speed.

[0348] [3] After the entire amount of the binder liquid was sprayed, the mixture was dried at an inlet air temperature of 80°C until the product temperature reached 45°C to obtain granules.

[0349] Mixing and tableting were carried out according to the following steps. (The amount is recorded as one batch)

[0350] [1] 252.0 g of low-substituted hydroxypropyl cellulose and 25.20 g of magnesium stearate were added to the granulated material in a mixer and the mixer was rotated at a speed of 36 min. -1 The mixture is mixed to obtain mixed granules. It should be noted that the amounts of low-substituted hydroxypropylcellulose and magnesium stearate used in this step are theoretical values, and are adjusted according to the actual yield of the granulated product.

[0351] [2] The mixture of [1] was tableted to obtain 4 batches of plain tablets. It should be noted that, based on compound A, the weight ratio of the phosphoric acid eutectic of compound A in the plain tablets was 33.3%.

[0352] The coating solution and coating were carried out according to the following steps. (The amount recorded is for one batch)

[0353] [1] While stirring purified water, the coating ingredients are slowly added to the mixture so that the solid content concentration becomes 10 w / w%, and the mixture is stirred for 45 minutes or more.

[0354] [2] Sieve with a sieve to obtain a coating liquid.

[0355] [3] The tablets are coated using a vented coating system.

[0356] The production results are shown in Table 6.

[0357] [Table 6]

[0358]

[0359] In this example, in order to produce a pharmaceutical composition in which the content of the phosphoric acid cocrystal of Compound A in the plain tablet is 30% by weight as converted to Compound A, all the phosphoric acid cocrystal of Compound A is put into a granulator, granulated by fluidized bed granulation, mixed, tableted and coated. When multiple batches are produced under the same formulation and the same conditions, poor-appearance tablets due to sticking are observed in the tableting process of all batches, but the fluidity during granulation is good and no adhesion to the can body is observed.

[0360] [Example 6]

[0361] The phosphoric acid cocrystal of Compound A was used for fluidized bed granulation under the following conditions to obtain tablets.

[0362] Condition 6-1: The ratio of the phosphoric acid eutectic of compound A fed as powder to the fluidized bed granulator to the phosphoric acid eutectic of compound A added to the binding liquid is 7:3 by weight

[0363] The step of preparing the adhesive solution was carried out in the following steps.

[0364] [1] 36 g of hydroxypropyl cellulose was slowly added to 584 g of purified water and stirred to dissolve.

[0365] [2] The entire amount of the suspension prepared in [1] was sieved through a sieve, and the absence of undissolved hydroxypropyl cellulose was visually confirmed to prepare a binding liquid.

[0366] [3] 137.4 g of the phosphoric acid eutectic of compound A is slowly added to the aqueous solution of [2] while stirring as necessary, and the mixture is stirred and dispersed for 20 minutes or more.

[0367] [4] The entire amount of the suspension prepared in [3] was sieved through a sieve, and visually confirmed that there were no undissolved hydroxypropyl cellulose and no agglomerates of the added phosphoric acid eutectic of Compound A.

[0368] [5] Add 100 g of purified water to the SUS container used in [3], wash the attached original drug into it, and sieve it with a sieve to prepare an adhesive liquid.

[0369] Granulation and drying were carried out according to the following procedure.

[0370] [1] 602.0 g of lactose hydrate, 40 g of carboxymethylcellulose calcium and 320.6 g of phosphoric acid eutectic of compound A were placed in a fluidized bed granulation dryer in that order.

[0371] [2] After preheating and mixing at an inlet air temperature setting of 70°C, the binder liquid spraying rate is adjusted to a target liquid rate for granulation.

[0372] [3] After the entire amount of the binder liquid is sprayed, the mixture is dried at an inlet air temperature of 80°C until the product temperature reaches about 35°C or higher, thereby obtaining granules.

[0373] Mixing and tableting were carried out in the following steps.

[0374] [1] 29.7 g of carboxymethylcellulose calcium and 18 g of magnesium stearate were mixed with the granulated material by bag mixing 50 times to obtain mixed granules. It should be noted that the amounts of carboxymethylcellulose calcium and magnesium stearate used in this step are theoretical values ​​and are adjusted according to the actual yield of the granulated material.

