Stable letermovir liquid formulations

Abstract

Liquid pharmaceutical formulation of letermovir or pharmaceutically acceptable salt thereof is provided. The liquid formulation of letermovir comprises letermovir, a solubilizer or suspending agent, and one or more optional pharmaceutically acceptable excipients, wherein the formulation is suitable for oral or injectable route of administration. The method of preparing the liquid letermovir formulation and the use of such formulation for the treatment of diseases treatable by letermovir is described.

Description

TITLE OF THE INVENTIONSTABLE LETERMOVIR LIQUID FORMULATIONSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 690,681 filed on September 04, 2024, U.S. Provisional Application No. 63 / 703,627 filed on October 04, 2024, U.S. Provisional Application No. 63 / 730,141 filed on December 10, 2024, U.S. Provisional Application No. 63 / 769,759 filed on March 11, 2024, U.S. Provisional Application No. 63 / 830,459 filed on June 26, 2024, the disclosures of which are incorporated herein by reference in its entirety.FIELD OF THE INVENTION

[0002] The embodiments of the present invention relate to stable liquid formulations of letermovir or its pharmaceutically acceptable salt to be used in the pharmaceutical field.BACKGROUND OF THE INVENTION

[0003] Letermovir is an antiviral agent that functions as an inhibitor of the cytomegalovirus (CMV) DNA terminase complex. It is currently approved for use in the prevention of CMV infection and disease in adult CMV-seropositive recipients of allogeneic hematopoietic stem cell transplants as well as for prophylaxis of CMV disease in kidney transplant recipients at high risk. Commercially available formulations of letermovir include tablets and pellets for oral administration and an intravenous solution, marketed under the trade name PREVYMIS®. While these solid and parenteral dosage forms have provided options for administration, they are not without limitations and deficiencies.

[0004] Solid dosage forms, such as tablets and oral pellets, are not suitable for all patient populations. Individuals with dysphagia, including pediatric and elderly patients, may be unable to swallow tablets or handle oral pellets that require mixing with soft food. Moreover, the requirement to mix oral pellets with specific types of food at controlled temperatures, and to consume the mixture within a short time frame, presents logistical challenges which may lead to improper dosing or reduced adherence, potentially compromising therapeutic outcomes. Additionally, the size of available tablets (17mm and 21mm) further limits uses in populations with swallowing difficulties.

[0005] There remains a significant and unmet clinical need for a ready-to-use, stable liquid formulation of letermovir or its pharmaceutically acceptable salt that can simplify administration and facilitate accurate dosing, especially for those unable to swallow solid dosage forms. Such a formulation would ensure broader accessibility of letermovir therapy, improve patient adherence, and enhance the overall safety and effectiveness of CMV prophylaxis in diverse patient groups.The present invention addresses this need by providing stable liquid compositions of letermovir suitable for oral administration.

[0006] Additionally, parenteral (intravenous) preparations of letermovir often present their own challenges, particularly when they require filtration prior to administration. This extra step, necessary to remove particulate matter or ensure sterility, introduces complexity into the preparation process, increasing the potential for dosing errors, contamination, or inadvertent loss of drug product during filtration. In clinical settings, especially where immediate administration is required, the filtration process can delay therapy and place added burden on healthcare professionals. These factors underscore the need for an alternative formulation that avoids the complexities of filtration and provides reliable, ready-to-use dosing for a wide range of patients.

[0007] The lack of child-friendly formulations leaves 40% of the world's population at increased risk for avoidable adverse events, suboptimal dosing, noncompliance, and lack of access to new medicines. A primary challenge in developing oral liquid formulations is the effective masking of drug taste, as over 90% of pediatricians in the US have indicated that taste and palatability are significant obstacles to ensuring treatment completion.1The bitter taste found in many drugs has been suggested to result from evolutionary mechanisms that discourage consumption of potentially harmful substances.2In several cases, basic taste-masking approaches may not suffice, requiring more advanced formulation strategies to encapsulate the drug and provide taste-concealing properties. Excipients utilized in product development must be confirmed as safe and suitable for use in children. These excipients are typically incorporated to optimize medication formulation by enhancing palatability, shelf-life, or manufacturing processes.

[0008] The liquid formulation of letermovir disclosed in the prior art lacks critical components of taste masking and stability and therefore not suitable for Letermovir oral liquid dosage form. There is unmet clinical need for liquid formulation of letermovir suitable for oral administration with improved palatability and stability.

[0009] The parenteral formulation of letermovir available in the market require filtration prior to administration in hospital settings and therefore not a desirable option for healthcare provider. There is unmet clinical need for liquid formulation of letermovir suitable for parenteral administration that does not require filtration prior to use.1http s : / / pubmed . ncbi . nlm . nih . go v / 19108801 / 2https: / / pubmed.ncbi.nlm.nih.gov / 7878094 / SUMMARY OF THE INVENTION

[0010] The embodiments of the present invention provide pharmaceutical compositions, methods of preparation, and method of use of letermovir or its pharmaceutically acceptable salt in the liquid dosage form suitable for oral administration. Some other embodiments of the present invention also relate to pharmaceutical compositions, methods of preparation, and method of use of letermovir or its pharmaceutically acceptable salt in liquid dosage form suitable for parenteral administration.

[0011] The liquid pharmaceutical compositions of the present invention suitable for oral administration comprises letermovir, or its pharmaceutically acceptable salt, in the range from about 1 mg / mL to about 200 mg / mL, preferably from about 10 mg / mL to about 100 mg / mL, more preferably from about 16 mg / mL to about 100 mg / mL, more preferably from about 20mg / mL to about 80 mg / mL; at least one excipient selected from the group of sweetening agent, preservative, and flavoring agent; at least a vehicle; and are stable up to at least one month or more at room temperature. In some embodiments, the liquid pharmaceutical compositions of the present invention suitable for oral administration further comprise one or more excipients selected from group of pH adjusting agent, buffering agent, antioxidant, surfactant, solubilizer or co-solvent, complexing agent, suspending agent, viscosity adjusting agent, anti-foaming agent, dispersing agent, wetting agent, chelating agent, coloring agent, stabilizer, crystallization inhibitor, or combination thereof. In some embodiments, the liquid pharmaceutical compositions of the present invention suitable for oral administration is a solution. In some other embodiments, the liquid pharmaceutical compositions of the present invention suitable for oral administration is a suspension.

[0012] The liquid pharmaceutical compositions of the present invention suitable for parenteral or injectable route of administration comprises letermovir, or its pharmaceutically acceptable salt, in the range from about 0.01 mg / mL to about 50 mg / mL, preferably from about 0.5 mg / mL to about 40 mg / mL, more preferably from about 0.1 mg / mL to about 20 mg / mL; and at least a vehicle, wherein the composition is free from cyclodextrin and does not require filtration prior to administration. In some embodiments, the liquid pharmaceutical compositions of the present invention suitable for parenteral administration further comprise one or more excipients selected from group of tonicity adjusting agent, pH adjusting agent, buffering agent, antioxidant, surfactant, solubilizer or co-solvent, chelating agent, stabilizer, crystallization inhibitor, or combination thereof.

[0013] In some embodiments, the liquid pharmaceutical compositions of the present invention suitable for parenteral administration are prepared by terminal sterilization using moist heat sterilization at elevated temperature such as at about 110 to 130°C for about 2 to about 30 minutes, preferably at about 121 °C for 5 to 15 minutes for improved sterility assurance. In some embodiments, the liquid pharmaceutical compositions of the present invention suitable for parenteral administration are ready to use without requiring dilution. In yet other embodiments, the liquid pharmaceutical compositions of the present invention suitable for parenteral administration doesn’t require filtration prior to administration at the point of care.

[0014] In some embodiments of the present invention, the liquid formulation of letermovir or its pharmaceutically acceptable salt suitable for oral administration is prepared by dissolving or suspending letermovir in suitable vehicle(s), with at least one excipient selected from sweetener, preservative and flavoring agent, one or more additional optional excipients, filling the liquid in suitable containers, and closing the containers.

[0015] In some embodiments of the present invention, the liquid formulation of letermovir or its pharmaceutically acceptable salt suitable for parenteral administration is prepared by dissolving letermovir in suitable vehicle(s) with one or more optional excipients, sterile filtering using 0.2pm filter, filling into suitable containers, sealing the container, and optionally terminally sterilizing by moist heat sterilization.

[0016] In some embodiments, the present invention provides liquid pharmaceutical compositions of letermovir or its pharmaceutically acceptable salt for treating diseases treatable by letermovir, preferably for prophylaxis and / or treatment of infection caused by Herpesviridae or herpes viruses, in particular Cytomegalovirus (CMV) in patients in need thereof by administering therapeutic amount of letermovir liquid formulation of the present invention via oral or parenteral route of administration.BRIEF DESCRIPTION OF DRAWINGS

[0017] FIG. 4 represent stability of letermovir in PEG 400 with and without antioxidant at 70°C. Butylated hydroxytoluene and tocopherol significantly improved the stability of letermovir in PEG 400.

[0018] FIG. 2 represent the solubility of letermovir in PEG 400: water system. The solubility of letermovir in PEG 400: water system is not linear or predictable from lower concentrations. PEG 400 at concentration beyond 60%v / v in water significantly increases the solubility of letermovir.DETAILED DESCRIPTION OF THE INVENTION

[0019] As used herein, the term “letermovir” refers to letermovir free acid or its pharmaceutically acceptable salts (such as sodium, potassium, calcium, magnesium, etc.), solvates, or hydrates thereof. In principle, any crystalline or amorphous form of letermovir may be used to manufacture inventive pharmaceutical compositions of the present invention.

[0020] As used herein, the terms “about” or “approximately” refer to within a range of ±20%, optionally within ±10%, optionally within ±5%, optionally within ±3%, optionally within ±2%, optionally within ±1%, optionally within ±0.5%, optionally within ±0.1%, or optionally within ±0.01% of the stated value, except where such number would be less than 0% or exceed 100% of a possible value. As used herein, reference to “approximately” or “about” a value or parameter includes (and describes) embodiments that are directed to that value or parameter. For example, description referring to “about X” includes description of “X”.

[0021] As used herein, the term “or” means “and / or.” The term “and / or” as used in a phrase such as “A and / or B” herein is intended to include both A and B; A or B; A (alone); and B (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0022] The terms “impurity” or “degradation impurity” or “letermovir-related impurity” used herein refer to any chemical compound that is undesired and generated from the degradation of letermovir during the formulation process or storage of the formulation. These compounds are reported as a percentage (%), representing the area percent of the impurity peak with respect to active ingredient (letermovir) when separated from letermovir through HPLC analysis. Such impurities may be reported individually or in total. “Highest single impurity” or “maximum single impurity” or “maximum individual impurity” refers to any impurity (or mixture of impurities that may not be separated from each other but separated from letermovir) with highest percent peak area when tested by HPLC.

[0023] The team “stable” used herein refers to the invented composition that has less 10%, preferably less than 5%, preferably less than 3%, preferably less than 2% of the total degradation impurities after extended period at room temperature (15-25°C), or at refrigerated condition, i.e. 2-8°C. In some embodiments, the invented composition that has less than 10%, preferably less than 5%, preferably less than 3%, preferably less than 2% of the total degradation impurities after shorter period at accelerated conditions such as about 40°C, about 60°C, about 70°C, or about 120°C (such as terminal sterilization for about 5 to 15 minutes) will also be considered stable.

[0024] As used herein, the team “shelf-life” refers to the time during which the pharmaceutical composition of the present invention remains stable.

[0025] As used herein, the term “step” is not particularly limiting. For example, each step as described herein may be a discrete step such that steps are performed sequentially upon completion of a preceding step. Alternatively, at least a portion of the method may be continuous, or the steps may be performed out of the order stated.

[0026] It should be noted that the unit of measurement for the quantity of any ingredients in this invention, such as "%", typically represents %w / w. In certain embodiments, this quantity may also be expressed using the unit %w / v. If the units are presented in %w / w in the present disclosure, it is also considered as %w / v, if the difference in concentration resulting from the conversion is less than about 10%. It is also understood that units presented in “mg / mL” or “mg per mL” can be converted into “%w / v” using this formula: %w / v = [mg / mL] x 0.1; or mg / mL = [%w / v] x 10.

[0027] The terms “composition”, “formulation”, “dosage form” may be used interchangeably, and refer to the liquid pharmaceutical composition of the present invention. In some embodiments of the present invention, the liquid pharmaceutical composition is stable.

[0028] As used herein, the terms “injectable” or “parenteral” or “sterile” dosage form refers to the liquid pharmaceutical compositions of the present invention suitable for administration via intravenous, subcutaneous, intramuscular, preferably intravenous route of administration.

[0029] The present invention relates to liquid pharmaceutical compositions of letermovir or its pharmaceutically acceptable salt for treating diseases treatable by letermovir, wherein letermovir is present at a concentration of about 0.1 mg / mL to about 240 mg / mL.

[0030] In some embodiments, the present invention provides liquid pharmaceutical formulations, wherein the concentration of letermovir is about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.5 mg / mL, about 0.7 mg / mL, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 7.5 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, about 20 mg / mL, about 21 mg / mL, about 22 mg / mL, about 23 mg / mL, about 24 mg / mL, about 25 mg / mL, about 26 mg / mL, about 27 mg / mL, about 28 mg / mL, about 29 mg / mL, about 30 mg / mL, about 31 mg / mL, about 32 mg / mL, about 33 mg / mL, about 34 mg / mL, about 35 mg / mL, about 36 mg / mL, about 37 mg / mL, about 38 mg / mL, about 39 mg / mL, about 40 mg / mL, about 41 mg / mL, about 42 mg / mL, about 43 mg / mL, about 44 mg / mL, about 45 mg / mL, about 46 mg / mL, about 47 mg / mL, about 48 mg / mL, about 49 mg / mL, about 50 mg / mL, about 51 mg / mL, about 52 mg / mL, about 53 mg / mL, about 54 mg / mL, about 55 mg / mL, about 56 mg / mL,about 57 mg / mL, about 58 mg / mL, about 59 mg / mL, about 60 mg / mL, about 61 mg / mL, about 62 mg / mL, about 63 mg / mL, about 64 mg / mL, about 65 mg / mL, about 66 mg / mL, about 67 mg / mL, about 68 mg / mL, about 69 mg / mL, about 70 mg / mL, about 71 mg / mL, about 72 mg / mL, about 73 mg / mL, about 74 mg / mL, about 75 mg / mL, about 76 mg / mL, about 77 mg / mL, about 78 mg / mL, about 79 mg / mL, about 80 mg / mL, about 81 mg / mL, about 82 mg / mL, about 83 mg / mL, about 84 mg / mL, about 85 mg / mL, about 86 mg / mL, about 87 mg / mL, about 88 mg / mL, about 89 mg / mL, about 90 mg / mL, about 91 mg / mL, about 92 mg / mL, about 93 mg / mL, about 94 mg / mL, about 95 mg / mL, about 96 mg / mL, about 97 mg / mL, about 98 mg / mL, about 99 mg / mL, about 100 mg / mL, about 120 mg / mL, about 150 mg / mL, about 160 mg / mL, about 200 mg / mL or about 240 mg / mL. In some other embodiments of the present invention, the concentration of letermovir is from about 1 mg / mL to about 100 mg / mL, from about 16 mg / mL to about 80 mg / mL.

