Pharmaceutical composition

Abstract

Provided is a pharmaceutical composition of 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl) ethyl] propane-1, 3-diol or a salt thereof, which has excellent storage stability and is capable of suppressing the production of related substances. An excipient selected from the group consisting of calcium hydrogen phosphate, calcium dihydrogen phosphate, sodium hydrogen phosphate and sodium dihydrogen phosphate is used.

Description

[0001] This application is a divisional application of the patent application with the national application number 202180019567.1 given by the Patent Office of the State Intellectual Property Office, the international application number PCT / JP2021 / 013580, the international application date of March 30, 2021, and the invention name of "Pharmaceutical Composition". Technical Field

[0002] The present invention relates to a pharmaceutical composition of 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a salt thereof. Background Art

[0003] Patent Document 1 discloses 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride, which is useful as a medicine having excellent immunosuppressive action, rejection reaction suppressing action, and the like.

[0004] Prior art literature

[0005] Patent Literature

[0006] Patent document 1: WO2007 / 069712 Summary of the invention

[0007] Technical problem to be solved by the invention

[0008] An object of the present invention is to provide a pharmaceutical composition of 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof which has excellent storage stability and can suppress the production of related substances.

[0009] Means for solving technical problems

[0010] The present inventors have conducted intensive studies to solve the above-mentioned technical problems and have found that the use of (b) excipients such as calcium hydrogen phosphate, calcium dihydrogen phosphate, sodium hydrogen phosphate, and sodium dihydrogen phosphate as components of a pharmaceutical composition of 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a salt thereof can inhibit the production of related substances, thereby completing the present invention.

[0011] 2-Amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof is disclosed in, for example, U.S. Patent No. 8,809,314, the entire contents of which are incorporated herein by reference.

[0012] That is, the present invention is as follows.

[0013] [1] The present invention relates to a pharmaceutical composition comprising (a) 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof, and (b) one or more excipients selected from the group consisting of calcium hydrogen phosphate, calcium dihydrogen phosphate, sodium hydrogen phosphate, and sodium dihydrogen phosphate.

[0014] [2] The pharmaceutical composition according to [1] above, further comprising (c) a sugar alcohol.

[0015] [3] The pharmaceutical composition according to [2] above, wherein the sugar alcohol as component (c) is mannitol or sorbitol.

[0016] [4] The pharmaceutical composition according to [3] above, wherein the sugar alcohol as component (c) is mannitol.

[0017] [5] The pharmaceutical composition according to any one of [2] to [4] above, wherein the weight ratio of component (b) the excipient to component (c) the sugar alcohol (component (b):component (c)) is 10:90 to 75:25.

[0018] [6] The pharmaceutical composition according to any one of [1] to [5] above, wherein the excipient (b) is anhydrous calcium hydrogen phosphate.

[0019] [7] The pharmaceutical composition according to any one of [1] to [6] above, further comprising talc.

[0020] [8] The pharmaceutical composition according to any one of [1] to [7] above, which is filled in a gelatin capsule.

[0021] [9] The pharmaceutical composition according to any one of [1] to [8] above, wherein the component (a) 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof is 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride.

[0022]

[10] A pharmaceutical composition according to any one of 1 to 9 above, wherein the weight ratio of component (a) 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof to the total amount of component (b) excipient and component (c) sugar alcohol (component (a): total amount of components (b) and (c)) is 1:999 to 20:980.

[0023]

[11] A pharmaceutical composition according to any one of 1 to 10 above, wherein the content of component (a) 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof is 0.1 to 0.4 mg based on the amount of 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol relative to 60 mg of the pharmaceutical composition excluding the weight of the capsule when filled in a capsule.

[0024]

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

[11] above, wherein the pharmaceutical composition is a solid pharmaceutical composition.

[0025]

[13] The present invention relates to a pharmaceutical composition comprising (a) 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof, and

[0026] (b') a pharmaceutical composition of an excipient,

[0027] The excipient of the component (b') is mixed in a weight ratio of component (a) to component (b') (component (a): component (b')) of 1:999, and when the mixture is stored in an open state at 40°C and 75% RH for 4 weeks, in the peak area obtained by detecting the stored mixture by HPLC (high performance liquid chromatography), the total peak area of ​​related substances of component (a) (i.e., the total value of the peak areas of related substances) is less than 0.3% of the sum of the peak area of ​​component (a) and the total peak area of ​​related substances of component (a).

[0028]

[14] The pharmaceutical composition according to

[13] above, wherein the total peak area of ​​the related substances of component (a) is less than 0.2% relative to the sum of the peak area of ​​component (a) and the total peak area of ​​the related substances of component (a).

