Pharmaceutical compositions and use thereof

Abstract

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

Description

PHARMACEUTICAL COMPOSITIONS AND USE THEREOFFIELD OF THE INVENTION

[0001] The present disclosure relates to liquid pharmaceutical compositions comprising Milvexian, methods for their preparation, and methods of their use.BACKGROUND

[0002] Thromboembolic diseases such as stroke, myocardial infarction, deep venous thrombosis are clinically common causes of death. Anticoagulants are commonly used drugs in the clinical treatment of thromboembolic diseases. One approach has been to inhibit factor Xia (FXIa). Factor Xia is a plasma serine protease involved in the regulation of blood coagulation. Factor Xia is an activated form of factor XI, which is activated by factor Xlla, thrombin, and it is also autocatalytic. FXIa is a member of the “contact pathway” and activates factor IX by selectively cleaving Arg-Ala and Arg-Val peptide bonds. Factor IXa, in turn, activates factor X. The safety of this target is supported by the observations that FXI deficiency in humans (hemophilia C) results in a mild bleeding disorder. In addition, the efficacy and side effects of this target have been shown using experimental thrombosis and bleeding models in mice lacking FXI, and in baboons and rabbits treated with anti-FXI neutralizing antibodies. These results suggest that FXIa inhibitors induce potent anti -thrombotic effects without bleeding. As a result, factor Xia has been an attractive target for anti -thrombotic therapy without any bleeding side effects.

[0003] Milvexian, also known as (9R,13S)-13-{4-[5-chloro-2-(4-chloro-lH-l,2,3- triazol-l-yl)phenyl]-6-oxo-l,6-dihydropyrimidin-l-yl}-3-(difluoromethyl)-9-methyl- 3,4,7, 15-tetraazatricyclo[12.3.1.02,6]octadeca-l(18),2(6),4, 14, 16-pentaen-8-one, is an inhibitor of FXIa that may be useful in the treatment of thromboembolic diseases. Solid dosage forms of Milvexian (e.g., Milvexian tablets) have been studied for the treatment of Ischemic Stroke, Acute Coronary Syndrome and Atrial Fibrillation. However, solid dosage forms of Milvexian are faced with several challenges for drug administration. For instance, solid dosage forms of Milvexian may irritate the gastrointestinal tract. These solid dosage forms may also break down inconsistently, which can decrease the medication’s effectiveness and overall absorption. Because of these factors, the medication may be prone to dosing errors, thereby inducing bioavailability issues. Solid dosage forms of Milvexian may also have stability issues caused during the tampering process of preparing the solid dosage forms. Importantly, children and elderly patients may face significant difficulty in swallowing the solid dosage forms. Incontrast, liquid pharmaceutical compositions of Milvexian have advantages over the solid dosage forms of Milvexian, as they are preferred dosage formulations for children and adults with difficulties in swallowing solid dosage forms. Liquid formulations also have higher bioavailability than solid dosage forms, and they allow for higher precision in dosing. Liquid pharmaceutical compositions of Milvexian can provide uniformly dispersed API and reduce any irritation due to their dilution factor.

[0004] Accordingly, there exists a strong need for liquid pharmaceutical compositions of Milvexian that are safe, convenient, therapeutically effective, and stable under a variety of storage conditions.SUMMARY

[0005] In one aspect, provided herein are liquid pharmaceutical composition comprising a compound of Formula (I), a lipid vehicle, and water, wherein said compound of Formula (I) is represented by:and wherein the water is present in the liquid pharmaceutical composition at about 20 % w / w or less.

[0006] In one aspect, provided herein are liquid pharmaceutical composition comprising a compound of Formula (I), a lipid vehicle, a surfactant and water, wherein said compound of Formula (I) is represented by:and wherein the water is present in the liquid pharmaceutical composition at about 20 % w / w or less.BRIEF DESCRIPTION OF THE FIGURES

[0007] Figure 1 depicts Poly dispersity Index (PDI) and Droplet Size of Formulation 7.

[0008] Figure 2 depicts comparative Dissolution Profile of Milvexian microemulsion 5mg / mL and 25mg IR tablet.DETAILED DESCRIPTION

[0009] As generally described herein, the present disclosure provides liquid pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0010] The following paragraphs detail various embodiments of the invention. For avoidance of doubt, it is specifically intended that any feature(s) described individually in any one of these paragraphs (or part thereof) may be combined with one or more other features described in one or more of the remaining paragraphs (or part thereof). Unless defined otherwise, all the technical and scientific terms herein have the same meanings as commonly known by the person skilled in the art.I. Compound of Formula (I)

[0011] Milvexian has the structure below and is also referred to as (9R, 13S)-13-{4-[5- chloro-2-(4-chloro-lH-l,2,3-triazol-l-yl)phenyl]-6-oxo-l,6-dihydropyrimidin-l-yl}-3- (difhioromethyl)-9-methyl-3,4,7, 15-tetraazatricyclo[12.3.1.02’6]octadeca-1 (18), 2(6), 4, 14,16-pentaen-8-one:

[0012] Milvexian is also a compound of Formula (I).

[0013] The compound of Formula (I) may also be referred to as “Compound 1” or “Milvexian” throughout the present disclosure. A method of chemically synthesizing the compound of Formula (I) is described in U.S. Patent Application No. 2016 / 0096839.II. Liquid Pharmaceutical Compositions

[0014] Provided herein are pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In preferred embodiments, the pharmaceutical composition is a liquid oral solution comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In various embodiments, the pharmaceutical compositions comprise a pharmaceutically acceptable excipient.

[0015] The liquid pharmaceutical compositions comprising a compound of Formula (I), as described herein, exhibit high stability and low degradation. Presently known Milvexian compositions in the art (e.g., solid dispersion and liquid compositions of Milvexian) are prone to stability issues (e.g. hydrolytic and / or oxidative degradation) which may have a significant impact on drug safety, quality and efficacy. Additionally, known Milvexian liquid pharmaceutical compositions contain a high amount of TPGS, which is beyond the Inactive Ingredient Database (IIG) limits, and thus not recommended by the FDA for human administration. In the known Milvexian compositions, stability issues are often associated with the high water content.

[0016] In one embodiment, liquid pharmaceutical compositions of the disclosure comprise a compound of Formula (I), a lipid vehicle, and water, wherein the water is present in the liquid pharmaceutical composition at about 20% w / w or less.

[0017] In certain embodiments, liquid pharmaceutical compositions of the disclosure comprise a compound of Formula (I), a lipid vehicle, and water, wherein the water is present in the liquid pharmaceutical composition at about 15% w / w or less.

[0018] In certain embodiments, liquid pharmaceutical compositions of the disclosure comprise a compound of Formula (I), a lipid vehicle, and water, wherein the water is present in the liquid pharmaceutical composition at about 10% w / w or less.

[0019] In certain embodiments, liquid pharmaceutical compositions of the disclosure comprise a compound of Formula (I), a lipid vehicle, and water, wherein the water is present in the liquid pharmaceutical composition at about 5% w / w or less.

[0020] In certain embodiments, liquid pharmaceutical compositions of the disclosure comprise a compound of Formula (I), a lipid vehicle, and water, wherein the water is present in the liquid pharmaceutical composition at about 3% w / w or less.

[0021] In certain embodiments, liquid pharmaceutical compositions of the disclosure comprise a compound of Formula (I), a lipid vehicle, and water, wherein the water is present in the liquid pharmaceutical composition at about 2.5% w / w or less.

[0022] In certain embodiments, liquid pharmaceutical compositions of the disclosure comprise a compound of Formula (I), a lipid vehicle, and water, wherein the water is present in the liquid pharmaceutical composition at about 2% w / w or less.

[0023] In certain embodiments, liquid pharmaceutical compositions of the disclosure comprise a compound of Formula (I), a lipid vehicle, and water, wherein the water is present in the liquid pharmaceutical composition at about 1% w / w or less.

[0024] In certain embodiments, liquid pharmaceutical compositions of the disclosure comprise a compound of Formula (I), a lipid vehicle, and water, wherein the water is present in the liquid pharmaceutical composition at an amount that does not impact the stability of the formulation. For example, water is not added as a component in the pharmaceutical composition but may be present in other pharmaceutically acceptable excipients.

[0025] In some embodiments, the present invention relates to liquid pharmaceutical composition comprising a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; a lipid vehicle; water in an amount of less than about 20% w / w; and optionally, one or more pharmaceutically acceptable excipients. In some embodiments, the present invention relates to liquid pharmaceutical composition comprising a compound ofFormula (I) at a concentration of about 5 mg / mL; a lipid vehicle; water in an amount of less than about 20% w / w; and optionally, one or more pharmaceutically acceptable excipients.

[0026] In some embodiments, the present invention relates to liquid pharmaceutical composition comprising a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; a lipid vehicle; water in an amount of less than about 15% w / w; and optionally, one or more pharmaceutically acceptable excipients. In some embodiments, the present invention relates to liquid pharmaceutical composition comprising a compound of Formula (I) at a concentration of about 5 mg / mL; a lipid vehicle; water in an amount of less than about 15% w / w; and optionally, one or more pharmaceutically acceptable excipients.

[0027] In some embodiments, the present invention relates to liquid pharmaceutical composition comprising a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; a lipid vehicle; water in an amount of less than about 10% w / w; and optionally, one or more pharmaceutically acceptable excipients. In some embodiments, the present invention relates to liquid pharmaceutical composition comprising a compound of Formula (I) at a concentration of about 5 mg / mL; a lipid vehicle; water in an amount of less than about 10% w / w; and optionally, one or more pharmaceutically acceptable excipients.

[0028] In some embodiments, the present invention relates to liquid pharmaceutical composition comprising a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; a lipid vehicle; water in an amount of less than about 5% w / w; and optionally, one or more pharmaceutically acceptable excipients. In some embodiments, the present invention relates to liquid pharmaceutical composition comprising a compound of Formula (I) at a concentration of about 5 mg / mL; a lipid vehicle; water in an amount of less than about 5% w / w; and optionally, one or more pharmaceutically acceptable excipients.

