Solid dispersion comprising an sGC stimulant

Abstract

To provide a sGC stimulator useful to treat many NO and / or cGMP related disorders or reduce their severity.SOLUTION: The present invention relates to solid dispersions of amorphous 1,1,1,3,3,3-hexafluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)propan-2-ol or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001]

[0001] The present invention relates to amorphous 1,1,1,3,3,3-hexafluoro-2-(((5- The present invention relates to a solid dispersion of fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)propan-2-ol (Compound I) or a pharma- ceutically acceptable salt thereof. It also relates to pharmaceutical compositions and medical oral unit dosage forms comprising them and their uses.

[0002] [ka] [Background technology]

[0003]

[0002] The heme-containing enzyme soluble guanylate cyclase (sGC) is a catalyzer that converts nitric oxide (NO ) in vivo. sGC is a primary receptor for NO-dependent and NO-independent mechanisms. In response to this activation, sGC converts guanosine triphosphate (GTP) to the second messenger cyclic guanosine monophosphate (cGMP). Increased levels of cGMP in turn regulate the activity of downstream effectors, including protein kinases, phosphodiesterases (PDEs), and ion channels.

[0004]

[0003] Experimental and clinical evidence supports the reduced bioavailability and / or endoscopy of NO. Studies have shown that reduced responsiveness to intrinsically produced NO contributes to the development of vascular, endothelial, inflammatory, fibrotic, and metabolic processes or diseases. Disruption of sGC and / or reduced NO bioavailability has been implicated in the pathogenesis of, for example, cardiovascular, pulmonary, renal, and hepatic diseases.

[0005] In the body, NO is synthesized by the synthesis of arginine and oxygen through the enzymes nitric oxide synthase (NIS). NOS is synthesized by the endothelial cell membrane (ECM) and by the continuous reduction of inorganic nitrate. Three distinct isoforms of NOS have been identified: inducible NOS (i-NOS or NOS II), found in activated macrophage cells; constitutive / neuronal NOS (nNOS or NOS I), involved in neurotransmission and long-term potentiation; and constitutive / endothelial NOS (eNOS or NOS III), which regulates smooth muscle relaxation and blood pressure.

[0006]

[0005] NO-independent, heme-dependent sGC stimulators, such as Compound I, inhibit soluble guar They are molecules that stimulate sGC activity and have several important features that differentiate them from activators, including a critical dependence of their activity on the presence of the reduced prosthetic heme moiety, a strong synergistic enzyme activation when bound to NO, and a direct stimulation of sGC, independent of NO, leading to stimulation of cGMP synthesis. The benzylindazole compound YC-1 was the first sGC stimulator to be identified. Additional sGC stimulators with improved potency and specificity have been developed.

[0007] Adempas® (riociguat) is the first drug to receive FDA regulatory approval. It is the first sGC stimulator. Currently, it is approved for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). Adempas® is taken orally three times a day and must be titrated very carefully on a patient-by-patient basis due to the variable risk of serious adverse events such as hypotension (low blood pressure).

[0008]

[0007] Therefore, a new and improved sGC stimulation method that avoids some of these problems is proposed. There is a need for drugs and their pharmaceutical compositions and unit dosage forms. Additionally, there is a need for methods of treating NO- and cGMP-related diseases or disorders using said drugs and their pharmaceutical compositions and unit dosage forms. Summary of the Invention

[0009] In a first aspect, the present invention provides an amorphous 1,1,1,3,3,3-hexafluorophenyl ether. The present invention relates to a solid dispersion of oro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)propan-2-ol (Compound I) or a pharma- ceutically acceptable salt thereof. Compound I has the structure depicted below and is an sGC stimulant useful for treating or reducing the severity of a number of NO and / or cGMP-related disorders.

[0010] [ka]

[0011] In a second aspect, the present invention provides a pharmaceutical composition comprising at least one pharma- ceutical acceptable excipient. and a solid dispersion of amorphous 1,1,1,3,3,3-hexafluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)propan-2-ol (Compound I) or a pharma- ceutically acceptable salt thereof.

[0012]

[0010] In a third aspect, the present invention relates to a unit dosage form described herein comprising a solid dispersion of amorphous 1,1,1,3,3,3-hexafluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)propan-2-ol (Compound I) or a pharma- ceutically acceptable salt thereof.

[0013] In a fourth aspect, the present invention relates to a unit dosage form comprising the pharmaceutical composition described herein.

[0012] In a fifth aspect, the present invention relates to the amorphous solid dispersion, pharmaceutical composition, or single The present invention relates to a method for treating an sGC- and / or cGMP-associated disorder by administering one of the dosage forms to a patient in need thereof. [Brief description of the drawings]

[0014]

[0013] [Figure 1] FIG. 1 shows the XRPD pattern of a polymer-free spray-dried dispersion of Compound I of the present invention after 2 hours of production, overlaid with the XRPD pattern of pure crystalline Compound I. [Diagram 2] FIG. 2 illustrates XRPD patterns under various conditions for an embodiment of a spray-dried dispersion of the present invention with a CAP polymer.

[0015] [Diagram 3] FIG. 3 shows XRPD patterns under various conditions for an embodiment of a spray dried dispersion of the present invention with an HRMCAS-M polymer.

[0016] [Figure 4] FIG. 4 illustrates the as-prepared XRPD patterns for various spray dried dispersions of the present invention.

[0017] [Diagram 5] FIG. 5 illustrates XRPD patterns under various conditions and at various times for an embodiment of a spray dried dispersion of the present invention.

[0018] [Figure 6] FIG. 6 illustrates XRPD patterns under various conditions and at various times for an embodiment of a spray dried dispersion of the present invention.

[0019] [Figure 7] FIG. 7 illustrates XRPD patterns at the time of manufacture (time 0) for various spray dried dispersions of the present invention.

[0020] [Figure 8] FIG. 8 is a chart showing the kinetic solubility in FaSSIF of various dispersants of the present invention.

[0021] [Figure 9]FIG. 9 is a chart showing the kinetic solubility in FeSSIF of various dispersants of the present invention.

[0022] [Figure 10] FIG. 10 illustrates the dissolution in FaSSIF of various tablets containing amorphous spray-dried dispersions of Compound I.

[0023] [Figure 11] FIG. 11 shows the dissolution of a batch of 5 mg tablets prepared as described in an embodiment of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015]

[0024] In a first aspect, the present invention relates to a solid dispersion of amorphous 1,1,1,3,3,3-hexafluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)propan-2-ol (Compound I) or a pharma- ceutically acceptable salt thereof. Compound I, having the structure depicted below, is an sGC stimulant useful for treating or reducing the severity of a number of NO and / or cGMP-related disorders.

[0016] [ka]

[0017]

[0025] For purposes of this disclosure, "compound" includes pharma- ceutically acceptable salts of said compound, unless the term "pharmaceutically acceptable salt" is expressly noted.

[0026] The phrase "pharmaceutical acceptable salt" as used herein refers to a pharmaceutical acceptable organic or inorganic salt of compound I. The pharmaceutical acceptable salt of compound I is used in medicine. However, non-pharmaceutical acceptable salts may be useful in the preparation of compound I or its pharmaceutical acceptable salts. A pharmaceutical acceptable salt may involve the inclusion of another molecule, such as an acetate ion, a succinate ion, or other counterion. A counterion may be any organic or inorganic moiety that stabilizes the charge of the parent compound. In addition, a pharmaceutical acceptable salt may have more than one charged atom in its structure. The case where multiple charged atoms are part of a pharmaceutical acceptable salt may have multiple counterions. Thus, a pharmaceutical acceptable salt may have one or more charged atoms and / or one or more counterions.

[0018]

[0027] Pharmaceutically acceptable salts of Compound I include those derived from certain compounds of inorganic or organic acids or bases. In some embodiments, the salts can be prepared in situ during the final isolation and purification of the compound. In other embodiments, the salts can be prepared in situ during the final isolation and purification of the compound. can be prepared from the free form of the compound in a separate synthetic step.

[0019]

[0028] Salts of Compound I may be prepared from pharma- ceutically acceptable, non-toxic acids, including inorganic and organic acids. Such acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucoic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like. Particular embodiments include citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid. Other exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid) salts.

[0020]

[0029] The preparation of the pharma- ceutically acceptable salts described above, as well as other exemplary pharma- ceutically acceptable salts, is more fully described by Berg et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977:66:1-19, which is incorporated herein by reference in its entirety.

[0021]

[0030] As used herein, the term "dispersion" refers to a dispersion in which a first substance, the "dispersed phase," is dispersed in a second substance, the "continuous phase" or "vehicle" or "Dispersant" or "Dispersing medium" or "Matrix" or "Carrier" "Dispersion" refers to a system in which the dispersed phase is distributed in discrete units throughout a solid, liquid, or gas. The dispersed and continuous phases may be in the same or different physical states, and therefore may be solids, liquids, or gases. The size of the dispersed phase particles may vary, so dispersions are classified as solutions, colloids, or suspensions, depending on the size of the dispersed phase particles. Some common dispersion types are, for example, solutions, aerosols, solid aerosols, gels, emulsions, foams, and solid foams.

[0022]

[0031] A "solid dispersion" is a dispersion in which both the dispersed phase and the matrix are solids. Typically, a solid active pharmaceutical ingredient (API), such as Compound I, is dispersed in a second inert carrier or vehicle, usually a polymer, to form a solid-state homogeneous mixture. In some cases, the solid dispersion contains a polymer as the dispersed phase and a drug or API as the continuous phase. More typically, the API is the dispersed phase and the polymer is the matrix. Solid dispersions have been successfully applied to improve the solubility, dissolution rate and, consequently, bioavailability of poorly soluble drugs.

[0023]

[0032] Solid dispersions are usually prepared by creating a homogenous solution or melt of two solid components, either alone or in the presence of other additives (i.e., pharma- ceutically acceptable additives or excipients), and then solidifying the mixture by either cooling or removing the solvent. A variety of techniques may be used to accomplish this. For example, the solvent may be removed by vacuum drying, spray drying, tray drying, freeze drying, lyophilization, or similar procedures. In the case of a melt, hot-melt extrusion may be used to prepare the solid dispersion.

[0024]

[0033] A solid dispersion of Compound I can be, for example, a co-precipitate or co-melt of Compound I with at least one polymeric carrier. A "co-precipitate" is a solid dispersion obtained after dissolving a drug (e.g., Compound I) and a polymeric carrier in a solvent or solvent mixture, followed by removal of the solvent or solvent mixture. The solvent or solvent mixture can include organic solvents and supercritical fluids. A "co-melt" is a solid dispersion obtained after heating a drug (e.g., Compound I) and a polymeric carrier to a melt, with or without the presence of a solvent or solvent mixture, followed by mixing, removal of at least a portion of the solvent, if applicable, and cooling to room temperature at a selected rate.

[0025]

[0034] A "crystalline" solid is one in which the structural units are arranged in a definite geometric pattern or lattice, such that the crystalline solid has strict long-range order. The structural units that make up the crystal can be atoms, molecules, or ions. A crystalline solid exhibits a definite melting point. A crystalline material displays sharp, characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern.

[0026]

[0035] Other analytical techniques that may be used to determine the level of crystallinity of a solid (eg, a solid dispersion) or the stability of its amorphous form include, for example, differential scanning calorimetry (DSC) or microscopy.

[0027]

[0036] The term "amorphous," as used herein, refers to a solid material that does not have the long-range order in the positions of its ions, atoms, or molecules characteristic of a crystal. Amorphous materials have one or more broad peaks (or "halos") in their XRPD patterns instead of sharp peaks.

[0028]

[0037] In pharmaceutical applications, a solid dispersion may comprise a crystalline drug or API (dispersed phase) dispersed in an amorphous continuous phase (e.g., a polymer) or may comprise an amorphous drug or API dispersed in an amorphous continuous phase (e.g., a polymer). An "amorphous solid dispersion" is one in which the dispersed phase is amorphous. The dispersion of the present invention is a solid dispersion of amorphous Compound I.

[0029]

[0038] The amorphous solid dispersion of the present invention contains Compound I in its amorphous state. , has low solubility in aqueous media and easily crystallizes out of solution. This effect is pH independent. It has been found that certain solid dispersions of amorphous Compound I can maintain Compound I in a stable amorphous state in aqueous media and other use environments, preventing crystallization and exhibiting improved solubility, as compared to Compound I itself (i.e., pure Compound I). Solid amorphous dispersions of Compound I exhibit enhanced solubility when compared to Compound I in the absence of a dispersant polymer. The compound exhibits improved physical stability and / or solubility and / or dissolution rate.

[0030]

[0039] In some embodiments, the solid dispersion of amorphous Compound I of the present invention comprises substantially amorphous Compound I and a polymeric carrier. As used herein, the term "solid dispersion of amorphous Compound I" is used interchangeably with the term "solid amorphous dispersion of Compound I."

[0031]

[0040] As used herein, the term "substantially amorphous Compound I" is used interchangeably with the term "amorphous Compound I substantially free of crystalline Compound I". In some embodiments, the substantially amorphous Compound I comprises less than about 20% crystalline Compound I, less than about 15% crystalline Compound I, less than about 10% crystalline Compound I, less than about 8% crystalline Compound I, less than about 5% crystalline Compound I, less than about 2% crystalline Compound I, less than about 1% crystalline Compound I, or less than about 0.5% crystalline Compound I. In other embodiments, the amorphous Compound I is substantially free of crystalline Compound I as determined by XRPD, DSC, or microscopy.

[0032]

[0041] As used herein, the term "substantially free" is used to describe amorphous compound I containing less than about 20% crystalline compound I. In some embodiments, "substantially free" is used to describe amorphous compound I containing less than about 15% crystalline compound I. In some embodiments, "substantially free" is used to describe amorphous compound I containing less than about 10% crystalline compound I. In some embodiments, "substantially free" is used to describe amorphous compound I containing less than about 8% crystalline compound I. In some embodiments, "substantially free" is used to describe amorphous compound I containing less than about 5% crystalline compound I. In some embodiments, "substantially free" is used to describe amorphous compound I containing less than about 2% crystalline compound I. In some embodiments, "substantially free" is used to describe amorphous compound I containing less than about 1% crystalline compound I. In some embodiments, "substantially free" is used to describe amorphous compound I containing less than about 0.5% crystalline compound I.

[0033]

[0042] In some embodiments, the solid dispersion of amorphous Compound I of the present invention comprises less than about 20% crystalline Compound I, less than about 15% crystalline Compound I, less than about 10% crystalline Compound I, less than about 8% crystalline Compound I, less than about 5% crystalline Compound I, less than about 2% crystalline Compound I, less than about 1% crystalline Compound I, or less than about 0.5% crystalline Compound I. In other embodiments, the solid dispersion of amorphous Compound I is substantially free of crystalline Compound I as determined by XRPD, DSC, or microscopy. In some embodiments, the solid dispersion of amorphous Compound I is a stable solid dispersion of amorphous Compound I.