[0029] Effects of the Invention

[0030] The pharmaceutical composition of the present invention exhibits excellent storage stability because 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof inhibits the production of related substances. Therefore, a pharmaceutical composition having sufficient storage stability as a medicine can be provided. DETAILED DESCRIPTION

[0031] The present invention provides a pharmaceutical composition comprising (a) 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof (hereinafter, also referred to as "main agent"), and (b) one or more excipients selected from calcium hydrogen phosphate, calcium dihydrogen phosphate, sodium hydrogen phosphate, and sodium dihydrogen phosphate. The present invention further provides a pharmaceutical composition containing (c) a sugar alcohol.

[0032] The pharmaceutically acceptable salt of the main agent of component (a) is usually a pharmaceutically acceptable acid addition salt. There are no particular restrictions on the acid addition salt, and examples thereof include inorganic acid salts, organic acid salts, alkali metal salts, and alkaline earth metal salts. Among them, hydrochloride is preferred.

[0033] The main agent of the component (a) is preferably 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride.

[0034] The amount of the main agent of component (a) is preferably 0.05 to 1.0 parts by weight, more preferably 0.1 to 0.4 parts by weight, based on the amount of 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol, relative to 60 parts by weight of the pharmaceutical composition (when filled in a capsule, 60 parts by weight of the pharmaceutical composition minus the weight of the capsule). When component (a) is less than 0.1 parts by weight relative to 60 parts by weight of the pharmaceutical composition, more related substances may be generated.

[0035] The amount of the main agent of component (a) is not particularly limited, and may be an effective dose as a medicine. It is preferably 0.05 to 1.0 mg, more preferably 0.1 to 0.4 mg, based on the amount of 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol.

[0036] The amount of the main agent of component (a) is not particularly limited, and may be an effective dose as a medicine. When filled in a capsule, the amount of 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol is preferably 0.05 to 1.0 mg, more preferably 0.1 to 0.4 mg, relative to 60 mg of the pharmaceutical composition excluding the weight of the capsule. When the amount of component (a) is small, especially less than 0.1 mg, more related substances may be generated.

[0037] Examples of the excipient of the component (b) used in the present invention include one or more excipients selected from the group consisting of calcium hydrogen phosphate, calcium dihydrogen phosphate, sodium hydrogen phosphate, and sodium dihydrogen phosphate.

[0038] In this specification, unless otherwise specified, "calcium hydrogen phosphate", "monocalcium phosphate", "sodium hydrogen phosphate", and "sodium dihydrogen phosphate" are concepts including their hydrates and their anhydrates.

[0039] As the excipient of component (b) used in the present invention, the chemical formula of the preferred excipient is shown below. The excipient of component (b) used in the present invention also has aliases, and those with different names but the same chemical formula are also included in the present invention.

[0040] Calcium hydrogen phosphate hydrate: CaHPO4·n 1 H2O(n 1 =0.5, 1, 1.5, 2)

[0041] Anhydrous calcium hydrogen phosphate: CaHPO4

[0042] Calcium hydrogen phosphate: CaHPO4·0~2H2O

[0043] Calcium dihydrogen phosphate hydrate: Ca(H2PO4)2·H2O

[0044] Anhydrous monocalcium phosphate: Ca(H2PO4)2

[0045] Calcium dihydrogen phosphate: Ca(H2PO4)2·0~1H2O

[0046] Sodium hydrogen phosphate hydrate: Na2HPO4·n 2 H2O(n 2 =1,2,5,7,8,10,12)

[0047] Anhydrous sodium hydrogen phosphate: Na2HPO4

[0048] Sodium hydrogen phosphate: Na2HPO4·0~12H2O

[0049] Sodium dihydrogen phosphate hydrate: NaH2PO4·n 3 H2O(n 3 =1,2)

[0050] Anhydrous sodium dihydrogen phosphate: NaH2PO4

[0051] Sodium dihydrogen phosphate: NaH2PO4·0~2H2O

[0052] That is, as preferred excipients, there can be listed calcium hydrogen phosphate, calcium dihydrogen phosphate, sodium hydrogen phosphate, and sodium dihydrogen phosphate. As the excipient used in the present invention, calcium hydrogen phosphate and calcium dihydrogen phosphate are more preferred, calcium hydrogen phosphate is particularly preferred, and anhydrous calcium hydrogen phosphate is most preferred.

[0053] The amount of the excipient of component (b) is preferably 10 to 30 parts by weight relative to 60 parts by weight of the pharmaceutical composition (60 parts by weight of the pharmaceutical composition minus the weight of the capsule when filled in a capsule). When the amount of component (b) is greater than 30 parts by weight relative to 60 parts by weight of the pharmaceutical composition, the dissolution rate tends to decrease, while when it is less than 10 parts by weight, the generation of related substances tends to increase.