[0029] In some embodiments, the present invention relates to liquid pharmaceutical composition comprising a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; a lipid vehicle; water in an amount of less than about 3% w / w; and optionally, one or more pharmaceutically acceptable excipients. In some embodiments, the present invention relates to liquid pharmaceutical composition comprising a compound of Formula (I) at a concentration of about 5 mg / mL; a lipid vehicle; water in an amount of less than about 3% w / w; and optionally, one or more pharmaceutically acceptable excipients.

[0030] In some embodiments, the present invention relates to liquid pharmaceutical composition comprising a compound of Formula (I) at a concentration of about 1 mg / mL toabout 10 mg / mL; a lipid vehicle; water in an amount of less than about 2.5% w / w; and optionally, one or more pharmaceutically acceptable excipients. In some embodiments, the present invention relates to liquid pharmaceutical composition comprising a compound of Formula (I) at a concentration of about 5 mg / mL; a lipid vehicle; water in an amount of less than about 2.5% w / w; and optionally, one or more pharmaceutically acceptable excipients.

[0031] In some embodiments, the present invention relates to liquid pharmaceutical composition comprising a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; a lipid vehicle; water in an amount of less than about 2% w / w; and optionally, one or more pharmaceutically acceptable excipients. In some embodiments, the present invention relates to liquid pharmaceutical composition comprising a compound of Formula (I) at a concentration of about 5 mg / mL; a lipid vehicle; water in an amount of less than about 2% w / w; and optionally, one or more pharmaceutically acceptable excipients.

[0032] In some embodiments, the present invention relates to liquid pharmaceutical composition comprising a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; a lipid vehicle; water in an amount of less than about 1% w / w; and optionally, one or more pharmaceutically acceptable excipients. In some embodiments, the present invention relates to liquid pharmaceutical composition comprising a compound of Formula (I) at a concentration of about 5 mg / mL; a lipid vehicle; water in an amount of less than about 1% w / w; and optionally, one or more pharmaceutically acceptable excipients.

[0033] In some embodiments, the present invention relates to liquid pharmaceutical composition comprising a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; a lipid vehicle; water in an amount that does not impact the stability of the formulation; and optionally, one or more pharmaceutically acceptable excipients. In some embodiments, the present invention relates to liquid pharmaceutical composition comprising a compound of Formula (I) at a concentration of about 5 mg / mL; a lipid vehicle; water in an amount that does not impact the stability of the formulation; and optionally, one or more pharmaceutically acceptable excipients.

[0034] In some embodiments, the present invention relates to liquid pharmaceutical compositions comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 20% w / w; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients. In some embodiments, the present invention relates to liquid pharmaceuticalcompositions comprising (a) a compound of Formula (I) at a concentration of about 5 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 20% w / w; (d) at least one antioxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients.

[0035] In some embodiments, the present invention relates to liquid pharmaceutical compositions comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 15% w / w; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients. In some embodiments, the present invention relates to liquid pharmaceutical compositions comprising (a) a compound of Formula (I) at a concentration of about 5 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 15% w / w; (d) at least one antioxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients.

[0036] In some embodiments, the present invention relates to liquid pharmaceutical compositions comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 10% w / w; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients. In some embodiments, the present invention relates to liquid pharmaceutical compositions comprising (a) a compound of Formula (I) at a concentration of about 5 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 10% w / w; (d) at least one antioxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients.

[0037] In some embodiments, the present invention relates to liquid pharmaceutical compositions comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 5% w / w; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients. In some embodiments, the present invention relates to liquid pharmaceutical compositions comprising (a) a compound of Formula (I) at a concentration of about 5 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 5% w / w; (d) at least one antioxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients.

[0038] In some embodiments, the present invention relates to liquid pharmaceutical compositions comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 3% w / w; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients. In some embodiments, the present invention relates to liquid pharmaceuticalcompositions comprising (a) a compound of Formula (I) at a concentration of about 5 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 3% w / w; (d) at least one antioxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients.

[0039] In some embodiments, the present invention relates to liquid pharmaceutical compositions comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 2.5% w / w; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients. In some embodiments, the present invention relates to liquid pharmaceutical compositions comprising (a) a compound of Formula (I) at a concentration of about 5 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 2.5% w / w; (d) at least one antioxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients.

[0040] In some embodiments, the present invention relates to liquid pharmaceutical compositions comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 2% w / w; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients. In some embodiments, the present invention relates to liquid pharmaceutical compositions comprising (a) a compound of Formula (I) at a concentration of about 5 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 2% w / w; (d) at least one antioxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients.

[0041] In some embodiments, the present invention relates to liquid pharmaceutical compositions comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 1% w / w; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients. In some embodiments, the present invention relates to liquid pharmaceutical compositions comprising (a) a compound of Formula (I) at a concentration of about 5 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 1% w / w; (d) at least one antioxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients.

[0042] In some embodiments, the present invention relates to liquid pharmaceutical compositions comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount that does not impact the stability of the formulation; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients. In some embodiments, the present invention relatesto liquid pharmaceutical compositions comprising (a) a compound of Formula (I) at a concentration of about 5 mg / mL; (b) a lipid vehicle; (c) water in an amount that does not impact the stability of the formulation; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients.

[0043] In some embodiments, the present invention relates to stable liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 20% w / w; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients, wherein the pH of pharmaceutical composition ranges from about 3.0 to about 8.0, and wherein the pharmaceutical composition is stable for at least about 3 months when stored at 25° C / 60% RH or 40° C / 75% RH. In certain embodiments, the pharmaceutical composition is stable for at least about 3 months, about 4 months, about 5 months, or about 6 months when stored at 25° C / 60% RH or 40° C / 75% RH.

[0044] In some embodiments, the present invention relates to stable liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 15% w / w; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients, wherein the pH of pharmaceutical composition ranges from about 3.0 to about 8.0, and wherein the pharmaceutical composition is stable for at least about 3 months when stored at 25° C / 60% RH or 40° C / 75% RH. In certain embodiments, the pharmaceutical composition is stable for at least about 3 months, about 4 months, about 5 months, or about 6 months when stored at 25° C / 60% RH or 40° C / 75% RH.

[0045] In some embodiments, the present invention relates to stable liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 10% w / w; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients, wherein the pH of pharmaceutical composition ranges from about 3.0 to about 8.0, and wherein the pharmaceutical composition is stable for at least about 3 months when stored at 25° C / 60% RH or 40° C / 75% RH. In certain embodiments, the pharmaceutical composition is stable for at least about 3 months, about 4 months, about 5 months, or about 6 months when stored at 25° C / 60% RH or 40° C / 75% RH.

[0046] In some embodiments, the present invention relates to stable liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 5% w / w; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients, wherein the pH of pharmaceutical composition ranges from about 3.0 to about 8.0, and wherein the pharmaceutical composition is stable for at least about 3 months when stored at 25° C / 60% RH or 40° C / 75% RH. In certain embodiments, the pharmaceutical composition is stable for at least about 3 months, about 4 months, about 5 months, or about 62 months when stored at 25° C / 60% RH or 40° C / 75% RH.

[0047] In some embodiments, the present invention relates to stable liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 3% w / w; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients, wherein the pH of pharmaceutical composition ranges from about 3.0 to about 8.0, and wherein the pharmaceutical composition is stable for at least about 3 months when stored at 25° C / 60% RH or 40° C / 75% RH. In certain embodiments, the pharmaceutical composition is stable for at least about 3 months, about 4 months, about 5 months, or about 6 months when stored at 25° C / 60% RH or 40° C / 75% RH.

[0048] In some embodiments, the present invention relates to stable liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 2.5% w / w; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients, wherein the pH of pharmaceutical composition ranges from about 3.0 to about 8.0, and wherein the pharmaceutical composition is stable for at least about 3 months when stored at 25° C / 60% RH or 40° C / 75% RH. In certain embodiments, the pharmaceutical composition is stable for at least about 3 months, about 4 months, about 5 months, or about 6 months when stored at 25° C / 60% RH or 40° C / 75% RH.

[0049] In some embodiments, the present invention relates to stable liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 2% w / w; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients, wherein the pH of pharmaceutical composition ranges from about 3.0 to about 8.0, and wherein the pharmaceutical composition is stable for at least about 3 months when storedat 25° C / 60% RH or 40° C / 75% RH. In certain embodiments, the pharmaceutical composition is stable for at least about 3 months, about 4 months, about 5 months, or about 6 months when stored at 25° C / 60% RH or 40° C / 75% RH.

[0050] In some embodiments, the present invention relates to stable liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 1% w / w; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients, wherein the pH of pharmaceutical composition ranges from about 3.0 to about 8.0, and wherein the pharmaceutical composition is stable for at least about 3 months when stored at 25° C / 60% RH or 40° C / 75% RH. In certain embodiments, the pharmaceutical composition is stable for at least about 3 months, about 4 months, about 5 months, or about 6 months when stored at 25° C / 60% RH or 40° C / 75% RH.

[0051] In some embodiments, the present invention relates to stable liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount that does not impact the stability of the formulation; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients, wherein the pH of pharmaceutical composition ranges from about 3.0 to about 8.0, and wherein the pharmaceutical composition is stable for at least about 3 months when stored at 25° C / 60% RH or 40° C / 75% RH. In certain embodiments, the pharmaceutical composition is stable for at least about 3 months, about 4 months, about 5 months, or about 6 months when stored at 25° C / 60% RH or 40° C / 75% RH.

