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

Abstract

The present invention relates to a novel stable pharmaceutical composition comprising 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, essentially free of complexing solubilizers such as PEG, cyclodextrin, lysine, arginine, in particular HPBCD. The present invention further relates to a method for the preparation of said pharmaceutical composition. The present invention further relates to the use of said pharmaceutical composition in a method for the treatment of a disease and / or as a prophylactic agent, in particular its use as an antiviral agent, preferably against cytomegalovirus.

Description

Technical Field

[0001] The present invention relates to a new stable pharmaceutical composition, also known as letelmovir, 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, which is suitable for oral and intravenous administration and injection. The pharmaceutical composition essentially does not contain specific complexing solubilizing agents such as PEG, cyclodextrin, lysine, arginine, especially HPBCD. The formulation is suitable for use in a method for treating viral diseases, particularly human cytomegalovirus (hereinafter, HCMV) infections. The present invention also relates to a method for preparing the pharmaceutical composition.

Background Art

[0002] Cytomegalovirus (CMV) is a common opportunistic infection that causes serious morbidity and preventable death after solid organ transplantation and allogeneic hematopoietic stem cell transplantation.

[0003] HCMV is a virus belonging to the family of viruses known as the Herpesviridae or Herpes viruses. 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 and includes other cytomegaloviruses derived from mammals.

[0004] 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.

[0005] 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: [ka]

[0006] Letermovir was developed as an antiviral agent, particularly for the treatment, 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, salts of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazoline-4-yl]acetic acid were also prepared.

[0007] A liquid pharmaceutical formulation containing amorphous letermovir is described in International Publication No. 2013 / 127970, relating to a pharmaceutical composition that can be used 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, and as a result, a stable pharmaceutical composition for intravenous administration can be obtained.

[0008] However, there remains a need for a pharmaceutical composition containing letermovir that is suitable for use in subjects of all ages requiring solid organ transplantation and allogeneic hematopoietic stem cell transplantation, and that has long-term stability at a substantially physiological pH. Furthermore, pharmaceutical compositions containing letermovir and complexing solubilizers such as PEG, lysine, arginine, cyclodextrin, 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. [Overview of the project]

[0009] In a first embodiment, the present invention relates to a pharmaceutical composition comprising letermovir of formula (I) and potassium ions, [ka] • Containing potassium ions in a molar ratio of 0.80 to <1.00:1.00 relative to letermovil, preferably 0.88 to <1.00:1.00, more preferably 0.90 to <1.00:1.00; 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 range of 7 to 8; and • Essentially free of complexing solubilizers selected from the group consisting of PEG, lysine, arginine, cyclodextrin, and especially hydroxypropyl-β-cyclodextrin (HPBCD). Regarding pharmaceutical compositions.

[0010] 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 achieve the desired therapeutic effect without the need for further solubilizing agents, particularly complexing solubilizing agents such as cyclodextrins. Furthermore, pharmaceutical compositions containing potassium ions in the above ratio have a substantially physiological pH and exhibit long-term stability.

[0011] Furthermore, it has been discovered that the pharmaceutical composition can be obtained in the form of a lyophilized product that can be completely resoluble in parenterally acceptable diluents such as water, aqueous glucose solution, or Ringer's lactate solution. When resoluble, the lyophilized product exhibits a pH in the range of 7 to 8, preferably 7.4 to 7.8, when letermovir is present in the resoluble solution at a concentration range of 1 to 100 mg / mL, preferably 20 to 100 mg / mL. The pH of the resoluble solution is stable when the molar ratio of potassium ions to letermovir is in the range 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, and is within the physiological range of 7 to 8, preferably 7.4 to 7.8, which is clear evidence of the remarkable self-buffering effect of potassium ions within a given range. The resulting resoluble solution exhibits long-term stability.

[0012] In another embodiment, the present invention involves the following steps: i) A solution of letermovil and potassium ions having a molar ratio of potassium ions to letermovil in the range 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; and optionally, at least one excipient selected from the group consisting of carbohydrates such as sucrose or mannitol, amino acids such as phenylalanine, polyalkoxy compounds such as poloxamers, particularly poloxamer 188, and polyvinylpyrrolidone (PVP) such as PVP PF12; ii) If necessary, adjust the pH of the solution obtained in step i) to a range of 7-8, preferably using HCl; iii) Optionally, filter the solution. The present invention relates to a method for producing the pharmaceutical composition, which includes the above.

[0013] In particular, the method according to the present invention may further include the following steps: freeze-drying the solution obtained in step iii above to obtain a freeze-dried product; optionally redissolving the freeze-dried product in a first parenterally acceptable diluent to obtain a redissolved solution with respect to letermovir in a concentration range of 1 to 100 mg / mL, preferably 20 to 100 mg / mL; optionally further diluting the redissolved solution with a second parenterally acceptable diluent to a final concentration acceptable for injection or infusion, wherein the first and second parenterally acceptable diluents may be the same or different.

[0014] Another aspect of the present invention relates to the use of the pharmaceutical compositions described herein for the preparation of agents for treating and / or preventing diseases, particularly viral infections, preferably human cytomegalovirus (HCMV) infections or infections caused by other members of the herpesvirus group.

[0015] Another aspect of the present invention relates to a method for treating and / or preventing viral infections, preferably human cytomegalovirus (HCMV) infections or infections caused by other members of the herpesvirus group, in subjects requiring such treatment by administering the pharmaceutical composition. In particular, the pharmaceutical composition according to the present invention is suitable for the treatment of neonates, subjects requiring certain solid organ transplants, such as subjects with renal impairment and subjects requiring allogeneic hematopoietic stem cell transplants. [Modes for carrying out the invention]

[0016] It should be noted that the term "includes" also includes the meaning of "consisting of," and for example, a group of members that includes the aforementioned members also includes a group of members that consists only of those members.

[0017] As used herein, the term "room temperature" is synonymous with "standard room temperature" and refers to temperatures in the range of 19°C to 26°C. For example, "stirring at room temperature" means "stirring at temperatures in the range of 19°C to 26°C."

[0018] Within the scope of this invention, the term "stability" is understood to mean not only the chemical stability of the components of the pharmaceutical composition, particularly the active substance, but also the physicochemical stability of the composition itself. In particular, the composition according to the present invention must be stable against precipitation of its constituent components.

[0019] In this context, the term “stability” means that the liquid pharmaceutical composition, when measured according to the HPLC method of the present invention, contains at least >90%, preferably >95%, more preferably >98% of the active substance at a storage period of at least 1 month, preferably at least 3 months, more preferably at least 6 months, more preferably 12 months, more preferably 18 months, and most preferably at least 36 months at 2°C to 8°C, or 25°C, or 40°C.

[0020] The cyclodextrins according to the present invention are understood to encompass any modified or unmodified cyclodextrin, particularly those selected from α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin. Examples of modified β-cyclodextrins include, in particular, hydroxyalkyl-β-cyclodextrins, e.g., hydroxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, or hydroxypropyl-β-cyclodextrin, and alkyl-hydroxyalkyl-β-cyclodextrins, e.g., methyl-hydroxypropyl-β-cyclodextrin, ethyl-hydroxypropyl-cyclodextrin, or sulfoalkyl-cyclodextrin. Hydroxypropyl-β-cyclodextrins are available in various degrees of substitution, and 2-hydroxypropyl-β-cyclodextrin in particular is available as Cavasol® W7 HP, Cavitron® W7 HP5, and Cavitron® W7 HP7.

[0021] As used herein, the term "complexing solubilizer" refers to a compound that enhances the solubility of the active ingredient of the pharmaceutical composition of the present invention, particularly in an aqueous solution, by forming a coordination bond between the compound and the molecule of the active ingredient, i.e., by actually and detectably forming a complex with the active ingredient of the pharmaceutical composition of the present invention. Non-limiting examples of complexing solubilizers include non-polymeric solubilizers such as lysine or arginine, and polymeric solubilizers such as PEG or cyclodextrin.