[0054] The amount of the excipient of component (b) is not particularly limited, but when filled in a capsule, it is preferably 10 to 30 mg relative to 60 mg of the pharmaceutical composition minus the weight of the capsule. When it is greater than 30 mg, there is a tendency for the dissolution rate to decrease, and when it is less than 10 mg, there is a tendency for the generation of related substances to increase.

[0055] The excipient for component (b') used in the present invention is an excipient in which component (a) and component (b') are mixed in a weight ratio (component (a): component (b')) of 1:999, and the mixture is stored in an open state at 40°C and 75% RH for 4 weeks. In the peak area detected by HPLC for the mixture after storage, the total peak area of ​​related substances of component (a) (i.e., the total value of the peak areas of related substances) is less than 0.3% relative to the total value of the peak area of ​​component (a) and the total peak area of ​​related substances of component (a). Preferably, the excipient is 0.28% or less, more preferably, 0.25% or less, further preferably, 0.23% or less, and particularly preferably, 0.2% or less.

[0056] The peak area obtained by the above HPLC can be measured according to the conditions described in the following "Method for measuring the amount of total related substances (A)".

[0057] The ratio (%) of the total peak area of ​​the above-mentioned related substances of component (a) to the sum of the peak area of ​​component (a) and the total peak area of ​​the related substances of component (a) can be calculated according to the following "Calculation method (B) of total related substance mass [%]".

[0058] Determination method of total related substances (A)

[0059] 10 mL of diluent was added to a test tube containing a sample containing 1 mg of component (a) (a mixture obtained by mixing component (a) and component (b') at a weight ratio (component (a): component (b')) of 1:999 and then stored) to fully dissolve and disperse the sample, and then centrifuge. The supernatant was taken as a sample solution and analyzed by HPLC under the following measurement conditions.

[0060] HPLC assay conditions

[0061] Detection wavelength: 225nm

[0062] Chromatographic column: Ascentis (registered trademark) Express C18, 4.6 mm × 15 cm, 2.7 μm particle size, SUPELCO Co.

[0063] Column temperature: 40°C

[0064] Injection volume: 50μL

[0065] Mobile phase A: pH 2.8 sodium perchlorate buffer

[0066] Mobile phase B: acetonitrile

[0067] Flow rate: 1.0mL / min

[0068] Gradient Program:

[0069] [Table 1]

[0070] Time (minutes) ％A ％B 0～30 65→35 35→65 30～35 35→10 65→90 35～35.1 10→65 90→35 35.1～45 65 35

[0071] Calculation method of total related substance mass [%] (B)

[0072] The HPLC chart (SC) of the sample (mixture of component (a) and component (b′)), the HPLC chart containing only the additive (component (b′)), and the HPLC chart (CC) of the standard solution (component (a)) were compared and analyzed, and the total amount of related substances [%] was calculated in the following order.

[0073] Procedure 1. The difference in peak area between the peak of a related substance different from the peak of component (a) and the peak of a related substance considered to be the same from the retention time and peak shape is calculated according to the following formula.

[0074] A SC -A CC =D

[0075] A: Peak area

[0076] D: Difference in peak area

[0077] Procedure 2. Calculate the total related substance amount [%] (i.e., the ratio (%) of the total peak area of ​​the related substances of component (a) to the sum of the peak area of ​​component (a) and the total peak area of ​​the related substances of component (a)) by the following formula.

[0078] [Formula 1]

[0079]

[0080] The excipient of component (b') used in the present invention may be any pharmaceutically acceptable excipient, and examples thereof include calcium hydrogen phosphate, calcium dihydrogen phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, calcium carbonate, calcium silicate, corn starch, etc., and preferably, the excipients of (b) mentioned above are used.

[0081] Examples of the sugar alcohol of component (c) include mannitol and sorbitol, and mannitol is preferred. Mannitol may be either L-type or D-type, and the D-type, which is abundant in nature, is usually used.

[0082] The amount of the sugar alcohol of component (c) relative to 60 parts by weight of the pharmaceutical composition tends to increase the generation of related substances when it is greater than 45 parts by weight, and tends to reduce the dissolution rate of the main agent when it is less than 25 parts by weight. Therefore, relative to 60 parts by weight of the pharmaceutical composition (when filled in a capsule, it is 60 parts by weight of the pharmaceutical composition excluding the weight of the capsule), it is, for example, 0 to 45 parts by weight, and preferably 25 to 45 parts by weight.

[0083] The amount of the sugar alcohol of component (c) is not particularly limited. When it is greater than 45 mg, there is a tendency to increase the formation of related substances, and when it is less than 25 mg, there is a tendency to reduce the dissolution rate of the main agent. When filled in a capsule, it is, for example, 0 to 45 mg, preferably 25 to 45 mg, relative to 60 mg of the pharmaceutical composition excluding the weight of the capsule.

