Pharmaceutical compositions comprising asundexian and use thereof

Abstract

The present invention is directed to liquid pharmaceutical compositions comprising Asundexian, methods for their preparation, and methods of their use. The present invention also relates to stable liquid pharmaceutical compositions comprising Asundexian and one or more pharmaceutically acceptable excipient(s) suitable for oral administration.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING ASUNDEXIANAND USE THEREOFFIELD OF THE INVENTION

[0001] The present disclosure relates to liquid pharmaceutical compositions comprising Asundexian, methods for their preparation, and methods of their use in the control of disorder.BACKGROUND

[0002] Thrombosis is the formation of a blood clot (partial or complete blockage) within blood vessels, whether venous or arterial, limiting the natural flow of blood and resulting in clinical sequela. The clinical sequela includes stroke, myocardial infarction, deep venous thrombosis, which are clinically common causes of death. The biochemistry process of thrombosis involves coagulation cascade, in which factor XI, a protein in the blood, is converted into its active enzyme form (Factor Xia) as part of the blood coagulation cascade. FXIa inhibition specifically targets the FXIa protein involved in pathological thrombus formation, while leaving hemostasis intact. Asundexian, a potent inhibitor of activated coagulation factor FXIa, selectively target the coagulation cascade, thereby offering the potential to prevent events like stroke or other disorders caused by the thrombosis without a corresponding increase in bleeding risk associated the current standard of care (SoC).

[0003] WO2022 / 189278 reports amorphous form, crystalline modification I or as a mixture of amorphous form and crystalline modification I of Asundexian. However, it was found that the relative bioavailability in rats decreases down to 11% when the crystalline modification I is administered. Also, the dissolution behavior of the oral solid dosage forms is inferior when the oral solid dosage forms contain the crystalline modification I. Additionally, the amorphous form may not be stable in the solid pharmaceutical dosage forms during long-term storage. Therefore, there is a need to develop a new dosage form of Asundexian while maintaining its good bioavailability. The aim of the development was, therefore, to provide liquid pharmaceutical dosage forms for oral administration comprising Asundexian to meet these needs and others.

[0004] Anticoagulants like Asundexian are being increasingly used in elderly population and as oral solid dosage forms. Many of these elderly patients are very old and smaller in body weights and may require titrated doses of Asundexian, to account for their body weights and diminishedmetabolic capabilities. In addition, for elderly population having other concomitant disabilities like difficulty in swallowing a liquid formulation is easy to administer. Also, oral solid dosage forms are associated with certain other disadvantages that could be overcome by the liquid oral pharmaceutical dosage forms. Firstly, solid forms of Asundexian may irritate the gastrointestinal tract. Importantly, children and elderly patients may face significant difficulty in swallowing the solid forms and therefore, prefer liquid oral pharmaceutical compositions of Asundexian. Also, in stroke or other severely debilitating diseases or conditions, for example where the patient may be unconscious or unable to swallow an oral solid dosage form, liquid oral composition disclosed herein may be preferred. Secondly, these solid oral dosage forms may also break down inconsistently, which can decrease the medication’s effectiveness and overall absorption, resulting in being prone to dosing errors, thereby inducing bioavailability issues. The rate of absorption of oral solid dosage forms usually decreases in the following order: aqueous solution>aqueous suspension-tablets or capsules. A drug administered in solution is immediately available for absorption from the gastrointestinal tract and is more rapidly and efficiently absorbed than the same amount of drug administered in a tablet or capsule. Thirdly, oral solid dosage forms of Asundexian may also have stability issues caused during the tampering process of preparing the solid forms. In contrast, liquid oral formulations of Asundexian can provide uniformly dispersed API or solution and reduce any irritation due to their dilution factor. Furthermore, aqueous liquid oral formulations of Asundexian can be flavored to mask unpleasant tastes, making them more acceptable to patients.SUMMARY

[0005] The present invention provides a liquid pharmaceutical compositions of Asundexian or its pharmaceutically acceptable salts, isomers, complexes, polymorphs, hydrates or esters thereof.

[0006] In one aspect, provided herein are liquid pharmaceutical composition including an aqueous solution or suspension of Asundexian or its pharmaceutically acceptable salts, isomers, complexes, polymorphs, hydrates or esters thereof.

[0007] In another aspect, provided herein are aqueous pharmaceutical compositions comprising (i) a compound of Formula (I), wherein the said compound of Formula (I) is represented by:and (ii) an aqueous vehicle, wherein the pharmaceutical composition is suitable for oral administration.

[0008] In some embodiments, the aqueous vehicle comprises an emulsifier. In some embodiment, the aqueous vehicle comprises a solvent. In other embodiments, the aqueous vehicle comprises a co-solvent. In some embodiments, the aqueous pharmaceutical composition comprises one or more pharmaceutically acceptable excipient(s).

[0009] In another aspect, the present invention provides a method for treating a mammal in need by administering to a patient a liquid pharmaceutical composition including an aqueous solution or suspension of Asundexian or its pharmaceutically acceptable salts, isomers, complexes, polymorphs, hydrates or esters thereof.BRIEF DESCRIPTION OF THE FIGURES

[0010] Figure 1 depicts Polydispersity index (PDI) and droplet Size of Asundexian liquid composition (Initial).

[0011] Figure 2 depicts Polydispersity index (PDI) and droplet Size of Asundexian liquid composition (After storage at 25°C, 60% RH for 6 months).

[0012] Figure 3 depicts Polydispersity index (PDI) and droplet Size of Asundexian liquid composition (After storage at 40°C, 75% RH for 6 months).

[0013] Figure 4 depicts comparative invitro dissolution profile of Asundexian liquid composition 5mg / mL and 25 mg immediate release capsule.DETAILED DESCRIPTION

[0014] The following description of the preferred embodiment(s) is merely exemplary in nature and is in no way intended to limit the disclosure, its application, or uses.I. Compound of Formula (I)

[0015] Asundexian is referred to as 4-({(2S)-2-[4-{5-chloro-2-[4-(trifhioromethyl)-lH-l,2,3- triazol-l-yl]phenyl}-5-methoxy-2-oxopyridin-l(2H)-yl]butanoyl}amino)-2-fluorobenzamide and has the structure below:Formula (I)

[0016] The compound of Formula (I) may be referred to as “Compound I” or “Asundexian” throughout the present disclosure.II. Liquid Pharmaceutical Compositions

[0017] Provided herein are liquid pharmaceutical compositions for oral administration comprising a compound of Formula (I). The liquid pharmaceutical compositions of the present inventions may be aqueous or non-aqueous, but will generally be formulated as aqueous.

[0018] Provided herein are liquid pharmaceutical compositions comprising: (i) a compound of Formula (I), and (ii) an aqueous vehicle, wherein the pharmaceutical composition is suitable for oral administration.

[0019] Provided herein are aqueous pharmaceutical compositions comprising: (i) a compound of Formula (I), and (ii) an aqueous vehicle, wherein the pharmaceutical composition is suitable for oral administration. In some embodiments, the aqueous vehicle comprises an emulsifier. In some embodiments, the aqueous vehicle comprises a solvent. In some embodiments, the aqueous vehicle comprises a co-solvent. In various embodiments, the aqueous pharmaceutical composition comprises one or more pharmaceutically acceptable excipient(s). In Preferred embodiments, provided herein are aqueous pharmaceutical compositions comprising: (i) a compound of Formula (I), (ii) an aqueous vehicle, and (iii) one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition is an aqueous oral solution.

[0020] The liquid pharmaceutical compositions comprising a compound of Formula (I), as described herein, exhibit high stability and low degradation.A. Asundexian drug substance

[0021] In one aspect, the present invention relates to liquid pharmaceutical compositions comprising: (i) a compound of Formula (I), and (ii) an aqueous vehicle.

[0022] In another aspect, the present invention relates to aqueous pharmaceutical compositions comprising: (i) a compound of Formula (I), and (ii) an aqueous vehicle.

[0023] In one embodiment, the compound of Formula (I) used to make the pharmaceutical compositions as described herein is in a crystalline form, amorphous form, or a combination thereof.

[0024] In some embodiments, the amount of the compound of Formula (I) in used to make the pharmaceutical compositions of the present disclosure is from about 1 mg / mLto about 20 mg / mL.