[0031] In an embodiment of the present invention, the liquid pharmaceutical formulation of letermovir is provided in a dosage form suitable for oral administration such as solution, suspension, or emulsion, preferably solution or suspension.

[0032] In another embodiment of the present invention, the liquid pharmaceutical formulation of letermovir is provided in a dosage form, such as solution, suitable for injectable or parenteral route of administration.

[0033] In some embodiments, the present invention provides the methods of treatment or prophylaxis of cytomegalovirus (CMV) infection and disease in patients by administering a therapeutic effective amount of the liquid pharmaceutical formulation of letermovir by oral route of administration.

[0034] In some other embodiments, the present invention provides the methods of treatment or prophylaxis of cytomegalovirus (CMV) infection and disease in patients by administering a therapeutic effective amount of the liquid pharmaceutical formulation of letermovir by parenteral route of administration.

[0035] In an embodiment, the present invention provides a liquid pharmaceutical formulation of letermovir suitable for oral administration, wherein the formulation comprises (i) letermovir at a concentration from about 10 mg / mL to about 200 mg / mL, preferably from about 16 mg / mL to about 100 mg / mL; (ii) at least one vehicle; and (iii) one or more optional pharmaceutical excipients.

[0036] In an embodiment of the present invention, the liquid pharmaceutical formulation of letermovir suitable for oral administration comprises at least one vehicle selected from the group comprising water, propylene glycol, and polyethylene glycol.

[0037] In an embodiment of the present invention, the liquid pharmaceutical formulation of letermovir suitable for oral administration comprises at least one excipient selected from the group comprising sweetener, preservative, and flavoring agent.

[0038] In an embodiment of the present invention, the liquid pharmaceutical formulation of letermovir suitable for oral administration comprises at least one antioxidant.

[0039] In an embodiment of the present invention, the liquid pharmaceutical formulation of letermovir suitable for oral administration comprises at least one surfactant.

[0040] In an embodiment of the present invention, the liquid pharmaceutical formulation of letermovir suitable for oral administration comprises at least one alkalizer and / or pH adjusting agent.

[0041] In an embodiment of the present invention, the liquid pharmaceutical formulation of letermovir suitable for oral administration comprises at least one antioxidant and at least one surfactant.

[0042] In an embodiment of the present invention, the liquid pharmaceutical formulation of letermovir suitable for oral administration comprises (i) letermovir at a concentration from about 20 mg / mL to about 80 mg / mL; (ii) at least one excipient selected from the group comprising sweetener, preservative, and flavoring agent; (iii) at least one pH adjusting agent; (iv) at least one vehicle selected from the group comprising water, propylene glycol, and polyethylene glycol; and (v) optionally, one or more pharmaceutical excipients.

[0043] In an embodiment of the present invention, the liquid pharmaceutical formulation of letermovir suitable for oral administration comprises (i) letermovir at a concentration from about 20 mg / mL to about 80 mg / mL, preferably about 40 mg / mL; (ii) at least one excipient selected from the group comprising sweetener, preservative, and flavoring agent; (iii) at least one pH adjusting agent; (iv) at least one antioxidant; (v) at least one vehicle selected from the group comprising water, polyethylene glycol, and propylene glycol; and (vi) optionally, one or more pharmaceutical excipients.

[0044] In an embodiment, the present invention provides a liquid pharmaceutical formulation of letermovir suitable for parenteral route of administration comprises (i) letermovir at a concentration from about 0.5 mg / mL to about 40 mg / mL; (ii) at least one vehicle selected from the group comprising water, propylene glycol, and polyethylene glycol; and (iii) optionally, one or more pharmaceutical excipients.

[0045] In an embodiment, the present invention provides a liquid pharmaceutical formulation of letermovir suitable for parenteral route of administration, wherein the formulation is sterilized byterminal sterilization using methods selected from the group comprising, moist heat sterilization, gamma irradiation, and electron beam sterilization, preferably moist heat sterilization.

[0046] In an embodiment, the present invention provides a liquid pharmaceutical formulation of letermovir suitable for parenteral route of administration, wherein the formulation is sterilized by moist heat sterilization at about 110 to about 130°C from about 2 minutes to about 30 minutes, preferably at about 121 °C for about 5 minutes to 15 minutes, preferably at about 121 °C for about 15 minutes.

[0047] In another embodiment, the present invention provides a liquid pharmaceutical formulation of letermovir suitable for parenteral route of administration, wherein the formulation is sterilized by moist heat sterilization at about 121°C for about 5 minutes to about 15 minutes.

[0048] In yet another embodiment, the present invention provides a liquid pharmaceutical formulation of letermovir suitable for parenteral route of administration, wherein the formulation is sterilized by sterile filtration without use of heat.

[0049] In an embodiment, the present invention provides a liquid pharmaceutical formulation of letermovir suitable for parenteral route of administration, wherein the formulation is ready-to- dilute without requiring reconstitution at time of use prior to administration.

[0050] In another embodiment, the present invention provides a liquid pharmaceutical formulation of letermovir suitable for parenteral route of administration, wherein the formulation is ready-to-use without requiring dilution at the time of administration prior to use.

[0051] In another embodiment, the present invention provides a liquid pharmaceutical formulation of letermovir suitable for parenteral route of administration, wherein the formulation is free from cyclodextrins, particularly hydroxypropyl-beta-cyclodextrin.

[0052] In another embodiment, the present invention provides a liquid pharmaceutical formulation of letermovir suitable for parenteral route of administration, wherein the formulation is free from polyethylene glycol or propylene glycol.

[0053] As used herein, the term “solvent”, “solubilizer”, “solubilizing agent” or “pharmaceutically acceptable solvent” refer to any liquid medium used for dilution or dissolution of letermovir oral or parenteral formulations of the present invention.

[0054] The terms “vehicle”, “pharmaceutically acceptable vehicle” or “filler” as used herein is any ingredient or mixture or combination of ingredients, either in liquid form or solid form, that can be dissolved, homogenized or suspended, to increase the volume of the liquid composition of present invention. Non-limiting examples of vehicles are water (preferably purified water for oral dosage and water for injection for parenteral dosage form), sorbitol, sucrose, sugar, mannitol,xylitol, propylene glycol, polyethylene glycol, glycerin, lactose, cellulose, starch, triglycerides, or oil. In an embodiment, the concentration of vehicles ranges from about 5% to about 99%, from about 10% to about 99%, from about 20% to about 99.9%, from about 30% to about 99.9%, from about 40% to about 99%, from about 50% to about 99%, from about 50% to about 99%, from about 60% to about 99%, from about 70% to about 99%, from about 80% to about 99%, from about 90% to about 99% based on the total weight of the composition. In some embodiments, the preferred vehicles are water, propylene glycol and polyethylene glycol. In some embodiments, polyethylene glycol (PEG) is PEG 200, PEG 300, PEG 400 or PEG 600, preferably PEG 400. Higher molecular weight PEG may be used in combination with water or other liquid ingredients to prepare liquid formulation of the present invention.

[0055] In an embodiment of the present invention, water is used at concentration from about 0.5% to 99.9%, from about 1% to about 99%, from about 5% to about 99%, 10% to about 95%, from about 15% to about 95%, from about 20% to about 95%, from about 25% to about 95%, from about 30% to about 95%, from about 35% to about 95%, from about 40% to about 95%, from about 45% to about 95%, from about 50% to about 95%, from about 55% to about 95%, from about 60% to about 95%, from about 65% to about 95%, from about 70% to about 95%, from about 75% to about 95%, from about 80% to about 95%, from about 85% to about 95%, from about 90% to about 95% based on the total weight of the composition.

[0056] In an embodiment of the present invention, water is used at concentration from less than about 0.1%, less than about 0.2%, less than about 0.3%, less than about 0.4%, less than about 0.5%, less than about 0.6%, less than about 0.7%, less than about 0.8%, less than about 0.9%, less than about 1%, less than about 1.5%, less than about 2%, less than about 2.5%, less than about 3%, less than about 3.5%, less than about 4%, less than about 5%, less than about 6%, less than about 7%, less than about 8%, less than about 9%, less than about 10%, less than about 12%, less than about 14%, less than about 15%, less than about 16%, less than about 18%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, less than about 40%, less than about 40%, less than about 45%, less than about 50%, less than about 55%, less than about 60%, less than about 65%, less than about 70%, less than about 75%, less than about 80%, less than about 85%, less than about 90%, less than about 95%, less than about 99% based on the total weight or total volume of the composition.

[0057] In an embodiment of the present invention, water is added in sufficient quantity (quantum satis or q.s.) to achieve the target concentration of the liquid formulation of letermovir, after accounting for the amount of all other ingredients.

[0058] In an embodiment, water is used at concentration in the range from about 0.1% to about 1%, from about 1% to about 5%, from about 5% to about 10%, from about 10% to about 15%, from about 15% to about 20%, from about 20% to about 25%, from about 25% to about 30%, from about 30% to about 35%, from about 35% to about 40%, from about 40% to about 45%, from about 45% to about 50%, from about 50% to about 55%, from about 55% to about 60%, from about 60% to about 65%, from about 65% to about 70%, from about 70% to about 75%, from about 75% to about 80%, from about 80% to about 85%, from about 85% to about 90%, from about 90% to about 95%, and from about 95% to about 99% based on the total weight of the composition.

[0059] In an embodiment, vehicle is used at concentration from about 0.5% to 99%, from about 1% to about 99%, from about 5% to about 99%, 10% to about 99%, from about 15% to about 99%, from about 20% to about 99%, from about 99% to about 99%, from about 99% to about 99%, from about 35% to about 99%, from about 40% to about 99%, from about 45% to about 99%, from about 50% to about 99%, from about 55% to about 99%, from about 60% to about 99%, from about 65% to about 99%, from about 70% to about 99%, from about 75% to about 99%, from about 80% to about 99%, from about 85% to about 99%, from about 90% to about 99% based on the total weight of the composition.

[0060] In an embodiment, vehicle is used at a concentration specifically within a range such as from about 0% to about 10%, from about 10% to about 20%, from about 20% to about 30%, from about 30% to about 40%, from about 40% to about 50%, from about 50% to about 60%, from about 60% to about 70%, from about 70% to about 80%, from about 80% to about 90%, and from about 90% to about 99% based on the total weight of the composition.

[0061] In an embodiment of the present invention, vehicle is added in sufficient quantity (quantum satis or q.s.) to achieve the target concentration of the liquid formulation of letermovir, after accounting for the amount of all other ingredients.

[0062] In another aspect of the invention, the liquid formulation is stable for at least 1 week, preferably for at least 2 weeks, preferably for at least 1 month, preferably for at least 3 months, preferably for at least 6 months, preferably for at least 9 months, preferably for at least 12 months, preferably for at least 15 months, preferably for at least 18 months, preferably for at least 24 months, preferably for at least 30 months at room temperature (about 15 - 25°C).

[0063] In one aspect of the invention, the formulation of the present invention is stable for at least 1 month, preferably for at least 3 months, preferably for at least 6 months, preferably for at least 9 months, preferably for at least 12 months, preferably for at least 15 months, preferably for at least18 months, preferably for at least 24 months, preferably for at least 30 months at refrigerated condition (about 2 - 8 °C).

[0064] According to some aspects, the pharmaceutical composition of the present invention may have an initial total impurity concentration of no more than about 5%, more preferably no more than about 4.5%, more preferably no more than about 4%, more preferably no more than about 3.5%, more preferably no more than about 3%, more preferably no more than about 2.5%, more preferably no more than about 2%, more preferably no more than about 1.5%, more preferably no more than about 1%, and most preferably no more than about 0.5%.

[0065] According to some aspects, the pharmaceutical composition of the present invention may have an initial total impurity concentration of no more than about 1%, more preferably no more than about 0.99%, more preferably no more than about 0.98%, more preferably no more than about 0.97%, more preferably no more than about 0.96%, more preferably no more than about 0.95%, more preferably no more than about 0.94%, more preferably no more than about 0.93%, more preferably no more than about 0.92%, more preferably no more than about 0.91%, more preferably no more than about 0.90%, more preferably no more than about 0.89%, more preferably no more than about 0.88%, more preferably no more than about 0.87%, more preferably no more than about 0.86%, more preferably no more than about 0.85%, more preferably no more than about 0.84%, more preferably no more than about 0.83%, more preferably no more than about 0.82%, more preferably no more than about 0.81%, more preferably no more than about 0.80%, more preferably no more than about 0.79%, more preferably no more than about 0.78%, more preferably no more than about 0.77%, more preferably no more than about 0.76%, more preferably no more than about 0.75%, more preferably no more than about 0.74%, more preferably no more than about 0.73%, more preferably no more than about 0.72%, more preferably no more than about 0.71%, more preferably no more than about 0.97%, more preferably no more than about 0.69%, more preferably no more than about 0.68%, more preferably no more than about 0.67%, more preferably no more than about 0.66%, more preferably no more than about 0.65%, more preferably no more than about 0.64%, more preferably no more than about 0.63%, more preferably no more than about 0.62%, more preferably no more than about 0.61%, more preferably no more than about 0.60%, more preferably no more than about 0.59%, more preferably no more than about 0.58%, more preferably no more than about 0.57%, more preferably no more than about 0.56%, more preferably no more than about 0.55%, more preferably no more than about 0.54%, more preferably no more than about 0.53%, more preferably no more than about 0.52%, more preferably no more than about 0.51%, more preferably no more than about 0.50%, more preferably no more than about 0.49%, morepreferably no more than about 0.48%, more preferably no more than about 0.47%, more preferably no more than about 0.46%, more preferably no more than about 0.45%, more preferably no more than about 0.44%, more preferably no more than about 0.43%, more preferably no more than about 0.42%, more preferably no more than about 0.41%, more preferably no more than about 0.40%, more preferably no more than about 0.39%, more preferably no more than about 0.38%, more preferably no more than about 0.37%, more preferably no more than about 0.36%, more preferably no more than about 0.35%, more preferably no more than about 0.34%, more preferably no more than about 0.33%, more preferably no more than about 0.32%, more preferably no more than about 0.31%, more preferably no more than about 0.30%, more preferably no more than about 0.29%, more preferably no more than about 0.28%, more preferably no more than about 0.27%, more preferably no more than about 0.26%, more preferably no more than about 0.25%, more preferably no more than about 0.24%, more preferably no more than about 0.23%, more preferably no more than about 0.22%, more preferably no more than about 0.21%, more preferably no more than about 0.20%, more preferably no more than about 0.19%, more preferably no more than about 0.18%, more preferably no more than about 0.17%, more preferably no more than about 0.16%, more preferably no more than about 0.15%, more preferably no more than about 0.14%, more preferably no more than about 0.13%, more preferably no more than about 0.12%, more preferably no more than about 0.11%, and most preferably no more than about 0.10%.

