Pharmaceutical composition

Abstract

To provide a pharmaceutical composition of 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a salt thereof, which exhibits excellent storage stability and can suppress generation of analogous substances.SOLUTION: The present invention employs 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof, and one or more excipients selected from calcium hydrogen phosphate, calcium dihydrogen phosphate, sodium hydrogen phosphate, and sodium dihydrogen phosphate.SELECTED DRAWING: None

Description

[Technical Field]

[0001] 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 technology]

[0002] 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 and anti-rejection effects. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] WO2007 / 069712 Summary of the Invention [Problem to be solved by the invention]

[0004] 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 formation of related substances. [Means for solving the problem]

[0005] As a result of intensive research conducted by the present inventors to solve the above-mentioned problems, they found that the production of related substances can be suppressed by using (b) an excipient such as calcium hydrogen phosphate, calcium dihydrogen phosphate, sodium hydrogen phosphate, or sodium dihydrogen phosphate as a component of a pharmaceutical composition of 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a salt thereof, and thus completed the present invention. 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof is disclosed, for example, in U.S. Pat. No. 8,809,314, the entire contents of which are incorporated herein by reference.

[0006] That is, the present invention is as follows. [1] 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 calcium hydrogen phosphate, calcium dihydrogen phosphate, sodium hydrogen phosphate, and sodium dihydrogen phosphate. [2] (c) The pharmaceutical composition according to [1] above, further comprising a sugar alcohol. [3] The pharmaceutical composition according to [2] above, wherein the sugar alcohol of component (c) is mannitol or sorbitol. [4] The pharmaceutical composition according to [3] above, wherein the sugar alcohol of component (c) is mannitol. [5] The pharmaceutical composition according to any one of the above [2] to [4], wherein the weight ratio of the excipient component (b) to the sugar alcohol component (c) (component (b):component (c)) is 10:90 to 75:25. [6] The pharmaceutical composition according to any one of the above [1] to [5], wherein the excipient of component (b) is anhydrous calcium hydrogen phosphate. [7] The pharmaceutical composition according to any one of the above [1] to [6], further comprising talc. [8] The pharmaceutical composition according to any one of the above [1] to [7], which is filled in a gelatin capsule. [9] The pharmaceutical composition according to any one of the above [1] to [8], 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.

[10] The pharmaceutical composition according to any one of the above [1] to [9], 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.

[11] The pharmaceutical composition according to any one of the above [1] to

[10] , wherein the content of 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof as component (a) is 0.1 to 0.4 mg as 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol per 60 mg of the pharmaceutical composition excluding the weight of the capsule when filled in a capsule.

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

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

[13] (a) 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof, and (b') an excipient, The pharmaceutical composition is an excipient for component (b'), wherein when components (a) and (b') are mixed so that the weight ratio (component (a):component (b')) is 1:999 and the mixture is stored in the open at 40°C and 75% RH for 4 weeks, the peak area of ​​the mixture after storage is detected by HPLC (high performance liquid chromatography), and the total peak area of ​​related substances of component (a) (i.e., the sum of the peak areas of the related substances) is less than 0.3% of the sum of the peak area of ​​component (a) and the total peak area of ​​the related substances of component (a).

[14] The pharmaceutical composition according to

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

[0007] The pharmaceutical composition of the present invention exhibits excellent storage stability by suppressing the formation of analogues of 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof, thereby providing a pharmaceutical composition with sufficient storage stability for use as a medicine. DETAILED DESCRIPTION OF THE INVENTION

[0008] The present invention provides a pharmaceutical composition containing (a) 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as the "principal 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 particularly provides a pharmaceutical composition further containing (c) a sugar alcohol.

[0009] The pharmaceutically acceptable salt of the active ingredient (a) is usually a pharmaceutically acceptable acid addition salt. The acid addition salt is not particularly limited, and examples thereof include inorganic acid salts, organic acid salts, alkali metal salts, and alkaline earth metal salts. Among these, hydrochloride is preferred.

[0010] The active ingredient of component (a) is preferably 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride.

[0011] The amount of the active ingredient, component (a), expressed as 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol is preferably 0.05 to 1.0 parts by weight, more preferably 0.1 to 0.4 parts by weight, per 60 parts by weight of the pharmaceutical composition (60 parts by weight of the pharmaceutical composition excluding the weight of the capsule if the composition is filled in a capsule). If component (a) is used in an amount less than 0.1 part by weight per 60 parts by weight of the pharmaceutical composition, more related substances may be produced.