[0025] In certain embodiments, the amount of the compound of Formula (I) in the aqueous pharmaceutical compositions of the present disclosure is from about 1 mg / mLto about 10 mg / mL, such as, for example, at least about 2 mg / mL, at least about 3 mg / mL, at least about 4 mg / mL, at least about 5 mg / mL, at least about 6 mg / mL, at least about 7 mg / mL, at least about 8 mg / mL, at least about 9 mg / mL, or at least about 10 mg / mL.

[0026] In certain embodiments, the amount of the compound of Formula (I) in the pharmaceutical compositions of the present disclosure is about 5 mg / mL.B. Water

[0027] In one aspect, the present invention relates to liquid pharmaceutical compositions comprising: (i) a compound of Formula (I), and (ii) an aqueous vehicle, wherein the aqueous vehicle comprises water.

[0028] In another aspect, the present invention relates to aqueous pharmaceutical compositions comprising: (i) a compound of Formula (I), and (ii) an aqueous vehicle, wherein the aqueous vehicle comprises water.

[0029] In an embodiment, the water present in the aqueous vehicle can be added water or water present in pharmaceutically acceptable excipients.

[0030] In one embodiment, the amount of the water present in the pharmaceutical compositions is at least about 10 mg / mL to about 400 mg / mL. In another embodiment, the amount of the water present in the pharmaceutical compositions is at least about 50 mg / mL to about 300 mg / mL. In another embodiment, the amount of the water present in the pharmaceutical compositions is at least about 100 mg / mL to about 200 mg / mL. In certain embodiments, the amount of the water present in the pharmaceutical compositions is at least about 150 mg / mL.

[0031] In one embodiment, the amount of the water present in the pharmaceutical compositions is at least 1 % (w / w) to about 40% (w / w). In another embodiment, the amount of the water present in the pharmaceutical compositions is from about 5 % (w / w) to about 30% (w / w). In another embodiments, the amount of the water present in the aqueous pharmaceutical compositions is from about 10% (w / w) to about 20% (w / w). In another embodiments, the amount of the water present in the aqueous pharmaceutical compositions is from about 15% (w / w)to about 25% (w / w). In certain embodiments, the amount of the water present in the aqueous pharmaceutical compositions is about 15% (w / w). In certain embodiments, the amount of the water present in the aqueous pharmaceutical compositions is about 20% (w / w). In certain embodiments, the amount of the water present in the aqueous pharmaceutical compositions is about 30% (w / w).C. Solvents and Co-solvents

[0032] In one aspect, the present invention relates to liquid pharmaceutical compositions comprising: (i) a compound of Formula (I), and (ii) an aqueous vehicle, wherein the aqueous vehicle comprises a solvent.

[0033] In one aspect, the present invention relates to aqueous pharmaceutical compositions comprising: (i) a compound of Formula (I), and (ii) an aqueous vehicle, wherein the aqueous vehicle comprises a solvent.

[0034] Exemplary solvents include but are not limited to liquid PEG (polyethylene glycol, for example PEG 100, PEG 200, PEG 400), low or medium chain-length triglycerides fatty oils and Labrasol ALF or combinations thereof.

[0035] In certain embodiments, the solvent comprises PEG (for example PEG 100, PEG 200, PEG 400). In certain embodiments, the solvent comprises Labrasol ALF. In certain embodiments, the solvent comprises PEG (for example PEG 100, PEG 200, PEG 400), Labrasol ALF, or a combination thereof. In certain embodiments, the solvent comprises PEG 400, Labrasol ALF, or a combination thereof.

[0036] In one embodiment, the amount of the solvent present in the aqueous pharmaceutical composition is from about 50 mg / mLto about 700 mg / mL. In certain embodiments, the amount of the solvent present in the aqueous pharmaceutical composition is about 200 mg / mL. In certain embodiments, the amount of the solvent present in the aqueous pharmaceutical composition is about 300 mg / mL. In certain embodiments, the amount of the solvent present in the aqueous pharmaceutical composition is about 400 mg / mL. In certain embodiments, the amount of thesolvent present in the aqueous pharmaceutical composition is about 500 mg / mL. In certain embodiments, the amount of the solvent present in the aqueous pharmaceutical composition is about 600 mg / mL. In certain embodiments, the amount of the solvent present in the aqueous pharmaceutical composition is about 700 mg / mL.

[0037] In some embodiments, the amount of the solvent present in the aqueous pharmaceutical composition is from about 10% (w / w) to about 70% (w / w). In some embodiments, the amount of the solvent present in the aqueous pharmaceutical composition is about 10% (w / w), about 20% (w / w), about 30% (w / w), about 40% (w / w), about 50% (w / w), about 60% (w / w).

[0038] In certain embodiments, the amount of the solvent present in the aqueous pharmaceutical composition is from about 400 mg / mL to about 700 mg / mL, wherein the solvent is PEG 400.

[0039] In certain embodiments, the amount of the solvent present in the aqueous pharmaceutical composition is from about 400 mg / mL to about 700 mg / mL, wherein the solvent is Labrasol ALF.

[0040] In one aspect, the present invention relates to liquid pharmaceutical compositions comprising: (i) a compound of Formula (I), and (ii) an aqueous vehicle, wherein the aqueous vehicle comprises a co-solvent.

[0041] In another aspect, the present invention relates to aqueous pharmaceutical compositions comprising: (i) a compound of Formula (I), and (ii) an aqueous vehicle, wherein the aqueous vehicle comprises a co-solvent.

[0042] In one aspect, the present invention relates to liquid pharmaceutical compositions comprising: (i) a compound of Formula (I), and (ii) an aqueous vehicle, wherein the aqueous vehicle In one aspect, the present invention relates to liquid pharmaceutical compositions comprising: (i) a compound of Formula (I), and (ii) an aqueous vehicle, wherein the aqueous vehicle comprises a co-solvent.

[0043] In another aspect, the present invention relates to aqueous pharmaceutical compositions comprising: (i) a compound of Formula (I), and (ii) an aqueous vehicle, wherein the aqueous vehicle comprises a solvent and a co-solvent.

[0044] As used herein, the term "co-solvent" refers to a second solvent which differs from the solvent included in the formulation. Exemplary co-solvents include but are not limited to ethanol, glycerin, propylene glycol, or a combination thereof. In certain embodiments, the co-solvent is ethanol, glycerin, propylene glycol, or a combination thereof. In certain embodiments, the co-solvent is glycerin, propylene glycol, or a combination thereof. In certain embodiments, the cosolvent is glycerin. In certain embodiments, the co-solvent is propylene glycol.

[0045] In one embodiment, the amount of the co-solvent present in the aqueous pharmaceutical composition is from about 50 mg / mLto about 350 mg / mL. In certain embodiments, the amount of the co-solvent present in the aqueous pharmaceutical composition is about 100 mg / mL. In certain embodiments, the amount of the co-solvent present in the aqueous pharmaceutical composition is about 150 mg / mL. In certain embodiments, the amount of the co-solvent present in the aqueous pharmaceutical composition is about 200 mg / mL. In certain embodiments, the amount of the cosolvent present in the aqueous pharmaceutical composition is about 250 mg / mL. In certain embodiments, the amount of the co-solvent present in the aqueous pharmaceutical composition is about 300 mg / mL.

[0046] In some embodiments, the amount of the co-solvent present in the aqueous pharmaceutical composition is from about 5% (w / w) to about 35% (w / w). In certain embodiments, the amount of the co-solvent present in the aqueous pharmaceutical composition is about 5% (w / w), about 10% (w / w), about 15% (w / w), about 20% (w / w), about 25% (w / w), about 30% (w / w).

[0047] In certain embodiments, the amount of the co-solvent present in the aqueous pharmaceutical composition is from about 200 mg / mL to about 250 mg / mL, wherein the cosolvent is glycerin.

[0048] In certain embodiments, the amount of the co-solvent present in the aqueous pharmaceutical composition is from about 200 mg / mL to about 250 mg / mL, wherein the cosolvent is propylene glycol.

[0049] In certain embodiments, the aqueous pharmaceutical composition of the compound of Formula (I) is a solution. In certain embodiments, the aqueous pharmaceutical composition of the compound of Formula (I) is a suspension. In certain embodiments, the aqueous pharmaceutical composition of the compound of Formula (I) is an emulsion.D. Emulsifiers

[0050] In one aspect, the present invention relates to liquid pharmaceutical compositions comprising: (i) a compound of Formula (I), and (ii) an aqueous vehicle, wherein the aqueous vehicle comprises an emulsifier.

