2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5- (trifluoromethyl)phenyl]-4H-quinolizin-4-yl] acetic acid sodium salt and pharmaceutical compositions thereof

Abstract

The present invention relates to a new stable pharmaceutical composition containing sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate, which is essentially free of complexing solubilizers, such as PEG, cyclodextrins, lysine, arginine, in particular HPBCD. The present invention also relates to a process for preparing said pharmaceutical composition. The present invention also relates to the use of said pharmaceutical composition in a method of treating a disease and / or as a prophylactic against a disease, in particular its use as an antiviral agent, preferably against cytomegalovirus.

Description

Technical Field

[0001] This invention relates to novel stable pharmaceutical compositions suitable for oral and intravenous administration as well as for injection, comprising the sodium salt of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid, also known as letermovir. The pharmaceutical compositions are substantially free of specific complexing solubilizing agents, such as PEG, cyclodextrin, lysine, arginine, and especially hydroxypropyl-β-cyclodextrin (HPBCD). The formulations are suitable for use in the treatment of viral diseases, particularly human cytomegalovirus (HCMV) infection. The invention also relates to methods for preparing the pharmaceutical compositions. Background Technology

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

[0003] HCMV is a virus belonging to the family Herpesviridae, or herpesviruses. It is commonly abbreviated as HCMV, or human herpesvirus 5 (HHV-5). Within the Herpesviridae family, HCMV belongs to the subfamily Betaherpesvirinae, which also includes cytomegaloviruses from other mammals.

[0004] Letermovir is considered a highly active drug against HCMV infection and is extensively described in the following literature: Lischka et al., In Vitro and In Vivo Activities of the Novel Anticytomegalovirus Compound Letermovir. Antimicrob. Agents Chemother. 2010, 54:1290–1297; and 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 Herpesvirus and Other Human Pathogenic Viruses. Herpesviruses and Other Human Pathogenic Viruses). Antimicrob. Agents Chemother. 2012, 56: 1135-1137.

[0005] The chemical name of Letermovir is 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid, and its chemical structure is shown below:

[0006]

[0007] Letemovir has been developed as an antiviral agent, particularly for the treatment, prevention, or control of infections caused by human cytomegalovirus (HCMV), and is disclosed in International Publication WO 2004 / 096778. Additionally, salts of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid have been prepared, as described in International Publication WO2013 / 127971.

[0008] International publication WO 2013 / 127970 describes a liquid pharmaceutical preparation containing amorphous letermovir, relating to a pharmaceutical composition specifically for intravenous administration. This composition contains letermovir, exhibits long-term stability and is storable, and also possesses a substantially physiological pH. Further findings indicate that such a composition can be lyophilized to obtain a stable solid pharmaceutical composition, which can be reconstituted in a simple manner for injection purposes, for example, by adding water, thereby obtaining a stable pharmaceutical composition, for example, for intravenous administration.

[0009] However, there remains a need for pharmaceutical compositions containing letermovir that exhibit long-term stability at essentially physiological pH levels, suitable for use in patients of all ages requiring solid organ transplantation and allogeneic hematopoietic stem cell transplantation. Furthermore, pharmaceutical compositions containing letermovir and complexing solubilizers such as PEG, lysine, arginine, cyclodextrin, and particularly hydroxypropyl-β-cyclodextrin (HPBCD) tend to cause particle problems when dissolved in parenteral diluents such as water, thus requiring additional post-treatment prior to intended use, such as filtering the pharmaceutical composition before administration. Therefore, there remains a need for ready-to-use, particle-free parenteral solutions containing letermovir. Summary of the Invention

[0010] In a first aspect, the present invention relates to a pharmaceutical composition comprising a sodium lemetmovir salt of formula (I) or a solvate thereof.

[0011]

[0012] The composition therein is substantially free of compounds selected from PEG, lysine, arginine, and cyclodextrins (especially hydroxypropyl-β-cyclodextrin (HPBCD)).

[0013] These pharmaceutical compositions contain litomovir at concentrations sufficient to achieve the desired therapeutic effect, while maintaining long-term stability and essentially physiological pH.

[0014] Further findings revealed that a lyophilized form of the pharmaceutical composition can be obtained, which can be completely reconstituted in parenteral diluents such as water, glucose solution, or lactated Ringer's solution. The lyophilized form exhibits surprising long-term stability, and the reconstituted form in parenteral diluents has a substantially physiological pH.

[0015] In another aspect, the present invention relates to a method for producing the pharmaceutical composition, the method comprising the following steps:

[0016] i) A solution of sodium litomovir salt or a solvate thereof and optionally at least one excipient selected from: carbohydrates, particularly sucrose and mannitol; amino acids, particularly phenylalanine; polyalkoxy compounds, particularly poloxamer, more particularly poloxamer 188; and polyvinylpyrrolidone (PVP), particularly PVP PF12;

[0017] ii) If necessary, adjust the pH of the solution obtained in step i) to the range of 7 to 8, preferably using HCl;

[0018] iii) Optionally, the solution is filtered.

[0019] In particular, the method of the present invention may further include the following subsequent steps: freeze-drying the solution obtained in step iii above to provide a lyophilized product, and optionally reconstitute the lyophilized product in a first parenteral acceptable diluent to provide a reconstituted solution with a concentration ranging from 1 to 100 mg / mL, and optionally further diluting the reconstituted solution with a second parenteral acceptable diluent to a final concentration acceptable for injection or infusion, wherein the first and second parenteral acceptable diluents may be the same or different.

[0020] In another aspect, the present invention relates to the use of the pharmaceutical compositions described herein in the preparation of medicaments for treating and / or preventing diseases, particularly viral infections, preferably human cytomegalovirus (HCMV) infections or infections by other members of the herpesvirus class.

[0021] Another aspect of the invention relates to a method of treating and / or preventing viral infections, preferably human cytomegalovirus (HCMV) infection or infection by other members of the herpesvirus class, in subjects with such need by administering the pharmaceutical composition. In particular, the pharmaceutical compositions of the invention are suitable for treating neonates, subjects requiring specific solid organ transplants such as those with kidney damage, and subjects requiring allogeneic hematopoietic stem cell transplants. Detailed Implementation

[0022] It should be noted that the term “contains” also includes the meaning of “composed of”, for example, a member group that contains a set of members also includes a member group that consists only of those members.

[0023] As used herein, the term “room temperature” is synonymous with the term “standard room temperature”, referring to a temperature in the range of 19°C to 26°C. For example, “stirring at room temperature” means “stirring at a temperature in the range of 19°C to 26°C”.

[0024] Within the scope of this invention, the term "stability" is understood to refer not only to the chemical stability of the components of the pharmaceutical composition, particularly the active substance, but also to the physicochemical stability of the composition itself. In particular, the compositions of this invention must be stable against precipitation of the components.

[0025] In this context, the term "stability" means that, at 2°C to 8°C, or at 25°C or 40°C, for 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, when the liquid pharmaceutical composition is measured using the HPLC method according to the invention, the pharmaceutical composition of the invention contains at least >90%, preferably >95%, more preferably >98% of the active substance.

[0026] Within the scope of this invention, the term "solvent" refers to those forms of letemovir sodium salt that form complexes by coordination with solvent molecules. A hydrate is a specific form of solvate in which coordination with water occurs. In particular, letemovir sodium salt can be a monohydrate or a trihydrate.

[0027] As used herein, the term "cyclodextrin" is understood to encompass any modified or unmodified cyclodextrin, particularly selected from α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin. Examples of modified β-cyclodextrins specifically include hydroxyalkyl-β-cyclodextrins such as hydroxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, or hydroxypropyl-β-cyclodextrin; alkyl-hydroxyalkyl-β-cyclodextrins such as methyl-hydroxypropyl-β-cyclodextrin or ethyl-hydroxypropyl-cyclodextrin; or sulfonyl-cyclodextrins. Hydroxypropyl-β-cyclodextrins with various degrees of substitution are available, particularly the existing 2-hydroxypropyl-β-cyclodextrin. W7HP, W7HP5 and W7 HP7.

[0028] As used herein, the term "complexing solubilizer" refers to a compound, particularly in aqueous solutions, that enhances the solubility of an active ingredient by forming a coordination bond between the compound and the molecules of the active ingredient in the pharmaceutical composition of the present invention, i.e., by actually and detectably forming a complex with the active ingredient in the pharmaceutical composition of the present invention. Non-limiting examples of complexing solubilizers include non-polymerizing solubilizers, such as lysine or arginine, and polymerizing solubilizers, such as PEG or cyclodextrin.