[0022] As used herein, the terms "parenterally acceptable diluent", "parenteral mixing diluent" and "commercially available diluent" refer to liquid materials used to dilute the active ingredient, which are suitable for administration to a subject by a route other than topical or oral. Examples of parenteral routes include intramuscular, intravascular (including intra-arterial or intravenous), intraorbital, retrobulbar, intranasal, intrathecal, intraventricular, intraspinal, intraperitoneal, intralung, intrathecal, intra-articular, intrasternal, periorbital or intralesional administration. Examples of parenterally acceptable diluents include water, aqueous glucose solution or lactated Ringer's solution. In the present application, the terms "commercially available diluent", "parenteral mixture diluent" and "parenterally acceptable diluent" have the same meaning and are used interchangeably.

[0023] As used herein, the term "carbohydrate" refers to a compound that is a polyhydroxy aldehyde or ketone, or a substance that yields such a compound upon hydrolysis. Carbohydrates may further contain nitrogen, phosphorus, or sulfur. Examples of carbohydrates include monosaccharides, disaccharides, oligosaccharides, and polysaccharides, particularly sucrose or mannitol.

[0024] As used herein, the term "amino acid" refers to any of the 20 naturally occurring amino acids or their synthetic analogs having non-natural side chains and including both D and L optical isomers. Examples of amino acids include, in particular, alanine and phenylalanine.

[0025] As used herein, the term “polyalkoxy compound” refers to a polymer compound in which the repeating unit represents an alkyl group having a linear or branched chain linked to an oxygen atom. Examples of polyalkoxy compounds include poloxamers, particularly poloxamer 188.

[0026] Within the scope of this invention, the terms "obtained by" and "can be obtained by" have the same meaning and are used interchangeably.

[0027] Within the scope of this invention, the term "equivalent" is understood to mean "molar equivalent."

[0028] As used herein, the term "aqueous solution" refers to a homogeneous mixture of liquids containing water.

[0029] As used herein, the terms “lyophilization” and “freeze-drying” are interchangeable and mean a process in which a desired product containing a solvent, in particular water, is cooled to a sufficient temperature, in particular by using liquid nitrogen or a cooling rack, in which part or all of the solvent is frozen, and the frozen solvent is further removed by one or more drying steps, in particular by the removal of unbound solvents by sublimation and desorption. The terms “lyophilized product” and “lyophilized product” mean the product obtained by lyophilization and are interchangeable throughout this specification.

[0030] As used herein, the terms “redissolve” or “redissolve” refer to the process of dissolving a lyophilized material in a diluent, preferably a parenterally acceptable diluent, in particular water. “Redissolved solution” refers to the product obtained by redissolution.

[0031] As used herein, the terms “treatment” or “to treat” are defined as the application or administration of a therapeutic agent, i.e., letermovir (alone or in combination with another agent), to a subject, or the application or administration of a therapeutic agent to an isolated tissue or cell line derived from a subject with HCMV infection, symptoms of HCMV infection, or the potential to develop HCMV infection, with the aim of curing, resolving, reducing, mitigating, modifying, treating, improving, or influencing HCMV infection, symptoms of HCMV infection, or the potential to develop HCMV infection. Such treatments may be specifically modified or altered based on knowledge derived from the field of genomic pharmacology.

[0032] As used herein, the terms “prevent,” “prevention,” or “prevention” mean, if the disability or disease had not occurred, that the disability or disease would not occur, or, if the disability or disease had already occurred, that there would be no further progression of the disability or disease. The ability to prevent some or all of the disease or symptoms associated with the disease is also considered. Prevention of disease encompasses prophylaxis.

[0033] As used herein, the term “subject” refers to a human or a non-human mammal. Examples of non-human mammals include livestock and pets such as sheep, cattle, pigs, cats, dogs, and rodents. Preferably, the subject is a human. In one embodiment, the subject is a human infant. In a preferred embodiment, the subject is a human neonatal. In another preferred embodiment, the subject is a subject requiring a specific solid organ transplant, such as a subject with kidney damage and a subject requiring an allogeneic hematopoietic stem cell transplant.

[0034] As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, that does not impair the biological activity or properties of the compound and is relatively non-toxic. That is, the material can be administered to a subject without causing undesirable biological effects and without interacting in a harmful manner with any component of the composition in which it is contained.

[0035] As used herein, the term “essentially not present” refers to a content of less than 5 mol%.

[0036] The subject of the present invention is a pharmaceutical composition comprising letermovir of formula (I) and potassium ions, [ka] • Containing potassium ions in a molar ratio of 0.80 to <1.00:1.00 relative to letermovil, preferably 0.88 to <1.00:1.00, more preferably 0.90 to <1.00:1.00; and When the pharmaceutical composition is dissolved in water at a concentration range of 1 to 100 mg / mL, preferably 20 to 100 mg / mL, with respect to letermovir, it can exhibit a pH in the range of 7 to 8, preferably 7.4 to 7.8; and • Essentially free of complexing solubilizers selected from the group consisting of PEG, lysine, arginine, cyclodextrin, and especially hydroxypropyl-β-cyclodextrin (HPBCD). Regarding pharmaceutical compositions.

[0037] The subject of the present invention is a pharmaceutical composition further comprising letermovir of formula (I) and potassium ions, [ka] • Contains potassium ions in a molar ratio of 0.80 to <1.00:1.00 relative to letermovil, preferably in the range of 0.80 to 0.90:1.00; and When the pharmaceutical composition is dissolved in a glucose aqueous solution, preferably a 5% (weight / volume) glucose solution in water, at a concentration range of 1 to 100 mg / mL, preferably 20 to 100 mg / mL, with respect to letermovir, it can exhibit a pH in the range of 7 to 8, preferably 7.4 to 7.8; and • Essentially free of complexing solubilizers selected from the group consisting of PEG, lysine, arginine, cyclodextrin, and especially hydroxypropyl-β-cyclodextrin (HPBCD). Regarding pharmaceutical compositions.

[0038] The subject of the present invention is a pharmaceutical composition further comprising letermovir of formula (I) and potassium ions, [ka] • Containing potassium ions in a molar ratio of 0.80 to <1.00:1.00 relative to letermovil, preferably 0.88 to <1.00:1.00, more preferably 0.90 to <1.00:1.00; and When the pharmaceutical composition is dissolved in Ringer's lactate solution at a concentration range of 1 to 100 mg / mL, preferably 20 to 100 mg / mL, with respect to letermovil, it can exhibit a pH in the range of 7 to 8, preferably 7.4 to 7.8; and • Essentially free of complexing solubilizers selected from the group consisting of PEG, lysine, arginine, cyclodextrin, and especially hydroxypropyl-β-cyclodextrin (HPBCD). Regarding pharmaceutical compositions.

[0039] In one embodiment, potassium ions in the pharmaceutical composition are contained in the form of a solution of potassium hydroxide (KOH), preferably an aqueous solution of KOH.

[0040] In one embodiment, the pharmaceutical composition according to the present invention essentially does not contain a compound selected from the group consisting of PEG, lysine, arginine, and cyclodextrin. In one embodiment, the pharmaceutical composition according to the present invention essentially does not contain lysine. In another embodiment, the pharmaceutical composition according to the present invention essentially does not contain arginine. In yet another embodiment, the pharmaceutical composition according to the present invention essentially does not contain PEG. In yet another embodiment, the pharmaceutical composition according to the present invention essentially does not contain cyclodextrin. In a preferred embodiment, the pharmaceutical composition according to the present invention essentially does not contain hydroxypropyl-β-cyclodextrin. In another preferred embodiment, the pharmaceutical composition according to the present invention essentially does not contain PEG, lysine, arginine, and cyclodextrin, in particular hydroxypropyl-β-cyclodextrin (HPBCD).

[0041] In one embodiment, the pharmaceutical composition according to the present invention is essentially free of complexing solubilizers, particularly PEG, lysine, arginine, and cyclodextrin, especially hydroxypropyl-β-cyclodextrin (HPBCD).

[0042] In one embodiment, the content of the complexing solubilizer in the pharmaceutical composition according to the present invention is less than 5 mol%. In a preferred embodiment, the content of the complexing solubilizer in the pharmaceutical composition according to the present invention is less than 3 mol%. In a more preferred embodiment, the content of the complexing solubilizer in the pharmaceutical composition according to the present invention is less than 1 mol%. In a more preferred embodiment, the content of the complexing solubilizer in the pharmaceutical composition according to the present invention is less than 0.5 mol%. Most preferably, the content of the complexing solubilizer in the pharmaceutical composition according to the present invention is less than 0.3 mol%.