[0034]

[0043] In some embodiments, the solid dispersions of amorphous Compound I are characterized by X-ray powder diffraction patterns at time 0 substantially similar to those shown in FIG. 4 for any of Dispersants 5 through 13.

[0035]

[0044] In some embodiments, the solid amorphous dispersion of Compound I is characterized by the absence of any distinct crystalline form when analyzed by microscopy.

[0045] In some embodiments, the solid amorphous dispersion of Compound I is characterized by the absence of recrystallization or melting events when analyzed by DSC.

[0036]

[0046] The term "stable solid dispersion of amorphous Compound I," as used herein, refers to a dispersion that, when kept under certain storage conditions for a given period or time, is stable enough to form a solid dispersion of crystalline Compound I. The term "solid dispersion" refers to a solid dispersion of amorphous Compound I (i.e., substantially amorphous Compound I) in which the amount of

[0037]

[0047] In some embodiments, the above storage conditions involve a temperature of 25° C. and a relative humidity (RH) of 60%. Throughout this disclosure, the above storage conditions are referred to as Stability Chamber conditions. In other embodiments, the storage conditions involve a temperature of 40° C. and a relative humidity (RH) of 75%. Throughout this disclosure, the storage conditions are referred to as stability chamber 2 conditions. In some embodiments, the solid amorphous dispersion of Compound I is placed under the stability conditions of Stability Chamber 1 or Stability Chamber 2 in a non-sealed vial (also referred to as open tray conditions). In other embodiments, the solid amorphous dispersion of Compound I is placed under the stability conditions of Stability Chamber 1 or Stability Chamber 2 in a sealed bottle (e.g., HDPE (high density polyethylene) bottle). In other embodiments, the solid amorphous dispersion of Compound I is placed under the stability conditions of Stability Chamber 1 or Stability Chamber 2 in a sealed bottle (e.g., HDPE bottle) either in the presence or absence of a desiccant. In some embodiments, the desiccant is selected from silica gel. In other embodiments, the desiccant is selected from molecular sieves.

[0038]

[0048] In some embodiments, the stable solid dispersion of amorphous compound I remains substantially free of crystalline compound I in stability chamber 1 for at least 12 months when stored in a vial. In some embodiments, the stable solid dispersion of amorphous compound I remains substantially free of crystalline compound I in stability chamber 1 for at least 6 months when stored in a vial. In other embodiments, the stable solid dispersion of amorphous compound I remains substantially free of crystalline compound I in stability chamber 1 for at least 4 months when stored in a vial. In still other embodiments, the stable solid dispersion of amorphous compound I remains substantially free of crystalline compound I in stability chamber 1 for at least 3 months when stored in a vial. In yet other embodiments, the stable solid dispersion of amorphous compound I remains substantially free of crystalline compound I in stability chamber 1 for at least 2 months when stored in a vial. In some embodiments, the stable solid dispersion of amorphous Compound I remains substantially free of crystalline Compound I for at least one month in stability chamber 1 when stored in a vial.

[0039]

[0049] In some embodiments, the stable solid dispersion of amorphous compound I remains substantially free of crystalline compound I in stability chamber 1 for at least 12 months when stored in a sealed bottle. In some embodiments, the stable solid dispersion of amorphous compound I remains substantially free of crystalline compound I in stability chamber 1 for at least 6 months when stored in a sealed bottle. In other embodiments, the stable solid dispersion of amorphous compound I remains substantially free of crystalline compound I in stability chamber 1 for at least 4 months when stored in a sealed bottle. In still other embodiments, the stable solid dispersion of amorphous compound I remains substantially free of crystalline compound I in stability chamber 1 for at least 3 months when stored in a sealed bottle. In yet other embodiments, the stable solid dispersion of amorphous compound I remains substantially free of crystalline compound I in stability chamber 1 for at least 2 months when stored in a sealed bottle. In some embodiments, the stable solid dispersion of amorphous Compound I remains substantially free of crystalline Compound I for at least one month in stability chamber 1 when stored in a sealed bottle. In some embodiments, the solid amorphous dispersion of Compound I is stored in the presence of a desiccant. In other embodiments, it is stored in the absence of a desiccant.

[0040]

[0050] In some embodiments, the stable solid dispersion of amorphous compound I remains substantially free of crystalline compound I in stability chamber 2 for at least 12 months when stored in a vial. In some embodiments, the stable solid dispersion of amorphous compound I remains substantially free of crystalline compound I in stability chamber 2 for at least 6 months when stored in a vial. In other embodiments, the stable solid dispersion of amorphous compound I remains substantially free of crystalline compound I in stability chamber 2 for at least 4 months when stored in a vial. In yet other embodiments, the stable solid dispersion of amorphous compound I remains substantially free of crystalline compound I in stability chamber 2 for at least 3 months when stored in a vial. In some embodiments, the stable solid dispersion of amorphous compound I remains substantially free of crystalline compound I in stability chamber 2 for at least 2 months when stored in a vial. In some embodiments, the stable solid dispersion of amorphous Compound I remains substantially free of crystalline Compound I for at least one month in stability chamber 2 when stored in a vial.

[0041]

[0051] In some embodiments, the stable solid dispersion of amorphous compound I remains substantially free of crystalline compound I in stability chamber 2 for at least 12 months when stored in a sealed bottle. In some embodiments, the stable solid dispersion of amorphous compound I remains substantially free of crystalline compound I in stability chamber 2 for at least 6 months when stored in a sealed bottle. In other embodiments, the stable solid dispersion of amorphous compound I remains substantially free of crystalline compound I in stability chamber 2 for at least 4 months when stored in a sealed bottle. In still other embodiments, the stable solid dispersion of amorphous compound I remains substantially free of crystalline compound I in stability chamber 2 for at least 3 months when stored in a sealed bottle. In yet other embodiments, the stable solid dispersion of amorphous compound I remains substantially free of crystalline compound I in stability chamber 2 for at least 2 months when stored in a sealed bottle. In some embodiments, the stable solid dispersion of amorphous Compound I remains substantially free of crystalline Compound I for at least one month in stability chamber 2 when stored in a sealed bottle. In some embodiments, the dispersion is stored in the absence of a desiccant. In other embodiments, it is stored in the presence of a desiccant.

[0042]

[0052] As used herein, a "use environment" or "use medium" refers to the "in vivo" environment of the gastrointestinal tract of an animal, particularly a human, or a test solution (e.g., a fasting solution (FaSSIF)). The "in vitro" environments of the two fluids are defined as Fasted State Simulated Intestinal Fluid (Fed State Simulated Intestinal Fluid) and FeSSIF (Fed State Simulated Intestinal Fluid). FaSSIF is characterized by a pH of 6.5, which mimics the pH that would characterize the small intestine of an animal, particularly a human, in a fasted state. FeSSIF is characterized by a pH of 5.8, which mimics the pH that would characterize the small intestine of an animal, particularly a human, in a fed state. Thus, as described in the Examples section, a solid dispersion of Compound I can be tested in vivo, or more conveniently, in vitro, to see if it is within the scope of the present invention.

[0043]

[0053] "Solubility testing of a solid amorphous dispersion of Compound I" in a use environment is performed by introducing a solid dispersion of Compound I into the use environment (e.g., a test tube solution as described in the previous paragraph) at given conditions of temperature, pressure, agitation rate, etc., removing aliquots of the solution at predetermined times, and analyzing the aliquots (e.g., using HPLC or other analytical techniques known in the art) to quantify the concentration of Compound I present in the solution at each time point. Throughout this disclosure, the terms "solubility testing" or "kinetic solubility testing" (or "kinetic solubility") are generally used only with respect to testing of solid dispersions of Compound I.

[0044]

[0054] As used herein, a "supersaturated solution of Compound I" refers to a solution that contains more Compound I than can be dissolved by a given solvent under normal circumstances, even if Compound I is soluble by itself in the absence of other components of the solid dispersion. A solution of the amorphous Compound I solid dispersion of the present invention is a supersaturated solution of Compound I in a certain use environment (e.g., FaSSIF or FeSSIF). A solid dispersion of amorphous Compound I is a solution of Compound I that is supersaturated in a certain use environment (e.g., FaSSIF or FeSSIF) in a certain use environment (e.g., FaSSIF or FeSSIF). It is within the scope of the present invention if the maximum supersaturation concentration of Compound I achievable with the solid dispersion, when solubility tested in FaSSIF or FeSSIF, is at least 1.5 times higher than the equilibrium concentration achieved by solubility testing a composition comprising an equivalent amount of Compound I in the absence of a dispersant polymer (e.g., pure Compound I, amorphous or crystalline, e.g., pure Compound I, spray-dried). In some embodiments, the solid dispersion of Compound I, when solubility tested in FaSSIF or FeSSIF, achieves a maximum supersaturation concentration (MSSC) of Compound I that is at least 20 times higher than a composition comprising an equivalent amount of Compound I in the absence of a dispersant polymer. In other embodiments, it is at least 15 times higher. In other embodiments, it is at least 10 times higher. In other embodiments, it is at least 5 times higher.

[0045]

[0055] When conducting solubility tests of solid amorphous dispersions of Compound I, the maximum supersaturated concentration of Compound I in solution is reached shortly after the dispersant dissolves in the use environment and then it decays as Compound I slowly precipitates out of solution or it remains the same if the given dispersant is capable of maintaining Compound I in a supersaturated state for a time longer than the test time. An example of this type of behavior is displayed in Figure 8.

[0046]

[0056] Polymers that are capable of maintaining Compound I in its supersaturated state in solution in a given use environment for extended periods of time are said to be better "stabilizers of amorphous Compound I," and solid amorphous dispersions of Compound I comprising said polymers are preferred embodiments of the present invention.

[0047]

[0057] In some embodiments, the amorphous Compound I solid dispersion of the present invention is characterized by a maximum supersaturation concentration of Compound I greater than 0.040 mg / mL when solubility tested in FaSSIF. In other embodiments, it is characterized by a maximum supersaturation concentration of Compound I between 0.040 mg / mL and 0.050 mg / mL when solubility tested in FaSSIF.

[0048]

[0058] In another embodiment, the amorphous Compound I solid dispersion of the present invention is characterized by a supersaturation concentration of Compound I between 0.040 mg / mL and 0.050 mg / mL after 2 hours of solubility testing in FaSSIF. In another embodiment, it is characterized by a supersaturation concentration of Compound I between 0.040 mg / mL and 0.050 mg / mL after 4 hours of solubility testing in FaSSIF. In another embodiment, it is characterized by a supersaturation concentration of Compound I between 0.040 mg / mL and 0.050 mg / mL after 24 hours of solubility testing in FaSSIF.

[0049]

[0059] In some embodiments, the amorphous Compound I solid dispersion of the present invention is characterized by a maximum supersaturation concentration of Compound I greater than 0.250 mg / mL when solubility tested in FeSSIF. In other embodiments, it is characterized by a maximum supersaturation concentration between 0.250 mg / mL and 0.450 mg / mL when solubility tested in FeSSIF. In other embodiments, it is characterized by a maximum supersaturation concentration between 0.250 mg / mL and 0.350 mg / mL when solubility tested in FeSSIF. In other embodiments, it is characterized by a maximum supersaturation concentration between 0.350 mg / mL and 0.450 mg / mL when solubility tested in FeSSIF.

[0050]

[0060] In another embodiment, the amorphous solid dispersion of Compound I of the present invention is characterized by a supersaturation concentration of Compound I between 0.250 mg / mL and 0.450 mg / mL after 1 hour of solubility testing in FeSSIF. In another embodiment, it is characterized by a supersaturation concentration of Compound I between 0.250 mg / mL and 0.450 mg / mL after 3 hours of solubility testing in FeSSIF. In another embodiment, it is characterized by a supersaturation concentration of Compound I between 0.250 mg / mL and 0.450 mg / mL after 3 hours of solubility testing in FeSSIF. In another embodiment, it is characterized by a supersaturation concentration of Compound I between 0.250 mg / mL and 0.450 mg / mL after 4 hours of solubility testing. In another embodiment, it is characterized by a supersaturation concentration of Compound I between 0.250 mg / mL and 0.450 mg / mL after 6 hours of solubility testing in FeSSIF.

[0051]

[0061] In some embodiments of the solid dispersion of amorphous compound I, the polymer carrier is a water-soluble or partially water-soluble polymer. In some embodiments, a mixture of more than one such polymer can be used in the solid dispersion of the present invention. In some embodiments of the solid dispersion of amorphous compound I, the at least one polymer carrier is selected from cellulose polymers. In other embodiments, the at least one polymer carrier is selected from polyvinylpyrrolidone (PVP)-based polymers.

[0052]

[0062] In some embodiments of the solid dispersion of amorphous Compound I, the at least one polymeric carrier is selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), or cellulose acetate phthalate (CAP). In some embodiments, the polymeric carrier is selected from HPMCAS or CAP. In other embodiments, the at least one polymeric carrier is selected from polyvinylpyrrolidone (PVP) or a copolymer of polyvinylpyrrolidone.

[0053]

[0063] In some embodiments, the polymer comprises between about 40% and about 95% of the total weight of the amorphous Compound I solid dispersion. In other embodiments, the polymer comprises between about 50% and about 95% of the total weight of the amorphous Compound I solid dispersion. In other embodiments, the polymer comprises between about 60% and about 95% of the total weight of the Compound I solid dispersion. In other embodiments, the polymer comprises between about 70% and about 95% of the total weight. In other embodiments, it comprises between about 75% and about 95% of the total weight. In other embodiments, it comprises between about 80% and about 95%. In other embodiments, it comprises between about 90% and about 95%. In some embodiments, the polymer comprises between about 40% and about 90% of the total weight of the amorphous Compound I solid dispersion. In other embodiments, the polymer comprises between about 50% and about 90% of the total weight of the amorphous Compound I solid dispersion. In some embodiments, the polymer comprises between about 40% and about 80% of the total weight of the solid dispersion of amorphous Compound I. In other embodiments, the polymer comprises between about 70% and about 90% of the total weight of the solid dispersion of amorphous Compound I. In some embodiments, the polymer comprises between about 75% and about 90% of the total weight of the solid dispersion of amorphous Compound I. In other embodiments, the polymer comprises between about 60% and about 95% of the total weight of the solid dispersion of amorphous Compound I. In still other embodiments, the polymer comprises between about 60% and about 90% of the total weight of the solid dispersion of amorphous Compound I.

