Prasugrel hydrochloride-containing formulation

Abstract

One embodiment of the present invention provides a prasugrel hydrochloride-containing formulation in which the production of similar substances is suppressed. According to one embodiment of the present invention, provided is a prasugrel hydrochloride-containing formulation comprising prasugrel hydrochloride and at least one disintegrant selected from the group consisting of carmellose calcium, croscarmellose sodium, and sodium carboxymethyl starch. An uncoated tablet containing prasugrel hydrochloride and the disintegrant may contain 1-20 mass% of the disintegrant.

Description

Prasugrel hydrochloride-containing preparations

[0001] One embodiment of the present invention relates to a formulation containing prasugrel hydrochloride.

[0002] Prasugrel hydrochloride (5-[(1RS)-2-Cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c ]pyridin-2-yl acetate monohydrochloride) is used as an antiplatelet agent. Prasugrel hydrochloride is a prodrug, and after being converted into an active metabolite in vivo, it binds to the ADP receptor (P2Y) on the platelet membrane. １２ It is known that it inhibits platelet aggregation by selectively and irreversibly inhibiting the ATP-dependent agonist activity (see, for example, Patent Document 1).

[0003] Previous studies on prasugrel hydrochloride-containing preparations have focused on disintegration, tablet hardness, and dissolution, as disclosed in Patent Document 1, for example.

[0004] Patent No. 7148319

[0005] As will be described later, the inventors have conducted studies and found that when a prasugrel hydrochloride-containing preparation is stored under humid conditions, several types of related substances are produced, which reduces the purity of prasugrel hydrochloride in the preparation.

[0006] An object of one embodiment of the present invention is to provide a prasugrel hydrochloride-containing preparation in which the production of related substances is suppressed.

[0007] According to one embodiment of the present invention, there is provided a prasugrel hydrochloride-containing formulation comprising prasugrel hydrochloride and one or more disintegrants selected from the group consisting of carmellose calcium, croscarmellose sodium, and sodium starch glycolate.

[0008] The uncoated tablet containing prasugrel hydrochloride and a disintegrant may contain 1% by mass or more and 20% by mass or less of the disintegrant.

[0009] According to one embodiment of the present invention, there is provided a prasugrel hydrochloride-containing preparation in which the production of related substances is suppressed.

[0010] The prasugrel hydrochloride-containing formulation of the present invention will be described below. Note that the prasugrel hydrochloride-containing formulation of the present invention should not be construed as being limited to the description of the following embodiments and examples. Note that in this embodiment and the examples described below, repeated description of components having the same configuration or similar functions will be omitted.

[0011] Prasugrel has the potential to produce seven analogues. In this specification, the analogs of prasugrel are thienotetrahydropyridinone (referred to as analog 1), acetylthienotetrahydropyridine (referred to as analog 2), prasugrel thiol analog (referred to as analog 3), desacetyl hydroxyprasugrel (referred to as analog 4), desacetyl prasugrel distereoisomer-1 (referred to as analog 5), desacetyl prasugrel distereoisomer-2 (referred to as analog 6), and prasugrel diketone (referred to as analog 7).

[0012] As a result of investigations conducted by the present inventors, it was revealed that when a conventional preparation containing prasugrel hydrochloride is stored under humidified conditions, three types of related substances, namely, related substances 4 to 6, are mainly produced, which reduces the purity of prasugrel hydrochloride in the preparation.

[0013] As shown in the Examples below, the inventors have conducted studies and found that related substances 4 to 6 are produced by hydrolysis of prasugrel hydrochloride when a prasugrel hydrochloride-containing preparation is stored under humidified conditions.