[0012] The amount of the active ingredient of component (a) is not particularly limited as long as it contains a pharmaceutically effective amount, but it is preferably contained in an amount of 0.05 to 1.0 mg, more preferably 0.1 to 0.4 mg, as 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol. The amount of the active ingredient in component (a) is not particularly limited as long as it is a pharmaceutically effective amount, but when filled in a capsule, it is preferably contained in an amount of 0.05 to 1.0 mg, more preferably 0.1 to 0.4 mg, per 60 mg of the pharmaceutical composition excluding the weight of the capsule, as 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol. If the amount of component (a) is small, especially less than 0.1 mg, there is a possibility that more related substances will be produced.

[0013] The excipient of component (b) used in the present invention may be one or more excipients selected from calcium hydrogen phosphate, calcium dihydrogen phosphate, sodium hydrogen phosphate, and sodium dihydrogen phosphate. In this specification, the terms "calcium hydrogen phosphate," "calcium dihydrogen phosphate," "sodium hydrogen phosphate," and "sodium dihydrogen phosphate" encompass their hydrates and anhydrous forms, unless otherwise specified.

[0014] The chemical formulas of preferred excipients as component (b) used in the present invention are shown below. Some excipients as component (b) used in the present invention have other names, but even if the names are different, they are included in the present invention as long as they have the same chemical formula. Calcium hydrogen phosphate hydrate: CaHPO4·n 1 H2O(n 1 =0.5,1,1.5,2) Anhydrous calcium hydrogen phosphate: CaHPO4 Calcium hydrogen phosphate: CaHPO4·0~2H2O Calcium dihydrogen phosphate hydrate: Ca(H2PO4)2·H2O Anhydrous calcium dihydrogen phosphate: Ca(H2PO4)2 Calcium dihydrogen phosphate: Ca(H2PO4)2·0~1H2O Sodium hydrogen phosphate hydrate:Na2HPO4·n 2 H2O(n 2 =1,2,5,7,8,10,12) Anhydrous sodium hydrogen phosphate: Na2HPO4 Sodium hydrogen phosphate: Na2HPO4·0~12H2O Sodium dihydrogen phosphate hydrate:NaH2PO4·n 3 H20(n 3 =1,2) Anhydrous sodium dihydrogen phosphate: NaH2PO4 Sodium dihydrogen phosphate: NaH2PO4·0~2H2O That is, preferred excipients include calcium hydrogen phosphate, calcium dihydrogen phosphate, sodium hydrogen phosphate, and sodium dihydrogen phosphate. The excipient used in the present invention is more preferably calcium hydrogen phosphate or calcium dihydrogen phosphate, particularly preferably calcium hydrogen phosphate, and most preferably anhydrous calcium hydrogen phosphate.

[0015] The amount of excipient component (b) is preferably 10 to 30 parts by weight per 60 parts by weight of the pharmaceutical composition (60 parts by weight of the pharmaceutical composition excluding the weight of the capsule if the pharmaceutical composition is filled in a capsule). If the amount of component (b) is more than 30 parts by weight per 60 parts by weight of the pharmaceutical composition, the dissolution rate tends to decrease, and if it is less than 10 parts by weight, the production of related substances tends to increase.

[0016] The amount of excipient (component (b)) is not particularly limited, and when filled in a capsule, it is preferably 10 to 30 mg per 60 mg of the pharmaceutical composition excluding the weight of the capsule. If the amount is more than 30 mg, the dissolution rate tends to decrease, and if it is less than 10 mg, the production of related substances tends to increase.

[0017] The excipient for component (b') used in the present invention is an excipient such that, when components (a) and (b') are mixed at a weight ratio (component (a):component (b')) of 1:999 and the mixture is stored in the open at 40°C and 75% RH for 4 weeks, the peak area of ​​the mixture after storage is detected by HPLC, and the total peak area of ​​related substances of component (a) (i.e., the sum of the peak areas of the related substances) is less than 0.3%, preferably 0.28% or less, more preferably 0.25% or less, even more preferably 0.23% or less, and particularly preferably 0.2% or less, of the sum of the peak area of ​​component (a) and the total peak area of ​​the related substances of component (a). The above peak area by HPLC can be measured according to the conditions described in the "Method for measuring the total amount of related substances (A)" below. The percentage (%) 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) can be calculated according to the "Method (B) for calculating the total amount of related substances [%]" below.