[0084] The weight ratio of the main agent of component (a), the excipient of component (b) or component (b') and the total amount of sugar alcohol of component (c) (component (a): the total amount of component (b) or (b') and component (c)) is not particularly limited, but is preferably 1:999 to 20:980, and more preferably 1.5:998.5 to 8:992.

[0085] Regarding the weight ratio of the excipient of component (b) or component (b') to the sugar alcohol of component (c), from the viewpoint of maintaining stability, the excipient of component (b) or component (b') may be contained in an amount of 10% or more. From the viewpoint of maintaining solubility, the preferred weight ratio (component (b) or (b'): component (c)) is 10:90 to 75:25, and more preferably 25:75 to 50:50.

[0086] The pharmaceutical composition of the present invention is preferably a solid pharmaceutical composition.

[0087] The pharmaceutical composition of the present invention preferably further contains a lubricant.

[0088] The lubricant is not particularly limited, and examples thereof include talc, magnesium stearate, calcium stearate, magnesium silicate, sucrose fatty acid esters (e.g., sucrose behenate, sucrose stearate), polyethylene glycol, stearic acid, light anhydrous silicic acid, hydrogenated oil (e.g., hydrogenated rapeseed oil, hydrogenated castor oil), glycerol fatty acid ester, sodium stearyl fumarate, etc. Among them, talc, sucrose behenate, sucrose stearate, hydrogenated oil (hydrogenated castor oil type), sodium stearyl fumarate are preferred, talc and sodium stearyl fumarate are more preferred, and talc is particularly preferred.

[0089] The pharmaceutical composition of the present invention may further contain additives such as disintegrants, binders, solubilizers, fluidizers, sweeteners, foaming agents, surfactants, preservatives, pH adjusters, colorants, flavoring agents, and excipients other than component (b) and component (c).

[0090] The amount of the additive is not particularly limited and can be appropriately set.

[0091] The dosage form of the pharmaceutical composition of the present invention is not particularly limited, and for example, tablets, capsules, pills, lozenges, granules, and powders can be listed, preferably capsules. As capsules used in capsules, gelatin capsules, hydroxypropyl methylcellulose (HPMC) capsules, pullulan capsules, etc. can be listed. Among them, the pharmaceutical composition of the present invention is preferably filled in a gelatin capsule from the viewpoint of stability.

[0092] The pharmaceutical composition of the present invention can be produced by a known method generally used in the technical field of medical preparations.

[0093] For example, the capsule preparation of the present invention can be produced by filling a capsule filling composition into a capsule, wherein the capsule filling composition is prepared by mixing a main agent as component (a), an excipient as component (b) or component (b'), a sugar alcohol as component (c), and a lubricant.

[0094] As the capsule filling composition, for example, a powdery or granular capsule filling composition can be used.

[0095] For example, the capsule preparation included in the present invention can be produced by a production method comprising the following steps 1) to 6).

[0096] 1) If necessary, the excipient of the component (b) or the component (b') is mixed with the sugar alcohol of the component (c) in a mixer to obtain a first mixture (excipient mixture).

[0097] 2) The obtained first mixture is mixed with the main agent of component (a) in a mixer to obtain a second mixture.

[0098] 3) If necessary, the obtained second mixture is mixed with a lubricant in a mixer to obtain a third mixture.

[0099] 4) The obtained third mixture is sieved in a granulator to obtain a fourth mixture.

[0100] 5) The fourth mixture obtained is mixed in a mixer to obtain a fifth mixture (mixed powder for capsule filling).

[0101] 6) The obtained fifth mixture is passed through a capsule filling machine and filled into capsules.

[0102] In the method for producing the capsule preparation, the first mixture obtained in step 1) may not contain the sugar alcohol of component (c) but may be composed of the excipient of component (b) or component (b').

[0103] In the method for producing the capsule preparation, in order to obtain a mixture in which the main agent of component (a) is uniformly dispersed as the second mixture obtained in step 2), the second mixture can be repeatedly sieved using a granulator as needed after mixing in a mixer in step 2 and before step 3), and then mixed again in a mixer.

[0104] The method for producing the capsule preparation includes a case where the third mixture obtained in step 3) does not contain a lubricant and is composed of the second mixture.

[0105] As a method for producing the above-mentioned capsule preparation, in order to obtain a fifth mixture suitable for filling into capsules, after the fourth mixture is sieved in a granulator in step 4) and before step 5), it can be mixed again in a mixer as needed, and the sieving operation can be repeatedly performed in a granulator.

[0106] In the above-mentioned method for producing a capsule preparation, the capsule is not particularly limited, and may be, for example, a hard capsule. Examples of hard capsules include gelatin capsules, HPMC capsules, and pullulan capsules, and gelatin capsules are preferred.