[0375] [2] The mixture of [1] was tableted to obtain plain tablets. During tableting, in order to confirm the adhesion of the powder to the tablet over time, the tableting was stopped at 5 minutes, 10 minutes, and 20 minutes after the start of tableting, and the tablets were evaluated using a colorimeter. It should be noted that the weight ratio of the phosphoric acid eutectic of compound A in the plain tablets was 33% based on compound A.

[0376] The production results are shown in Table 7.

[0377] [Table 7]

[0378] Table 7

[0379]

[0380] Under Condition 6-1, the fluidity during granulation was also good, and no adhesion to the can body was observed.

[0381] The time-dependent change of the colorimeter is shown in Figure 2 .

[0382] As described above, the content of the phosphoric acid eutectic of compound A in one tablet is 33% by weight, calculated as compound A. The weight ratio of the phosphoric acid eutectic of compound A put into the fluidized bed granulator to the amount dispersed in the binding liquid is set to 70:30, and granulation is performed by fluidized bed granulation to obtain Figure 2 The results recorded show that Figure 1 The ΔE values ​​of the formulations with improved stickiness are the same as those of the formulations of conditions 2-3 or 2-4. It should be noted that the measurement conditions of the colorimeter are shown in Table 3.

[0383] [Example 7]

[0384] The phosphoric acid cocrystal of Compound A was used for fluidized bed granulation under the following conditions to obtain tablets.

[0385] Condition 7-1: The ratio of the phosphoric acid eutectic of compound A fed as powder to the fluidized bed granulator to the phosphoric acid eutectic of compound A added to the binding liquid is 3:7 by weight

[0386] The step of preparing the adhesive solution was carried out in the following steps.

[0387] [1] 37.2 g of hydroxypropyl cellulose was slowly added to 606.8 g of purified water and stirred to dissolve.

[0388] [2] The entire amount of the suspension prepared in [1] was sieved through a sieve, and the absence of undissolved hydroxypropyl cellulose was visually confirmed to prepare a binding liquid.

[0389] [3] 320.6 g of the phosphoric acid eutectic of compound A is slowly added to the aqueous solution of [2] while stirring as necessary, and the mixture is stirred and dispersed for 20 minutes or more.

[0390] [4] The entire amount of the suspension prepared in [3] was sieved through a sieve, and visually confirmed that there were no undissolved hydroxypropyl cellulose and no agglomerates of the added phosphoric acid eutectic of Compound A.

[0391] [5] Add 100 g of purified water to the SUS container used in [3], wash the attached original drug into it, and sieve it with a sieve to prepare an adhesive liquid.

[0392] Granulation and drying were carried out according to the following procedure.

[0393] [1] 64.4 g of lactose hydrate, 24.0 g of carboxymethylcellulose calcium and 137.4 g of phosphoric acid eutectic of compound A were placed in a fluidized bed granulation dryer in that order.

[0394] [2] After preheating and mixing at an inlet air temperature setting of 70°C, the binder liquid spraying rate is adjusted to a target liquid rate for granulation.

[0395] [3] After the entire amount of the binder liquid is sprayed, the mixture is dried at an inlet air temperature of 80°C until the product temperature reaches about 35°C or higher, thereby obtaining granules.

[0396] Mixing and tableting were carried out in the following steps.

[0397] [1] 19.8 g of carboxymethylcellulose calcium and 10.4 g of magnesium stearate were mixed with the granulated material by bag mixing 50 times to obtain mixed granules. It should be noted that the amounts of carboxymethylcellulose calcium and magnesium stearate used in this step are theoretical values ​​and are adjusted according to the actual yield of the granulated material.

[0398] [2] The mixture of [1] was tableted to obtain plain tablets. During tableting, in order to confirm the adhesion of the powder to the tablet over time, tableting was stopped at 5 minutes, 10 minutes, and 20 minutes after the start of tableting, and the tablets were evaluated using a colorimeter. It should be noted that the weight ratio of the phosphoric acid eutectic of compound A in the plain tablets was 65% when converted to compound A.

[0399] The production results are shown in Table 8.

[0400] [Table 8]

[0401] Table 8

[0402]

[0403] Under Condition 7-1, the fluidity during granulation was also good, and no adhesion to the can body was observed.

