CRAC Channel Inhibitor Compositions

Abstract

Provided herein are pharmaceutical compositions, such as emulsions and nanosuspensions, that comprise CRAC channel inhibitors.Furthermore, provided herein are methods for treating pancreatitis, viral infection, stroke, traumatic brain injury, fibrosis, inflammation and autoimmune disease by administering such pharmaceutical compositions. [Selected Figure] Figure 1

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Patent Application No. 62 / 451,020, filed January 26, 2017, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Calcium plays a critical role in cellular function and survival. For example, calcium is a key element in the transmission of signals to and within cells. Cellular responses to growth factors, neurotransmitters, hormones, and a variety of other signaling molecules are initiated through calcium-dependent processes.

[0003] Virtually all cell types use cytosolic Ca in some way to regulate cellular function or to trigger specific responses. 2+ Dependent on signal generation. Cytosolic Ca 2+ Signals control a wide range of cellular functions, ranging from short-term responses such as contraction and secretion to longer-term regulation of cell growth and proliferation. Typically, these signals involve the release of Ca from intracellular stores, such as the endoplasmic reticulum (ER). 2+ release of Ca across the plasma membrane 2+ In one example, cell activation begins with an agonist binding to a surface membrane receptor that is coupled to phospholipase C (PLC) via a G protein mechanism. PLC activation leads to the generation of inositol 1,4,5-triphosphate (IP3), which in turn activates IP3 receptors, resulting in the release of Ca from the ER. 2+ causes the release of ER Ca 2+ The decrease in calcium then signals to activate store-operated calcium (SOC) channels in the plasma membrane. Store-operated calcium (SOC) entry is a pathway that includes, but is not limited to, intracellular Ca 2+It is a process in cell physiology that controls such diverse functions as storage (Putney et al. Cell, 75, 199-201, 1993), activation of enzyme activity (Fagan et al., J. Biol. Chem. 275:26530-26537, 2000), gene transcription (Lewis, Annu. Rev. Immunol. 19:497-521, 2001), cell proliferation (Nunez et al., J. Physiol. 571.1, 57-73, 2006), and cytokine release (Winslow et al., Curr. Opin. Immunol. 15:299-307, 2003). In some non-excitable cells, such as blood cells, immune cells, hematopoietic cells, T lymphocytes, and mast cells, SOC influx occurs through one type of SOC channel, the calcium release-activated calcium (CRAC) channel. Summary of the Invention

[0004] Provided herein are embodiments relating to pharmaceutical compositions comprising CRAC channel inhibitors and methods of using such pharmaceutical compositions to treat pancreatitis, viral infections, stroke, traumatic brain injury, fibrosis, inflammation, and autoimmune diseases in mammals, such as humans.

[0005] Disclosed herein are pharmaceutical compositions comprising N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated as a homogenous liquid, emulsion, nanosuspension, or powder for reconstitution. In some embodiments, the pharmaceutical composition is suitable for injection. In some embodiments, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide is present as the free base. In some embodiments, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, is crystalline. In some embodiments, the crystalline N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide is crystalline Form A having at least one of the following characteristics: (a) an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG. 1; (b) an X-ray powder diffraction (XRPD) pattern including characteristic peaks at about 13.8° 2-theta, about 14.2° 2-theta, about 16.8° 2-theta, about 19.2° 2-theta, about 19.7° 2-theta, about 21.1° 2-theta, about 22.5° 2-theta, about 22.7° 2-theta, about 26.5° 2-theta, and about 27.5° 2-theta; (c) a DSC thermogram substantially similar to that shown in FIG. 2; or (d) a RI of about 156.6° 2-theta. DSC thermogram with an endotherm peaking at 0°C. In some embodiments, the pharmaceutical composition is formulated as an emulsion. In some embodiments, the emulsion is suitable for injection. In some embodiments, the pharmaceutically acceptable excipient is selected from the group consisting of lecithin, soybean oil (SBO), medium chain triglycerides (MCT), cholesterol, vitamin E succinate (VES), sucrose, glycerin, EDTA-Na2, and any combination thereof.In some embodiments, the pharmaceutical composition comprises: (i) N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide; (ii) lecithin; (iii) medium-chain triglyceride (MCT); (iv) glycerin; and (v) water. In some embodiments, the N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide is present in a concentration of about 0.1 mg / mL to about 4.0 mg / mL. In some embodiments, the N(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide is present in a concentration of less than about 1.8 mg / mL. In some embodiments, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide is present at a concentration of about 1.6 mg / mL. In some embodiments, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide is present at a concentration of about 0.1% to about 1% (w / w). In some embodiments, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide is present at a concentration of about 0.1% to about 0.3% (w / w). In some embodiments, the lecithin comprises egg lecithin. In some embodiments, lecithin is present at a concentration of about 5% to about 15% (w / w). In some embodiments, lecithin is present at a concentration of about 10% (w / w). In some embodiments, medium chain triglycerides (MCTs) are present at a concentration of about 1% to about 10% (w / w). In some embodiments, medium chain triglycerides (MCTs) are present at a concentration of about 5% (w / w). In some embodiments, glycerin is present at a concentration of about 1% to about 5% (w / w). In some embodiments, glycerin is present at a concentration of about 2.25% (w / w).In some embodiments, the pharmaceutical composition further comprises EDTA-Na2. In some embodiments, the EDTANa2 is present at a concentration of about 0.001% to about 0.01% (w / w). In some embodiments, the EDTANa2 is present at a concentration of about 0.005%. In some embodiments, the pharmaceutical composition has a pH of about 4 to about 9. In some embodiments, the pharmaceutical composition has a pH of about 6 to about 8. In some embodiments, the pharmaceutical composition has a pH of about 7. In some embodiments, the pH is adjusted by adding HCl or NaOH. In some embodiments, the pharmaceutical composition is substantially free of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide crystalline Form B having at least one of the following characteristics: (a) an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG. 4; (b) an X-ray powder diffraction (XRPD) pattern including characteristic peaks at about 14.2° 2-theta, about 17.1° 2-theta, about 21.5° 2-theta, about 25.4° 2-theta, about 26.5° 2-theta, and about 26.9° 2-theta; (c) a DSC thermogram substantially similar to that shown in FIG. 5; or (d) a DSC thermogram with endotherms peaking at about 54.3°C and about 155.9°C. In some embodiments, the pharmaceutical composition is stable at about 5±3° C. for at least 3 months. In some embodiments, the pharmaceutical composition is stable at about 5±3° C. for at least 6 months. In some embodiments, the pharmaceutical composition is stable at about 5±3° C. for at least 12 months. In some embodiments, the pharmaceutical composition is stable at about 25±3° C. for at least 3 months. In some embodiments, the pharmaceutical composition is stable at about 25±3° C. for at least 6 months. In some embodiments, the pharmaceutical composition is stable at about 25±3° C. for at least 12 months. In some embodiments, the pharmaceutical composition is formulated as a powder for reconstitution. In some embodiments, the pharmaceutical composition is suitable for injection once reconstituted with an aqueous carrier.In some embodiments, the aqueous carrier is selected from the group consisting of water, saline, 5% dextrose in water, 5% dextrose in saline, and any combination thereof. In some embodiments, the pharmaceutical composition is in the form of a nanosuspension once reconstituted. In some embodiments, the nanosuspension comprises nanoparticles. In some embodiments, each nanoparticle has an average diameter of about 50 nm to about 500 nm. In some embodiments, each nanoparticle has an average diameter of about 50 nm to about 150 nm. In some embodiments, each nanoparticle has an average diameter of about 100 nm. In some embodiments, the pharmaceutically acceptable excipient is selected from the group consisting of polyvinylpyrrolidone (PVP), sodium deoxycholate, and any combination thereof. In some embodiments, the pharmaceutical composition further comprises a cryoprotectant. In some embodiments, the cryoprotectant is selected from sucrose, sucrose / mannitol, trehalose, trehalose / mannitol, and any combination thereof. In some embodiments, the pharmaceutical composition comprises: (i) N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide; (ii) polyvinylpyrrolidone (PVP); (iii) sodium deoxycholate; and (iv) sucrose. In some embodiments, the N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, once reconstituted, is present at a concentration of about 1 mg / mL to about 100 mg / mL. In some embodiments, the N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, once reconstituted, is present at a concentration of about 50 mg / mL. In some embodiments, polyvinylpyrrolidone is present at a concentration of about 0.1% to about 5% (w / w). In some embodiments, polyvinylpyrrolidone (PVP) is present at a concentration of about 0.5% (w / w).In some embodiments, deoxycholic acid sodium salt is present at a concentration of about 0.1% to about 1% (w / w). In some embodiments, deoxycholic acid sodium salt is present at a concentration of about 0.125% (w / w). In some embodiments, sucrose is present at a concentration of about 1% to about 20% (w / w). In some embodiments, sucrose is present at a concentration of about 10% (w / w). In some embodiments, once reconstituted, the pharmaceutical composition has a pH of about 4 to about 9. In some embodiments, once reconstituted, the pharmaceutical composition has a pH of about 7. In some embodiments, once reconstituted, the pharmaceutical composition is stable at about 5±3°C for at least 3 months. In some embodiments, once reconstituted, the pharmaceutical composition is stable at about 5±3°C for at least 6 months. In some embodiments, once reconstituted, the pharmaceutical composition is stable at about 5±3°C for at least 12 months. In some embodiments, once reconstituted, the pharmaceutical composition is stable at about 25±3°C for at least 3 months. In some embodiments, the pharmaceutical composition, once reconstituted, is stable at about 25±3° C. for at least 6 months. In some embodiments, the pharmaceutical composition, once reconstituted, is stable at about 25±3° C. for at least 12 months.

[0006] Further disclosed herein is a method for treating pancreatitis in an individual, comprising administering to the individual a pharmaceutical composition disclosed herein. Further disclosed herein is a method for treating idiopathic pulmonary fibrosis (IPF) in an individual, comprising administering to the individual a pharmaceutical composition disclosed herein. Further disclosed herein is a method for treating stroke or traumatic brain injury in an individual, comprising administering to the individual a pharmaceutical composition disclosed herein. [Brief explanation of the drawings]

[0007] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth embodiments in which the principles of the invention are utilized, and the accompanying drawings in which: [Figure 1] 1 shows the XRPD pattern of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide form A. [Figure 2] 1 shows TGA and DSC curves of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide form A. [Figure 3] FIG. 1 shows the DVS of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide form A. [Figure 4] 1 shows the XRPD pattern of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide form B compared to form A. [Figure 5] 1 shows the DSC curves of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide form B compared to form A. [Figure 6] 1 shows the XRPD pattern of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide form C compared to form A. [Figure 7] 1 shows the DSC curves of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide form C compared to form A. [Figure 8]1 shows the XRPD pattern of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide form D compared to form A. [Figure 9] 1 shows the DSC curves of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide form D compared to form A. [Figure 10] 1 shows a manufacturing process flow chart for the production of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide emulsion. DETAILED DESCRIPTION OF THE INVENTION

[0008] Disclosed herein is a pharmaceutical composition comprising a CRAC channel inhibitor and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated as a homogeneous liquid, emulsion, nanosuspension, or powder for reconstitution. In some embodiments, the pharmaceutical composition is formulated as an emulsion. In some embodiments, the pharmaceutical composition is formulated as a nanosuspension. In some embodiments, the pharmaceutical composition is formulated as a powder for reconstitution. In some embodiments, the powder for reconstitution is reconstituted with an aqueous carrier to form a nanosuspension. In some embodiments, the CRAC channel inhibitor has the following structure:

[0009] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the CRAC channel inhibitor is N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the CRAC channel inhibitor is N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide free base. In some embodiments, the CRAC channel inhibitor is crystalline N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the CRAC channel inhibitor is crystalline N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide free base.