[0029] As used herein, the terms “parenterally acceptable diluent,” “parenteral mixed diluent,” and “commercial diluent” refer to any liquid material used to dilute an active ingredient suitable for administration to a subject via a route other than topical or oral. Examples of parenteral routes include intramuscular, intravascular (including intra-arterial or intravenous), intraorbital, retrobulbar, intranasal, intrathecal, intracardiac, intraspinal, intraperitoneal, intrapulmonary, intracisional, intracystic, intrasternal, peribulbar, or intralesional administration. Examples of parenterally acceptable diluents include water, aqueous glucose solution, or lactated Ringer's solution. In this application, the terms “commercial diluent,” “parenteral mixed diluent,” and “parenterally acceptable diluent” have the same meaning and are used interchangeably.

[0030] As used herein, the term "carbohydrate" refers to a compound that is a polyhydroxy aldehyde or ketone, or a substance that produces such a compound upon hydrolysis. Some carbohydrates may also contain nitrogen, phosphorus, or sulfur. Examples of carbohydrates include monosaccharides, disaccharides, oligosaccharides, and polysaccharides, particularly sucrose or mannitol.

[0031] As used herein, the term "amino acid" refers to any one of the twenty naturally occurring amino acids or its synthetic analogues having non-natural side chains, including D and L optical isomers. Examples of amino acids include, in particular, alanine and phenylalanine.

[0032] As used herein, the term "polyalkoxy compound" refers to a polymer in which repeating units represent straight-chain or branched alkyl groups connected to oxygen atoms. Examples of polyalkoxy compounds include poloxamers, particularly poloxamer 188.

[0033] Within the scope of this invention, the terms "obtained by..." and "available through..." have the same meaning and are used interchangeably.

[0034] As used in this article, the term "aqueous solution" refers to a homogeneous mixture of liquids containing water.

[0035] As used herein, the terms "lyophilization" and "freeze-drying" are used interchangeably to refer to a process by which a target product containing a solvent, particularly water, is cooled to a sufficient temperature, said cooling being particularly by using liquid nitrogen or a cooling rack, wherein some or all of the solvent is frozen and further removed by one or more drying steps, particularly by removing unbound solvent through sublimation and desorption. The terms "lyophilized product" and "lyophilized product" refer to products obtained by freeze-drying and are used interchangeably throughout this application.

[0036] As used herein, the term "reconstruction" refers to the process of dissolving lyophilized material in a diluent (preferably a parenteral-acceptable diluent, particularly water). The term "reconstruction solution" refers to the product obtained through reconstruction.

[0037] As used herein, the term "liquid pharmaceutical composition" refers to a solution, suspension, or dispersion of an active ingredient in a liquid, optionally combined with one or more pharmaceutically acceptable excipients. Specifically, a liquid pharmaceutical composition refers to a solution of an active ingredient in a physiologically acceptable diluent (particularly a parenteral diluent, such as water), combined with one or more pharmaceutically acceptable excipients.

[0038] As used herein, the term "solid pharmaceutical composition" refers to a solid composition of an active ingredient optionally combined with one or more pharmaceutically acceptable excipients. In particular, the solid pharmaceutical composition refers to a lyophilized product comprising an active ingredient combined with one or more pharmaceutically acceptable excipients.

[0039] As used herein, the term "treatment" is defined as the application or administration of a therapeutic agent, namely letemovir sodium or its solvates or hydrates (alone or in combination with another agent), to a subject, or the application or administration of a therapeutic agent to tissues or cell lines isolated from a subject with HCMV infection, HCMV infection symptoms, or the likelihood of developing HCMV infection, with the aim of curing, treating, alleviating, reducing, altering, remedying, improving, ameliorating, or influencing HCMV infection, HCMV infection symptoms, or the likelihood of developing HCMV infection. Based on knowledge derived from the field of pharmacogenomics, such treatments can be specifically tailored or modified.

[0040] As used in this article, "prevention" means that a symptom or disease will not develop if it does not occur, or will not develop further if it has already developed. The ability to prevent some or all of the symptoms associated with a symptom or disease is also considered. Disease prevention includes disease avoidance.

[0041] As used herein, the term "object" refers to a human or non-human mammal. Non-human mammals include, for example, livestock and pets such as sheep, cattle, pigs, cats, dogs, and rodents. Preferably, the object is a human. In one embodiment, the object is a human infant. In a preferred embodiment, the object is a human newborn. In another preferred embodiment, the object is an individual requiring a specific solid organ transplant, such as an individual with kidney damage, or an individual requiring an allogeneic hematopoietic stem cell transplant.

[0042] As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, that does not eliminate the biological activity or properties of a compound and is relatively non-toxic; that is, the material can be applied to a subject without causing undesirable biological effects or interacting with any component of the composition containing it in a harmful manner.

[0043] As used in this article, “substantially free” means a content of less than 5 mol%.

[0044] The subject matter of this invention relates to a pharmaceutical composition comprising a sodium lemetmovir salt of formula (I) or a solvate thereof.

[0045]

[0046] The composition is substantially free of complexing solubilizers selected from PEG, lysine, arginine, and cyclodextrin. In one embodiment, the cyclodextrin is hydroxypropyl-β-cyclodextrin (HPBCD).

[0047] In one embodiment, the pharmaceutical composition of the present invention is a liquid pharmaceutical composition comprising a sodium salt of formula (I) or a solvate thereof dissolved in a physiologically acceptable diluent, particularly a parenteral diluent.

[0048]

[0049] The liquid pharmaceutical composition is substantially free of complexing solubilizers selected from PEG, lysine, arginine, and cyclodextrin. In one embodiment, the cyclodextrin is hydroxypropyl-β-cyclodextrin (HPBCD).

[0050] In one embodiment, the liquid pharmaceutical composition of the present invention is an aqueous solution. In another embodiment, the liquid pharmaceutical composition of the present invention is a solution in at least one physiologically acceptable diluent. A physiologically acceptable diluent is a pharmaceutically acceptable diluent, and particularly an orally acceptable diluent (i.e., a diluent acceptable for oral application) or a parenteral diluent (i.e., a diluent acceptable for parenteral application). Non-limiting examples of parenteral diluents include water, aqueous glucose solutions, and lactated Ringer's solution.

[0051] In one embodiment, the liquid pharmaceutical composition of the present invention is substantially free of compounds selected from PEG, lysine, arginine, and cyclodextrin. In one embodiment, the liquid pharmaceutical composition of the present invention is substantially free of lysine. In another embodiment, the liquid pharmaceutical composition of the present invention is substantially free of arginine. In yet another embodiment, the liquid pharmaceutical composition of the present invention is substantially free of PEG. In yet another embodiment, the liquid pharmaceutical composition of the present invention is substantially free of cyclodextrin. In a preferred embodiment, the liquid pharmaceutical composition of the present invention is substantially free of hydroxypropyl-β-cyclodextrin. In another preferred embodiment, the liquid pharmaceutical composition of the present invention is substantially free of PEG, lysine, arginine, and cyclodextrin, particularly hydroxypropyl-β-cyclodextrin (HPBCD).

[0052] In one embodiment, the liquid pharmaceutical composition of the present invention is substantially free of complexing solubilizers, particularly substantially free of PEG, lysine, arginine, and cyclodextrin, especially hydroxypropyl-β-cyclodextrin (HPBCD).

[0053] In one embodiment, the liquid pharmaceutical composition of the present invention is substantially free of any additional buffers.

[0054] In one embodiment, the content of the complexing solubilizer in the liquid pharmaceutical composition of the present invention is less than 5 mol%. In a preferred embodiment, the content of the complexing solubilizer in the liquid pharmaceutical composition of the present invention is less than 3 mol%. In a more preferred embodiment, the content of the complexing solubilizer in the liquid pharmaceutical composition of the present invention is less than 1 mol%. In a more preferred embodiment, the content of the complexing solubilizer in the liquid pharmaceutical composition of the present invention is less than 0.5 mol%. Most preferably, the content of the complexing solubilizer in the liquid pharmaceutical composition of the present invention is less than 0.3 mol.

[0055] In one embodiment, a liquid pharmaceutical composition comprising sodium lemetmovir of formula (I) or a solvate thereof,

[0056]

[0057] The liquid composition is substantially free of complexing solubilizers selected from PEG, lysine, arginine, and cyclodextrin (especially hydroxypropyl-β-cyclodextrin (HPBCD)), and also contains at least one drug carrier or excipient.

[0058] In one embodiment, the liquid pharmaceutical composition of the present invention comprises at least one excipient selected from: carbohydrates, such as sucrose or mannitol; amino acids, such as phenylalanine; polyalkoxy compounds, such as poloxamer, e.g., poloxamer 188; and polyvinylpyrrolidone (PVP), e.g., PVP PF12. In a preferred embodiment, the excipient is mannitol or sucrose or a combination thereof.

