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JP-7855696-B2 - Pharmaceutical composition containing 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazoline-4-yl]acetate and potassium ions

JP7855696B2JP 7855696 B2JP7855696 B2JP 7855696B2JP-7855696-B2

Inventors

  • ヘルムート ブッシュマン
  • トーマス ゴルトナー
  • ホルディ カルレス セロン ベルトラン

Assignees

  • アーイーツェー２４６ アクチェンゲゼルシャフト ウント コンパニー コマンディトゲゼルシャフト

Dates

Publication Date
20260508
Application Date
20221221
Priority Date
20211221

Claims (20)

  1. A pharmaceutical composition comprising letermovir of formula (I) and potassium ions, - Containing potassium ions in a molar ratio of 0.80 to <1.00:1.00 relative to letermovir; and - When the pharmaceutical composition is dissolved in water at a concentration range of 20 to 100 mg/mL relative to letermovir, it can exhibit a pH range of 7 to 8; and - Essentially free from complexing solubilizers selected from the group consisting of PEG, lysine, arginine, and cyclodextrin. Pharmaceutical composition.
  2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition contains potassium ions in a molar ratio of 0.88 to <1.00:1.00 with respect to letermovir.
  3. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition contains potassium ions in a molar ratio of 0.90 to <1.00:1.00 with respect to letermovir.
  4. The pharmaceutical composition according to claim 1, wherein the potassium ions are contained in the form of a solution of potassium hydroxide (KOH).
  5. The pharmaceutical composition according to claim 1, wherein the potassium ions are contained in the form of an aqueous solution of potassium hydroxide (KOH).
  6. The pharmaceutical composition according to claim 1, wherein when the pharmaceutical composition is dissolved in water at a concentration range of 20 to 100 mg/mL with respect to letermovir, it can exhibit a pH in the range of 7.4 to 7.8.
  7. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition essentially does not contain hydroxypropyl-β-cyclodextrin (HPBCD).
  8. The pharmaceutical composition according to claim 1, further comprising at least one excipient selected from the group consisting of carbohydrates, amino acids, polyalkoxy compounds, and polyvinylpyrrolidone (PVP).
  9. The pharmaceutical composition according to claim 8, wherein the carbohydrate is sucrose or amannitol, the amino acid is phenylalanine, the polyalkoxy compound is poloxamer, and the polyvinylpyrrolidone (PVP) is PVP PF12.
  10. The pharmaceutical composition according to claim 9, wherein the poloxamer is poloxamer 188.
  11. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition essentially does not contain a complexing solubilizing agent.
  12. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises a polyalkoxy compound and essentially does not contain other complexing solubilizing agents.
  13. The pharmaceutical composition according to claim 12, wherein the polyalkoxy compound is a poloxamer.
  14. The pharmaceutical composition according to claim 13, wherein the poloxamer is poloxamer 188.
  15. The pharmaceutical composition according to claim 8 , wherein the excipient is mannitol, sucrose, or a combination thereof.
  16. The pharmaceutical composition according to claim 1, further comprising a buffer.
  17. The pharmaceutical composition according to claim 16, wherein the buffer is tris(hydroxymethyl)aminomethane (Tris).
  18. A method for producing a pharmaceutical composition according to any one of claims 1 to 17 , comprising the following steps: i) Prepare a solution of letermovir and potassium ions in which the molar ratio of potassium ions to letermovir is in the range of 0.80 to <1.00:1.00, and optionally, at least one excipient selected from the group consisting of carbohydrates, amino acid polyalkoxy compounds, and polyvinylpyrrolidone (PVP); ii) If necessary, adjust the pH of the solution obtained in step i) to a range of 7 to 8; iii) Optionally, filter the solution. Methods that include...
  19. The method according to claim 18, wherein the molar ratio of potassium ions to letermovil in the solution of letermovil and potassium ions in step i) is in the range of 0.88 to <1.00:1.00.
  20. The method according to claim 19, wherein the molar ratio of potassium ions to letermovil in the solution of letermovil and potassium ions in step i) is in the range of 0.90 to less than 1.00:1.00.