[0014] A prasugrel hydrochloride-containing formulation according to one embodiment of the present invention comprises prasugrel hydrochloride and one or more disintegrants selected from the group consisting of carmellose calcium, croscarmellose sodium, and sodium starch glycolate. In this embodiment, the prasugrel hydrochloride-containing formulation contains one or more of these disintegrants, thereby suppressing hydrolysis of prasugrel hydrochloride and significantly suppressing the production of prasugrel hydrochloride analogs 4 to 6. It has not been reported before that the use of these specific disintegrants in a prasugrel hydrochloride-containing formulation can significantly suppress the production of prasugrel hydrochloride analogs 4 to 6, and this is a surprising and novel finding. Note that, in this specification, prasugrel hydrochloride includes solvates thereof, such as hydrates.

[0015] In one embodiment, the prasugrel hydrochloride-containing formulation preferably does not substantially contain one or more disintegrants selected from the group consisting of low-substituted hydroxypropyl cellulose, carmellose, and crospovidone. As used herein, the term "substantially free" is intended to mean either that the formulation does not contain one or more disintegrants selected from the group consisting of low-substituted hydroxypropyl cellulose, carmellose, and crospovidone, or that the formulation contains these disintegrants in amounts that do not impair the effect of suppressing the production of prasugrel hydrochloride analogs 4 to 6. Alternatively, in one embodiment, the formulation may contain one or more disintegrants selected from the group consisting of low-substituted hydroxypropyl cellulose, carmellose, and crospovidone in an amount that is sufficient to suppress the production of prasugrel hydrochloride analogs 4 to 6 within a predetermined range, in combination with one or more disintegrants selected from the group consisting of carmellose calcium, croscarmellose sodium, and sodium starch glycolate. In one embodiment, the prasugrel hydrochloride-containing formulation preferably does not contain one or more disintegrants selected from the group consisting of low-substituted hydroxypropyl cellulose, carmellose, and crospovidone. It has not been reported so far that the amount of prasugrel hydrochloride analogues increases due to the influence of these specific disintegrants, and it has not been reported so far that the production of prasugrel hydrochloride analogues 4 to 6 can be suppressed by substantially not including these specific disintegrants, which is a surprising and novel finding.

[0016] In one embodiment, the prasugrel hydrochloride-containing formulation may comprise an uncoated tablet containing prasugrel hydrochloride and one or more disintegrants selected from the group consisting of carmellose calcium, croscarmellose sodium, and sodium starch glycolate, and the uncoated tablet may contain 1% by mass or more and 20% by mass or less of these disintegrants.

[0017] In one embodiment, the prasugrel hydrochloride-containing formulation contains, for example, 2.5 mg, 3.75 mg, 5 mg, or 20 mg of prasugrel hydrochloride per tablet; however, the content of prasugrel hydrochloride in the prasugrel hydrochloride-containing formulation according to the present invention is not limited to these amounts and can be set arbitrarily within a range in which a therapeutic effect is obtained.

[0018] In one embodiment, the prasugrel hydrochloride-containing formulation may contain one or more pharmaceutically acceptable additives in the uncoated tablet in addition to the above-mentioned prasugrel hydrochloride and disintegrant. Examples of the one or more pharmaceutically acceptable additives include excipients, binders, lubricants, colorants, flavoring agents, sweeteners, taste-masking agents, flow agents, effervescent agents, surfactants, etc.

[0019] Examples of excipients include, but are not limited to, mannitol, erythritol, sorbitol, xylitol, trehalose, cyclodextrin, corn starch, potato starch, sucrose, anhydrous calcium hydrogen phosphate, calcium carbonate, white sugar, partially pregelatinized starch, lactose hydrate, and crystalline cellulose.

[0020] Examples of binders include, but are not limited to, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol (fully saponified), macrogol, sugar alcohols (e.g., mannitol, erythritol, sorbitol, and xylitol), trehalose, cyclodextrin, corn starch, sucrose, crystalline cellulose, anhydrous calcium hydrogen phosphate, and calcium carbonate.

[0021] Examples of lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, light anhydrous silicic acid, hydrogenated vegetable oil, microcrystalline wax, sucrose fatty acid ester, polyethylene glycol, and talc.