[0059] In one embodiment, the liquid pharmaceutical composition of the present invention is substantially free of complexing solubilizers.

[0060] In one embodiment, the liquid pharmaceutical composition of the present invention may contain an excipient exhibiting complexing solubilizing properties. In one embodiment, such an excipient is a polyalkoxylated compound, such as poloxamer. In one embodiment, the poloxamer is poloxamer 188.

[0061] In one embodiment, the liquid pharmaceutical composition of the present invention comprises a polyalkoxy compound, poloxamer, or particularly poloxamer 188, and is substantially free of other complexing solubilizers.

[0062] In one embodiment, the excipient used is suitable for use on a patient requiring a specific solid organ transplant, such as a patient with kidney damage. Non-limiting examples of such excipients include sucrose, mannitol, phenylalanine, and poloxamers such as poloxamer 188, and polyvinylpyrrolidone (PVP) such as PVP PF12.

[0063] In one embodiment, the liquid pharmaceutical composition of the present invention further comprises a buffer, preferably tris(hydroxymethyl)aminomethane (Tris).

[0064] In one embodiment, the liquid pharmaceutical composition of the present invention further comprises HCl. In another embodiment, HCl is used to adjust the pH of the liquid pharmaceutical composition.

[0065] In a preferred embodiment, the liquid pharmaceutical composition of the present invention has a pH in the range of 7 to 8. In a more preferred embodiment, the liquid pharmaceutical composition of the present invention has a pH in the range of 7.4 to 7.8.

[0066] In one embodiment, the liquid pharmaceutical composition of the present invention is suitable for oral administration.

[0067] In one embodiment, the pharmaceutical composition of the present invention is in solid form. In a preferred embodiment, the solid form of the pharmaceutical composition is a lyophilized product. Preferably, the solid form of the pharmaceutical composition can be obtained by freeze-drying a liquid pharmaceutical composition as defined in any of the foregoing embodiments.

[0068] In one embodiment, the solid form of the pharmaceutical composition of the present invention comprises an amorphous form of sodium lemetmovir or a solvate thereof. In one embodiment, the solid form of the pharmaceutical composition of the present invention comprises sodium lemetmovir as a crystalline monohydrate or a crystalline trihydrate.

[0069] In one embodiment, the solid pharmaceutical composition of the present invention is substantially free of complexing solubilizers selected from PEG, lysine, arginine, and cyclodextrin. In one embodiment, the cyclodextrin is hydroxypropyl-β-cyclodextrin (HPBCD).

[0070] In one embodiment, the solid pharmaceutical composition of the present invention is substantially free of compounds selected from PEG, lysine, arginine, and cyclodextrin. In one embodiment, the solid pharmaceutical composition of the present invention is substantially free of lysine. In another embodiment, the solid pharmaceutical composition of the present invention is substantially free of arginine. In yet another embodiment, the solid pharmaceutical composition of the present invention is substantially free of PEG. In yet another embodiment, the solid pharmaceutical composition of the present invention is substantially free of cyclodextrin. In a preferred embodiment, the solid pharmaceutical composition of the present invention is substantially free of hydroxypropyl-β-cyclodextrin. In another preferred embodiment, the solid pharmaceutical composition of the present invention is substantially free of PEG, lysine, arginine, and cyclodextrin, particularly hydroxypropyl-β-cyclodextrin (HPBCD).

[0071] In one embodiment, the solid pharmaceutical composition of the present invention is substantially free of complexing solubilizers, particularly substantially free of PEG, lysine, arginine, and cyclodextrin, especially hydroxypropyl-β-cyclodextrin (HPBCD).

[0072] In one embodiment, the solid pharmaceutical composition of the present invention is substantially free of any additional buffers.

[0073] In one embodiment, the content of the complexing solubilizer in the solid pharmaceutical composition of the present invention is less than 5 mol%. In a preferred embodiment, the content of the complexing solubilizer in the solid pharmaceutical composition of the present invention is less than 3 mol%. In a more preferred embodiment, the content of the complexing solubilizer in the solid pharmaceutical composition of the present invention is less than 1 mol%. In a more preferred embodiment, the content of the complexing solubilizer in the solid pharmaceutical composition of the present invention is less than 0.5 mol%. Most preferably, the content of the complexing solubilizer in the solid pharmaceutical composition of the present invention is less than 0.3 mol.

[0074] In one embodiment, a solid pharmaceutical composition comprising sodium lemetmovir of formula (I) or a solvate thereof,

[0075]

[0076] The solid pharmaceutical composition therein is substantially free of complexing solubilizers selected from PEG, lysine, arginine, and cyclodextrin (especially hydroxypropyl-β-cyclodextrin (HPBCD)), and further comprises at least one pharmaceutical carrier or excipient.

[0077] In one embodiment, the solid pharmaceutical composition of the present invention comprises at least one excipient selected from: carbohydrates, such as sucrose or mannitol; amino acids, such as phenylalanine; polyalkoxy compounds, such as poloxamer, e.g., poloxamer 188; and polyvinylpyrrolidone (PVP), e.g., PVP PF12. In a preferred embodiment, the excipient is mannitol or sucrose or a combination thereof.

[0078] In one embodiment, the solid pharmaceutical composition of the present invention is substantially free of complexing solubilizers.

[0079] In one embodiment, the solid pharmaceutical composition of the present invention may contain an excipient exhibiting complexing and solubilizing properties. In one embodiment, such an excipient is a polyalkoxylated compound, such as poloxamer. In one embodiment, the poloxamer is poloxamer 188.

[0080] In one embodiment, the solid pharmaceutical composition of the present invention comprises a polyalkoxy compound, poloxamer, or particularly poloxamer 188, and is substantially free of other complexing solubilizers.

[0081] In one embodiment, the excipient used is suitable for use on a patient requiring a specific solid organ transplant, such as a patient with kidney damage. Non-limiting examples of such excipients include sucrose, mannitol, phenylalanine, and poloxamers such as poloxamer 188, and polyvinylpyrrolidone (PVP) such as PVP PF12.

[0082] In one embodiment, the solid pharmaceutical composition of the present invention further comprises a buffer, preferably tris(hydroxymethyl)aminomethane (Tris).

[0083] In a preferred embodiment, the solid pharmaceutical composition of the present invention, after being dissolved in a parenteral diluent, has a pH of 7 to 8 without any additional buffer. In a more preferred embodiment, the solid pharmaceutical composition, after being dissolved in a parenteral diluent, has a pH in the range of 7.4 to 7.8 without any additional buffer. In one embodiment, the solid pharmaceutical composition optionally further comprises HCl.

[0084] In a preferred embodiment, the solid pharmaceutical composition is capable of providing a solution in water without any additional buffer or additional complexing solubilizer, wherein the complexing solubilizer is selected from PEG, lysine, arginine, cyclodextrin, and particularly hydroxypropyl-β-cyclodextrin (HPBCD), wherein the solution

[0085] ○ Contains sodium lemetribose or its solvates in concentrations ranging from 20 to 100 mg / mL, calculated as lemetribose free base.

[0086] ○ It exhibits a pH range of 7 to 8, preferably 7.4 to 7.8.

[0087] In a preferred embodiment, the solid pharmaceutical composition:

[0088] - It is essentially free of complexing solubilizers selected from PEG, lysine, arginine, and cyclodextrin, especially hydroxypropyl-β-cyclodextrin (HPBCD), and

[0089] - Capable of providing a solution in water without any additional buffer or complexing solubilizer, wherein the complexing solubilizer is selected from PEG, lysine, arginine, cyclodextrin, and particularly hydroxypropyl-β-cyclodextrin (HPBCD), wherein the solution

[0090] ○ Contains sodium lemetribose or its solvates in concentrations ranging from 20 to 100 mg / mL, calculated as lemetribose free base.

[0091] ○ It exhibits a pH range of 7 to 8, preferably 7.4 to 7.8.

[0092] In one embodiment, the pharmaceutical composition of the present invention is a liquid pharmaceutical composition comprising a solid pharmaceutical composition as defined in any of the foregoing embodiments dissolved in a parenteral acceptable diluent, said diluent being substantially free of complexing solubilizers selected from PEG, lysine, arginine, and cyclodextrins (especially hydroxypropyl-β-cyclodextrin (HPBCD)). Preferably, the liquid pharmaceutical composition comprises a sodium salt of letermovir or a solvate thereof in a concentration in the range of 20 to 100 mg / mL, calculated as letermovir free base.