[0404] The time-dependent change of the colorimeter is shown in Figure 3 .

[0405] As described above, the content of the phosphoric acid eutectic of compound A in one tablet is 65% by weight, calculated as compound A. The weight ratio of the phosphoric acid eutectic of compound A put into the fluidized bed granulator to the amount dispersed in the binding liquid is set to 30:70, and granulation is performed by fluidized bed granulation to obtain Figure 3 The results recorded show that Figure 1 The ΔE values ​​of the formulations with improved stickiness are the same as those of the formulations of conditions 2-3 or 2-4. It should be noted that the measurement conditions of the colorimeter are shown in Table 3.

[0406] Thus, it was shown that a pharmaceutical composition having a content of 30% by weight or more of the phosphoric acid eutectic of compound A per tablet in terms of compound A conversion can be manufactured without problems during granulation. In particular, it was confirmed that by dispersing a part or all of the phosphoric acid eutectic of compound A in a binder liquid for granulation, the poor appearance caused by sticking can be improved. In addition, it was confirmed that for a pharmaceutical composition having a more stringent condition of 50% by weight of the phosphoric acid eutectic of compound A per tablet in terms of compound A conversion, by dispersing a part of the phosphoric acid eutectic of compound A in a fluidized bed granulator and dispersing the rest in a binder liquid for granulation, not only sticking can be avoided, but also all problems in the manufacturing process such as poor fluidity and adhesion to the can body can be avoided, and productivity can be improved.

[0407] As shown above, condition 2-3 in Example 2 improves the degree of sticking compared to condition 2-2, and can be manufactured without problems in the manufacturing process. Under condition 6-1 in Example 6 and condition 7-1 in Example 7, manufacturing can also be carried out without problems in the manufacturing process.

[0408] For the four conditions 2-2, 2-3, 6-1, and 7-1, the X-axis is set to the content (%) of compound A etc. converted to compound A based on the total weight of the pharmaceutical composition, and the Y-axis is set to the weight ratio (%) of compound A etc. in the binder liquid during granulation. The relationship between the four points was calculated using the least square method, and the result was Y=1.23X-15.79. The range of the weight ratio (%) of compound A etc. in the binder liquid during granulation above this formula also includes the conditions 1-1 and 1-2 of Example 1, the condition 2-1 of Example 3, and the condition 4-1 of Example 4, which can avoid problems in the production process, and is considered to be a preferred range.

[0409] [Example 8]

[0410] The contact angle of the phosphoric acid cocrystal of Compound A was measured by the following procedure.

[0411] [1] The phosphoric acid eutectic of compound A was compressed using a single punch tablet press to produce granules with a smooth surface.

[0412] [2] 5 μL of purified water was dropped onto the pellets, and an image was acquired using a CCD camera 10 seconds after the dropwise addition.

[0413] [3] The static contact angle, which is the angle between the pellet and the added liquid droplet, is measured based on the image captured by the CCD camera.

[0414] The static contact angle of the phosphoric acid eutectic of Compound A obtained by the above-mentioned procedure was 52.77°±2.72° (n=5). The average value and the standard deviation were calculated according to JIS Z 8401.

Claims

1. A pharmaceutical composition comprising 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid (Compound A) or a pharmaceutically acceptable salt or cocrystal thereof as an active ingredient, wherein: Based on the total weight of the pharmaceutical composition, the content of compound A or its pharmaceutically acceptable salt or co-crystal is 30% by weight or more, calculated as compound A.

2. The pharmaceutical composition according to claim 1, further comprising one or more selected from the group consisting of a disintegrant, a binder and an excipient.

3. The pharmaceutical composition according to claim 2, wherein The content of the disintegrant is 0.1 wt% to 30 wt% based on the total weight of the pharmaceutical composition.

4. The pharmaceutical composition according to claim 2 or 3, wherein The disintegrant is carboxymethylcellulose calcium or low-substituted hydroxypropyl cellulose.

5. The pharmaceutical composition according to any one of claims 2 to 4, wherein Based on the total weight of the pharmaceutical composition, the content of the binder is 1 wt% to 15 wt%.

6. The pharmaceutical composition according to any one of claims 2 to 5, wherein The adhesive is a water-soluble polymer.