[0052] In another aspect, the present invention relates to stable liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 20% w / w; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients, wherein the pH of pharmaceutical composition ranges from about 3.0 to about 8.0, wherein total level of impurities in the composition is less than about 5% w / w as measured by HPLC when stored at 25°C for at least about 3 months. In certain embodiments, the pharmaceutical composition is stable for at least about 3 months, about 6 months, about 9 months, or about 12 months.

[0053] In another aspect, the present invention relates to stable liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mLto about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 15% w / w; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients, wherein the pH of pharmaceutical composition ranges from about 3.0 to about 8.0, wherein total level of impurities in the composition is less than about 5% w / w as measured by HPLC when stored at 25°C for at least about 3 months. In certain embodiments, the pharmaceutical composition is stable for at least about 3 months, about 6 months, about 9 months, or about 12 months.

[0054] In another aspect, the present invention relates to stable liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 10% w / w; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients, wherein the pH of pharmaceutical composition ranges from about 3.0 to about 8.0, wherein total level of impurities in the composition is less than about 5% w / w as measured by HPLC when stored at 25°C for at least about 3 months. In certain embodiments, the pharmaceutical composition is stable for at least about 3 months, about 6 months, about 9 months, or about 12 months.

[0055] In another aspect, the present invention relates to stable liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 5% w / w; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients, wherein the pH of pharmaceutical composition ranges from about 3.0 to about 8.0, wherein total level of impurities in the composition is less than about 5% w / w as measured by HPLC when stored at 25°C for at least about 3 months. In certain embodiments, the pharmaceutical composition is stable for at least about 3 months, about 6 months, about 9 months, or about 12 months.

[0056] In another aspect, the present invention relates to stable liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 3% w / w; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients, wherein the pH of pharmaceutical composition ranges from about 3.0 to about 8.0, wherein total level of impurities in the composition is less than about 5% w / w as measured by HPLC when stored at 25°C for at least about 3 months. In certain embodiments, thepharmaceutical composition is stable for at least about 3 months, about 6 months, about 9 months, or about 12 months.

[0057] In another aspect, the present invention relates to stable liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 2.5% w / w; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients, wherein the pH of pharmaceutical composition ranges from about 3.0 to about 8.0, wherein total level of impurities in the composition is less than about 5% w / w as measured by HPLC when stored at 25°C for at least about 3 months. In certain embodiments, the pharmaceutical composition is stable for at least about 3 months, about 6 months, about 9 months, or about 12 months.

[0058] In another aspect, the present invention relates to stable liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 2% w / w; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients, wherein the pH of pharmaceutical composition ranges from about 3.0 to about 8.0, wherein total level of impurities in the composition is less than about 5% w / w as measured by HPLC when stored at 25°C for at least about 3 months. In certain embodiments, the pharmaceutical composition is stable for at least about 3 months, about 6 months, about 9 months, or about 12 months.

[0059] In another aspect, the present invention relates to stable liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount of less than about 1% w / w; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients, wherein the pH of pharmaceutical composition ranges from about 3.0 to about 8.0, wherein total level of impurities in the composition is less than about 5% w / w as measured by HPLC when stored at 25°C for at least about 3 months. In certain embodiments, the pharmaceutical composition is stable for at least about 3 months, about 6 months, about 9 months, or about 12 months.

[0060] In another aspect, the present invention relates to stable liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle; (c) water in an amount that does not impact the stabilityof the formulation; (d) at least one anti-oxidant; and (e) optionally, one or more other pharmaceutically acceptable excipients, wherein the pH of pharmaceutical composition ranges from about 3.0 to about 8.0, wherein total level of impurities in the composition is less than about 5% w / w as measured by HPLC when stored at 25°C for at least about 3 months. In certain embodiments, the pharmaceutical composition is stable for at least about 3 months, about 6 months, about 9 months, or about 12 months.

[0061] In yet another aspect, the present invention relates to an essentially non-aqueous liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of from about 1 mg / mL to about 10 mg / mL; (b) a lipid vehicle and (c) optionally, one or more other pharmaceutically acceptable excipients.

[0062] Advantageously, the compositions of the present invention 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 milvexian (e.g., >96%, >97%, >98%, >99%) and with total impurities <5% (e.g., <4%, <3%, <2%, <1%, <0.1%), as determined by HPLC at a wavelength of 220 nm.

[0063] In various embodiments, the concentration of the compound of Formula (I) in the liquid composition of the present disclosure is about 1 mg / mL to 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.

[0064] In various embodiments, the concentration of the compound of Formula (I) in the liquid composition of the present disclosure is about 5 mg / mL.

[0065] In various embodiments, the lipid vehicle present in the liquid composition of the present disclosure is selected from the group consisting of one or more of medium-chain fatty acids, medium-chain fatty acid esters of glycerol, medium-chain fatty acid esters of polyethylene glycol, medium-chain fatty acid esters of propylene glycol, long-chain fatty acids, long-chain fatty acid esters of glycerol, long-chain fatty acid esters of polyethylene glycol, and long-chain fatty acid esters of propylene glycol. In some embodiments, the lipid vehicle may be a solubilizer and / or a surfactant.

[0066] In some embodiments, one or more lipid vehicles (e.g., one, two, or three lipid vehicles) are present in the liquid composition of the present disclosure.

[0067] In certain embodiments, lipid vehicle is selected from the group consisting of Labrasol® ALF (Caprylocaproyl Polyoxyl-8 glycerides), Gelucire 48 / 16 (Polyoxyl-32 stearate (type I) NF), Kolliphor RH 40 (Polyoxyl 40 Hydrogenated Castor Oil), Kollisolv® MCT 70*( Medium-chain triglycerides), Kolliphor® EL, Maisine® CC, Labrafac™ lipophile WL 1349, MIGLYOL® 812N or combinations thereof.

[0068] The amount of lipid vehicle in the liquid compositions can vary. In one embodiment, the lipid vehicle is present in the composition form about 1% (w / w) to about 80% (w / w) of the liquid composition. In another embodiment, the lipid vehicle is present in the composition form about 5% (w / w) to about 50% (w / w) of the liquid composition. In some embodiments, Maisine® CC is present in the composition from about 1% (w / w) to about 50% (w / w) of the liquid composition. In another embodiment, Labrasol® ALF is present in the composition from about 1% (w / w) to about 50% (w / w) of the liquid composition.

[0069] In certain embodiments, the lipid vehicle is comprised of two lipids, or a composition comprises two lipid vehicles. In some embodiments, the composition comprises two, three, or four different lipids or lipid vehicles, selected from the group consisting of Labrasol® ALF (Caprylocaproyl Polyoxyl-8 glycerides), Gelucire 48 / 16 (Polyoxyl-32 stearate (type I) NF), Kolliphor RH 40 (Polyoxyl 40 Hydrogenated Castor Oil), Kollisolv® MCT 70* (Medium-chain triglycerides), Kolliphor® EL, Maisine® CC, Labrafac™ lipophile WL 1349, and MIGLYOL® 812N.

[0070] In certain embodiments, the lipid vehicle has a concentration of about 50 mg / mL to about 600 mg / mL. In other embodiments, the lipid vehicle has a concentration of about 80 mg / mL to about 350 mg / mL; about 100 mg / mL to about 300 mg / mL; about 150 mg / mL to about 300 mg / mL; about 150 mg / mL to about 250 mg / mL; about 200 mg / mL; about 300 mg / mL to about 600 mg / mL; about 350 mg / mL to about 500 mg / mL; about 400 mg / mL to about 500 mg / mL; about 430 mg / mL; and about 450 mg / mL.

[0071] In certain embodiments, the lipid vehicle has a concentration of about 5.0% (w / w) to about 60.0% (w / w). In other embodiments, the lipid vehicle has a concentration of about 8.0% (w / w) to about 35.0% (w / w); about 10.0% (w / w) to about 30.0% (w / w); about 15.0% (w / w) to about 30.0% (w / w); about 15.0% (w / w) to about 25.0% (w / w); about 20.0% (w / w); about 30.0% (w / w) to about 60.0% (w / w); about 35.0% (w / w) to about 50.0% (w / w); about 40.0% (w / w) to about 50.0% (w / w); about 43.0% (w / w); and about 45.0% (w / w).

[0072] In certain embodiments, the lipid vehicle comprises Labrasol® ALF (Caprylocaproyl Polyoxyl-8 glycerides) and Kolliphor RH 40 (Polyoxyl 40 Hydrogenated Castor Oil).

[0073] In certain embodiments, Labrasol® ALF (Caprylocaproyl Polyoxyl-8 glycerides) has a concentration of about 150 mg / mL to about 600 mg / mL; about 250 mg / mL to about 600 mg / mL; about 350 mg / mL to about 500 mg / mL; about 400 mg / mL to about 400 mg / mL; about 400 mg / mL to about 450 mg / mL; or about 430 mg / mL; and Kolliphor RH 40 (Polyoxyl 40 Hydrogenated Castor Oil) has a concentration of about 80 mg / mL to about 350 mg / mL; about 100 mg / mL to about 300 mg / mL; about 150 mg / mL to about 250 mg / mL; about 180 mg / mL to about 220 mg / mL; or about 200 mg / mL.

[0074] In certain embodiments, Labrasol® ALF (Caprylocaproyl Polyoxyl-8 glycerides) has a concentration of about 15.0% (w / w) to about 60.0% (w / w); about 25.0% (w / w) to about 60.0% (w / w); about 35.0% (w / w) to about 50.0% (w / w); about 40.0% (w / w) to about 40.0% (w / w); about 40.0% (w / w) to about 45.0% (w / w); or about 43.0% (w / w); and Kolliphor RH 40 (Polyoxyl 40 Hydrogenated Castor Oil) has a concentration of about 8.0% (w / w) to about 35.0% (w / w); about 10.0% (w / w) to about 30.0% (w / w); about 15.0% (w / w) to about 25.0% (w / w); about 18.0% (w / w) to about 22.0% (w / w); or about 20.0% (w / w).