[0010] Described herein are pharmaceutical compositions comprising crystalline N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide free base Form A, having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern nearly identical to that shown in Figure 1 ; (b) an X-ray powder diffraction (XRPD) pattern containing characteristic peaks at about 13.8° 2-theta, about 14.2° 2-theta, about 16.8° 2-theta, about 19.2° 2-theta, about 19.7° 2-theta, about 21.1° 2-theta, about 22.5° 2-theta, about 22.7° 2-theta, about 26.5° 2-theta, and about 27.5° 2-theta; (c) a DSC thermogram substantially similar to that shown in Figure 2; or (d) DSC thermogram with an endotherm peaking at approximately 156.6 °C.

[0011] Described herein are pharmaceutical compositions comprising crystalline N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide free base Form B, having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern nearly identical to that shown in Figure 4 ; (b) an X-ray powder diffraction (XRPD) pattern containing characteristic peaks at about 14.2° 2-theta, about 17.1° 2-theta, about 21.5° 2-theta, about 25.4° 2-theta, about 26.5° 2-theta, and about 26.9° 2-theta; (c) a DSC thermogram substantially similar to that shown in Figure 5; or (d) DSC thermogram with endotherms peaking at approximately 54.3°C and 155.9°C.

[0012] Described herein are pharmaceutical compositions comprising crystalline N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide free base Form C, having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern nearly identical to that shown in Figure 6 ; (b) an X-ray powder diffraction (XRPD) pattern containing characteristic peaks at about 14.1° 2-theta, about 17.1° 2-theta, about 19.6° 2-theta, about 21.4° 2-theta, about 22.5° 2-theta, about 25.4° 2-theta, about 25.9° 2-theta, and about 34.3° 2-theta; (c) a DSC thermogram substantially similar to that shown in Figure 7; or (d) DSC thermogram with endotherms peaking at approximately 82.4°C and 104.6°C.

[0013] Described herein is a pharmaceutical composition comprising crystalline N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide free base Form D, having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern nearly identical to that shown in Figure 8 ; (b) an X-ray powder diffraction (XRPD) pattern containing characteristic peaks at about 13.9° 2-theta, about 14.4° 2-theta, about 19.0° 2-theta, about 19.2° 2-theta, about 19.6° 2-theta, about 20.0° 2-theta, about 22.8° 2-theta, about 25.3° 2-theta, about 26.4° 2-theta, and about 30.4° 2-theta; (c) a DSC thermogram substantially similar to that shown in Figure 9; or (d) DSC thermogram with endotherms peaking at approximately 100.5°C and 155.7°C.

[0014] Described herein are pharmaceutical compositions comprising crystalline N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide free base A that is substantially free of crystalline Form B, crystalline Form C, crystalline Form D, or any combination thereof. In some embodiments, the pharmaceutical composition comprising crystalline N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide free base Form A is substantially free of crystalline Form B. In some embodiments, the pharmaceutical composition comprising crystalline N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide free base Form A is substantially free of crystalline Form C. In some embodiments, the pharmaceutical composition comprising crystalline N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide free base Form A is substantially free of crystalline Form D.

[0015] emulsion Pharmaceutical compositions are described herein in the form of emulsions. In some embodiments, the emulsions contain two immiscible phases: an aqueous phase and an oil phase. In some embodiments, the emulsions contain N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide is in the form of a free base. In some embodiments, the N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide is crystalline. In some embodiments, the N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide free base is in crystalline form A. In some embodiments, the emulsion is substantially free of crystalline form B. In some embodiments, the emulsion is suitable for injection. In some embodiments, the N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, is completely dissolved in the emulsion. In some embodiments, the pharmaceutically acceptable excipient is selected from an emulsifier, an oil, a tonicity adjuster, a chelating agent, a pH adjuster, and any combination thereof. In some embodiments, the pharmaceutically acceptable excipient is selected from lecithin, soybean oil (SBO), medium chain triglycerides (MCT), cholesterol, vitamin E succinate (VES), sucrose, glycerin, EDTA-Na2, and any combination thereof.In some embodiments, the emulsion comprises lecithin, soybean oil (SBO), medium chain triglycerides (MCT), cholesterol, vitamin E succinate (VES), sucrose, glycerin, EDTA-Na, or any combination thereof. In some embodiments, the lecithin comprises egg lecithin. In some embodiments, the lecithin comprises soybean lecithin. In some embodiments, the emulsion further comprises a pH adjuster selected from NaOH, HCl, and any combination thereof. In some embodiments, the emulsion further comprises water.

[0016] CRAC channel inhibitors In one aspect, the emulsion described herein comprises N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, is present in the emulsion at a concentration of about 0.1 mg / mL to about 4.0 mg / mL. In some embodiments, the N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, is present in the emulsion at a concentration of about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about 1.5 mg / mL, or about 1.6 mg / mL.

[0033] In some embodiments, the agonist is present at a concentration of about 1.6 mg / mL, about 1.7 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, about 2 mg / mL, about 2.1 mg / mL, about 2.2 mg / mL, about 2.3 mg / mL, about 2.4 mg / mL, about 2.5 mg / mL, 2.6 mg / mL, about 2.7 mg / mL, about 2.8 mg / mL, about 2.9 mg / mL, about 3 mg / mL, about 3.1 mg / mL, about 3.2 mg / mL, about 3.3 mg / mL, about 3.4 mg / mL, about 3.5 mg / mL, about 3.6 mg / mL, about 3.7 mg / mL, about 3.8 mg / mL, about 3.9 mg / mL, or about 4 mg / mL. In some embodiments, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, is present in the emulsion at a concentration of about 0.1 mg / mL to about 3.0 mg / mL.In some embodiments, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, is present in the emulsion at a concentration of about 0.1 mg / mL to about 2.0 mg / mL. In some embodiments, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, is present in the emulsion at a concentration of about 1.0 mg / mL to about 2.0 mg / mL. In some embodiments, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, is present in the emulsion at a concentration of about 1.0 mg / mL to about 1.8 mg / mL. In some embodiments, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, is present in the emulsion at a concentration of about 1.0 mg / mL to about 1.6 mg / mL. In some embodiments, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, is present in the emulsion at a concentration of less than about 1.8 mg / mL. In some embodiments, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, is present in the emulsion at a concentration of less than about 1.6 mg / mL. In some embodiments, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, is present in the emulsion at a concentration of less than about 1.8 mg / mL to prevent precipitation of crystalline Form B.In some embodiments, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, is present in the emulsion at a concentration of about 0.1% to about 1% (w / w). In some embodiments, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, is present in the emulsion at a concentration of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, or about 1% (w / w). In some embodiments, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, is present in the emulsion at a concentration of about 0.1% to about 0.3% (w / w). In some embodiments, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, is present in the emulsion at a concentration of about 0.1% to about 0.25% (w / w). In some embodiments, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, is present in the emulsion at a concentration of about 0.1% to about 0.18% (w / w). In some embodiments, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, is present in the emulsion at a concentration of about 0.1% to about 0.16% (w / w).

[0017] oil In one aspect, the emulsion described herein comprises an oil. The oil in the emulsion can be any pharmaceutical-grade oil, preferably a triglyceride, such as, but not limited to, soybean oil (SBO), safflower seed oil, olive oil, cottonseed oil, sunflower oil, fish oil (containing the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)), castor oil, sesame oil, peanut oil, corn oil, medium-chain triglycerides (MCT), and any combination thereof. In some embodiments, the oil is medium-chain triglyceride (MCT). In some embodiments, the oil is soybean oil (SBO). In some embodiments, the oil is present in the emulsion at a concentration of about 1% to about 10% (w / w). In some embodiments, the oil is present in the emulsion at a concentration of about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% (w / w). In some embodiments, the oil is present in the emulsion at a concentration of about 1% to about 5% (w / w). In some embodiments, the oil is present in the emulsion at a concentration of about 5% to about 10% (w / w). In some embodiments, the oil is present in the emulsion at a concentration of about 3% to about 7% (w / w). In some embodiments, the oil is present in the emulsion at a concentration of about 5% (w / w). In some embodiments, the oil is a medium chain triglyceride (MCT) and is present in the emulsion at a concentration of about 5% (w / w).

[0018] emulsifier In one aspect, the emulsions described herein include an emulsifier. In some embodiments, the coalescence process is reduced by the addition of an emulsifier in addition to the oil and water solvent. In some embodiments, the emulsifier is surface active and reduces the surface tension to about 10 dynes / cm or less. In some embodiments, the emulsifier quickly absorbs around the dispersed droplets as a condensed, non-adhesive film to prevent coalescence. In some embodiments, the emulsifier provides an appropriate electrical potential to the droplets so that they repel each other. In some embodiments, the emulsifier increases the viscosity of the emulsion. Exemplary emulsifiers include, but are not limited to, potassium laurate, triethanolamine stearate, sodium lauryl sulfate, alkyl polyoxyethylene sulfates, dioctyl sodium sulfosuccinate, cetyltrimethylammonium bromide, lauryl dimethylbenzyl ammonium chloride, sorbitan fatty acid esters, polyoxyethylene, polyoxyethylene fatty alcohol ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene / polyoxypropylene block copolymers (poloxamers), lanolin alcohol, acacia, gelatin, lecithin, cholesterol, and any combination thereof. In some embodiments, the emulsifier is lecithin. Lecithin is a generic name designating any of a group of yellow-brown fatty substances occurring in amphiphilic animal and plant tissues, which attract both water and fatty substances (and therefore are both hydrophilic and lipophilic). Lecithins are typically phospholipids composed of phosphoric acid with choline, glycerol, or other fatty acids, usually glycolipids or triglycerides. The glycerophospholipids in the lecithin include phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, and phosphatidic acid. In some embodiments, the lecithin comprises egg lecithin. In some embodiments, the lecithin comprises soybean lecithin. In some embodiments, the emulsifier is present in the emulsion at a concentration of about 5% to about 15% (w / w).In some embodiments, the emulsifier is present in the emulsion at a concentration of about 5%, about 5.5%, 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, about 10%, about 10.5%, about 11%, about 11.5%, about 12%, about 12.5%, about 13%, about 13.5%, about 14%, about 14.5%, or about 15% (w / w). In some embodiments, the emulsifier is present in the emulsion at a concentration of about 5% to about 10% (w / w). In some embodiments, the emulsifier is present in the emulsion at a concentration of about 10% to about 15% (w / w). In some embodiments, the emulsifier is present in the emulsion at a concentration of about 8% to about 12% (w / w). In some embodiments, the emulsifier is present in the emulsion at a concentration of about 10% (w / w). In some embodiments, the emulsifier is lecithin and is present in the emulsion at a concentration of about 10% (w / w).