[0107] The pharmaceutical composition of the present invention can be used for: the treatment or prevention of autoimmune diseases (for example, rheumatoid arthritis, inflammatory bowel disease (ulcerative colitis, Crohn's disease, etc.), multiple sclerosis, encephalomyelitis, systemic lupus erythematosus, lupus nephritis, nephrotic syndrome, psoriasis, type I diabetes, etc.); the prevention or inhibition of resistance or acute rejection or chronic rejection caused by transplantation of organs or tissues of mammals such as humans, dogs, cats, cattle, horses, pigs, monkeys, mice, etc. (for example, transplantation and xenotransplantation of heart, kidney, liver, lung, bone marrow, cornea, pancreas, small intestine, limbs, muscle, nerve, fat marrow, duodenum, skin, pancreatic islet cells, etc.); graft-versus-host (GvH) disease caused by bone marrow transplantation; the treatment or prevention of allergic diseases (for example, allergic dermatitis, allergic rhinitis, asthma, etc.).

[0108] Example

[0109] The present invention is further described in detail with reference to the following examples, but the present invention is not limited thereto and can be varied without departing from the scope of the present invention.

[0110] (I. Method for determining the amount of total related substances (1))

[0111] 10 mL of diluent was added to a test tube containing a sample containing 1 mg of 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride, and the sample was fully dissolved and dispersed, followed by centrifugation. The supernatant was used as a sample solution and analyzed by HPLC under the following measurement conditions, and the total amount of related substances was calculated based on the following calculation method.

[0112] HPLC assay conditions

[0113] Detection wavelength: 225nm

[0114] Chromatographic column: Ascentis (registered trademark) Express C18, 4.6 mm × 15 cm, 2.7 μm particle size, SUPELCO Co.

[0115] Column temperature: 40°C

[0116] Injection volume: 50μL

[0117] Mobile phase A: pH 2.8 sodium perchlorate buffer

[0118] Mobile phase B: acetonitrile

[0119] Flow rate: 1.0mL / min

[0120] Gradient Program:

[0121] [Table 2]

[0122] Time (minutes) ％A ％B 0～30 65→35 35→65 30～35 35→10 65→90 35～35.1 10→65 90→35 35.1～45 65 35

[0123] Calculation method of total related substance mass [%]

[0124] The HPLC chart of the sample (SC), the HPLC chart containing only the additive, and the HPLC chart of the standard solution (CC) were compared and analyzed, and the total amount of related substances [%] was calculated by the following procedure.

[0125] Procedure 1. Calculate the difference in peak area based on the following formula between the peak of a related substance that is different from the peak of the main agent (2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride) and the peak of a related substance that is considered to be the same as the main agent in terms of retention time and peak shape.

[0126] A SC -A CC =D

[0127] A: Peak area

[0128] D: Difference in peak area

[0129] Step 2. Calculate the total amount of related substances [%] from the following formula.

[0130] [Formula 2]

[0131]

[0132] (II. Method for determining the amount of related substances (2))

[0133] A sample containing 1.1 mg of 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride was placed in a 10 mL volumetric flask, fixed with a diluent and fully dissolved and dispersed, and then filtered using a 0.45 μm membrane filter (PALL, Nylon Acrodisc (registered trademark) 25 mm syringe filter). The solution after discarding the first 2 mL was used as a sample solution and analyzed by HPLC under the same measurement conditions as in the aforementioned "Measurement method for the amount of total related substances (1)", and the amount of related substances was calculated based on the following calculation method.

[0134] Calculation method of relevant substance amount [%]

[0135] The amount [%] of each related substance was calculated from the following formula using the peak area (Ri) of each related substance in the sample solution and the peak area (Rm) of the main agent (2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride) of the sample solution.

[0136] [Formula 3]

[0137]

[0138] The total amount of related substances [%] was calculated by summing the related substances that were 0.05% or more.

[0139] (III. Study on Excipients)

[0140] Reference Example 1

[0141] 1 g of 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride and 19 g of anhydrous calcium hydrogen phosphate (Tomita Pharmaceutical Co., Ltd.) as an excipient were mixed in a mechanical grinder (OKADA SEIKO CO., LTD.) at a rotation speed of 800 rpm for 3 minutes, and the mixed powder was sieved with a sieve (mesh size: 500 μm). 1 g of the sieved material was taken and mixed with 49 g of anhydrous calcium hydrogen phosphate as an excipient in a mechanical grinder for 3 minutes, and then sieved again. 1 g of the sieved mixed powder was added to each test tube and stored in an open state at 40°C and 75% RH for 4 weeks. After 4 weeks, the total amount of related substances was measured according to the above-mentioned "Determination method of the amount of total related substances (1)".