[0022] Examples of coloring agents include food dyes such as Food Yellow No. 5, Food Red No. 2, and Food Blue No. 2; food lake dye, yellow ferric oxide, ferric oxide, titanium oxide, β-carotene, and riboflavin, but are not limited to these.

[0023] Examples of flavoring agents include orange, lemon, strawberry, mint, menthol, menthol micron, and various flavorings, but are not limited to these.

[0024] Examples of sweeteners include, but are not limited to, saccharin sodium, saccharin, aspartame, acesulfame potassium, dipotassium glycyrrhizinate, sucralose, stevia, and thaumatin.

[0025] Examples of flavoring agents include, but are not limited to, sodium chloride, magnesium chloride, disodium inosinate, sodium L-glutamate, and honey.

[0026] Examples of the fluidizing agent include, but are not limited to, hydrous silicon dioxide, light anhydrous silicic acid, magnesium aluminometasilicate, and talc.

[0027] Examples of foaming agents include, but are not limited to, tartaric acid and / or anhydrous citric acid.

[0028] Examples of surfactants include, but are not limited to, polyoxyl 40 stearate, sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polysorbate, glycerin monostearate, and sodium lauryl sulfate.

[0029] In one embodiment, the uncoated tablet can be coated with a coating agent. Examples of the coating agent include, but are not limited to, hypromellose, ethyl cellulose, aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, dried methacrylic acid copolymer LD, methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer RS, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer, polyvinyl acetal-diethylaminoacetate, and polyvinyl acetate resin.

[0030] The coating agent may also be combined with a plasticizer, such as, but not limited to, hydroxypropyl cellulose, diethyl sebacate, dibutyl sebacate, triethyl citrate, stearic acid, polyethylene glycol, and triacetin.

[0031] [Method for Manufacturing Prasugrel Hydrochloride-Containing Preparations] In one embodiment, prasugrel hydrochloride-containing preparations are preferably manufactured by direct compression. Prasugrel hydrochloride, one or more disintegrants selected from the group consisting of carmellose calcium, croscarmellose sodium, and sodium starch glycolate, and one or more pharmaceutically acceptable additives described above are mixed to prepare a pharmaceutical composition, and the resulting pharmaceutical composition is compressed to obtain uncoated tablets. Generally, dry granulation and wet granulation are also known methods for manufacturing uncoated tablets. However, dry granulation is not preferred for the manufacture of prasugrel hydrochloride-containing preparations because it reduces the dissolution rate of prasugrel hydrochloride. Furthermore, wet granulation is not preferred because it hydrolyzes prasugrel hydrochloride to produce prasugrel hydrochloride analogs 4 to 6.

[0032] In one embodiment, the plain tablet can be coated with the above-mentioned coating agent to provide a prasugrel hydrochloride-containing formulation as a film-coated tablet.

[0033] Comparative Example 1 A prasugrel hydrochloride-containing formulation containing low-substituted hydroxypropyl cellulose, the disintegrant contained in commercially available Efient® tablets, was produced. Specifically, 4.12 g of prasugrel hydrochloride, 59.88 g of lactose hydrate (Dilactose® S, Freund Corporation), 25 g of crystalline cellulose (PH-102, Asahi Kasei Corporation), 5 g of low-substituted hydroxypropyl cellulose (L-HPC® LH 21, Shin-Etsu Chemical Co., Ltd.), and 5 g of hydroxypropyl cellulose (HPC-L, Nippon Soda Co., Ltd.) were mixed in a plastic bag and sieved through a No. 30 sieve. Then, 1 g of magnesium stearate (plant-derived, Taihei Chemical Industry Co., Ltd.) was added and mixed in a plastic bag. The resulting mixture was compression-molded using a rotary tablet press to produce plain tablets.