7. The pharmaceutical composition according to claim 6, wherein The water-soluble polymer is hydroxypropyl cellulose.

8. The pharmaceutical composition according to any one of claims 2 to 7, wherein Based on the total weight of the pharmaceutical composition, the content of the excipient is 10% to 50% by weight.

9. The pharmaceutical composition according to any one of claims 2 to 8, wherein The excipient is lactose hydrate.

10. The pharmaceutical composition according to any one of claims 1 to 9, further comprising a lubricant.

11. The pharmaceutical composition according to claim 10, wherein Based on the total weight of the pharmaceutical composition, the content of the lubricant is 0.1 wt% to 5 wt%.

12. The pharmaceutical composition according to claim 10 or 11, wherein The lubricant is magnesium stearate.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein Based on the total weight of the pharmaceutical composition, the content of compound A or a pharmaceutically acceptable salt or co-crystal thereof is 50% by weight or more, calculated as compound A. 14 . The pharmaceutical composition according to claim 1 , which is a granulated product of Compound A or a pharmaceutically acceptable salt or co-crystal thereof, a capsule comprising the granulated product, or a tablet obtained by compressing the granulated product.

15. The solid dosage pharmaceutical composition according to claim 14, wherein The granulated material is obtained by granulating a powder containing Compound A or a pharmaceutically acceptable salt or co-crystal thereof by fluidized bed granulation.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein The granulated material is a granulated material consisting of a portion containing Compound A or a pharmaceutically acceptable salt or co-crystal thereof and substantially no binder, and a portion containing Compound A or a pharmaceutically acceptable salt or co-crystal thereof and a binder.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein The granulated material is obtained by spraying a powder containing compound A or a pharmaceutically acceptable salt or co-crystal thereof with a binding liquid containing compound A or a pharmaceutically acceptable salt or co-crystal and a binder.

18. The pharmaceutical composition according to any one of claims 1 to 17, wherein The granulated material is obtained by spraying a powder containing compound A or a pharmaceutically acceptable salt or co-crystal thereof with a binding liquid containing compound A or a pharmaceutically acceptable salt or co-crystal and a binder.

19. The pharmaceutical composition according to claim 17 or 18, wherein The ratio of the total weight of compound A or its pharmaceutically acceptable salt or co-crystal in the powder to the total weight of compound A or its pharmaceutically acceptable salt or co-crystal in the binding liquid is 70:30 to 0:

100.

20. The pharmaceutical composition according to any one of claims 14 to 19, wherein The median value of the particle size of the granulated material is 90 μm to 400 μm.

21. The pharmaceutical composition according to any one of claims 14 to 20, wherein The angle of repose of the granulated material is 50 degrees or less.

22. The pharmaceutical composition according to any one of claims 14 to 21, which is a tablet obtained by compressing the granulated material.

23. The pharmaceutical composition of claim 22, wherein The hardness of the tablet is above 30N.

24. The pharmaceutical composition according to claim 22 or 23, wherein 6.5 g of the tablet was tested at a drum rotation speed of 25 rpm for 4 minutes using a cylinder described in the tablet abrasion test method of the Japanese Pharmacopoeia, and the abrasion after correction for moisture absorption was 1% or less.

25. The pharmaceutical composition according to any one of claims 22 to 24, wherein When the tablet was subjected to a stability test for 6 months at a temperature of 40° C. and a relative humidity of 75%, the amount of each decomposition product was less than 1%.

26. The pharmaceutical composition according to any one of claims 1 to 25, wherein Compound A or a pharmaceutically acceptable salt or co-crystal thereof is a phosphoric acid co-crystal of Compound A.

27. The method for producing a pharmaceutical composition according to any one of claims 1 to 26, comprising a granulation step of obtaining a granulated material by fluidized bed granulation.

28. A method for producing a pharmaceutical composition according to any one of claims 1 to 26, comprising a granulation step of spraying a powder that may contain compound A or a pharmaceutically acceptable salt or co-crystal thereof with a binding liquid containing compound A or a pharmaceutically acceptable salt or co-crystal and a binder in a fluidized bed granulator to obtain a granulated material.