[0142] Reference Examples 2 and 3 Comparison with Reference Examples 1 and 2

[0143] A mixed powder sieve was prepared in the same manner as in Reference Example 1 using D-mannitol (Merck KGaA), D-sorbitol (Merck KGaA), lactose (DMV Fonterra Excipients), or crystalline cellulose (Asahi Kasei Chemicals) instead of anhydrous calcium hydrogen phosphate as an excipient, and the total amount of related substances was measured.

[0144] The above results are summarized in Table 3 below.

[0145] [Table 3]

[0146] excipient Total related substances mass (%) Reference Example 1 Anhydrous calcium hydrogen phosphate 0.2 Reference Example 2 D-Mannitol 0.3 Reference Example 3 D-Sorbitol 1.7 Comparative Reference Example 1 lactose 6.5 Comparative Reference Example 2 Crystalline cellulose 2.0

[0147] Reference Example 4

[0148] 0.138 g of 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride and 53.862 g of calcium hydrogen phosphate hydrate (Tomita Pharmaceutical Co., Ltd.) as an excipient were mixed at 800 rpm for 3 minutes using a mechanical grinder (OKADA SEIKO CO., LTD.), 6 g of talc sieved in advance (22 mesh) was added thereto, and further mixed at 400 rpm for 1 minute using a mechanical grinder. 2 g of each of the mixed powders was taken and stored in an open state at 40°C and 75% RH for 1 month. After 1 month, the total amount of related substances was measured based on the above-mentioned "Determination method of the amount of related substances (2)".

[0149] Reference Example 5

[0150] Using anhydrous calcium hydrogen phosphate (Merck KGaA) as an excipient instead of calcium hydrogen phosphate hydrate, a mixed powder was prepared in the same manner as in Reference Example 4, and the total amount of related substances was measured.

[0151] The above results are summarized in Table 4 below.

[0152] [Table 4]

[0153] excipient Total related substances mass (%) Reference Example 4 Calcium Hydrogen Phosphate Hydrate 0.11 Reference Example 5 Anhydrous calcium hydrogen phosphate 0.13

[0154] (IV. Lubricant Research)

[0155] Reference Examples 6 to 10

[0156] 0.5 g of 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride and 49.5 g of a lubricant listed in Table 5 below were mixed in a mechanical grinder (Okada Seiko Co., Ltd.) at 800 rpm for 3 minutes, and the mixed powder was sieved with a sieve (mesh size: 500 μm). 100 mg of each sieved product was put into a test tube and stored in an open state at 40°C and 75% RH, and in a sealed state at 60°C for 4 weeks. After 4 weeks, the total amount of related substances was measured based on the above-mentioned "Measurement method (1) for the amount of total related substances".

[0157] The above results are summarized in Table 5 below.

[0158] [Table 5]

[0159]

[0160] (V. Study on the Storage Stability of Capsule Preparations Combining Excipients and Lubricants)

[0161] Comparative Reference Example 3

[0162] 0.345 g of 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride and 134.655 g of D-mannitol (Merck KGaA) as an excipient were mixed in a mechanical grinder (Okada Seiko Co., Ltd.) at a speed of 800 rpm for 3 minutes, and the mixed powder was sieved using a Frewitt pulverizer granulator (Flurry Industry, TC-LABO) at a mesh size of 700 μm and a speed of 2500 rpm. The sieved material was divided into two portions, each of which was 54 g. 6 g of talc (Merck KGaA) as a lubricant was added to each portion and mixed in a mechanical grinder (Okada Seiko Co., Ltd.) at a speed of 800 rpm for 3 minutes. 60 mg of the mixed powder was taken and placed in a gelatin capsule. The obtained capsule was placed in a high-density polyethylene bottle and stored in a sealed state at 40°C and 75% RH for 1 month. Separately, the obtained capsules were placed in a glass bottle and stored in a sealed state at 60° C. for 1 month. The total amount of related substances at the start of storage and after storage was measured according to the above-mentioned "Measurement method of related substance amount (2)".

[0163] Comparative Reference Example 4

[0164] Sodium stearyl fumarate (JRS PHARMA) was used as a lubricant instead of talc, and a mixed powder was prepared in the same manner as in Comparative Reference Example 3, and the total amount of related substances was measured.

[0165] Reference Example 11

[0166] A mixed powder was prepared in the same manner as in Comparative Reference Example 3 using anhydrous calcium hydrogen phosphate (Tomita Pharmaceutical Co., Ltd.) as an excipient instead of D-mannitol, and the total amount of related substances was measured.