[0043] In one embodiment, the pharmaceutical composition according to the present invention comprises letermovir and potassium ions, wherein the pharmaceutical composition is: • Contains potassium ions in a molar ratio of 0.80 to <1.00:1.00 relative to letermovil; 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 range of 7 to 8, preferably 7.4 to 7.8; and It essentially does not contain a complexing solubilizer selected from the group consisting of PEG, lysine, arginine, and cyclodextrin, particularly hydroxypropyl-β-cyclodextrin (HPBCD).

[0044] In one embodiment, the pharmaceutical composition according to the present invention comprises letermovir and potassium ions, wherein the pharmaceutical composition is: • Contains potassium ions in a molar ratio of 0.84 to <1.00:1.00 relative to letermovil; 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 range of 7 to 8, preferably 7.4 to 7.8; and It essentially does not contain a complexing solubilizer selected from the group consisting of PEG, lysine, arginine, and cyclodextrin, particularly hydroxypropyl-β-cyclodextrin (HPBCD).

[0045] In a preferred embodiment, the pharmaceutical composition according to the present invention comprises letermovir and potassium ions, wherein the pharmaceutical composition is: • Contains potassium ions in a molar ratio of 0.88 to <1.00:1.00 relative to letermovil; 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 range of 7 to 8, preferably 7.4 to 7.8; and It essentially does not contain a complexing solubilizer selected from the group consisting of PEG, lysine, arginine, and cyclodextrin, particularly hydroxypropyl-β-cyclodextrin (HPBCD).

[0046] In a more preferred embodiment, the pharmaceutical composition according to the present invention comprises letermovir and potassium ions, wherein the pharmaceutical composition is: • Contains potassium ions in a molar ratio of 0.90 to <1.00:1.00 relative to letermovil; 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 range of 7 to 8, preferably 7.4 to 7.8; and It essentially does not contain a complexing solubilizer selected from the group consisting of PEG, lysine, arginine, and cyclodextrin, particularly hydroxypropyl-β-cyclodextrin (HPBCD).

[0047] In one embodiment, the pharmaceutical composition according to the present invention comprises letermovir and potassium ions, wherein the pharmaceutical composition is: • Contains potassium ions in a molar ratio of 0.80 to <1.00:1.00 relative to letermovil; and 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 range of 7 to 8, preferably 7.4 to 7.8; and It essentially does not contain a complexing solubilizer selected from the group consisting of PEG, lysine, arginine, and cyclodextrin, particularly hydroxypropyl-β-cyclodextrin (HPBCD).

[0048] In one embodiment, the pharmaceutical composition according to the present invention comprises letermovir and potassium ions, wherein the pharmaceutical composition is: • Contains potassium ions in a molar ratio of 0.84 to <1.00:1.00 relative to letermovil; and 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 range of 7 to 8, preferably 7.4 to 7.8; and It essentially does not contain a complexing solubilizer selected from the group consisting of PEG, lysine, arginine, and cyclodextrin, particularly hydroxypropyl-β-cyclodextrin (HPBCD).

[0049] In a preferred embodiment, the pharmaceutical composition according to the present invention comprises letermovir and potassium ions, wherein the pharmaceutical composition is: • Contains potassium ions in a molar ratio of 0.88 to <1.00:1.00 relative to letermovil; and 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 range of 7 to 8, preferably 7.4 to 7.8; and It essentially does not contain a complexing solubilizer selected from the group consisting of PEG, lysine, arginine, and cyclodextrin, particularly hydroxypropyl-β-cyclodextrin (HPBCD).

[0050] In a more preferred embodiment, the pharmaceutical composition according to the present invention comprises letermovir and potassium ions, wherein the pharmaceutical composition is: • Contains potassium ions in a molar ratio of 0.90 to <1.00:1.00 relative to letermovil; and 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 range of 7 to 8, preferably 7.4 to 7.8; and It essentially does not contain a complexing solubilizer selected from the group consisting of PEG, lysine, arginine, and cyclodextrin, particularly hydroxypropyl-β-cyclodextrin (HPBCD).

[0051] In one embodiment, the pharmaceutical composition according to the present invention comprises letermovir and potassium ions, wherein the pharmaceutical composition is: • Contains potassium ions in a molar ratio of 0.80 to <1.00:1.00 relative to letermovil; and When the pharmaceutical composition is dissolved in an aqueous glucose solution, preferably a 5% (weight / volume) glucose solution in water, at a concentration range of 20 to 100 mg / mL with respect to letermovir, it can exhibit a pH range of 7 to 8, preferably 7.4 to 7.8; and It essentially does not contain a complexing solubilizer selected from the group consisting of PEG, lysine, arginine, and cyclodextrin, particularly hydroxypropyl-β-cyclodextrin (HPBCD).

[0052] In one embodiment, the pharmaceutical composition according to the present invention comprises letermovir and potassium ions, wherein the pharmaceutical composition is: • Contains potassium ions in a molar ratio of 0.84 to <1.00:1.00 relative to letermovil; and When the pharmaceutical composition is dissolved in an aqueous glucose solution, preferably a 5% (weight / volume) glucose solution in water, at a concentration range of 20 to 100 mg / mL with respect to letermovir, it can exhibit a pH range of 7 to 8, preferably 7.4 to 7.8; and It essentially does not contain a complexing solubilizer selected from the group consisting of PEG, lysine, arginine, and cyclodextrin, particularly hydroxypropyl-β-cyclodextrin (HPBCD).

[0053] In one embodiment, the pharmaceutical composition according to the present invention comprises letermovir and potassium ions, wherein the pharmaceutical composition is: • Contains potassium ions in a molar ratio of 0.88 to <1.00:1.00 relative to letermovil; and When the pharmaceutical composition is dissolved in an aqueous glucose solution, preferably a 5% (weight / volume) glucose solution in water, at a concentration range of 20 to 100 mg / mL with respect to letermovir, it can exhibit a pH range of 7 to 8, preferably 7.4 to 7.8; and It essentially does not contain a complexing solubilizer selected from the group consisting of PEG, lysine, arginine, and cyclodextrin, particularly hydroxypropyl-β-cyclodextrin (HPBCD).

[0054] In one embodiment, the pharmaceutical composition according to the present invention comprises letermovir and potassium ions, wherein the pharmaceutical composition is: • Contains potassium ions in a molar ratio of 0.90 to <1.00:1.00 relative to letermovil; and When the pharmaceutical composition is dissolved in an aqueous glucose solution, preferably a 5% w / v glucose solution in water, at a concentration range of 20 to 100 mg / mL with respect to letermovil, it can exhibit a pH range of 7 to 8, preferably 7.4 to 7.8; and It essentially does not contain a complexing solubilizer selected from the group consisting of PEG, lysine, arginine, and cyclodextrin, particularly hydroxypropyl-β-cyclodextrin (HPBCD).

[0055] In one embodiment, the pharmaceutical composition according to the present invention comprises letermovir and potassium ions, wherein the pharmaceutical composition is: • Contains potassium ions in a molar ratio of 0.80 to <1.00:1.00 relative to letermovil; and When the pharmaceutical composition is dissolved in Ringer's lactate solution at a concentration range of 20 to 100 mg / mL with respect to letermovil, it can exhibit a pH in the range of 7 to 8, preferably 7.4 to 7.8; and It essentially does not contain a complexing solubilizer selected from the group consisting of PEG, lysine, arginine, and cyclodextrin, particularly hydroxypropyl-β-cyclodextrin (HPBCD).

[0056] In one embodiment, the pharmaceutical composition according to the present invention comprises letermovir and potassium ions, wherein the pharmaceutical composition is: • Contains potassium ions in a molar ratio of 0.84 to <1.00:1.00 relative to letermovil; and When the pharmaceutical composition is dissolved in Ringer's lactate solution at a concentration range of 20 to 100 mg / mL with respect to letermovil, it can exhibit a pH in the range of 7 to 8, preferably 7.4 to 7.8; and It essentially does not contain a complexing solubilizer selected from the group consisting of PEG, lysine, arginine, and cyclodextrin, particularly hydroxypropyl-β-cyclodextrin (HPBCD).