[0018] Measurement method for total related substances (A) A test tube containing a sample containing 1 mg of component (a) (a mixture obtained by mixing components (a) and (b') at a weight ratio of 1:999 (component (a):component (b')), after storage, is filled with 10 mL of diluent, thoroughly dissolved and dispersed, and then centrifuged. The resulting supernatant is used as the sample solution and analyzed by HPLC under the following measurement conditions.

[0019] HPLC measurement conditions Detection wavelength: 225 nm Column: Ascentis® Express C18, 4.6 mm × 15 cm, 2.7 μm particle size, SUPELCO Co. Column temperature: 40℃ Injection volume: 50μL Mobile phase A: pH 2.8 sodium perchlorate buffer Mobile phase B: acetonitrile Flow rate: 1.0mL / min Gradient Program:

[0020] [Table 1]

[0021] Calculation method for total related substance amount [%] (B) The HPLC chart (SC) of the sample (mixture of component (a) and component (b')) is compared with the HPLC chart (CC) of the additive (component (b')) alone and the HPLC chart (CC) of the standard solution (component (a)), and the total amount of related substances [%] is calculated using the following procedure.

[0022] Step 1: Based on the peak of a related substance other than the peak of component (a) and a peak that is thought to be the same related substance based on the retention time and peak shape, calculate the difference in peak area using the following formula. A SC -A CC =D A: Peak area D: Peak area difference

[0023] Step 2: Calculate the total amount of related substances [%] (i.e., the percentage (%) of the total peak area of ​​related substances of component (a) to the sum of the peak area of ​​component (a) and the total peak area of ​​related substances of component (a)) using the following formula.

[0024]

number

[0025] 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) above.

[0026] Examples of the sugar alcohol of component (c) include mannitol and sorbitol, with mannitol being preferred. Mannitol may be either the L- or D-form, but the D-form is usually used as it is more abundant in nature.

[0027] If the amount of sugar alcohol of component (c) is more than 45 parts by weight relative to 60 parts by weight of the pharmaceutical composition, the production of related substances tends to increase, and if it is less than 25 parts by weight, the dissolution rate of the active ingredient tends to decrease. Therefore, the amount is, for example, 0 to 45 parts by weight, preferably 25 to 45 parts by weight, relative to 60 parts by weight of the pharmaceutical composition (60 parts by weight of the pharmaceutical composition excluding the weight of the capsule if the composition is filled in a capsule).

[0028] The amount of sugar alcohol in component (c) is not particularly limited, but if it is more than 45 mg, the production of related substances tends to increase, and if it is less than 25 mg, the dissolution rate of the active ingredient tends to decrease. Therefore, when it is filled in a capsule, the amount is, for example, 0 to 45 mg, preferably 25 to 45 mg, per 60 mg of the pharmaceutical composition excluding the weight of the capsule.

[0029] The weight ratio of the active ingredient of component (a) to the total amount of the excipient of component (b) or component (b') and the sugar alcohol of component (c) (component (a):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.

[0030] 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, however, the weight ratio (component (b) or (b'):component (c)) is preferably 10:90 to 75:25, more preferably 25:75 to 50:50.

[0031] The pharmaceutical composition of the present invention is preferably a solid pharmaceutical composition.

[0032] The pharmaceutical composition of the present invention preferably further contains a lubricant.

[0033] 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 oils (e.g., hydrogenated rapeseed oil, hydrogenated castor oil), glycerin fatty acid esters, sodium stearyl fumarate, etc. Among these, talc, sucrose behenate, sucrose stearate, hydrogenated oils (hydrogenated castor oil type), and sodium stearyl fumarate are preferred, talc and sodium stearyl fumarate are more preferred, and talc is particularly preferred.

[0034] The pharmaceutical composition of the present invention may further contain additives such as disintegrants, binders, solubilizing agents, fluidizing agents, sweeteners, foaming agents, surfactants, preservatives, pH adjusters, colorants, flavorings, and excipients other than components (b) and (c).

[0035] The amount of the additive is not particularly limited and can be set appropriately.