[0167] Reference Example 12

[0168] A mixed powder was prepared in the same manner as in Comparative Reference Example 4 using anhydrous calcium hydrogen phosphate (Tomita Pharmaceutical Co., Ltd.) as an excipient instead of D-mannitol, and the total amount of related substances was measured.

[0169] The above results are summarized in Table 6 below.

[0170] [Table 6]

[0171] Capsules containing D-mannitol

[0172]

[0173] Capsules containing anhydrous calcium hydrogen phosphate

[0174]

[0175] For the capsules containing D-mannitol (Comparative Reference Examples 3 and 4) and the capsules containing anhydrous calcium hydrogen phosphate (Reference Examples 11 and 12), when the same lubricant was compared, the total amount of related substances in the capsule group containing anhydrous calcium hydrogen phosphate was significantly less. In the case of capsule preparations, the storage stability of the group containing anhydrous calcium hydrogen phosphate was significantly better than that of D-mannitol, which shows that it can inhibit the generation of related substances.

[0176] For the capsules containing D-mannitol (Comparison Reference Examples 3 and 4) and the capsules containing anhydrous calcium hydrogen phosphate (Reference Examples 11 and 12), when different lubricants were compared, the total amount of related substances in the capsule preparation containing talc (Comparison Reference Example 3 and Reference Example 11) was significantly reduced compared with the capsule preparation containing sodium stearyl fumarate (Comparison Reference Example 4 and Reference Example 12). It can be seen that in the case of capsule preparations, the group with talc as a lubricant has significantly excellent storage stability and can inhibit the formation of related substances.

[0177] (VI. Study on capsules)

[0178] Reference Example 13

[0179] 0.345 g of 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride and 134.655 g of D-mannitol (Merck KGaA) were mixed in a mechanical grinder (Okada Seiko Co., Ltd.) at a rotation speed of 800 rpm for 3 minutes, and the mixed powder was sieved with a Frewitt pulverizer granulator (Flurry Industry, TC-LABO) at a mesh size of 700 μm and a rotation speed of 2500 rpm. The sieved material was divided into two portions of 54 g each, and each was mixed with 6 g of talc (Merck KGaA) in a mechanical grinder (Okada Seiko Co., Ltd.) at a rotation speed of 800 rpm for 3 minutes. 60 mg of the mixed powder was taken and loaded into a gelatin capsule (Quori Kapus) and a hydroxypropyl methylcellulose (HPMC) capsule (Quori Kapus). The obtained capsules were placed in a high-density polyethylene bottle and stored in a sealed state at 40°C and 75% RH for 1 month. In addition, the obtained capsules were placed in a glass bottle and stored in a sealed state at 60°C for 1 month. The total amount of related substances at the beginning of storage and after storage, and the amount of individual related substances with a relative retention time (RRT) of 1.19 when the retention time of the main agent was set to 1, were measured using the above-mentioned "Determination method of the amount of related substances (2)".

[0180] The above results are summarized in Tables 7 and 8 below.

[0181] [Table 7]

[0182]

[0183] [Table 8]

[0184]

[0185] (VII. Method for determining the amount of related substances (3))

[0186] The contents were taken out from the capsule, and a diluent (50% aqueous acetonitrile) was added to the 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride in a concentration of 0.11 mg / mL. After being fully dissolved and dispersed, the mixture was filtered with a 0.45 μm membrane filter (PALL, Ekicrodisc 25CR (registered trademark) 25 mm syringe filter), and the first 3 mL of the solution was discarded as a sample solution. The sample solution was diluted to 1 / 100 with the diluent as a standard solution. The analysis was performed by HPLC under the following measurement conditions, and the amount of the related substance was calculated based on the following calculation method.

[0187] HPLC assay conditions

[0188] Detection wavelength: 225nm

[0189] Chromatographic column: X-Bridge (registered trademark) C18, 4.6 mm × 75 mm, 2.5 μm particle size, Waters

[0190] Column temperature: 40°C

[0191] Injection volume: 50μL

[0192] Mobile phase A: pH 2.8 sodium perchlorate buffer / acetonitrile mixture (9:1)

[0193] Mobile phase B: acetonitrile / pH 2.8 sodium perchlorate buffer mixture (9:1)

[0194] Flow rate: 1.5mL / min

[0195] Gradient Program:

[0196] [Table 9]

[0197] Time (minutes) ％A ％B 0～1 60 40 1～8 60→45 40→55 8～12 45→0 55→100 12～20 0 100

[0198] Calculation method of relevant substance amount [%]

[0199] The peak area (Ri) of each related substance in the sample solution and the peak area (Rst) of the main agent (2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride) of the standard solution were used to calculate the amount [%] of each related substance from the following formula.

[0200] [Formula 4]

[0201] Amount of related substances [%] = Ri / Rst

[0202] The total amount of related substances [%] was calculated by summing the related substances with a content of 0.1% or more.