[0093] In one embodiment, the liquid pharmaceutical composition comprises a solid pharmaceutical composition as defined in any of the foregoing embodiments dissolved in a first parenteral acceptable diluent, the first parenteral acceptable diluent being substantially free of complexing solubilizers selected from PEG, lysine, arginine, cyclodextrin (especially hydroxypropyl-β-cyclodextrin (HPBCD)), the liquid pharmaceutical composition having a concentration in the range of 20 to 100 mg / mL based on letromoride free base, and further diluted in a second parenteral acceptable diluent to a concentration acceptable for intravenous (IV) injection or infusion, the second parenteral acceptable diluent being substantially free of complexing solubilizers selected from PEG, lysine, arginine, cyclodextrin (especially hydroxypropyl-β-cyclodextrin (HPBCD)), wherein the first and second parenteral acceptable diluents may be the same as or different from each other.

[0094] In one embodiment, the pharmaceutical composition of the present invention is a liquid pharmaceutical composition comprising a solid pharmaceutical composition as defined in any of the foregoing embodiments dissolved in water. In another embodiment, the pharmaceutical composition of the present invention is a liquid pharmaceutical composition comprising a solid pharmaceutical composition as defined in any of the foregoing embodiments dissolved in at least one parenteral-acceptable diluent. Non-limiting examples of parenteral-acceptable diluents include water, aqueous glucose solutions, and lactated Ringer's solution. In a preferred embodiment, the liquid pharmaceutical composition of the present invention has a pH in the range of 7 to 8. In a more preferred embodiment, the liquid pharmaceutical composition of the present invention has a pH in the range of 7.4 to 7.8. In one embodiment, the concentration of letemovir sodium salt or a solvate thereof in the liquid pharmaceutical composition of the present invention is in the range of 1 to 100 mg / mL. In a preferred embodiment, the concentration of letemovir sodium salt or a solvate thereof in the liquid pharmaceutical composition of the present invention is in the range of 20 to 100 mg / mL.

[0095] Within the scope of this invention, the mass concentration is given in terms of the free base of letermovir. Specifically, 20 mg / mL in terms of free base of letermovir means that the molar concentration of the sodium letermovir salt or its solvate should be equal to the molar concentration of the free letermovir base corresponding to a mass concentration of 20 mg / mL of the free letermovir base. For example, the molar mass of the sodium letermovir trihydrate is 650.6 g / mol. The molar mass of the free letermovir base is 572.6 g / mol. In this respect, a mass concentration of 20 mg / mL in terms of the free letermovir base corresponds to a mass concentration of 20·650.6 / 572.6 = 22.7 mg / mL for the sodium letermovir trihydrate.

[0096] In one embodiment, the liquid pharmaceutical composition comprising a solid pharmaceutical composition as defined in any of the foregoing embodiments dissolved in at least one parenteral-acceptable diluent (e.g., water) is suitable for intravenous (IV) application, i.e., for intravenous infusion or injection.

[0097] In one embodiment, the pharmaceutical composition of the present invention exhibits stability covering climate zones I to IV according to ICH Q1A(R2) (Stability testing of new drug substances and drug products). In a preferred embodiment, the pharmaceutical composition of the present invention, as defined in any of the foregoing embodiments, is stable for at least one month. In a more preferred embodiment, the pharmaceutical composition of the present invention, as defined in any of the foregoing embodiments, is stable for at least three months. In a more preferred embodiment, the pharmaceutical composition of the present invention, as defined in any of the foregoing embodiments, is stable for at least six months. In a more preferred embodiment, the pharmaceutical composition of the present invention, as defined in any of the foregoing embodiments, is stable for at least 12 months. In a more preferred embodiment, the pharmaceutical composition of the present invention, as defined in any of the foregoing embodiments, is stable for at least 18 months. In a more preferred embodiment, the pharmaceutical composition of the present invention, as defined in any of the foregoing embodiments, is stable for at least 36 months.

[0098] The subject matter of this invention also relates to a method for producing the pharmaceutical composition of this invention, the method comprising the following steps:

[0099] i) Provide a solution of sodium litomovir salt or a solvate thereof and optionally at least one excipient selected from: carbohydrates, particularly sucrose and mannitol; amino acids, particularly phenylalanine; polyalkoxy compounds, particularly poloxamer, more particularly poloxamer 188; and polyvinylpyrrolidone (PVP), particularly PVP PF12.

[0100] In one embodiment, the solution provided in step i) above is a solution in a physiologically acceptable diluent (particularly a parenteral diluent, such as water).

[0101] In one embodiment, the solution provided in step i above is substantially free of any additional buffers and any complexing solubilizers selected from PEG, lysine, arginine, cyclodextrin (especially hydroxypropyl-β-cyclodextrin (HPBCD)).

[0102] In one embodiment, providing the solution according to step i) above includes the following steps:

[0103] a-1) Dissolve the trihydrate of said litomovir sodium salt in a parenteral diluent (especially water);

[0104] b-1) Add at least one excipient to the solution obtained in step a-1, said excipient being selected from: carbohydrates, particularly sucrose and mannitol; amino acids, particularly phenylalanine; polyalkoxy compounds, particularly poloxamer, more particularly poloxamer 188; and polyvinylpyrrolidone (PVP), particularly PVP PF12;

[0105] c-1) Optionally, stir the solution for at least 30 minutes.

[0106] In a preferred embodiment, the solution in step c-1 is stirred for at least 2 hours.

[0107] In another embodiment, the method of providing the solution according to step i) includes replacing steps a-1 to c-1 with steps a-2 to c-2.

[0108] a-2) Dissolve at least one excipient in a parenteral acceptable diluent (especially water), said excipient being selected from: carbohydrates, especially sucrose and mannitol; amino acids, especially phenylalanine; polyalkoxy compounds, especially poloxamer, more especially poloxamer 188; and polyvinylpyrrolidone (PVP), especially PVP PF12;

[0109] b-2) Add the sodium lytemovir trihydrate in water to the solution obtained in step a-2;

[0110] c-2) Optionally, stir the solution for at least 30 minutes.

[0111] In a preferred embodiment, the solution in step c-2 is stirred for at least 2 hours.

[0112] In a preferred embodiment, the method for producing the pharmaceutical composition of the present invention further includes adjusting the pH of the solution obtained in step i) to a range of 7 to 8. In a more preferred embodiment, the method for producing the pharmaceutical composition of the present invention further includes adjusting the pH of the solution obtained in step i) to a range of 7.4 to 7.8. In a preferred embodiment, the adjustment is performed by adding HCl. In some embodiments, the pH of the solution obtained in step i) is in the range of 7 to 8, more preferably in the range of 7.4 to 7.8, and pH adjustment is not required.

[0113] In one embodiment, the pH-adjusted solution is optionally stirred for at least 10 minutes, preferably at least 30 minutes.

[0114] In one embodiment, the method for producing the pharmaceutical composition of the present invention optionally includes filtering the solution obtained in step i). In one embodiment, the method for producing the pharmaceutical composition of the present invention optionally includes filtering the solution obtained after pH adjustment of the solution obtained in step i).

[0115] In some embodiments, the sodium letermovir used in step i) is in an amorphous form or a solvate of the sodium letermovir, or a crystalline monohydrate or a crystalline trihydrate.

[0116] In one embodiment, the method for producing the pharmaceutical composition of the present invention further includes freeze-drying the obtained solution to provide a lyophilized product.

[0117] In one embodiment, the method of producing the pharmaceutical composition of the present invention further includes reconstituted the lyophilized material in a first parenteral-acceptable diluent to provide a reconstituted solution with a concentration ranging from 0.1 to 100 mg / mL based on letemovir free base, and optionally further diluting the reconstituted solution with a second parenteral-acceptable diluent to a final concentration acceptable for injection or infusion. The first and second parenteral-acceptable diluents may be the same or different.

[0118] In one embodiment, the acceptable final concentration for injection or infusion is in the range of 0.1 to 100 mg / mL. In another embodiment, the acceptable final concentration for injection or infusion is in the range of 0.8 to 100 mg / mL. In another embodiment, the acceptable final concentration for injection or infusion is in the range of 20 to 100 mg / mL. In another embodiment, the acceptable final concentration for injection or infusion is in the range of 50 to 100 mg / mL. In yet another embodiment, the acceptable final concentration for injection or infusion is in the range of 20 to 50 mg / mL. In a preferred embodiment, the acceptable final concentration for injection or infusion is 0.8 mg / mL.