[0075] The table below illustrates solubility data of milvexian:

[0076] In certain embodiments, the liquid pharmaceutical composition of the present disclosure comprises one or more pharmaceutically acceptable excipients, such as, for example, cosolvents, surfactant, solubilizer, stabilizers, antioxidants, chelating agents, pH adjusting agents, buffering agents, preservatives, thickening agents, anti-foaming agents, flavoring agents, coloring agents, sweetening agents and / or mixtures thereof.

[0077] In one embodiment, the present invention relates to a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of from about 1 mg / mL to about 10 mg / mL; (b) lipid vehicle; (c) surfactant; and (d) optionally, one or more other pharmaceutically acceptable excipients.

[0078] In one embodiment, the present invention relates to a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of from about 1 mg / mL to about 10 mg / mL; (b) lipid vehicle; (c) surfactant; (d) solubilizer and (e) optionally, one or more other pharmaceutically acceptable excipients.

[0079] In one embodiment, the present invention relates to a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of from about 1 mg / mL to about 10 mg / mL; (b) lipid vehicle; (c) surfactant; (d) solubilizer; (e) antioxidant; and (f) optionally, one or more other pharmaceutically acceptable excipients.

[0080] In one embodiment, the present invention relates to a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of from about 1 mg / mL to about 10 mg / mL; (b) lipid vehicle; (c) surfactant; (d) solubilizer; (e) antioxidant; (f) chelating agent; and (g) optionally, one or more other pharmaceutically acceptable excipients.

[0081] In one embodiment, the present invention relates to a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of from about 1 mg / mL to about 10 mg / mL; (b) lipid vehicle; (c) surfactant; (d) solubilizer; (e) antioxidant; (f) chelating agent; (g) cosolvent; and (h) optionally, one or more other pharmaceutically acceptable excipients.

[0082] In one embodiment, the present invention relates to a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of from about 1 mg / mL to about 10 mg / mL; (b) lipid vehicle; (c) surfactant; (d) solubilizer; (e) antioxidant; (f) chelating agent; (g) cosolvent; (h) buffering agent and (i) optionally, one or more other pharmaceutically acceptable excipients.

[0083] In some embodiments, the pharmaceutical compositions described herein comprise a cosolvent. As used herein, the term "co-solvent" refers to a second solvent included in a formulation which differs from a liquid vehicle included in the formulation. Exemplary cosolvents include, but are not limited to, glycerin or glycerol, benzyl alcohol, ethanol, isopropyl alcohol, polyethylene glycol of various molecular weights, including but not limited to PEG 300 and PEG 400, or propylene glycol, or a mixture of one or more thereof. In certain embodiments, the cosolvent is selected from polyethylene glycol, ethanol and glycerol.

[0084] In certain embodiments, the pharmaceutical compositions described herein comprise a surfactant selected from the group consisting of phospholipid surfactant, non-ionic surfactants, cationic surfactants, anionic surfactants, and zwitterionic surfactants.

[0085] In certain embodiments, the surfactant is selected from among, for example, poloxamers, PEGylated fatty acids, polyoxyethylenes, polyoxyethylene sorbitan fatty acid derivatives, polyoxyethylenes, hydrogenated castor oil ethoxylates, glycerol esters of fatty acids, PEGylated fatty acids, polyoxyl castor oil surfactants, poloxamers, amine oxides, and alcohol ethoxylates (non-ionic). Exemplary of these are polyethylene glycol sorbitan monolaurate (polysorbate 20; TWEEN 20), polyethylene glycol sorbitan monooleate (polysorbate 80; TWEEN 80), and polyethylene glycol sorbitan monopalmitate (polysorbate 40; MONTANOX 40. In other embodiments the surfactants are selected from among polyoxyl35 castor oil (CREMOPHOR EL, KOLLIPHOR EL), polyoxyl 40 hydrogenated castor oil (CREMOPHOR RH40; KOLLIPHOR RH 40), PEG 40 castor oil (ETOCAS 40), PEG- 60 hydrogenated castor oil (CRODURET 60), and polyethylene glycol 15- hydroxystearate (KOLLIPHOR HS 15).

[0086] In certain embodiments, the 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.

[0087] In some embodiments, the pharmaceutical compositions described herein comprise 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, sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, thioglycolic acid, sodium metabisulfite and propyl gallate. 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. In various embodiments, the antioxidant is present in the composition at an amount of about 1 mg / mL to about 10 mg / mL or about 0.10 % w / w to about 1.00 % w / w.

[0088] In some embodiments, the pharmaceutical compositions described herein comprise a chelating agent. Exemplary chelating agents include 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, glycerin, sorbitol and pharmaceutically acceptable salts thereof. In various embodiments, the chelating agent is present in the composition at an amount of about 0.1 mg / mL to about 1 mg / mL.

[0089] In some embodiments, the pharmaceutical compositions described herein comprise a cosolvent. Exemplary cosolvents include disodium ethylenediaminetetraacetic acid (disodium EDTA), diethylenetriaminepentaacetic acid (DTPA), 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, glycerin, sorbitol and pharmaceutically acceptable salts thereof. In various embodiments, the cosolvent is present in the composition at an amount of about 0.1 mg / mL to about 1 mg / mL. In various embodiments, the cosolvent is present in the composition at an amount of about 100 mg / mL to about 200 mg / mL. In various embodiments, the cosolvent is present in the composition at an amount of about 150 mg / mL. In some embodiments, the cosolvent is glycerin.

[0090] In some embodiments, the pharmaceutical compositions described herein comprise a buffering agent. Exemplary buffering agents include, but are not limited to, benzoic acid, phosphoric acid, tartaric acids, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, hydrochloric acid, sulfuric acid, glutamic acid, and salts thereof. In a particular embodiment, the buffering agent comprises sodium benzoate and benzoic acid.

[0091] In some embodiments, the pharmaceutical compositions described herein comprise a preservative. Exemplary preservative include, but are not limited to, 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. In some embodiments, the preservative is selected from the group consisting of sodium benzoate and methyl paraben / propyl paraben. In various embodiments, the preservative is present in the composition at an amount of about 0.10 % w / w to about 1.00 % w / w.

[0092] In some embodiments, the pharmaceutical compositions described herein comprise 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). In various embodiments, the sweetener is present in the composition at an amount of about 0.10% w / w to about 5.00 % w / w. In some embodiments, the sweetener is present in the composition at an amount of about 5.00 % w / w to about 30.00 % w / w.

[0093] In some embodiments, the pharmaceutical compositions described herein comprise 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. In some embodiments, the flavor is selected from the group consisting of bubble gum flavor, menthol flavor, strawberry flavor, peppermint flavor, banana flavor, and lemon flavor. In various embodiments, the flavor is present in the composition at an amount of about 0.10 % w / w to about 1.00 % w / w.

[0094] In some embodiments, the pharmaceutical compositions described herein comprise a coloring agent. Exemplary coloring agents include, without limitation, natural and / or artificial compounds such as FD & C coloring agents, natural juice concentrates, pigments such as titanium oxide, silicon dioxide, and zinc oxide, combinations thereof, and the like.

[0095] In some embodiments, the pharmaceutical compositions described herein comprise an acidifier. In some embodiments, the acidifier is selected from the group consisting of citric acid monohydrate, lactic acid, ascorbic acid, and malic acid. In various embodiments, the acidifier is present in the composition at an amount of about 0.10 % w / w to about 3.00 % w / w.

[0096] The pH of the liquid formulation comprising the compound of Formula (I) described herein is in the range of about 3.0 to about 8.0. In some embodiments, the pH of the liquid formulation of milvexian described herein is the range of about 4.0 to about 6.0. In some embodiments, the pH of the liquid formulation of Milvexian described herein is the range of about 4.0 to about 5.0. In some embodiments, the pH of the liquid formulation of Milvexian described herein is the range of about 4.0 to about 4.5. In some embodiments, the pH of the liquid formulation of Milvexian described herein is about 4, about 4.1, about 4.2, about 4.3, about 4.4, or about 4.5.

[0097] The density of the liquid formulation comprising the compound of Formula (I) described herein may vary. In one embodiment, the density is between about 0.8 and about 1.8, such as, for example, between about 0.8 and about 1.0, about 1.0 and about 1.2, about 1.2 and about 1.4, about 1.4 and about 1.6, about 1.6 and about 1.8.

[0098] In one embodiment, the liquid compositions described herein are microemulsion.

[0099] In one embodiment, the liquid compositions described herein are oil-in-water microemulsion.

[0100] In certain embodiments, liquid microemulsion compositions described herein have certain poly dispersity index and globule or droplet sizes.

[0101] In some embodiments, the liquid microemulsion composition 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.

[0102] In an embodiment, the liquid microemulsion compositions described herein have poly dispersity index (PDI) within the range of 0.02 to 0.380. In some embodiments, the liquid microemulsion 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 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 compositions described herein have PDI less than 0.1. In some embodiments, the liquid microemulsion compositions described herein have PDI within the range of 0.05.

[0103] In another embodiment, the present invention relates to liquid pharmaceutical composition that is an oil-in-water microemulsion, comprising: (a) a compound of Formula (I); (b) a lipid phase comprising a lipid vehicle, one or more surfactant(s); and (c) an aqueous phase comprising one or more surfactant(s).

[0104] In another embodiment, the present invention relates to liquid pharmaceutical composition that is an oil-in-water microemulsion, comprising: (a) a compound of Formula (I); (b) a lipid phase comprising a lipid vehicle, one or more surfactant(s) and one or more co-surfactant(s); and (c) an aqueous phase comprising one or more surfactant(s) and one or more co-surfactant(s).

[0105] In yet another embodiment, the present invention relates to liquid pharmaceutical composition that is an oil-in-water microemulsion, comprising: (a) a compound of Formula (I); (b) a lipid phase comprising a lipid vehicle, one or more surfactant(s) and one or more co- surfactan^s); and (c) an aqueous phase comprising one or more surfactant(s) and one or more co-surfactant(s), wherein the size distribution of particles in the resulting microemulsion is less than 30 nm.