[0051] In one aspect, the present invention relates to aqueous pharmaceutical compositions comprising: (i) a compound of Formula (I), and (ii) an aqueous vehicle, wherein the aqueous vehicle comprises an emulsifier.

[0052] In another aspect, the present invention relates to aqueous pharmaceutical compositions comprising: (i) a compound of Formula (I), and (ii) an aqueous vehicle, wherein the aqueous vehicle comprises water, solvent, co-solvent and an emulsifier.

[0053] Exemplary emulsifier have a HLB (Hydrophilicity-Lipophilicity Balance) value which is usually in the range 6-20, preferably 10 to 18 or 12 to 16, or 13 to 14 or 15. In certain embodiments, the emulsifier used in the pharmaceutical composition described herein has a HLB value about 12, about 13, about 14, about 15, about 16, about 17, or about 18.

[0054] In some embodiments, the emulsifier is selected from the group consisting of phospholipid surfactant, non-ionic surfactants, cationic surfactants, anionic surfactants, and zwitterionic surfactants. In some embodiments, the emulsifier is selected from the group consisting of nonionic surfactants. In some embodiments, the emulsifier is selected from TPGS (e.g., TPGS 1000), Acconon mixture (mixture of polyoxyethylene mono- and diglycerides, fatty acids or fatty alcohols), Gellucire (e.g., Gellucire 48 / 16), Capmul MCG (mono- and diglyceride), mono, di and triglycerides, propylyene glycol esters, polyethylene glycol, and a polyethylene glycol derivative (e.g., PEG esters of fatty acids) or any combination thereof. In certain embodiments, the emulsifier is TPGS 1000, Gellucire 48 / 16, or combination thereof. In certain embodiments, the emulsifier is TPGS 1000. In certain embodiments, the emulsifier is Gellucire 48 / 16.

[0055] In one embodiment, the amount of the emulsifier present in the aqueous pharmaceutical composition is from about 5 mg / mL to about 250 mg / mL. In certain embodiments, the amount of the emulsifier present in the aqueous pharmaceutical composition is from about 30 mg / mL to about 200 mg / mL. In certain embodiments, the amount of the emulsifier present in the aqueous pharmaceutical composition is from about 50 mg / mL to about 150 mg / mL.

[0056] In one embodiment, the amount of the emulsifier present in the aqueous pharmaceutical composition is from about 0.5% (w / w) to about 25% (w / w). In certain embodiments, the amount of the emulsifier present in the aqueous pharmaceutical composition is about 1% (w / w), about 2% (w / w) to about 3% (w / w), about 4% (w / w), about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w) or about 10% (w / w).

[0057] In certain embodiments, the amount of the emulsifier present in the aqueous pharmaceutical composition is from about 20 mg / mLto 60 mg / mL, wherein the emulsifier is TPGS 1000. In certain embodiments, the amount of the emulsifier present in the aqueous pharmaceutical composition is from about 30 mg / mL, wherein the emulsifier is TPGS 1000.

[0058] In certain embodiments, the amount of the emulsifier present in the aqueous pharmaceutical composition is from about 20 mg / mL to 250 mg / mL, wherein the emulsifier is gelucire 48 / 16. In certain embodiments, the amount of the emulsifier present in the aqueous pharmaceutical composition is from about 30 mg / mL to 60 mg / mL, wherein the emulsifier is gelucire 48 / 16. In certain embodiments, the amount of the emulsifier present in the aqueous pharmaceutical composition is from about 150 mg / mL to 250 mg / mL, wherein the emulsifier is gelucire 48 / 16.E. Other Pharmaceutically Acceptable Excipients

[0059] In one aspect, the present invention relates to liquid pharmaceutical compositions comprising: (i) a compound of Formula (I), (ii) an aqueous vehicle, and (iii) one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition is suitable for oral administration.

[0060] In one aspect, the present invention relates to aqueous pharmaceutical compositions comprising: (i) a compound of Formula (I), (ii) an aqueous vehicle, and (iii) one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition is suitable for oral administration.

[0061] In another aspect, the present invention relates to liquid pharmaceutical compositions comprising: (i) a compound of Formula (I), (ii) an aqueous vehicle, and (iii) one or more pharmaceutically acceptable excipients, such as, for example, surfactant, acidifier, solubilizer, stabilizers, chelating agents, pH adjusting agents, buffering agents, preservatives, thickening agents, anti-foaming agents, flavoring agents, coloring agents, sweetening agents and / or mixtures thereof.

[0062] In one embodiment, the pharmaceutically acceptable excipient comprises an antioxidant. Exemplary antioxidants include sodium bisulfate, ascorbic acid, ascorbyl palmitate, citric acid, tartaric acid, glycine, L-cysteine hydrochloride, L-methionine, butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), hydro phosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium citrate anhydrous, sodium citrate dihydrate, sodium sulfide, sodiumsulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, thioglycolic acid, sodium metabisulfite and propyl gallate.

[0063] In some embodiments, the antioxidant is selected from the group consisting of propyl gallate, ascorbic acid, ascorbyl palmitate, L-cysteine hydrochloride, L-methionine, butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), hydro phosphorous acid, monothioglycerol, sodium ascorbate, sodium citrate anhydrous, sodium citrate dehydrate, sodium sulfide, sodium sulfite, thioglycolic acid and sodium metabisulfite, vitamin E (tocopherol), citric acid, and sodium metabisulfite.

[0064] In some embodiments, the amount of antioxidant present in the aqueous pharmaceutical composition is from about 0.1 mg / mL to about 10 mg / mL. In certain embodiments, the aqueous pharmaceutical compositions comprise propyl gallate as an antioxidant at an amount of about 0.5 mg / mL to about 2 mg / mL.

[0065] In some embodiments, the amount of antioxidant present in the aqueous pharmaceutical composition is from about 0.010 % (w / w) to about 2.00 % (w / w). In certain embodiments, the amount of antioxidant present in the aqueous pharmaceutical composition is about 0.01% (w / w) to about 1% (w / w).

[0066] In certain embodiments, the aqueous pharmaceutical compositions described herein comprise a solubilizer selected from the group consisting of propylene glycol, polyethylene glycol, glycerol, Tween 20, Tween 80, and sodium lauryl sulfate (SLS), or combinations thereof.

[0067] In some embodiments, the pharmaceutically acceptable excipient comprises a chelating agent. Exemplary chelating agents include disodium ethylenediaminetetraacetic acid (disodium EDTA), diethylenetriaminepentaacetic acid (DTPA), ethylene glycol-bis (P-aminoethyl ethertetra acetic acid (EGTA), N-(hydroxy ethyl) ethylenediaminetriacetic acid (HEDTA), nitrilotriacetic acid (NTA), triethanolamine, 8-hydroxyquinoline, phosphoric acid, gluconic acid, saccharic acid, thiodipropionic acid, acetonic dicarboxylic acid, lecithin, di(hydroxyethyl)glycine, phenylalanine, tryptophan, glycerine, sorbitol and pharmaceutically acceptable salts thereof.

[0068] In some embodiments, the amount of chelating agent present in the aqueous pharmaceutical composition is from about 0.1 mg / mL to about 1 mg / mL.

[0069] In some embodiments, the pharmaceutically acceptable excipient comprises a preservative. Exemplary preservative include, but are not limited to, methylparaben, propylparaben, ethylparaben, butylparaben, isobutylparaben, isopropylparaben, benzylparaben, sodium salts ofthe referenced parabens, a sorbate (salt of sorbic acid and / or sorbic acid), benzoate (salt of benzoic acid and / or benzoic acid), sulfur dioxide, sulfite, nitrite, nitrate, lactic acid, propionic acid, propionate, ascorbic acid, ascorbate, butylated hydroxytoluene or combinations thereof. In certain embodiments, the aqueous pharmaceutical compositions described herein comprises a preservative selected from sodium benzoate, methyl paraben, propyl paraben or combinations thereof.

[0070] In some embodiments, the amount of the preservative present in the aqueous pharmaceutical composition is from about 0.1 mg / mL to 5 mg / mL. In certain embodiments, the amount of the preservative present in the aqueous pharmaceutical composition is from 1 mg / mL to about 2 mg / mL, wherein the preservative is sodium benzoate. In certain embodiments, the amount of the preservative present in the aqueous pharmaceutical composition is from 0.1 mg / mL to about 1 mg / mL, wherein the preservative is propyl gallate.

