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JP-7854809-B2 - Method for manufacturing anamorelin tablets with improved stability

JP7854809B2JP 7854809 B2JP7854809 B2JP 7854809B2JP-7854809-B2

Inventors

  • 谷口 幸司
  • 飯田 香
  • 林 明日香
  • デ グロート， エレノア

Assignees

  • ヘルシン ヘルスケア ソシエテ アノニム
  • 小野薬品工業株式会社

Dates

Publication Date
20260507
Application Date
20200828
Priority Date
20190830

Claims (20)

  1. A method for manufacturing tablets containing anamorelin hydrochloride, a) a method comprising mixing anamorelin hydrochloride with one or a combination thereof from among pharmaceutically acceptable carriers selected from microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, anhydrous calcium hydrogen phosphate, lactose monohydrate, D-mannitol, corn starch, sodium starch glycolate, carmellose calcium, carmellose, crospovidone, partially gelatinized corn starch, and stearic acid to form a mixture; and b) compressing the mixture into a tablet, wherein the mixing ratio of the pharmaceutically acceptable carrier is 0.33 to 20 parts by weight per 1 part by weight of anamorelin hydrochloride.
  2. The method according to claim 1, comprising mixing anamorelin hydrochloride with two or more of the pharmaceutically acceptable carriers.
  3. The method according to claim 2, comprising mixing anamorelin hydrochloride with three or more of the pharmaceutically acceptable carriers.
  4. The method according to claim 3, comprising mixing anamorelin hydrochloride with four or more of the pharmaceutically acceptable carriers.
  5. The method according to claim 1, comprising mixing 0.5 to 10 parts by weight of one or a combination thereof of the pharmaceutically acceptable carriers with 1 part by weight of anamorelin hydrochloride.
  6. The method according to claim 5, comprising mixing 1 to 6 parts by weight of one or a combination thereof of the pharmaceutically acceptable carriers with 1 part by weight of anamorelin hydrochloride.
  7. The method according to any one of claims 1 to 6, wherein the mixture is compressed into tablets with a compressive force of 0.5 to 15 kN.
  8. The method according to any one of claims 1 to 7, wherein the mixture is compressed to a hardness of 40 to 200 Newtons.
  9. The method according to any one of claims 1 to 8, wherein one of the pharmaceutically acceptable carriers or a combination thereof is present in an amount sufficient to prevent the formation of impurity A, which has an HPLC relative retention time of 0.34 when the retention time of anamorelin hydrochloride is 1 minute, as measured according to the high-performance liquid chromatography (HPLC) conditions described in Example 3.
  10. The method according to claim 9, wherein the amount of impurity A generated after storage at 40°C and 75% relative humidity for 2 to 6 months is less than 0.1% of the weight of the anamorelin hydrochloride.
  11. The method according to claim 10, wherein the amount of impurity A generated after storage at 40°C and 75% relative humidity for two months is less than 0.05% of the weight of the anamorelin hydrochloride.
  12. A tablet containing anamorelin hydrochloride, manufactured by the method described in any one of claims 1 to 11.
  13. A tablet comprising anamorelin hydrochloride as an active ingredient, further comprising one or a combination thereof from among pharmaceutically acceptable carriers selected from the group consisting of microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, anhydrous calcium hydrogen phosphate, lactose monohydrate, D-mannitol, corn starch, sodium starch glycolate, carmellose calcium, carmellose, crospovidone, partially gelatinized corn starch, and stearic acid, wherein the mixing ratio of the pharmaceutically acceptable carriers is 0.33 to 20 parts by weight per 1 part by weight of anamorelin hydrochloride.
  14. The tablet according to claim 13, comprising two or more of the aforementioned pharmaceutically acceptable carriers.
  15. The tablet according to claim 14, comprising three or more of the aforementioned pharmaceutically acceptable carriers.
  16. The tablet according to claim 15, comprising four or more of the aforementioned pharmaceutically acceptable carriers.
  17. The tablet according to claim 13, comprising 0.5 to 10 parts by weight of one or a combination thereof of the pharmaceutically acceptable carriers per 1 part by weight of anamorelin hydrochloride.
  18. The tablet according to claim 17, comprising 1 to 6 parts by weight of one or a combination thereof of the pharmaceutically acceptable carriers per 1 part by weight of anamorelin hydrochloride.
  19. A tablet according to any one of claims 13 to 18, wherein the tablet substantially does not contain impurity A, which has an HPLC relative retention time of 0.34 when the retention time of anamorelin hydrochloride is 1 minute, as measured according to the high-performance liquid chromatography (HPLC) conditions of Example 3, or the amount of impurity A after storage at 40°C and 75% relative humidity for 2 to 6 months is less than 0.1% of the weight of anamorelin hydrochloride.
  20. The tablet according to claim 19, wherein it substantially does not contain impurity A, or the amount of impurity A after storage at 40°C and 75% relative humidity for two months is less than 0.05% of the weight of anamorelin hydrochloride.