[0057] In one embodiment, the pharmaceutical composition according to the present invention comprises letermovir and potassium ions, wherein the pharmaceutical composition is: • Contains potassium ions in a molar ratio of 0.88 to <1.00:1.00 relative to letermovil; and When the pharmaceutical composition is dissolved in Ringer's lactate solution at a concentration range of 20 to 100 mg / mL with respect to letermovil, it can exhibit a pH in the range of 7 to 8, preferably 7.4 to 7.8; and It essentially does not contain a complexing solubilizer selected from the group consisting of PEG, lysine, arginine, and cyclodextrin, particularly hydroxypropyl-β-cyclodextrin (HPBCD).

[0058] In one embodiment, the pharmaceutical composition according to the present invention comprises letermovir and potassium ions, wherein the pharmaceutical composition is: • Contains potassium ions in a molar ratio of 0.90 to <1.00:1.00 relative to letermovil; and When the pharmaceutical composition is dissolved in Ringer's lactate solution at a concentration range of 20 to 100 mg / mL with respect to letermovil, it can exhibit a pH in the range of 7 to 8, preferably 7.4 to 7.8; and It essentially does not contain a complexing solubilizer selected from the group consisting of PEG, lysine, arginine, and cyclodextrin, particularly hydroxypropyl-β-cyclodextrin (HPBCD).

[0059] In one embodiment, the pharmaceutical composition according to the present invention contains potassium ions with respect to letermovir in a molar ratio of 0.80 to <1.00:1.00, preferably 0.81 to <1.00:1.00, more preferably 0.82 to <1.00:1.00, more preferably 0.83 to <1.00:1.00, more preferably 0.84 to <1.00:1.00, more preferably 0.85 to <1.00:1.00, more preferably 0.86 to <1.00:1.00, more preferably 0.87 to <1.00:1.00, more preferably 0.88 to <1.00:1.00, more preferably 0.89 to <1.00:1.00, and more preferably 0.90 to <1.00:1.00.

[0060] In one embodiment, the pharmaceutical composition according to the present invention contains potassium ions in the form of a potassium hydroxide solution (KOH), preferably an aqueous solution of KOH, in a molar ratio of 0.80 to <1.00:1.00, preferably 0.81 to <1.00:1.00, more preferably 0.82 to <1.00:1.00, more preferably 0.83 to <1.00:1.00, more preferably 0.84 to <1.00:1.00, more preferably 0.85 to <1.00:1.00, more preferably 0.86 to <1.00:1.00, more preferably 0.87 to <1.00:1.00, more preferably 0.88 to <1.00:1.00, more preferably 0.89 to <1.00:1.00, and more preferably 0.90 to <1.00:1.00 relative to letermovil.

[0061] In one embodiment, the pharmaceutical composition according to the present invention can exhibit a pH in the range of 7 to 8 when the pharmaceutical composition is dissolved in water at a concentration range of 1 to 100 mg / mL with respect to letermovir. In a preferred embodiment, the pharmaceutical composition according to the present invention can exhibit a pH in the range of 7 to 8 when the pharmaceutical composition is dissolved in water at a concentration range of 20 to 100 mg / mL with respect to letermovir.

[0062] In a preferred embodiment, the pharmaceutical composition according to the present invention can exhibit a pH in the range of 7.4 to 7.8 when the pharmaceutical composition is dissolved in water at a concentration range of 1 to 100 mg / mL with respect to letermovir. In a more preferred embodiment, the pharmaceutical composition according to the present invention can exhibit a pH in the range of 7.4 to 7.8 when the pharmaceutical composition is dissolved in water at a concentration range of 20 to 100 mg / mL with respect to letermovir.

[0063] In one embodiment, the pharmaceutical composition according to the present invention can exhibit a pH in the range of 7 to 8 when the pharmaceutical composition is dissolved in a glucose aqueous solution, preferably a 5% (weight / volume) glucose solution in water, at a concentration range of 20 to 100 mg / mL with respect to letermovir. In a preferred embodiment, the pharmaceutical composition according to the present invention can exhibit a pH in the range of 7.4 to 7.8 when the pharmaceutical composition is dissolved in a glucose aqueous solution, preferably a 5% (weight / volume) glucose solution in water, at a concentration range of 20 to 100 mg / mL with respect to letermovir.

[0064] In one embodiment, the pharmaceutical composition according to the present invention can exhibit a pH in the range of 7 to 8 when the pharmaceutical composition is dissolved in Ringer's lactate solution at a concentration range of 20 to 100 mg / mL with respect to letermovir. In a preferred embodiment, the pharmaceutical composition according to the present invention can exhibit a pH in the range of 7.4 to 7.8 when the pharmaceutical composition is dissolved in Ringer's lactate solution at a concentration range of 20 to 100 mg / mL with respect to letermovir.

[0065] In one embodiment, a pharmaceutical composition comprising letermovir of formula (I) and potassium ions, [ka] • Containing potassium ions in a molar ratio of 0.80 to <1.00:1.00 relative to letermovil, preferably 0.88 to <1.00:1.00, more preferably 0.90 to <1.00:1.00; 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 range of 7 to 8, preferably 7.4 to 7.8; and • Essentially free of complexing solubilizers selected from the group consisting of PEG, lysine, arginine, cyclodextrin, and especially hydroxypropyl-β-cyclodextrin (HPBCD), Furthermore, comprising at least one pharmaceutical carrier or excipient, Pharmaceutical composition.

[0066] In one embodiment, a pharmaceutical composition comprising letermovir of formula (I) and potassium ions, [ka] • Containing potassium ions in a molar ratio of 0.80 to <1.00:1.00 relative to letermovil, preferably 0.88 to <1.00:1.00, more preferably 0.90 to <1.00:1.00; and When the pharmaceutical composition is dissolved in a glucose aqueous solution, preferably a 5% (weight / volume) glucose solution in water, at a concentration range of 1 to 100 mg / mL, preferably 20 to 100 mg / mL, with respect to letermovir, it can exhibit a pH in the range of 7 to 8, preferably 7.4 to 7.8; and • Essentially free of complexing solubilizers selected from the group consisting of PEG, lysine, arginine, cyclodextrin, and especially hydroxypropyl-β-cyclodextrin (HPBCD), Furthermore, comprising at least one pharmaceutical carrier or excipient, Pharmaceutical composition.

[0067] In one embodiment, the pharmaceutical composition is a pharmaceutical composition comprising letermovir of formula (I) and potassium ions, [ka] • Containing potassium ions in a molar ratio of 0.80 to <1.00:1.00, more preferably 0.88 to <1.00:1.00, and more preferably 0.90 to <1.00:1.00 relative to letermovil; and When the pharmaceutical composition is dissolved in Ringer's lactate solution at a concentration range of 1 to 100 mg / mL, preferably 20 to 100 mg / mL, with respect to letermovil, it can exhibit a pH in the range of 7 to 8, preferably 7.4 to 7.8; and • Essentially free of complexing solubilizers selected from the group consisting of PEG, lysine, arginine, cyclodextrin, and especially hydroxypropyl-β-cyclodextrin (HPBCD), Furthermore, comprising at least one pharmaceutical carrier or excipient, Pharmaceutical composition.

[0068] In one embodiment, the pharmaceutical composition according to the present invention comprises at least one excipient selected from the group consisting of carbohydrates such as sucrose or mannitol, amino acids such as phenylalanine, polyalkoxy compounds such as poloxamer, more particularly poloxamer 188, and polyvinylpyrrolidone (PVP) such as PVP PF12. In a preferred embodiment, the excipient is mannitol or sucrose or a combination thereof.

[0069] In one embodiment, the pharmaceutical composition according to the present invention is essentially free of complexing solubilizing agents.

[0070] In one embodiment, the pharmaceutical composition according to the present invention may contain an excipient exhibiting complexing and solubilizing properties. In one embodiment, such an excipient is a polyalkoxy compound such as poloxamer. In one embodiment, the poloxamer is poloxamer 188.

[0071] In one embodiment, the pharmaceutical composition according to the present invention contains a polyalkoxy compound such as poloxamer 188 and essentially does not contain other complexing solubilizers.

[0072] In one embodiment, the excipients used are suitable for administration to subjects requiring specific solid organ transplants, such as those with renal impairment and those requiring allogeneic hematopoietic stem cell transplants. Non-limiting examples of such excipients include sucrose, mannitol, phenylalanine, poloxamers such as poloxamer 188, and polyvinylpyrrolidone (PVP) such as PVP PF12.