[0066] According to some aspects, the pharmaceutical composition of the present invention may have a total impurity concentration after a certain period of shelf life of no more than about 5%, more preferably no more than about 4.5%, more preferably no more than about 4%, more preferably no more than about 3.5%, more preferably no more than about 3%, more preferably no more than about 2.5%, more preferably no more than about 2%, more preferably no more than about 1.5%, more preferably no more than about 1%, and most preferably no more than about 0.5%.

[0067] According to some aspects, the pharmaceutical composition of the present invention may have a total impurity concentration after a certain period of shelf life of no more than about 1%, more preferably no more than about 0.99%, more preferably no more than about 0.98%, more preferably no more than about 0.97%, more preferably no more than about 0.96%, more preferably no more than about 0.95%, more preferably no more than about 0.94%, more preferably no more than about 0.93%, more preferably no more than about 0.92%, more preferably no more than about 0.91%, more preferably no more than about 0.90%, more preferably no more than about 0.89%, more preferably no more than about 0.88%, more preferably no more than about 0.87%, morepreferably no more than about 0.86%, more preferably no more than about 0.85%, more preferably no more than about 0.84%, more preferably no more than about 0.83%, more preferably no more than about 0.82%, more preferably no more than about 0.81%, more preferably no more than about 0.80%, more preferably no more than about 0.79%, more preferably no more than about 0.78%, more preferably no more than about 0.77%, more preferably no more than about 0.76%, more preferably no more than about 0.75%, more preferably no more than about 0.74%, more preferably no more than about 0.73%, more preferably no more than about 0.72%, more preferably no more than about 0.71%, more preferably no more than about 0.97%, more preferably no more than about 0.69%, more preferably no more than about 0.68%, more preferably no more than about 0.67%, more preferably no more than about 0.66%, more preferably no more than about 0.65%, more preferably no more than about 0.64%, more preferably no more than about 0.63%, more preferably no more than about 0.62%, more preferably no more than about 0.61%, more preferably no more than about 0.60%, more preferably no more than about 0.59%, more preferably no more than about 0.58%, more preferably no more than about 0.57%, more preferably no more than about 0.56%, more preferably no more than about 0.55%, more preferably no more than about 0.54%, more preferably no more than about 0.53%, more preferably no more than about 0.52%, more preferably no more than about 0.51%, more preferably no more than about 0.50%, more preferably no more than about 0.49%, more preferably no more than about 0.48%, more preferably no more than about 0.47%, more preferably no more than about 0.46%, more preferably no more than about 0.45%, more preferably no more than about 0.44%, more preferably no more than about 0.43%, more preferably no more than about 0.42%, more preferably no more than about 0.41%, more preferably no more than about 0.40%, more preferably no more than about 0.39%, more preferably no more than about 0.38%, more preferably no more than about 0.37%, more preferably no more than about 0.36%, more preferably no more than about 0.35%, more preferably no more than about 0.34%, more preferably no more than about 0.33%, more preferably no more than about 0.32%, more preferably no more than about 0.31%, more preferably no more than about 0.30%, more preferably no more than about 0.29%, more preferably no more than about 0.28%, more preferably no more than about 0.27%, more preferably no more than about 0.26%, more preferably no more than about 0.25%, more preferably no more than about 0.24%, more preferably no more than about 0.23%, more preferably no more than about 0.22%, more preferably no more than about 0.21%, more preferably no more than about 0.20%, more preferably no more than about 0.19%, more preferably no more than about 0.18%, more preferably no more than about 0.17%, more preferably no more than about 0.16%, more preferably no more than about 0.15%, more preferably no more than about0.14%, more preferably no more than about 0.13%, more preferably no more than about 0.12%, more preferably no more than about 0.11%, and most preferably no more than about 0.10%.

[0068] In some embodiments of the present invention, pharmaceutically acceptable excipients for liquid formulation of letermovir suitable for oral administration are selected from the group comprising flavoring agents, sweetening agents, buffering agents, pH adjusting agents, preservatives, antioxidants, chelating agents, suspending agents, complexing agents, wetting agents, anti-foaming agents, dispersing agents, coloring agents, surfactants, stability enhancing agents, crystallization inhibitors, viscosity adjusting agents, solubilizers, vehicles or combination thereof.

[0069] In some embodiments of the present invention, pharmaceutically acceptable excipients for liquid formulation of letermovir suitable for parenteral administration comprise tonicity adjusting agents, buffering agents, pH adjusting agents, preservatives, antioxidants, chelating agents, surfactants, stability enhancing agents, crystallization inhibitors, viscosity adjusting agents or combination thereof.

[0070] The term “solubilizer” described herein refers to any ingredient that enhances the solubility of letermovir in liquid medium. Examples of solubilizer include, without limitation surfactant, hydrophilic polymer, ethanol, polyhydric alcohol, polyethylene glycol, carbohydrate, glycerin, propylene glycol, polyethylene glycol (PEG, such as PEG 200, PEG 300, PEG 400, PEG 600, or PEG 1000), polysorbate (PS, such as PS 20, PS 40, PS 60 or PS 80), polyvinylpyrrolidone (PVP, such as PVP K12, PVP K15, PVP K17, PVP K25, PVP K30, PVP K60, PVP K90, or PVP K120), sodium lauryl sulfate, copovidone, poloxamer, fructose, sucrose, sorbitol, etc.

[0071] The term "suspension" as used herein means a liquid with solid particles dispersed substantially throughout the formulation. The properties of a liquid suspension, according to the invention, are greatly influenced by the particle size of the drug substance, i.e. letermovir. As used herein, a "particle" may be a crystal, a granule, agglomerate, or any undissolved solid material. To achieve the rapid onset of activity, which is desirable, a small particle size is essential, ensuring the fastest possible dissolution of drug substance. The particle size distribution in suspension is also a very important factor characterizing the physical stability (for example, sedimentation ratio, etc.) of the formulation. Generally, as the particle size becomes smaller, the sedimentation ratio increases, and the physical stability is improved.

[0072] As used herein, the terms “micron”, or “microns” or “micrometer” or “pm” refer to one millionth of a meter.

[0073] In some embodiments, the particle size distribution (PSD) of letermovir in pharmaceutical suspension formulation of the present invention comprises at least 10% of particles smaller than about 30 microns, and / or at least 50% of particles smaller than about 70 microns, and / or at least 90% of particles smaller than about 150 microns.

[0074] In some preferred embodiments, the particle size distribution (PSD) of letermovir in pharmaceutical suspension formulation of the present invention comprises at least 10% of particles smaller than about 10 microns, and / or at least 50% of particles smaller than about 50 microns, and / or at least 90% of particles smaller than about 100 microns.

[0075] In some preferred embodiments, the particle size distribution (PSD) of letermovir in pharmaceutical suspension formulation of the present invention comprises at least 10% of particles smaller than about 10 microns, and / or at least 50% of particles smaller than about 25 microns, and / or at least 90% of particles smaller than about 50 microns.

[0076] In some preferred embodiments, the particle size distribution (PSD) of letermovir in pharmaceutical suspension formulation of the present invention comprises at least 10% of particles smaller than about 2 microns, and / or at least 50% of particles smaller than about 5 microns, and / or at least 90% of particles smaller than about 10 microns.

[0077] In some embodiments of the present invention, the particle size of letermovir in suspension formulation comprises at least 90% of particles smaller than about 300 microns, preferably smaller than about 200 microns, more preferably smaller than about 100 microns, more preferably smaller than about 90 microns, more preferably smaller than about 80 microns, more preferably smaller than about 70 microns, more preferably smaller than about 60 microns, more preferably smaller than about 50 microns, more preferably smaller than about 45 microns, more preferably smaller than about 40 microns, more preferably smaller than about 35 microns, more preferably smaller than about 33 microns, more preferably smaller than about 30 microns, more preferably smaller than about 28 microns, more preferably smaller than about 25 microns, more preferably smaller than about 23 microns, more preferably smaller than about 20 microns, more preferably smaller than about 18 microns, more preferably smaller than about 16 microns, more preferably smaller than about 15 microns, more preferably smaller than about 14 microns, more preferably smaller than about 13 microns, more preferably smaller than about 12 microns, more preferably smaller than about 11 microns, more preferably smaller than about 10 microns, more preferably smaller than about 9 microns, more preferably smaller than about 8 microns, more preferably smaller than about 7 microns, more preferably smaller than about 6 microns, or more preferably smaller than about 5 microns. In some other embodiments, the particle size of letermovir in suspensionformulation comprises at least 90% of particles are within the range from about 5 microns to about 10 microns.

[0078] Suspending agents suitable for use in the liquid oral suspensions of the present invention include cellulose derivatives such as methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone (PVP, such as PVP K12, PVP K15, PVP K17, PVP K25, PVP K30, PVP K60, PVP K90, or PVP K120), alginate, guar gum, xanthan gum, acacia gum, chitosan, aluminum magnesium silicate, dextran, gelatin, polyethylene glycol, polyoxyethylene and polyoxypropylene ether.

[0079] In an embodiment of the present invention, the concentration of suspending agent ranges from about 0.01% to 5%, preferably from about 0.05% to about 5%, preferably from about 0.1% to about 4%, preferably from about 0.1% to about 3%, preferably from about 0.1% to about 2% based on the total weight of the composition.

[0080] In some embodiments of the present invention, the letermovir liquid formulation is preservative-free.

[0081] In an embodiment, the liquid formulation of letermovir may contain suitable surfactants such as ionic or non-ionic surface-active agents. Suitable ionic surfactants include, but are not limited to, those containing carboxylate, sulfonate, and sulfate ions. Examples of anionic surfactants include potassium, sodium, ammonium salts of long chain alkyl sulfonates, and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2- ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate; quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene. In an embodiment, the concentration of ionic surfactant ranges from about 0.01% to 3%, preferably from about 0.05% to about 2%, preferably from about 0.05% to about 1%, preferably from about 0.05% to about 0.5%, preferably from about 0.05% to about 0.25% based on the total weight of the composition.

[0082] Suitable nonionic surfactants optionally used include, but are not limited to, glycol stearates such as ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, polyethylene glycol dilaurate, polyethylene glycol monolaurate, polysorbates, polyoxyethylene octylphenylether, polyethylene glycol cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, stearoyl monoisopropanolamide, polyoxyethylene hydrogenated tallow amide, polyoxyl-ethylated castor oils (CREMOPHOR®), polyoxyethylene esters of 12-hydroxy stearic acid (SOLUTOL®)and PEGylated glycerides (LABRASOL®). In another embodiment, the concentration of nonionic surfactant ranges from about 0.02% to 2%, based on the total weight of the composition. In another embodiment, polysorbate is the non-ionic surfactant at a concentration of less than 7% (w / w) of the total composition, less than 6% (w / w) of the total composition, less than 5% (w / w) of the total composition, less than 4% (w / w) of the total composition, less than 3% (w / w) of the total composition, less than 2% (w / w) of the total composition, less than 1% (w / w) of the total composition.

[0083] A polyhydric alcohol, as referred to herein, is a compound with more than one hydroxyl group. Non-limiting examples of polyhydric alcohols that can be used are glycerin, propylene glycol, polyethylene glycol, xylitol, maltitol, sorbitol, sucrose, sucralose, glucose, and mannitol.

[0084] In some embodiments of the present invention, the concentration of polyhydric alcohol ranges from about 0.1% to 40%, preferably from about 0.1% to about 30%, preferably from about 0.1% to about 5%, preferably from about 0.1% to about 1%, preferably from about 0.1% to 0.5% based on the total weight of the composition. In some other embodiments, the concentration of polyhydric alcohol ranges from about 1% to 40%, preferably from about 5% to about 40%, preferably from about 10% to about 40%, preferably from about 20% to about 40%, preferably from about 30% to 40% based on the total weight of the composition.

[0085] The pharmaceutical composition of the present invention may contain a “stability enhancing agent” or “stabilizer”. The terms “stability enhancing agent” or “stabilizer” are used herein to inhibit, prevent, slow down, or reduce the degradation of letermovir. More specifically, stability-enhancing agents include alkalizers, weak acidifiers (such as lactic acid), amino acids such as alanine, glycine, glutamate, sodium glutamate, L-arginine, lysine, L-cysteine or methionine; sodium chloride or sodium sulfate salts; sodium hydroxide, potassium hydroxide, calcium hydroxide, lactic acid, glycolic acid, succinic acid, pyruvic acid, citric acid, ethylenediaminetetraacetic acid (EDTA), metal ions such as zinc, magnesium and calcium or mixtures thereof; natural or synthetic gums, cellulosic derivatives such as carboxy methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyl propyl cellulose, hydroxyl propyl methylcellulose, methylcellulose, polyanionic cellulose; cyclodextrins; sugars; sugar alcohols; monosaccharides, disaccharides or polysaccharides or combinations thereof.

[0086] In some embodiments of the present invention, the concentration of the stabilizer ranges from 0.001% to 20%, preferably from about 0.001% to about 10%, preferably from about 0.01% to about 5%, preferably from about 0.1% to about 1%, preferably from about 0.15% to 0.5%, preferably from about 0.15% to 0.25% based on the total weight of the composition.