Description

The present disclosure relates to anamorelin hydrochloride, formulations of anamorelin hydrochloride with improved stability, methods for producing such formulations, therapeutic methods using such formulations, and methods for reducing and controlling impurity formation. Background of the Invention : Anamorelin is a synthetic orally active compound first synthesized in the 1990s as a growth hormone secretagogue currently under development for the treatment of cancer-related cachexia. The free base of anamorelin is • (3R) 1-(2-methylalanyl-D-tryptophyl)-3-(phenylmethyl)-3-piperidinecarboxylic acid 1,2,2-trimethylhydrazide, Chemically defined as 3-{(2R)-3-{(3R)-3-benzyl-3-[(trimethylhydrazino)carbonyl]piperidine-1-yl}-2-[(2-methylalanyl)amino]-3-oxopropyl}-1H-indole, or 2-amino-N-[(1R)-2-[(3R)-3-benzyl-3-(N,N',N'-trimethylhydrazinocarbonyl)piperidine-1-yl]-1-(1H-indole-3-ylmethyl)-2-oxoethyl]-2-methylpropionamide, and having the following chemical structure: The commercially available dosage form is developed as hydrochloride by Ono Pharmaceutical Co., Ltd. (Osaka, Japan) and Helsin Healthcare (Lugano, Switzerland). Ankersen et al.'s International Publication No. 01/34593 describes a method for preparing anamorelin as fumarate using the hydrochloride salt produced as an intermediate in step (j) of Example 1. Lorimer et al.'s International Publication No. 2006/016995 describes a method for preparing the crystalline form of the free base of anamorelin. Kuwabe et al.'s International Publication No. 2013/158874 describes a method for producing anamorelin hydrochloride with controlled chloride content and low residual solvent. Mann et al.'s International Publication No. 2016/036598 describes a method for using anamorelin hydrochloride for the treatment of cancer cachexia. Other methods of using anamorelin are described in Polvino et al.'s International Publication Nos. 2010/099522 and Polvino et al.'s International Publication Nos. 2008/100448. Despite the aforementioned developments, when anamorelin hydrochloride, particularly with excess chloride, is formulated into pharmaceutically acceptable dosage forms, methods are needed to prevent the formation of undesirable degradation products of anamorelin hydrochloride. Controlling the formation of anamorelin impurity A, an analog and degradation product of anamorelin hydrochloride with an HPLC response coefficient of 1.53 relative to anamorelin, has become particularly important. Summary of the Invention Unexpectedly, it was discovered that compressing certain tableting excipients together with anamorelin hydrochloride to form tablets improves the stability of anamorelin hydrochloride, and that these excipients prevent the decomposition of anamorelin hydrochloride into impurity A. While we do not wish to be bound by any theory, it is thought that when these excipients are completely (intimally) mixed with anamorelin hydrochloride, they physically or chemically segregate the hydrochloride from the free anamorelin base molecule, thereby preventing the decomposition of anamorelin into impurity A. Therefore, in the first main embodiment, the present invention provides a method for producing anamorelin hydrochloride tablets and tablets produced by means of, the method comprising (a) mixing anamorelin hydrochloride with one or a combination of pharmaceutically acceptable carriers selected from microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, and anhydrous calcium hydrogen phosphate to form a mixture, and (b) compressing the mixture into tablets. Other embodiments relate to a method for producing an anamorelin hydrochloride dosage form by detecting and controlling impurity A. Therefore, in a second primary embodiment, the present invention provides a method for producing anamorelin hydrochloride tablets and tablets produced by means of such method, comprising: (a) mixing anamorelin hydrochloride with a pharmaceutically acceptable carrier means for preventing the formation of impurity A to form a mixture; (b) compressing the mixture into tablets; (c) isolating impurity A from anamorelin hydrochloride in one or more of the tablets; (d) quantifying the amount of impurity A in the one or more tablets; and (e) optionally repeating steps (c) and (d) six months or one year after step (b). Other embodiments relate to impurity A itself. Therefore, in a third primary embodiment, the present invention provides impurity A isolated from anamorelin hydrochloride. Another embodiment relates to the anamorelin hydrochloride tablet itself. Therefore, in a fourth main embodiment, the present invention provides a tablet comprising anamorelin hydrochloride as an active ingredient, further comprising a pharmaceutically acceptable carrier selected from microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, and anhydrous calcium hydrogen phosphate. In a fifth primary embodiment, the present invention provides a tablet compris