[0071] In some embodiments, the pharmaceutically acceptable excipient comprises a sweetener (also referred to as sweetening agents). Exemplary sweetening agents include but are not limited to aspartame, saccharin, sucralose, acesulfame potassium and the like. In some embodiments, the sweetener is selected from the group consisting of sucralose, mannitol, xylitol, erythritol, saccharin sodium IP, aspartame, and acesulfame potassium (Ace-K).

[0072] In certain embodiments, the amount of sweetener present in the aqueous pharmaceutical compositions described herein is from about 5 mg / mL to about 250 mg / mL.

[0073] In some embodiments, the pharmaceutically acceptable excipient comprises a flavor (also referred to as flavoring agent). Exemplary flavoring agents include but are not limited to, cherry flavor, artificial banana flavor, caramel, chocolate mint flavor, grape flavor, wild cherry flavor, maltitol, raspberry flavor, strawberry flavor, mixed berry flavor, citrus flavor, orange flavor, pineapple flavor, citrus lime flavor, citrus cream flavor, cherry vanilla flavor, cranberry flavor, creme de menthe flavor and mixtures thereof.

[0074] In some embodiments, the flavor is selected from the group consisting of bubble gum flavor, menthol oil, strawberry flavor, peppermint flavor, banana flavor, and lemon flavor.

[0075] In some embodiments, the amount of flavor present in the aqueous pharmaceutical compositions described herein is from about 0.1 mg / mL to about 10 mg / mL.

[0076] In some embodiments, the pharmaceutically acceptable excipient comprises a coloring agent. Exemplary coloring agents include, without limitation, natural and / or artificial compoundssuch as FD & C coloring agents, natural juice concentrates, pigments such as titanium oxide, silicon dioxide, and zinc oxide, combinations thereof, and the like.

[0077] In some embodiments, the pharmaceutically acceptable excipient comprises an acidifier. In certain embodiments, the acidifier is selected from the group consisting of citric acid monohydrate, lactic acid, ascorbic acid, and malic acid. In some embodiments, the amount of the acidifier present in the aqueous pharmaceutical composition is from about 1 mg / mLto 10 mg / mL. In some embodiments, the amount of the acidifier present in the aqueous pharmaceutical composition is from about 5 mg / mL to about 8 mg / mL, wherein the acidifier is citric acid.

[0078] In one aspect, the present invention relates to liquid pharmaceutical compositions comprising: (i) a compound of Formula (I), (ii) an aqueous vehicle, and (iii) one or more pharmaceutically acceptable excipients, wherein the pH of the composition is from about 3.0 to about 8.0.

[0079] In some embodiments, the pH of the pharmaceutical compositions described herein is in the range of about 4.0 to about 6.5. In some embodiments, the pH of the pharmaceutical compositions described herein is in the range of about 4.0 to about 5.0. In some embodiments, the pH of the pharmaceutical compositions described herein is in the range of about 5.0 to about 6.0. In some embodiments, the pH of the pharmaceutical compositions described herein is in the range of about 6.0 to about 7.0. In certain embodiments, the pH of the pharmaceutical compositions described herein is about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, or about 4.6. In some embodiments, the pH of the pharmaceutical compositions described herein is about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2 or about 7.3.F. Stability of the liquid pharmaceutical compositions

[0080] The liquid pharmaceutical compositions of the present invention do not exhibit substantial Asundexian degradation when exposed to certain stability conditions. Stability may be measured by any suitable method, e.g., by high-performance liquid chromatography (HPLC).

[0081] In a particular embodiment, the liquid pharmaceutical compositions of the present invention do not exhibit substantial Asundexian degradation under oxidative conditions, photolytic conditions, thermal conditions or combinations thereof.

[0082] In another embodiment, the liquid pharmaceutical compositions of the present invention do not exhibit substantial Asundexian degradation under forced stability conditions, accelerated stability conditions, or real-time stability conditions.

[0083] In one aspect, the aqueous pharmaceutical compositions disclosed herein do not exhibit substantial Asundexian degradation under accelerated conditions (e.g. 40°C ± 2°C and 75% ± 5% relative humidity) for at least 3 months, at least 4 months, at least 5 months, or at least 6 months.

[0084] In one embodiment, the aqueous pharmaceutical composition exhibits about 5% or less degradation of the compound of Formula (I) over at least a three month period when exposed to 40° C and 75% relative humidity, such as, for example, about 4.5% or less, 4.0% or less, about 3.5% or less, about 3.0% or less, about 2.5% or less, about 2.0% or less, about 1.5% or less or about 1.0% or less.

[0085] In some embodiments, the aqueous pharmaceutical compositions disclosed herein do not exhibit substantial degradation of the compound of Formula (I) under room temperature conditions (e.g. 25°C ± 2°C and 60% ± 5% relative humidity) for at least 3 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, or at least 24 months.

[0086] In certain embodiments, the aqueous pharmaceutical compositions disclosed herein exhibits about 5% or less degradation of the compound of Formula (I) over at least a six month period when exposed to 25°C and 60% relative humidity, such as, for example, about 4.5% or less, 4.0% or less, about 3.5% or less, about 3.0% or less, about 2.5% or less, about 2.0% or less, about 1.5% or less or about 1.0% or less.

[0087] In some embodiments, the aqueous pharmaceutical compositions disclosed herein have sufficient stability to allow for storage at room temperature conditions (about 25° C / 60% RH) for >6 months (e.g., >12 months, >18 months, >24 month), with >95% of un-degraded Asundexian (e.g., >96%, >97%, >98%, >99%), as determined by HPLC.

[0088] In one embodiment, the aqueous pharmaceutical compositions disclosed herein have sufficient stability to allow for storage at room temperature conditions (about 25° C / 60% RH) for >6 months (e.g., >12 months, >18 months, >24 month), with total impurities <5% (e.g., <4%, <3%, <2%, <1%, <0.5%), as determined by HPLC.

[0089] In another embodiment, total impurities in the aqueous pharmaceutical compositions resulting from the degradation of the compound of formula (I) is less than about 5% as determined by HPLC after at least about 12 months at a temperature of about 25° C, and thus have long term stability for at least the same period of time or longer.

[0090] In another embodiment, total impurities in the aqueous pharmaceutical compositions resulting from the degradation of the compound of formula (I) is less than about 3% as determinedby HPLC after at least about 12 months at a temicromperature of about 25° C, and thus have long term stability for at least the same period of time or longer.

[0091] In another embodiment, total impurities in the aqueous pharmaceutical compositions resulting from the degradation of the compound of formula (I) is less than about 3% as determined by HPLC after at least about 24 months at a temperature of about 25° C, and thus have long term stability for at least the same period of time or longer.

[0092] In another embodiment, the liquid pharmaceutical composition disclosed herein have less than about 5% peak area response of total impurities resulting from the degradation of the asundexian as determined by HPLC after at least 6 months at a temperature of from about 5° C. to about 25° C.

[0093] In another embodiment, the liquid pharmaceutical composition disclosed herein have less than about 5% peak area response of total impurities resulting from the degradation of the asundexian as determined by HPLC after at least 12 months at a temperature of from about 5° C. to about 25° C.

[0094] In another embodiment, the liquid pharmaceutical composition disclosed herein have less than about 5% peak area response of total impurities resulting from the degradation of the asundexian as determined by HPLC after at least 24 months at a temperature of from about 5° C. to about 25° C.

[0095] In another embodiment, the liquid pharmaceutical composition disclosed herein have about 0.001% to less than about 0.15% of peak area response for impurities identified at relative retention time (RRT) 0.1, RRT 0.31, RRT 0.39, RRT 0.56, RRT 0.73, RRT 0.79, RRT 0.90, RRT 1.18 and RRT 1.35 after 6 months at a temperature of from about 5° C to about 25° C and when analyzed by HPLC provided in Example 1.

[0096] In another embodiment, the liquid pharmaceutical composition disclosed herein have about 0.001% to less than about 0.15% of peak area response for impurities identified at RRT 0.1, RRT 0.31, RRT 0.39, RRT 0.56, RRT 0.73, RRT 0.79, RRT 0.90, RRT 1.18 and RRT 1.35 after 12 months at a temperature of from about 5° C to about 25° C and when analyzed by HPLC provided in Example 1.