[0087] In some other embodiments of the present invention, the concentration of the stabilizer ranges from 0.1% to 20%, preferably from about 1% to about 20%, preferably from about 1% to about 10%, preferably from about 1% to about 5% based on the total weight of the composition.

[0088] In addition to stabilizing pharmaceutical preparations against chemical and physical degradation, liquid preparations, especially multi-dose preparations, must usually be protected from microbial contamination. In one embodiment, the pharmaceutical composition of the liquid formulation of letermovir may optionally comprise a preservative selected from the group comprising of benzoic acid and the sodium or potassium salts thereof, ethanol, isopropanol, methanol, butyl alcohol, benzalkonium chloride, benzyl alcohol, benzethonium chloride, butylparaben, cetylpyridinium chloride, chlorobutanol, chlorocresol, cresol, dehydroacetic acid, ethylparaben, ethylparaben sodium, methylparaben, methylparaben sodium, phenol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric nitrate, potassium benzoate, potassium sorbate, propylparaben, propylparaben sodium, sodium dehydroacetate, sodium propionate, sorbic acid, thimerosal, thymol, or combinations thereof.

[0089] In some embodiments of the present invention, the concentration of preservatives ranges from 0.001% to about 10%, preferably from about 0.01% to about 5%, preferably from about 0.01% about 2%, preferably from about 0.01% to about 1%, preferably from about 0.01% to about 0.5% based on the total weight of the composition.

[0090] In some other embodiments of the present invention, the concentration of preservatives ranges from 0.1% to about 10%, preferably from about 0.1% to about 5%, preferably from about 0.1% about 2%, preferably from about 0.1% to about 1%, preferably from about 0.1% to about 0.5% based on the total weight of the composition.

[0091] In some embodiments, liquid formulation of the present invention may contain an ingredient or a group of ingredients at concentration that is sufficient to prevent microbial growth by generating higher osmotic pressure. Non-limiting examples for such ingredients are sugars (sorbitol, mannitol, xylitol, dextrose, sucrose, lactose, etc.) at concentration from about 5% to about 90%, preferably from about 10% to about 70%, preferably from about 40%; and salts (such as sodium chloride, potassium chloride, etc.) at concentration from about 0.5% to about 10%, preferably from about 1% to about 5%. In some other embodiments, letermovir or its pharmaceutically acceptable salt may be present at a concentration that prevents microbial growth and act as self-preservative and it is still within the scope of the present invention. In yet other embodiments of the present invention, non-aqueous solvent used as vehicle, such as polyethylene glycol, propylene glycol, glycerin, ethanol or combination thereof at quantity enough (for examplefrom about 5 - 99%, preferably from about 50 - 99%, preferably more than about 50% of the total weight of the composition) preventing microbial growth acting as preservative and it is still within the scope of the invention.

[0092] The term “sweetening agents” refers to both bulk (caloric) and intense (non-caloric) sweeteners, which impart a sweet taste to the preparation. Non-limiting examples of sweeteners include glucose, sucralose, neotame, aspartame, advantame, trehalose, fructose, xylose, dextrose, galactose, tagatose, maltose, sucrose, glycerol, dulcitol, mannitol, lactitol, sorbitol, xylitol, saccharine or the corresponding sodium, potassium or calcium salt, cyclamate or the corresponding sodium or calcium salt, acesulfame or the potassium salt thereof, dulcin or ammonium glycyrrhizinate (Magnasweet® 110 or similar), alitame, inulin, steviol glycoside, isomalt, neohesperidin dihydrochalcone, thaumatin and the like or any combinations thereof.

[0093] In some embodiments of the present invention, the concentration of sweeteners ranges from about 0.001% to about 90%„ preferably from about 0.001% to about 40%, preferably from about 0.01% to about 30%, preferably from about 0.01% to about 20%, preferably from about 0.01% to about 10%, preferably from about 0.01% to about 5%, preferably from about 0.01% to about 2%, preferably from about 0.1% to about 2% based on the total weight of the composition.

[0094] In some other embodiments of the present invention, the concentration of sweeteners ranges from about 0.01% to about 70%, preferably from about 0.1% to about 40%, preferably from about 1% to about 40%, preferably from about 5% to about 40%, preferably from about 10% to about 40%, preferably from about 20% to about 40%, preferably from about 30% to about 40%, preferably from about 10% to about 20%, preferably from about 20% to about 30%, preferably from about 5% to about 15% based on the total weight of the composition. In some embodiments of the present invention, the intense sweetener may require less quantity for taste masking (for example sweetener like aspartame, neotame, advantame, sucralose, saccharin, etc.) while low- intensity sweetener (such as glucose, sorbitol, xylitol, mannitol, etc.) may require larger quantity of sweetener for taste masking.

[0095] The term “flavoring agent,” as used herein, refers to an agent or a mixture of agents that adds flavor to a mixture. A flavoring agent is selected from the group comprising of a natural flavor, an artificial flavor, and mixtures thereof. Non-limiting examples of flavoring agents are vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, banana, pear, peach, strawberry, raspberry, cherry, plums pineapple, apricot, peppermint, tutti frutti flavor and so forth and the like or any combinations thereof. Solid forms, such as spray dried forms of flavoring agents, may also be useful in the liquid dosage forms disclosed herein.

[0096] In some embodiments of the present invention, the concentration of flavoring agent ranges from about 0.001% to about 5%, preferably from about 0.001% to about 2%, preferably from about 0.001% to about 1%, preferably from about 0.001% to about 0.1%, preferably from about 0.01% to about 0.1% based on total weight of the composition.

[0097] In some other embodiments of the present invention, the concentration of flavoring agent ranges from about 0.01% to about 5%, preferably from about 0.01% to about 5%, preferably from about 0.1% to about 5%, preferably from about 1% to about 5%, preferably from about 2% to about 5% based on total weight of the composition.

[0098] The term “pH adjusting agent” refers to both acidic and basic chemicals used for the adjustment of pH of the formulation. Example of pH adjusting agents includes without limitation, hydrochloric acid, sodium hydroxide, benzoic acid, gluconic acid, formic acid, fumaric acid, lactic acid, isothionic acid, malic acid, maleic acid, mandelic acid, nitric acid, mucic acid, oxalic acid, pantothenic acid, p-toluenesulfonic acid, ascorbic acid, citric acid, tartaric acid, phosphoric acid, acetic acid, carbonic acid, phthalic acid, succinic acid, glutamic acid, methane sulfonic acid, sulfuric acid, potassium hydroxide, ammonia, or combination thereof.

[0099] In some embodiments of the present invention, the concentration of pH adjusting agent ranges up to about 10%, preferably up to about 8%, preferably up to about 5%, preferably up to about 2% based on total weight of the composition. In some embodiments of the present invention, pH adjusting agent (such as sodium hydroxide or potassium hydroxide) may be used in mole ratio of letermovir such as from about 0.5 to about 1.5: 1.0 (pH adjusting agent: letermovir), optionally from about 0.9 to 1.1 : 1.0, optionally from about 1.0 to 1.1 : 1.0, optionally from about 1.00 to 1.05: 1.00, optionally >1.00: 1.00.

[0100] In some other embodiments of present invention, pH adjusting agent accepting more than one proton or donating more than one anion (such as calcium hydroxide) may have reduced ratio by dividing provided mole above by number of donating anions.

[0101] In some other embodiments of the present invention, the concentration of pH adjusting agent may depends on the pH of formulation and quantity to be used is generally considered as “quantity sufficient (q.s.) to target pH”.

[0102] In some embodiments of the present invention, the pH of the liquid composition of present invention is between about 6 and 12, optionally between about 7 and 10, optionally between about 8 and 10, optionally between about 6 and 9, optionally between 7 and 9, optionally between 8 and 9, optionally between 8.0 and 9.0, optionally between 8.0 and 10.0, optionally between 7.0 and 9.0, optionally between about 7.5 and 8.5, optionally between about 8.5 and 9.5, optionallybetween about 8.4 and 9.4, optionally about 7.5, optionally about 8.0, optionally about 8.5, optionally about 9.0, optionally about 9.5, or optionally about 8.4 to 10.

[0103] In some other embodiments of the present invention, the pH of the liquid composition of present invention is between about 6 and 8.5, optionally between about 6 and 8, optionally between about 6 and 7.5, optionally between about 6 and 7, optionally about 6.5.

[0104] The term “complexing agent,” as used herein, refers to a compound or mixture of compounds that interacts with an active pharmaceutical ingredient to form a stable complex, thereby enhancing solubility, stability, or bioavailability within the formulation. In the context of letermovir liquid pharmaceutical compositions, suitable complexing agents may include, but are not limited to, Cyclodextrins (such as a-cyclodextrin, P-cyclodextrin, y-cyclodextrin, and their derivatives like hydroxypropyl-P-cyclodextrin, sulfobutyl ether-P-cyclodextrin), ethylenediaminetetraacetic acid (EDTA), citric acid, tartaric acid, or other pharmaceutically acceptable agents capable of forming inclusion or coordination complexes. The concentration of complexing agent in these compositions typically ranges from about 0.01% to about 20% by weight of the total formulation, preferably from about 0.05% to about 10%, more preferably from about 0.1% to about 5%, depending on the nature and binding affinity of the selected agent, the desired improvement in solubility or stability, and the specific formulation requirements for letermovir. In some embodiments of the present inevntion, the complexing agent may be used in a mole ratio from about 1 : 1 to about 15: 1 (complexing agent: letermovir).

[0105] The term “buffering agent”, also known as buffer system, refers to ingredients that helps maintaining the pH of formulation. Examples of buffering agents include, without limitation, salts of citric acid, tartaric acid, ascorbic acid, phosphoric acid, acetic acid, carbonic acid, phthalic acid, succinic acid, glutamic acid, benzoic acid, gluconic acid, formic acid, fumaric acid, lactic acid, isothionic acid, malic acid, maleic acid, mandelic acid, nitric acid, mucic acid, oxalic acid, pantothenic acid, p-toluenesulfonic acid, methane sulfonic acid, sulfuric acid, hydrochloric acid, or combination thereof. Additionally, pharmaceutically acceptable amino acids such as methionine, cysteine, glycine, etc. can also be used as buffering agents.

[0106] In some embodiments of the present invention, the concentration of buffering agent ranges from 0.0001% to 10%, preferably from about 0.0001% to about 5%, preferably from about 0.0001% to about 2%, preferably about 0.0001% to about 1%, preferably about 0.0001% to 0.5%, preferably about 0.0001% to about 0.25% based on the total weight of the composition.

[0107] In some embodiments of the present invention, an alkalizing agent or a base (such as sodium hydroxide or potassium hydroxide) is used in liquid pharmaceutical formulation of letermovir with water quantity of less than 5%.

[0108] In some embodiments of the present invention, an alkalizing agent or a base (such as sodium hydroxide or potassium hydroxide) is used in liquid pharmaceutical formulation of letermovir with water quantity of less than 5%, wherein at least one vehicle is used selected from propylene glycol or polyethylene glycol.

[0109] In some embodiments of the present invention, an alkalizing agent or a base (such as sodium hydroxide or potassium hydroxide) is used in liquid pharmaceutical formulation of letermovir at a mole ratio of about 0.5: about 1 (base: letermovir), preferably about 0.8: 1, preferably about 0.9: 1, preferably about 1.0: 1.0, with water quantity of less than 5%, wherein at least one vehicle is used selected from propylene glycol or polyethylene glycol.

[0110] In some embodiments of the present invention, an alkalizing agent or a base (such as sodium hydroxide or potassium hydroxide) is used in liquid pharmaceutical formulation of letermovir at a mole ratio of about 0.5: about 1 (base: letermovir), preferably about 0.8: 1, preferably about 0.9:1, preferably about 1.0: 1.0, wherein at least one vehicle is used selected from group comprising water, propylene glycol or polyethylene glycol.[OHl] In some embodiments of the present invention, an alkalizing agent or a base (such as sodium hydroxide or potassium hydroxide) is used in liquid pharmaceutical formulation of letermovir at a mole ratio of about 0.5: about 1 (base: letermovir), optionally about 0.8: 1, optionally about 0.9: 1, optionally about 1.0: 1.0, optionally >1.00: 1.00, wherein at least one vehicle is used selected from group comprising water, propylene glycol or polyethylene glycol and at least one excipient is used selected from group comprising sweetener, preservative, flavoring agent, and antioxidant.

[0112] In some other embodiments of the present invention, the concentration of buffering agent ranges from 0.001% to 10%, preferably from about 0.001% to about 5%, preferably from about 0.001% to about 2%, preferably about 0.001% to about 1%, preferably about 0.001% to 0.5%, preferably about 0.001% to about 0.25% based on the total weight of the composition.

[0113] In some other embodiments of the present invention, the concentration of buffering agent ranges from 0.01% to 10%, preferably from about 0.01% to about 5%, preferably from about 0.01% to about 2%, preferably about 0.01% to about 1%, preferably about 0.01% to 0.5%, preferably about 0.01% to about 0.25% based on the total weight of the composition.

[0114] In some other embodiments of the present invention, the concentration of buffering agent ranges from 0.1% to 10%, preferably from about 0.1% to about 5%, preferably from about 0.1% to about 2%, preferably about 0.1% to about 1%, preferably about 0.1% to 0.5%, preferably about 0.1% to about 0.25% based on the total weight of the composition.

[0115] It is understood that a higher quantity of alkalizer or acidifier can be used in higher than range mentioned in the disclosure considering that they neutralize the effect of each other and are still within the scope of the invention. In some embodiments of the present invention, the concentration of alkalizer or acidifier is net quantity after neutralization by counter ions.

[0116] The term “antioxidant” refers to agents that protect any ingredients of the composition from oxidative degradation. Examples include, without limitation, methionine, sodium / potassium bisulfite, sodium metabisulfite, potassium metabisulfite, sodium ascorbate, ascorbic acid, butylated hydroxytoluene, butylated hydroxyanisole, cysteine, glutathione, monothioglycerol, propyl gallate, sodium / potassium sulfite, tocopherol (such as alpha-tocopherol) or its salt and esters (such as D-alpha-tocopheryl polyethylene glycol 1000 succinate), or combination thereof.

[0117] In some embodiments of the present invention, the concentration of antioxidants ranges from about 0.001% to about 5%, preferably from about 0.01% to about 2%, preferably from about 0.01% to about 1%, preferably from about 0.01% to about 0.5%, preferably from about 0.01% to about 0.2% based on total weight of the composition.