[0106] In yet another embodiment, the present invention relates to liquid pharmaceutical composition that is an oil-in-water microemulsion, comprising: (a) a compound of Formula (I); (b) a lipid phase comprising a lipid vehicle, one or more surfactant(s) and one or more cosurfactants); and (c) an aqueous phase comprising one or more surfactant(s) and one or more co-surfactant(s), wherein the size distribution of particles in the resulting microemulsion is 15 nm ± 10 nm.

[0107] In yet another embodiment, the present invention relates to liquid pharmaceutical composition that is an oil-in-water microemulsion, comprising: (a) a compound of Formula (I); (b) a lipid phase comprising a lipid vehicle, one or more surfactant s) and one or more cosurfactants); and (c) an aqueous phase comprising one or more surfactant(s) and one or more co-surfactant(s), wherein the microemulsion has a poly dispersity index (PDI) within the range of 0.02 to 0.380.

[0108] In yet another embodiment, the present invention relates to liquid pharmaceutical composition that is an oil-in-water microemulsion, comprising: (a) a compound of Formula (I); (b) a lipid phase comprising a lipid vehicle, one or more surfactant s) and one or more cosurfactants); and (c) an aqueous phase comprising one or more surfactant(s) and one or more co-surfactant(s), wherein the microemulsion has a poly dispersity index (PDI) within the range of 0.02 to 0.15.

[0109] In yet another embodiment, the present invention relates to liquid pharmaceutical composition that is an oil-in-water microemulsion, comprising: (a) a compound of Formula (I); (b) a lipid phase comprising a lipid vehicle, one or more surfactant s) and one or more cosurfactants); and (c) an aqueous phase comprising one or more surfactant(s) and one or more co-surfactant(s), wherein the microemulsion has a poly dispersity index (PDI) less than 0.1.

[0110] In yet another embodiment, the present invention relates to liquid pharmaceutical composition that is an oil-in-water microemulsion, comprising: (a) a compound of Formula (I);(b) a lipid phase comprising a lipid vehicle, one or more surfactant(s) and one or more co- surfactan^s); and (c) an aqueous phase comprising one or more surfactant(s) and one or more co-surfactant(s), wherein the microemulsion has a poly dispersity index (PDI) of 0.05.[oni] In one embodiment, the surfactant(s) and co-surfactant(s) all can be the same, so that the resulting microemulsion contains a single surfactant. In another embodiment, both the lipid phase and aqueous phase can contain the same surfactant and co-surfactant so that the resulting microemulsion has one surfactant and one co-surfactant. In another embodiment, two or three of the surfactants and co- surfactants can be the same in the lipid phase and aqueous phase, so that the resulting microemulsion contains two or three different surfactants, or all can be different, so the resulting microemulsion contains four different surfactants. In another embodiment, the microemulsions can contain more than one surfactants and one co- surfactants in either phase. In another embodiment, the microemulsions can contain more than two surfactants and co-surfactants in either phase.

[0112] In some embodiments, liquid microemulsion composition described herein release about 98% of the compound of Formula I in about 30 minutes. In other embodiments, liquid microemulsion described herein release at least 95% of the compound of Formula I in about 30 minutes.

[0113] In a particular embodiment, the present invention provides a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) PEG400; (c) MAISINE CC; (d) LABRASOL ALF; (d) KOLLIPHOR RH40; (e) water in an amount of less than about 5% w / w; and (f) optionally, one or more other pharmaceutically acceptable excipients. In a particular embodiment, the present invention provides a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 5 mg / mL; (b) PEG400; (c) MAISINE CC; (d) LABRASOL ALF; (d) KOLLIPHOR RH40; (e) water in an amount of less than about 5% w / w; and (f) optionally, one or more other pharmaceutically acceptable excipients. In a particular embodiment, the present invention provides a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 5 mg / mL; (b) PEG400 in an amount of about 20% w / w;(c) MAISINE CC in an amount of about 20% w / w; (d) LABRASOL ALF in an amount of about 20% w / w; (d) KOLLIPHOR RH40 in an amount of about 37% w / w; (e) water in anamount of about 2.5% w / w; and (f) optionally, one or more other pharmaceutically acceptable excipients.

[0114] In a particular embodiment, the present invention provides a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) LABRASOL ALF; (c) KOLLIPHOR RH40; (d) water in an amount of about 20% w / w; and (e) optionally, one or more other pharmaceutically acceptable excipients. In a particular embodiment, the present invention provides a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 5 mg / mL; (b) LABRASOL ALF; (c) KOLLIPHOR RH40; (d) water in an amount of about 20% w / w; and (e) optionally, one or more other pharmaceutically acceptable excipients. In a particular embodiment, the present invention provides a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 5 mg / mL; (b) LABRASOL ALF in an amount of about 50% w / w; (c) KOLLIPHOR RH40 in an amount of about 30% w / w; (d) water in an amount of about 20% w / w; and (e) optionally, one or more other pharmaceutically acceptable excipients.

[0115] In a particular embodiment, the present invention provides a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) LABRASOL ALF; (c) KOLLIPHOR RH40; (d) water in an amount of about 20% w / w; and (e) optionally, one or more other pharmaceutically acceptable excipients. In a particular embodiment, the present invention provides a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 5 mg / mL; (b) LABRASOL ALF; (c) KOLLIPHOR RH40; and (d) optionally, one or more other pharmaceutically acceptable excipients. In a particular embodiment, the present invention provides a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 5 mg / mL; (b) LABRASOL ALF in an amount of about 60% w / w; (c) KOLLIPHOR RH40 in an amount of about 40% w / w; and (d) optionally, one or more other pharmaceutically acceptable excipients.

[0116] In a particular embodiment, the present invention provides a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) LABRASOL ALF; (c) KOLLIPHOR RH40; (d) Neosorb 70 / 70 B; (e) Bubble gum flavor; (f) menthol flavor; (g) propyl gallate; (h) citric acid mono; and (i) sodium benzoate; and (j) optionally, one or more other pharmaceutically acceptable excipients. In a particular embodiment, the present invention provides a liquid pharmaceutical compositioncomprising (a) a compound of Formula (I) at a concentration of about 5 mg / mL; (b) LABRASOL ALF; (c) KOLLIPHOR RH40; (d) NEOSORB 70 / 70 B; (e) Bubble gum flavor; (f) menthol flavor; (g) propyl gallate; (h) citric acid mono; and (i) sodium benzoate; and (j) optionally, one or more other pharmaceutically acceptable excipients. In a particular embodiment, the present invention provides a liquid pharmaceutical composition comprising(a) a compound of Formula (I) at a concentration of about 5 mg / mL; (b) LABRASOL ALF in an amount of about 50% w / w; (c) KOLLIPHOR RH40 in an amount of about 30% w / w; (d) NEOSORB 70 / 70 B in an amount of about 19% w / w; (e) Bubble gum flavor in an amount of about 0.2% w / w; (f) menthol flavor in an amount of about 0.1% w / w; (g) propyl gallate in an amount of aobut 0.1% w / w; (h) citric acid mono in an amount of about 0.5% w / w; and (i) sodium benzoate in an amount of about 0.1% w / w; and (j) optionally, one or more other pharmaceutically acceptable excipients.

[0117] In a particular embodiment, the present invention provides a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) LABRASOL ALF; (c) GELUCIRE 48 / 16; (d) 0527441 Bubble gum flavor; (e) menthol oil; (f) propyl gallate; (g) citric acid monohydrate; (h) sodium benzoate; (i) sucralose; and (j) water; and (k) optionally, one or more other pharmaceutically acceptable excipients. In a particular embodiment, the present invention provides a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 5 mg / mL;(b) LABRASOL ALF; (c) GELUCIRE 48 / 16; (d) 0527441 Bubble gum flavor; (e) menthol oil; (f) propyl gallate; (g) citric acid monohydrate; (h) sodium benzoate; (i) sucralose; and (j) water; and (k) optionally, one or more other pharmaceutically acceptable excipients. In a particular embodiment, the present invention provides a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 5 mg / mL; (b) LABRASOL ALF in an amount of about 50% w / w; (c) GELUCIRE 48 / 16 in an amount of about 30% w / w; (d) 0527441 Bubble gum flavor in an amount of about 0.2% w / w; (e) menthol oil in an amount of about 0.1% w / w; (f) propyl gallate in an amount of about 0.1% w / w; (g) citric acid monohydrate in an amount of about 0.8% w / w; (h) sodium benzoate in an amount of about 0.1% w / w; (i) sucralose in an amount of about 0.2% w / w; and (j) water in an amount of about 18.5% w / w; and (k) optionally, one or more other pharmaceutically acceptable excipients.

[0118] In a particular embodiment, the present invention provides a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mLto about 10 mg / mL; (b) LABRASOL ALF; (c) KOLLIPHOR RH40; (d) propyl gallate; and (e) optionally, one or more other pharmaceutically acceptable excipients. In a particular embodiment, the present invention provides a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 5 mg / mL; (b) LABRASOL ALF; (c) KOLLIPHOR RH40; (d) propyl gallate; and (e) optionally, one or more other pharmaceutically acceptable excipients. In a particular embodiment, the present invention provides a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 5 mg / mL; (b) LABRASOL ALF in an amount of about 60% w / w; (c) KOLLIPHOR RH40 in an amount of about 39% w / w; (d) propyl gallate in an amount of about 0.1% w / w; and (e) optionally, one or more other pharmaceutically acceptable excipients.