[0097] Exemplary method of analyzing the liquid pharmaceutical composition by HPLC is provided in Example 1.G. Exemplary Embodiments

[0098] In one embodiment, the present invention relates to aqueous pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 20 mg / mL; (ii) an aqueous vehicle; and (iii) one or more other pharmaceutically acceptable excipients.

[0099] In another embodiment, the present invention relates to aqueous pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) an aqueous vehicle; and (iii) one or more other pharmaceutically acceptable excipients.

[0100] In one embodiment, the present invention relates to aqueous pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) an aqueous vehicle; and (iii) one or more other pharmaceutically acceptable excipients, wherein the aqueous vehicle comprises water from about 1% (w / w) to about 30% (w / w).

[0101] In one embodiment, the present invention relates to aqueous pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) an aqueous vehicle; and (iii) one or more other pharmaceutically acceptable excipients, wherein the aqueous vehicle comprises water and solvent.

[0102] In another embodiment, the present invention relates to aqueous pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) an aqueous vehicle; and (iii) one or more other pharmaceutically acceptable excipients, wherein the aqueous vehicle comprises water from about 1% (w / w) to about 30% (w / w) and solvent from about 5% (w / w) to about 70% (w / w).

[0103] In one embodiment, the present invention relates to aqueous pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) an aqueous vehicle; and (iii) one or more other pharmaceutically acceptable excipients, wherein the aqueous vehicle comprises water, solvent and co-solvent.

[0104] In another embodiment, the present invention relates to aqueous pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) an aqueous vehicle; and (iii) one or more other pharmaceutically acceptable excipients, wherein the aqueous vehicle comprises water from about 1% (w / w) to about 30%(w / w), a solvent from about 5% (w / w) to about 70% (w / w) and a co-solvent from about 5% (w / w) to about 35% (w / w).

[0105] In one embodiment, the present invention relates to aqueous pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) an aqueous vehicle; and (iii) one or more other pharmaceutically acceptable excipients, wherein the aqueous vehicle comprises water, solvent, co-solvent and emulsifier.

[0106] In another embodiment, the present invention relates to a aqueous pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) an aqueous vehicle; and (iii) one or more other pharmaceutically acceptable excipients, wherein the aqueous vehicle comprises water from about 1% (w / w) to about 30% (w / w), a solvent from about 5% (w / w) to about 70% (w / w), a co-solvent from about 5% (w / w) to about 35% (w / w) and emulsifier from about 0.5% (w / w) to about 15% (w / w).

[0107] In one embodiment, the present invention relates to a aqueous pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) an aqueous vehicle; (iii) anti-oxidant and (iv) one or more other pharmaceutically acceptable excipients.

[0108] In another embodiment, the present invention relates to a aqueous pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) an aqueous vehicle; (iii) anti-oxidant and (iv) one or more other pharmaceutically acceptable excipients, wherein the amount of anti-oxidant from about 0.02% w / w to about 0.5% w / w.

[0109] In one embodiment, the present invention relates to liquid pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) water from about 1% (w / w) to about 30% (w / w); (ii) a solvent from about 5% (w / w) to about 70% (w / w); (iv) a co-solvent from about 5% (w / w) to about 35% (w / w); (v) emulsifier from about 0.5% (w / w) to about 15% (w / w); and (vi) optionally, one or more pharmaceutically acceptable excipients.

[0110] In one embodiment, the present invention relates to a aqueous pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) water from about 1% (w / w) to about 30% (w / w); (ii) a solvent from about 5% (w / w) to about 70% (w / w); (iv) a co-solvent from about 5% (w / w) to about 35% (w / w); (v) emulsifierfrom about 0.5% (w / w) to about 15% (w / w); and (vi) optionally, one or more pharmaceutically acceptable excipients.

[0111] In one embodiment, the present invention relates to a aqueous pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) water from about 1% (w / w) to about 30% (w / w); (ii) a solvent from about 5% (w / w) to about 70% (w / w); (iv) a co-solvent from about 5% (w / w) to about 35% (w / w); (v) emulsifier from about 0.5% (w / w) to about 15% (w / w); and (vi) optionally, one or more pharmaceutically acceptable excipients.

[0112] In another embodiment, the present invention relates to a aqueous pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) water from about 1% (w / w) to about 30% (w / w); (ii) a solvent from about 5% (w / w) to about 70% (w / w); (iv) a co-solvent from about 5% (w / w) to about 35% (w / w); (v) emulsifier from about 0.5% (w / w) to about 15% (w / w); (vi) an anti-oxidant from about 0.5% (w / w) to about 5% (w / w); and (vi) optionally, one or more pharmaceutically acceptable excipients.

[0113] In another embodiment, the present invention relates to a aqueous pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) water from about 1% (w / w) to about 30% (w / w); (ii) a solvent from about 5% (w / w) to about 70% (w / w); (iv) a co-solvent from about 5% (w / w) to about 35% (w / w); (v) emulsifier from about 0.5% (w / w) to about 15% (w / w); (vi) an anti-oxidant from about 0.5% (w / w) to about 5% (w / w); and (vi) optionally, one or more pharmaceutically acceptable excipients, wherein the total impurities are less than about 5% as determined by HPLC after 6 months at a temperature of from about 25° C.

[0114] In another embodiment, the present invention relates to a aqueous pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) water from about 1% (w / w) to about 30% (w / w); (ii) a solvent from about 5% (w / w) to about 70% (w / w); (iv) a co-solvent from about 5% (w / w) to about 35% (w / w); (v) emulsifier from about 0.5% (w / w) to about 15% (w / w); (vi) an anti-oxidant from about 0.5% (w / w) to about 5% (w / w); and (vi) optionally, one or more pharmaceutically acceptable excipients, wherein the total impurities are less than about 5% as determined by HPLC after 12 months at a temperature of from about 25°C.

[0115] In another embodiment, the present invention relates to a aqueous pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) water from about 1% (w / w) to about 30% (w / w); (ii) a solvent from about 5% (w / w) to about 70% (w / w); (iv) a co-solvent from about 5% (w / w) to about 35% (w / w); (v) emulsifier from about 0.5% (w / w) to about 15% (w / w); (vi) an anti-oxidant from about 0.5% (w / w) to about 5% (w / w); and (vi) optionally, one or more pharmaceutically acceptable excipients, wherein the total impurities are less than about 5% as determined by HPLC after 24 months at a temperature of from about 25°C and about 60% relative humidity.

[0116] In another embodiment, the present invention relates to a aqueous pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) water from about 1% (w / w) to about 30% (w / w); (ii) a solvent from about 5% (w / w) to about 70% (w / w); (iv) a co-solvent from about 5% (w / w) to about 35% (w / w); (v) emulsifier from about 0.5% (w / w) to about 15% (w / w); (vi) an anti-oxidant from about 0.5% (w / w) to about 5% (w / w); and (vi) optionally, one or more pharmaceutically acceptable excipients, wherein the total impurities are less than about 5% as determined by HPLC after 6 months at a temperature of from about 40°C and about 75% relative humidity.

[0117] In another embodiment, the present invention relates to liquid pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) water from about 1% (w / w) to about 30% (w / w); (iii) a solvent from about 5% (w / w) to about 70% (w / w); (iv) a co-solvent from about 5% (w / w) to about 35% (w / w); and (v) one or more other pharmaceutically acceptable excipients.

[0118] In another embodiment, the present invention relates to liquid pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) water from about 1% (w / w) to about 30% (w / w); (iii) a solvent from about 5% (w / w) to about 70% (w / w); (iv) a co-solvent from about 5% (w / w) to about 35% (w / w); (v) an emulsifier from about 0.5% (w / w) to about 15% (w / w); and (vi) one or more other pharmaceutically acceptable excipients.

[0119] In another embodiment, the present invention relates to liquid pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) water from about 1% (w / w) to about 30% (w / w); (ii) a solvent from about 5% (w / w) to about 70% (w / w); (iv) a co-solvent from about 5% (w / w) to about 35% (w / w); (v) emulsifierfrom about 0.5% (w / w) to about 15% (w / w); (vi) an anti-oxidant from about 0.5% (w / w) to about 5% (w / w); and (vi) optionally, one or more pharmaceutically acceptable excipients, wherein the total impurities are less than about 5% as determined by HPLC after 12 months at a temperature of about 25°C.