[0118] In some embodiments of the present invention, the concentration of antioxidants ranges from about 0.05% to about 2%, preferably from about 0.1% to about 2%, preferably from about 0.1% to about 2%, preferably from about 0.1% to about 1%, preferably from about 0.1% to about 0.5% based on total weight of the composition.

[0119] In some embodiments of the present invention, the liquid formulation of letermovir may not require antioxidant and oxidative degradation may be prevented by other ingredients with unknown mechanism such as alkalizing agent, preferably sodium hydroxide or potassium hydroxide, preferably sodium hydroxide at mole ratio of about 1 : about 1 (sodium hydroxide: letermovir), optionally at mole ratio of 0.50-1.00: 1.00, optionally mole ratio of 0.90-1.00: 1.00, mole ratio of 1.05: 1.00, mole ratio of >1.00: 1.00 (sodium hydroxide: letermovir).

[0120] In some embodiments of the present invention, surfactant is used along with water insoluble antioxidants, for example when alpha-tocopherol is used in non-aqueous solution, a surfactant such as polyvinylpyrrolidone (such as PVP K30), sodium lauryl sulfate or polysorbate 80 (as range provided in this disclosure) can be used to avoid separation of antioxidant upon dilution with water. It is still within the scope of the present invention.

[0121] The term “chelating agent” refers to compounds that helps to stabilize the formulation by means of chelating undesired compounds or elements or ions. Suitable chelating agents which may be used in the present invention include, but are not limited to, edetate disodium (EDTA); edetate trisodium, edetate tetrasodium; and diethylene amine pentaacetate or derivatives thereof. In certain preferable embodiments, the formulations comprise disodium edetate. In some embodiments, any hydrate or polymorphs of the said chelating agents are within the scope of the invention.

[0122] In some embodiments of the present invention, the concentration of chelating agents ranges from 0.001% to 5%, preferably from about 0.001% to about 2%, preferably from about 0.001% to about 1%, preferably from about 0.001% to about 0.5%, preferably from about 0.001% to about 0.1% based on the total weight of the composition.

[0123] In some other embodiments of the present invention, the concentration of chelating agents ranges from 0.01% to 5%, preferably from about 0.01% to about 2%, preferably from about 0.01% to about 1%, preferably from about 0.01% to about 0.5%, preferably from about 0.01% to about 0.1% based on the total weight of the composition.

[0124] In an embodiment, the liquid formulation of letermovir suitable for oral administration is suspension comprising letermovir (from about 2%w / v to about 12%w / v), vehicle (q.s. to 100%w / v) and an optional ingredient selected from group comprising of suspending agent (from about 0.1%w / v to about 4%w / v), surfactant (from about 0.01% to about 2%), sweetener (from about 0.1%w / v to about 40%w / v, preferably from about 0.1%w / v to about 5% w / v), viscosity adjusting agent (from about 0.1%w / v to about 5%w / v, preferably from about 0.1% to about 2%, preferably from about 0.1% to 0.5%), pH adjusting agent (from about 6.5 to about 9.5), stabilizer (from about 0.01%w / v to about l%w / v), preservative (from about 0.01%w / v to about l%w / v), antioxidant (from about 0.01%w / v to about 0.5%w / v), and flavoring agent (from about 0.01%w / v to about l%w / v).

[0125] In an embodiment, the liquid formulation of letermovir suitable for oral administration is suspension comprising letermovir (from about 2%w / v to about 10%w / v), vehicle (q.s. to 100%w / v) and an optional ingredient selected from group comprising of suspending agent (from about 0.1%w / v to about 2%w / v), viscosity adjusting agent (from about 0.1%w / v to about 4%w / v), surfactant (from about 0.01%w / v to about 0.5%w / v), sweetener (from about 0.1%w / v to about 30%w / v, preferably from about 0.1%w / v to about 2%w / v), pH adjusting agent (from about 6.5 to about 9.5), stabilizer (from about 0.01%w / v to about l%w / v), preservative (from about 0.01%w / v to about l%w / v), antioxidant (from about 0.01%w / v to about 0.5%w / v), and flavoring agent (from about 0.01%w / v to about l%w / v).

[0126] In an embodiment, the present invention provides a process for preparing letermovir suspension suitable for oral administration comprising the steps provided below:(1) adding vehicle to manufacturing vessel;(2) adding optional ingredients one-by-one with mixing until dissolved or suspended and homogenized; and(3) adding Letermovir drug substance with mixing until homogenous suspension is obtained.

[0127] In an embodiment, the process of preparation of the liquid oral suspension of Letermovir is comprising steps of: (a) adding and dissolving required quantity of buffering agent, preservative and sweetening agent one by one in vehicle; (b) optionally, adding anti-foaming agent mixing to homogeneity; (c) optionally, adding wetting agent and mixing to homogeneity; (d) optionally, adding stabilizer and mixing to homogeneity; (e) optionally, adding dispersing agents and mixing to homogeneity, and (f) adding Letermovir and mixing till uniform homogenous suspension obtained.

[0128] In an embodiment, the liquid formulation of letermovir suitable for oral administration is solution comprising letermovir (from about 2%w / v to about 12%w / v, preferably about 4%), vehicle or solubilizer (q.s. to 100%w / v) and an optional ingredient selected from group comprising of sweetener (from about 0.1%w / v to about 5%w / v), pH adjusting agent (from about 6.5 to about 9.5, optionally from about 7 to 9, optionally from about 8 to 9), stabilizer (from about 0.01%w / v to about l%w / v, preferably from about 0.1%w / v to about l%w / v), surfactant (from about 0.01%w / v to about l%w / v, preferably from about 0.01%w / v to about 0.2%w / v), preservative (from about 0.01%w / v to about 4%w / v), antioxidant (from about 0.01%w / v to about 0.5%w / v), and flavoring agent (from about 0.01%w / v to about 2%w / v).

[0129] In an embodiment, the liquid formulation of letermovir suitable for oral administration is solution comprising letermovir (from about 2%w / v to about 10%w / v), vehicle or solubilizer (q.s. to 100%w / v) and an optional ingredient selected from group of sweetener (from about 0. l%w / v to about 2%w / v), pH adjusting agent (from about 6.5 to about 9.5, optionally from about 7 to 9, optionally from about 8 to 9), stabilizer (from about 0.01%w / v to about l%w / v, preferably from about 0.1% to about 0.5%, preferably from about 0.1% to about 0.25%), surfactant (from about 0.01% to about 0.5%), preservative (from about 0.01%w / v to about l%w / v), antioxidant (from about 0.01%w / v to about 0.5%w / v), and flavoring agent (from about 0.01%w / v to about l%w / v).

[0130] In an embodiment, the present invention provides a process for preparing letermovir suspension suitable for oral administration comprising the steps provided below:(1) adding vehicle to manufacturing vessel;(2) Optionally, adding one or more ingredients one-by-one with mixing until dissolved or suspended; and(3) adding and suspending Letermovir drug substance with mixing homogeneous suspension obtained.

[0131] It is understood that the order of addition of ingredients in preparing the liquid formulation of letermovir could be changed depending on functionality of the ingredient, manufacturing capabilities, convenience and batch size.

[0132] In some embodiments, the letermovir liquid formulation of the present invention has water like viscosity such as about 1 cP. In some other embodiments, the viscosity of the formulation is higher than 1 cP, such as about 1 to 3 cP, about 3 to 10 cP, about 10 to 20 cP, about 20 to 30 cP, about 30 to 50 cP, about 50 to 100 cP, about 1 to 1000 cP. In some other embodiments, the viscosity of the formulation is from about 10 cP to 1000 cP, about 40 cp to 1000 cP. The viscosity range provided here is when tested using capillary viscometer, such as U-tube Ostwald capillary viscometer with ID of about 0.5 mm or about 1 mm, using water as reference.

[0133] In some embodiments of the present invention, the liquid formulation of letermovir suitable for oral administration has viscosity of which an IDDSI (International Dysphagia Diet Standardization Initiative) level is classified in a range of 0-3, optionally 1-3, optionally 2 when viscosity is measured suing Framework Flow Test.

[0134] In an embodiment, the letermovir liquid formulation is filled into a suitable pharmaceutically acceptable container selected from the group consisting of bottles, bags, sprayers, ampules (plastic or glass), blisters, sachets, syringes, cartridges, and vials.

[0135] In another embodiment, the letermovir liquid formulation is filled into a pharmaceutically acceptable container suitable for single or multiple-dose delivery for oral or injectable administration.

[0136] In an embodiment, the letermovir liquid formulation is filled into a suitable pharmaceutically acceptable container that reasonably protects the composition from air and light that otherwise may degrade letermovir or any vehicle or excipient within the container.

[0137] In an embodiment, the letermovir liquid formulation is administered via oral route to the patient as a fluid stream, drop(s), droplet(s), spray, or combination thereof.

[0138] In an embodiment, the pharmaceutically acceptable container for the liquid letermovir containers may be a bottle, wherein the bottle is selected from a group consisting of glass bottles or plastic bottles, wherein glass bottle is selected from a group consisting of Type I, II, and IIIborosilicate glass bottles, wherein the glass bottle may be amber color glass bottle or clear glass bottle.

[0139] In another embodiment, the pharmaceutically acceptable container for the liquid letermovir formulations may be a bottle, wherein the bottle is selected from a group consisting of high-density polyethylene (HDPE) bottle, polyethylene terephthalate (PET) and polypropylene (PP), wherein the plastic bottle may be amber color, white opaque or translucent plastic bottle or any other color.

[0140] In an embodiment, the ready-to-use liquid formulation of letermovir is packaged in flexible polymeric bag contained in secondary outer packaging.

[0141] In some embodiments, the glass and HDPE bottles for the liquid letermovir formulations may be available in range from about 1 mL, about 2mL, about 3mL, about 5mL, about lOmL, about 30mL, about 50 mL, about 60mL, about 80mL, about 90 mL, about lOOmL, about 115mL, about 120mL, about 150mL, about 180 mL, about 200mL, about 210mL, about 240mL, about 250mL, about 270mL, about 300mL, about 320mL, about 350mL, about 400mL, about 450mL or up to about 500 mL fill volumes. In some other embodiments, the volume filled in primary container is about 0.5 ounce, about 1 ounce, about 2 ounce, about 3 ounce, about 4 ounce, about 5 ounce, about 6 ounce, about 7 ounce, about 8ounce, about 9 ounce, about 10 ounce, about 11 ounce, about 12 ounce, about 14 ounce, about 15 ounce, or up to about 16 ounce. Any volume within this range is within the scope of the present invention.

[0142] In an embodiment, the pharmaceutical composition of the present invention may be further packaged as a convenience kit comprising a bottle with a child-resistant cap, adapter or flow restrictor, and dosing syringe.

[0143] In another embodiment, the liquid letermovir formulations may be packaged in a metered device that protects the composition from air, light, and microbial contamination during storage and use.

[0144] In an embodiment of the present invention, the liquid formulation of letermovir or its pharmaceutically acceptable salt is administered to patients using syringe and delivery tube, such as nasogastric tube, gastrostomy tube, jejunostomy tube, or gastrojejunal tube.

[0145] In an embodiment, the liquid formulation of letermovir is prepared by solubilizing letermovir in solvent and one or more pharmaceutical ingredients with or without heating, filling the formulated letermovir liquid into a primary packaging container, and closing the container using closure. In some embodiments, the nitrogen or argon or other inert gas can be overlayedbefore capping. In some embodiments, the containers are sealing using induction sealing to make them air tight and protect from oxygen or microbial contamination.

[0146] In an embodiment, the liquid formulation of letermovir is prepared by suspending letermovir in oil or a mixture of oil and one or more pharmaceutical ingredients, filling formulated letermovir liquid into the primary packaging container, and closing the container.

[0147] An embodiment of the present invention relates to a method of treatment for prophylaxis of cytomegalovirus (CMV) infection and disease in patients with the need by administering a therapeutic effective amount of the liquid pharmaceutical formulation of Letermovir via oral route of administration.

[0148] In some embodiments of the present invention, the liquid formulation is administered to the patient for prophylaxis or treatment of cytomegalovirus (CMV) infection and disease in amount from about 0.4 mL to about 30 mL, optionally from about 2.5 mL to about 30 mL, optionally from about 2 mL to about 24 mL, optionally from about 1 mL to about 12 mL, optionally from about 0.5 mL to about 6 mL, optionally from about 0.4 mL to about 4.8 mL. Non-limiting examples for comparative dose administered by oral route of administration are given in the table below. Oral liquid dose is given for different strength from 16 mg / mL to 100 mg / mL. The larger doses of 480 mg and 240 mg can be administered using liquid formulation of present invention at concentrations of 48 mg / mL (10 mL for 480 mg dose; 5 mL for 240 mg dose) or 96 mg / mL (5 mL for 480 mg dose; 2.5 mL for 240 mg dose).Table 1. Examples for use of present invention in some of the disease with approved therapy.

[0149] In some embodiments, the present invention provides methods for manufacturing a liquid pharmaceutical composition of letermovir or its pharmaceutically acceptable salt in the form of aqueous solution suitable for oral administration, comprising the steps of:(a) adding and homogenizing a base or alkali, preferably sodium hydroxide or potassium hydroxide at mole ratio from about 0.5 to 1.5: 1.0 (base: letermovir), preferably from about 0.8 to 1.2: 1.0, preferably from about 1.0 to 1.2: 1.0, preferably from about 1.05: 1.00, optionally at >1.00: 1.00, into about 20 to about 95% (preferably about 50 to 95%, more preferably about 70 to 95%) of purified water;(b) adding and mixing letermovir until complete dissolution;(c) optionally adjusting pH between 7 and 10, optionally between 7 and 9, optionally between 8 and 10, optionally between 8 and 9, optionally between 8.0 and 9.0, optionally at about 8.5 using an acid (preferably hydrochloric acid) or a base (preferably sodium hydroxide or potassium hydroxide, more preferably sodium hydroxide);(d) dissolving at least one excipient from the group comprising of sweeteners, preservatives and flavoring agents;(e) optionally dissolving one or more excipients from the group comprising of antioxidant, complexing agent, stabilizer, buffering agent, chelating agent, viscosity adjusting agent, and surfactant;(f) if required, make up volume quantum satis (q.s.) with purified water and mix to homogeneity;(g) if required, filter the liquid to remove particulate matter; and(h) fill the liquid pharmaceutical composition in suitable containers and seal it with suitable closures.