[0119] In a preferred embodiment, the method for producing the pharmaceutical composition of the present invention includes the following steps:

[0120] i) A solution of sodium litomovir salt or a solvate thereof and optionally at least one excipient selected from: carbohydrates, such as sucrose and mannitol; amino acids, such as phenylalanine; polyalkoxy compounds, such as poloxamer, particularly poloxamer 188; and polyvinylpyrrolidone (PVP), such as PVP PF12;

[0121] ii) If necessary, adjust the pH of the solution obtained in step i) to the range of 7 to 8 using a suitable organic or inorganic acid;

[0122] iii) Optionally, filter the obtained solution.

[0123] In one embodiment of step ii, the organic or inorganic acid is HCl.

[0124] In another preferred embodiment, the method for producing the pharmaceutical composition of the present invention includes the following steps:

[0125] i) A solution of sodium litomovir salt or a solvate thereof and optionally at least one excipient selected from: carbohydrates, such as sucrose and mannitol; amino acids, such as phenylalanine; polyalkoxy compounds, such as poloxamer, particularly poloxamer 188; and polyvinylpyrrolidone (PVP), such as PVP PF12;

[0126] ii) If necessary, adjust the pH of the solution obtained in step i) to the range of 7 to 8 using a suitable organic or inorganic acid;

[0127] iii) Optionally, filter the obtained solution;

[0128] iv) Freeze-dry the obtained solution to provide a lyophilized product.

[0129] In one embodiment of step ii, the organic or inorganic acid is HCl.

[0130] In another preferred embodiment, the method for producing the pharmaceutical composition of the present invention includes the following steps:

[0131] i) A solution of sodium litomovir salt or a solvate thereof and optionally at least one excipient selected from: carbohydrates, particularly sucrose and mannitol; amino acids, particularly phenylalanine; polyalkoxy compounds, particularly poloxamer, more particularly poloxamer 188; and polyvinylpyrrolidone (PVP), particularly PVP PF12;

[0132] ii) If necessary, adjust the pH of the solution obtained in step i) to the range of 7 to 8 using a suitable organic or inorganic acid;

[0133] iii) Optionally, filter the obtained solution;

[0134] iv) Freeze-dry the obtained solution to provide a lyophilized product;

[0135] v) The lyophilized material is reconstituted in a first parenteral acceptable diluent to provide a reconstituted solution with a concentration range of 1 to 100 mg / mL, and optionally the reconstituted solution is further diluted with a second parenteral acceptable diluent to a final concentration acceptable for injection or infusion, wherein the first and second parenteral acceptable diluents may be the same or different.

[0136] In one embodiment of step ii, the organic or inorganic acid is HCl.

[0137] In a preferred embodiment, the method for producing the pharmaceutical composition of the present invention includes the following steps:

[0138] i) Providing a solution of lemetmovir sodium salt or a solvate thereof and at least one excipient in a physiologically acceptable diluent (particularly a parenteral acceptable diluent), said excipient being selected from: carbohydrates, particularly sucrose and mannitol; amino acids, particularly phenylalanine; polyalkoxy compounds, particularly poloxamer, more particularly poloxamer 188; and polyvinylpyrrolidone (PVP), particularly PVP PF12, wherein said solution is substantially free of any additional buffers and any complexing solubilizer selected from PEG, lysine, arginine, cyclodextrin (particularly hydroxypropyl-β-cyclodextrin (HPBCD));

[0139] ii) If necessary, adjust the pH of the solution obtained in step i) to the range of 7 to 8, preferably using HCl;

[0140] iii) Optionally, filter the obtained solution.

[0141] In a preferred embodiment, the method for producing the pharmaceutical composition of the present invention includes the following steps:

[0142] i) Providing a solution of lemetmovir sodium salt or a solvate thereof and at least one excipient in a physiologically acceptable diluent (particularly a parenteral acceptable diluent), said excipient being selected from: carbohydrates, particularly sucrose and mannitol; amino acids, particularly phenylalanine; polyalkoxy compounds, particularly poloxamer, more particularly poloxamer 188; and polyvinylpyrrolidone (PVP), particularly PVP PF12, wherein said solution is substantially free of any additional buffers and any complexing solubilizer selected from PEG, lysine, arginine, cyclodextrin (particularly hydroxypropyl-β-cyclodextrin (HPBCD));

[0143] ii) If necessary, adjust the pH of the solution obtained in step i) to the range of 7 to 8, preferably using HCl;

[0144] iii) Optionally, filter the obtained solution;

[0145] iv) Freeze-dry the obtained solution to provide a lyophilized product.

[0146] In a preferred embodiment, the method for producing the pharmaceutical composition of the present invention includes the following steps:

[0147] i) Providing a solution of lemetmovir sodium salt or a solvate thereof and at least one excipient in a physiologically acceptable diluent (particularly a parenteral acceptable diluent), said excipient being selected from: carbohydrates, particularly sucrose and mannitol; amino acids, particularly phenylalanine; polyalkoxy compounds, particularly poloxamer, more particularly poloxamer 188; and polyvinylpyrrolidone (PVP), particularly PVP PF12, wherein said solution is substantially free of any additional buffers and any complexing solubilizer selected from PEG, lysine, arginine, cyclodextrin (particularly hydroxypropyl-β-cyclodextrin (HPBCD));

[0148] ii) If necessary, adjust the pH of the solution obtained in step i) to the range of 7 to 8, preferably using HCl;

[0149] iii) Optionally, filter the obtained solution;

[0150] iv) Freeze-dry the obtained solution to provide a lyophilized product;

[0151] v) Reconstitute the lyophilized product in a parenteral acceptable diluent, which is substantially free of complexing solubilizers selected from PEG, lysine, arginine, and cyclodextrins (especially hydroxypropyl-β-cyclodextrin (HPBCD)).

[0152] Steps i to v above do not necessarily represent a specific order or step number. However, preferably, the steps of the method are performed in the order shown above. Some of the steps may be optional, and in some embodiments, optional steps are not performed. For example, in one embodiment, step ii may be followed directly by step iv without performing step iii. Furthermore, the steps shown above do not exclude additional steps not explicitly mentioned. For example, the solution obtained in steps i and / or ii may optionally be stirred.

[0153] The subject matter of this invention also relates to a pharmaceutical composition that can be obtained by any of the methods disclosed herein. In particular, the subject matter of this invention relates to a liquid pharmaceutical composition obtained by a method comprising steps i to iii as defined in any of the foregoing embodiments. The subject matter of this invention also relates to a solid pharmaceutical composition obtained by a method comprising steps i to iv as defined in any of the foregoing embodiments. The subject matter of this invention also relates to a liquid pharmaceutical composition comprising the solid pharmaceutical composition dissolved in a parenteral acceptable diluent, said liquid pharmaceutical composition obtained by a method comprising steps i to v as defined in any of the foregoing embodiments.

[0154] The pharmaceutical compositions of the present invention can be used to manufacture pharmaceuticals suitable for use in methods of preventing and / or treating infections with representative viruses of the herpesvirus class (particularly cytomegalovirus, particularly human cytomegalovirus).

[0155] In another aspect, the present invention relates to a method of using the pharmaceutical composition of the invention for treating and / or preventing diseases, preferably viral infections, particularly human cytomegalovirus (HCMV) infection or other representative herpesvirus infections.

[0156] An additional aspect of the invention relates to the use of the pharmaceutical compositions of the invention in methods of treating and / or preventing diseases, preferably viral infections, particularly human cytomegalovirus (HCMV) infection or other representative viral infections of the herpesvirus class.

[0157] Another aspect of the invention relates to the use of the pharmaceutical compositions of the invention in the preparation of a medicament for treating and / or preventing diseases, particularly viral infections, preferably human cytomegalovirus (HCMV) infection or infection by other members of the herpesvirus class.

[0158] Another aspect of the invention relates to a method for treating and / or preventing viral infection, preferably human cytomegalovirus (HCMV) infection or infection with other members of the herpesvirus class, in subjects requiring treatment by administering the pharmaceutical composition of the invention. In one embodiment, the subjects are selected from newborns, subjects requiring specific solid organ transplantation such as those with kidney damage, and subjects requiring allogeneic hematopoietic stem cell transplantation.

[0159] Generally, it has been shown that administering the pharmaceutical composition with 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid (letmovir) at a dose of about 0.001 to 10 mg per kg body weight, preferably 0.01 to 5 mg per kg body weight, is advantageous.

[0160] However, it may be necessary to deviate from the described dose of letemovir, as this depends on body weight, individual response to the active substance, and the timing and interval of administration. For example, in some cases, administering less than the minimum dose described above may be sufficient, while in others, exceeding the described upper limit may be necessary. When administering large doses, it is recommended to distribute these doses in several separate doses throughout the day.