[0019] Tonicity adjuster In one aspect, the emulsions described herein include a tonicity adjuster. In some embodiments, the emulsions described herein are isotonic. Tonicity adjusters include, but are not limited to, dextrose, glycerin, sucrose, mannitol, potassium chloride, sodium chloride, and any combination thereof. In some embodiments, the tonicity adjuster is glycerin. In some embodiments, the tonicity adjuster is sucrose. In some embodiments, the tonicity adjuster is present in the emulsion at a concentration of about 1% to about 5% (w / w). In some embodiments, the tonicity adjuster is present in the emulsion at a concentration of about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5% (w / w). In some embodiments, the tonicity adjuster is present in the emulsion at a concentration of about 1% to about 2.5% (w / w). In some embodiments, the tonicity modifier is present in the emulsion at a concentration of about 2.5% to about 5% (w / w). In some embodiments, the tonicity modifier is present in the emulsion at a concentration of about 2% to about 4% (w / w). In some embodiments, the tonicity modifier is present in the emulsion at a concentration of about 2.25% (w / w). In some embodiments, the tonicity modifier is glycerin and is present in the emulsion at a concentration of about 2.25% (w / w).

[0020] Chelating Agents In one aspect, the emulsions described herein include a chelating agent. In some embodiments, the chelating agent is EDTA. In some embodiments, the chelating agent is EDTA-Na2. In some embodiments, the tonicity-adjusting agent is present in the emulsion at a concentration of about 0.001% to about 0.01% (w / w). In some embodiments, the chelating agent is present in the emulsion at a concentration of about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, or about 0.01% (w / w). In some embodiments, the chelating agent is present in the emulsion at a concentration of about 0.001% to about 0.005% (w / w). In some embodiments, the chelating agent is present in the emulsion at a concentration of about 0.005% to about 0.01% (w / w). In some embodiments, the chelating agent is present in the emulsion at a concentration of about 0.005% (w / w). In some embodiments, the chelating agent is present in the emulsion at a concentration of about 0.0055% (w / w). In some embodiments, the chelating agent is EDTA-Na2 and is present in the emulsion at a concentration of about 0.0055% (w / w).

[0021] Additional excipients In some embodiments, the emulsion further comprises a polymer as a co-solvent or other solubility enhancer, a preservative (exemplary preservatives include ascorbic acid, ascorbyl palmitate, BHA, BHT, citric acid, erythorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, sodium sulfite, parabens (such as methylparaben, ethylparaben, propylparaben, butylparaben, and salts thereof), benzoic acid, sodium benzoate, potassium sorbate, vanillin, etc.), an antioxidant, a stabilizer, a pH adjuster (NaOH or HCl), a suspending agent, a sweetener, and any combination thereof. These additional excipients are selected based on their function and compatibility with the pharmaceutical compositions described herein and may be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, PA: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, (Easton, PA: Mack Publishing Co 1975); Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms (New York, NY: Marcel Decker 1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference as they relate to excipients and emulsion formulations.

[0022] Emulsion pH In one aspect, the pH of the emulsions described herein is adjusted with one or more pH adjusters. Non-limiting examples of pH adjusters include, but are not limited to, sodium hydroxide (NaOH) and hydrochloric acid (HCl). In some embodiments, the pH of the emulsions described herein is about 4 to about 9. In some embodiments, the pH of the emulsions described herein is about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, or about 9. In some embodiments, the pH of the emulsions described herein is about 6 to about 8. In some embodiments, the pH of the emulsions described herein is about 6 to about 7. In some embodiments, the pH of the emulsions described herein is about 7 to about 8. In some embodiments, the pH of the emulsions described herein is about 7.

[0023] Average Droplet Size In one aspect, an emulsion is a mixture of two immiscible liquids (an organic "oil" and water) in which one liquid (the dispersed phase) is in the form of microscopic droplets dispersed in the other (continuous) phase. In some embodiments, the average droplet size is about 100 to about 500 nm. In some embodiments, the average droplet size is about 100 nm, about 150 nm, about 200 nm, about 250 nm, about 300 nm, about 350 nm, about 400 nm, about 450 nm, or about 500 nm. In some embodiments, the average droplet size is less than 200 nm.

[0024] Emulsion Stability chemical stability The N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide emulsions described herein are stable under a variety of storage conditions, including refrigerated, ambient, and accelerated storage conditions. In some embodiments, a stable N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide emulsion as used herein refers to an emulsion having about 80% or more of the original (N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide). In some embodiments, a stable N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide emulsion as used herein refers to an emulsion having about 4% (w / w) or less total related substances at the end of a predetermined storage period. The percentage of related substances is calculated from the amount of related substances relative to the amount of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. Stability is assessed by HPLC or other known testing methods. In some embodiments, the stable N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide emulsion contains about 4% (w / w), about 3% (w / w), about 2.5% (w / w), about 2% (w / w), about 1.5% (w / w), about 1% (w / w), about 0.9% (w / w), about 0.8% (w / w), about 0.7% (w / w), about 0.6% (w / w), about 0.5% (w / w), about 0.4% (w / w), about 0.3% (w / w), about 0.2% (w / w), or about 0.1% (w / w) of total related substances.In yet another embodiment, the stable N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide emulsion contains about 4% (w / w) total related substances. In yet another embodiment, the stable N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide emulsion contains about 3% (w / w) total related substances. In yet another embodiment, the stable N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide emulsion contains about 2% (w / w) total related substances. In yet other embodiments, the stable N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide emulsion contains about 1% (w / w) total related substances. Under refrigerated conditions (5±3°C) and ambient conditions, the N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide emulsion described herein is stable for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months. Under accelerated conditions, the N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide emulsions described herein are stable for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 hours, at least 10 hours, at least 11 months, or at least 12 months.

[0025] physical stability The physical stability of an emulsion is related to three main phenomena:

[0026] (1) Creaming or Sedimentation: Creaming is the upward movement of dispersed droplets relative to a continuous phase. The reverse process, sedimentation, is the descent of particles. In any emulsion, one process or the other occurs depending on the densities of the dispersed and continuous phases. In some embodiments, the emulsions described herein do not exhibit any creaming for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months. In some embodiments, the emulsions described herein do not exhibit any sedimentation for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months.

[0027] (2) Aggregation and coalescence: Coalescence (or flocculation) is the process by which dispersed droplets gather but do not condense. Coalescence is the process by which droplets fully condense, resulting in a reduction in the number of droplets and the eventual separation of two immiscible phases. Coalescence precedes coalescence, but coalescence does not necessarily follow coalescence. In some embodiments, the emulsions described herein do not exhibit any coalescence for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months. In some embodiments, the emulsions described herein do not exhibit any coalescence for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months.

[0028] (3) Conversion: An emulsion is said to invert when it goes from an O / W (oil-in-water) emulsion to a W / O (water-in-oil) emulsion, or vice versa. In some embodiments, the emulsions described herein do not show any signs of inversion for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months.

[0029] Powder for reconstitution / nanosuspension Pharmaceutical compositions in the form of powders for reconstitution are described herein. In some embodiments, the powders for reconstitution are reconstituted with an aqueous carrier to form a nanosuspension. In some embodiments, the nanosuspension comprises nanoparticles. In some embodiments, the aqueous carrier is selected from water, saline, 5% dextrose in water, 5% dextrose in saline, and any combination thereof. In some embodiments, the aqueous carrier is water. In some embodiments, the powder for reconstitution comprises N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide is in the form of a free base. In some embodiments, the N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide free base is crystalline. In some embodiments, the N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide free base is crystalline Form A. In some embodiments, the nanosuspension is substantially free of crystalline Form B. In some embodiments, the nanosuspension is suitable for injection. In some embodiments, the pharmaceutically acceptable excipient is a stabilizer. In some embodiments, the activating agent is a surfactant or polymeric surfactant. In some embodiments, the pharmaceutically acceptable excipient is selected from polyvinylpyrrolidone (PVP), sodium deoxycholate, and any combination thereof. In some embodiments, the powder for reconstitution further comprises a cryoprotectant. In some embodiments, the cryoprotectant is selected from sucrose, sucrose / mannitol, trehalose, trehalose / mannitol, and any combination thereof.In some embodiments, the cryoprotective system is sucrose.

[0030] CRAC channel inhibitors In one aspect, the powder for reconstitution described herein comprises N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, is present in the nanosuspension at a concentration of about 1 mg / mL to about 100 mg / mL once reconstituted. In some embodiments, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, once reconstituted, is present in the nanosuspension at a concentration of about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, or about 100 mg / mL. In some embodiments, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, is present in the nanosuspension at a concentration of about 1 mg / mL to about 10 mg / mL once reconstituted. In some embodiments, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, is present in the nanosuspension at a concentration of about 50 mg / mL to about 100 mg / mL once reconstituted.In some embodiments, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, is present in the nanosuspension at a concentration of about 30 mg / mL to about 70 mg / mL once reconstituted. In some embodiments, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, is present in the nanosuspension at a concentration of about 40 mg / mL to about 60 mg / mL once reconstituted. In some embodiments, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, is present in the nanosuspension at a concentration of about 50 mg / mL once reconstituted.

[0031] stabilizers The nanosuspensions described herein contain a stabilizer to stabilize the nanosuspension by preventing aggregation of nanoparticles in solution and by preventing or minimizing the formation of large particles, e.g., particles >1 μm in size. Examples of such stabilizers are well known to those skilled in the art. In some embodiments, the stabilizer is a surfactant, a surfactant polymer, or any combination thereof. In some embodiments, the stabilizer is water-soluble. Suitable surfactants for use in the nanosuspensions of the present invention include, but are not limited to, polysorbate surfactants, poloxamer surfactants, dioctyl sodium sulfosuccinate (DOSS), sodium deoxycholate, or any combination thereof. Exemplary polysorbate surfactants are Tween® surfactants, e.g., Tween 20®, Tween 80®. Exemplary poloxamer surfactants include poloxamer 188 and poloxamer 228. Polyvinylpyrrolidone (also known as povidone or PVP) is a water-soluble polymer made from N-vinylpyrrolidone monomers. A suitable surfactant polymer is polyvinylpyrrolidone (PVP). PVP is often defined in terms of a K value that characterizes the average molecular weight, for example, Povidone K 12, Povidone K 17, Povidone K 25, Povidone K 30, and Povidone K 90. PVP is available under a variety of trade names, including Plasdone C-15®, Kollidon 12PF®, Kollidon 17PF®, and Kollidon 30®. In one embodiment, the PVP has an average molecular weight of about 2,000 Da to about 5,000 Da; about 6,000 Da to about 12,000 Da; about 25,000 Da to about 40,000 Da; about 41,000 Da to about 65,000 Da, or about 1,000,000 Da to about 1,500,000 Da. Suitably, the PVP has an average molecular weight of about 2,000 Da to about 3,000 Da (corresponding to Kollidon 12).

[0032] In one aspect, the powders for reconstitution described herein contain a stabilizer. In some embodiments, the stabilizer is polyvinylpyrrolidone (PVP) and is present in the powder for reconstitution at a concentration of about 0.1% to about 5% (w / w). In some embodiments, the polyvinylpyrrolidone (PVP) is present in the powder for reconstitution at a concentration of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5% (w / w). In some embodiments, the polyvinylpyrrolidone (PVP) is present in the powder for reconstitution at a concentration of about 0.1% to about 2.5% (w / w). In some embodiments, polyvinylpyrrolidone (PVP) is present in the powder for reconstitution at a concentration of about 0.1% to about 0.5% (w / w). In some embodiments, polyvinylpyrrolidone (PVP) is present in the powder for reconstitution at a concentration of about 0.5% (w / w).

[0033] In one aspect, the powders for reconstitution described herein include a second stabilizing agent. In some embodiments, the second stabilizing agent is sodium deoxycholate, which is present in the powder for reconstitution at a concentration of about 0.1% to about 5% (w / w). In some embodiments, the sodium deoxycholate is present in the powder for reconstitution at a concentration of about 0.1%, about 0.2%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, or about 1% (w / w). In some embodiments, the sodium deoxycholate is present in the powder for reconstitution at a concentration of about 0.1% to about 0.5% (w / w). In some embodiments, the sodium deoxycholate is present in the powder for reconstitution at a concentration of about 0.1% to about 0.2% (w / w). In some embodiments, deoxycholic acid sodium salt is present in the reconstituted powder at a concentration of about 0.125% (w / w).