[0073] In one embodiment, the pharmaceutical composition according to the present invention further comprises a buffer, preferably trishydroxyaminomethane (Tris).

[0074] In one embodiment, the pharmaceutical composition according to the present invention further comprises HCl.

[0075] In one embodiment, the pharmaceutical composition according to the present invention exhibits stability according to ICH Q1A(R2) (Stability Test for Novel Active Pharmaceutical Ingredients and Formulations) covering climate zones I to IV. In a preferred embodiment, the pharmaceutical composition according to the present invention is stable for at least one month. In a more preferred embodiment, the pharmaceutical composition according to the present invention is stable for at least three months. In a more preferred embodiment, the pharmaceutical composition according to the present invention is stable for at least six months. In a more preferred embodiment, the pharmaceutical composition according to the present invention is stable for at least twelve months. In a more preferred embodiment, the pharmaceutical composition according to the present invention is stable for at least eighteen months. In a more preferred embodiment, the pharmaceutical composition according to the present invention is stable for at least thirty-six months.

[0076] In one embodiment, the pharmaceutical composition according to the present invention is in solid form. In a preferred embodiment, the solid form of the pharmaceutical composition is a freeze-dried product.

[0077] In one embodiment, the pharmaceutical composition according to the present invention is in liquid form. In a preferred embodiment, the liquid form of the pharmaceutical composition according to the present invention is an aqueous solution. In another preferred embodiment, the liquid form of the pharmaceutical composition according to the present invention is a solution in at least one parenterally acceptable diluent. Non-limiting examples of parenterally acceptable diluents include water, an aqueous glucose solution, and Ringer's lactate solution.

[0078] In one embodiment, the pharmaceutical composition according to the present invention is suitable for intravenous (IV) administration or injection.

[0079] The subject of this invention further involves the following steps: i) A solution of letermovir and potassium ions having a molar ratio of potassium ions to letermovir in the range of 0.80 to <1.00:1.00, preferably 0.84 to <1.00:1.00, more preferably 0.88 to <1.00:1.00, more preferably 0.90 to <1.00:1.00, and optionally, at least one excipient selected from the group consisting of carbohydrates, particularly sucrose or mannitol, amino acids, particularly phenylalanine, polyalkoxy compounds, particularly poloxamer, more specifically poloxamer 188, and polyvinylpyrrolidone (PVP), particularly PVP PF12. The present invention relates to a method for producing a pharmaceutical composition, including the present invention.

[0080] In one embodiment, the solution obtained in step i is a solution in a parenterally acceptable diluent such as water.

[0081] In one embodiment, potassium ions are provided in step i in the form of a KOH solution, preferably an aqueous KOH solution.

[0082] In one embodiment, preparing the solution according to step i above involves the following steps: a-1) Prepare a parenterally acceptable diluent, especially a suspension of letermovir in water; b-1) Add KOH to the suspension obtained in step a-1 to obtain the mixture; c-1) Optionally, stir the mixture obtained in step b-1 for at least 30 minutes; d-1) Optionally, add at least one excipient selected from the group consisting of carbohydrates, particularly sucrose and mannitol; amino acids, particularly phenylalanine; polyalkoxy compounds, particularly poloxamer, more specifically poloxamer 188; and polyvinylpyrrolidone (PVP), particularly PVP PF12, to the mixture; e-1) Optionally, stir the mixture for at least 30 minutes. Includes.

[0083] In a preferred embodiment, an aqueous solution of KOH is added in step b-1.

[0084] In a preferred embodiment, the solution in step c-1 is stirred for at least 2 hours.

[0085] In a preferred embodiment, the solution in step e-1 is stirred for at least 2 hours.

[0086] In a preferred embodiment, 0.80 to <1.00 equivalents of KOH are added to letermovir in step b-1. In a more preferred embodiment, 0.84 to <1.00 equivalents of KOH are added to letermovir in step b-1. In a more preferred embodiment, 0.88 to <1.00 equivalents of KOH are added to letermovir in step b-1. In a more preferred embodiment, 0.90 to <1.00 equivalents of KOH are added to letermovir in step b-1.

[0087] In one embodiment, 0.80 equivalents of KOH are added to letermovir in step b-1. In one embodiment, 0.82 equivalents of KOH are added to letermovir in step b-1. In one embodiment, 0.84 equivalents of KOH are added to letermovir in step b-1. In one embodiment, 0.86 equivalents of KOH are added to letermovir in step b-1. In one embodiment, 0.88 equivalents of KOH are added to letermovir in step b-1. In one embodiment, 0.90 equivalents of KOH are added to letermovir in step b-1.

[0088] In another embodiment, the method for preparing the solution according to step i is as follows: instead of steps a-1 to e-1, steps a-2 to e-2: a-2) Prepare a parenterally acceptable diluent, especially a solution of KOH in water; b-2) Add letermovil to the solution obtained in step a-2 to obtain a mixture; c-2) Optionally, stir the mixture obtained in step b-2 for at least 30 minutes; d-2) Optionally, add at least one excipient selected from the group consisting of carbohydrates, particularly sucrose and mannitol; amino acids, particularly phenylalanine; polyalkoxy compounds, particularly poloxamer, more specifically poloxamer 188; and polyvinylpyrrolidone (PVP), particularly PVP PF12, to the mixture; e-2) Optionally, stir the mixture for at least 30 minutes. This includes using [the following].

[0089] In a preferred embodiment, the solution in step c-2 is stirred for at least 2 hours.

[0090] In a preferred embodiment, the solution in step e-2 is stirred for at least 2 hours.

[0091] In a preferred embodiment, 1.25 to >1.00 equivalents of letermovir relative to KOH are added in step b-2. In a more preferred embodiment, 1.19 to >1.00 equivalents of letermovir relative to KOH are added in step b-2. In a more preferred embodiment, 1.14 to >1.00 equivalents of letermovir relative to KOH are added in step b-2. In a more preferred embodiment, 1.11 to >1.00 equivalents of letermovir relative to KOH are added in step b-2.

[0092] In one embodiment, 1.25 equivalents of letermovir are added to KOH in step b-2. In one embodiment, 1.22 equivalents of letermovir are added to KOH in step b-2. In one embodiment, 1.19 equivalents of letermovir are added to KOH in step b-2. In one embodiment, 1.16 equivalents of letermovir are added to KOH in step b-2. In one embodiment, 1.14 equivalents of letermovir are added to KOH in step b-2. In one embodiment, 1.11 equivalents of letermovir are added to KOH in step b-2.

[0093] In one embodiment, the method for producing a pharmaceutical composition according to the present invention further includes adjusting the pH of the solution obtained in step i to a range of 7 to 8, preferably 7.4 to 7.8. In one preferred embodiment, the adjustment is made by adding HCl. In a more preferred embodiment, the pH of the solution obtained in step i is in the range of 7 to 8, preferably 7.4 to 7.8, and no pH adjustment is necessary.

[0094] In one embodiment, the solution obtained after pH adjustment is optionally stirred for at least 10 minutes, preferably at least 30 minutes.

[0095] In one embodiment, a method for producing a pharmaceutical composition according to the present invention optionally includes filtering the solution obtained in step i. In one embodiment, a method for producing a pharmaceutical composition according to the present invention optionally includes filtering the solution obtained after adjusting the pH of the solution obtained in step i.

[0096] In one embodiment, a method for producing a pharmaceutical composition according to the present invention further includes freeze-drying the obtained solution to obtain a freeze-dried product.

[0097] In one embodiment, a method for producing a pharmaceutical composition according to the present invention further comprises redissolving a lyophilized material in a first parenterally acceptable diluent to obtain a redissolved solution with respect to letermovir in a concentration range of 0.1 to 100 mg / mL, and optionally further diluting the redissolved solution with a second parenterally acceptable diluent to a final concentration acceptable for injection or infusion. The first and second parenterally acceptable diluents may be the same or different. In one embodiment, when letermovir is present in the redissolved solution at a concentration range of 0.1 to 100 mg / mL, the redissolved solution exhibits a pH in the range of 7 to 8, preferably 7.4 to 7.8. In a preferred embodiment, when letermovir is present in the redissolved solution at a concentration range of 20 to 100 mg / mL, the redissolved solution exhibits a pH in the range of 7 to 8, preferably 7.4 to 7.8.