[0036] The dosage form of the pharmaceutical composition of the present invention is not particularly limited, and examples thereof include tablets, capsules, pills, lozenges, granules, and powders, with capsules being preferred. Examples of capsules used in capsules include gelatin capsules, hydroxypropylmethylcellulose (HPMC) capsules, and pullulan capsules. Among these, it is preferable that the pharmaceutical composition of the present invention be filled in a gelatin capsule from the viewpoint of stability.

[0037] The pharmaceutical composition of the present invention can be prepared by known methods commonly used in the technical field of pharmaceutical preparations.

[0038] For example, the capsule formulation of the present invention can be produced by mixing the active ingredient (component (a)), the excipient (component (b) or component (b')), the sugar alcohol (component (c)), and a lubricant to prepare a capsule filling composition, and filling the composition into capsules. As the composition for filling capsules, for example, a powdery or granular composition for filling capsules can be used.

[0039] For example, the capsule formulation included in the present invention can be produced by a production method including the following steps 1) to 6). 1) A first mixture (excipient mixture) is obtained by mixing the excipient component (b) or (b') with the sugar alcohol component (c) as needed in a mixer. 2) The obtained first mixture is mixed with the main ingredient of component (a) in a mixer to obtain a second mixture. 3) The obtained second mixture is mixed with a lubricant, if necessary, in a mixer to obtain a third mixture. 4) The obtained third mixture is sieved using a sieving machine to obtain a fourth mixture. 5) The resulting fourth mixture is mixed in a mixer to obtain a fifth mixture (mixed powder for capsule filling). 6) The resulting fifth mixture is filled into capsules using a capsule filling machine.

[0040] The method for producing the above capsule formulation also includes a case where the first mixture obtained in step 1) does not contain the sugar alcohol of component (c), and the excipient of component (b) or component (b') becomes the first mixture. In the manufacturing method of the above capsule formulation, in order to obtain a mixture in which the main drug of component (a) is uniformly dispersed as the second mixture obtained in step 2), after mixing the second mixture in a mixer in step 2) and before step 3), the process of sieving the mixture using a granulator and mixing it again using a mixer can be repeated as necessary. The method for producing the above capsule formulation also includes a case where the third mixture obtained in step 3) does not contain a lubricant and the second mixture becomes the third mixture. In the manufacturing method of the above capsule formulation, after the fourth mixture is sieved in a sieving machine in step 4) and before step 5), the process of mixing again in a mixer and sieving in a sieving machine can be repeated as necessary to obtain a fifth mixture that is optimal for filling into capsules. In the above-mentioned method for producing a capsule formulation, the capsule is not particularly limited, but may be, for example, a hard capsule. Examples of hard capsules include gelatin capsules, HPMC capsules, and pullulan capsules, with gelatin capsules being preferred.

[0041] The pharmaceutical composition of the present invention is useful for the treatment or prevention of autoimmune diseases (e.g., rheumatoid arthritis, inflammatory bowel diseases (e.g., ulcerative colitis, Crohn's disease, etc.), multiple sclerosis, encephalomyelitis, systemic lupus erythematosus, lupus nephritis, nephrotic syndrome, psoriasis, type I diabetes, etc.); prevention or suppression of resistance to, or acute or chronic rejection of, organ or tissue transplants (e.g., transplants of heart, kidney, liver, lung, bone marrow, cornea, pancreas, small intestine, limbs, muscle, nerve, fatty marrow, duodenum, skin, pancreatic islet cells, etc., and xenotransplants) in mammals such as humans, dogs, cats, cows, horses, pigs, monkeys, and mice; graft-versus-host (GvH) disease following bone marrow transplants; and the treatment or prevention of allergic diseases (e.g., atopic dermatitis, allergic rhinitis, asthma, etc.). [Example]

[0042] The present invention will be further illustrated by the following examples, which are not intended to limit the invention and may be modified without departing from the scope of the invention.

[0043] (I. Measurement method for total amount of related substances (1)) 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 after thorough dissolution and dispersion, the sample was centrifuged. The resulting supernatant was used as the sample solution and analyzed by HPLC under the following measurement conditions. The total amount of related substances was calculated using the following calculation method.