[0034] cryoprotectant In one aspect, the powder for reconstitution described herein includes a cryoprotectant. In some embodiments, the powder for reconstitution includes nanoparticles. In some embodiments, the nanoparticles are prepared in a liquid medium and by a drying method, such as lyophilization. When the dried form is reconstituted in an aqueous carrier, it redisperses to achieve its original particle size. In some embodiments, the redispersibility of the dried nanoparticles depends on the parameters of the lyophilization process. In some embodiments, the redispersibility of the dried nanoparticles depends on the use of a cryoprotectant. Exemplary cryoprotectants include, but are not limited to, sucrose, lactose, mannitol, trehalose, sucrose / mannitol, trehalose / mannitol, polyethylene glycol, and any combination thereof. In some embodiments, the cryoprotectant is sucrose. In some embodiments, the cryoprotectant is present in the powder for reconstitution at a concentration of about 1% to about 20% (w / w). In some embodiments, the cryoprotectant is present in the powder for reconstitution at a concentration of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%. In some embodiments, the cryoprotectant is present in the powder for reconstitution at a concentration of about 1% to about 10% (w / w). In some embodiments, the cryoprotectant is present in the powder for reconstitution at a concentration of about 10% to about 20% (w / w). In some embodiments, the cryoprotectant is present in the powder for reconstitution at a concentration of about 8% to about 12% (w / w). In some embodiments, the cryoprotectant salt is present in the powder for reconstitution at a concentration of about 10% (w / w).

[0035] Additional excipients In some embodiments, the powder for reconstitution further comprises a preservative (exemplary preservatives include ascorbic acid, ascorbyl palmitate, BHA, BHT, citric acid, erythorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfate, sodium metabisulfite, sodium sulfite, parabens (such as methylparaben, ethylparaben, propylparaben, butylparaben, and salts thereof), benzoic acid, sodium benzoate, potassium sorbate, vanillin, etc.), antioxidant, lubricant, disintegrant, stabilizer, sweetener, and any combination thereof. These additional excipients are selected based on their functionality and compatibility with the pharmaceutical compositions described herein and may be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, PA: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, (Easton, PA: Mack Publishing Co 1975); Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms (New York, NY: Marcel Decker 1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference as they relate to excipients and powder or nanosuspension formulations for reconstitution.

[0036] pH of nanosuspension In one embodiment, the powder for reconstitution is reconstituted with an aqueous carrier. In some embodiments, the pH of the nanosuspensions described herein is about 4 to about 9. In some embodiments, the pH of the nanosuspensions described herein is about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, or about 9. In some embodiments, the pH of the nanosuspensions described herein is about 6 to about 8. In some embodiments, the pH of the nanosuspensions described herein is about 6 to about 7. In some embodiments, the pH of the nanosuspensions described herein is about 7 to about 8. In some embodiments, the pH of the nanosuspensions described herein is about 7.

[0037] Nanoparticle size In one embodiment, the powder and nanosuspension for reconstitution contain nanoparticles. In some embodiments, the average nanoparticle diameter is about 50 nm to about 500 nm. In some embodiments, the average droplet size is about 100 nm, about 150 nm, about 200 nm, about 250 nm, about 300 nm, about 350 nm, about 400 nm, about 450 nm, or about 500 nm. In some embodiments, the average droplet size is less than 200 nm.

[0038] Powder stability for reconstitution The N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide powder for reconstitution described herein is stable under various storage conditions, including refrigerated, ambient, and accelerated storage conditions. In some embodiments, stable N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide powder for reconstitution as used herein refers to a powder for reconstitution having about 80% or more of the original (N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide) amount. In some embodiments, stable N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide powder for reconstitution, as used herein, refers to a powder for reconstitution having about 4% (w / w) or less total related substances at the end of a predetermined storage period. The percent related substances is calculated from the amount of related substances relative to the amount of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. Stability is assessed by HPLC or other known testing methods. In some embodiments, the stable N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide powder for reconstitution contains about 4% (w / w), about 3% (w / w), about 2.5% (w / w), about 2% (w / w), about 1.5% (w / w), about 1% (w / w), about 0.9% (w / w), about 0.8% (w / w), about 0.7% (w / w), about 0.6% (w / w), about 0.5% (w / w), about 0.4% (w / w), about 0.3% (w / w), about 0.2% (w / w), or about 0.1% (w / w) of total related substances.In yet another embodiment, the stable N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide powder for reconstitution contains about 4% (w / w) total related substances. In yet another embodiment, the stable N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide powder for reconstitution contains about 3% (w / w) total related substances. In yet another embodiment, the stable N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide powder for reconstitution contains about 2% (w / w) total related substances. In yet other embodiments, the stable N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide powder for reconstitution contains about 1% (w / w) total related substances. Under refrigerated (5±3°C) and ambient conditions, the N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide powder for reconstitution described herein is stable for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months. Under accelerated conditions, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide powder for reconstitution described herein is stable for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months.

[0039] Stability of nanosuspensions The N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide nanosuspensions described herein are stable under a variety of storage conditions, including refrigerated, ambient, and accelerated conditions. In some embodiments, a stable N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide nanosuspension as used herein refers to a nanosuspension having about 80% or more of the original (N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide) amount. In some embodiments, a stable N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide nanosuspension, as used herein, refers to a nanosuspension having about 4% (w / w) or less total related substances at the end of a predetermined storage period. The percent related substances is calculated from the amount of related substances relative to the amount of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. Stability is assessed by HPLC or other known testing methods. In some embodiments, the stable N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide nanosuspension contains about 4% (w / w), about 3% (w / w), about 2.5% (w / w), about 2% (w / w), about 1.5% (w / w), about 1% (w / w), about 0.9% (w / w), about 0.8% (w / w), about 0.7% (w / w), about 0.6% (w / w), about 0.5% (w / w), about 0.4% (w / w), about 0.3% (w / w), about 0.2% (w / w), or about 0.1% (w / w) of total related substances. In yet another embodiment, the stable N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide nanosuspension contains about 4% (w / w) total related substances.In yet another embodiment, the stable N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide nanosuspension contains about 3% (w / w) total related substances. In yet another embodiment, the stable N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide nanosuspension contains about 2% (w / w) total related substances. In yet another embodiment, the stable N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide nanosuspension contains about 1% (w / w) total related substances. Under refrigerated (5±3°C) and ambient conditions, the N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide nanosuspensions described herein are stable for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months. Under accelerated conditions, the N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide nanosuspensions described herein are stable for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 hours, at least 10 hours, at least 11 months, or at least 12 months.

[0040] method Provided herein are methods of treatment comprising administering to a subject a pharmaceutical composition described herein.

[0041] Described herein are pharmaceutical compositions for modulating intracellular calcium to ameliorate or prevent symptoms of pancreatitis. In some embodiments, the pancreatitis is acute pancreatitis. In some embodiments, the pancreatitis is chronic pancreatitis.

[0042] The pharmaceutical composition described herein is for regulating intracellular calcium to improve or prevent the symptoms of viral disease.In some aspects, the viral disease is hemorrhagic fever virus.In some embodiments, the hemorrhagic fever virus is arenavirus, filovirus, bunyavirus, flavivirus, rhabdovirus, or a combination thereof.Hemorrhagic fever virus includes, but is not limited to, Ebola virus, Marburg virus, Lassa virus, Junin virus, rotavirus, West Nile virus, Zika virus, Coxsackie virus, hepatitis B virus, and Epstein-Barr virus.

[0043] Described herein are pharmaceutical compositions for modulating intracellular calcium to ameliorate or prevent symptoms of Th17-induced diseases. In some embodiments, the Th17-induced disease is an inflammatory disease. In further embodiments, the Th17-induced disease is an autoimmune disorder.

[0044] Pharmaceutical compositions for modulating intracellular calcium to ameliorate or prevent fibrosis are described herein. In some embodiments, the fibrosis is pulmonary fibrosis. In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). In some embodiments, the pulmonary fibrosis is cystic fibrosis. In some embodiments, the fibrosis comprises hepatic fibrosis. In some embodiments, the hepatic fibrosis is cirrhosis. In some embodiments, the fibrosis is atrial fibrosis, endomyocardial fibrosis, previous myocardial infarction, glial scar, arthrofibrosis, Crohn's disease, Dupuytren's contracture, keloid, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, or scleroderma / systemic sclerosis.

[0045] Described herein are pharmaceutical compositions for modulating intracellular calcium to improve or prevent non-alcoholic fatty liver disease (NAFLD). In some embodiments, the non-alcoholic fatty liver disease (NAFLD) is non-alcoholic steatohepatitis (NASH).

[0046] Described herein are pharmaceutical compositions for modulating intracellular calcium to ameliorate or prevent stroke.

[0047] Described herein are pharmaceutical compositions for modulating intracellular calcium to ameliorate or prevent traumatic brain injury.

[0048] Dosage parameters In one embodiment, the pharmaceutical compositions described herein are used for the treatment of the diseases and conditions described herein. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment comprises administering to the subject a therapeutically effective amount of the pharmaceutical compositions described herein.

[0049] The dosage of the pharmaceutical compositions described herein is determined by any suitable method. In some embodiments, the maximum tolerated dose (MTD) and maximum response dose (MRD) of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenamide are determined by established animal and human experimental protocols. In some embodiments, the toxicity and therapeutic effects of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenamide are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as the ratio between LD50 and ED50. Data obtained from cell culture assays and animal studies can be used to formulate a range of dosages for use in humans. The dosage of such compounds preferably lies within a range of circulating concentrations that include the ED50 with minimal toxicity. Dosages may vary within this range depending on the dosage form used and the route of administration utilized. Stress-relative doses, expressed as a percentage of the maximum response or maximum tolerated dose, are readily obtained via protocol. In another embodiment, pharmaceutical compositions are provided at the maximum tolerated dose (MTD) for N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenamide. In other embodiments, the amount of the pharmaceutical composition administered is about 10% to about 90% of the maximum tolerated dose (MTD) for N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenamide, about 25% to about 75% of the MTD, or about 50% of the MTD.In particular embodiments, the amount of the pharmaceutical composition administered is about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more of the MTD for N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or any range derivable therein. In some embodiments, the pharmaceutical composition is provided at a dosage ranging from about 0.5 mg / kg to about 25 mg / kg. In some embodiments, the pharmaceutical composition contains about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, about 5.5 mg / kg, about 6 mg / kg, about 6.5 mg / kg, about 7 mg / kg, about 7.5 mg / kg, about 8 mg / kg, about 8.5 mg / kg, about 9 mg / kg, about 9.5 mg / kg, about 10 mg / kg, about 10.5 mg / kg, about 11 mg / kg, about 11.5 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg In some embodiments, the pharmaceutical composition is provided at a dosage ranging from about 0.5 mg / kg to about 3.5 mg / kg. In some embodiments, the pharmaceutical composition is provided at a dosage ranging from about 0.5 mg / kg to about 5 mg / kg, hi some embodiments, the pharmaceutical composition is provided at a dosage ranging from about 0.5 mg / kg to about 10 mg / kg.