[0034] A film coating solution was prepared by stirring and dissolving and dispersing 114 g of hypromellose (TC-5 (registered trademark) M, Shin-Etsu Chemical Co., Ltd.), 12 g of hydroxypropyl cellulose (HPC-SL, Nippon Soda Co., Ltd.), 12 g of titanium oxide (NA61, Toho Titanium Co., Ltd.), 12 g of talc (Fuji Talc Industry Co., Ltd.), and 0.2 g of ferric oxide (Kishi Kasei Co., Ltd.) in 1,400 g of purified water using a mixer. The produced uncoated tablets were coated with the film coating solution until the mass per tablet increased by approximately 7.5 mg, thereby producing a prasugrel hydrochloride-containing formulation.

[0035] A prasugrel hydrochloride-containing formulation of Comparative Example 2 was produced by the same production method as in Comparative Example 1, except that L-HPC was replaced with carmellose, the disintegrant contained in commercially available Effient (registered trademark) tablets. NS300 (Godo Pharmaceutical Co., Ltd.) was used as the carmellose.

[0036] A prasugrel hydrochloride-containing formulation of Comparative Example 3 was produced by the same production method as in Comparative Example 1, except that L-HPC was replaced with crospovidone, which is a disintegrant contained in commercially available Efient (registered trademark) tablets. Kollidon (registered trademark) CL-F (BASF) was used as the crospovidone.

[0037] Example 1 A prasugrel hydrochloride-containing formulation of Example 1 was produced by the same production method as in Comparative Example 1, except that L-HPC was changed to sodium starch glycolate (Primogel (registered trademark) (DFE Pharma)).

[0038] Example 2 A prasugrel hydrochloride-containing formulation of Example 2 was produced by the same production method as in Comparative Example 1, except that L-HPC was changed to croscarmellose sodium (Acdisol (registered trademark), FMC International).

[0039] Example 3 A prasugrel hydrochloride-containing formulation of Example 3 was produced by the same production method as in Comparative Example 1, except that L-HPC was changed to carmellose calcium (ECG (registered trademark)-505, Gotoku Pharmaceutical Co., Ltd.).

[0040] The prasugrel hydrochloride-containing preparations of Comparative Examples 1 to 3 and Examples 1 to 3 were stored for two weeks or one month under open conditions at 25°C and a relative humidity of 75%. Furthermore, the prasugrel hydrochloride-containing preparations of Comparative Examples 1 to 3 and Examples 1 to 3 packaged in aluminum foil (with a desiccant) were stored at 25°C and a relative humidity of 60% for two weeks. The amounts of related substances in the prasugrel hydrochloride-containing preparations of Comparative Examples 1 to 3 and Examples 1 to 3 after storage were measured using high-performance liquid chromatography. The measurement results are shown in Table 1.

[0041] [Table 1]

[0042] The results in Table 1 show that there was no significant difference in the amount of related substances between the prasugrel hydrochloride-containing formulations stored in aluminum packaging (with desiccants) of Comparative Examples 1 to 3 and Examples 1 to 3. On the other hand, when stored under humidified conditions (open conditions at 25°C and 75% relative humidity), the prasugrel hydrochloride-containing formulations of Comparative Examples 1 to 3, which contained L-HPC, carmellose, or crospovidone, which are disintegrants contained in commercially available Efient (registered trademark) tablets, showed an increase in the amounts of related substances 4 to 6, which are hydrolysates of prasugrel hydrochloride, and an increase in the total amount of related substances. However, the prasugrel hydrochloride-containing formulations of Examples 1 to 3, which contained carmellose calcium, croscarmellose sodium, or sodium starch glycolate, showed an inhibition of the production of related substances 4 to 6 and a decrease in the total amount of related substances.

Claims

1. A prasugrel hydrochloride-containing formulation comprising prasugrel hydrochloride and one or more disintegrants selected from the group consisting of carmellose calcium, croscarmellose sodium and sodium starch glycolate.

2. The prasugrel hydrochloride-containing formulation according to claim 1, wherein the uncoated tablet containing the prasugrel hydrochloride and the disintegrant contains 1% by mass or more and 20% by mass or less of the disintegrant.

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