[0150] In some embodiments, the letermovir can be suspended in water, followed by addition of base, dissolving one or more excipients from sweetener, preservative and flavoring agent, optionalpH adjustment, optionally adding one or more excipients, volume make up to batch size, optional filtration, filling into containers and sealing of such containers.

[0151] In some embodiments, dissolution of some ingredients in water (such as methylparaben or propylparaben) may require heating up to about 60 to 70°C and then cooling the solution to room temperature prior to adding other ingredients.

[0152] In some embodiments, the present invention provides methods for manufacturing a liquid pharmaceutical composition of letermovir or its pharmaceutically acceptable salt in the form of non-aqueous solution (wherein the water content is less than about 10%, preferably less than about 5%) suitable for oral administration, comprising the steps of(a) adding letermovir in about 5 to about 95% of at least one or more non-aqueous solvents (preferably polyethylene glycol or propylene glycol, more preferably polyethylene glycol 400) and mixing until complete dissolution;(b) dissolving at least one excipient from the group comprising of sweeteners, preservatives and flavoring agents;(c) optionally dissolving one or more excipients from the group comprising of antioxidant, pH adjusting agent, complexing agent, stabilizer, buffering agent, chelating agent, viscosity adjusting agent, and surfactant;(d) if required, make up volume quantum satis (q.s.) with non-aqueous solvent and mix to homogeneity;(e) if required, filter the liquid to remove particulate matter; and(f) fill the liquid pharmaceutical composition in suitable containers and seal it with suitable closures.

[0153] In some embodiments, the present invention provides methods for manufacturing a liquid pharmaceutical composition of letermovir or its pharmaceutically acceptable salt in the form of non-aqueous solution (wherein the water content is less than 10%, preferably less than 5%, preferably less than 2%) suitable for oral administration, comprising the steps of(g) adding letermovir in about 5 to about 95% of at least one or more non-aqueous solvents (preferably polyethylene glycol or propylene glycol, preferably polyethylene glycol 400) and mixing until complete dissolution;(h) adding and homogenizing a base (preferably sodium hydroxide or potassium hydroxide, more preferably sodium hydroxide);(i) dissolving at least one excipient from the group comprising of sweeteners, preservatives and flavoring agents;(j) optionally dissolving one or more excipients from the group comprising of antioxidant, pH adjusting agent, complexing agent, stabilizer, buffering agent, chelating agent, viscosity adjusting agent, and surfactant;(k) if required, make up volume quantum satis (q.s.) with non-aqueous solvent and mix to homogeneity;(l) if required, filter the liquid to remove particulate matter; and(m)fill the liquid pharmaceutical composition in suitable containers and seal it with suitable closures.

[0154] In some embodiments, the present invention provides methods for manufacturing a liquid pharmaceutical composition of letermovir or its pharmaceutically acceptable salt in the form of solution using non-aqueous solvents and purified water suitable for oral administration, comprising the steps of:(a) adding letermovir in about 5 to 90% of at least one or more non-aqueous solvents (preferably polyethylene glycol or propylene glycol, more preferably polyethylene glycol 400) and mixing until complete dissolution;(b) dissolving at least one excipient from the group comprising of sweeteners, preservatives and flavoring agents;(c) optionally dissolving one or more excipients from the group comprising of antioxidant, pH adjusting agent, complexing agent, stabilizer, buffering agent, chelating agent, viscosity adjusting agent, and surfactant;(d) make up volume quantum satis (q.s.) with purified water and mix to homogeneity;(e) if required, filter the liquid to remove particulate matter; and(f) fill the liquid pharmaceutical composition in suitable containers and seal it with suitable closures.

[0155] In some embodiments, the present invention provides methods for manufacturing a liquid pharmaceutical composition of letermovir or its pharmaceutically acceptable salt in the form of suspension using non-aqueous solvents and purified water suitable for oral administration, comprising the steps of:(a) adding letermovir in at least one or more non-aqueous solvents (preferably polyethylene glycol or propylene glycol, more preferably polyethylene glycol 400) and mixing until complete dissolution (the quantity of non-aqueous solvent is selected in such a way that when water is added, letermovir precipitates and form suspension, for example theconcentration of letermovir is at least more than its saturated solubility in the final composition);(b) dissolving at least one excipient from the group comprising of sweeteners, preservatives and flavoring agents;(c) dissolving or suspending at least one viscosity adjusting agent or suspending agent;(d) optionally dissolving or suspending one or more excipients from the group comprising of wetting agent, dispersing agent, antioxidant, complexing agent, pH adjusting agent, stabilizer, buffering agent, chelating agent, and surfactant;(e) make up volume quantum satis (q.s.) with purified water and mix to until a homogenous suspension is obtained. In some embodiments, the rate of addition of water, mixing speed, mixing mechanism and presence of other excipients such as sodium hydroxide and surfactant impacts the final particle size of letermovir precipitated during water addition, for example sodium hydroxide and surfactant, slow addition of water and higher mixing speed may help generating smaller and more uniform particle size distribution); and(f) fill the liquid pharmaceutical composition in suitable containers and seal it with suitable closures, wherein, the steps can be changed based on manufacturing feasibility, material properties and intended applications. In some embodiments of the present invention, excipients soluble in water (such as sweetener, flavoring agent, surfactant) can be dissolved in water prior to mixing with non-aqueous solution. Change in order of addition described herein is still within the scope of the present invention.

[0156] In some embodiments, the present invention provides methods for manufacturing a liquid pharmaceutical composition of letermovir or its pharmaceutically acceptable salt in the form of suspension using purified water, suitable for oral administration, comprising the steps of:(a) adding partial quantity of water in compounding vessel;(b) adding at least one excipient from the group comprising of sweeteners, preservatives and flavoring agents and mixing until dissolved;(c) adding one or more excipients selected from the group of suspending agent, wetting agent, dispersing agent, and anti-foaming agent one-by-one with mixing until dissolved or dispersed;(d) adding letermovir with mixing until homogenous suspension is obtained;(e) optionally adjusting pH;(f) making up the volume to batch size using purified water; and(g) filling the liquid into containers and closing the containers, wherein, the steps can be changed based on manufacturing feasibility, material properties and intended applications. In some embodiments of the present invention, Letermovir can be levigated using wetting agent and small quantity of solvent in which the drug is not soluble or has very low solubility such as water. Levigation helps to fully coat the particles with wetting agent. In a separate vessel suspending agent / thickening agent or viscosity adjusting agent can be dissolved in water along with one or more ingredients from sweetening agent, flavoring agent, preservative, to make a base and let it fully hydrate. Then levigated slurry or paste is added to the base with continuous mixing until homogeneous suspension is obtained. Change in order of addition described herein is still within the scope of the present invention.

[0157] In some embodiments, the present invention provides methods for manufacturing a liquid pharmaceutical composition of letermovir or its pharmaceutically acceptable salt in the form of aqueous solution suitable for parenteral administration, comprising the steps of(a) adding and homogenizing a base or alkali, preferably sodium hydroxide or potassium hydroxide at mole ratio from about 0.5 to 1.5: 1.0 (base: letermovir), preferably from about 0.8 to 1.2: 1.0, preferably from about 1.0 to 1.2: 1.0, preferably from about 1.05: 1.00, optionally at >1.00: 1, into about 20 to about 95% (preferably about 50 to 95%, more preferably about 70 to 95%) of water for injection;(b) adding and mixing letermovir until complete dissolution;(c) optionally adjusting pH between 7 and 10, optionally between 7 and 9, optionally between 8 and 10, optionally between 8 and 9, optionally between 8.0 and 9.0, optionally at about 8.5 using an acid (preferably hydrochloric acid) or a base (preferably sodium hydroxide or potassium hydroxide, more preferably sodium hydroxide);(d) dissolving at least one excipient from the group comprising of tonicity adjusting agent, antioxidant, stabilizer, surfactant, buffering agent, and chelating agent;(e) if required, make up volume quantum satis (q.s.) with water for injection and mix to homogeneity;(f) sterile filtering the solution using 0.2pm or 0.22pm polymeric filter; and(g) aseptically filling the liquid pharmaceutical composition in suitable containers and sealing it with suitable closures, wherein, the formulation is free from cyclodextrins.

[0158] In some embodiments, the present invention provides method of manufacturing aqueous liquid formulation in form of solution by suspending letermovir in water for injection, followed byaddition of base and mixing until complete dissolution of letermovir, adding and dissolving one or more excipients, optional pH adjustment, volume make up to batch size using water for injection, optional filtration, filling into containers and sealing of such containers.

[0159] In some embodiments, the present invention provides manufacturing method of liquid pharmaceutical composition of letermovir or its pharmaceutically acceptable salt in the form of solution suitable for parenteral administration, wherein the product is sterilized by terminal sterilization using moist heat at about 110 to about 130°C for about 2 minutes to about 30 minutes, preferably at about 121 °C for about 5 minutes to about 20 minutes, preferably for about 15 minutes.

[0160] In some embodiments, the present invention provides manufacturing method of liquid pharmaceutical composition of letermovir or its pharmaceutically acceptable salt in the form of solution suitable for parenteral administration, wherein the product is sterilized by aseptic filtration without use of heat.

[0161] In some embodiments, the present invention provides methods for manufacturing a liquid pharmaceutical composition of letermovir or its pharmaceutically acceptable salt in the form of solution using non-aqueous solvents and water for injection suitable for parenteral administration, comprising the steps of:(a) adding letermovir in about 5 to 90% of batch required quantity, preferably less than 50%, more preferably less than 20%, more preferably less than 15%, more preferably from about 5% to about 10% of at least one or more non-aqueous solvents (preferably polyethylene glycol or propylene glycol, more preferably polyethylene glycol 400) and mixing until complete dissolution;(b) adding and homogenizing a base, preferably sodium hydroxide or potassium hydroxide, preferably sodium hydroxide;(c) adding water for injection to make up the volume of the batch up to about 95%;(d) adding and dissolving at least one excipient from the group comprising of tonicity adjusting agent, antioxidant, stabilizer, surfactant, buffering agent, and chelating agent;(e) optionally adjusting pH between 7 and 10, optionally between 7 and 9, optionally between 8 and 10, optionally between 8 and 9, optionally between 8.0 and 9.0, optionally at about 8.5 using an acid (preferably hydrochloric acid) or a base (preferably sodium hydroxide or potassium hydroxide, more preferably sodium hydroxide);(f) if required, make up volume quantum satis (q.s.) with water for injection and mix to homogeneity;(g) sterile filtering the solution using 0.2pm or 0.22pm polymeric filter; and(h) aseptically filling the liquid pharmaceutical composition in suitable containers and sealing it with suitable closures, wherein the formulation is free from cyclodextrins.

[0162] In some embodiments, the present invention provides methods for manufacturing a liquid pharmaceutical composition of letermovir or its pharmaceutically acceptable salt in the form of solution using non-aqueous solvents suitable for parenteral administration after dilution with parenteral diluents, comprising the steps of(a) adding letermovir in about 10 to 70% of least one or more non-aqueous solvents (preferably polyethylene glycol or propylene glycol, more preferably polyethylene glycol 400) and mixing until complete dissolution;(b) adding and homogenizing a base, preferably sodium hydroxide or potassium hydroxide, preferably sodium hydroxide at a mole ratio of about 0.50: 1.00 (baseletermovir), preferably about 0.90: 1.00, preferably about 1.00: 1.00, preferably about 1.05: 1.00, optionally about >1.00: 1;(c) adding non-aqueous solvent to make up the volume of the batch up to about 95%;(d) Optionally adding and dissolving one or more excipient from the group comprising of tonicity adjusting agent, antioxidant, stabilizer, surfactant, buffering agent, and chelating agent;(e) optionally adjusting pH between 7 and 10, optionally between 7 and 9, optionally between 8 and 10, optionally between 8 and 9, optionally between 8.0 and 9.0, optionally at about 8.5 using an acid (preferably hydrochloric acid) or a base (preferably sodium hydroxide or potassium hydroxide, more preferably sodium hydroxide);(f) if required, make up volume quantum satis (q.s.) with non-aqueous solvent and mix to homogeneity;(g) sterile filtering the solution using 0.2pm or 0.22pm polymeric filter; and(h) aseptically filling the liquid pharmaceutical composition in suitable containers and sealing it with suitable closures, wherein the formulation is free from cyclodextrins.

[0163] The present invention is further illustrated by, but is by no means limited to, the following examples. %Purity, %maximum single impurity and %total impurities were tested using HPLC analysis and reported as %peak area.EXAMPLESExamples 1-7

[0164] Example 1-7 describe the liquid formulations of letermovir prepared using ingredients detailed in Table 2. Letermovir was added to about 75% of batch required quantity of Polyethylene glycol (PEG 400) or propylene glycol and mixed until dissolved. Where applicable, sucralose, methylparaben, propylparaben, strawberry flavor, and glycerin were added one-by-one and mixed until dissolved and / or homogenized. Volume for the batches were made up to batch size (, i.e. quantum satis, or q.s.) using, as applicable, PEG 400, water, or propylene glycol and mixed to homogeneity. The final solutions were filtered and filled in containers, sealed with closure. Stability test results for these examples are shown in Table 3.Table 2. Liquid formulation of letermovir solutionTable 3. Stability test results for example 1-7.

[0165] Example 8-9 describe the liquid formulations of letermovir prepared using ingredients detailed in Table 4 by dissolving tocopherol or butylated hydroxytoluene in partial quantity (about 80% of the batch size), followed by adding and dissolving letermovir. Finally, volume was made up to the batch size (quantum satis, or q.s.) using PEG 400. Tocopherol and butylated hydroxytoluene are not soluble in water. The formulation samples were filled in containers and closed with closure. Stability test results for these examples are shown in Table 5.Table 4. Liquid formulation of letermovir solutionTable 5. Stability test results for example 8-10.*Note: %Purity and %Total impurities were not tested in drug product sample for initial, however, they are reported here based on purity of drug substance for comparison.