[0050] In some embodiments, the pharmaceutical composition comprises N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide in an amount of about 0.1 mg / mL to about 4 mg / mL. In certain embodiments, the pharmaceutical composition comprises N(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide in an amount less than about 1.8 mg / mL. In other embodiments, the pharmaceutical composition comprises N(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide in an amount of about 1.6 mg / mL. In some embodiments, the pharmaceutical composition comprises N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide in an amount of about 0.1 mg / mL to about 100 mg / mL. In certain embodiments, the pharmaceutical composition comprises N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide in an amount of about 40 mg / mL to 60 mg / mL. In other embodiments, the pharmaceutical composition comprises N(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide in an amount of about 50 mg / mL.

[0051] Administration of any pharmaceutical composition described herein may follow any suitable dosing schedule. In certain embodiments, the pharmaceutical composition is administered on days 1 and 8 of each 21-day cycle. In other embodiments, the pharmaceutical composition is administered on days 1, 8, and 15 of each 28-day cycle. In some embodiments, the pharmaceutical composition is administered once or twice weekly. In other embodiments, the pharmaceutical composition is administered three times, four times, five times, six times, or seven times weekly. In some embodiments, the pharmaceutical composition is administered once daily, twice daily, or every other day. In some embodiments, the pharmaceutical composition is administered once every three days, once every four days, once every five days, or once every six days. One schedule may be preferable over another schedule, taking into account schedules using other concomitant therapies. The dosage of the composition may be maintained or may be changed, for example, due to the observation of unacceptable side effects. In various embodiments of the treatments described herein, the dosing schedule may be repeated at will, for example, in the absence of disease progression or unacceptable side effects.

[0052] Administration Described herein are pharmaceutical compositions formulated as injectable pharmaceutical compositions. In some embodiments, the emulsions described herein are formulated as injectable emulsions. In some embodiments, the nanosuspensions described herein are formulated as injectable nanosuspensions. In some embodiments, the injectable pharmaceutical compositions are suitable for intravenous administration. In some embodiments, the injectable pharmaceutical compositions are suitable for intramuscular administration. In certain embodiments, the pharmaceutical compositions described herein are administered for prophylactic and / or therapeutic treatment. In certain therapeutic applications, the pharmaceutical compositions are administered to a patient already suffering from a disease in an amount sufficient to treat the disease or at least partially arrest or ameliorate its symptoms. Amounts effective for this use will depend on the severity of the disease; previous treatments; the patient's health, weight, and response to the pharmaceutical composition; and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation clinical trials.

[0053] In prophylactic applications, the pharmaceutical compositions described herein are administered to a patient susceptible to or otherwise at risk of a particular disease. Such an amount is defined to be a "prophylactically effective amount or dose." For this use, the precise amounts also vary depending on the patient's health, weight, and the like. When used in a patient, the amount effective for this use will depend on the patient's risk of or susceptibility to developing the particular disease, previous therapy, the patient's health and response to the pharmaceutical composition, and the judgment of the treating physician.

[0054] In certain embodiments in which the patient's disease does not improve, at the physician's discretion, the pharmaceutical compositions described herein are administered chronically, i.e., for an extended period of time, including the patient's entire lifespan, to improve or otherwise control or limit the symptoms of the patient's disease. In other embodiments, administration of the pharmaceutical compositions described herein continues until a complete or partial response of the disease occurs.

[0055] In certain embodiments where the patient's condition improves, the dosage of the pharmaceutical compositions described herein being administered may be temporarily reduced or temporarily stopped for a period of time (i.e., a drug holiday). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, and 365 days. Dose reductions during drug holidays can be 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0056] In some embodiments, the pharmaceutical compositions described herein are administered chronically. For example, in some embodiments, the pharmaceutical compositions described herein are administered in continuous dosages, i.e., administered daily to a subject. In other embodiments, the pharmaceutical compositions described herein are administered intermittently (e.g., with a drug holiday, during which the formulation is not administered or is administered at a reduced dose).

[0057] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the disease or condition and its severity, and the identity (e.g., body weight) of the subject or host requiring treatment, but may nevertheless be determined in an art-recognized manner according to the particular circumstances surrounding the situation, including, for example, the particular agent being administered, the condition being treated, and the subject or host being treated. In general, however, dosages employed for adult treatment will typically range from about 0.02 to about 5000 mg per day, and in some embodiments, from about 1 to 1500 mg per day. The desired dosage may conveniently be presented as a single dose or as divided doses administered simultaneously (or closely spaced) or at appropriate intervals, e.g., as two, three, four or more sub-doses per day.

[0058] Specific Terms Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods similar or equivalent to those described herein can be used in the practice or testing of the embodiments described herein, certain preferred methods, devices, and materials are described herein.

[0059] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to an "excipient" is a reference to one or more excipients and equivalents thereof known to those skilled in the art, etc.

[0060] The term "about" is used to indicate that a value includes a typical level of error for the device or method being utilized to determine the value. In some embodiments, the level of error is 10%.

[0061] Use of the term "or" in the claims is used to mean "and / or" unless expressly intended to refer to alternatives only or unless the alternatives are mutually exclusive; however, the present disclosure supports a definition that refers to alternatives only or "and / or."

[0062] The terms "comprise," "have," and "include" are open-ended linking verbs. One or more forms or tenses of these verbs, such as "comprises," "comprising," "has," "having," "includes," or "including," are also open-ended. For example, a method that "comprises," "has," or "includes" one or more steps is not limited to having only those one or more steps, but also encompasses other unlisted steps.

[0063] "Optional" or "optionally" may be interpreted to mean that the subsequently described structure, event, or circumstance may or may not occur, and that the description includes instances in which the event occurs and instances in which it does not occur.

[0064] As used herein, the term "therapeutic agent" means an agent utilized to treat, eradicate, reverse, prevent, or ameliorate an unwanted disease or disorder in a patient.

[0065] "Administering," when used in conjunction with a therapeutic agent, means administering the therapeutic agent systemically or locally, such as into or directly to a target tissue, or administering the therapeutic agent to a patient so that the therapeutic agent positively affects the targeted tissue. Thus, as used herein, the term "administering," when used in conjunction with a Compound A formulation, includes, but is not limited to, providing the Compound A formulation to or within the target tissue, and providing the Compound A formulation systemically to a patient, for example, by oral administration, so that the therapeutic agent reaches the target tissue or cell. "Administering" a formulation may be accomplished by injection, topical administration, oral administration, or other methods, alone or in combination with other known techniques.

[0066] The term "animal" as used herein includes, but is not limited to, humans and non-human vertebrates such as wild animals, domestic animals, and livestock. As used herein, the terms "patient," "subject," and "individual" are intended to include living organisms in which a particular disease as described herein may occur. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. In preferred embodiments, the patient is a primate. In certain embodiments, the primate or subject is a human. In certain examples, the human is an adult. In certain examples, the human is a child. Other examples of subjects include laboratory animals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows.

[0067] By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0068] The term "pharmaceutical composition," as used herein, refers to a composition comprising at least one active ingredient, whereby the composition is applicable for investigation for a specified effective outcome in a mammal (e.g., but not limited to, a human). Those skilled in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired effective outcome based on the needs of the artisan.

[0069] As used herein, a "therapeutically effective amount" or "effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, physician, or other clinician, including one or more of the following: (1) preventing a disease; e.g., preventing a disease, illness, or disorder in an individual who is prone to the disease, illness, or disorder but who has not yet experienced or exhibited the symptoms or symptomology of the disease; (2) inhibiting a disease; e.g., inhibiting a disease, illness, or disorder (i.e., halting further progression of the symptoms and / or symptomology) in an individual who is experiencing or exhibiting the symptoms or symptomology of the disease, illness, or disorder; and (3) reversing a disease; e.g., reversing a disease, illness, or disorder (i.e., reversing the symptoms and / or symptomology) in an individual who is experiencing or exhibiting the symptoms or symptomology of the disease, illness, or disorder.

[0070] As provided herein, the terms "treat," "treated," "treatment," or "treating" refer, in some embodiments, to both therapeutic treatment and, in other embodiments, to prophylactic or preventative measures, where the objective is to prevent or slow (reduce) an undesirable physiological disease, disorder, or condition, or to obtain a beneficial or desired clinical result. For purposes described herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; reduction in the severity of the disease, disorder, or condition; stabilization of the disease, disorder, or condition (i.e., not worsening); delay in the onset or slowing of progression of the disease, disorder, or condition; improvement of the disease, disorder, or disease state; and remission (whether partial or total), whether detectable or undetectable, or whether enhancement or amelioration of the disease, disorder, or condition. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment further includes prolonging survival compared to expected survival in the absence of treatment. Prophylactic benefits of treatment include prevention of disease, slowing the progression of disease, stabilizing disease, or reducing the incidence of disease. As used herein, "treat," "treated," "treatment," or "treating" includes prevention, in some embodiments.

[0071] The term "carrier," as used herein, refers to a relatively nontoxic chemical compound or agent that facilitates the incorporation of a compound into cells or tissues. In some embodiments, the carrier is an aqueous carrier.

[0072] The term "diluent" refers to a compound used to dilute a desired compound prior to delivery. Diluents may also be used to stabilize compounds, as they can provide a more stable environment. Salts dissolved in buffers (which can control or maintain pH) are utilized as diluents in the art, including, but not limited to, phosphate buffered saline solutions.

[0073] The term "accelerated conditions" includes temperatures and / or relative humidity (RH) above ambient levels (e.g., 25±3°C; 55±10% RH). In some examples, the accelerated conditions are about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, or about 60°C. In other examples, the accelerated conditions are about 65% RH, about 70% RH, about 75% RH, or about 80% RH. In a further example, the accelerated conditions are about 40°C or 60°C with ambient humidity. In yet a further example, the accelerated conditions are about 40°C with a humidity of 75±5% RH.

[0074] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Example]

[0075] Example 1: Polymorph Screening of Free Base N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide

[0076] X-ray powder diffraction (XRPD) A PANalytical Empyrean X-ray powder diffractometer (XRPD) with a 12-well automated sample stage was used. Typical XRPD parameters used are listed in Table 1.

[0077] [Table 1]

[0078] Differential Scanning Calorimetry (DSC)

[0079] Equipment: TA Instruments TA Q200 / 2000 DSC

[0080] Method: Thermogravimetric analysis (TGA) with the pan crimped and heated from room temperature to the desired temperature at a heating rate of 10°C / min using N2 as the purge gas.

[0081] Equipment: TA Instruments TA Q500 / Q5000 TGA

[0082] Method: Heat from room temperature to the desired temperature at a heating rate of 10°C / min using N2 as the purge gas.

[0083] To discover as many crystalline forms as possible, various crystallization or solid-state transition methods were used in the polymorph screening. The methods used are summarized in Table 2, including slow evaporation, slow cooling, polymer-induced crystallization, slurry conversion, antisolvent addition, sonication-induced crystallization, and thermal cooling.

[0084] [Table 2]

[0085] Slow evaporation Slow evaporation experiments were conducted with 12 different solvent systems. Approximately 8 mg of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide Form A was dissolved in 0.1-1.6 mL of solvent in each HPLC glass vial. The visually clear solutions were subjected to slow evaporation at ambient temperature until dry. The resulting solids were isolated for XRPD analysis. The results, summarized in Table 3, indicate that only Form A was obtained.