[0161] Based on the above text, the following sequentially numbered embodiments provide other specific aspects of the invention:

[0162] 1. A pharmaceutical composition comprising a sodium lemetmovir salt of formula (I) or a solvate thereof,

[0163]

[0164] The composition is substantially free of complexing solubilizers selected from PEG, lysine, arginine, and cyclodextrins (especially hydroxypropyl-β-cyclodextrin (HPBCD)).

[0165] 2. The pharmaceutical composition according to embodiment 1 further comprises at least one excipient selected from: carbohydrates, particularly sucrose and mannitol; amino acids, particularly phenylalanine; polyalkoxy compounds, particularly poloxamer, more particularly poloxamer 188; and polyvinylpyrrolidone (PVP), particularly PVP PF12.

[0166] 3. The pharmaceutical composition according to Embodiment 1, wherein the pharmaceutical composition is substantially free of complexing solubilizers.

[0167] 4. The pharmaceutical composition according to any one of embodiments 1 or 2, wherein the pharmaceutical composition comprises a polyalkoxy compound, particularly poloxamer, more particularly poloxamer 188, and is substantially free of other complexing solubilizers.

[0168] 5. The pharmaceutical composition according to embodiment 2, wherein the excipient is mannitol or sucrose or a combination thereof.

[0169] 6. The pharmaceutical composition according to any one of embodiments 1 to 5 further comprises a buffer, preferably tris(hydroxymethyl)aminomethane (Tris).

[0170] 7. The pharmaceutical composition according to any one of embodiments 1 to 6 further comprises HCl.

[0171] 8. The pharmaceutical composition according to any one of embodiments 1 to 7 is in solid form.

[0172] 9. The pharmaceutical composition according to embodiment 8, wherein the retermovir sodium salt is in an amorphous form.

[0173] 10. The pharmaceutical composition according to embodiment 8 or 9, wherein, after being dissolved in a parenteral diluent, the solid form of the pharmaceutical preparation has a pH of 7 to 8 and wherein the pharmaceutical composition optionally further comprises HCl.

[0174] 11. The pharmaceutical composition according to any one of embodiments 1 to 7, wherein the pharmaceutical composition is in liquid form.

[0175] 12. The pharmaceutical composition according to any one of embodiments 1 to 11, wherein the pharmaceutical composition is an oral dosage form.

[0176] 13. The pharmaceutical composition according to embodiment 11, wherein the liquid form of the pharmaceutical composition is suitable for intravenous (IV) administration or injection.

[0177] 14. The pharmaceutical composition according to embodiment 11 or 13 has a pH in the range of 7 to 8.

[0178] 15. The pharmaceutical composition according to any one of embodiments 11 to 14, wherein the concentration of litromoride sodium salt or its solvate in the pharmaceutical composition, calculated as litromoride free base, is in the range of 1 to 100 mg / mL, preferably in the range of 20 to 100 mg / mL.

[0179] 16. The pharmaceutical composition according to any one of embodiments 1 to 15, having stability covering climate zones I to IV according to ICH Q1A(R2).

[0180] 17. The pharmaceutical composition according to any one of embodiments 8 to 10, wherein the solid form of the pharmaceutical composition is a lyophilized product.

[0181] 18. A method for producing a pharmaceutical composition as defined in any one of embodiments 1 to 17, the method comprising the steps of:

[0182] i) A solution of sodium litomovir salt or a solvate thereof and optionally at least one excipient selected from: carbohydrates, particularly sucrose and mannitol; amino acids, particularly phenylalanine; polyalkoxy compounds, particularly poloxamer, more particularly poloxamer 188; and polyvinylpyrrolidone (PVP), particularly PVP PF12;

[0183] ii) If necessary, adjust the pH of the solution obtained in step i) to the range of 7 to 8 using HCl;

[0184] iii) Optionally, filter the obtained solution.

[0185] 19. The method according to embodiment 18, wherein the sodium letermowei is in an amorphous form, or a crystalline monohydrate or a crystalline trihydrate.

[0186] 20. The method according to embodiment 18 or 19 further includes the additional step of freeze-drying the obtained solution to provide a lyophilized product.

[0187] 21. The method according to embodiment 20 further includes the following additional step: reconstitute the lyophilized material in a first parenteral acceptable diluent to provide a reconstituted solution with a concentration ranging from 1 to 100 mg / mL and optionally further dilute the reconstituted solution with a second parenteral acceptable diluent to a final concentration acceptable for injection or infusion, wherein the first and second parenteral acceptable diluents may be the same or different from each other.

[0188] 22. The pharmaceutical composition according to any one of embodiments 1 to 17 can be obtained by any one of embodiments 18 to 20.

[0189] 23. The pharmaceutical composition according to any one of embodiments 1 to 16 or 22, used in a method of treating and / or preventing a disease, particularly a viral infection, preferably human cytomegalovirus (HCMV) infection or infection with other members of the herpesvirus class.

[0190] 24. Use of the pharmaceutical composition according to any one of embodiments 1 to 16 or 22 for the preparation of a medicament for the treatment and / or prevention of a disease, particularly a viral infection, preferably human cytomegalovirus (HCMV) infection or infection by other members of the herpesvirus class.

[0191] 25. A method for treating and / or preventing viral infection, preferably human cytomegalovirus (HCMV) infection or infection with other members of the herpesvirus class, in a subject in need, said method comprising administering a pharmaceutical composition according to any one of embodiments 1 to 16 or 22.

[0192] The invention will now be described in detail based on non-limiting embodiments.

[0193] Unless otherwise stated, percentages given in the following tests and examples are weight percentages, parts are weight proportions, and solvent ratios, dilution ratios, and concentrations of liquid solutions are volume-dependent in each case.

[0194] abbreviation

[0195] API active pharmaceutical ingredients

[0196] h hours

[0197] HCl hydrochloric acid

[0198] HEPES (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid)

[0199] HPBCD Hydroxypropyl-β-Cyclodextrin

[0200] HPLC (High-Performance Liquid Chromatography)

[0201] conc. thick

[0202] min. minutes

[0203] LO photoresist

[0204] LAF (Laminar Air Flow)

[0205] NMR (Nuclear Magnetic Resonance) spectroscopy

[0206] NTU (Non-Turbidity Unit)

[0207] PEG (Polyethylene Glycol)

[0208] PDE Permissible Daily Exposure

[0209] R T Retention time (in HPLC)

[0210] RP-HPLC (Reversed-Phase High-Performance Liquid Chromatography)

[0211] rpm (revolutions per minute)

[0212] Analytical methods

[0213] Sample reconstruction and reconstruction time

[0214] Samples were reconstructed before analysis by visual inspection, pH, osmolarity, turbidity, light obscuration, and RP-HPLC. One sample was taken from each formulation, and the time until complete reconstruction of the lyophilized cake was measured. The lyophilized product was reconstructed under LAF conditions.

[0215] To account for the varying solids content of the selected formulations, a gravimetric determination of water loss during lyophilization was performed. Six vials of each formulation were weighed before and after lyophilization, and the water loss was calculated. The samples were then reconstructed using the calculated water loss. After reconstruction, the samples were stored at 2–8°C.

[0216] Add the determined amount of water to the lyophilized product (to the center of the vial) using a suitable pipette. Carefully rotate the vial. The reconstitution time is measured as the time required for complete reconstitution of the lyophilized product after the addition of the liquid.

[0217] Visual inspection

[0218] According to the European Pharmacopoeia (9th edition; Monograph 2.9.20), the sample was examined for the presence of visible particles under gentle manual radial stirring for 5 seconds against a white background and 5 seconds against a black background. The examination was performed independently by two trained inspectors. If visible particles were observed, they were further classified as few, moderate, or many particles.

[0219] Before sample inspection, the system performance is checked by measuring the illumination intensity with a lux meter.

[0220] pH

[0221] The pH value of the sample was determined using a calibrated pH meter equipped with a standard ionic strength electrode (InLab Micro Pro-ISM) and a temperature sensor. Measurements were taken using a Mettler Toledo AG (Schwerzenbach, Switzerland) instrument. The measurement probe was thoroughly rinsed with water after each measurement. pH measurements were performed using an analytical volume of approximately 150 μl at n=1 and a defined temperature of 22 °C ± 3 °C.

[0222] The pH meter was calibrated daily using buffer solutions at pH 7.00, pH 4.01, and pH 9.21 (InLab Solutions, Mettler Toledo AG). Additionally, the pH 7.00 reference buffer was checked before starting sample measurements.