[0119] In a particular embodiment, the present invention provides a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) LABRASOL ALF; (c) KOLLIPHOR RH40; (d) glycerin; (e) sucralose; (f) bubblegum flavor; (g) menthol flavor (h) propyl gallate; (i) citric acid monohydrate; (j) sodium benzoate; and (k) optionally, one or more other pharmaceutically acceptable excipients. In a particular embodiment, the present invention provides a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 5 mg / mL; (b) LABRASOL ALF; (c) KOLLIPHOR RH40; (d) propyl gallate; and (e) optionally, one or more other pharmaceutically acceptable excipients. In a particular embodiment, the present invention provides a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 5 mg / mL; (b) LABRASOL ALF in an amount of about 43% w / w; (c) KOLLIPHOR RH40 in an amount of about 20% w / w; (d) propyl gallate in an amount of about 0.1% w / w; and (e) optionally, one or more other pharmaceutically acceptable excipients.

[0120] In a particular embodiment, the present invention provides a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) LABRASOL ALF; (c) KOLLIPHOR RH40; (d) glycerin; (e) sucralose; (h) propyl gallate; (i) citric acid monohydrate; (j) sodium benzoate; and (k) optionally, one or more other pharmaceutically acceptable excipients.

[0121] In a particular embodiment, the present invention provides a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) LABRASOL ALF; (c) KOLLIPHOR RH40; (d) glycerin; (e) propylgallate; (e) citric acid monohydrate; (g) sodium benzoate; and (h) optionally, one or more other pharmaceutically acceptable excipients.

[0122] In a particular embodiment, the present invention provides a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) LABRASOL ALF; (c) KOLLIPHORRH40; (d) glycerin; (e) sucralose; (f) propyl gallate; (g) sodium benzoate; and (h) optionally, one or more other pharmaceutically acceptable excipients.

[0123] In a particular embodiment, the present invention provides a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) LABRASOL ALF; (c) KOLLIPHORRH40; (d) glycerin; (e) sucralose; (f) propyl gallate; and (g) optionally, one or more other pharmaceutically acceptable excipients.

[0124] In a particular embodiment, the present invention provides a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at a concentration of about 1 mg / mL to about 10 mg / mL; (b) LABRASOL ALF; and (c) KOLLIPHOR RH40. The composition further comprises a co-solvent, such as glycerin, at a concentration of about 50 mg / mL to about 250 mg / mL, about 100 mg / mL to about 200 mg / mL or about 150 mg / mL. The composition further comprising a sweetener, such as sucralose, at a concentration of about 2 mg / mL to about 20 mg / mL, about 5 mg / mL to about 15 mg / mL or about 10 mg / mL. The composition further comprising one or more flavoring agents, such as bubblegum and menthol flavors, at a concentration each of about 1 mg / mL to about 5 mg / mL, about 1 mg / mL to about 8 mg / mL, or about 3 mg / mL, or about 5 mg / mL. The composition further comprising an antioxidant, such as propyl gallate, at a concentration of 0.5 mg / mL to about 2 mg / mL, about 0.1 mg / mL to about 5 mg / mL, or about 1 mg / mL. The composition further comprising an acidifier, such as citric acid monohydrate, at a concentration of about 3 mg / mL to about 10 mg / mL, about 2 mg / mL to about 12 mg / mL, or about 6 mg / mL. The composition further comprising a preservative, such as sodium benzoate, at a concentration of about 0.5 mg / mL to about 2 mg / mL, about 0.1 mg / mL to about 5 mg / mL, or about 1 mg / mL. The composition further comprising water, such as purified water, at a concentration of about 150 mg / mL to 200 mg / mL or about 189 mg / mL.

[0125] In a particular embodiment, the present invention provides a liquid pharmaceutical composition comprising (a) a compound of Formula (I) at about 0.3 % w / w to about 0.7 % w / w; (b) LABRASOL ALF; and (c) KOLLIPHOR RH40. The composition further comprises a cosolvent, such as glycerin, at about 10 % w / w to about 20 % w / w, about 13 % w / w to about18 % w / w or about 15 % w / w. The composition further comprising a sweetener, such as sucralose, at about 0.1 % w / w to about 2 % w / w, about 0.5 % w / w to about 1.5 % w / w or about 1 % w / w. The composition further comprising one or more flavoring agents, such as bubblegum and menthol flavors, each of about 0.1 % w / w to about 1 % w / w, about 0.1 % w / w to about .08 % w / w, or about 0.3 % w / w, or about 0.5 % w / w. The composition further comprising an antioxidant, such as propyl gallate, at about 0.1 % w / w to about 2 % w / w, about 0.5 % w / w to about 1.5 % w / w or about 1 % w / w. The composition further comprising an acidifier, such as citric acid monohydrate, at about 0.3 % w / w to about 1 % w / w, about 0.2 % w / w to about 1.2 % w / w, or about 0.6 % w / w. The composition further comprising a preservative, such as sodium benzoate, at about 0.05 % w / w to about 0.5 % w / w, about 0.05 % w / w to about 0.3 % w / w, or about 0.1 % w / w. The composition further comprising water, such as purified water, at about 15 % w / w to 20 % w / w or about 18.9 % w / w. Formulations described herein can have less than 20 % w / w of water, less than 19 % w / w of water, less than 18 % w / w of water, less than 17 % w / w of water, less than 15 % w / w of water, or about 16 % w / w to about 19 % w / w of water, about 15 % w / w to about 20 % w / w of water, about 16 % w / w to about 19 % w / w of water, about 17 % w / w to about 20 % w / w of water, about 17 % w / w to about 19 % w / w of water, or about 18 % w / w to about 19 % w / w of water.

[0126] In certain embodiments, the liquid pharmaceutical composition comprises milvexian, the lipid vehicles Labrasol® ALF (Caprylocaproyl Polyoxyl-8 glycerides) and Kolliphor RH 40 (Polyoxyl 40 Hydrogenated Castor Oil), and further comprises glycerin, sucralose, bubblegum flavor, menthol flavor, propyl gallate, citric acid monohydrate, sodium benzoate, and purified water.

[0127] The liquid compositions of the present invention do not exhibit substantial milvexian degradation when exposed to certain study conditions. Stability may be measured by any suitable method, e.g., by high-performance liquid chromatography (HPLC). In a particular embodiment, the liquid compositions of the present invention do not exhibit substantial milvexian degradation under hydrolytic conditions, oxidative conditions, photolytic conditions, thermal conditions or combinations thereof. In another particular embodiment, the liquid compositions of the present invention do not exhibit substantial milvexian degradation under forced stability conditions, accelerated stability conditions, real-time stability conditions or a combination thereof.

[0128] In some embodiments, the liquid compositions disclosed herein do not exhibit substantial degradation under accelerated conditions (e.g. 40° C. and 75% relative humidity) for at least 3 months, at least 4 months, at least 6 months, or at least 6 months.

[0129] In one embodiment, the liquid 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.

[0130] In some embodiments, the liquid composition disclosed herein do not exhibit substantial degradation under room temperature conditions (e.g. 25° C. and 60% 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.

[0131] In some embodiments, the liquid composition exhibits about 5% or less degradation of the compound of Formula (I) over at least a three 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.

[0132] Methods of measuring Compound 1 degradation are known to a person of skill in the art, e.g., monitoring the amount of milvexian in the liquid composition by HPLC over a period of time. An exemplary method is provided in Example 1.

[0133] In some particular embodiments, the liquid compositions of the present invention do not exhibit substantial milvexian degradation when exposed to the normal light.

[0134] The descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans.III. Method of Use and Treatment

[0135] In one aspect, provided herein are methods of treating thromboembolic disorders such as stroke, myocardial infarction, deep venous thrombosis. In various embodiments, provided herein is a method of treating a thromboembolic disorder in a subject in need thereof, comprising administering to the subject a composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof. In certain embodiments, the composition is a liquid oral solution.III. Definitions

[0136] To facilitate an understanding of the present disclosure, a number of terms and phrases are defined below.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] 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.

[0142] The term “and / or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

[0143] 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.

[0144] The use of the term “comprise,” “comprises,” “comprising,” “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and nonlimiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context.

[0145] 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.

[0146] 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.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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 active pharmaceutical substance, such as their reaction with excipients or on contact with the packaging material.

[0152] As used herein, the term “non-aqueous” refers to compositions containing substantially no water, i.e. less than 1% by volume. In a particular embodiment, the nonaqueous liquid compositions of the present invention contain less than 0.5% by volume.

[0153] As used herein, the term “microemulsion” refers to a two-phase systems composed of a lipid phase and an aqueous phase, finely interspersed. Microemulsions are liquid mixtures, transparent, isotropic and stable, of a lipid phase and an aqueous phase, held together by a surfactant, generally in conjunction with a co-surfactant. Microemulsions are clear, thermodynamically stable, isotropic liquid mixtures of oil, water and surfactant, and optionally a co-surfactant.

[0154] “Pharmaceutically acceptable” refers to compounds, molecular entities, compositions, materials and / or dosage forms that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate, and / or that are approved or approvable by a regulatory agency of the federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.EXAMPLES

[0155] 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

[0156] 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; “MeOH” refers to methanol; “PEG” refers to polyethylene glycol; “PVDF” refers to polyvinylidene fluoride; “RH” refers to relative humidity; and “TPGS” refers to d -a-Tocopheryl polyethylene glycol 1000 succinate.Example 1. Analytical Methods for Formulations with Compound 1

[0157] Chromatographic conditions:

[0158] Preparation of Standard solution: Milvexian standard solution at 0.5 mg / mL concentration in diluent.

[0159] Preparation of test solution: 0.5 mg / mL concentration test solution in diluent with the help of vortex and sonication. Filter the test solution through 0.45 pm PVDF filter.Example 2. Preparation and Stability Results of Liquid Pharmaceutical Compositions

[0160] General method of preparation: (1) Mix co-solvent / lipid vehicle; (2) add surfactant / co-surf actant and mix well; (3) add Compound 1 and mix well to get clear solution; and (4) add other additives and purified water.