[0166] Example 11-16, example 17-23, example 24-27, and example 28-34 describe the liquid formulations of letermovir prepared using ingredients detailed in Table 6, Table 7, Table 8, and Table 9 respectively. Where applicable, required quantity of sucralose, methylparaben, propylparaben, strawberry flavor, tocopherol, and butylated hydroxytoluene (BHT) were added, one-by-one, into partial quantity (70% of the batch size) of polyethylene glycol 400 (example 11 to 23) or propylene glycol (example 24 to 34) and mixed until dissolved. Required quantity of glycerin (example 17 to 20, 28 to 31) and water (example 21 to 23, 32 to 34) were added and mixed to homogenize. Volume of batch size were made up to the batch size using PEG 400 (example 11 to 23) or propylene glycol (example 24 to 34). The solutions were filtered and filled into containers, closed with closure. Stability test results for these examples are given in table 10 and table 11Table 6. Liquid formulation of letermovir solutionTable 7. Liquid formulation of letermovir solutionTable 8. Liquid formulation of letermovir solutionTable 9. Liquid formulation of letermovir solutionTable 10. Stability test results for example 11-34.Table 11. Stability test results for example 11-34.

[0167] Examples 35-37 the liquid formulation of letermovir prepared using ingredients detailed in Table 12. Sucralose, methylparaben, propylparaben, tocopherol, glycerin and strawberry flavor were added and mixed until dissolved in partial quantity (about 50%) of PEG 400. Volume was made up to batch size using PEG 400. The final solutions were filtered and filled in containers, closed with closure. Stability test results for these examples are given in Table 13.Table 12. Liquid formulation of letermovir solutionTable 13. Stability test results for example 35 - 37.

[0168] Example 38 to 41 are the liquid formulation of letermovir prepared using ingredients detailed in Table 14. Where applicable, sucralose, methylparaben, propylparaben, strawberry flavor, and tocopherol were added and mixed until dissolved in partial quantity of PEG 400 or propylene glycol (about 70% of the batch size). Letermovir was added and mixed until dissolved. Where applicable, sodium hydroxide was added and mixed to homogenize. Volume was made up to batch size using PEG 400 or propylene glycol. The final solutions were filtered, and filled in containers, closed with closure. Stability test results for these examples are provided in table 15. Table 14. Liquid formulation of letermovir solution.Table 15. Stability test results for example 38 - 41.

[0169] Example 42 to 46 are the liquid formulation of letermovir prepared using ingredients detailed in Table 16, by dissolving (where applicable) sucralose, methylparaben, propylparaben, strawberry flavor, polysorbate 80, and tocopherol, on-by-one, in about 70% of the batch required quantity of PEG 400. Letermovir was added and mixed until dissolved. Sodium hydroxide was added and mixed until dissolved and homogenized. The volume of the batch was made up to batch size using polyethylene glycol 400. The final solutions were filtered and filled in containers and closed with closure. Stability test results for these examples are provided in Table 17.Table 16. Liquid formulation of letermovir solution.Table 17. Stability test results for example 42 - 46.

[0170] Examples 47 to 53 are the liquid formulation of letermovir prepared using ingredients detailed in Table 18, by dissolving and / or homogenizing (where applicable) sucralose, methylparaben, propylparaben, strawberry flavor, tocopherol and polysorbate 80 in about 70% of batch quantity of PEG 400. Letermovir was added and mixed until dissolved. Sodium hydroxide and lactic acid were added one-by-one (where applicable) and mixed to homogenize. The batch was made up to batch size using PEG 400. The final solutions were filtered, filled in containers and closed with closure. Stability test results for these examples are provided in Table 19.Table 18. Liquid formulation of letermovir solution.Table 19. Stability test results for example 47 - 53.

[0171] Examples 54 to 62 are the liquid formulation of letermovir prepared using ingredients detailed in Table 20, by dissolving and / or homogenizing (where applicable) sucralose, methylparaben, propylparaben, strawberry flavor, polysorbate 80, and tocopherol in about 70% of batch required quantity of PEG 400 or Propylene glycol and PEG 400 mixture. Letermovir was added and mixed until dissolved. Where applicable, sodium hydroxide and lactic acid were added one-by-one and mixed to homogenize. Volumes were made up to the batch size using PEG 400.The solutions were filtered, filled into containers, closed with closure. Stability test results for these examples are provided in Table 21.Table 20. Liquid formulation of letermovir solution.Table 21. Stability test results for example 54 - 62.

[0172] Examples 63 to 67 are the liquid formulation of letermovir prepared using ingredients detailed in Table 22, by dissolving and / or homogenizing (where applicable) sucralose, methylparaben, propylparaben, strawberry flavor, polysorbate 80, sodium lauryl sulfate and tocopherol, one-by-one, in about 70% of batch required quantity of PEG. Letermovir was added and mixed until dissolved. Where applicable, sodium hydroxide and lactic acid were added one- by-one (except for example 65, where sodium hydroxide and lactic acid were mixed separately prior to addition, forming a sodium lactate buffer) and mixed to homogenize. Volumes were made up to the batch size using PEG. The solutions were filtered, filled into containers, closed with closure. Stability test results for these examples are shown in table 23.Table 22. Liquid formulation of letermovir solution.Table 23. Stability test results for example 63 - 67.

[0173] Examples 68 to 71 are the liquid formulation of letermovir prepared using ingredients detailed in Table 24, by dissolving and / or homogenizing (where applicable) sucralose, methylparaben, propylparaben, strawberry flavor, and tocopherol, one-by-one, in about 70% of batch required quantity of PEG. Letermovir was added and mixed until dissolved. Where applicable, sodium hydroxide and lactic acid were added one-by-one and mixed to homogenize. Volumes were made up to the batch size using PEG. The solutions were filtered, filled into containers, closed with closure. Stability test results for these examples are shown in table 25.Table 24. Liquid formulation of letermovir solution.Table 25. Stability test results for example 68 - 71.

[0174] Examples 72 to 77 are the liquid formulation of letermovir prepared using ingredients detailed in Table 26, by dissolving and / or homogenizing (where applicable) sucralose, methylparaben, propylparaben, cherry flavor, and tocopherol, one-by-one, in about 70% of batch required quantity of PEG 400. Letermovir was added and mixed until dissolved. Where applicable, sodium hydroxide and lactic acid were added one-by-one and mixed to homogenize. Volumes weremade up to the batch size using PEG. The solutions were filtered, filled into containers, closed with closure. Stability test results for these examples are provided in table 27.Table 26. Liquid formulation of letermovir solution.Table 27. Stability test results for example 62 - 77.

[0175] Examples 78-80 are the liquid formulation of letermovir suspension prepared using ingredients detailed in Table 28.Example 78: Letermovir, sodium hydroxide, methylparaben, and propylparaben were dissolved one-by-one in required quantity of PEG 400. In a separate container, sucralose, charry flavor, and Xanthan gum, one-by-one, were dissolved in partial quantity of water with fast mixing. Water solution was slowly added into PEG solution with fast mixing and mixed until homogeneous suspension is obtained. Volume of the batch was made up to the batch size using water. The suspension was filled into container and sealed with closure.Example 79-80: Sodium carboxymethylcellulose was dissolved in partial quantity of water (about 20% in example 79 and 50% in example 80). Where applicable, Neosorb® 70 / 70 and Sorbitol were added and mixed until homogenized or dissolved. Letermovir was suspended and mixed until homogenous suspension was obtained. Volume was made with water. The suspension was filled into containers and sealed with closure.Table 28. Liquid formulation of letermovir suspension.Table 29. Stability test results for example 78 - 80.

[0176] Examples 81-86 are the liquid formulation of letermovir solutions prepared using ingredients detailed in Table 30. Required quantity of letermovir was suspended in about 80% (30% for example 87) of the required quantity of purified water and mixed. Sodium hydroxide was slowly added (dropwise, in multiple steps) to adjust the pH with continuous mixing until clear solution is obtained. Sodium hydroxide did not exceed about 0.075 mg (1.875pL of IN) per mg of letermovir. Where applicable, required quantity of methylparaben, propylparaben, sucralose, cherry flavor, peppermint flavor, PEG 400 were added one-by-one and mixed until dissolved or homogenized. pH was adjusted to 8 where needed. Volume of the batch was made up to the batch size using purified water. The solution was filtered, filled into containers, and sealed with closure. Stability test results for these examples are provided in Table 31.Table 30. Liquid formulation of letermovir solution.Table 31. Stability test results for example 81 - 86.

[0177] Examples 87-89 are the liquid formulation of letermovir solutions prepared using ingredients detailed in Table 32. Required quantity of sodium hydroxide was added to about 80% of the required quantity of water and mixed. Required quantity of letermovir was added and mixed until clear solution was obtained. For example 89, pH was adjusted to 8.5 using hydrochloric acid. Water was added to make the volume up to batch size. The solution was filtered using 0.2pm filter and filled into glass vial, closed with stopper and sealed with aluminum crimp seals. The sealed vials were terminally sterilized at about 121°C for about 15 minutes. Stability test results are provided in table 33.Table 32. Liquid formulation of letermovir solution.Table 33. Stability test results for example 87 - 89.

[0178] Examples 90-91 are the liquid formulation of letermovir suspension prepared using ingredients detailed in Table 34. Required quantity of methylparaben and propylparaben were dissolved in about 80% of required quantity of water. Where applicable, sucralose, cherry flavor, polysorbate 80, and simethicone emulsion were added one-by-one and mixed to dissolve or suspend. Required quantity of letermovir was added with high-speed mixing and suspended. The formulation was mixed until homogenous suspension was obtained. Volume was made up to the batch size using water and mixed to homogeneity. The suspension was filled into container closed with closure. Stability test results for these examples are provided in table 35.Table 34. Liquid formulation of letermovir suspension.Table 35. Stability test results for example 90 - 81.

[0179] Examples 92-94 are the liquid formulation of letermovir solutions prepared using ingredients detailed in Table 36. Required quantity of sodium hydroxide was added to about 40% of the required quantity of water and mixed. Required quantity of letermovir was added and mixed until clear solution was obtained. Methylparaben, propylparaben, sucralose and cherry flavor were added one-by-one and mixed until dissolved and homogenized. Where applicable, glycerin and propylene glycol were added and mixed. Volume of the batches were made up to batch size using PEG 400. The solution was filtered, filled into containers, and closed with closure. Stability data of these examples are provided in table 37.Table 36. Liquid formulation of letermovir solution.Table 37. Stability test results for example 92 - 94.

[0180] Examples 95-98 are the liquid formulation of letermovir solutions prepared using ingredients detailed in Table 38. Required quantity of sodium hydroxide was added to about 80% of the required quantity of water and mixed. Required quantity of letermovir was added and mixed until clear solution was obtained. Methylparaben, propylparaben, sucralose and cherry flavor were added one-by-one and mixed until dissolved and homogenized. pH was adjusted using sodium hydroxide or hydrochloric acid, where needed. Volume of the batches were made up to batch size using water. The solution was filtered, filled into containers, and closed with closure. Stability data of these examples are provided in table 39.Table 38. Liquid formulation of letermovir solution.Table 39. Stability test results for example 92 - 94.

[0181] Examples 99(A-C) are the liquid formulation of letermovir solutions (20 mg / mL and 2 mg / mL) prepared using ingredients detailed in Table 40. Required quantity of sodium hydroxide (added as IN, reported in mg for clarity) was added to about 80% of the required quantity of water for injection and mixed. Required quantity of letermovir was added and mixed until clear solution was obtained. Where applicable, sodium chloride, mannitol, and dextrose were added and mixed until dissolved. Volume of the batches were made up to batch size using water for injection. The solution was filtered using 0.2pm filter, filled into glass vials, stoppered and sealed with aluminum crimp seals. The samples were terminally sterilized at 121°C for 15 minutes and test results are provided in table 41.Table 40. Liquid formulation of letermovir solution.Table 41. Stability test results for example 99.*Peak area of the letermovir peak was reduced to 2 / 3 (-66%) compared with standard due to precipitation. pH also dropped from about 8.5 to about 7.7 and that could be the reason for precipitation.STABILITY OF LETERMOVIR IN VARIOUS CONDITIONS

[0182] An experiment was conducted by preparing letermovir solutions to evaluate the effect of different concentrations in various solvent system and sodium hydroxideletermovir (NaOHLTMR) mole ratio on stability of letermovir. Samples were prepared from 20 mg / mL to 100 mg / mL in PEG 400, Propylene glycol, PEG 400: water mixture (60:40), and water at different mole ratio of sodium hydroxideletermovir (added as IN NaoH) at 0.90: 1.00, 1.00: 1.00, and 1.10: 1.00. Solutions were transferred into glass vials, stoppered and crimped, then treated at accelerated condition at 130°C for 60 minutes in autoclave. These samples then tested for %purity and %impurities using HPLC analysis. Results are provided in Table 42.Table 42. Test results for stability of letermovir in various conditions.

[0183] In another experiment, target quantity of letermovir was added in PEG 400 and dissolved. Target quantity of sodium hydroxide (added as IN, reported in mole ratio) was mixed with water and added to letermovir-PEG solution and mixed. Description of final samples reported. Where precipitation observed, supernatant was tested for concentration using HPLC and reported. The samples were filled in glass vials, closed with closure and stored at 60°C for 7 days. Samples were tested for % purity, % highest single impurity and % total impurity using HPLC and reported in Table 43.Table 43. Test results for stability of letermovir in various conditions.SOLUBILITY OF LETERMOVIR IN WATER PEG 400 SOLVENT SYSTEM

[0184] Solubility of letermovir in PEG 400: water solvent system was performed by adding excess amount of letermovir in solvent at different ratio, mixed for 24 hours and analyzed using HPLC. The solubility of letermovir in PEG 400: water system is unpredictable and surprisingly increases significantly above 60%v / v PEG400 in water.Table 44. Solubility of letermovir in PEG400 - water system.PROFETIC EXAMPLES

[0185] In some embodiments of the present invention, below are the non-limiting examples of Letermovir suspension suitable for oral administration. These compositions could be prepared by following steps. It is understood that in each step, ingredients are added when listed in the composition. It is also understood that the different ingredients listed in the invention can be selected within appropriate range for the same purpose.(a) adding partial quantity of vehicle in compounding vessel;(b) adding at least one ingredient from sweetener, preservative, antioxidant and flavoring agent one-by-one with mixing until dissolved and / or homogenized;(c) adding at least one ingredient from suspending agent, dispersing agent, and antifoaming agent with mixing until dissolved or dispersed;(d) adding Letermovir with mixing until homogenous suspension is obtained;(e) optionally adjusting pH;(f) making up the volume to batch size using vehicle; and(g) filling the liquid into containers and closing the containers with optional inert gas overlay.Table 45. Liquid formulation of letermovir suspension.Table 46. Liquid formulation of letermovir suspension.