[0044] HPLC measurement conditions Detection wavelength: 225 nm Column: Ascentis® Express C18, 4.6 mm × 15 cm, 2.7 μm particle size, SUPELCO Co. Column temperature: 40℃ Injection volume: 50μL Mobile phase A: pH 2.8 sodium perchlorate buffer Mobile phase B: acetonitrile Flow rate: 1.0mL / min Gradient Program:

[0045] [Table 2]

[0046] Calculation method for total related substance amount [%] The HPLC chart of the sample (SC) was compared with the HPLC chart of the additive only and the HPLC chart of the standard solution (CC), and the total amount of related substances [%] was calculated using the following procedure.

[0047] Step 1: Based on the peaks of related substances that are different from the peak of the main drug (2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride) and peaks that are thought to be the same related substance based on their retention time and peak shape, the difference in peak area was calculated using the following formula. A SC -A CC =D A: Peak area D: Peak area difference

[0048] Step 2: The total amount of related substances [%] was calculated using the following formula.

[0049]

number

[0050] (II. Measurement method of the amount of related substances (2)) 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, diluted with diluent, and thoroughly dissolved and dispersed. The solution was then filtered through a 0.45 μm membrane filter (PALL, Nylon Acrodisc® 25 mm syringe filter). The first 2 mL was discarded, and the resulting solution was used as the sample solution. This solution was analyzed by HPLC under the same measurement conditions as in the "Method (1) for measuring the amount of total related substances," and the amount of related substances was calculated using the following calculation method.

[0051] Calculation method for the amount of related substances [%] The amount of each related substance [%] was calculated using the peak area (Ri) of each related substance in the sample solution and the peak area (Rm) of the main compound in the sample solution (2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride) according to the following formula:

[0052]

number

[0053] The total amount of related substances [%] was calculated by adding up related substances with a concentration of 0.05% or more.

[0054] (III. Excipient Considerations) Reference example 1 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 Pharmaceuticals) as an excipient were mixed in a Mechanomill (Okada Seiko) at 800 rpm for 3 minutes, and the resulting mixture was sieved through a 500 μm mesh sieve. 1 g of the sieved mixture was mixed with 49 g of anhydrous calcium hydrogen phosphate as an excipient in a Mechanomill for 3 minutes and then sieved again. The sieved mixture was divided into 1 g portions and stored in an open atmosphere at 40°C and 75% RH for 4 weeks. After 4 weeks, the total amount of related substances was measured according to the "Method (1) for measuring the amount of total related substances" described above.

[0055] Reference examples 2, 3・Comparative reference examples 1, 2 A sieved mixed powder was prepared in the same manner as in Reference Example 1, except that D-mannitol (Merck KGaA), D-sorbitol (Merck KGaA), lactose (DMV Fonterra Excipients), or crystalline cellulose (Asahi Kasei Chemicals) was used as an excipient instead of anhydrous calcium hydrogen phosphate, and the total amount of related substances was measured.

[0056] The above results are summarized in Table 3 below.

[0057] [Table 3]

[0058] Reference example 4 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 Pharmaceuticals) as an excipient were mixed in a Mechanomill (Okada Seiko) at 800 rpm for 3 minutes. 6 g of pre-sieved (22 mesh) talc was added and mixed in the Mechanomill at 400 rpm for an additional 1 minute. 2 g aliquots of this mixed powder were stored open at 40°C and 75% RH for 1 month. After 1 month, the total amount of related substances was measured according to the "Method for Determining the Amount of Related Substances (2)" described above.

[0059] Reference example 5 A mixed powder was prepared in the same manner as in Reference Example 4, except that anhydrous calcium hydrogen phosphate (Merck KGaA) was used as an excipient instead of calcium hydrogen phosphate hydrate, and the total amount of related substances was measured.

[0060] The above results are summarized in Table 4 below.

[0061] [Table 4]

[0062] (IV. Lubricant Considerations) Reference examples 6~10 0.5 g of 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride and 49.5 g of one of the lubricants listed in Table 5 below were mixed in a Mechanomill (Okada Seiko) at 800 rpm for 3 minutes, and the resulting mixture was sieved through a sieve (mesh opening: 500 μm). 100 mg of the sieved material was dispensed into test tubes and stored open at 40°C, 75% RH, and sealed at 60°C for 4 weeks. After 4 weeks, the total amount of related substances was measured according to the "Method (1) for measuring the amount of total related substances" described above.