[0120] In another embodiment, the present invention relates to liquid pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) water from about 1% (w / w) to about 30% (w / w); (ii) a solvent from about 5% (w / w) to about 70% (w / w); (iv) a co-solvent from about 5% (w / w) to about 35% (w / w); (v) emulsifier from about 0.5% (w / w) to about 15% (w / w); (vi) an anti-oxidant from about 0.5% (w / w) to about 5% (w / w); and (vi) optionally, one or more pharmaceutically acceptable excipients, wherein the total impurities are less than about 5% as determined by HPLC after 6 months at a temperature of from about 40°C and about 75% relative humidity.

[0121] In one embodiment, the present invention relates to an aqueous pharmaceutical composition comprising: (i) asundexian; (ii) water; (ii) polyethylene glycol; (iv) propylene glycol; and (v) gelucire 48 / 16.

[0122] In one embodiment, the present invention relates to an aqueous pharmaceutical composition comprising: (i) asundexian; (ii) water; (ii) polyethylene glycol; (iv) glycerin; and (v) gelucire 48 / 16.

[0123] In another embodiment, the present invention relates to an aqueous pharmaceutical composition comprising: (i) asundexian; (ii) water; (ii) polyethylene glycol; (iv) propylene glycol; and (v) TPGS 1000.

[0124] In another embodiment, the present invention relates to an aqueous pharmaceutical composition comprising: (i) asundexian; (ii) water; (ii) polyethylene glycol; (iv) glycerin; and (v) TPGS 1000.

[0125] In one embodiment, the present invention relates to an aqueous pharmaceutical composition comprising: (i) asundexian; (ii) water; (ii) labrasol ALF; (iv) glycerin; and (v) gelucire 48 / 16.

[0126] In another embodiment, the present invention relates to an aqueous pharmaceutical composition comprising: (i) asundexian; (ii) water; (ii) labrasol ALF; (iv) glycerin; and (v) TPGS 1000.

[0127] In another embodiment, the present invention relates to an aqueous pharmaceutical composition comprising: (i) asundexian; (ii) water; (ii) labrasol ALF; (iv) glycerin; and (v) TPGS 1000.

[0128] In another embodiment, the present invention relates to a aqueous pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) water from about 10 mg / mLto about 250 mg / mL; (ii) a solvent from about 50 mg / mLto about 700 mg / mL; (iv) a co-solvent from about 50 mg / mL to about 350 mg / mL; (v) emulsifier from about 5 mg / mL to about 250 mg / mL; (vi) an anti-oxidant from about 0.1 mg / mL to about 10 mg / mL; and (vi) optionally, one or more pharmaceutically acceptable excipients.

[0129] In another embodiment, the present invention relates to a liquid pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) water from about 10 mg / mLto about 250 mg / mL; (ii) a solvent from about 50 mg / mLto about 700 mg / mL; (iv) a co-solvent from about 50 mg / mL to about 350 mg / mL; (v) emulsifier from about 5 mg / mL to about 250 mg / mL; (vi) an anti-oxidant from about 0.1 mg / mL to about 10 mg / mL; and (vi) optionally, one or more pharmaceutically acceptable excipients.

[0130] In another embodiment, the present invention relates to a aqueous pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) water from about 10 mg / mL to about 250 mg / mL; (ii) labrasol ALF from about 400 mg / mLto about 700 mg / mL; (iv) glycerin from about 150 mg / mLto about 250 mg / mL; (v) gellucire 48 / 16 from about 10 mg / mL to about 60 mg / mL; and (vi) optionally, one or more pharmaceutically acceptable excipients.

[0131] In another embodiment, the present invention relates to a aqueous pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) water from about 10 mg / mL to about 250 mg / mL; (ii) PEG400 from about 400 mg / mL to about 700 mg / mL; (iv) glycerin from about 150 mg / mL to about 250 mg / mL; (v) TPGS 1000 from about 10 mg / mL to about 60 mg / mL; and (vi) optionally, one or more pharmaceutically acceptable excipients.

[0132] In another embodiment, the present invention relates to a aqueous pharmaceutical composition comprising: (i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (ii) water from about 10 mg / mL to about 250 mg / mL; (ii) PEG400 from about 400 mg / mL to about 700 mg / mL; (iv) propylene glycol from about 150 mg / mL to about 250mg / mL; (v) TPGS 1000 from about 10 mg / mL to about 60 mg / mL; and (vi) optionally, one or more pharmaceutically acceptable excipients.

[0133] In one embodiment, the liquid pharmaceutical composition described herein is a microemulsion.

[0134] In certain embodiments, liquid pharmaceutical compositions described herein have certain polydispersity index and average particle size or globule size.

[0135] In some embodiments, the liquid microemulsion pharmaceutical compositions described herein comprises globules with a globule or droplet size of less than 50 nanometers (nm). In some embodiments, the liquid microemulsion compositions described herein comprises globules with a globule size of less than 30 nm. In some embodiments, the liquid microemulsion compositions described herein comprises globules with a globule size of less than 20 nm. In some embodiments, the liquid microemulsion compositions described herein comprises globules with a globule size of about 8 nm to about 20 nm, about 10 nm to about 18 nm, about 12 nm to about 16 nm. In some embodiments, the liquid microemulsion compositions described herein comprises globules with a globule size of about 15 nm ± 10 nm. In some embodiments, the liquid microemulsion compositions described herein comprises globules with a globule size of about 11.8 nm ± 5 nm.

[0136] In an embodiment, the liquid microemulsion pharmaceutical compositions described herein have poly dispersity index (PDI) within the range of 0.02 to 0.380. In some embodiments, the liquid microemulsion pharmaceutical compositions described herein have PDI within the range of 0.02 to 0.15. In some embodiments, the liquid microemulsion compositions described herein have PDI of less than 0.2. In some embodiments, the liquid microemulsion pharmaceutical compositions described herein have PDI of about 0.19. In some embodiments, the liquid microemulsion pharmaceutical compositions described herein have PDI of about 0.17. In some embodiments, the liquid microemulsion pharmaceutical compositions described herein have PDI of about 0.15.

[0137] In an embodiment, the liquid pharmaceutical compositions described herein do not change color when exposed to light.

[0138] In another embodiment, the liquid pharmaceutical compositions described herein do not have phase separation when stored at a temperature of about 25°C for about 6 months, about 12 months or about 24 months.H. Method of Use and Treatment

[0139] In one aspect, provided herein are methods of treating and / or prophylaxis of diseases, preferably of thrombotic or thromboembolic disorders and / or thrombotic or thromboembolic complications. In some embodiments, provided herein are methods for the treatment and / or prophylaxis of cardiovascular disorders including coronary artery disease, angina pectoris, myocardial infarction or stent thrombosis, as well as disorders in the cerebrovascular arteries and other disorders, leading to transitory ischaemic attacks (TIA), ischemic strokes including cardioembolic as well as non-cardioembolic strokes, and / or disorders of peripheral arteries, leading to peripheral artery disease, including peripheral artery occlusion, acute limb ischemia, amputation, reocclusions and restenoses after interventions such as angioplasty, stent implantation or surgery and bypass, and / or stent thrombosis.

[0140] In another aspect, provided herein is a method of treating a thromboembolic disorder in a subject in need thereof, comprising administering to the subject an aqueous pharmaceutical composition of the compound Formula (I) described herein.

[0141] In another aspect, the dosage of the aqueous pharmaceutical compositions of the present invention may be determined using laboratory techniques known to evaluate compounds useful for the treatment of disorders, by pharmacological assays for the determination of treatment of the conditions identified above in mammals such as a human, and by comparison of these results with the results of known medicaments that are used to treat these conditions. As such, the therapeutically effective dosage of the compound of this invention can readily be determined for treatment of each desired indication.

[0142] The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, time or interval of administration, the age and sex and body weight of the patient treated, individual behaviour towards the active ingredient, and the nature and extent of the condition treated.I. Definitions

[0143] To facilitate an understanding of the present disclosure, a number of terms and phrases are defined below.

[0144] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0145] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

[0146] In the application, where an element or component is said to be included in and / or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from the group consisting of two or more of the recited elements or components.