[0098] In one embodiment, the final concentration acceptable for injection or infusion is in the range of 0.1 to 100 mg / mL. In another embodiment, the final concentration acceptable for injection or infusion is in the range of 0.8 to 100 mg / mL. In yet another embodiment, the final concentration acceptable for injection or infusion is in the range of 20 to 100 mg / mL. In yet another embodiment, the final concentration acceptable for injection or infusion is in the range of 50 to 100 mg / mL. In yet another embodiment, the final concentration acceptable for injection or infusion is in the range of 20 to 50 mg / mL. In a preferred embodiment, the final concentration acceptable for injection or infusion is 0.8 mg / mL.

[0099] In a preferred embodiment, a method for producing a pharmaceutical composition according to the present invention involves the following steps: i) A solution of letermovir and potassium ions having a molar ratio of potassium ions to letermovir in the range of 0.80 to <1.00:1.00, preferably 0.84 to <1.00:1.00, more preferably 0.88 to <1.00:1.00, and more preferably 0.90 to <1.00:1.00; and optionally, at least one excipient selected from the group consisting of carbohydrates such as sucrose or mannitol; amino acids such as phenylalanine; polyalkoxy compounds such as poloxamer, particularly poloxamer 188; and polyvinylpyrrolidone (PVP) such as PVP PF12; ii) If necessary, adjust the pH of the solution obtained in step i to a range of 7 to 8, preferably 7.4 to 7.8, using suitable organic and inorganic acids; iii) Optionally, filter the obtained solution. Includes.

[0100] In one embodiment of step ii, the organic acid or inorganic acid is HCl.

[0101] In another preferred embodiment, a method for producing a pharmaceutical composition according to the present invention involves the following steps: i) A solution of letermovir and potassium ions having a molar ratio of potassium ions to letermovir in the range of 0.80 to <1.00:1.00, preferably 0.84 to <1.00:1.00, more preferably 0.88 to <1.00:1.00, and more preferably 0.90 to <1.00:1.00; and optionally, at least one excipient selected from the group consisting of carbohydrates such as sucrose or mannitol; amino acids such as phenylalanine; polyalkoxy compounds such as poloxamer, particularly poloxamer 188; and polyvinylpyrrolidone (PVP) such as PVP PF12; ii) If necessary, adjust the pH of the solution obtained in step i to a range of 7 to 8, preferably 7.4 to 7.8, using suitable organic and inorganic acids; iii) Optionally, filter the resulting solution; iv) Freeze-dry the obtained solution to obtain a freeze-dried product. Includes.

[0102] In one embodiment of step ii, the organic acid or inorganic acid is HCl.

[0103] In another preferred embodiment, a method for producing a pharmaceutical composition according to the present invention involves the following steps: i) A solution of letermovir and potassium ions having a molar ratio of potassium ions to letermovir in the range of 0.80 to <1.00:1.00, preferably 0.84 to <1.00:1.00, more preferably 0.88 to <1.00:1.00, and more preferably 0.90 to <1.00:1.00; and optionally, at least one excipient selected from the group consisting of carbohydrates such as sucrose or mannitol; amino acids such as phenylalanine; polyalkoxy compounds such as poloxamer, particularly poloxamer 188; and polyvinylpyrrolidone (PVP) such as PVP PF12; ii) If necessary, adjust the pH of the solution obtained in step i to a range of 7 to 8, preferably 7.4 to 7.8, using suitable organic and inorganic acids; iii) Optionally, filter the resulting solution; iv) Freeze-dry the obtained solution to obtain a freeze-dried product; v) Redissolve the lyophilized product in a first parenterally permissible diluent to obtain a redissolved solution with a concentration range of 1 to 100 mg / mL, preferably 20 to 100 mg / mL, with respect to letermovir, and optionally further dilute the redissolved solution with a second parenterally permissible diluent to a final concentration permissible for injection or infusion, where the first and second parenterally permissible diluents may be the same or different. Includes.

[0104] In one embodiment of step ii, the organic acid or inorganic acid is HCl.

[0105] Steps i-v described above do not necessarily imply a specific order or number of steps. However, preferably, the steps of the method of the present invention are carried out in the order described above. Some of the steps may be optional, and in some embodiments, optional steps may not be performed. For example, in one embodiment, step iv may follow immediately after step ii without performing step iii. Furthermore, the steps described above do not exclude additional steps that are not explicitly mentioned. For example, the solution obtained in steps i and / or ii may be optionally stirred.

[0106] The subject of the present invention further relates to pharmaceutical compositions that can be obtained by any of the methods disclosed herein.

[0107] The pharmaceutical compositions according to the present invention can be used to manufacture drugs suitable for use in methods of preventing and / or treating infections caused by representative herpesviridae viruses, particularly cytomegaloviruses, and especially human cytomegaloviruses.

[0108] Furthermore, the subject matter of the present invention relates to pharmaceutical compositions according to the present invention for use in methods of treating and / or preventing diseases, preferably viral infections, in particular infections caused by human cytomegalovirus (HCMV) or other representative members of the herpesvirus group.

[0109] Further aspects of the present invention relate to the use of pharmaceutical compositions according to the present invention in methods for treating and / or preventing diseases, preferably viral infections, in particular infections caused by human cytomegalovirus (HCMV) or other representatives of the herpesvirus group.

[0110] Another aspect of the present invention relates to the use of pharmaceutical compositions according to the present invention for the preparation of pharmaceuticals for the treatment and / or prevention of diseases, in particular viral infections, preferably human cytomegalovirus (HCMV) infections or infections caused by other members of the herpesvirus group.

[0111] A further aspect of the present invention relates to a method for treating and / or preventing viral infections, preferably human cytomegalovirus (HCMV) infections or infections caused by other members of the herpesvirus group, in subjects requiring a method for treating and / or preventing infections by administering a pharmaceutical composition according to the present invention. In one embodiment, the subjects are selected from the group consisting of neonates, subjects requiring specific solid organ transplants, for example, subjects with renal impairment and subjects requiring allogeneic hematopoietic stem cell transplants.

[0112] In general, it has been proven advantageous to administer a pharmaceutical composition in a manner in which approximately 0.001 to 10 mg, preferably 0.01 to 5 mg, of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazoline-4-yl]acetic acid (letermovil) is administered per kg of body weight.

[0113] Nevertheless, deviations from the aforementioned doses of letermovir may be necessary, particularly depending on body weight, individual response to the active substance, and the time and interval at which it is administered. For example, in certain cases, it may be sufficient to administer a smaller dose of letermovir than the aforementioned minimum dose, while in other cases, the stated upper limit may be exceeded. When administering large doses, it may be recommended to divide them into several individual doses per day.

[0114] The present invention will be described in detail below based on non-limiting examples.

[0115] Unless otherwise stated, the percentages in the following tests and examples are weight percentages, parts are weight proportions, and solvent ratios, dilution ratios, and concentrations of liquid solutions all relate to volume.

[0116] Abbreviation API (Active Ingredients in Pharmaceuticals) h (singular or plural) time HCl (hydrochloric acid) HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) HPBCD (Hydroxypropyl-β-Cyclodextrin) HPLC (High-Pressure Liquid Chromatography) conc. concentration min. LAF laminar flow PEG polyethylene glycol PDE daily exposure allowance RT (Retention time in HPLC) RP-HPLC (Reverse-Phase High-Pressure Liquid Chromatography) rpm (revolutions per minute) rt room temperature

[0117] Analysis method Visual inspection The sample was gently and manually stirred radially for 5 seconds in front of a white background to check for the presence of visible particles.

[0118] pH The pH value of the sample was measured using a calibrated pH meter, EUTEGH CAKTON PH / Ion 510, serial number 172361, along with a Polilite laboratory electrode. The sample was stirred, and the electrode was introduced. Measurement was performed until the pH value stabilized. Between measurements, the electrode was thoroughly rinsed with water. pH measurements were performed using an analysis volume of ~1~2 mL at a specified temperature of 22°C ± 3°C. Three-point calibration of the pH meter was performed daily using buffers (Hamilton Duracal buffer) at pH 7.00, pH 4.01, and pH 10.01.