[0063] The above results are summarized in Table 5 below.

[0064] [Table 5]

[0065] (V. Storage stability study of capsule formulations combining excipients and lubricants)

[0066] Comparative Example 3 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 Mechanomill (Okada Seiko) at 800 rpm for 3 minutes. The mixed powder was then sieved in a Frebit granulator (Freund Corporation, TC-LABO) using a 700 μm mesh size and a rotation speed of 2500 rpm. The sieved product was divided into two 54 g portions, and each portion was mixed with 6 g of talc (Merck KGaA) as a lubricant in a Mechanomill (Okada Seiko) at 800 rpm for 3 minutes. 60 mg of this mixed powder was dispensed into gelatin capsules. The resulting capsules were placed in high-density polyethylene bottles, sealed, and stored at 40°C and 75% RH for 1 month. Separately, the resulting capsules were placed in a glass bottle, sealed, and stored at 60°C for one month. The total amount of related substances at the start and end of storage was measured according to the above-mentioned "Method for measuring the amount of related substances (2)."

[0067] Comparative Example 4 A mixed powder was prepared in the same manner as in Comparative Reference Example 3, except that sodium stearyl fumarate (JRS PHARMA) was used as a lubricant instead of talc, and the total amount of related substances was measured.

[0068] Reference example 11 A mixed powder was prepared in the same manner as in Comparative Reference Example 3, except that anhydrous calcium hydrogen phosphate (Tomita Pharmaceuticals) was used as an excipient instead of D-mannitol, and the total amount of related substances was measured.

[0069] Reference example 12 A mixed powder was prepared in the same manner as in Comparative Reference Example 4, except that anhydrous calcium hydrogen phosphate was used as an excipient in place of D-mannitol, and the total amount of related substances was measured.

[0070] The above results are summarized in Table 6 below.

[0071] [Table 6]

[0072] When comparing D-mannitol-containing capsules (Comparative Reference Examples 3 and 4) and anhydrous calcium hydrogen phosphate-containing capsules (Reference Examples 11 and 12), both of which contain the same lubricant, the anhydrous calcium hydrogen phosphate-containing capsules have a significantly lower amount of total related substances. This indicates that when formulated as a capsule, anhydrous calcium hydrogen phosphate is clearly more stable during storage than D-mannitol and can suppress the production of related substances.

[0073] When comparing D-mannitol-containing capsules (Comparative Reference Examples 3 and 4) and anhydrous calcium hydrogen phosphate-containing capsules (Reference Examples 11 and 12) using different lubricants, the capsule formulations containing talc (Comparative Reference Examples 3 and 11) had significantly less total related substances than the capsule formulations containing sodium stearyl fumarate (Comparative Reference Examples 4 and 12). This shows that, when used in capsule formulations, talc is clearly superior in storage stability as a lubricant and can suppress the production of related substances.

[0074] (VI. Capsule Considerations) Reference example 13 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 Mechanomill (Okada Seiko) at 800 rpm for 3 minutes. The mixed powder was then sieved in a Frevit granulator (Freund Corporation, TC-LABO) with a 700 μm mesh size and a rotation speed of 2500 rpm. The sieved product was divided into two 54 g portions, and each portion was mixed with 6 g of talc (Merck KGaA) in a Mechanomill (Okada Seiko) at 800 rpm for 3 minutes. 60 mg of this mixed powder was dispensed into gelatin capsules (Qualicaps) and hydroxypropyl methylcellulose (HPMC) capsules (Qualicaps). The resulting capsules were placed in high-density polyethylene bottles and stored in a sealed state at 40°C and 75% RH for one month. Separately, the resulting capsules were placed in glass bottles and stored in a sealed state at 60°C for one month. The total amount of related substances at the start and end of storage, as well as the amount of individual related substances with a relative retention time (RRT) of 1.19 (when the retention time of the active ingredient is set to 1), were measured according to the above-mentioned "Method for measuring the amount of related substances (2)."

[0075] The above results are summarized in Tables 7 and 8 below.