Description

This invention relates to a novel, stable pharmaceutical composition containing 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid and potassium ions, also known as letermovir, suitable for oral, intravenous, and injection administration. The pharmaceutical composition is essentially free from specific complexing solubilizing agents, such as PEG, cyclodextrin, lysine, arginine, and especially HPBCD. The formulation is suitable for use in methods of treating viral diseases, particularly human cytomegalovirus (HCMV) infection. This invention also relates to a method for preparing the pharmaceutical composition. Cytomegalovirus (CMV) is a common opportunistic infection that causes serious pathological conditions and preventable deaths after solid organ transplantation and allogeneic hematopoietic stem cell transplantation. HCMV is a type of virus belonging to the Herpesviridae family, also known as herpesviruses. It is typically abbreviated as HCMV and is alternatively known as human herpesvirus 5 (HHV-5). Within the Herpesviridae family, HCMV belongs to the Betaherpesvirinae subfamily, which also includes other mammalian cytomegaloviruses. Letermovir is known as a highly active drug for treating HCMV infections and is described in detail in Lischka et al., *In Vitro and In Vivo Activities of the Novel Anticytomegalovirus Compound Letermovir*, *Antimicrob. Agents Chemother.* 2010, 54: p.1290-1297; Kaul et al., *First report of successful treatment of multidrug-resistant cytomegalovirus disease with the novel anti-CMV compound Letermovir*, *Am. J. Transplant.* 2011, 11:1079-1084; and Marschall et al., *In Vitro Evaluation of the Activities of the Novel Anticytomegalovirus Compound Letermovir against Herpesviruses and Other Human Pathogenic Viruses*, *Antimicrob. Agents Chemother.* 2012, 56:1135-1137. The exact chemical name of letermovir is 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazoline-4-yl]acetic acid, and the chemical structure of letermovir is shown below: Letermovir was developed as an antiviral agent, particularly for the treatment and prevention (prevention or prophylaxis) of infections caused by human cytomegalovirus (HCMV), and is disclosed in International Publication No. 2004/096778. Furthermore, as described in International Publication No. 2013/127971, a salt of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazoline-4-yl]acetic acid was also prepared. A liquid pharmaceutical formulation containing amorphous letermovir is described in International Publication No. 2013/127970, relating to a pharmaceutical composition that can be used particularly for intravenous administration, contains letermovir, is long-term stable, storable, and has a substantially physiological pH. Furthermore, it has been discovered that such a composition can be freeze-dried to obtain a stable solid pharmaceutical composition that can be redissolved in a simple manner for injection, for example by adding water, thereby obtaining a stable pharmaceutical composition for intravenous administration. However, there remains a need for a pharmaceutical composition containing letermovir that is suitable for use in patients of all ages requiring solid organ transplantation and allogeneic hematopoietic stem cell transplantation, and that possesses long-term stability at a substantially physiological pH. Furthermore, pharmaceutical compositions containing letermovir and complexing solubilizers such as PEG, lysine, arginine, cyclodextrins, and especially hydroxypropyl-β-cyclodextrin (HPBCD) tend to cause particle-related problems when dissolved in parenterally acceptable diluents such as water, and therefore require additional work-up before intended use, such as filtering the pharmaceutical composition before administration. Thus, there remains a need for a ready-to-use, particle-free parenteral solution containing letermovir. In a first embodiment, the present invention relates to a pharmaceutical composition comprising letermovir of formula (I) and potassium ions, - Containing potassium ions in a molar ratio of 0.80 to <1.00:1.00, preferably 0.88 to <1.00:1.00, more preferably 0.90 to <1.00:1.00 with respect to letermovir; and - When the pharmaceutical composition is dissolved in water at a concentration range of 1 to 100 mg/mL with respect to letermovir, it can exhibit a pH in the range of 7 to 8; and - Essentially free from complexing solubilizers selected from the group consisting of PEG, lysine, arginine, cyclodextrin, and especially hydroxypropyl-β-cyclodextrin (HPBCD); Regarding pharmaceutical compositions. When the molar ratio of potassium ions to letermovir is 0.80 to <1.00:1.00, preferably 0.88 to <1.00:1.00, and more preferably 0.90 to <1.00:1.00, letermovir exhibits improved solubility and is present at a sufficient concentration to