[0147] Further, it should be understood that elements and / or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present invention, whether explicit or implicit herein. For example, where a reference is made to a particular compound, that compound can be used in various embodiments of methods of the present invention, unless otherwise understood from the context. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and invention(s). For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the invention(s) described and depicted herein.

[0148] The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., at least one) of the grammatical object of the article, unless the context is inappropriate. By way of example, “an element” means one element or more than one element.

[0149] The term “and / or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

[0150] Where the use of the term “about” is before a quantitative value, the present invention also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ±10% variation from the nominal value unless otherwise indicated or inferred from the context.

[0151] The use of the term “comprise,” “comprises,” “comprising,” “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” includinggrammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context.

[0152] At various places in the present specification, variable or parameters are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0153] The use of any and all examples, or exemplary language herein, for example, “such as” or “including,” is intended merely to illustrate better the present invention and does not pose a limitation on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present invention.

[0154] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.

[0155] As used herein, the term “aqueous” means that its water content is preferably above the typical water content of solid pharmaceutical dosage forms which are humidified from the atmosphere due to the more or less pronounced hygroscopic properties of their constituents.

[0156] As used herein, “composition” or “pharmaceutical composition” or “pharmaceutical formulation” refers to the combination of an active agent with an excipient or a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0157] As used herein, the term “stable,” refers to chemical stability, wherein not more than 5% % w / w of total degradation products are formed on storage at 25° C / 60% RH or 40° C / 75% RH for a period of at least three months.

[0158] As used herein, “v / v” means “volume per volume” and express the concentration of a substance in a solution on a volume per volume basis.

[0159] As used herein, the term “degradation product” refers to impurities resulting from chemical changes that occur during drug manufacturing, storage and / or transportation in response to changes in light, temperature, pH, and humidity, or due to inherent characteristics of the activepharmaceutical substance, such as their reaction with excipients or on contact with the packaging material.J. EXAMPLES

[0160] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.Abbreviations

[0161] In the Examples provided below, the following abbreviations are used: “ACN” refers to acetonitrile; “HPLC” refers to high-performance liquid chromatography; “KOH” refers to potassium hydroxide; “PEG” refers to polyethylene glycol; “RH” refers to relative humidity; RRT refers to relative retention time and “TPGS” refers to d -a-Tocopheryl polyethylene glycol 1000 succinate.

[0162] Example 1. Analytical Methods for Formulations of AsundexianChromatographic conditions:

[0163] Preparation of Standard solution: Prepare asundexian standard solution at 0.5mg / ml concentration in diluent.

[0164] Preparation of test solution: Prepare sample solution at 0.5mg / ml concentration in diluent with the help of vortex for 5 minutes followed by sonication for 30 minutes with intermittent shaking. Filter the test solution through 0.45pm PVDF filter.

[0165] Example 2. Preparation and Stability Results of Aqueous Pharmaceutical Compositions of Asundexian

[0166] General method of preparation: (1) Mix a solvent and a co-solvent; (2) add an emulsifier and mix well; (3) add Compound 1 and mix well to get clear solution; and (4) add other additives and purified water and mix well.

[0167] Tables 1 - 4 describe the composition of aqueous pharmaceutical compositions, Formulations 1-10.

[0168] Table 1 Pharmaceutical compositions of Asundexian (Formulations 1-3)

[0169] Table 2 Pharmaceutical compositions of Asundexian (Formulations 4-5)

[0170] Table 3. Pharmaceutical compositions of Asundexian with emulsifier (Formulations 6-8)

[0171] Table 4. Comparative Pharmaceutical compositions of Asundexian with and without TPGS(Formulations 9 -10)

[0172] Table 5. describes the stability and degradation data of aqueous pharmaceutical composition of Asundexian.

[0173] General method for stability study shown in Table 5: Place each formulation in 10 mL amber-color glass bottles, and store in the following conditions: (1) 40°C ± 2°C / 75% RH ± 5% RH) for 1, 2 & 3 months, and (2) 25°C ± 2°C / 60% RH ± 5% RH for 3 months. Stability and / or degradation was measured using the HPLC analysis as described in Example 1.

[0174] Example 3. Analysis of Particles Size of the Emulsion

[0175] Particle size of the emulsion was measured using a Particle size analyzer according to the manufacturer's instructions. Test solutions were prepared by addition 1 mL of the composition prepared according to formulation 11 or 1 mL of placebo of formulation 11 to 25 ml of water. Particle sizes are reported as the Z- Average (ZAve).

[0176] As shown in Table 6, the average diameter of emulsion particles of the aqueous pharmaceutical composition of Asundexian described herein is from about 15 nm to about 20 nm.

[0177] Table 6. Globule Size Distribution

[0178] Example 4: Determination of Polydispersity index (PDI) and droplet Size of Microemulsions from Aqueous Dilution

[0179] General method for droplet size determination: (1) Add 50 ml of Milli Q Water to a 250 ml glass beaker and add magnetic bead and stir at 200 RPM on magnetic stirrer; (2) Add 1 gm of sample drop wise (1 drop per second) with the help of dropper in the above beaker during stirring stage; (3) Continue the stirring for 10 minutes after addition of sample; (4) Add 1-2 mL of the sample solution in cuvette, ensure no air bubble is present after addition of sample in cuvette; (5) Measure the globule size distribution as per instrument parameter; (6) Select the three measurements and create average result of the three measurements of each preparation individually from the list for corresponding batch number of sample; (7) Report the Z-average, Pdl, D(v) 0.1, D(v) 0.5 and D(v) 0.9. Measurements were performed on the Malvern Zetasizer Model: Nano- ZSP.

[0180] Figure 1 depicts Polydispersity index (PDI) and droplet Size of Asundexian liquid composition prepared according to Formulation 10 (Initial).

[0181] Figure 2 depicts Polydispersity index (PDI) and droplet Size of Asundexian liquid composition prepared according to Formulation 10 and after storage at 25°C, 60% RH for 6 months.

[0182] Figure 3 depicts Polydispersity index (PDI) and droplet Size of Asundexian liquid composition prepared according to Formulation 10 and after storage at 40°C, 75% RH for 6 months.

[0183] Example 5: Comparative Dissolution Profile of Asundexian 5 mg / mL Microemulsion and 25mg Immediate Release Capsule

[0184] General method for comparing dissolution profile:

[0185] (1) Both asundexian microemulsion 5 mg / mL (10 mL) and IR capsule 25 mg (2 capsules) were added to the pH 6.8 phosphate buffer +0.25% SLS media (50 rpm) at a concentration of 50 mg equivalent per formulation. (2) Aliquots were taken at different time points (15min, 30min, 45 min and 60 min for IR formulation and 15 min and 30 min for microemulsion) and % dissolution was measured.

[0186] Figure 4 describes the comparative invitro dissolution profile of Asundexian liquid composition 5 mg / mL prepared according to Formulation 10 and 25 mg immediate release capsule prepared according to Example 3-1 of WO2022 / 189278A1.

Claims

What is claimed:

1. A liquid pharmaceutical composition comprising:(i) a compound of Formula (I) at a concentration of about 1 mg / mL to about 20 mg / mL;(ii) an aqueous vehicle; and(iii) one or more other pharmaceutically acceptable excipients.

2. The liquid pharmaceutical composition of claim 1 , wherein the aqueous vehicle comprises water, solvent, co-solvent, emulsifier or combinations thereof.

3. The liquid pharmaceutical composition of claim 2, wherein the amount of water present in the composition is from about 1% (w / w) to about 30% (w / w).

4. The liquid pharmaceutical composition of claim 2, wherein the amount of water present in the composition is from about 10 mg / mL to about 400 mg / mL.

5. The liquid pharmaceutical composition of claim 2, wherein the amount of water present in the composition is from about 100 mg / mL to about 200 mg / mL.

6. The liquid pharmaceutical composition of claim 2, wherein the amount of water present in the composition is about 150 mg / mL.

7. The liquid pharmaceutical composition of claim 2, wherein the solvent is selected from polyethylene glycol 100, polyethylene glycol 200, polyethylene glycol 400, Labrasol ALF or a combination thereof.

8. The liquid pharmaceutical composition of claim 7, wherein the amount of solvent present in the composition is from about 50 mg / mL to about 700 mg / mL.

9. The liquid pharmaceutical composition of claim 7, wherein the amount of the solvent present in the composition is from about 10% (w / w) to about 70% (w / w).