29. A method for producing a pharmaceutical composition, the pharmaceutical composition comprising 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid (Compound A) or a pharmaceutically acceptable salt or cocrystal thereof as an active ingredient, The production method includes a granulation step of spraying a powder containing compound A or its pharmaceutically acceptable salt or co-crystal with a binding liquid containing compound A or its pharmaceutically acceptable salt or co-crystal and a binder in a fluidized bed granulator to obtain a granulated product.

30. A method for producing a pharmaceutical composition according to any one of claims 1 to 26, comprising a granulation step of spraying a powder containing compound A or its pharmaceutically acceptable salt or co-crystal with a binding liquid containing compound A or its pharmaceutically acceptable salt or co-crystal and a binder in a fluidized bed granulator to obtain a granulated material.

31. The method according to any one of claims 27 to 30, which comprises, before the granulation step, a first mixing step of mixing compound A or a pharmaceutically acceptable salt thereof or co-crystal with an excipient and / or a disintegrant to obtain a mixture, or a first mixing step of mixing only an excipient and a disintegrant to obtain a mixture.

32. The method according to claim 31, comprising a first mixing step of mixing Compound A or a pharmaceutically acceptable salt thereof or a co-crystal with an excipient and / or a disintegrant to obtain a mixture before the granulation step.

33. The method according to any one of claims 27 to 32, comprising a second mixing step of further mixing a disintegrant and / or a lubricant with the granulated material obtained in the granulation step.

34. The method according to any one of claims 27 to 33, wherein: The ratio of the total weight of compound A or its pharmaceutically acceptable salt or co-crystal in the powder to the total weight of compound A or its pharmaceutically acceptable salt or co-crystal in the binding liquid used in the granulation step is 70:30 to 0:

100.

35. The method according to any one of claims 27 to 34, wherein: The ratio of the total weight of compound A or its pharmaceutically acceptable salt or co-crystal in the powder to the total weight of compound A or its pharmaceutically acceptable salt or co-crystal in the binding liquid used in the granulation step is 65:35 to 0:

100.

36. The method according to any one of claims 27 to 35, wherein The ratio of the total weight of compound A or its pharmaceutically acceptable salt or co-crystal in the powder to the total weight of compound A or its pharmaceutically acceptable salt or co-crystal in the binding liquid used in the granulation step is 50:50 to 30:

70.

37. The method of claim 36, wherein: In the granulation step, the content of Compound A or a pharmaceutically acceptable salt or co-crystal thereof contained in the obtained solid preparation pharmaceutical composition is 50% by weight or more, calculated as Compound A, based on the total weight of the pharmaceutical composition.

38. The method of claim 37, wherein: In the granulation step, the content of Compound A or its pharmaceutically acceptable salt or co-crystal contained in the obtained pharmaceutical composition is 50% by weight, calculated as Compound A, based on the total weight of the pharmaceutical composition. The ratio of the total weight of Compound A or its pharmaceutically acceptable salt or co-crystal in the powder to the total weight of Compound A or its pharmaceutically acceptable salt or co-crystal in the binding liquid is 50:

50.

39. The method of claim 37, wherein: In the granulation step, the content of Compound A or its pharmaceutically acceptable salt or co-crystal contained in the obtained pharmaceutical composition is 50% by weight, calculated as Compound A, based on the total weight of the pharmaceutical composition. The ratio of the total weight of Compound A or its pharmaceutically acceptable salt or co-crystal in the powder to the total weight of Compound A or its pharmaceutically acceptable salt or co-crystal in the binding liquid is 30:

70.

40. The method according to any one of claims 27 to 39, further comprising a drying step of drying the granulated material.

41. The method according to any one of claims 27 to 40, further comprising a tableting step of tableting the granulated product obtained in the second mixing step.

42. The method according to claim 41, further comprising a coating step of coating the tablets obtained in the tableting step.

43. A pharmaceutical composition, characterized in that A pharmaceutical composition containing 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid (Compound A) or a pharmaceutically acceptable salt or cocrystal thereof as an active ingredient, wherein the pharmaceutical composition is produced by the following method, which includes a granulation step of spraying a binding liquid containing Compound A or a pharmaceutically acceptable salt or cocrystal thereof and a binder onto a powder containing Compound A or a pharmaceutically acceptable salt or cocrystal thereof in a fluidized bed granulator to obtain a granulated material.

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