[0161] Table 1 and Table 2 describe the composition of liquid pharmaceutical compositions, Formulations 1-7.Table 1. Liquid Pharmaceutical Compositions of Compound 1 (Formulations 1-3)Table 2. Liquid Pharmaceutical Compositions of Compound 1 (Formulation 4-7)

[0162] General method for stability study: place each formulation in 100 mL glass bottles, and store in the following conditions: (1) 40°C ± 2°C / 75% RH ± 5% RH) for 1, 2, 3 & 6 months, (2) 25°C ± 2°C / 60% RH ± 5% RH for 1, 2, 3 & 6 months. Degradation was measured using the HPLC analysis as described in Example 1.

[0163] Table 3 and Table 4 describe the stability and degradation data of liquid pharmaceutical compositions, Formulations 1-7.Table 3. Stability and Degradation data of Formulations 1-3Table 4. Stability and Degradation data of Formulations 4-7

[0164] As shown in the above Table 3 and Table 4, the “% Assay” provides the % amount of Compound 1 in the composition.

[0165] General method for freeze-thaw test and photostability study of Formulation 7:Milvexian Formulation 7 sample vial was exposed to the light with an illumination of about 1.2 million lux hours and near ultraviolet energy of about 400 watt hours / square meter by using ATLAS Material Testing solution (FR660) instrument and the amount of Compound I was measured using the HPLC chromatographic conditions described in Example 1. Milvexian Formulation 7 sample vial was taken and stored in the refrigerator for 28 hours and the HPLC analysis was conducted following the chromatographic conditions described in Example 1.

[0166] Table 5 describes the stability data of liquid pharmaceutical compositions, Formulations 7 under stress conditions.Table 5. Stability Data of Formulation 7 under Stress Conditions.

[0167] As shown in the above Table 5, the “% Assay” provides the % amount of Compound 1 in the composition.Example 3. Characterization of Impurities of Liquid Pharmaceutical Composition of Formulation 7

[0168] General method of the characterization of impurities in Formulation 7:Diluent Preparation: Mix Acetonitrile and water in the ratio of 800:200 v / v.Buffer Preparation: Dissolve 1.36 g of Potassium hydrogen phosphate into 1000 mL of Water and adjust pH to 6.2 with dilute KOH solution.Mobile Phase preparation: Mobile Phase A preparation: Mix buffer and acetonitrile in the ratio of 900: 100 v / v and degas it. Mobile Phase B preparation: Mix Acetonitrile and buffer in the ratio of 700:300 v / v and degas it.Preparation of standard solution: Transfer about 4 mg of Milvexian into 10 mL volumetric flask and add about 6 mL of diluent. Dissolve it and dilute to volume with diluent.Preparation of test solution: Transfer test sample equivalent to 8 mg of Milvexian into 20 mL volumetric flask, add about 15 mL of diluent and vortex it for 5 minutes followed by sonication for 30 minutes with intermittent shaking. Dilute to volume with diluent and filter it through 0.45pm PVDF filter. The HPLC analysis was conducted following the chromatographic conditions described in Example 1.

[0169] Table 6 describes the impurities of liquid pharmaceutical compositions Formulation 7) under different conditions.Table 6. Impurities Profile of Liquid Pharmaceutical Compositions, Formulation 7.Example 4: Dilution Studies of Formulation 7 over All Physiological pH

[0170] General method for dilution study over all physiological pH: Place 1.0 mL of Formulation 7 in the 50 mL of media and record visual observations.

[0171] Table 7 describes the impacts of dilution on the liquid pharmaceutical composition, Formulation 7.Table 7. Dilution Data of Formulation 7 over all Physiological pHExample 5: Determination of Polydispersity index (PDI) and droplet Size of Microemulsions from Aqueous Dilution

[0172] 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 (Formulation 7) 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.

[0173] Figure 1 describes the PDI and droplet size of the microemulsion of Formulation.Example 6: Comparative Dissolution Profile of Milvexian 5mg / mL Microemulsion and 25mg IR Tablet

[0174] General method for comparing dissolution profile:(1) Both milvexian microemulsion 5mg / mL (lOmL) and IR tablet 25mg (2 tablets) 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 15min and 30 min for microemulsion) and % dissolution was measured.

[0175] Figure 2 describes the dissolution profile of Milvexian 5mg / mL Microemulsion, and 25mg IR tablet.

Claims

CLAIMSWhat is claimed:

1. A liquid pharmaceutical composition comprising a lipid vehicle, water, and a compound of Formula (I), wherein said compound of Formula I is represented by:

2. The liquid pharmaceutical composition of claim 1, wherein the water is present in the liquid pharmaceutical composition at about 20 % w / w or less.

3. The liquid pharmaceutical composition of claim 1, wherein the water is present in the liquid pharmaceutical composition at about 15 % w / w or less.

4. The liquid pharmaceutical composition of claim 1, where the lipid vehicle is selected from the group consisting of Labrasol® ALF (Capryl ocaproyl Polyoxyl-8 glycerides), Gelucire 48 / 16 (Polyoxyl-32 stearate (type I) NF), Kolliphor RH 40 (Polyoxyl 40 Hydrogenated Castor Oil), Kollisolv® MCT 70* (Medium-chain triglycerides), Kolliphor® EL, Maisine® CC, Labrafac™ lipophile WL 1349, and MIGLYOL® 812N.

5. The liquid pharmaceutical composition of claim 1, where the lipid vehicle is a combination of two lipid vehicles selected from the group consisting of Labrasol® ALF (Caprylocaproyl Polyoxyl-8 glycerides), Gelucire 48 / 16 (Polyoxyl-32 stearate (type I) NF), Kolliphor RH 40 (Polyoxyl 40 Hydrogenated Castor Oil), Kollisolv® MCT 70* (Medium-chaintriglycerides), Kolliphor® EL, Maisine® CC, Labrafac™ lipophile WL 1349, and MIGLYOL® 812N.

6. The liquid pharmaceutical composition of claim 1, where the lipid vehicle is a combination of three or more lipid vehicles selected from the group consisting of Labrasol® ALF (Capryl ocaproyl Polyoxyl-8 glycerides), Gelucire 48 / 16 (Polyoxyl-32 stearate (type I) NF), Kolliphor RH 40 (Polyoxyl 40 Hydrogenated Castor Oil), Kollisolv® MCT 70*(Medium- chain triglycerides), Kolliphor® EL, Maisine® CC, Labrafac™ lipophile WL 1349, and MIGLYOL® 812N.

7. The liquid pharmaceutical composition of claim 1 comprising at least two lipid vehicles selected from the group consisting of Labrasol® ALF (Caprylocaproyl Polyoxyl-8 glycerides), Gelucire 48 / 16 (Polyoxyl-32 stearate (type I) NF), Kolliphor RH 40 (Polyoxyl 40 Hydrogenated Castor Oil), Kollisolv® MCT 70*(Medium-chain triglycerides), Kolliphor® EL, Maisine® CC, Labrafac™ lipophile WL 1349, and MIGLYOL® 812N.

8. The liquid pharmaceutical composition of claim 1 comprising two lipid vehicles selected from the group consisting of Labrasol® ALF (Caprylocaproyl Polyoxyl-8 glycerides), Gelucire 48 / 16 (Polyoxyl-32 stearate (type I) NF), Kolliphor RH 40 (Polyoxyl 40 Hydrogenated Castor Oil), Kollisolv® MCT 70*(Medium-chain triglycerides), Kolliphor® EL, Maisine® CC, Labrafac™ lipophile WL 1349, and MIGLYOL® 812N.

9. The liquid pharmaceutical composition of claim 8, wherein the lipid vehicles are Labrasol® ALF (Caprylocaproyl Polyoxyl-8 glycerides) and Kolliphor RH 40 (Polyoxyl 40 Hydrogenated Castor Oil).

10. The liquid pharmaceutical composition of claim 9, wherein Labrasol® ALF (Caprylocaproyl Polyoxyl-8 glycerides) has a concentration of about 150 mg / mL to about 600 mg / mL and Kolliphor RH 40 (Polyoxyl 40 Hydrogenated Castor Oil) has a concentration of about 80 mg / mL to about 350 mg / mL.

11. The liquid pharmaceutical composition of claim 9, wherein Labrasol® ALF (Caprylocaproyl Polyoxyl-8 glycerides) has a concentration of about 250 mg / mL to about 500 mg / mL and Kolliphor RH 40 (Polyoxyl 40 Hydrogenated Castor Oil) has a concentration of about 150 mg / mL to about 250 mg / mL.

12. The liquid pharmaceutical composition of claim 9, wherein Labrasol® ALF (Caprylocaproyl Polyoxyl-8 glycerides) has a concentration of about 400 mg / mL to about 460mg / mL and Kolliphor RH 40 (Polyoxyl 40 Hydrogenated Castor Oil) has a concentration of about 170 mg / mL to about 230 mg / mL.

13. The liquid pharmaceutical composition of claim 9, wherein Labrasol® ALF (Caprylocaproyl Polyoxyl-8 glycerides) has a concentration of about 430 mg / mL and Kolliphor RH 40 (Polyoxyl 40 Hydrogenated Castor Oil) has a concentration of about 2000 mg / mL.

14. The liquid pharmaceutical composition of claim 1, wherein the compound of Formula I has a concentration of about 0.05 mg / mL to about 10 mg / mL.

15. The liquid pharmaceutical composition of claim 1, wherein the compound of Formula I has a concentration of about 2 mg / mL to about 8 mg / mL.

16. The liquid pharmaceutical composition of claim 1, wherein the compound of Formula I has a concentration of about 3 mg / mL to about 7 mg / mL.

17. The liquid pharmaceutical composition of claim 1, wherein the compound of Formula I has a concentration of about 5 mg / mL.