[0086] [Table 3]

[0087] slow cooling Slow cooling experiments were conducted with 18 different solvent systems. Approximately 8 mg of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide Form A was suspended in 0.5 mL of the corresponding solvent at 50 °C and allowed to equilibrate for 0.5 hours. The resulting suspension was then filtered at 50 °C using a syringe and a nylon membrane (0.45 μm pore size). The filtrate was collected and cooled from 50 °C to 5 °C at a rate of 0.1 °C / min. If no precipitation was observed, the solution was allowed to evaporate at ambient temperature to induce precipitation. The solid was isolated for XRPD analysis, and the results, summarized in Table 4, indicate that only Form A was obtained.

[0088] [Table 4]

[0089] Polymer-induced crystallization Polymer-induced crystallization experiments were conducted in nine different solvent systems. Approximately 8 mg of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide Form A was dissolved in 0.1-1.5 mL of solvent in each HPLC glass vial. Approximately 1.0 mg of polymer (a mixture of six polymers containing PVA, PVC, PVAC, PVP, HPMC, and MC in a 1.0 mass ratio) was added to the visually clear solution. All samples were allowed to slowly evaporate at ambient temperature until dry. The resulting solids were isolated for XRPD analysis. The results, summarized in Table 5 below, indicate that Form A and two potentially new crystalline forms (Form B and Formula C) were obtained.

[0090] [Table 5]

[0091] Slurry Conversion Slurry conversion experiments were performed under 34 conditions. Approximately 8 mg of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide Form A was suspended in 0.5 mL of each solvent. The suspension was stirred for 3 days at ambient temperature or 50°C, after which the solid was isolated for XRPD analysis. Once the suspension had converted to a clear solution over the slurry, the clear solution was subjected to slow evaporation at ambient temperature. The results, summarized in Tables 6 and 7, indicate that Form A and a potentially new crystalline form, Form D, were obtained.

[0092] [Table 6]

[0093] [Table 7]

[0094] Anti-solvent addition Anti-solvent addition experiments were performed under 16 conditions. Approximately 15 mg of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide Form A was dissolved in 0.1-3.0 mL of each solvent to obtain a clear solution. 3.0-18.0 mL of each solvent was added dropwise to the above clear solution at ambient temperature. The precipitate was isolated for XRPD analysis. Slow evaporation experiments were performed on the clear solutions. The results, summarized in Table 8, suggest that only Form A was obtained.

[0095] [Table 8]

[0096] Sonication-induced crystallization Sonication-induced crystallization experiments were conducted in seven different solvent systems. Approximately 15 mg of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide A was suspended in 0.3 mL of solvent in each HPLC glass vial. All samples were sonicated for 0.5 hours at ambient temperature. The resulting solids were isolated for XRPD analysis. The results, summarized in Table 9 below, indicate that only Form A was obtained.

[0097] [Table 9]

[0098] thermal cooling Slow-cooling experiments were performed with 11 different solvent systems. Approximately 15 mg of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide Form A was suspended in 0.5 mL of solvent. The sample was maintained in a temperature-controlled biochemical incubator and slurried with a magnetic stirrer at a speed of 1000 r / min for approximately 9 hours. The thermal-cooling cycle was programmed as follows: 1) ramp to 50°C in approximately 30 minutes and equilibrate at 50°C for approximately 30 minutes; 2) cool to 5°C in 450 minutes and equilibrate at 5°C for approximately 30 minutes; 3) repeat the thermal-cooling cycle three times before analyzing the precipitate. Slow-evaporation experiments were performed on clear solutions. The results, summarized in Table 10 below, suggest that only Form A was obtained.

[0099] [Table 10]

[0100] In-depth slurry experiments Extensive slurry experiments were conducted under 22 conditions at various water activities. Approximately 20 mg of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide A was suspended in 0.5 mL of each solvent. The suspension was stirred for 22 days at ambient temperature or 50°C, after which the solid was isolated for XRPD analysis. The results, summarized in Tables 11 and 12, indicate that only Form A was obtained.

[0101] [Table 11]

[0102] [Table 12]

[0103] Example 1A: Characterization of a new crystalline form

[0104] Four crystalline forms (Form A, Form B, Form C, and Form D) were obtained as summarized in Table 13.

[0105] [Table 13]

[0106] Characterization of Form A The XRPD pattern shown in Figure 1 indicates that N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide free base form A is highly crystalline. As displayed in Figure 2, the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) curves show a sharp melting point at 156.6 °C (onset temperature) and a maximum weight loss of 1.0% at 150 °C, respectively. The DVS isotherm plot in Figure 3 indicates that form A is not hygroscopic, with a water uptake level of <0.03% at 80% RH. The crystal size of form A ranges from a few μm to approximately 50 μm.

[0107] Solubility of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide Form A The solubility of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide free base Form A was determined in 20 solvents at room temperature. These experiments were performed by adding approximately 2 mg of sample to a 3-mL glass vial. 50 μL of the solvent from Table 14 was then added to the vial until the solid dissolved or a total volume of 2 mL was reached. The solubility assessment was used to guide solvent selection in polymorph screening. N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide free base Form A is soluble in MeOH, acetic acid, acetonitrile, acetone, MIBK, EtOAc, IPAc, MTBE, THF, 2-MeTHF, 1,4-dioxane, NMP, DMSO, DCM, toluene, and DMAc (>18.0 mg / mL), while it is insoluble in heptane and HO (<1.3 mg / mL).

[0108] [Table 14]

[0109] Characterization of Form B Form B was obtained from polymer-induced crystallization in EtOH / HO (19 / 1, v / v). The XRPD pattern of Form B in Figure 4 shows slight differences compared to Form A. The DSC curve of Form B (Figure 5) exhibits an endotherm at 54.3 °C (onset temperature) due to dehydration / desolvation, before melting at 155.9 °C (onset temperature).

[0110] Characterization of Form C Form C was obtained from polymer-induced crystallization in MeOH / acetone / HO (1 / 1 / 1, v / v / v). The XRPD pattern of Form C in Figure 6 shows slight differences compared to Form A. The DSC curve of Form C in Figure 7 presents two endotherms at 82.4 °C and 104.6 °C (peak temperatures) due to dehydration / desolvation, before melting at 155.9 °C (onset temperature).

[0111] Characterization of Form D Form D was obtained from solution evaporation after slurrying in EtOH / HO (0.85 / 0.15, v / v) at 50 °C for 3 days. The XRPD pattern of Form D in Figure 8 shows slight differences compared to Form A. The DSC curve of Form D in Figure 9 exhibits an endotherm at 100.5 °C (onset temperature) due to dehydration / desolvation, before melting at 155.9 °C (onset temperature).

[0112] Example 2: Initial suspension formulation

[0113] Ten compositions were prepared using various template compositions containing lecithin, soybean oil (SBO), or medium-chain triglycerides (MCT), glycerin or sucrose (non-ionic tonicity agents), and edetate disodium dihydrate (EDTA, a chelating agent) in deionized water. Compound A (Form A) was added and stirred to reach solubility equilibrium at ambient room temperature. Each formulation was prepared by the following steps: Compound A (5 mg) was dispersed in each template vehicle. The formulations were then homogenized at room temperature for >24 hours, after which samples were passed through a 0.45 μm filter for analysis (HPLC). The test compositions and analysis are shown in Table 15:

[0114] [Table 15]

[0115] Conclusion: The solubility of Compound A was ≧2.4 mg / mL in emulsion compositions containing ≧10% egg lecithin. The emulsion compositions were sticky when lecithin was ≧15%.

[0116] Example 3: Stability of Formulation F-9 (Small Scale)

[0117] The formulations were prepared on a scale of approximately 1.2 g and the compositions are shown in Table 16.

[0118] [Table 16]

[0119] Procedure: Compound A (Form A) was added to an F-9 vehicle containing MCT / egg / lecithin / sucrose / EDTA in a plastic tube. The formulation was mixed until homogeneous and complete drug dissolution was achieved. The emulsion was sterilized through a 0.2 μm membrane filter. Samples were placed at 2-8°C and 25°C for stability evaluation for two weeks. Appearance, pH, Compound A assay, and purity by HPLC, mean droplet size, and lipid injectable emulsion (USP) were analyzed. <729> The samples were tested for globule size distribution in the granules, and the results are shown in Table 17.

[0120] [Table 17]

[0121] Conclusion: Compound A showed no changes in appearance and HPLC assay after 2 weeks at 2-8°C and 25°C.

[0122] Example 4: Stability of Formulation F-9 (large scale)

[0123] The formulations were prepared on an approximately 100 g scale and the compositions are shown in Table 18.

[0124] [Table 18]

[0125] Procedure: Compound A (Form A) was added to egg lecithin, MCT, EDTA, sucrose, and SWFI in a container. The mixture was mixed until homogenous, and the pH was adjusted to pH ~8 with NaOH / HCl. The coarse emulsion was homogenized under high pressure until the droplet size was <120 nm and then sterilized through a 0.2 μm membrane filter. The final emulsion was filled into sterile glass vials, closed with serum stoppers, and crimp-sealed for stability evaluation at 2-8°C and 25°C, sampling at 0, 15, and 30 days. Appearance, pH, Compound A assay, and purity by HPLC, mean droplet size, and the lipid injectable emulsion (USP) were analyzed. <729> The emulsions were tested for globule size distribution in 1000 ml of water and the results are summarized in Table 19.

[0126] [Table 19]

[0127] Conclusion: The 0.2% Compound A emulsion (F-9A) remained unchanged in appearance and HPLC assay, PFAT5, and mean droplet size after 3 months at 2-8°C and 25°C. Analysis of fat globule size distribution, PFAT5 (USP <729> Method II) was used to evaluate the emulsion physical stability. The PFAT5 acceptance criterion was no more than 0.05%.

[0128] Example 5: Emulsion optimization

[0129] Thirty-six or more emulsion compositions were prepared to rationally define the optimal oil, phospholipid, concentration, ratio, pH, etc. for Compound A ≥ 2.5 mg / mL formulations. Formulations were prepared containing Compound A (Form A), egg lecithin (E-80), medium-chain triglycerides (MCT), glycerin USP, edetate disodium dihydrate USP (EDTA), NaOH (as a pH adjuster), and sterile water for injection USP (SWFI) according to the compositions shown in Tables 20-25. The pH of the aqueous phase was adjusted to 8 with diluted NaOH solution.

[0130] [Table 20]

[0131] [Table 21]

[0132] [Table 22]

[0133] [Table 23]

[0134] [Table 24]

[0135] [Table 25]

[0136] Acceptance Criteria: *Compound A at least 2.5 mg / mL *Average oil droplet (Z average, nm) size less than 150 nm *Pass through 0.2 μm sterile filtration *Droplet size distribution specification USP <729> , i.e., PFAT5 NMT 0.05% is met *Neutral pH (range: 4-8) *Isotonic (range: 240-350 mOsm / kg). *Accelerated and long-term stability (>2-8 and 25°C, 1 month)

[0137] procedure: *All vehicles were prepared by mixing the lipid and aqueous phase ingredients and homogenizing. *Compound A (Form A) was added to each vehicle at a concentration of 0.3%. *Homogenized and mixed overnight until uniform or equilibrium is achieved. *The emulsion was filtered through a 0.45 μm nylon membrane filter. *Appearance, drug concentration by HPLC assay, mean droplet size, and PFAT5 were assessed. *The top 5-10 formulations that first achieved the acceptance criteria were selected. *Emulsion stability was monitored at 40°C for up to 2 weeks. *The top 3-5 formulations that met the proposed requirements after 1-2 weeks at 40°C were selected.