[0119] Reverse-phase high-performance liquid chromatography (RP-HPLC) The concentrations of free letermovir base and potential degradation products were measured using RP-HPLC.

[0120] Table 1 shows an overview of the eluents used in the RP-HPLC analysis. Table 1: Elutions used in RP-HPLC analysis [Table 1]

[0121] The following parameters were used in the RP-HPLC method. Instrument: Agilent Technologies 1200 series and VWD G131413 detector Column: Agilent Zorbax Eclipse XDB C-18, 150 × 4.6 mm, 5 μm Flow rate: 1.0ml / min Solvent A: 0.1% formic acid in water Solvent B: 0.1% formic acid in 100% methanol End time: 26 minutes Injection volume: 10μl Column temperature: 35℃ Wavelength: 260nm

[0122] Table 2 shows the gradients used in the RP-HPLC method. Table 2: Gradient applied during RP-HPLC analysis [Table 2]

[0123] A calibration curve using a reference standard was used to quantify the free letermovyl base in solution.

[0124] The sample was diluted in water to approximately 2 mg / mL (corrected for free letermovil base in the solution) and analyzed with an injection volume of 10 μl. Before injection, the diluted sample was filtered through a syringe filter (nylon, 0.45 μm).

[0125] Peak integration was performed manually for all API-related peaks. Peaks that were present in the blank or with formulation buffer injection were ignored.

[0126] Powder X-ray diffraction (PXRD) Instrument: Powder diffraction patterns were acquired using transmission geometry with a Bruker D8 Advance Series 2 Theta / Theta powder diffraction system using the CuKα1 line. The system is equipped with a VÅNTEC-1 single-photon counting PSD, germanium monochromator, fixed divergent slit, and radial solar. Software used: Data acquisition was performed using DIFFRAC and XRD Commander V.2.5.1, and evaluation was performed using EVA V.5.0.0.22 (Bruker-AXS 2010-2018).

[0127] Sample preparation: Approximately 15 mg of untreated sample was prepared in a standard sample holder using two polyacetate foils.

[0128] Measurement conditions: Samples were measured at room temperature in a 2θ range of 4° to 40° using a 0.1-hour measurement with an angular step of 0.049° and a time of 2787 seconds per step. [Examples]

[0129] Example 1. Observation of solutions of free letermovyl base containing different equivalents of potassium hydroxide at different temperatures. a) Initial drying Twenty-six samples of letermovyl free base were prepared by weighing the substance, removing residual water, and drying overnight in a vacuum oven at 90°C (approximately 5 mbar) to avoid weighing errors, and the equivalent weight of KOH was calculated (Table 3). Approximately 80 mg and 300 mg of the sample were weighed and dissolved in 4 mL and 3 mL of water, respectively, to prepare 20 mg / mL and 100 mg / mL solutions.

[0130] Table 3. Initial drying process of 26 samples of free letermovyl base. [Table 3]

[0131] b) Preparation of suspensions / solutions, and analysis of pH and solubility. Procedure: Corresponding amounts of water and equivalent amounts of 1 M KOH aqueous solution were added to each sample. The suspensions were stirred at room temperature, 40°C, or 60°C. pH, solubility, and precipitation were observed after 12 hours, 24 hours, 48 ​​hours, and 7 days (Tables 4, 5, 6, and 7).

[0132] Table 4. Preparation of 20 mg / mL samples of free letermovil in water containing different equivalents of KOH at room temperature. [Table 4]

[0133] Table 5. Preparation of 100 mg / mL samples of letermovyl free base in water containing different equivalents of KOH at room temperature. [Table 5]

[0134] Table 6. Preparation of 20 mg / mL samples of free letermovyl in water containing different equivalents of KOH at 40°C and 60°C. [Table 6]

[0135] Table 7. Preparation of 100 mg / mL samples of letermovyl free base in water containing different equivalents of KOH at 40°C and 60°C. [Table 7]

[0136] result In a sample of 20 mg / mL of free letermovil base and KOH, particles are always present in the suspension, except for the sample with 1 equivalent of KOH (where only a few particles remain in the solution, between the gas and aqueous phases). All samples of 100 mg / mL of letermovyl free base and KOH are completely dissolved (for the first two days, only a few particles remain in the solution, between the gas and aqueous phases). The effect differs slightly depending on the temperature: 40℃ - In samples containing 20 mg / mL of letermovil free base and 0.84, 0.86, and 0.88 equivalents of KOH, particles were present in the suspension, and the appearance was cloudy. - In samples containing 100 mg / mL of letermovil free base and 0.84, 0.86, and 0.88 equivalents of KOH, particles are present in the suspension. 60℃ - In a sample of 20 mg / mL of letermovir free base and 0.84 equivalents of KOH, particles were present in the suspension. - Samples of 20 mg / mL of free letermovil with 0.86 and 0.88 equivalents of KOH, and samples of 100 mg / mL of free letermovil with 0.84, 0.86, and 0.88 equivalents of KOH, remained clear solutions from the first day to one week later.

[0137] Example 2. Freeze-drying and reconstitution with water after 7 days. a) Initial drying Fourteen samples of letermovyl free base were prepared by weighing the substance, removing residual water, and drying overnight in a vacuum oven at 90°C (approximately 5 mbar) to avoid weighing errors, and the equivalent weight of KOH was calculated (Table 15). Approximately 80 mg and 300 mg of the sample were weighed and dissolved in 4 mL and 3 mL of water, respectively, to prepare solutions of 20 mg / mL and 100 mg / mL.

[0138] Table 8. Initial drying process of 14 samples of free letermovyl base. [Table 8]

[0139] b) Preparation of suspensions / solutions and analysis of solubility Procedure: Corresponding amounts of water and equivalent amounts of 1 M KOH aqueous solution were added to each sample. The suspensions were stirred at room temperature, and their effects on solubility and precipitation were examined (Table 9).

[0140] Table 9. Preparation of samples of free letermovyl base containing different equivalent amounts of KOH in water. [Table 9]

[0141] Solubility over 7 days After one week, precipitates remained in the samples of 20 mg / mL with 0.8, 0.82, 0.84, and 0.86 equivalents of KOH. A small amount of solid matter was observed in the sample of 20 mg / mL with 0.88 equivalents of KOH, and the samples of 20 mg / mL with 0.9 and 1 equivalent of KOH were clear solutions. All 100 mg / mL samples were clear solutions after one week.

[0142] The remaining samples were visually inspected one week later and were found to be clear solutions.

[0143] c) Freeze-drying and reconstitution with water One week later, the samples were freeze-dried.

[0144] procedure: For the 20 mg / mL sample, a 3 mL aliquot was placed in a freezer for 2 hours. The sample was frozen using liquid nitrogen, and the freeze-drying process was carried out over 2 days (average vacuum approximately 0.05 mbar, temperature approximately -86°C). A white amorphous powder was obtained. The obtained solid was analyzed by PXRD to confirm the amorphous nature of the freeze-dried material. To obtain the final concentration of 20 mg / mL, the obtained solid was dissolved in approximately 3 mL of water, and the precipitation and pH were examined (Table 8).

[0145] For the 100 mg / mL sample, a 2.6 mL aliquot was placed in a freezer for 2 hours. The sample was frozen using liquid nitrogen, and the freeze-drying process was carried out over 2 days (average vacuum approximately 0.05 mbar, temperature approximately -86°C). A white amorphous powder was obtained. The obtained solid was analyzed by PXRD to confirm the amorphous nature of the freeze-dried material. To obtain the final concentration of 100 mg / mL, the obtained solid was dissolved in approximately 13 mL of water, and precipitation and pH were examined (Table 10).

[0146] Table 10. Reconstitution by freeze-drying and water [Table 10]

[0147] The behavior of samples with initial and final concentrations of 20 mg / mL is the same before and after lyophilization and reconstitution with water. However, the solubility of samples with an initial concentration of 100 mg / mL is low when reconstituted with water at a concentration of 20 mg / mL. Only samples with a larger amount of KOH dissolve completely.