[0223] Turbidity

[0224] The turbidity of the samples was measured using a Hach 2100AN turbidimeter (Hach Lange, Duesseldorf, Germany), which operates at 400-600 nm (using USEPA filters) and measures at a 90° angle. This system uses... Turbidity standards (Hach Lange, Duesseldorf, Germany) were calibrated periodically. The measurements were performed on 2.0 ml samples. Results are given in scattering turbidity units (NTU).

[0225] Optical obscuration (LO)

[0226] Photoresistance measurements were performed using a PAMAS SVSS-C sensor HCB-LD-25 / 25 (Partikelmess- und AnalysensystemeGmbH, Rutesheim, Germany).

[0227] For light obscuration measurements, the sample is preferably analyzed undiluted or after being diluted to the instrument’s operating range with filtered formulation buffer.

[0228] All measurements were performed in accordance with USP. <787> The small-scale method was used. The average particle concentration was calculated based on the last three subruns for particle sizes ≥1, 2, 5, 10, 15, 25, 50, and 100 μm.

[0229] Before each sample measurement, a washing step is performed using high-purity water and the cleanliness is verified through a cleanliness check.

[0230] Reversed-phase high-performance liquid chromatography (RP-HPLC)

[0231] RP-HPLC was used to determine the concentrations of free base and potential degradation products of Letemovir. Table 1 summarizes the eluents used for RP-HPLC analysis.

[0232] Table 1

[0233]

[0234] The following parameters are used in the RP-HPLC method:

[0235]

[0236] Table 2 shows the gradients used for the RP-HPLC method.

[0237] Table 2: Gradients applied during RP-HPLC analysis

[0238] Time [min] Elution buffer B [%] 0.00 5.0 1.00 5.0 20.00 95.0 23.00 95.0 23.10 5.0 26.00 5.0

[0239] A reference solution of crystalline sodium trihydrate salt of letemovir was freshly prepared in water at a target concentration of 1.5 mg / ml (corrected for free base of letemovir in solution). This reference solution was injected at the beginning and end of each sequence. The free base of letemovir in solution was quantified using a calibration curve of the reference standard, provided that the injected 1.5 ml / ml reference solution showed complete recovery.

[0240] Dilute the sample in water to 1 mg / ml (corrected for free base of letemovir in the solution) and analyze in 5 μl injections. Centrifuge the diluted sample at 10,000 rpm for 3 minutes before injection. Perform two blank injections (water) after each sample or reference injection to minimize sample residue.

[0241] Manually integrate all API-related peaks. Ignore peaks that are also present in blank or formulation buffer injections. Non-baseline separated peaks are separated by a vertical descent at the valley / shoulder of the two peaks.

[0242] Appearance of freeze-dried cake blocks

[0243] Freeze-dried cakes were evaluated visually after drying. The parameters considered were the density, shape, color, and overall appearance of the cakes.

[0244] Freeze-drying microscope (FDM)

[0245] The behavior of the frozen formulation under vacuum was analyzed using a lyophilization microscope (FDSC 196, Resultec).

[0246] For each formulation, pipette 2 μl of sample onto a quartz crucible. Freeze the sample to -50°C, then apply vacuum and heat the sample, including an isothermal step at, for example, -40°C, until collapse and melting are observed.

[0247] Images were taken periodically during the collapse process. Based on the images, the collapse initiation temperature (T0) of the frozen solution was determined from the appearance of translucent points or cracks behind the ice sublimation interface. c,on ).

[0248] Differential scanning calorimetry (DSC)

[0249] Differential scanning calorimetry (DSC) in Mettler Toledo DSC1_943 (Mettler Toledo, Giessen, Germany) was used to determine the thermal events of the frozen formulation (the glass transition temperature of the maximum frozen concentrate). g’ The thermal events of freeze-dried products (glass transition temperature (T)) g )).

[0250] Karl Fischer titration (KF)

[0251] The moisture content of the lyophilized cake was determined using an Aqua 40.00 coulombic Fischer titrator equipped with a headspace module (Analytik Jena GmbH, Jena, Germany). The lyophilized product was weighed into a glass vial and heated to 120°C in an oven connected to the reaction vessel via a piping system. The evaporated water was transferred to the titration solution, and the amount of water was determined.

[0252] X-ray powder diffraction (XRD)

[0253] The morphology of the lyophilized products was studied using wide-angle X-ray powder diffraction (XRD). A copper anode (45 kV, 40 mA, K2) was used. α1 An Empyrean (Panalytical, Almelo, Netherlands) X-ray diffractometer with an emission wavelength of 0.154 nm and a PIXcel 3D detector was used. The lyophilized product was analyzed in reflectance mode within an angular range of 5–45°2θ to detect the presence of crystalline and / or amorphous structures.

[0254] Example

[0255] Example 1. Formulation screening before lyophilization

[0256] General procedure:

[0257] Prepare 50 ml of each formulation F1-F16 as follows: Weigh the corresponding excipient into a washed beaker and dissolve it in water to approximately 80% of the target volume. Then, dissolve the letemovir sodium trihydrate in the corresponding formulation buffer to a final API concentration of 20 mg / ml (corrected for free letemovir base in the solution with a correction factor of 1.13). Adjust the pH to the target value according to Table 3. For formulation F16, incorporate polysorbate 20 (PS20) into the pH-adjusted material to achieve a final PS20 concentration of 0.02% (w / v). Finally, fill the formulation to the target volume with water (as needed).

[0258] Under LAF conditions, the formulation was filtered through a 0.2-μm nylon membrane syringe filter.

[0259] Under LAF conditions, a 14 ml volume was transferred to washed, sterilized, and dried 20R glass vials. The vials were sealed with sterilized and dried rubber stoppers and crimped. These vials were then used for (i) zero-time analysis and (ii) storage stability studies at room temperature.

[0260] The following pre-lyophilized formulations were studied according to the general procedure, as shown in Table 3:

[0261] Table 3. Pre-lyophilized formulations studied

[0262]

[0263]

[0264] result

[0265] Three formulations (F3, F5, and F7) were not dissolved in the initial buffer formulation before pH adjustment. 20 mM sodium phosphate and 20 mM HEPES are not suitable buffer systems for dissolving the sodium letemovir trihydrate form.

[0266] During pH adjustment, unexpected precipitation of the active pharmaceutical ingredient was observed when citric acid and phosphoric acid (F10, F11) were used instead of HCl. Precipitation was still observed after prolonged stirring at room temperature for approximately 24 hours.

[0267] Tween 20, acting as a surfactant (F16), also caused precipitation. Precipitation was still observed after prolonged stirring at room temperature for approximately 24 hours.

[0268] Therefore, formulations F3, F5, F7, F10, F11, and F16 were excluded from further investigation. Only 10 of the 16 planned formulations were further studied.

[0269] No changes in pH, osmolarity, purity, or API content (as determined by RP-HPLC) were observed in any formulation over 72 hours. Formulations using histidine buffer (F6) and buffer-free formulations at pH 7.6 (F9) showed increased turbidity levels over time. Formulations with higher pH values ​​(F2 and F8) showed no visible particles after 72 hours.

[0270] Ten of the 16 formulations produced clear solutions after preparation and pH adjustment. HCl was the preferred acid for pH adjustment. TRIS buffer was the most suitable buffering system.

[0271] Example 2. Development of lyophilized formulations

[0272] Based on the screening results of Example 1, the following further candidate formulations were selected, as shown in Table 4:

[0273] Table 4. Lyophilized formulations studied

[0274]

[0275]

[0276] *After dilution in commercial thinner

[0277] Candidate formulations are studied according to the following general procedures:

[0278] Prepare 250 (250 ml) of each formulation as follows: Weigh the corresponding excipient into a washed beaker and dissolve it in water to approximately 80% of the target volume. Then, dissolve the letemovir sodium trihydrate in the corresponding formulation buffer to a final API concentration of 20 mg / ml (corrected for free letemovir base in the solution with a correction factor of 1.13). Adjust the pH to the target value by adding 0.4 M HCl. Fill the formulation with water (appropriate amount) to the target volume.

[0279] The formulation was filtered using a vacuum filtration system equipped with a 0.2-μm nylon membrane.

[0280] Under LAF conditions, a 13 ml volume was transferred to a washed, sterilized, and dried 20R glass vial. The vial was partially sealed with a sterilized and dried rubber stopper and lyophilized using the standard lyophilization cycle described in Table 5.

[0281] Table 5. Freeze-drying cycle

[0282]

[0283]

[0284] After freeze-drying, all vials were capped, labeled, analyzed, and stabilized for one month at 25℃ / 60% relative humidity and 40℃ / 75% relative humidity.