[0054]

[0064] In some embodiments, the amorphous solid dispersion of compound I of the present invention comprises between about 5% and about 60% by weight of compound I. In some embodiments, the amorphous solid dispersion of compound I of the present invention comprises between about 5% and about 50% by weight of compound I. In other embodiments, the amorphous solid dispersion of compound I of the present invention comprises between about 5% and about 40% by weight of compound I. In other embodiments, the amorphous solid dispersion of compound I of the present invention comprises between about 10% and about 30%. In other embodiments, the amorphous solid dispersion of compound I of the present invention comprises between about 10% and about 25%. In still other embodiments, the amorphous solid dispersion of compound I of the present invention comprises between about 15% and about 40%. In still other embodiments, the amorphous solid dispersion of compound I of the present invention comprises between about 20% and about 30%.

[0055]

[0065] In some embodiments, the weight to weight ratio of compound I to polymer is between about 10:90 and about 50:50. In other embodiments, the ratio of compound I to polymer is between about 20:80 and about 40:60. In some embodiments, the ratio of compound I to polymer is between about 20:80 and about 50:50. In yet other embodiments, the ratio of compound I to polymer is about 25:75. In some embodiments, the ratio of compound I to polymer is about 50:50.

[0056]

[0066] In some embodiments, the solid dispersion of amorphous Compound I is obtained by spray drying. In other embodiments, the solid dispersion of amorphous Compound I is obtained by melt extrusion. Any spray drying or melt extrusion that results in the desired solid dispersion of amorphous Compound I can be used.

[0057]

[0067] In some embodiments, the solid dispersion of amorphous Compound I may include one or more excipients or pharma- ceutically acceptable excipients.

[0068] The additives in the solid dispersion may be added directly to the spray drying solution when the mixture is formed. For example, the additives may be dissolved or suspended in the solution as a slurry and then spray dried. Alternatively, the additives may be added following the spray drying process to aid in the formation of the final formulation.

[0058]

[0069] In a second aspect, the present invention relates to a pharmaceutical composition comprising a solid dispersion of amorphous Compound I and at least one pharmaceutical excipient. In some embodiments, the pharmaceutical composition comprises a filler. In some embodiments, the pharmaceutical composition comprises a disintegrant. In other embodiments, they comprise a lubricant. In some embodiments, the pharmaceutical composition of the present invention may comprise a binder and / or a glidant. In some embodiments, the pharmaceutical composition of the present invention comprises a glidant.

[0059]

[0070] Non-limiting examples of fillers include microcrystalline cellulose, lactose, mannitol, maltodextrin, other compressible sugars, dicalcium phosphate, calcium sulfate, other salts, or starch. In some embodiments, the filler is selected from microcrystalline cellulose, lactose, mannitol, maltodextrin, other compressible sugars, dicalcium phosphate, calcium sulfate, other salts, or starch. In some embodiments, the filler is selected from microcrystalline cellulose.

[0060]

[0071] Non-limiting examples of disintegrants include polyvinylpyrrolidone (PVP), croscarmellose sodium, or sodium starch glycolate. In some embodiments, the disintegrant is selected from polyvinylpyrrolidone (PVP), croscarmellose sodium, or sodium starch glycolate. In some embodiments, it is selected from croscarmellose sodium.

[0061]

[0072] Non-limiting examples of lubricants include magnesium stearate, calcium stearate, stearic acid, or glyceryl behenate. In some embodiments, the lubricant is selected from magnesium stearate, calcium stearate, stearic acid, or glyceryl behenate. In some embodiments, it is selected from magnesium stearate.

[0062]

[0073] Non-limiting examples of flow agents include silica, hydrophilic fumed silica, or Aerosil 200.

[0074] In some embodiments, the pharmaceutical compositions comprising the solid dispersion of amorphous Compound I of the present invention contain less than about 20% crystalline Compound I, less than about 15% crystalline Compound I, less than about 10% crystalline Compound I, less than about 8% crystalline Compound I, less than about 5% crystalline Compound I, less than about 2% crystalline Compound I, less than about 1% crystalline Compound I, or less than about 0.5% crystalline Compound I. In other embodiments, the pharmaceutical compositions of the present invention are substantially free of crystalline Compound I as determined by XRPD, DSC, or microscopy.

[0063]

[0075] The term "stable pharmaceutical composition comprising a solid dispersion of amorphous Compound I" as used herein means a pharmaceutical composition comprising a solid dispersion of amorphous Compound I (i.e., substantially amorphous Compound I) in which the amount of crystalline Compound I does not increase substantially when kept under a storage condition for a given period or time. In some embodiments, the pharmaceutical composition of the present invention is stable under the storage conditions of Stability Chamber 1 when stored in a vial for a period of up to 2 years. In other embodiments, the pharmaceutical composition of the present invention is stable under the storage conditions of Stability Chamber 1 when stored in a vial for a period of up to 12 months. In still other embodiments, the pharmaceutical composition of the present invention is stable under the storage conditions of Stability Chamber 1 when stored in a vial for a period of up to 6 months. In some embodiments, the pharmaceutical composition of the present invention is stable under the storage conditions of Stability Chamber 1 when stored in a vial for a period of up to 4 months. In other embodiments, the pharmaceutical composition of the present invention is stable under the storage conditions of Stability Chamber 1 when stored in a vial for a period of up to 3 months. In still other embodiments, the pharmaceutical composition of the present invention, when stored in a vial, is stable for a period of up to 2 months under the storage conditions of stability chamber 1. In yet other embodiments, the pharmaceutical composition of the present invention, when stored in a vial, is stable for a period of up to 1 month under the storage conditions of stability chamber 1.

[0064]

[0076] In some embodiments, the pharmaceutical composition of the present invention is stable under the storage conditions of stability chamber 1 when stored in a sealed bottle for a period of up to 2 years. In other embodiments, the pharmaceutical composition of the present invention is stable under the storage conditions of stability chamber 1 when stored in a sealed bottle for a period of up to 12 months. In still other embodiments, the pharmaceutical composition of the present invention is stable under the storage conditions of stability chamber 1 when stored in a sealed bottle for a period of up to 6 months. In some embodiments, the pharmaceutical composition of the present invention is stable under the storage conditions of stability chamber 1 when stored in a sealed bottle for a period of up to 4 months. In other embodiments, the pharmaceutical composition of the present invention is stable under the storage conditions of stability chamber 1 when stored in a sealed bottle for a period of up to 3 months. In still other embodiments, the pharmaceutical composition of the present invention is stable under the storage conditions of stability chamber 1 when stored in a sealed bottle for a period of up to 2 months. In still other embodiments, the pharmaceutical composition of the present invention is stable under the storage conditions of stability chamber 1 when stored in a sealed bottle for a period of up to 1 month.

[0065]

[0077] In some embodiments, the pharmaceutical composition of the present invention is stable under the storage conditions of stability chamber 2 when stored in a vial for a period of up to 2 years. In other embodiments, the pharmaceutical composition of the present invention is stable under the storage conditions of stability chamber 2 when stored in a vial for a period of up to 12 months. In still other embodiments, the pharmaceutical composition of the present invention is stable under the storage conditions of stability chamber 2 when stored in a vial for a period of up to 6 months. In some embodiments, the pharmaceutical composition of the present invention is stable under the storage conditions of stability chamber 2 when stored in a vial for a period of up to 4 months. In other embodiments, the pharmaceutical composition of the present invention is stable under the storage conditions of stability chamber 2 when stored in a vial for a period of up to 3 months. In still other embodiments, the pharmaceutical composition of the present invention is stable under the storage conditions of stability chamber 2 when stored in a vial for a period of up to 2 months. In still other embodiments, the pharmaceutical composition of the present invention is stable under the storage conditions of stability chamber 2 when stored in a vial for a period of up to 1 month.

[0066]

[0078] In some embodiments, the pharmaceutical composition of the present invention is stable under the storage conditions of stability chamber 2 when stored in a sealed bottle for a period of up to 2 years. In other embodiments, the pharmaceutical composition of the present invention is stable under the storage conditions of stability chamber 2 when stored in a sealed bottle for a period of up to 12 months. In still other embodiments, the pharmaceutical composition of the present invention is stable under the storage conditions of stability chamber 2 when stored in a sealed bottle for a period of up to 6 months. In some embodiments, the pharmaceutical composition of the present invention is stable under the storage conditions of stability chamber 2 when stored in a sealed bottle for a period of up to 4 months. In other embodiments, the pharmaceutical composition of the present invention is stable under the storage conditions of stability chamber 2 when stored in a sealed bottle for a period of up to 3 months. In still other embodiments, the pharmaceutical composition of the present invention is stable under the storage conditions of stability chamber 2 when stored in a sealed bottle for a period of up to 2 months. In still other embodiments, the pharmaceutical composition of the present invention is stable under the storage conditions of stability chamber 2 when stored in a sealed bottle for a period of up to 1 month.

[0067]

[0079] Compound I or its pharmaceutically acceptable salt can be formulated into pharmaceutical unit dosage form to provide an easily adjustable drug dosage and allow patient compliance with prescribed regimen.The pharmaceutical unit dosage form of Compound I or its pharmaceutically acceptable salt can be prepared for different routes and types of administration.Different medical conditions may require different routes of administration, so there may be different dosage forms for the same compound.

[0068]

[0080] In a third aspect, the present invention relates to a unit dosage form comprising a solid dispersion or pharmaceutical composition of amorphous Compound I as described herein. In some embodiments, the unit dosage form is suitable for oral administration. In some embodiments, the unit dosage form is selected from a capsule, a suspension, a powder, or a tablet. In other embodiments, it is a tablet.

[0069]

[0081] In some embodiments, the unit dosage form comprising the solid dispersion of amorphous Compound I further comprises at least one pharmaceutical excipient. In some embodiments, it is a coating agent. As a non-limiting example, the coating agent is selected from cellulose-based materials. In some embodiments, it is selected from PVP-based materials.

[0070]

[0082] In some embodiments, the unit dosage form comprising a stable solid dispersion of amorphous Compound I is substantially free of crystalline Compound I when stored in a vial and placed under the storage conditions of stability chamber 1 for a period of up to 2 years. In other embodiments, the unit dosage form is stable when stored in a vial under the storage conditions of stability chamber 1 for a period of up to 12 months. In yet other embodiments, the unit dosage form is stable when stored in a vial under the storage conditions of stability chamber 1 for a period of up to 6 months. In some embodiments, the unit dosage form is stable when stored in a vial under the storage conditions of stability chamber 1 for a period of up to 4 months. In other embodiments, the unit dosage form is stable when stored in a vial under the storage conditions of stability chamber 1 for a period of up to 3 months. In still other embodiments, the unit dosage form is stable when stored in a vial under the storage conditions of stability chamber 1 for a period of up to 2 months. In yet other embodiments, the unit dosage form, when stored in a vial, is stable under the storage conditions of stability chamber 1 for a period of up to one month.

[0071]

[0083] In some embodiments, the unit dosage form is stable under the storage conditions of stability chamber 1 when stored in a sealed bottle for a period of up to 2 years. In other embodiments, the unit dosage form is stable under the storage conditions of stability chamber 1 when stored in a sealed bottle for a period of up to 12 months. In still other embodiments, the unit dosage form is stable under the storage conditions of stability chamber 1 when stored in a sealed bottle for a period of up to 6 months. In some embodiments, the unit dosage form is stable under the storage conditions of stability chamber 1 when stored in a sealed bottle for a period of up to 4 months. In other embodiments, the unit dosage form is stable under the storage conditions of stability chamber 1 when stored in a sealed bottle for a period of up to 3 months. In still other embodiments, the unit dosage form is stable under the storage conditions of stability chamber 1 when stored in a sealed bottle for a period of up to 2 months. In still other embodiments, the unit dosage form is stable under the storage conditions of stability chamber 1 when stored in a sealed bottle for a period of up to 1 month.

[0072]

[0084] In some embodiments, the unit dosage form is stable under the storage conditions of stability chamber 2 when stored in a vial for a period of up to 2 years. In other embodiments, the unit dosage form is stable under the storage conditions of stability chamber 2 when stored in a vial for a period of up to 12 months. In still other embodiments, the unit dosage form is stable under the storage conditions of stability chamber 2 when stored in a vial for a period of up to 6 months. In some embodiments, the unit dosage form is stable under the storage conditions of stability chamber 2 when stored in a vial for a period of up to 4 months. In other embodiments, the unit dosage form is stable under the storage conditions of stability chamber 2 when stored in a vial for a period of up to 3 months. In still other embodiments, the unit dosage form is stable under the storage conditions of stability chamber 2 when stored in a vial for a period of up to 2 months. In still other embodiments, the unit dosage form is stable under the storage conditions of stability chamber 2 when stored in a vial for a period of up to 1 month.

[0073]

[0085] In some embodiments, the unit dosage form is stable under the storage conditions of stability chamber 2 when stored in a sealed bottle for a period of up to 2 years. In other embodiments, the unit dosage form is stable under the storage conditions of stability chamber 2 when stored in a sealed bottle for a period of up to 12 months. In still other embodiments, the unit dosage form is stable under the storage conditions of stability chamber 2 when stored in a sealed bottle for a period of up to 6 months. In some embodiments, the unit dosage form is stable under the storage conditions of stability chamber 2 when stored in a sealed bottle for a period of up to 4 months. In other embodiments, the unit dosage form is stable under the storage conditions of stability chamber 2 when stored in a sealed bottle for a period of up to 3 months. In still other embodiments, the unit dosage form is stable under the storage conditions of stability chamber 2 when stored in a sealed bottle for a period of up to 2 months. In still other embodiments, the unit dosage form is stable under the storage conditions of stability chamber 2 when stored in a sealed bottle for a period of up to 1 month.

[0074]

[0086] The amount of active ingredient that can be combined with carrier materials and other pharma- ceutically acceptable excipients to produce a single dosage form will vary depending on the subject being treated and the particular mode of administration. The term "therapeutically effective amount," as used herein, refers to an amount of active compound or pharmaceutical agent that induces the biological or medical response in a tissue, system, animal, or human that is desired by a researcher, veterinarian, physician, or other clinician. The therapeutically or pharma-ceutical effective amount of a compound to be administered is governed by such considerations and is the minimum amount necessary to ameliorate, cure, or treat a disease or disorder or one or more of its symptoms.

[0075]

[0087] "Treatment" may involve administering the compounds described herein to a patient diagnosed with a disease, and may involve administering the compounds to a patient with no active symptoms. Conversely, treatment may involve administering the composition to a patient at risk of developing a particular disease, or to a patient who reports one or more physiological symptoms of a disease, even if the disease has not been diagnosed. The term "prophylactically effective amount" refers to an amount effective to reduce the severity of a disease or disorder before it is acquired, or to reduce the severity of one or more symptoms before the symptoms are manifested.