10. The liquid pharmaceutical composition of claim 2, wherein co-solvent is selected from ethanol, glycerin, propylene glycol, or a combination thereof.

11. The liquid pharmaceutical composition of claim 10, wherein the amount of co-solvent present in the composition is from about 50 mg / mL to about 350 mg / mL.

12. The liquid pharmaceutical composition of claim 10, wherein the amount of co-solvent present in the composition is from about 5% (w / w) to about 35% (w / w).

13. The liquid pharmaceutical composition of claim 2, wherein the emulsifier has HLB value which is usually in the range 6 to 20.

14. The liquid pharmaceutical composition of claim 2, wherein the emulsifier is selected from the group consisting of phospholipid surfactant, non-ionic surfactants, cationic surfactants, anionic surfactants, and zwitterionic surfactants.

15. The liquid pharmaceutical composition of claim 2, wherein the emulsifier is selected from TPGS 1000, Acconon mixture (mixture of polyoxyethylene mono- and diglycerides, fatty acids or fatty alcohols), Gellucire 48 / 16, propylyene glycol esters, polyethylene glycol, and a polyethylene glycol derivative or any combination thereof.

16. The liquid pharmaceutical composition of claim 15, wherein the amount of emulsifier in the composition is from about 5 mg / mL to about 250 mg / mL.

17. The liquid pharmaceutical composition of claim 15, wherein the amount of emulsifier in the composition is from about 0.5% (w / w) to about 25% (w / w).

18. The liquid pharmaceutical composition of claim 1, wherein the one or more pharmaceutically acceptable excipients is surfactant, acidifier, solubilizer, stabilizers, chelating agents, pH adjusting agents, buffering agents, preservatives, thickening agents, anti-foaming agents, flavoring agents, coloring agents, sweetening agents or combinations thereof.

19. The liquid pharmaceutical composition of claim 18, wherein the antioxidant is selected from the group consisting of sodium bisulfate, ascorbic acid, ascorbyl palmitate, citric acid, tartaric acid, glycine, L-cysteine hydrochloride, L-methionine, butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), hydro phosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium citrate anhydrous, sodium citrate dihydrate, sodium sulfide, sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, thioglycolic acid, sodium metabisulfite and propyl gallate.

20. The liquid pharmaceutical composition of claim 19, wherein the amount of antioxidant present in the composition is from about 0.1 mg / mL to about 10 mg / mL.

21. The liquid pharmaceutical composition of claim 18, wherein the solubilizer is selected from the group consisting of propylene glycol, polyethylene glycol, glycerol, Tween 20, Tween 80, and sodium lauryl sulfate (SLS), or combinations thereof.

22. The liquid pharmaceutical composition of claim 18, wherein the chelating agent is selected from the group consisting of disodium ethylenediaminetetraacetic acid (disodium EDTA), diethylenetriaminepentaacetic acid (DTP A), ethylene glycol-bis (P-aminoethyl ether)-tetra acetic acid (EGTA), N-(hydroxyethyl) ethylenediaminetriacetic acid (HEDTA), nitrilotriacetic acid (NTA), triethanolamine, 8-hydroxyquinoline, phosphoric acid, gluconic acid, saccharic acid, thiodipropionic acid, acetonic dicarboxylic acid, lecithin, di(hydroxyethyl)glycine, phenylalanine, tryptophan, glycerine, sorbitol or combinations thereof.

23. The liquid pharmaceutical composition of claim 22, wherein the amount of chelating agent present in the composition is from about 0.1 mg / mL to about 1 mg / mL.

24. The liquid pharmaceutical composition of claim 18, wherein the preservative is selected from the group consisting of methylparaben, propylparaben, ethylparaben, butylparaben, isobutylparaben, isopropylparaben, benzylparaben, sodium salts of the referenced parabens, a sorbate (salt of sorbic acid and / or sorbic acid), benzoate (salt of benzoic acid and / or benzoic acid), sulfur dioxide, sulfite, nitrite, nitrate, lactic acid, propionic acid, propionate, ascorbic acid, ascorbate, butylated hydroxytoluene or combinations thereof.

25. The liquid pharmaceutical composition of claim 24, wherein the amount of preservative present in the composition is from about 0.1 mg / mL to 5 mg / mL.

26. The liquid pharmaceutical composition of claim 18, wherein the sweetener is selected from the group consisting of aspartame, saccharin, sucralose, acesulfame potassium and the like. In some embodiments, the sweetener is selected from the group consisting of sucralose, mannitol, xylitol, erythritol, saccharin sodium IP, aspartame, and acesulfame potassium (Ace-K) or combinations thereof.

27. The liquid pharmaceutical composition of claim 26, wherein the amount of sweetener present in the composition is from about 5 mg / mL to about 250 mg / mL.

28. The liquid pharmaceutical composition of claim 18, wherein the flavoring agent is selected from the group consisting of cherry flavor, artificial banana flavor, caramel, chocolate mint flavor, grape flavor, wild cherry flavor, maltitol, raspberry flavor, strawberry flavor, mixed berry flavor, citrus flavor, orange flavor, pineapple flavor, citrus lime flavor, citrus cream flavor, cherry vanilla flavor, cranberry flavor, creme de menthe flavor and mixtures thereof.

29. The liquid pharmaceutical composition of claim 28, wherein the amount of flavoring agent present in the composition is from about 0.1 mg / mL to about 10 mg / mL.

30. The liquid pharmaceutical composition of claim 18, wherein the acidifier is selected from the group consisting of citric acid monohydrate, lactic acid, ascorbic acid, and malic acid.

31. The liquid pharmaceutical composition of claim 30, wherein the amount of acidifier present in the composition is from about 1 mg / mL to 10 mg / mL.

32. The liquid pharmaceutical composition of claim 1, wherein the amount of compound of Formula (I) in the composition is from about 2 mg / mL to about 8 mg / mL.

33. The liquid pharmaceutical composition of claim 1, wherein the amount of compound of Formula (I) in the composition is from about 3 mg / mL to about 7 mg / mL.

34. The liquid pharmaceutical composition of claim 1, wherein the amount of compound of Formula (I) in the composition is about 5 mg / mL.

35. The liquid pharmaceutical composition of claim 1, wherein the pH of the compositions is in the range of about 4.0 to about 7.0.

36. The liquid pharmaceutical composition of claim 1, wherein the composition has less than about 5% peak area response of total impurities resulting from the degradation of the asundexian as determined by HPLC after at least 6 months at a temperature of from about 5° C to about 25° C.

37. The liquid pharmaceutical composition of claim 1, wherein the composition has less than about 5% peak area response of total impurities resulting from the degradation of the asundexian as determined by HPLC after at least 12 months at a temperature of from about 5° C to about 25° C.

38. The liquid pharmaceutical composition of claim 1 , wherein about 98% of the compound of Formula (I) is released in about 30 minutes.

39. A liquid pharmaceutical composition comprising:(i) Asundexian;(ii) water from about 1% (w / w) to about 30% (w / w);(iii) solvent from about 5% (w / w) to about 70% (w / w); and(iv) one or more other pharmaceutically acceptable excipients.

40. A liquid pharmaceutical composition comprising:(i) Asundexian;(ii) water from about 1% (w / w) to about 30% (w / w);(iii) solvent from about 5% (w / w) to about 70% (w / w);(iv) co-solvent from about 5% (w / w) to about 35% (w / w); and(v) one or more other pharmaceutically acceptable excipients.

41. A liquid pharmaceutical composition comprising:(i) Asundexian;(ii) water from about 1% (w / w) to about 30% (w / w);(iii) solvent from about 5% (w / w) to about 70% (w / w);(iv) co-solvent from about 5% (w / w) to about 35% (w / w);(v) emulsifier from about 0.5% (w / w) to about 15% (w / w); and(vi) one or more other pharmaceutically acceptable excipients.

42. A liquid pharmaceutical composition comprising:(i) Asundexian;(ii) water from about 1% (w / w) to about 30% (w / w);(iii) solvent from about 5% (w / w) to about 70% (w / w);(iv) co-solvent from about 5% (w / w) to about 35% (w / w);(v) emulsifier from about 0.5% (w / w) to about 15% (w / w);(vi) anti-oxidant from about 0.5% (w / w) to about 5% (w / w); and(vi) optionally, one or more pharmaceutically acceptable excipients.

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