[0186] In some embodiment of the present invention, below are the non-limiting examples of letermovir solution suitable for oral administration. These compositions could be prepared by following steps. It is understood that in each step, ingredients are added when listed in the composition. It is also understood that the different ingredients listed in the invention can be selected for the same purpose.(a) adding partial quantity of solubilizer in compounding vessel;(b) adding at least one ingredients from group comprising sweetener, preservative, antioxidant, surfactant, and flavoring agent, one-by-one, with mixing and / or homogenizing until dissolved;(c) adding letermovir with mixing until dissolved;(d) optionally adding stabilizing agents or adjusting pH;(e) making up the volume to batch size using vehicle;(f) optionally filtering the solution; and(g) filling the solution into container and closing the container with optional inert gas overlay.Optionally, water soluble ingredients, such as surfactant, may be dissolved in water separately and added after dissolution of letermovir.Table 47. Liquid formulation of letermovir solution.ADDITIONAL PROFETIC EXAMPLES

[0187] Example 116-119 describe the liquid formulations of letermovir prepared using ingredients detailed in the following table.Table 48. Aqueous solution of Letermovir liquid formulation

[0188] Example 116-119 are prepared using following steps:(a) Sodium hydroxide at mole ratio of about 1.0 to 1.2 with respect to letermovir is added into about 80% of purified water and mixed to homogeneity.(b) Letermovir is added in above step and mixed until clear solution obtained.(c) Methylparaben, propylparaben, sucralose and peppermint flavor are added in above step, one-by-one, and mixed until clear solution was obtained.(d) Optionally, pH is adjusted to 8.5 (range 8.0 to 9.0) using hydrochloric acid or sodium hydroxide.(e) Volume was made up to the batch size using purified water and mixed to homogeneity.(f) The solution was filtered to remove foreign particulate matter.(g) The solution was filled into containers and sealed with suitable closure.Example 120 - 123

[0189] Examples 120-123 describe the liquid formulations of letermovir prepared using ingredients detailed in the following table.Table 49. Non-aqueous solution of Letermovir liquid formulation

[0190] Examples 120-123 are prepared using following steps:(a) Letermovir is added into about 80% of polyethylene glycol 400 and mixed until dissolved.(b) Sodium hydroxide is added in above step and mixed to homogeneity.(c) Methylparaben, propylparaben, sucralose and peppermint flavor are added in above step, one-by-one, and mixed until dissolved or homogenized.(d) Volume is made up to the batch size using PEG 400 and mixed to homogeneity.(e) The solution is filtered to remove foreign particulate matter.(f) The solution is filled into containers and sealed with suitable closure.Example 124 - 127

[0191] Example 124-127 describe the liquid formulations of letermovir prepared using ingredients detailed in the following table.Table 50. Aqueous formulation of Letermovir prepared using non-aqueous solvent with water.

[0192] Example 124-127 are prepared using following steps:(a) Sodium hydroxide is added into propylene glycol and mixed to homogeneity.(b) Letermovir is added in above step and mixed until dissolved.(c) Methylparaben, propylparaben, sucralose and peppermint flavor are added in above step, one-by-one, and mixed until dissolved or homogenized.(d) Volume is made up to 90% of batch size using purified water and mixed to homogeneity.(e) Optionally, pH is adjusted to 8.5 (range 8.0 to 9.0).(f) Volume is made up to the batch size using purified water and mixed to homogeneity.(g) The solution is filtered to remove foreign particulate matter.(h) The solution is filled into containers and sealed with suitable closure.Example 128-131

[0193] Example 128-131 describe the liquid formulations of letermovir prepared using ingredients detailed in the following table.Table 51. Aqueous suspension of Letermovir prepared using non-aqueous solvent with water.

[0194] Example 128-131 are prepared using following steps:(a) Letermovir is added to the required quantity of PEG 400 and mixed until clear solution was obtained.(b) Methylparaben, propylparaben, sucralose, tocopherol and peppermint flavor are added in above step, one-by-one, and mixed until dissolved or homogenized.(c) Xanthan gum is added in the step above and mixed to suspend.(d) In a separate container, sodium lauryl sulfate (or polysorbate 80), sucralose and peppermint flavor are dissolved to partial quantity of water (about 50% of the required quantity) then the solution is slowly added to the step above and mixed until homogenous suspension is obtained.(e) Volume is made up to the batch size using water.(f) The suspension is filled into containers and sealed with suitable closure.Example 132-135

[0195] Example 132-135 describe the liquid formulations of letermovir prepared using ingredients detailed in the following table.Table 52. Aqueous suspension of Letermovir liquid formulation

[0196] Example 132-135 are prepared using following steps:(a) Methylparaben and propylparaben are added in about 70% of batch required water, and mixed until dissolved or homogenized, optionally by heating about 50 to 70°C and cooling to room temperature.(b) Sucralose and cherry flavor are added mixed until dissolved or homogenized.(c) Xanthan gum is added with rapid mixing until dissolved completely.(d) Letermovir (preferably micronized, D90 about 10 micron) is added to the mixture above with rapid mixing and mixed until homogeneous suspension obtained.(e) If required, purified water is added to the batch size mixed until homogenous suspension is obtained.(f) The suspension is filled into containers and sealed with suitable closure.Example 136-139

[0197] Example 136-139 describe the liquid formulations of letermovir prepared using ingredients detailed in the following table.Table 53. Aqueous solution of Letermovir liquid formulation suitable for parenteral use

[0198] Example 136-139 are prepared using following steps:(a) Sodium hydroxide at mole ratio of about 1.0 to 1.2 with respect to letermovir is added into about 80% of purified water and mixed to homogeneity.(b) Letermovir is added in above step and mixed until clear solution obtained.(c) Sodium chloride is added in the above step and mixed until dissolved.(d) If required, pH is adjusted to 8.5 (range 8.0 to 9.0) using dilute sodium hydroxide or hydrochloric acid.(e) Volume is made up to the batch size using water for injection and mixed to homogeneity.(f) The solution is sterile filtered using 0.2pm filter to remove microorganism & foreign particulate matter.(g) The solution is filled into containers and sealed with suitable closure.(h) Optionally, the containers are terminally sterilized by moist heat sterilization at about 121 °C for about 15 minutes.Example 140-143

[0199] Example 140-143 describe the liquid formulations of letermovir prepared using ingredients detailed in the following table.Table 54. Aqueous solution of Letermovir liquid formulation suitable for parenteral use

[0200] Example 140-143 are prepared using following steps:(a) Letermovir is added into required quantity of polyethylene glycol 400 and mixed until dissolved.(b) Sodium hydroxide at mole ratio of about 1.0 to 1.2 with respect to letermovir is added in above step and mixed to homogeneity.(c) Water for injection is added to make the batch up to 90%.(d) Sodium chloride is added in the above step and mixed until dissolved.(e) If required, pH was adjusted to 8.5 (range 8.0 to 9.0) using dilute sodium hydroxide or hydrochloric acid.(f) Volume is made up to the batch size using water for injection and mixed to homogeneity.(g) The solution is sterile filtered using 0.2pm filter to remove microorganism & foreign particulate matter.(h) The solution is filled into containers and sealed with suitable closure.(i) Optionally, the containers are terminally sterilized by moist heat sterilization at about 121°C for about 15 minutes.Example 144-147

[0201] Example 144-147 describe the liquid formulations of letermovir prepared using ingredients detailed in the following table.Table 55. Aqueous solution of Letermovir liquid formulation suitable for oral use

[0202] Example 144-147 are prepared using following steps:(a) Required quantity of sodium hydroxide is added to partial quantity of water from 5 - 95% of batch size, preferably from about 5 - 50% and mixed to homogenize.(b) Hydroxypropye-beta-cyclodextrin is added and mixed at or above room temperature until clear solution is obtained.(c) Required quantity of methylparaben, propylparaben, sucralose and cherry flavor added one-by-one and mixed to dissolve. Preservatives may be dissolved at or above room temperature prior to adding sucralose and flavor.(d) If required, pH is adjusted using dilute sodium hydroxide.(e) Volume is made up to the batch size using purified water and mixed to homogeneity.(f) The solution is filtered using suitable filter to remove foreign particulate matter.(g) The solution is filled into containers and sealed with suitable closure.

Claims

CLAIMS1. A liquid pharmaceutical formulation comprising: a) letermovir or its pharmaceutically acceptable salt at a concentration from about 16 mg / mL to about 200 mg / mL; b) at least one excipient selected from group of sweetener, preservative, and / or flavoring agent; and c) at least one vehicle selected from group of water, polyethylene glycol, glycerin, and / or propylene glycol, wherein the formulation is suitable for enteral route of administration at volume of not more than about 30 mL per dose.

2. A liquid formulation of claim 1, wherein the formulation is suitable for oral administration.

3. A liquid formulation of claim 1, wherein the letermovir concentration is from about 16 mg / mL to about 80 mg / mL.

4. A liquid formulation of claim 1, wherein the formulation further contains a pH adjusting agent.

5. A liquid formulation of claim 1, wherein the formulation is aqueous solution.

6. A liquid formulation of claim 1, wherein the formulation is non-aqueous solution.

7. A liquid formulation of claim 1, wherein the formulation is suspension.

8. A liquid formulation of claim 1, wherein the water concentration is less than about5%w / v.

9. A liquid formulation of claim 1, wherein one or more excipients selected from the group comprising of buffering agent, pH adjusting agent, antioxidants, complexing agent, chelating agents, suspending agent, anti-foaming agent, dispersing agent, wetting agent, coloring agents, stabilizing agent, surfactants, stability enhancing agents, crystallization inhibitors, viscosity adjusting agent or combination thereof.

10. A method of manufacturing liquid formulation of letermovir comprising the steps of: a) solubilizing letermovir and one or more pharmaceutically acceptable excipients in suitable solubilizer; b) optionally filtering the liquid formulation using suitable filter; c) filling formulated letermovir liquid into primary packaging container; d) optionally overlaying with inert gas such as nitrogen or argon; and e) closing the container.

11. A liquid formulation of letermovir or pharmaceutically acceptable salt thereof suitable for parenteral route of administration comprising: a) letermovir at a concentration from about 0.1 mg / mL to 40 mg / mL; and b) one or more optional pharmaceutical excipients, wherein the formulation is free from hydroxypropyl-P-cyclodextrin.

12. A liquid formulation of claim 11, wherein the formulation is non-aqueous or aqueous solution.

13. A liquid formulation of claim 11, wherein the formulation is ready -to-use without requiring dilution prior to administration.

14. A liquid formulation of claim 11, wherein at least one excipient selected from the group comprising of tonicity adjusting agents, buffering agent, pH adjusting agent, preservatives, antioxidants, chelating agents, stabilizers, surfactants, stability enhancing agents, crystallization inhibitors, viscosity adjusting agent or mixtures thereof.

15. A liquid formulation of claim 11, wherein the formulation is sterilized by terminal sterilization using moist heat at about 121°C for about 5 to 15 minutes.

16. A liquid formulation of claim 11, wherein the formulation is sterilized sterile filtration without use of heat.

17. A liquid formulation of claim 11, wherein the formulation contains at least one tonicity adjusting agent other than dextrose.

18. Aliquid formulation of claim 1 or 11, wherein the pH of the formulation is between about7 and about 10.

19. Aliquid formulation of claim 1 or 11, wherein the pH of the formulation is between about8 and about 10.

20. Aliquid formulation of claim 1 or 11, wherein the formulation contains sodium hydroxide at mole ratio of 0.80 to 1.10:1.00 (sodium hydroxide: letermovir).

21. Aliquid formulation of claim 1 or 11, wherein the formulation contains sodium hydroxide at mole ratio of 1.00-1.05:1.00 (sodium hydroxide: letermovir).

22. Aliquid formulation of claim 1 or 11, wherein the formulation contains sodium hydroxide at mole ratio of >1.00:1.00 (sodium hydroxide: letermovir).

23. Aliquid formulation of claim 1 or 11, wherein the total degradation impurities are not more than about 5% after 1 month of storage at controlled room temperature (15-25°C).

24. Aliquid formulation of claim 1 or 11, wherein the total degradation impurities are not more than about 5% after 3 months of storage at controlled room temperature (15-25°C).

25. A liquid formulation of claim 1 or 11, wherein any single individual degradation impurity is not more than about 1% after 1 month of storage at controlled room temperature (15- 25°C).

26. A liquid formulation of claim 1 or 11, wherein any single individual degradation impurity is not more than about 1% after 3 months of storage at controlled room temperature (15- 25°C).

27. A method of treatment for prophylaxis of cytomegalovirus (CMV) infection and disease in patients undergoing transplant surgery, comprising administering a therapeutically effective amount of liquid formulation of letermovir according to claim 1 or 11 to a patient in need thereof.

28. A method of treatment for prophylaxis of cytomegalovirus (CMV) infection and disease in CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant, comprising administering a therapeutically effective amount of liquid formulation according to claim 1 or 11 to a patient in need thereof.

29. A method of treatment for prophylaxis of CMV disease in kidney transplant recipients at high risk (Donor CMV seropositive / Recipient CMV seronegative [D+ / R-]), comprising administering a therapeutically effective amount of the liquid formulation according to claim 1 or 11 to a patient in need thereof.

30. A liquid formulation of letermovir according to claim 20, 21 or 22, wherein the sodium hydroxide amount used for calculation of mole ratio with respect to letermovir is nonneutralized amount by acid(s) other than letermovir.

31. A method of manufacturing liquid formulation of letermovir comprising the steps of: a) solubilizing letermovir with one or more optional pharmaceutically acceptable excipients in suitable solubilizer; b) sterile filtering through 0.22pm filter; c) filling formulated letermovir liquid into primary packaging container; d) optionally overlaying with inert gas such as nitrogen or argon; e) closing the container; and f) optionally, terminally sterilizing in autoclave at about 121 °C for about 5 to 15 minutes, g) wherein the liquid formulation is free from hydroxypropyl-P-cyclodextrin.

32. A Letermovir suspension for oral administration, comprising: a) at least one vehicle as water;b) letermovir at a concentration from about 1.6% (w / v) to about 12%(w / v); and c) at least one excipient selected from group of suspending agent, dispersing agent, anti-foaming agent, surfactant, viscosity enhancing agent, sweetener, flavoring agent, preservative, pH adjusting agent, buffering agent, antioxidant, crystallization inhibitor, or combination thereof.

33. A Letermovir suspension for oral administration, comprising: a) at least one vehicle is water; and b) at least one excipient is suspending agent, c) wherein the letermovir concentration is from about 1.6% (w / v) to about 12% (w / v).

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