[0138] method: *Appearance: Visual observations are recorded *Z-average (nm): Average oil droplet size measured by ZetaSizer (Malvern Instrument). Dilute 50 μL of sample with 950 μL DI water at room temperature. *Assay (%): Using current HPLC method. *SpinX: Pass 0.5 mL of emulsion through a CoStar® Spin-X 0.2 μm nylon filter (0.7 cm2 surface area) in a centrifuge at 3,144 g for 60 seconds at ambient room temperature. Evaluate the integrity of the emulsion passing through the filter.

[0139] result: T: Translucent off-white to yellowish emulsion O: unclear off-white to yellowish emulsion PPT: drug precipitation test

[0140] Time-0 test results are shown in Tables 26-31.

[0141] [Table 26]

[0142] [Table 27]

[0143] [Table 28]

[0144] [Table 29]

[0145] [Table 30]

[0146] [Table 31]

[0147] The stability of emulsions F-56, F-57, F58, F-63, F-64, F-65, and F-71 at 40°C for the first week is shown in Table 32.

[0148] [Table 32]

[0149] Conclusion: *Compound A remained stable in emulsions F-57, F-58, F-63, F-64, F-65, and F-71 at 2-8°C and after 8 days at 40°C. HPLC assay data supports a drug concentration of >0.25% Compound A in the formulation. % purity remains 99.9% unchanged with stability. *Drug precipitation reaction was observed in F-56 after 8 days at 40°C and did not support the 0.25% emulsion. *Fat globule size distribution analysis (PFAT5 (%)) was used to evaluate the physical stability of the emulsions at 2-8°C and 40°C. Three formulations, F-58, F-63, and F-71, exhibited a globule size distribution (PFAT5 (%)) of 100% relative to the USP standard after 8 days at 40°C. <729> Does not meet acceptance criteria (below 0.05%). *F57 was recommended for further preclinical development for Compound A. The formulation supported a drug concentration of ≥ 2.5 mg / mL in the emulsion.

[0150] Example 6: Evaluation of Alternative Oils and Phospholipids in F-57 Composition

[0151] Formulation F74-76 was prepared according to the composition shown in Table 33 to contain Compound A (Form A), E-80 or soybean lecithin, medium chain triglycerides (MCT) or soybean oil, glycerin USP, edetate disodium dihydrate USP (EDTA), NaOH (as a pH adjuster), and sterile water for injection USP (SWFI).

[0152] [Table 33]

[0153] procedure: *90% of the required lecithin, glycerin, EDTA, and 30% of the required SWFI were added to a 250 mL primary container. *Mixed (high shear) until a uniform coarse emulsion was formed. *10% required lecithin. For one composition, API and oil were added to separate (50 mL) containers. Mix until API was completely dissolved in the oil phase at <65°C. *The oil phase was added to the primary vessel and mixed using high shear until a uniform coarse emulsion was obtained. *Adjust pH to 8.0-8.5 with NaOH and qs to batch weight (200g) with SWFI. *The coarse emulsion was passed through a Microfluidizer® for three passes. *The emulsion was passed through a 0.2 um filter. *5 mL was filled into glass vials, stoppered and crimp sealed. *Vials were placed under stability conditions of 2-8°C and 40°C for 4 weeks. *Tested for pH, appearance, HPLC assay / impurities, Z-average, and %PFAT5. The results are shown in Table 34.

[0154] [Table 34]

[0155] Conclusion: *Only F-75 (containing PL90G / MCT) met its target Compound A concentration (2.5 mg / mL) compared to F-57. *F74 (containing E-80 / soybean oil) and F-76 (containing PL90G / soybean oil) did not support sufficient solubility and showed drug precipitation immediately after microfluidization preparation.

[0156] Example 7: F-75 Stability Study

[0157] To assess its stability compared to F-57, F-75 was placed at 2-8°C, 25°C, and 40°C for 1, 2, and 3 months. The results at time 0, 1 month, 2 months, and 3 months are shown in the table below:

[0158] Time:0

[0159] [Table 35]

[0160] [Table 36]

[0161] [Table 37]

[0162] [Table 38]

[0163] Conclusion: *F75 remained stable after 3 months at 2-8 and 25°C and after 2 months at 40°C. *A significant increase in mean droplet size (Z-average) was observed at 40°C after 1 and 2 months compared to F-57. *F75 showed oil phase separation after 3 months at 40°C.

[0164] Example 8: Preparation of a 2.5 mg / mL emulsion

[0165] Compound A (nanoemulsion) was off-white to yellow translucent in appearance. The final product was sterilized by 0.2 μm membrane filtration and had a tonicity and pH close to physiological conditions. The product was filled into 100 mL USPI-type clear glass vials, stoppered with Flurotec stoppers, and crimp-sealed with flip-off overseals. Each mL of nanoemulsion contained 2.5 mg of Compound A, 100 mg of egg lecithin, 50 mg of medium-chain triglycerides (MCTs), 22.5 mg of glycerin, and 0.055 mg of edetate disodium dihydrate (EDTA-Na). A flowchart of the manufacturing process is outlined in Figure 10. Preparation involved the use of a high-shear (rotor-stator) homogenizer to homogenize the crude emulsion and a high-pressure Microfluidizer® to reduce the average oil droplet size to no more than 100 nm. The sequence of addition and mixing steps (adding the organic phase to the aqueous phase) is specific to creating a stable coarse emulsion. The composition and functionality are shown in Table 35:

[0166] [Table 39]

[0167] Example 9: Evaluation of nanoemulsions for toxicity testing

[0168] A large-scale F-57 formulation (F57#0) was also prepared, as was a vehicle formulation (Vehicle#0) (without Compound A). The composition of each formulation is shown in Table 36.

[0169] [Table 40]

[0170] The stability of the F-57 formulation (F57#0), vehicle formulation (Vehicle#0), and diluted formulations at time 0 and 6 months is shown in the table below.

[0171] [Table 41]

[0172] [Table 42]

[0173] [Table 43]

[0174] Conclusion: The diluted emulsion was stable at room temperature after 8 hours and at 2-8°C after 24 hours. Lots Vehicle#0 and F57#0 (2 mg / mL) remained stable at 2-8°C for 6 months.

[0175] Example 10: 3-Month Stability Study for Formulation F57 Emulsion

[0176] A large-scale F-57 formulation (F57#1) was also prepared, as was a vehicle formulation (Vehicle#1). The composition of each formulation is shown in Table 37.

[0177] [Table 44]

[0178] [Table 45]

[0179] [Table 46]

[0180] [Table 47]

[0181] [Table 48]

[0182] The stability of F57#1 and its vehicle (Vehicle#1) was evaluated. The data are shown in the table below:

[0183] [Table 49]

[0184] [Table 50]

[0185] [Table 51]

[0186] [Table 52]

[0187] [Table 53]

[0188] [Table 54]

[0189] [Table 55]

[0190] [Table 56]

[0191] Conclusion: *F57#1 remained stable at 2-8°C, 25°C, and 30°C after 8 months and at 40°C after 3 months, meeting USP PFAT5 requirements (≤0.05%). % assay recovery by HPLC remained 95-105% and >99% pure. Phase separation was observed at 40°C after 8 months. *Vehicle #1 remained stable at 2-8°C and 25°C after 8 months and at 30°C and 40°C after 3 months, meeting USP PFAT5 requirements (≤0.05%). Phase separation was observed at 30°C and 40°C after 8 months. *A significant increase in Z-average (nm) of approximately 80-110 and 160 for F57#1 was observed at 30°C and 40°C after 3 months, respectively. *Significant increases in Z average (nm) of approximately 70 to 120 and 150 for Vehicle#1 were observed at 30°C and 40°C, respectively, after 3 months. *The appearance of all 2-8°C stability samples remained unchanged after 8 months and were off-white to yellow translucent emulsions. Their pH remained neutral (pH > 6). *The appearance of all 30°C and 40°C stability samples became slightly opaque after 3 months. A decrease in pH to 4 was observed in the 40°C samples after 3 months.

[0192] Example 11: Free Fatty Acid (FFA) and Peroxide Analysis

[0193] Vehicle formulation (Vehicle#2) and Compound A emulsion (F57#2) were prepared at a 14 kg scale. The compositions are shown in Table 38. Free fatty acid (FFA) and peroxide content were analyzed at 3 and 6 months and are shown in Table 39.

[0194] [Table 57]

[0195] [Table 58]

[0196] Example 12: Analysis of precipitates in 2.5 mg / mL emulsions

[0197] In later batches prepared, including one GMP batch (2.5 mg / mL), precipitation was detected after a short time at 2-8°C.

[0198] A study was conducted to determine the saturated solubility of Compound A (Form A) in F57 vehicle. The precipitate in the GMP batch was collected and examined for crystal structure and found to be Form B.

[0199] The precipitation reaction was speculated to be due to the following reasons: 1. Compound A was converted from Form A to Form B, which is less soluble in F57; and 2. The concentration of Compound A in F57 exceeded the solubility of Compound A in the F57 vehicle, resulting in supersaturation, which delayed the precipitation reaction. The precipitation reaction time varied from one month to over a year.

[0200] As used herein, the term "solubility" is defined as the concentration of compound A at which compound A reaches dissolution-precipitation equilibrium in F57 at a selected temperature. If the concentration of compound A in F57 is below its solubility, compound A will not precipitate. On the other hand, if the concentration of compound A is higher than its solubility, compound A is expected to precipitate over time.

[0201] To accurately determine the solubility of Compound A in F57, it was important to ensure the following: *Solubility was determined when the dissolved precipitate reached equilibrium; *Equilibrium was reached in actual time (i.e., 1-2 months or less instead of 1-2 years); *The relationship between solubility and crystalline form (A or B) is well understood.

[0202] To investigate the cause of precipitation and determine the solubility of Compound A in the F57 vehicle, the following seven methods were applied to accurately determine the solubility of Compound A in F57:

[0203] Method 1: Compound A is formulated in F57 at various concentrations using GMP grade of Compound A and excipients following a regulatory process.

[0204] Method 2: Compound A is formulated in F57 by incorporating Compound A into a preformed F57 vehicle.

[0205] Method 3: Observe Compound A in pre-made batches that have already undergone extended incubation.

[0206] Method 4: Conduct "top-down" and "bottom-up" solubility studies in F57 vehicle.

[0207] Method 5: A Compound A GMP batch of F57 is stirred to induce dissolution-precipitation equilibrium.

[0208] Method 6: Extra Form B seeds are added to a Compound A GMP batch of F57 to facilitate Compound A crystal growth and precipitation.

[0209] Method 7: Form B seeds are added to the sample produced in Method 1 to promote crystal growth and precipitation of Compound A.

[0210] Solubility and HPLC Methods for Determining Compound A Concentration in F57

[0211] For solubility determination, an F57 sample (usually about 0.5 mL) was filtered through a 0.22 μm centrifuge filter (Costar Spin-XR+, P / N 8169), and the filtrate (not containing any solid particulates) was collected, diluted with isopropanol, and tested for Compound A concentration using the following HPLC method: Once the measured concentration of the filtrate is constant, dissolution-precipitation equilibrium has been reached and that concentration can be considered the solubility.

[0212] [Table 59]

[0213] equilibrium method Table 40 summarizes the general conditions used in the seven methods to induce dissolution-precipitation equilibrium. Detailed procedures are provided in each method paragraph.

[0214] [Table 60]

[0215] Method 1 procedure: Four batches (batch size: 1 L) of Compound A emulsion were prepared, each containing 1.5, 2.0, 2.5, and 3.0 mg / mL of Compound A. The composition of each batch is shown in Table 41 below.