[0076]

[0088] In some embodiments, unit dosage forms comprising stable solid dispersions of amorphous Compound I contain a therapeutically effective amount of Compound I. In other embodiments, they contain a prophylactically effective amount of Compound I. In some embodiments, they contain about 5 mg of Compound I, about 10 mg of Compound I, about 15 mg of Compound I, about 20 mg of Compound I, about 25 mg of Compound I, about 30 mg of Compound I, about 35 mg of Compound I, about 40 mg of Compound I, about 45 mg of Compound I, about 50 mg of Compound I, about 55 mg of Compound I, about 60 mg of Compound I, about 65 mg of Compound I, about 70 mg of Compound I, about 75 mg of Compound I, about 80 mg of Compound I, about 85 mg of Compound I, about 90 mg of Compound I, about 95 mg of Compound I, about 100 mg of Compound I, about 100 mg of Compound I, about 15 ... g of Compound I, about 70 mg of Compound I, about 75 mg of Compound I, about 80 mg of Compound I, about 85 mg of Compound I, about 90 mg of Compound I, about 95 mg of Compound I, about 100 mg of Compound I, about 105 mg of Compound I, about 110 mg of Compound I, about 115 mg of Compound I, about 120 mg of Compound I, about 125 mg of Compound I, about 130 mg of Compound I, about 135 mg of Compound I, about 140 mg of Compound I, about 140 mg of Compound I, about 145 mg of Compound I, or about 150 mg of Compound I. In some embodiments, the unit dosage form comprising the solid dispersion of amorphous Compound I contains between about 5 mg and 150 mg of Compound I. In other embodiments, the unit dosage form comprising the solid dispersion of amorphous Compound I comprises between about 10 mg and 130 mg of Compound I, or between about 10 mg and 100 mg of Compound I, or between about 10 mg and 80 mg of Compound I. In some embodiments, the unit dosage form comprising the solid dispersion of amorphous Compound I comprises between about 10 mg and 50 mg of Compound I, or between about 10 mg and 40 mg of Compound I, or between about 10 mg and 30 mg of Compound I. In some embodiments, the unit dosage form comprising the solid dispersion of amorphous Compound I comprises between about 5 mg and 50 mg of Compound I, or between about 5 mg and 40 mg of Compound I, or between about 5 mg and 30 mg of Compound I. In some embodiments, the unit dosage form comprising the solid dispersion of amorphous Compound I comprises between about 5 mg and 25 mg of Compound I, or between about 10 mg and 25 mg of Compound I. In some embodiments, a unit dosage form comprising a solid dispersion of amorphous Compound I contains between about 5 mg and 20 mg of Compound I, or between about 10 mg and 20 mg of Compound I, or between about 15 mg and 25 mg of Compound I.

[0077]

[0089] A "unit dosage form dissolution test comprising a solid dispersion of Compound I" in a given use environment is performed by introducing a unit dosage form comprising a solid dispersion of Compound I into the use environment (e.g., a test tube solution as described above) under given conditions of temperature, pressure, agitation rate, etc., removing aliquots of the solution at predetermined times, and analyzing the aliquots (e.g., using HPLC or other analytical techniques known in the art) to quantify the concentration of Compound I present in solution at each time point, and then further determining the percentage of Compound I present in solution relative to the total amount of Compound I known to be present in the amount of unit dosage form used for the dissolution test (e.g., the total amount of Compound I known to be present in a certain number of tablets comprising a given solid amorphous dispersion of Compound I of the present invention).

[0078]

[0090] When performing a dissolution test, the percentage of Compound I present in solution is initially 0, and it increases as the dosage form slowly releases the dispersion of Compound I into the use environment, reaching the maximum percentage of Compound I that the solution can maintain in a stable supersaturated state after a period of time. After reaching the maximum percentage of Compound I in solution (ideally, this percentage would be 100%, but in reality, in many cases, it is less than 100%), it can be maintained for a long time, or it may decay as Compound I begins to precipitate out of solution, depending on the time of the test and the stability of a given solid dispersion of Compound I in the use environment.

[0079]

[0091] In some embodiments, the unit dosage forms of the present invention are characterized by achieving greater than 60% dissolution after a 30 minute dissolution test in FaSSIF. In other embodiments, the unit dosage forms of the present invention are characterized by achieving between 70% and 80% dissolution after a 60 minute dissolution test in FaSSIF. In other embodiments, they are characterized by achieving between 75% and 85% dissolution after a 60 minute dissolution test in FaSSIF. In other embodiments, they are characterized by achieving between 75% and 80% dissolution after a 60 minute dissolution test in FaSSIF.

[0080]

[0092] The unit dosage forms of the present invention may also be tested in vivo, either in humans or in a suitable animal model (eg, dog).

[0093] In some embodiments, a pharmaceutical composition comprising a solid dispersion of amorphous Compound I, or a unit dosage form comprising a solid dispersion of amorphous Compound I, is within the scope of the present invention if, when tested in vivo, the Cmax / dose value achieved by said pharmaceutical composition or unit dosage form is at least 1.5 times higher (i.e., at least 50% higher) than the Cmax / dose value achieved by a composition or unit dosage form comprising an equivalent amount of Compound I in the absence of a dispersion polymer (e.g., a pharmaceutical composition or unit dosage form comprising pure Compound I in either crystalline or amorphous form, e.g., a wet granulation formulation of "native Compound I" or "native API"), when both are tested under identical conditions (e.g., in the fed or fasted state, and at the same temperature, pressure, and agitation speed). Cmax / dose is an abbreviation for the maximum drug concentration (ng / mL) in the serum or plasma of the test subject divided by the administered dose (mg / Kg). In other embodiments, the Cmax / dose achieved by said pharmaceutical composition or unit dosage form is at least 2.0 times higher (i.e., at least 100% higher) than the Cmax / dose value achieved by a composition or unit dosage form comprising an equivalent amount of Compound I in the absence of a dispersant polymer. In other embodiments, the Cmax / dose is at least 2.5 times higher (i.e., at least 150% higher). In other embodiments, it is at least 3.0 times higher (i.e., 200% higher). In yet other embodiments, it is at least 1.25 times higher (i.e., 25% higher).

[0081]

[0094] In some embodiments, a pharmaceutical composition comprising a solid dispersion of amorphous Compound I, or a unit dosage form comprising a solid dispersion of amorphous Compound I, is within the scope of the present invention if, when tested in vivo, the AUC / dose achieved by said pharmaceutical composition or unit dosage form is at least 1.25 times higher (i.e., at least 25% higher) than the AUC / dose achieved by a composition or unit dosage form comprising an equivalent amount of Compound I in the absence of a dispersion polymer (e.g., a pharmaceutical composition or unit dosage form comprising pure Compound I in either crystalline or amorphous form, e.g., a wet granulation formulation of "native Compound I" or "native API"), when both are tested under identical conditions (e.g., in the fed or fasted state, under the same conditions of temperature, pressure, and agitation speed). AUC / dose is an abbreviation for the area under the curve (in units of time x ng / mL) divided by the administered dose (mg / Kg) obtained when plotting the serum or plasma concentration of Compound I for a test subject on the y-axis against time on the x-axis. In other embodiments, the AUC / dose achieved by the pharmaceutical composition or unit dosage form is at least 1.5-fold higher (i.e., at least 50% higher) than the AUC / dose value achieved by a composition or unit dosage form comprising an equivalent amount of Compound I in the absence of a dispersant polymer. In other embodiments, the AUC / dose is at least 2.0-fold higher (i.e., at least 100% higher). In other embodiments, it is at least 2.5-fold higher (i.e., 150% higher). In other embodiments, the AUC / dose is at least 3.0-fold higher (i.e., at least 200% higher).

[0082]

[0095] In some embodiments, a pharmaceutical composition comprising a solid dispersion of amorphous Compound I or a unit dosage form comprising a solid dispersion of amorphous Compound I is within the scope of the present invention if, when tested in vivo, the estimated bioavailability of said pharmaceutical composition or unit dosage form is at least 1.25 times higher (i.e., at least 25% higher) than the estimated bioavailability value achieved by a composition or unit dosage form comprising an equivalent amount of Compound I in the absence of a dispersion polymer (e.g., a pharmaceutical composition or unit dosage form comprising pure Compound I in either crystalline or amorphous form) when both are tested under the same conditions (e.g., in the fed or fasted state, under the same conditions of temperature, pressure, and agitation speed). Bioavailability is well understood in the art. In other embodiments, the estimated bioavailability of the pharmaceutical composition or unit dosage form is at least 1.5-fold higher (i.e., at least 50% higher) than the estimated bioavailability value achieved in a composition or unit dosage form comprising an equivalent amount of Compound I in the absence of a dispersant polymer. In other embodiments, the estimated bioavailability is at least 2.0-fold higher (i.e., at least 100% higher).

[0083]

[0096] The pharmaceutical compositions or unit dosage forms of the present invention may also include other types of excipients, such as one or more buffers, stabilizers, anti-adherents, surfactants, wetting agents, lubricants, emulsifiers, binders, suspending agents, disintegrants, fillers, adsorbents, coatings (e.g., enteric or sustained release), preservatives, antioxidants, opacifying agents, flow agents, processing aids, colorants, sweeteners, aromas, flavorings, and other known additives to provide an elegant presentation of the drug or to aid in the manufacture of the pharmaceutical product (i.e., drug product).

[0084]

[0097] The pharmaceutical compositions or unit dosage forms of the present invention include those suitable for the routes of administration detailed herein. The pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations are generally found in "Remington's". Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0085]

[0098] The terms "administer", "administering" or "administration" in connection with a solid dispersion, pharmaceutical composition or unit dosage form of Compound I of the present invention means introducing said solid dispersion, pharmaceutical composition or unit dosage form of Compound I into the system of an animal in need of treatment. When Compound I is provided in combination with one or more other active agents, "administration" and its variants are understood to include simultaneous and / or sequential introduction of said solid dispersion, pharmaceutical composition or unit dosage form of Compound I with the other active agents, respectively.

[0086]

[0099] The pharmaceutical compositions described herein may be orally administered in any orally acceptable solid dosage form. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be mixed with at least one inert pharma- ceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or leavening agents such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. The tablets may be uncoated or coated by known techniques including microencapsulation to mask unpleasant tastes. Water soluble taste masking materials such as hydroxypropyl-methylcellulose or hydroxypropyl-cellulose may be used.

[0087]

[0100] Compressed tablets combine active ingredients that are in a free-floating form, such as a powder or granules. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent, optionally mixed with a liquid agent, lubricant, inert diluent, preservative, surface active agent or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.

[0088]

[0101] The pharmaceutical composition or unit dosage form of the present invention may be used to administer a drug The pharmaceutical formulation may be packaged in a variety of ways depending on the intended use. Generally, the distribution includes a container having the pharmaceutical formulation in the appropriate form disposed therein. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include tamper-proof features to prevent inadvertent access to the contents of the package. In addition, the container bears a label on its surface that describes the contents of the container. The label may also include appropriate warnings.

[0089]

[0102] A solid dispersion, pharmaceutical composition, or unit dosage form of Compound I as disclosed herein. The formulations may be packaged in unit-dose or multi-dose containers. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, of an active ingredient, or an appropriate fraction thereof.

[0090]

[0103] In another aspect, Compound I or a pharma- ceutical acceptable salt thereof is used in veterinary medicine. The veterinary compositions may be formulated to comprise a carrier. A veterinary carrier is a material useful for the purpose of administering the composition, which may be an otherwise inert or solid material accepted in the veterinary art and is compatible with the active ingredient. These veterinary compositions may be administered orally.

[0091] treatment

[0104] In another aspect, the present invention relates to the amorphous compound I of the present invention (alone or in combination) or relates to the treatment of certain disorders by using solid dispersions of pharma- ceutical acceptable salts thereof, or pharmaceutical compositions or unit dosage forms comprising them, in patients in need thereof.

[0092]

[0105] The solid amorphous dispersions, pharmaceutical compositions, or unit dosage forms described above can be used to treat a variety of diseases. They may be used alone or in combination with one or more additional agents to treat and / or prevent conditions in which an increase in NO levels or an increase in cGMP levels may be desired. Diseases that may be treated include, but are not limited to, pulmonary hypertension, arterial hypertension, heart failure, atherosclerosis, inflammation, thrombosis, renal fibrosis and renal failure, cirrhosis of the liver, erectile dysfunction, female sexual dysfunction, diabetes-related disorders, eye disorders, and other related cardiovascular disorders.

[0093]

[0106] Increased cGMP concentration induces vasodilation, inhibition of platelet aggregation and adhesion, and antihypertensive effects. provides blood pressure, anti-remodeling, anti-apoptotic, anti-inflammatory, and neurosignaling effects. Thus, the solid amorphous dispersions, pharmaceutical compositions, and unit dosage forms described above may be used to treat and / or prevent a wide range of diseases and disorders, including, but not limited to, peripheral, pulmonary, hepatic, hepatic, cardiac or cerebrovascular / endothelial disorders or conditions, genitourinary-gynecological or sexual disorders or conditions, thromboembolic diseases, ischemic diseases, fibrotic disorders, topical or skin disorders, pulmonary or respiratory disorders, renal or hepatic disorders, metabolic disorders, atherosclerosis, or lipid-related disorders.

[0094]

[0107] In another aspect, the solid amorphous dispersions, pharmaceutical compositions, and unit dosage forms described above are In particular, these compounds may be useful in the prevention and / or treatment of diseases and disorders characterized by an unwanted decrease in the bioavailability of and / or sensitivity to NO, such as those associated with conditions of oxidative or nitrosative stress.

[0095]

[0108] Throughout this disclosure, the terms "hypertension," "arterial hypertension," or "high blood pressure (HBP)" may refer to The terms "hypertension" and "hypertensive disorders" are used interchangeably to refer to a common and highly preventable chronic condition in which arterial blood pressure (BP) is higher than normal. If not properly controlled, it is a significant risk factor for several serious cardiovascular and renal conditions. Hypertension can be a primary disease, called "essential hypertension" or "idiopathic hypertension," or it can be due to other diseases, in which case it is classified as "secondary hypertension." Essential hypertension accounts for 90-95% of all cases.