[0076] [Table 7]

[0077] [Table 8]

[0078] (VII. Measurement method of the amount of related substances (3)) The contents were removed from the capsule, and a diluent (50% aqueous acetonitrile) was added to give a concentration of 0.11 mg / mL of 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride. After thorough dissolution and dispersion, the solution was filtered through a 0.45 μm membrane filter (PALL, Ekicrodisc 25CR® 25 mm syringe filter). The first 3 mL was discarded and the remaining solution was used as the sample solution. This sample solution was diluted 1 / 100 with the diluent to give the standard solution. Analysis was performed by HPLC under the following measurement conditions, and the amount of related substances was calculated using the following calculation method.

[0079] HPLC measurement conditions Detection wavelength: 225 nm Column: X-Bridge® C18, 4.6 mm x 75 mm, 2.5 μm particle size, Waters Column temperature: 40℃ Injection volume: 50μL Mobile phase A: pH 2.8 sodium perchlorate buffer / acetonitrile mixture (9:1) Mobile phase B: Acetonitrile / pH 2.8 sodium perchlorate buffer mixture (9:1) Flow rate: 1.5mL / min Gradient Program:

[0080] [Table 9]

[0081] Calculation method for the amount of related substances [%] The amount of each related substance [%] was calculated using the peak area (Ri) of each related substance in the sample solution and the peak area (Rst) of the main compound (2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride) in the standard solution using the following formula.

[0082]

number

[0083] The total amount of related substances [%] was calculated by adding up related substances present at 0.1% or more.

[0084] (VIII. Stability Test of the Solid Pharmaceutical Composition (Gelatin Capsule Formulation) of the Present Invention) Examples 1 to 3 The preparations of the present invention were produced according to the following method so as to have the formulations shown in Table 10 below. D-mannitol (Merck KGaA) and anhydrous calcium hydrogen phosphate (Merck KGaA) were mixed to obtain an excipient mixture. Approximately three times the amount of the excipient mixture per 1 weight of 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride was added to 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride and mixed. This mixture was added to the remaining excipient mixture obtained earlier, and talc (Merck KGaA) was added and mixed. This mixed powder was sieved using a sieving machine. Subsequently, blending using a blender, sieving using a sieving machine, and blending using a blender were repeated. 60 mg of the resulting mixed powder was filled into gelatin capsules using a capsule filling machine to obtain a capsule formulation of the solid pharmaceutical composition of the present invention. The resulting capsule preparation was divided into two, one of which was placed in a high density polyethylene bottle, and the other was packaged in a PTP (press through pack) and stored at 40°C and 75% RH for 6 months. The total amount of related substances at the start of storage and after 6 months of storage for each capsule formulation is shown in Table 11. The total amount of related substances was measured in accordance with the above-mentioned "Method for measuring the amount of related substances (3)."

[0085] [Table 10]

[0086] [Table 11]

[0087] In all of the forms of Examples 1 to 3, the total amount of related substances after the 6-month storage test was less than 0.10%, the same as at the start of storage. These results demonstrate that the pharmaceutical composition of the present invention has excellent storage stability and can suppress the production of related substances. [Industrial Applicability]

[0088] The pharmaceutical composition of the present invention has excellent storage stability and can suppress the formation of related substances, and is therefore useful in the field of pharmaceutical production.

[0089] This application is based on patent application No. 2020-063606 filed in Japan, the contents of which are incorporated in full herein.

Claims

1. 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 calcium hydrogen phosphate, calcium dihydrogen phosphate, sodium hydrogen phosphate, and sodium dihydrogen phosphate.

2. The pharmaceutical composition of claim 1, further comprising (c) a sugar alcohol.

3. 3. The pharmaceutical composition according to claim 2, wherein the sugar alcohol of component (c) is mannitol or sorbitol.

4. 4. The pharmaceutical composition according to claim 3, wherein the sugar alcohol of component (c) is mannitol.

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

25.

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

7. The pharmaceutical composition according to any one of claims 1 to 6, further comprising talc.

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

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

10. 10. The pharmaceutical composition according to any one of claims 1 to 9, 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.

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

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the pharmaceutical composition is a solid pharmaceutical composition.

13. (a) 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof, and (b') an excipient, The pharmaceutical composition is an excipient for component (b'), wherein when components (a) and (b') are mixed so that the weight ratio (component (a):component (b')) is 1:999 and the mixture is stored in the open at 40°C and 75% RH for 4 weeks, in the peak areas of the mixture after storage detected by HPLC, the total peak area of ​​related substances of component (a) is less than 0.3% of the sum of the peak areas of component (a) and the related substances of component (a).

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