18. The liquid pharmaceutical composition of claim 1, further comprising a surfactant.

19. The liquid pharmaceutical composition of claim 1, further comprising a cosolvent.

20. The liquid pharmaceutical composition of claim 1, further comprising a cosolvent, wherein the cosolvent is glycerin.

21. The liquid pharmaceutical composition of claim 1, further comprising a sweetener.

22. The liquid pharmaceutical composition of claim 21, wherein the sweetener is sucralose.

23. The liquid pharmaceutical composition of claim 1, further comprising at least one flavoring agent.

24. The liquid pharmaceutical composition of claim 23, wherein the flavoring agents are bubblegum flavor and menthol flavor.

25. The liquid pharmaceutical composition of claim 1, further comprising an antioxidant.

26. The liquid pharmaceutical composition of claim 25, wherein the antioxidant is propyl gallate.

27. The liquid pharmaceutical composition of claim 1, further comprising an acidifier.

28. The liquid pharmaceutical composition of claim 27, wherein the acidifier is citric acid monohydrate.

29. The liquid pharmaceutical composition of claim 1, further comprising a preservative.

30. The liquid pharmaceutical composition of claim 29, wherein the preservative is sodium benzoate.

31. The liquid pharmaceutical composition of claim 1, wherein the composition is stable for 3 months.

32. The liquid pharmaceutical composition of claim 1, wherein the composition is stable for 6 months.

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

34. The liquid pharmaceutical composition of claim 1, wherein at least 95% of the compound of Formula I is released in about 30 minutes.

35. The liquid pharmaceutical composition of claim 1, wherein the composition exhibits about 5% or less degradation of the compound of Formula (I).

36. A liquid pharmaceutical composition comprising: a) a lipid vehicle comprising Labrasol® ALF (Capryl ocaproyl Polyoxyl-8 glycerides) and RH 40 (Polyoxyl 40 Hydrogenated Castor Oil), b) water, and c) a compound of Formula (I), wherein said compound of Formula I is represented by:

37. The liquid pharmaceutical composition of claim 36, wherein the water is present in the liquid pharmaceutical composition at about 20 % w / w or less.

38. The liquid pharmaceutical composition of claim 36, wherein the water is present in the liquid pharmaceutical composition at about 15 % w / w or less.

39. The liquid pharmaceutical composition of claim 36, further comprising a cosolvent.

40. The liquid pharmaceutical composition of claim 39, wherein the cosolvent is glycerin.

41. The liquid pharmaceutical composition of claim 36, further comprising a cosolvent.

42. The liquid pharmaceutical composition of claim 36, wherein Labrasol® ALF (Caprylocaproyl Polyoxyl-8 glycerides) has a concentration of about 150 mg / mL to about 600 mg / mL and Kolliphor RH 40 (Polyoxyl 40 Hydrogenated Castor Oil) has a concentration of about 80 mg / mL to about 350 mg / mL.

43. The liquid pharmaceutical composition of claim 36, wherein Labrasol® ALF (Caprylocaproyl Polyoxyl-8 glycerides) has a concentration of about 250 mg / mL to about 500 mg / mL and Kolliphor RH 40 (Polyoxyl 40 Hydrogenated Castor Oil) has a concentration of about 150 mg / mL to about 250 mg / mL.

44. The liquid pharmaceutical composition of claim 36, wherein Labrasol® ALF (Caprylocaproyl Polyoxyl-8 glycerides) has a concentration of about 400 mg / mL to about 460 mg / mL and Kolliphor RH 40 (Polyoxyl 40 Hydrogenated Castor Oil) has a concentration of about 170 mg / mL to about 230 mg / mL.

45. The liquid pharmaceutical composition of claim 36, wherein Labrasol® ALF (Caprylocaproyl Polyoxyl-8 glycerides) has a concentration of about 430 mg / mL and Kolliphor RH 40 (Polyoxyl 40 Hydrogenated Castor Oil) has a concentration of about 2000 mg / mL.

46. The liquid pharmaceutical composition of claim 40, wherein glycerin has a concentration of about 100 mg / mL to about 200 mg / mL.

47. The liquid pharmaceutical composition of claim 40, wherein glycerin has a concentration of about 150 mg / mL.

48. The liquid pharmaceutical composition of claim 36, further comprising a sweetener.

49. The liquid pharmaceutical composition of claim 48, wherein the sweetener is sucralose.

50. The liquid pharmaceutical composition of claim 49, wherein sucralose has a concentration of about 5 mg / mL to about 15 mg / mL, or about 10 mg / mL.

51. The liquid pharmaceutical composition of claim 36, further comprising at least one flavoring agent.

52. The liquid pharmaceutical composition of claim 51, wherein the flavoring agents are bubblegum flavor and menthol flavor, and each has a concentration of about 1 mg / mL to about 5 mg / mL.

53. The liquid pharmaceutical composition of claim 36, further comprising an antioxidant.

54. The liquid pharmaceutical composition of claim 53 wherein the antioxidant is propyl gallate, and propyl gallate has a concentration of about 0.5 mg / mL to about 2 mg / mL, or about 1 mg / mL.

55. The liquid pharmaceutical composition of claim 36, further comprising an acidifier.

56. The liquid pharmaceutical composition of claim 55, wherein the acidifier is citric acid monohydrate, and citric acid monohydrate has a concentration of about 3 mg / mL to about 10 mg / mL, or about 6 mg / mL.

57. The liquid pharmaceutical composition of claim 36, further comprising a preservative.

58. The liquid pharmaceutical composition of claim 57, wherein the preservative is sodium benzoate, and sodium benzoate has a concentration of about 0.5 mg / mL to about 2 mg / mL, or about 1 mg / mL.

59. The liquid pharmaceutical composition of claim 36, wherein the composition is stable for 1 months.

60. The liquid pharmaceutical composition of claim 36, wherein the composition is stable for 3 months.

61. The liquid pharmaceutical composition of claim 36, wherein the composition is stable for 6 months.

62. The liquid pharmaceutical composition of claim 36, wherein about 98% of the compound of Formula I is released in about 30 minutes.

63. The liquid pharmaceutical composition of claim 36, wherein at least 95% of the compound of Formula I is released in about 30 minutes.

64. The liquid pharmaceutical composition of claim 36, wherein the composition exhibits about 5% or less degradation of the compound of Formula (I).

65. The liquid pharmaceutical composition of claim 1, wherein the composition is a microemulsion.

66. The liquid pharmaceutical composition of claim 36, wherein the composition is a microemulsion.

67. The liquid pharmaceutical composition of claim 65, wherein the composition comprises droplets with a droplet size of less than 30 nm.

68. The liquid pharmaceutical composition of claim 65, wherein the composition comprises droplets with a droplet size of about 15 nm ± 10 nm.

69. The liquid pharmaceutical composition of claim 65, wherein the composition comprises droplets with a droplet size of about 12 nm.

70. The liquid pharmaceutical composition of claim 65, wherein the composition comprises droplets with a droplet size of about 11.81.

71. The liquid pharmaceutical composition of claim 66, wherein the composition comprises droplets with a droplet size of less than 30 nm.

72. The liquid pharmaceutical composition of claim 66, wherein the composition comprises droplets with a droplet size of about 15 nm ± 10 nm.

73. The liquid pharmaceutical composition of claim 66, wherein the composition comprises droplets with a droplet size of about 12 nm.

74. The liquid pharmaceutical composition of claim 66, wherein the composition comprises droplets with a droplet size of about 11.81.

75. A liquid pharmaceutical composition that is an oil-in-water microemulsion, comprising: a) a lipid phase comprising a lipid vehicle, one or more surfactant(s); b) an aqueous phase comprising one or more surfactant(s); and c) a compound of Formula (I), wherein said compound of Formula I is represented by:wherein the size distribution of particles in the resulting microemulsion is less than 30 nm.

76. The liquid pharmaceutical composition of claim 75, where in the lipid vehicle is Labrasol® ALF (Capryl ocaproyl Polyoxyl-8 glycerides).

77. The liquid pharmaceutical composition of claim 75, where in the surfactant is Kolliphor RH 40 (Polyoxyl 40 Hydrogenated Castor Oil).

78. The liquid pharmaceutical composition of claim 75, where in a surfactant in the lipid phase and the aqueous phase is the same.

79. The liquid pharmaceutical composition of claim 75, further comprising a cosolvent.

80. The liquid pharmaceutical composition of claim 79, wherein the cosolvent is glycerin.

81. The liquid pharmaceutical composition of claim 75, wherein the size distribution of particles in the resulting microemulsion of about 15 nm ± 10 nm.

82. The liquid pharmaceutical composition of claim 75, wherein the size distribution of particles in the resulting microemulsion of about 11.8 nm.

83. A liquid pharmaceutical composition that is an oil-in-water microemulsion, comprising: a) a lipid phase comprising a lipid vehicle, one or more surfactant(s); b) an aqueous phase comprising one or more surfactant(s); and c) a compound of Formula (I), wherein said compound of Formula I is represented by:wherein the microemulsion has a poly dispersity index (PDI) within the range of 0.02 to 0.380.

84. The liquid pharmaceutical composition of claim 83, where in the lipid vehicle is Labrasol® ALF (Capryl ocaproyl Polyoxyl-8 glycerides).

85. The liquid pharmaceutical composition of claim 83, where in the surfactant is Kolliphor RH 40 (Polyoxyl 40 Hydrogenated Castor Oil).

86. The liquid pharmaceutical composition of claim 83, where in a surfactant in the lipid phase and the aqueous phase is the same.

87. The liquid pharmaceutical composition of claim 83, further comprising a cosolvent.

88. The liquid pharmaceutical composition of claim 87, wherein the cosolvent is glycerin.

89. The liquid pharmaceutical composition of claim 83, wherein microemulsion has a poly dispersity index (PDI) within the range of 0.02 to 0.15.

90. The liquid pharmaceutical composition of claim 83, wherein microemulsion has a poly dispersity index (PDI) less than 0.1.

91. The liquid pharmaceutical composition of claim 83, wherein microemulsion has a poly dispersity index (PDI) of about 0.05.

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