[0096]

[0109] As used herein, the term "resistant hypertension" refers to hypertension caused by the induction of hypercalcaemia by different It refers to hypertension in which blood pressure remains higher than target (usually less than 140 / 90 mmHg, although a lower target of less than 130 / 80 mmHg is recommended for patients with diabetes or nephropathy) despite the simultaneous use of three antihypertensive drugs from the hypertensive drug group. People who require four or more drugs to control their blood pressure are also considered to have resistant hypertension. Hypertension is a common comorbid condition in diabetes, affecting approximately 20-60% of diabetic patients, depending on obesity, ethnicity, and age. This type of hypertension is referred to herein as "diabetic hypertension." In type 2 diabetes, hypertension is often present as part of the metabolic syndrome of insulin resistance, which also includes central obesity and dyslipidemia. In type 1 diabetes, hypertension may reflect the manifestation of diabetic nephropathy.

[0097]

[0110] "Pulmonary hypertension (PH)" as used herein refers to hypertension caused by pulmonary vasculature (pulmonary artery disease). PH is a disease characterized by persistent elevation of blood pressure in the right heart (the right ventricle, pulmonary veins, and pulmonary capillaries), resulting in right heart hypertrophy and ultimately right heart failure and death. Common symptoms of PH include shortness of breath, dizziness, and syncope, all of which are aggravated by exertion. Without treatment, the median life expectancy after diagnosis is 2.8 years. PH exists in many different forms, classified according to its etiology. The categories include pulmonary arterial hypertension (PAH), PH with left heart disease, PH associated with pulmonary disease and / or hypoxemia, PH due to chronic thrombotic and / or embolic disease, and other PH. PAH is rare in the general population, but the prevalence is increased in association with certain common conditions such as HIV infection, scleroderma, and sickle cell disease. In general, other forms of PH are more common than PAH, and the association of PH with, for example, chronic obstructive pulmonary disease (COPD) is of particular concern. Current treatments for pulmonary hypertension depend on the stage and mechanism of the disease.

[0098]

[0111] As used herein, "heart failure" refers to a condition that ultimately results in a complex clinical syndrome. Heart failure is a progressive disorder of left ventricular (LV) myocardial remodeling that results in inadequate delivery of blood and nutrients to body tissues, in which cardiac dysfunction and circulatory congestion are distinct features, resulting in inadequate delivery of blood and nutrients to body tissues. This condition occurs when the heart is injured or overworked and cannot pump all the blood returning to it from the systemic circulation. Because less blood is pumped, blood returning to the heart backs up and fluid accumulates in other parts of the body. Heart failure also impairs the kidneys' ability to process sodium and water, further complicating fluid retention. Heart failure is characterized by autonomic dysfunction, neurohormonal activation, and cytokine overproduction that contribute to progressive circulatory insufficiency. Symptoms of heart failure include: dyspnea (shortness of breath) on exercise or at rest and sudden nighttime awakenings due to shortness of breath, both of which are indicative of pulmonary edema, generalized fatigue or weakness, edema in the legs, ankles, and feet, rapid weight gain, and chronic cough (including those that produce phlegm or blood). Depending on its clinical manifestations, heart failure is classified as de novo, transient, or chronic. Acute heart failure (i.e., rapid or gradual onset of symptoms that require urgent treatment) may occur de novo or as a result of decompensation of chronic heart failure. Diabetes is a common comorbidity in patients with heart failure and is associated with poor outcomes as well as potentially compromising the efficacy of treatments. Other important comorbidities include systemic hypertension, chronic airway obstruction, sleep apnea, cognitive impairment, anemia, chronic kidney disease, and arthritis. Chronic left heart failure is often associated with the development of pulmonary hypertension. The frequency of certain comorbidities varies by sex: hypertension and thyroid disease are more common among women, whereas men are more likely to suffer from chronic obstructive pulmonary disease (COPD), peripheral vascular disease, coronary artery disease, and renal failure. Depression is a frequent comorbidity with heart failure, and the two conditions can, and often do, exacerbate each other. Cachexia has long been recognized as a serious and frequent complication of heart failure, affecting up to 15% of all heart failure patients and associated with poor prognosis. Cardiac cachexia is defined as a non-edematous, involuntary loss of at least 6% of body weight over a 6-month period.

[0099]

[0112] The term "sleep apnea" refers to the most common sleep-disordered breathing disorder. It is a condition characterized by intermittent, periodic reductions or complete cessation of airflow, with or without upper airway obstruction. There are three types of sleep apnea: obstructive sleep apnea (the most common form), central sleep apnea, and mixed sleep apnea.

[0100]

[0113] "Central sleep apnea (CSA)" is not a physical blockage of the airway, but rather a blockage caused by the brain. It is caused by a malfunction in the normal respiratory signals of the heart. Insufficient work of breathing leads to an increase in blood carbon dioxide, which may wake the patient. CSA is rare in the general population, but occurs more frequently in patients with systolic heart failure.

[0101]

[0114] As used herein, "metabolic syndrome," "insulin resistance syndrome," The term "complex," or "syndrome X," refers to a group or cluster of metabolic conditions (abdominal obesity, elevated fasting blood glucose, "dyslipidemia" (i.e., elevated lipid levels), and elevated blood pressure (HBP)) that occur together more frequently than coincidentally alone and that together promote the development of type 2 diabetes and cardiovascular disease. The metabolic syndrome is characterized by a specific lipid profile of increased triglycerides, decreased high density lipoprotein cholesterol (HDL-cholesterol), and (in some cases) moderately elevated low density lipoprotein cholesterol (LDL-cholesterol) levels, as well as the rapid progression of "atherosclerotic disease" due to the pressure of the component risk factors. There are several types of dyslipidemia, and "hypercholesterolemia" refers to elevated cholesterol levels. Familial hypercholesterolemia is a special form of hypercholesterolemia due to an abnormality on chromosome 19 (19p13.1-13.3). "Hyperglyceridemia" refers to elevated glyceride levels (e.g., "hypertriglyceridemia" involves elevated triglyceride levels). "Hyperlipoproteinemia" refers to elevated lipoprotein (usually LDL, unless otherwise specified) levels.

[0102]

[0115] As used herein, the term "peripheral artery disease (PAD)" or "peripheral The term "peripheral vascular disease (PVD)", also called "peripheral arterial occlusive disease (PAOD)", refers to blockages of large arteries that are not inside the coronary arteries, the aortic arch vasculature, or the brain. PVD can result from atherosclerosis, an inflammatory process that leads to stenosis, embolism, or thrombus formation. It can result in either acute or chronic "ischemia" (lack of blood supply). Often PVD is the term used to refer to atherosclerotic blockages found in the lower extremities. PVD also includes a subset of diseases classified as microvascular diseases that result from episodic narrowing of arteries (e.g., "Raynaud's phenomenon") or their dilation (erythromelalgia), i.e., vasospasm.

[0103]

[0116] The term "thrombosis" refers to the formation of a blood clot (or clots) in a blood vessel that obstructs blood flow through the circulatory system. When a blood vessel is damaged, the body uses platelets (thrombi) and fibrin to form clots to prevent blood loss. Alternatively, clots can form in the body when the right conditions are met, even when the blood vessel is not damaged. If the clot formation is too severe and the clot breaks off, the traveling clot is now known as an "embolus." The term "thromboembolism" refers to the combination of thrombosis and its major complication, "embolism." When a clot occupies more than 75% of the surface area of ​​the arterial lumen, the blood flow to the tissues is reduced enough to cause symptoms due to reduced oxygen (hypoxia) and accumulation of metabolic products such as lactic acid ("gout"). Blockages of more than 90% can result in anoxia, which is the complete loss of oxygen, and "infarction," a form of cell death.

[0104]

[0117] "Embolism" (multiple embolisms) refers to the infiltration of an embolus (arterial occlusion) into a narrow capillary in the arterial bed. (a detached intravascular mass capable of clogging a capillary bed at a site distant from its origin) Thrombosis is an event that causes a blockage (vasoocclusion) in a distant part of the body. This should not be confused with thrombosis, which causes a blockage at the site of origin.

[0105]

[0118] A "stroke" or cerebrovascular accident (CVA) is a brain injury caused by an interruption in the blood supply to the brain. It is the rapid loss of function or abilities. This can be due to "ischemia" (lack of blood flow) caused by blockage (thrombosis, arterial embolism) or hemorrhage (blood leakage). As a result, the affected brain area may be unable to function, resulting in the inability to move one or more limbs on one side of the body, the inability to understand or formulate speech, or the inability to see on one side of the field of vision. Risk factors for stroke include advanced age, hypertension, history of stroke or transient ischemic attack (TIA), diabetes, high cholesterol, smoking, and atrial fibrillation. Hypertension is the most important and reversible risk factor for stroke. "Ischemic strokes" are sometimes treated in hospitals with thrombolysis (also known as "clotbusters"), with some hemorrhagic strokes benefiting from neurosurgery. Prevention of recurrence may involve administration of antiplatelet drugs such as aspirin and dipyridamole, management and suppression of hypertension, and the use of statins. Selected patients may benefit from carotid endarterectomy and the use of anticoagulants.

[0106]

[0119] "Ischemia" is the restriction of blood supply to tissue, causing the tissue to lose its vitality. Ischemia causes a shortage of oxygen and glucose, which are needed for cellular metabolism. Ischemia is generally caused by problems with blood vessels, resulting in damage to tissues or their dysfunction. It also refers to local anemia in a given part of the body, which sometimes results from blood congestion (such as vasoconstriction, thrombosis, or embolism).

[0107]

[0120] The American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM- According to IV), the term "sexual dysfunction" includes a range of conditions "characterized by disturbances in sexual desire and in the neurophysiological changes associated with the sexual response cycle", while problems of this kind are common and sexual dysfunction is considered to exist only if they cause distress to the patient. Sexual dysfunction can be physical or psychological in origin. It can exist as a primary condition, generally of hormonal origin, but in most cases it is secondary to other medical conditions or to pharmacotherapy for said conditions. All types of sexual dysfunction can be further classified as lifelong, acquired, situational, or generalized (or a combination of these).

[0108]

[0121] In the DSM-IV-TR, it is defined as "sexual desire / interest disorder; sexual arousal disorder (genital type) Five major categories of "female sexual dysfunction" have been identified: "sexual dysfunction (including sexual, subjective, and mixed types)"; orgasmic disorder; sexual pain and vaginismus; and persistent sexual arousal disorder.

[0109]

[0122] "Female Sexual Arousal Disorder (FSAD)" causes personal distress FSAD is defined as the persistent or recurrent inability to achieve or maintain a sufficient level of sexual arousal. FSAD includes both a lack of subjective feelings of arousal (i.e., subjective sexual arousal disorder) and a lack of physical responses such as lubrication and swelling (i.e., genital / physical sexual arousal disorder). Although FSAD may be strictly psychological in origin, it is commonly caused or complicated by medical or physiological factors. Hypoestrogenism is the most common physiological condition associated with FSAD, resulting in urogenital atrophy and reduced vaginal lubrication.

[0110]

[0123] As used herein, "erectile dysfunction (ED)" refers to a condition in which the penis becomes inflamed during sexual intercourse. Penile erection is the hydraulic effect of blood flowing into and being held in the cavernous corpus of the penis. This process is often initiated as a result of sexual arousal, when signals from the brain are sent to the nerves in the penis. It is transmitted to the vagina. Erectile dysfunction is indicated when there is difficulty in achieving an erection. The most important organic causes are cardiovascular disease and diabetes, neurological problems (e.g. trauma from prostatectomy surgery), hormonal deficiency (hypogonadism), and drug side effects.

[0111]

[0124] As used herein, the term "bronchoconstriction" refers to the contraction of surrounding smooth muscle It is used to define the constriction of airways in the lungs due to squeezing of the airways and the subsequent coughing, wheezing, and shortness of breath. There are several causes for the condition, the most common of which is asthma. Exercise and allergies can introduce symptoms in otherwise asymptomatic individuals. Other conditions such as chronic obstructive pulmonary disease (COPD) can also present with bronchoconstriction.

[0112]

[0125] The characteristics that can be treated and / or prevented by administering the sGC stimulator of the present invention Certain diseases or disorders include, but are not limited to: hypertension (e.g., diabetic hypertension, arterial hypertension, pulmonary hypertension, resistant hypertension, peripheral arterial disease, etc.), heart failure (e.g., left ventricular diastolic dysfunction (LVDD) and left ventricular systolic dysfunction (LVSD)), heart failure with preserved ejection fraction (HFpEF; also known as diastolic heart failure), heart failure with reduced ejection fraction (HFrEF; also known as systolic heart failure), sleep apnea associated with heart failure, arteriosclerotic diseases (e.g., atherosclerosis), blood Thromboembolic disorders (e.g., chronic thromboembolic pulmonary hypertension, thrombosis, stroke, embolism, pulmonary embolism), Alzheimer's disease, renal disease (e.g., renal fibrosis, ischemic renal disease, renal failure, renal insufficiency, chronic kidney disease), liver disease (e.g., liver fibrosis or cirrhosis), respiratory disease (e.g., pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, interstitial lung disease), sexual disorders (e.g., erectile dysfunction, male and female sexual dysfunction, vaginal atrophy), sickle cell anemia, neuroinflammatory diseases or disorders, and metabolic disorders (e.g., lipid-related disorders).