[0285] result:

[0286] Two of the five arginine-containing formulations (F28 and F31) precipitated during pH adjustment. Precipitation was still observed after prolonged stirring at room temperature for approximately 24 hours.

[0287] Preparations containing phenylalanine do not require any pH adjustment.

[0288] Therefore, F28 and F31 were excluded from further investigation. Thirteen of the 15 planned formulations will continue to be studied.

[0289] Formulations containing arginine (F21, F24, and F25) showed increased turbidity levels. Arginine does not improve API solubility.

[0290] The formulation containing poloxamer (F29) showed minimal precipitation during the pH adjustment process, which can lead to improved manufacturability of such formulations.

[0291] Except for F27, all formulations showed an amorphous cake matrix.

[0292] Within one month, no changes were observed in the DSC, pH, cake appearance, water content (determined by Karl Fischer titration), osmotic pressure, purity, API content (determined by RP-HPLC), or XRD of any of the exemplary formulations.

[0293] Example 3. Reconstruction of lyophilized formulations

[0294] The lyophilized formulation of Example 2 was further reconstructed according to the following general procedure:

[0295] Add water for injection to the lyophilized material. After removing the tear-off cap, add the solution using a 20-ml syringe and a 20G needle (40mm in length). Carefully homogenize the contents of the vial by gentle manual rotation. Parallel, using a 50-ml syringe and a Mini-Spike dispensing puncture device, fill an empty infusion bag with 288ml of each of the two parenteral diluents (5% glucose and lactated Ringer's solution).

[0296] Using a 20-ml syringe and a 20G needle (40mm in length), dispense 12ml of the reconstituted lyophilized material at a concentration of 20mg / ml into each vial. Then, inject this volume directly into an infusion bag containing diluent to achieve a final concentration of 0.8mg / ml.

[0297] result:

[0298] All formulations reconstituted in lactated Ringer's solution were within the physiological pH range (7.4–7.8).

[0299] The formulation with a higher API concentration of 80 mg / mL (F30) showed a significantly prolonged remodeling time of approximately 33 minutes. All other formulations remodeled between 1 and 5 minutes.

[0300] The stable-stored lyophilized sample is reconstructed according to a standard procedure.

[0301] Within one month, no changes in remodeling time, turbidity, pH, osmotic pressure, and purity (as determined by RP-HPLC) were observed in any of the exemplary formulations.

[0302] Example 4. Further Formulation Optimization

[0303] Based on the results of the preceding embodiments, the following further candidate formulations were selected, as shown in Table 6:

[0304] Table 6: Final Candidate Formulations

[0305]

[0306] The lyophilized product was prepared according to the general procedure of Example 2. After lyophilization, all vials were capped, labeled, analyzed, and stabilized for 3 months at 25°C / 60% RH and 40°C / 75% RH.

[0307] Within 3 months, no changes were observed in the DSC, pH, cake appearance, water content (determined by Karl Fischer titration), osmotic pressure, purity, API content (determined by RP-HPLC), or XRD of any of the exemplary formulations.

[0308] The lyophilized material was reconstructed according to the general procedure of Example 3.

[0309] The formulation containing phenylalanine (F36) showed a remodeling time of more than 10 minutes. All other formulations remodeled in less than 2 minutes.

[0310] Within 3 months, no changes in remodeling time, turbidity, pH, osmotic pressure, and purity (as determined by RP-HPLC) were observed in any of the exemplary formulations.

[0311] Exemplary candidate formulations for intravenous administration

[0312] Based on the results of Examples 1-4, formulations F32, F33, F34, and F35 were identified as suitable for intravenous administration. Among these candidates, F32 and F33 were identified as suitable for intravenous administration in newborns due to their acceptable daily exposure to the different excipients listed in Table 7.

[0313] Table 7. Permissible Daily Exposure to Certain Excipients

[0314] excipient PDE sucrose 11.3 mg / day lactose 5.7 mg / day Trehalose 25.8 mg / day Mannitol 75 mg / day Polyvinylpyrrolidone PF12 Due to potential risks, it is not permitted for use in newborn populations. Polosham 11.3 mg / day

[0315] Example 5. Development of excipient-free formulations

[0316] Weigh 0.3164 g of letemovir sodium trihydrate directly into a washed, sterilized, and dried 20R glass vial. Considering the correction factor of 1.13 for the crystalline trihydrate salt, this corresponds to 280 mg of letemovir free base per vial. Prepare six vials accordingly. Plug and crimp the vials.

[0317] Add 14 ml of water for injection to each 20R vial containing 280 mg of free lemetmovir base to make a concentration of 20 mg / ml. After removing the tear cap from the vial, add the water for injection using a 20-ml disposable syringe and a 40 mm 20G needle.

[0318] The contents of the vials were carefully homogenized by gentle manual rotation. Parallel, using a 50-ml syringe and a Mini-Spike dispensing puncture device, 288 ml of each parenteral diluent mixture (lactated Ringer's solution, 0.9% saline, and 5% dextrose solution) was filled into two empty infusion bags. 12 ml of the vial contents was drawn using a 20-ml disposable syringe and a 40 mm 20G needle. This total 12 ml volume was injected directly into the infusion bag containing the diluent. After injection, the contents of the bag were carefully homogenized by gentle manual rotation. Two separate formulations of each diluent were prepared, for a total of six infusion bags. The prepared infusion bags were then stored at room temperature (protected from light), and another sample was analyzed after 24 hours (T24h).

[0319] Based on visual inspection, no precipitation was observed in the reconstituted formulation within 24 hours.

[0320] The solution reconstituted with lactated Ringer's solution was observed to have a pH of 7.8. Surprisingly, no pH adjustment was required.

[0321] The other two diluents have a slightly higher pH (pH 8.0).

Claims

1. A method for producing a liquid pharmaceutical composition comprising a sodium salt of formula (I) or a solvate thereof of formula (I) at a concentration of 20 mg / mL based on the free base of letermovir. (I) The method includes the following steps: i) Provide a solution of lemetmovir sodium salt or a solvate thereof with at least one excipient in a physiologically acceptable diluent, said excipient being selected from: a combination of 30 mg / mL sucrose, 30 mg / mL PVP PF12 and 0.8% poloxamer 188; a combination of 35 mM Tris-HCl, 30 mg / mL sucrose and 30 mg / mL PVP PF12; and a combination of 50 mg / mL sucrose and 20 mg / mL phenylalanine, wherein said solution has any additional buffer in a concentration of less than 5 mol% and any complexing solubilizer selected from PEG, lysine, arginine, cyclodextrin, hydroxypropyl-β-cyclodextrin; ii) Adjust the pH of the solution obtained in step i) to 7.8 using HCl; iii) Optionally, filter the obtained solution. The solvate of the sodium litomovir salt is a crystalline trihydrate.

2. The method according to claim 1, wherein the physiologically acceptable diluent is a parenteral diluent.

3. The method of claim 1 or 2, further comprising the subsequent additional step of freeze-drying the solution obtained to provide the freeze-dried product.

4. The method of claim 3, further comprising the step of reconstituted the lyophilized product in a parenteral acceptable diluent, said diluent having a complexing solubilizer selected from PEG, lysine, arginine, cyclodextrin, and hydroxypropyl-β-cyclodextrin in an amount of less than 5 mol%.

5. A liquid pharmaceutical composition comprising a sodium salt of formula (I) or a solvate thereof of which has a concentration of 20 mg / mL based on the free base of letemovir, dissolved in a physiologically acceptable diluent, and at least one excipient selected from: a combination of 30 mg / mL sucrose, 30 mg / mL PVP PF12 and 0.8% poloxamer 188; a combination of 35 mM Tris-HCl, 30 mg / mL sucrose and 30 mg / mL PVP PF12; and a combination of 50 mg / mL sucrose and 20 mg / mL phenylalanine. (I) The liquid pharmaceutical composition contains less than 5 mol% of a complexing solubilizer selected from PEG, lysine, arginine, cyclodextrin, and hydroxypropyl-β-cyclodextrin, wherein the pH of the liquid pharmaceutical composition is adjusted to 7.8 with HCl, and wherein the solvate of the sodium lemetrene is a crystalline trihydrate.

6. The liquid pharmaceutical composition according to claim 5, wherein the physiologically acceptable diluent is a parenteral diluent.

7. The liquid pharmaceutical composition according to claim 5 or 6, which can be obtained by the method of claim 1.

8. The liquid pharmaceutical composition according to claim 5 or 6, which is suitable for oral administration.

9. Use of the liquid pharmaceutical composition according to any one of claims 5 to 6 in the preparation of a medicament for treating and / or preventing human cytomegalovirus (HCMV) infection.

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