[0203] (VIII. Stability test of the solid pharmaceutical composition (gelatin capsule preparation) of the present invention)

[0204] Examples 1 to 3

[0205] The preparation of the present invention was produced by the following method according to the formulation shown in Table 10 below.

[0206] D-mannitol (Merck KGaA) and anhydrous calcium hydrogen phosphate (Merck KGaA) are mixed to obtain an excipient mixture. Relative to the weight of 1 of 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride, about 3 times the amount of the aforementioned excipient mixture is added to 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride and mixed. The mixture is added to the remaining excipient mixture obtained previously, and talc (Merck KGaA) is further added and mixed. The mixed powder is sieved in a granulator. Thereafter, it is mixed with a mixer, sieved with a granulator, and then mixed with a mixer. The obtained mixed powder is filled into gelatin capsules at 60 mg per portion in a capsule filling machine to obtain a capsule preparation of the solid pharmaceutical composition of the present invention. The obtained capsule preparation was divided into two parts, one was put into a high-density polyethylene bottle, and the other was packed with PTP (press through pack) and stored at 40° C. and 75% RH for 6 months.

[0207] The total amount of related substances at the start of storage and after 6 months of storage for each form of the capsule preparation is shown in the following Table 11. The total amount of related substances was measured according to the above-mentioned "Measurement method (3) for the amount of related substances".

[0208] [Table 10]

[0209] prescription

[0210]

[0211] *: Indicates the content of 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]1,3-propanediol hydrochloride

[0212] [Table 11]

[0213]

[0214] In any of Examples 1 to 3, the total amount of related substances after the 6-month storage test was less than 0.10% as at the beginning of storage. From the above results, it can be seen that the pharmaceutical composition of the present invention has excellent storage stability and can inhibit the production of related substances.

[0215] Industrial Applicability

[0216] The pharmaceutical composition of the present invention has excellent storage stability and can inhibit the production of related substances. Therefore, it is useful in the field of pharmaceutical production.

[0217] This application is based on Japanese Patent Application No. 2020-063606 filed in Japan, the entire contents of which are incorporated herein by reference.

Claims

1. A pharmaceutical composition, characterized in that It contains component (a) 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof, and component (b) one or more excipients selected from calcium hydrogen phosphate, calcium dihydrogen phosphate, sodium hydrogen phosphate, and sodium dihydrogen phosphate.

2. A pharmaceutical composition, characterized in that It contains component (a) 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof, and component (b) one or more excipients selected from calcium dihydrogen phosphate, sodium hydrogen phosphate, and sodium dihydrogen phosphate.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that It further contains a component (c) a sugar alcohol.

4. The pharmaceutical composition according to claim 3, characterized in that The sugar alcohol as ingredient (c) is mannitol or sorbitol.

5. The pharmaceutical composition according to claim 4, characterized in that The sugar alcohol as ingredient (c) is mannitol.

6. The pharmaceutical composition according to claim 4, characterized in that The sugar alcohol as component (c) is sorbitol.

7. The pharmaceutical composition according to claim 3, characterized in that The weight ratio of the component (b) excipient to the component (c) sugar alcohol (component (b):component (c)) is 10:90 to 75:

25.

8. The pharmaceutical composition according to claim 1, characterized in that The excipient of component (b) is anhydrous calcium hydrogen phosphate.

9. The pharmaceutical composition according to claim 1 or 2, characterized in that It further contains talc.

10. The pharmaceutical composition according to claim 1 or 2, characterized in that Filled in gelatin capsules.

11. The pharmaceutical composition according to claim 1 or 2, characterized in that Component (a) 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof is 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride.

12. The pharmaceutical composition according to claim 3, characterized in that The weight ratio of the total amount of component (a) 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof to component (b) excipient and component (c) sugar alcohol (component (a): total amount of components (b) and (c)) is 1:999 to 20:

980.

13. The pharmaceutical composition according to claim 1 or 2, characterized in that The content of component (a) 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof is 0.1 to 0.4 mg based on the amount of 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol relative to 60 mg of the pharmaceutical composition excluding the weight of the capsule when filled in the capsule.

14. The pharmaceutical composition according to claim 1 or 2, characterized in that The pharmaceutical composition is a solid pharmaceutical composition.

15. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises component (a): 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof, and component (b') an excipient. The excipient of the component (b') is mixed in a weight ratio of component (a) to component (b') (component (a): component (b')) of 1:999, and when the mixture is stored in an open state at 40°C and 75% RH for 4 weeks, in the peak area obtained by HPLC detection of the stored mixture, the total peak area of ​​related substances of component (a) is less than 0.3% of the sum of the peak area of ​​component (a) and the total peak area of ​​related substances of component (a).

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