[0113]

[0126] The solid dispersions, pharmaceutical formulations, and dosage forms of the present invention are capable of stimulating sGC or the NO pathway. The present invention is useful for the prevention and / or treatment of the following types of diseases, conditions, and disorders that may benefit from regulation of the following pathways:

[0114] (1) Peripheral, pulmonary, hepatic, renal, cardiac, or cerebral vascular / endothelial disorders / conditions or diseases that are otherwise related to the circulation: Disorders associated with hypertension and reduced coronary blood flow, such as acute and chronic increased coronary pressure, arterial hypertension, and vascular disorders resulting from cardiac and renal complications (e.g., heart disease, stroke, cerebral ischemia, renal failure); heart failure with preserved ejection fraction (HFpEF; also known as diastolic heart failure), heart failure with reduced ejection fraction (HFrEF; also known as systolic heart failure), resistant hypertension, diabetic hypertension, congestive heart failure; diastolic or systolic dysfunction; coronary insufficiency; cardiac arrhythmias; reduced ventricular preload; cardiac hypertrophy; heart failure / cardiorenal syndrome; portal hypertension; endothelial dysfunction or injury; Thromboembolic disorders and ischemia such as myocardial infarction, stroke and transient ischemic attacks (TIAs); thromboangiitis obliterans; stable and unstable angina; coronary artery spasm, variant angina and Prinzmetal angina; prevention of restenosis after thrombolytic therapy; thrombosis disorders; Peripheral arterial disease, peripheral occlusive arterial disease; peripheral vascular disease; hypertonia; Raynaud's syndrome or phenomenon, critical limb ischemia, vasculitis; peripheral embolism; intermittent claudication; vaso-occlusive crisis; Duchenne muscular dystrophy; Becker muscular dystrophy; microcirculatory abnormalities; vascular leakage or permeability control; Shock; Sepsis; Cardiogenic shock; Control of leukocyte activation; Inhibition or regulation of platelet aggregation; Pulmonary hypertension, pulmonary arterial hypertension, and associated pulmonary vascular remodeling (e.g., localized thrombosis and right ventricular hypertrophy); pulmonary hypertension; primary pulmonary hypertension, secondary pulmonary hypertension, familial pulmonary hypertension, sporadic pulmonary hypertension, precapillary pulmonary hypertension, idiopathic pulmonary hypertension, thrombotic pulmonary arteriopathy, multifactorial pulmonary arteriopathy; cystic fibrosis; bronchoconstriction or pulmonary bronchoconstriction; acute respiratory distress syndrome; pulmonary fibrosis, pulmonary metastasis pulmonary / respiratory conditions such as explants; Left ventricular dysfunction, hypoxemia, WHO Group I, II, III, IV, and V hypertension, mitral valve disease, constrictive pericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis, pulmonary fibrosis, anomalous pulmonary venous return, pulmonary venous obstructive disease, pulmonary vasculitis, collagen vascular disease, congenital heart disease, pulmonary venous hypertension, interstitial lung disease, sleep-disordered breathing, sleep apnea, impaired alveolar hypoventilation, chronic exposure to altitude, neonatal pulmonary disease, alveolar-capillary dysplasia, sickle cell disease, other coagulation disorders, chronic thromboembolism, pulmonary embolism (due to tumor, parasite, or foreign body), connective tissue disease, lupus, schistosomiasis, sarcoidosis, chronic obstructive pulmonary disease, asthma, emphysema, chronic bronchitis, pulmonary capillary hemangiomatosis; histiocytosis X, lymphangiomatosis, and pulmonary hypertension associated with or related to compressed pulmonary vessels (due to adenopathy, tumor, or fibrosing mediastinitis); · arteriosclerotic diseases or conditions such as atherosclerosis (e.g. associated with endothelial injury, platelet and monocyte adhesion and aggregation, smooth muscle proliferation and migration); restenosis (occurring, for example, after thrombolytic therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA) and bypass surgery); inflammation; Cardiovascular diseases associated with the metabolic syndrome (e.g., obesity, dyslipidemia, diabetes, hypertension); lipid-related disorders such as dyslipidemia, hypercholesterolemia, hypertriglyceridemia, sitosterolemia, fatty liver disease, and hepatitis; preeclampsia; progression of polycystic kidney disease; subcutaneous fat; obesity; · chronic liver disease, liver fibrosis, cirrhosis associated with hepatic stellate cell activation, hepatic fibrotic collagen and total collagen accumulation; liver diseases of necroinflammatory and / or immunological origin; and genitourinary system disorders such as renal fibrosis and renal failure resulting from chronic kidney disease or failure (e.g. due to accumulation / deposition and tissue damage, progressive sclerosis, glomerulonephritis); prostatic hyperplasia; systemic sclerosis; cardiac interstitial fibrosis; cardiac remodeling and fibrosis; cardiac hypertrophy; non-alcoholic steatohepatitis or NASH; (2) Ischemia and reperfusion injury; ischemia / reperfusion associated with solid organ transplantation, lung transplantation, and cardiac transplantation; storage of blood substitutes in trauma patients; (3) Sexual, gynecological, and urinary disorders or conditions: erectile dysfunction; impotence; premature ejaculation; female sexual dysfunction (e.g., female sexual arousal disorder, hypofunctional sexual arousal disorder), vaginal atrophy, dyspareunia, atrophic vaginitis; benign prostatic hyperplasia (BPH) or hypertrophy or enlargement, bladder outlet obstruction; painful bladder syndrome (BPS), interstitial cystic disease (IC), overactive bladder, neurogenic bladder and incontinence; diabetic nephropathy; (4) Eye diseases or disorders: glaucoma, retinopathy, diabetic retinopathy, blepharitis, dry eye syndrome, Sjogren's syndrome; (5) Hearing diseases or disorders: hearing impairment, partial or total deafness; partial hearing loss or total deafness; tinnitus; noise-induced hearing loss; (6) Local or skin disorders or conditions: dermal fibrosis, scleroderma, dermal fibrosis; (7) Wound healing: e.g. in diabetic patients; improving microvascular perfusion (e.g. after injury, combating inflammatory responses in perioperative care), anal fissures, diabetic ulcers; (8) Other diseases or conditions: cancer metastasis, osteoporosis, gastroparesis; functional dyspepsia; diabetic complications, diseases associated with endothelial dysfunction, and neurological disorders associated with reduced nitric oxide production; achalasia or esophageal achalasia.

[0115] (9) a CNS disease, condition or disorder selected from Alzheimer's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), Down's syndrome, dementia, vascular dementia, vascular cognitive impairment, Binswanger dementia (subcortical arteriosclerotic encephalopathy), autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL or CADASIL syndrome), frontotemporal lobar degeneration or dementia, HIV-associated dementia, dementia with Lewy bodies, presenile dementia (mild cognitive impairment, MCI), glaucoma, Huntington's disease (or chorea, HD), multiple sclerosis (MS), multiple system atrophy (MSA), Parkinson's disease, Parkinson-plus syndrome, spinocerebellar ataxia, Steele-Richardson-Olszewski disease (progressive supranuclear palsy), attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD); (10) A CNS disorder or condition selected from Alzheimer's disease or presymptomatic Alzheimer's disease, mild-moderate Alzheimer's disease, or moderate-severe Alzheimer's disease; (11) the CNS disorder is selected from any of the following: traumatic (closed or open, penetrating head injury), traumatic brain injury (TBI), or non-traumatic (stroke, aneurysm, hypoxia) injury to the brain, or cognitive impairment or dysfunction resulting from brain injury or neurodegenerative disorders; (12) The CNS disease or disorder is selected from dystonia (e.g., including generalized, focal, segmental, genital, intermediate, and acute dystonic reactions) and hereditary / primary dystonia; and dyskinesia (e.g., including acute, chronic / tardive, or nonmotor or levodopa-induced dyskinesia (LID)); (13) the CNS disease or disorder is selected from disorders characterized by a relative decrease in synaptic plasticity and synaptic processes (e.g., fragile X syndrome, Rett syndrome, Williams syndrome, Rempenning syndrome, autism spectrum disorder (including autism), Asperger syndrome, pervasive developmental disorder, or childhood disintegrative disorder); (14) The CNS disorder is neuropathic pain; (15) The CNS disorder is a neuropsychiatric, mental, mood, or affective disorder selected from bipolar disorder, schizophrenia, generalized psychosis, drug-induced psychosis, delusional disorder, schizoaffective disorder, obsessive-compulsive disorder (OCD), depressive disorder, anxiety disorder, panic disorder, or post-traumatic stress disorder (PTSD); or (16) The CNS disorder is selected from chemobrain, levodopa-induced addictive behavior, alcoholism, drug addiction (including but not limited to amphetamines, opiates, or other substances), or drug abuse.

[0116]

[0127] In another aspect of the present invention, the solid dispersions, pharmaceutical formulations, and solid dosage forms of the present invention are useful for the prevention and / or treatment of the following types of diseases, conditions and disorders that may benefit from sGC stimulation or upregulation of the NO pathway:

[0128] Hypertension, Resistant Hypertension, Diabetic Hypertension, Pulmonary Hypertension (PH), Pulmonary Artery Disease heart failure, diastolic dysfunction, systolic dysfunction, sleep apnea associated with heart failure, cirrhosis, renal fibrosis, renal failure resulting from chronic renal disease or dysfunction, metabolic disorders, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, sitosterolemia, fatty liver disease, hepatitis, erectile dysfunction, female sexual dysfunction, female sexual arousal disorder, or vaginal atrophy.

[0117]

[0129] In some embodiments, the present invention provides a compound of any of the formulae illustrated above. or a pharma- ceutical acceptable salt thereof to a subject in need of treatment, wherein the disease, condition, or disorder is selected from one of the diseases listed above.

[0118]

[0130] In other embodiments, the disease, condition, or disorder is peripheral, pulmonary, hepatic, renal , vascular / endothelial disorders or conditions of the heart or brain, or vascular disorders resulting from acute and chronic increased coronary blood pressure, arterial hypertension, and cardiac and renal complications, heart disease, stroke, cerebral ischemia, renal failure; resistant hypertension, diabetic hypertension, congestive heart failure; diastolic or systolic dysfunction; coronary insufficiency; arrhythmias; reduced ventricular preload; cardiac hypertrophy; heart failure / cardiorenal syndrome; portal hypertension; endothelial dysfunction or damage; myocardial infarction, stroke or transient ischemic attacks (TIAs); thromboangiitis obliterans; stable or unstable angina; coronary artery spasm, variant angina, Prinzmetal angina; restenosis as a result of thrombolytic therapy; or thrombosis disorders.

[0119]

[0131] In still other embodiments, the disease, condition, or disorder is peripheral vascular / endothelial dysfunction. Peripheral arterial disease; peripheral occlusive arterial disease; peripheral vascular disease; hypertension; Rayno - syndrome or phenomenon; critical limb ischemia; vasculitis; peripheral embolism; intermittent claudication; vaso-occlusive crisis; Duchenne and Becker muscular dystrophy; microcirculatory abnormalities; or vascular leakage or permeability problems or other diseases related to the circulation.

[0120]

[0132] In a further embodiment, the disease, condition, or disorder is a pulmonary disorder or condition; or an otherwise circulation-related disease selected from pulmonary hypertension; pulmonary vascular remodeling associated with pulmonary arterial hypertension; localized thrombosis; right ventricular hypertrophy; pulmonary hypertension; primary pulmonary hypertension, secondary pulmonary hypertension, familial pulmonary hypertension, sporadic pulmonary hypertension, precapillary pulmonary hypertension, idiopathic pulmonary hypertension, thrombotic pulmonary arteriopathy, multifactorial pulmonary arteriopathy; cystic fibrosis; bronchoconstriction or pulmonary bronchoconstriction; acute respiratory distress syndrome; pulmonary fibrosis, and lung transplantation. In some of the above embodiments, the pulmonary hypertension is selected from the group consisting of left ventricular dysfunction, hypoxemia, WHO Group I, II, III, IV, and V hypertension, mitral valve disease, constrictive pericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis, pulmonary fibrosis, anomalous pulmonary venous return, pulmonary venous obstructive disease, pulmonary vasculitis, collagen vascular disease, congenital heart disease, pulmonary venous hypertension, interstitial lung disease, sleep-disordered breathing, sleep apnea, impaired alveolar hypoventilation, chronic exposure to altitude, neonatal pulmonary disease, alveolar-capillary dysplasia, sickle cell disease, coagulation disorders, chronic thromboembolism, pulmonary embolism (due to tumor, parasite, or foreign body); connective tissue disease, lupus, schistosomiasis, sarcoidosis, chronic obstructive pulmonary disease, asthma, emphysema, chronic bronchitis, pulmonary capillary hemangiomatosis; histiocytosis X, lymphangiomatosis, or pulmonary hypertension associated with or related to compressed pulmonary vessels (due to adenopathy, tumor, or fibrosing mediastinitis).

[0121]

[0133] In yet other embodiments, the condition or disorder is a vascular or endothelial disorder or condition. atherosclerosis; atherosclerosis associated with endothelial injury, atherosclerosis associated with platelet and monocyte adhesion and aggregation, atherosclerosis associated with smooth muscle proliferation and migration; restenosis, restenosis after thrombolytic therapy, restenosis after percutaneous transluminal angioplasty; restenosis after percutaneous transluminal coronary angioplasty and bypass surgery; inflammation; cardiovascular disease associated with metabolic syndrome, obesity, dyslipidemia, diabetes, or hypertension; lipid-related disorders, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, sitosterolemia, fatty liver disease, and hepatitis; preeclampsia; progression of polycystic kidney disease, or subcutaneous fat.

[0122]

[0134] In yet another embodiment, the disease, condition, or disorder is cirrhosis of the liver, chronic liver disease, selected from: paraneoplastic liver disease associated with cirrhosis, hepatic fibrosis, hepatic stellate cell activation, hepatic fibrous collagen and total collagen accumulation; or liver diseases of necroinflammatory or immunological origin.

[0123]

[0135] In further embodiments, the disease, condition, or disorder is renal fibrosis; chronic renal renal failure resulting from disease or failure; renal failure due to accumulation or deposits and tissue damage, progressive sclerosis, or glomerulonephritis; or a genitourinary system disorder selected from prostatic hyperplasia.

[0124]

[0136] In a further embodiment, the disease, condition, or disorder is systemic sclerosis. do.

[0137] In a further aspect, the disease, condition, or disorder is cardiac interstitial fibrosis; The cardiac disorder is selected from cardiac remodeling and fibrosis, or cardiac hypertrophy.

[0125]

[0138] In some embodiments, the disorder is Alzheimer's disease, amyotrophic lateral sclerosis ALS or Lou Gehrig's disease, Down's syndrome, dementia, vascular dementia, vascular cognitive impairment, Binswanger dementia (subcortical arteriosclerotic encephalopathy), autosomal dominant cerebral arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL or CADASIL syndrome), frontotemporal lobar degeneration or dementia, HIV-associated dementia, dementia with Lewy bodies, presenile dementia (mild cognitive impairment, MCI), glaucoma, Huntington's disease (or chorea, HD), multiple sclerosis (MS), multiple system atrophy (MSA), Parkinson's disease, Parkinson-plus syndrome, spinocerebellar ataxia, Spinocere ... The CNS disease, condition, or disorder is selected from Teal-Richardson-Olszewski disease (progressive supranuclear palsy), attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD).

[0126]

[0139] In a further embodiment, the disease, condition, or disorder is Alzheimer's disease Or it is a CNS disorder or condition selected from pre-symptomatic Alzheimer's disease, mild-moderate Alzheimer's disease, or moderate-severe Alzheimer's disease.

[0127]

[0140] In other embodiments, the CNS injury is a traumatic (closed or open, penetrating head injury). The cognitive impairment or dysfunction is selected from either traumatic (cerebral infarction), traumatic brain injury (TBI), or non-traumatic (stroke, aneurysm, hypoxia) injury to the brain, or from brain injury or a neurodegenerative disorder.

[0128]

[0141] In other embodiments, the CNS disease or disorder is dystonia (e.g., generalized, and hereditary / primary dystonias (including, for example, focal, segmental, genital, intermediate, and acute dystonic reactions); and dyskinesias (including, for example, acute, chronic / tardive, or non-motor or levodopa-induced dyskinesias (LID)).