[0216] [Table 61]

[0217] *The water phase, oil phase, and coarse emulsion were synthesized and processed according to GMP batch processes. *Complete drug dissolution in the oil phase and final coarse emulsion was verified and ensured (visually and microscopically). Critical process parameters were recorded. Transfer 100 mL of each final coarse emulsion into containers and store at 2-8°C and 25°C for evaluation by appearance and microscopy after 24 and 48 hours. *The remaining 800 mL of coarse emulsion was processed through a Microfluidizer® to reach an average droplet size of NMT 100 nm. *Each MF-treated emulsion was passed through a 0.22 μm filter and 50 mL was filled into Type I 100 cc glass vials, stoppered and crimp-sealed as per GMP process. *Sufficient vials were placed at 2-8°C and 25°C for stability testing (7 vials at each condition). *Stability vials were removed at weeks 0, 1, 2, and 4 to test for appearance, microscopy, pH, and concentration. *In case of drug precipitation in the vial, the supernatant of the emulsion sample was used for HPLC testing.

[0218] result: All samples were visually clear and remained at the same pH value after 4 weeks of storage at both 2-8°C and 25°C. The concentrations of each sample are listed in Table 42. Considering that the GMP batch showed crystalline precipitation after 1 month, this result indicated that precipitation was likely a random process. Seeding was applied to all samples to induce and accelerate the precipitation process.

[0219] [Table 62]

[0220] Method 2 procedure: *Six emulsions (1 g each) containing approximately 1.0, 1.5, 2.0, 2.5, 3.0, and 3.5 mg / mL of Compound A (Form A) were prepared by mixing Compound A and preformed F57 vehicle. *Compound A (Form A) and F57 vehicle were weighed out in polypropylene vials. *Mixed to achieve complete drug dissolution or saturation (high speed bead beater, 600 seconds). *Samples (without 0.2 μm filtration) were stored at 2-8°C. *Examination was performed for appearance and microscopy at 0 and 48 hours. Results were recorded. *If there was no sign of precipitation in any sample after 1 week, each sample was seeded with 1-2 mg of Compound A (Form B) crystals. *Each sample was mixed gently to disperse the crystals. *Continue to store samples at 2-8°C (all samples should contain crystals at this stage). *0.5 mL of supernatant from each 2-8°C sample was tested and passed through a Spin-X 0.2 μm for HPLC assay after 1, 2, and 5 weeks.

[0221] result: All samples were visually clear one week after preparation. As shown in Table 43, after seeding with Compound A Form B crystals, samples at concentrations above 2.0 mg / mL began to decrease in API concentration, reaching a plateau (1.82-1.93 mg / mL) after two weeks. Samples (B1 and B2) that started at concentrations lower than 1.5 mg / mL slowly increased their API concentration. These results suggested that the Compound A API dissolution-precipitation equilibrium in F57 was 2.0-1.5 mg / mL. Therefore, the previous batch containing the API at 2.5 mg / L was supersaturated.

[0222] [Table 63]

[0223] Method 3 procedure: A sample was taken from a previously prepared batch and the concentration was determined by HPLC. Results:

[0224] The concentrations of the API in the previous batches (GMP batch and F57#1) were determined and listed in Table 44. Samples from the same batch (F57#1) showed different dissolution stabilities. One bottle of sample was still clear, but there was no decrease in concentration. On the other hand, another bottle showed visible precipitation, and the concentration dropped to 1.84 mg / mL. This result suggested that the precipitation of the API in the supersaturated solution was an opportunistic process. However, this result did not allow for a conclusion as to whether the API in those two batches had reached dissolution-precipitation equilibrium.

[0225] [Table 64]

[0226] Method 4 procedure: The top-down method used high-energy homogenization to dissolve a set amount of Compound A (Form A) in F57 vehicle to achieve supersaturation, thereby allowing precipitation to occur over time to reach dissolution-precipitation equilibrium in F57. The solubility of Compound A in F57 vehicle was then determined.

[0227] The bottom-up method utilized gentle mixing to slowly dissolve Compound A (Form A) in F57 vehicle to reach dissolution-precipitation equilibrium in F57. The solubility of Compound A in F57 vehicle was then determined. *Top-down method: Add Form A and B of API to separate tubes containing F57 vehicle, then apply high energy to each tube using a homogenizer (BB, 600 seconds) to obtain a clear solution, and store each tube at 2-8°C. *Bottom-up method: Add Forms A and B of API to separate tubes containing F57 vehicle and gently shake each tube on a platform shaker at 2-8°C. *Remove sample aliquots on day 1, day 2, week 1, and week 4 to test for appearance and concentration.

[0228] result: In the "top-down" approach, crystals of Forms A and B were dissolved in F57 vehicle at strengths of 2.69 and 3.00 mg / mL, respectively. After 4 weeks of storage at 2-8°C, the concentrations of each remained the same, as shown in Table 45, indicating that no precipitation occurred.

[0229] [Table 65]

[0230] In the "bottom-up" approach, the API spontaneously dissolved into the emulsion vehicle and reached equilibrium (Table 46) without the application of extensive energy. Overall, Form A crystals exhibited a faster dissolution rate than Form B crystals. The solubility of both crystalline forms could reach 1.8 mg / mL at 2-8°C in 7 weeks. This result further confirmed that the API in the previous GMP batch was supersaturated.

[0231] [Table 66]

[0232] Method 5 procedure: Shake the GMP batch vials on a platform shaker at 2-8 °C and 25 °C, respectively. Remove sample aliquots at weeks 0, 2, 5, 6, and 9 to test for appearance and concentration.

[0233] result: The GMP batch showed precipitation one month after preparation, but the concentration was still 2.26 mg / mL after five months. To find the final dissolution-precipitation equilibrium state early, agitation was applied to accelerate the precipitation process because agitation can increase the exposure of seeds in solution. As shown in Table 47, the concentration of API in the F57 GMP batch decreased to 1.88 mg / mL within a few weeks and reached equilibrium after five weeks.

[0234] [Table 67]

[0235] Method 6 procedure: Aliquot the GMP batch into small glass vials, seed each with Form B, and shake the vials on a platform at 2-8°C and 25°C, respectively. Remove sample aliquots at weeks 0, 2, 5, 6, and 9 to test for appearance and concentration.

[0236] result: Additional seeding of the API into the F57 GMP batch showed results consistent with the agitation test. The data also confirmed that the API solubility in F57 was in the range of 1.8-1.9 mg / mL at 2-8°C.

[0237] [Table 68]

[0238] Method 7 procedure Add Form B crystals (1 mg per 1 mL) to A1-A4 (samples made in paragraph 3.1) and shake the vials on a platform shaker at 2-8 °C. Remove sample aliquots at weeks 0, 2, 3, and 5 to test for appearance and concentration.

[0239] result Samples prepared by Method 1 were clear after 1 month at 2-8°C. Form B crystals were added to each to initiate and accelerate the precipitation process. The concentrations of all samples decreased to 1.8-1.9 mg / mL in 2 weeks and remained within that range for the remainder of the study (Table 49).

[0240] [Table 69]

[0241] Summary of Methods The general observations and findings from all seven methods are summarized in Table 50 based on detailed observations and discussions related to each method.

[0242] [Table 70]

[0243] Conclusion: *All methods indicated that Compound A (Form A) solubility in F57 was in the range of 1.8-1.9 mg / mL at 2-8°C. *Precipitation of Compound A (Form A) from previous batches was due to supersaturation. *Precipitation was predominant in Form B.

[0244] Example 13: Stability of 1.6 mg / mL emulsion

[0245] The stability of 1.6 mg / mL was evaluated as shown in Tables 51 (T=0), 52A and 52B (T=1 month), and 53A and 53B (T=3 months).

[0246] [Table 71]

[0247] [Table 72]

[0248] [Table 73]

[0249] [Table 74]

[0250] [Table 75]

[0251] Example 14: Nanosuspension Formulation

[0252] Five different cryoprotectants were prepared and evaluated: 10% sucrose, 2% sucrose + 5% mannitol, 5% sucrose + 5% mannitol, 10% trehalose, and 2% trehalose + 5% mannitol, containing polyvinylpyrrolidone (PVP) and sodium deoxycholate formulations.

[0253] Procedure for 10% sucrose nanosuspension: *Compound A (Form A) at 100 mg / mL was ground in 1% PVP and 0.25% sodium deoxycholate. *Diluted to 50 mg / mL in 20% sucrose (10% final sucrose concentration). *4 mL of 50 mg / mL suspension was filled into a 10 mL vial. *Lyophilized at -36°C and 100 mTorr until dry. *To determine the amount of WFI to use for reconstitution, loss on drying was determined by weighing vials before and after lyophilization (n=5).

[0254] The powder formulation was resuspended to 50 mg / mL based on solid content, allowed to stand at ambient temperature, and serially diluted to 10 and 1 mg / mL using D5W. The formulation was tested: by light microscopy and particle size distribution (5 hours and 1 day), and assay and related substances. result: PSD and OM: No discernible change over 24 hours in either formulation.

[0255] [Table 76]

[0256] [Table 77]

[0257] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Many modifications, changes, and substitutions will occur to those skilled in the art without departing from the invention. It is understood that various alternatives to the embodiments of the invention described herein may be utilized in practicing the invention. The following claims define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. A pharmaceutical composition comprising N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide and a pharmaceutically acceptable excipient; The N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide is a crystal, Here, crystalline N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide has the following properties: (a) X-ray powder diffraction (XRPD) pattern as set forth in Figure 1 below; (b) X-ray powder diffraction (XRPD) pattern including characteristic peaks at 13.8° 2-theta, 4.2° 2-theta, 16.8° 2-theta, 19.2° 2-theta, 19.7° 2-theta, 21.1° 2-theta, 22.5° 2-theta, 22.7° 2-theta, 26.5° 2-theta, and 27.5° 2-theta. The pharmaceutical composition is crystalline form A having at least one of:

2. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated as a homogenous liquid, emulsion, nanosuspension, or powder for reconstitution.

3. 3. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered by injection once reconstituted with an aqueous carrier.

4. 4. The pharmaceutical composition of claim 2 or 3, wherein the pharmaceutical composition is formulated as an emulsion.

5. 5. The pharmaceutical composition of claim 4, wherein the emulsion is administered by injection.

6. Pharmaceutically acceptable excipients include lecithin, soybean oil (SBO), medium chain triglycerides (MCT), cholesterol, vitamin E succinate (VES), sucrose, glycerin, and EDTA-Na. ２ 6. The pharmaceutical composition of any one of claims 1 to 5, wherein the compound is selected from the group consisting of:

7. (i) lecithin, (ii) medium chain triglycerides (MCTs); (iii) glycerin, and (iv) water 7. The pharmaceutical composition of claim 1, further comprising:

8. 2. The pharmaceutical composition of claim 1, wherein N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide is present in the emulsion at a concentration of less than 1.8 mg / mL.

9. 2. The pharmaceutical composition of claim 1, wherein N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide is present in the emulsion at a concentration of 1.6 mg / mL.

10. 10. The pharmaceutical composition of claim 1, wherein N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide is present in a concentration of 0.1% to about 1% (w / w).

11. 11. The pharmaceutical composition of claim 10, wherein N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide is present in a concentration of 0.1% to about 0.3% (w / w).

12. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is stable at about 5±3°C for at least 3 months.

13. 4. The pharmaceutical composition of any one of claims 1-3, wherein the pharmaceutical composition is formulated as a powder for reconstitution.

14. (i) polyvinylpyrrolidone (PVP); (ii) sodium deoxycholate, and (iii) sucrose further comprising: A pharmaceutical composition according to any one of claims 1-4 or 13.

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