[0148] Example 3. Freeze-drying and reconstitution with Ringer's lactate solution after 7 days. a) Initial drying Fourteen samples of letermovyl free base were prepared by weighing the substance, removing residual water, and drying overnight in a vacuum oven at 90°C (approximately 5 mbar) to avoid weighing errors, and the equivalent weight of KOH was calculated (Table 11). Approximately 80 mg and 300 mg of the sample were weighed and dissolved in 4 mL and 3 mL of water, respectively, to prepare solutions of 20 mg / mL and 100 mg / mL.

[0149] Table 11. Initial drying process of 14 samples of free letermovyl base. [Table 11]

[0150] b) Preparation of suspensions / solutions and analysis of solubility Procedure: Corresponding amounts of water and equivalent amounts of 1 M KOH aqueous solution were added to each sample. The suspensions were stirred at room temperature, and their effects on solubility and precipitation were examined (Table 19).

[0151] Table 12. Preparation of samples of free letermovyl base containing different equivalent amounts of KOH in water. [Table 12]

[0152] Solubility over 7 days After one week, precipitates remained in the samples of 20 mg / mL with 0.8, 0.82, 0.84, and 0.86 equivalents of KOH. A small amount of solid matter was observed in the sample of 20 mg / mL with 0.88 equivalents of KOH, and the samples of 20 mg / mL with 0.9 and 1 equivalent of KOH were clear solutions. All 100 mg / mL samples were clear solutions after one week.

[0153] c) Freeze-drying and reconstitution with Ringer's lactate solution One week later, the samples were freeze-dried.

[0154] procedure: For the 20 mg / mL sample, a 3 mL aliquot was placed in a freezer for 2 hours. The sample was frozen using liquid nitrogen, and the freeze-drying process was carried out over 2 days (average vacuum approximately 0.05 mbar, temperature approximately -86°C). A white amorphous powder was obtained. The obtained solid was analyzed by PXRD to confirm the amorphous nature of the freeze-dried material. To obtain the final concentration of 20 mg / mL, the obtained solid was dissolved in approximately 3 mL of Ringer's lactate solution, and the precipitation and pH were examined (Table 13).

[0155] For the 100 mg / mL sample, a 2.6 mL aliquot was placed in a freezer for 2 hours. The sample was frozen using liquid nitrogen, and the freeze-drying process was carried out over 2 days (average vacuum approximately 0.05 mbar, temperature approximately -86°C). A white amorphous powder was obtained. The obtained solid was analyzed by PXRD to confirm the amorphous nature of the freeze-dried material. To obtain the final concentration of 100 mg / mL, the obtained solid was dissolved in approximately 13 mL of Ringer's lactate solution, and the precipitation and pH were examined (Table 13).

[0156] Table 13. Reconstitution using freeze-drying and Ringer's solution with lactate. [Table 13]

[0157] In samples with a concentration of 20 mg / mL, the behavior before and after lyophilization and reconstitution with lactated Ringer's solution differed slightly. Samples with low amounts of KOH did not completely dissolve before lyophilization, while reconstitution resulted in complete dissolution and a clear solution.

[0158] Example 4. Freeze-drying after 7 days and reconstitution with a 5% glucose aqueous solution. a) Initial drying Fourteen samples of letermovyl free base were prepared by weighing the substance, removing residual water, and drying overnight in a vacuum oven at 90°C (approximately 5 mbar) to avoid weighing errors, and the equivalent weight of KOH was calculated (Table 14). Approximately 80 mg and 300 mg of the sample were weighed and dissolved in 4 mL and 3 mL of water, respectively, to prepare solutions of 20 mg / mL and 100 mg / mL.

[0159] Table 14. Initial drying process of 14 samples of free letermovyl base. [Table 14]

[0160] b) Preparation of suspensions / solutions and analysis of solubility Procedure: Corresponding amounts of water and equivalent amounts of 1 M KOH aqueous solution were added to each sample. The suspensions were stirred at room temperature, and their effects on solubility and precipitation were examined (Table 15).

[0161] Table 15. Preparation of samples of free letermovyl base containing different equivalent amounts of KOH in water. [Table 15]

[0162] Solubility over 7 days After one week, precipitates remained in the samples of 20 mg / mL with 0.8, 0.82, 0.84, and 0.86 equivalents of KOH. A small amount of solid matter was observed in the sample of 20 mg / mL with 0.88 equivalents of KOH, and the samples of 20 mg / mL with 0.9 and 1 equivalent of KOH were clear solutions. All 100 mg / mL samples were clear solutions after one week.

[0163] c) Reconstitution by freeze-drying and 5% aqueous glucose solution One week later, the samples were freeze-dried.

[0164] procedure: For the 20 mg / mL sample, a 3 mL aliquot was placed in a freezer for 2 hours. The sample was frozen using liquid nitrogen, and the freeze-drying process was carried out over 2 days (average vacuum approximately 0.05 mbar, temperature approximately -86°C). A white amorphous powder was obtained. The obtained solid was analyzed by PXRD to confirm the amorphous nature of the freeze-dried material. To obtain the final concentration of 20 mg / mL, the obtained solid was dissolved in approximately 3 mL of 5% glucose solution, and precipitation and pH were examined (Table 16).

[0165] For the 100 mg / mL sample, a 2.6 mL aliquot was placed in a freezer for 2 hours. The sample was frozen using liquid nitrogen, and the freeze-drying process was carried out over 2 days (average vacuum approximately 0.05 mbar, temperature approximately -86°C). A white amorphous powder was obtained. The obtained solid was analyzed by PXRD to confirm the amorphous nature of the freeze-dried material. To obtain the final concentration of 100 mg / mL, the obtained solid was dissolved in approximately 13 mL of 5% glucose solution, and precipitation and pH were examined (Table 16).

[0166] Table 16. Reconstitution by freeze-drying and 5% glucose aqueous solution [Table 16]

[0167] Reconstitution with a 5% glucose solution yields similar results to reconstitution with water. Only samples containing a larger amount of KOH dissolve completely.

Claims

1. A pharmaceutical composition comprising letermovir of formula (I) and potassium ions, 【Chemistry 1】 - The potassium ions are contained in a molar ratio of 0.80 to <1.00:1.00 relative to letermovil; and - 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 range of 7 to 8; and • Essentially free of 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 solubilizer.

12. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises a polyalkoxy compound and essentially does not contain other complexing solubilizers.

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.

21. The method according to claim 18, wherein the carbohydrate is sucrose or mannitol, the amino acid is phenylalanine, the polyalkoxy compound is poloxamer, and the polyvinylpyrrolidone (PVP) is PVPPF12.

22. The pharmaceutical composition according to claim 21, wherein the poloxamer is poloxamer 188.

23. The method according to claim 18, wherein the pH of the solution in step ii) is adjusted to a range of 7.4 to 7.

8.

24. The method according to claim 18, wherein the pH of the solution in step ii) is adjusted using hydrochloric acid (HCl).

25. The method according to claim 18, wherein the potassium ions are prepared in the form of a KOH solution in step i.

26. The method according to claim 25, wherein the potassium ions are prepared in the form of an aqueous KOH solution in step i.

27. The method according to claim 25, further comprising the additional step of freeze-drying the obtained solution to obtain a freeze-dried product.

28. The method according to claim 27, further comprising the additional step of reconstituting the lyophilized product into a first parenterally permissible diluent to obtain a reconstituted solution with a concentration range of 20 to 100 mg / mL with respect to letermovir, and then optionally diluting the reconstituted solution with a second parenterally permissible diluent to a final concentration permissible for injection or infusion, wherein the first and second parenterally permissible diluents may be the same or different.

29. A pharmaceutical composition according to any one of claims 1 to 17, for use in a method of treating and / or preventing a disease.

30. A pharmaceutical composition for use in a method for treating and / or preventing the disease according to claim 29, wherein the disease is a viral infection.

31. A pharmaceutical composition for use in a method for treating and / or preventing the disease according to claim 30, wherein the viral infection is a human cytomegalovirus (HCMV) infection or an infection caused by another member of the herpesviridae group.

32. Use of the pharmaceutical composition according to any one of claims 1 to 17 for the preparation of a pharmaceutical for the treatment and / or prevention of a disease.

33. The use according to claim 32, wherein the disease is a viral infection.

34. The use according to claim 33, wherein the viral infection is a human cytomegalovirus (HCMV) infection or an infection caused by another member of the herpesviridae group.

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