[0129]

[0142] In another embodiment, the CNS disease or disorder is a disorder characterized by a loss of synaptic plasticity and synaptic splicing. The disorder is selected from disorders characterized by a relative decline in cognitive functioning processes (e.g., fragile X syndrome, Rett syndrome, Williams syndrome, Rempenning syndrome, autism spectrum disorder (including autism), Asperger syndrome, pervasive developmental disorder, or childhood disintegrative disorder).

[0130]

[0143] In other embodiments, the CNS disorder is neuropathic pain.

[0144] In other embodiments, the CNS disorder is bipolar disorder, schizophrenia, generalized psychosis. The disorder is a neuropsychiatric, psychiatric, mood, or affective disorder selected from drug-induced psychosis, delusional disorder, schizoaffective disorder, obsessive-compulsive disorder (OCD), depressive disorder, anxiety disorder, panic disorder, or post-traumatic stress disorder (PTSD).

[0131]

[0145] In other embodiments, the CNS disorder is chemobrain, levodopa-induced addictive behavior. The disorder is selected from addiction, alcoholism, drug addiction (including but not limited to amphetamines, opiates, or other substances), or drug abuse.

[0132]

[0146] In some embodiments, the disease or disorder is achalasia or esophageal achalasia. A is.

[0147] In other embodiments, the disease or disorder is nonalcoholic steatohepatitis or NA. It's SH.

[0133]

[0148] In a further aspect, the disease, condition, or disorder is ischemia-reperfusion injury. ischemia / reperfusion injury associated with organ transplantation, lung transplantation, or heart transplantation; preservation of blood substitutes in trauma patients.

[0134]

[0149] In a further embodiment, the disease, condition, or disorder is erectile dysfunction; The sexual, gynecological, and urinary disorders or conditions are selected from: prostate gland syndrome (GPS); premature ejaculation; female sexual dysfunction; female sexual arousal disorder; hypoactive sexual arousal disorder, vaginal atrophy, dyspareunia, atrophic vaginitis; benign prostatic hyperplasia (BPH) or hypertrophy or enlargement; bladder outlet obstruction; painful bladder syndrome (BPS); interstitial cystic disease (IC); overactive bladder, neurogenic bladder; incontinence; or diabetic nephropathy.

[0135]

[0150] In a further embodiment, the disease, condition, or disorder is vaginal atrophy, dyspareunia (dyspareunia), yspaneuria, or atrophic vaginitis.

[0151] In a further aspect, the disease, condition, or disorder is benign prostatic hyperplasia (BPH). bladder pain syndrome (BPS); interstitial cystic disease (IC); overactive bladder, neurogenic bladder, or incontinence.

[0136]

[0152] In a further embodiment, the disease, condition, or disorder is erectile dysfunction; The sexual condition is selected from: sexual arousal disorder; premature ejaculation; female sexual dysfunction; female sexual arousal disorder, or hypofunctional sexual arousal disorder.

[0137]

[0153] In a further embodiment, the disease or disorder is diabetic nephropathy.

[0154] In a further embodiment, the disease or disorder is diabetic retinopathy.

[0155] In further embodiments, the disease or disorder is heart failure. In one embodiment, the heart failure is heart failure with preserved ejection fraction (HFpEF; also called diastolic heart failure). In another embodiment, the heart failure is heart failure with reduced ejection fraction (HFrEF; also called systolic heart failure).

[0138]

[0156] In a further aspect, the disease, condition, or disorder is Duchenne myopathy. dystrophy or Becker muscular dystrophy.

[0157] In a further embodiment, the disease is glaucoma, retinopathy, diabetic retinopathy, eyelid glaucoma, The ocular disease or disorder is selected from the group consisting of ocular inflammation, dry eye syndrome, and Sjogren's syndrome.

[0139]

[0158] In a further embodiment, the disease is hearing impairment, partial or total deafness; The hearing disease or disorder is selected from: partial or total hearing loss; tinnitus; or noise-induced deafness.

[0140]

[0159] In a further embodiment, the disease is dermal fibrosis, scleroderma, or dermal fibrosis. The present invention relates to a topical or cutaneous disorder or condition, which is selected from the group consisting of:

[0160] In a further aspect, the treatment is wound healing; wound healing in diabetic patients. improving microvascular perfusion; improving microvascular perfusion problems after injury; treating anal fissures; or in the treatment of diabetic ulcers.

[0141]

[0161] In further embodiments, the disease or condition is cancer metastasis; osteoporosis; gastroparesis; the disease is selected from: progressive dyspepsia; diabetic complications; diseases associated with endothelial dysfunction, or neuropathy associated with reduced nitric oxide production.

[0142]

[0162] The terms "disease," "disorder," and "condition" refer to the They may be used interchangeably herein to refer to an NO-mediated medical or pathological condition.

[0143]

[0163] As used herein, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "patient" are used interchangeably herein. The terms "subject" and "patient" refer to animals (e.g., birds such as chickens, quails, or turkeys, or mammals), where "mammals" specifically include non-primates (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), and more specifically, humans. In some embodiments, the subject is a non-human animal, such as a dairy animal (e.g., horses, cows, pigs, sheep), or a pet (e.g., dog, cat, guinea pig, or rabbit). In some embodiments, the subject is a human.

[0144]

[0164] The present invention also relates to the solid amorphous dispersions, pharmaceutical compositions, and unit dosage forms of the present invention. The method of treating one of the above diseases, conditions, and disorders, comprising administering to a subject in need of treatment. Alternatively, the present invention provides the use of the solid amorphous dispersions, pharmaceutical compositions, and unit dosage forms of the present invention in the treatment of one of the above diseases, conditions, and disorders in a subject in need of treatment. The present invention further provides a method of making or manufacturing a medicament useful for treating one of the above diseases, conditions, and disorders comprising using the solid amorphous dispersions, pharmaceutical compositions, or unit dosage forms of the present invention. The term "biological sample", as used herein, means an in vitro or ex vivo sample, and includes, without limitation, a cell culture or extract thereof; a biopsy obtained from a mammal, or extract thereof; blood, saliva, urine, feces, semen, tears, lymphatic fluid, ocular fluid, vitreous fluid, or other bodily fluids or extracts thereof.

[0145]

[0165] The compounds and pharmaceutical compositions described herein inhibit sGC, cGMP, and / or or NO.

[0146]

[0166] The solid amorphous dispersions, pharmaceutical compositions, and unit dosage forms disclosed herein also include The compounds are also useful for veterinary treatment of companion animals, exotic animals, and dairy animals, including, without limitation, dogs, cats, mice, rats, hamsters, gerbils, guinea pigs, rabbits, horses, pigs, and cows.

[0147]

[0167] In another aspect, the present invention relates to a method for treating a biological sample with the solid dispersion, pharmaceutical composition, or the like of the present invention. The present invention also provides a method for stimulating sGC activity in a biological sample, comprising contacting said biological sample with a solid dispersion, pharmaceutical composition, or unit dosage form of the present invention. The use of the solid dispersion, pharmaceutical composition, or unit dosage form of the present invention in a biological sample is useful for a variety of purposes known to those skilled in the art. Examples of such purposes include, without limitation, biological assays and biological specimen storage. EXAMPLES

[0148] device X-ray powder diffractometer (XRPD) Hydraulic Manual Tablet Press Turbula Shaker (Glen Mills) Analytical balance Top loading balance UPLC1: Waters Acquity UPLC incubator shaker Ultrasonic Disintegrator Eppendorf Centrifuge Tablet Hardness Tester Differential Scanning Calorimetry (DSC) Benchtop Spray Dryer: Buchi B290 Microscope / Digital Camera Thermogravimetric analyzer (TGA) Vacuum oven humidity scale 8 Station Automatic Tablet Press V-type Blender Thickness Measuring Instrument Tabletop roller compactor Quadro Comill Induction Sealer Disintegration Tester pH meter Example 1A: Small scale preparation of Compound I Compound I and its preparation have been previously described in published patent application WO2014 / 144100 (September 18, 2014). is incorporated herein by reference in its entirety.

[0149] Example 1B: Large-Scale Preparation of Compound I i): Coupling of compound (1') with N,O-dimethylhydroxylamine to give N-methoxy-N-methylisoxazole-3-carboxamide (2')

[0150] [ka]

[0151] A suitable reaction vessel equipped with a mechanical stirrer and digital thermometer was charged with isoxazole-3-carboxylic acid ((1'), 241.6 g, 2137 mmol, 1.0 equiv), toluene (1450 mL), and DMF (7.8 g, 107 mmol, 0.05 equiv). The resulting slurry was heated to 45-50°C. Oxalyl chloride (325 g, 2559 mmol, 1.2 equiv) was then charged via addition funnel over the course of 2 h while maintaining the reaction temperature between 45-50°C, and vigorous gas evolution was observed. After addition, a brown mixture was obtained. The brown mixture was heated to 87-92°C over 1 h and stirred at 87-92°C for 1 h. The reaction was complete by HPLC. During heating, the brown mixture became a dark solution. The reaction was monitored by quenching a portion of the reaction mixture into piperidine and monitoring the piperidine amide by HPLC. The dark mixture was cooled to 20-25° C. and then filtered through a sintered glass funnel to remove any insoluble material. The dark filtrate was concentrated under reduced pressure to a dark oil of 400 mL volume.

[0152] Potassium carbonate (413 g, 2988 mmol, 1.4 equiv) and water (1000 mL) were placed in a suitable reaction vessel equipped with a mechanical stirrer and digital thermometer. The reaction solution was cooled to -10 to -5 °C. N,O-Dimethylhydroxyamine hydrochloride (229 g, 2348 mmol, 1.1 equiv) was placed in a suitable reaction vessel and dissolved in water (1000 mL). The N,O-Dimethylhydroxyamine solution and dichloromethane (2500 mL) were then added to the potassium carbonate solution.

[0153] The dark oil (400 mL) was then slowly added via the dropping funnel while maintaining the reaction temperature at -10 to 0°C. The addition was slightly exothermic, resulting in a brown mixture after the addition. The mixture was stirred at 0 to 5°C for 20 minutes and then warmed to 20 to 25°C. The lower organic layer was collected and the upper aqueous layer was extracted with dichloromethane (400 mL). The combined organic layers were washed with 15% sodium chloride solution (1200 mL). The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate (2') (261.9 g, 97 wt%, 76% yield). 1 Toluene: 3 wt % by 1 H-NMR, water content: 0.04 wt % by KF was obtained as a dark oil. 1 H-NMR (500 MHz, CDCl3) δ ppm 8.48 (s, 1H); 6.71(s, 1H); 3.78 (s, 3H); 3.38 (s, 3H).

[0154] ii): Alkylation of compound (2') with ethyl propionate gives 4-(isoxazolidinediamine). to provide (E)-ethyl 2-(methoxy(methyl)amino)-4-oxobut-2-enoate (3'),

[0155] [ka]

[0156] A suitable reaction vessel equipped with a mechanical stirrer and digital thermometer was charged with intermediate (2') (72.2 g, 96 wt%, 444 mmol, 1.0 equiv), ethyl propionate (65.7 g, 670 mmol, 1.5 equiv), and anhydrous THF (650 mL). The solution was cooled to -65 to -55 °C. Sodium bis(trimethylsilyl)amide in THF (1 M, 650 mL, 650 mmol, 1.46 equiv) was then added slowly via an addition funnel while maintaining the reaction temperature at -65 to -55 °C. After the addition was complete, the mixture was stirred below -55 °C for 10 min. The reaction was then quenched with 1N HCl (650 mL, 650 mmol, 1.46 equiv.) while maintaining the reaction temperature below -20°C, immediately followed by the addition of ethyl acetate (1500 mL) and water (650 mL). The top ethyl acetate layer was collected and the bottom aqueous layer was extracted with ethyl acetate (800 mL). The combined organic layers were washed with 10% citric acid (1000 mL) and saturated sodium chloride solution (650 mL). The organic layer was concentrated under reduced pressure to give a dark oil.

[0157] The dark oil was dissolved in a solution of dichloromethane / ethyl acetate / heptane (150 mL / 100 mL / 100 mL). The solution was loaded onto a silica pad (410 g) and the silica pad was eluted with ethyl acetate / heptane (1 / 1 v / v). The filtrate (approximately 3000 mL) was collected and concentrated under reduced pressure to a volume of 150 mL and allowed to settle to give a slurry. Heptane (200 mL) was then added to the slurry and the slurry was concentrated under reduced pressure to a volume of 150 mL. The resulting slurry was filtered and the filter cake was washed with heptane (150 mL). The filter cake was then air-dried overnight to give intermediate (3') (63.4 g, 56% yield, >99% purity by HPLC) as a brown solid. 1 H-NMR (500 MHz, CDCl3) δ ppm 8.42 (d, J=1.53 Hz, 1H); 6.76 (d, 6.18 (s, 1H); 4.47 (q, J=7.07 Hz, 2H); 3.75 (s, 3H); 3.21 (s, 3H); 1.41 (t, J=7.17 Hz, 3H).

[0158] iii): Cyclization of compound 3' with 2-fluorobenzylhydrazine to provide ethyl 1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazole-3-carboxylate (4').

[0159] [ka]

[0160] A suitable reaction vessel equipped with a mechanical stirrer and digital thermometer was charged with intermediate (3') (72.9 g, 287 mmol, 1.0 equiv) and absolute ethanol (730 mL). The mixture was cooled to 0-5° C. The mixture was then charged with 2-fluorobenzylhydrazine (48.2 g, 344 mmol, 1.2 equiv). The mixture was stirred at 0-10° C. for 1 h, then warmed to 20-25° C. and stirred at 20-25° C. for 16 h. The reaction was complete by HPLC. Concentrated HCl (33.9 g, 37 wt %, 344 mmol, 1.2 equiv) was charged to the reaction mixture over 1 min, causing the batch temperature to exotherm from 20° C. to 38° C. A slurry was obtained. The mixture was cooled to 0-10° C. over 1 h and stirred at 0-10° C. for 1 h. The resulting slurry was filtered and the filter cake was washed with ethanol (200 mL). The filter cake was dried under vacuum at 30-40° C. for 16 hours to give intermediate (4′) (81.3 g, 90% yield, >99% purity by HPLC) as an off-white solid. 1 H-NMR (500 MHz, CDCl3) δ ppm 8.47 (d, J=1.68 Hz, 1H); 7.15-7.26 (m, 2H); 6.94-7.08 (m, 2H); 6.77-6.87 (m, 1H); 6.55 (d, J=1.68 Hz, 1H); 5.95 (s, 2H); 4.43 (q, J=7.02 Hz, 2H); 1.41 (t, J=7.17 Hz, 3H).

[0161] iv): Amination of compound (4') to provide 1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazole-3-carboximidamide hydrochloride (5'B).

[0162] [ka]

[0163] Anhydrous ammonium chloride (267 g, 4991 mmol, 5.0 equiv.) and toluene (5400 mL) were added to a suitable reaction vessel equipped with a mechanical stirrer and digital thermometer. Trimethylaluminum in toluene (2 M, 2400 mL, 4800 mmol, 4.8 equiv.) was added slowly via addition funnel while maintaining the reaction temperature at 20-40° C. (Note: methane gas evolution was observed during the addition). The mixture was then heated to 75-80° C. over 30 min to give a clear white solution. Intermediate (4') (315 g, 999 mmol, 1.0 equiv.) was added to the reaction mixture in 4 portions at 75-90° C. over 1 h. The reaction was stirred at 80-90° C. for 30 min and then heated to 100-110° C. The mixture was heated and stirred at 100-110°C for 3 hours. The reaction was complete by HPLC. The reaction mixture was cooled to 10-20°C and methanol (461 g, 14.4 moles, 14.4 equiv.) was added slowly via the addition funnel while maintaining the reaction temperature at 10-40°C (Note: A very exothermic quench and copious gas evolution was observed). A thick slurry was obtained. 3N HCl (6400 mL, 3N, 19.2 moles, 19.2 equiv.) was then added slowly via the addition funnel while maintaining the reaction temperature at 20-45°C. The mixture was heated to 80-85°C and stirred at 80-85°C for 10 minutes to obtain a clear biphasic mixture. The mixture was cooled to 0-5°C for 3 hours and stirred at 0-5°C for 1 hour. The resulting slurry was filtered and the filter cake was washed with water (3000 mL).The filter cake was dried under vacuum at 40-50° C. for 24 hours to give intermediate (5′B) (292 g, 91% yield, >99% purity by HPLC) as an off-white solid. 1H-NMR (500 MHz, DMSO-d6) δ ppm 9.52 (s, 2H); 9.33 (s, 2H); 9.18 (d, J=1.53 Hz, 1H); 7.88 (s, 1H); 7.29-7.38 (m, 1H); 7.19-7.25 (m, 1H); 7.10-7.16 (m, 1H); 7.03 (d, J=1.53 Hz, 1H); 6.92-6.98 (m, 1H); 5.91 (s, 2H). MP 180-185℃.

[0164] v): Cyclization of compound (5'B) with diethyl fluoromalonate to provide 5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidine-4,6-diol (6').

[0165] [ka]

[0166] A suitable reaction vessel equipped with a mechanical stirrer and digital thermometer was charged with intermediate (5'B) (224.6 g, 698 mmol, 1.0 equiv), methanol (2250 mL), and diethyl fluoromalonate (187 g, 1050 mmol, 1.5 equiv). A solution of sodium methoxide in methanol (567 g, 30 wt%, 3149 mmol, 4.5 equiv) was then added via the addition funnel while maintaining the reaction temperature at 20-35°C. The mixture was stirred at 20-35°C for 30 minutes to give a pale suspension. The reaction was complete by HPLC. A 1.5 N HCl solution (2300 mL, 3450 mmol, 4.9 equiv) was added via the addition funnel over 1 hour while maintaining the reaction temperature at 20-30°C. A white suspension was obtained. The pH of the reaction mixture was approximately 1 by pH paper. The slurry was stirred at 20-30° C. for 30 min. The resulting slurry was filtered and the filter cake was washed with a premixed solution of methanol and water (500 mL / 500 mL) and then with water (1000 mL). The filter cake was dried under vacuum at 50-60° C. for 16 h to give intermediate (6') (264 g, 97% yield, >99% purity by HPLC) as an off-white solid. 1 H-NMR (500 MHz, DMSO-d6) δ ppm 12.82 (br. s., 1H); 12.31 (br. s., 1H); 9.14 (d, J=1.53 Hz, 1H); 7.55 (s, 1H); 7.31-7.37 (m, 1H); 7.18-7.25 (m, 1H); 7.10-7.15 (m, 2H); 6.97-7.02 (t, J=7.55 Hz, 1H); 5.88 (s, 2H).

[0167] vi): Chlorination of compound (6') to provide 3-(3-(4,6-dichloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole (7')

[0168] [ka]

[0169] A suitable reaction vessel equipped with a mechanical stirrer and digital thermometer was charged with intermediate (6') (264 g, 711 mmol, 1.0 equiv), acetonitrile (4000 mL), and N,N-dimethylaniline (138 g, 1137 mmol, 1.6 equiv). The slurry mixture was heated to 70-80°C. Phosphorus oxychloride (655 g, 4270 mmol, 6.0 equiv) was then added via the addition funnel over 1 h while maintaining the reaction temperature at 70-80°C. The mixture was stirred at 75-80°C for 22 h to give a brown solution. The reaction was complete by HPLC. The mixture was then cooled to 0-5°C and a cotton-like solid precipitated at 25°C. Water (3000 mL) was slowly added via the addition funnel while maintaining the reaction temperature at 0-10°C. The slurry was stirred at 0-10° C. for 30 min. The resulting slurry was filtered and the filter cake was washed with a premixed solution of acetonitrile and water (500 mL / 500 mL). The filter cake was dried under vacuum at 35-45° C. for 16 h to give intermediate (7') (283 g, 98% yield, >99% purity by HPLC) as an off-white solid. 16.60 (d, J=1.68 Hz, 1H); 6.03 (s, 2H).

[0170] vii): Substitution of compound (7') with methoxide to provide 3-(3-(4-chloro-5-fluoro-6-methoxypyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole (8').

[0171] [ka]

[0172] A suitable reaction vessel equipped with a mechanical stirrer and digital thermometer was charged with methanol (3400 mL) and sodium methoxide in methanol (154 mL, 5.4 M, 832 mmol, 1.2 equiv). The reaction mixture was heated to 23-27° C. Intermediate (7') (283 g, 693 mmol, 1.0 equiv) was charged in small portions (5-10 g each portion) to the mixture over 40 min while maintaining the reaction temperature at 23-27° C. The slurry was stirred at 23-27° C. for 30 min. The reaction was complete by HPLC. The resulting slurry was filtered and the filter cake was washed with methanol (850 mL) followed by water (850 mL). The filter cake was dried under vacuum at 35-45° C. for 16 hours to give intermediate (8′) (277 g, 99% yield, 97% purity by HPLC) as an off-white solid. 1 H-NMR (500 MHz, CDCl3) δ ppm 8.47 (d, J=1.83 Hz, 1H); 7.38 (s, 1H); 7.18-7.25 (m, 1H); 7.01-7.08 (m, 1H); 6.94-7.00 (m, 1H); 6.81-6.88 (m, 1H); 6.60 (d, J=1.68 Hz, 1H); 6.00 (s, 2H); 4.21 (s, 3H).

[0173] viii): Hydrogenation of compound (8') to provide 3-(3-(5-fluoro-4-methoxypyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole (9').

[0174] [ka]

[0175] A suitable reaction vessel equipped with a mechanical stirrer and digital thermometer was charged with intermediate (8') (226 g, 560 mmol, 1.0 equiv.), palladium (10% on activated carbon, nominal moisture 50%, 22.6 g), tetrahydrofuran (3400 mL), and triethylamine (91 g, 897 mmol, 1.6 equiv.). Nitrogen was bubbled into the reaction mixture via Teflon tubing at 20-30° C. for 10 min. The mixture was then heated to 40-50° C. and hydrogen was bubbled into the reaction mixture via Teflon tubing for 6 h while maintaining the reaction temperature at 40-50° C. The reaction was complete by HPLC. Nitrogen was then bubbled into the reaction mixture via Teflon tubing at 40-50° C. for 10 min. The reaction mixture was purified using a Hypo Supercel TM The mixture was filtered hot through a 1000 ml column and the filter cake was washed with tetrahydrofuran (2000 mL). The filtrate was concentrated under reduced pressure to a volume of about 1300 mL to obtain a slurry. Tetrahydrofuran was then solvent exchanged with methanol by continuously feeding methanol (3000 mL) under reduced pressure. The final volume after solvent exchange was 1300 mL. The resulting slurry was filtered and the filter cake was washed with methanol (500 mL). The filter cake was dried under vacuum at 20-25° C. for 16 hours to obtain intermediate (9') (192 g, 93% yield, 98% purity by HPLC) as a white solid. 1 H-NMR (500 MHz, CDCl3) δ ppm 8.47 (d, J=1.68 Hz, 1H); 8.41 (d, J=2.59 Hz, 1H); 7.36 (s, 1H); 7.17-7.24 (m, 1H); 6.95-7.07 (m, 2H); 6.83-6.90 (m, 1H); 6.60 (d, J=1.68 Hz, 1H); 5.99 (s , 2H); 4.19 (s, 3H).

[0176] ix): Demethylation of compound (9') to provide 5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-ol (10').

[0177] [ka]

[0178] A suitable reaction vessel equipped with a mechanical stirrer and digital thermometer was charged with intermediate (9') (230 g, 623 mmol, 1.0 equiv), MeOH (3450 mL), and concentrated HCl (307 g, 37 wt%, 3117 mmol, 5.0 equiv). The mixture was heated to 60-65° C. to give a solution. The mixture was then stirred at 60-65° C. for 17 h to give a slurry. The reaction was complete by HPLC. The slurry was cooled to 20-25° C. over 2 h and stirred at 20-25° C. for 30 min. The resulting slurry was filtered and the filter cake was washed with methanol (1000 mL). The filter cake was dried under vacuum at 35-45° C. for 16 h to give intermediate (10') (214 g, 97% yield, >99% purity by HPLC) as a white solid. 1 H-NMR (500 MHz, DMSO-d6) δ ppm 12.90-13.61 (br. s., 1H); 9.11 (d, J=1.68 Hz, 1H); 8.16 (s, 1H); 7.64 (s, 1H); 7.29-7.42 (m, 1H); 7.17-7.28 (m, 2H); 7.08-7.15 (m, 1H); 6.97 (s, 1H); 5.91 (s, 3H).

[0179] x): Chlorination of compound (10') to provide 3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole (formula IV)

[0180] [ka]

[0181] A suitable reaction vessel equipped with a mechanical stirrer and digital thermometer was charged with intermediate (10') (214 g, 602 mmol, 1.0 equiv), acetonitrile (3000 mL), and N,N-dimethylaniline (109 g, 899 mmol, 1.5 equiv). The slurry mixture was heated to 70-80°C. Phosphorus oxychloride (276 g, 1802 mmol, 3.0 equiv) was then charged via the addition funnel over 30 min while maintaining the reaction temperature at 70-80°C. The mixture was stirred at 75-80°C for 2 h to give a green solution. The reaction was complete by HPLC. The mixture was then cooled to 0-5°C. Water (1500 mL) was slowly charged via the addition funnel while maintaining the reaction temperature at 0-10°C. The slurry was stirred at 0-10°C for 30 min. The resulting slurry was filtered and the filter cake was washed with a premixed solution of acetonitrile and water (500 mL / 500 mL) and water (500 mL). The filter cake was dried under vacuum at 30-40° C. for 16 hours to give the intermediate of formula IV (214 g, 95% yield, >99% purity by HPLC) as an off-white to pink solid. 1 H NMR (500 MHz, CDCl3) δ ppm 8.65 (s, 1H); 8.48 (d, J=1.68 Hz, 1H); 7.44 (s, 1H); 7.21-7.25 (m, 1H); 6.97-7.06 (m, 2H); 6.83-6.87 (m, 1H); 6.61 (d, J=1.68 Hz, 1H); 6.03 (s, 2H).

[0182] a): Amination of compound 12 to provide 2-(aminomethyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (14)

[0183] [ka]

[0184] Ammonium hydroxide (29% (as NH3) aqueous solution, 354 mL, 5435 mmol, 9.7 equiv.) and methyl t-butyl ether (354 mL) were added to a suitable reaction vessel equipped with a mechanical stirrer and digital thermometer. (Note: The condenser temperature was set at -20°C to minimize evaporation of the ammonium hydroxide.) 2,2-Bis(trifluoromethyl)oxirane ((12), 101 g, 561 mmol, 1.0 equiv.) was added via the addition funnel over 40 min while maintaining the reaction temperature at 20-26°C. After addition, the mixture was stirred at 20-26°C for 3 h. The mixture was allowed to separate and the lower aqueous layer was extracted with methyl t-butyl ether (2 x 354 mL). The combined organic layers were concentrated under reduced pressure to a volume of 303 mL. Methyl t-butyl ether (354 mL) was added and the mixture was concentrated under reduced pressure to a volume of 303 mL. Heptane (303 mL) was added and the mixture was concentrated under reduced pressure to a volume of 303 mL. The slurry was filtered and the filter cake was washed with heptane (100 mL). The solid was dried in a hood at 20-25° C. for 2 hours to a constant weight to give intermediate (14) (79.5 g, 71% yield) as a white solid. 1 H NMR (500 MHz, MeOD) δ ppm 3.09 (s, 2H).

[0185] b): Coupling of the compound of formula IV with compound 14 to provide 1,1,1,3,3,3-hexafluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)propan-2-ol (compound I).

[0186] [ka]

[0187] A suitable reaction vessel equipped with a mechanical stirrer and digital thermometer was charged with the intermediate of formula IV (133 g, 356 mmol, 1.0 equiv.), a dimethylsulfoxide solution of intermediate (14) (352 g, 60 wt %, 1071 mmol, 3.0 equiv.), and dimethylsulfoxide (1200 mL). The reaction mixture was heated to 125-130° C. and stirred at 125-130° C. for 4 hours. The reaction was complete by HPLC. The mixture was then cooled to 20-25° C. The reaction mixture was then charged with methyl t-butyl ether (3800 mL) and water (2600 mL). The organic layer was washed with saturated sodium bicarbonate solution (1000 mL) and 1N HCl solution (1000 mL) and then concentrated under reduced pressure to a volume of 1500 mL. The organic solution was loaded onto a silica pad (800 g) and the silica pad was eluted with methyl t-butyl ether. The clear fractions were collected and concentrated under reduced pressure to a volume of 2000 mL. The MTBE solution was heated to 45-55° C. and heptane (2000 mL) was added through the addition funnel over 30 min while maintaining the reaction temperature at 45-55° C. to obtain a slurry. The slurry was cooled to 20-25° C. and stirred at 20-25° C. for 30 min. The resulting slurry was filtered and the filter cake was washed with a premixed solution of MTBE and heptane (400 mL / 600 mL). The filter cake was then dried under vacuum at 45-55° C. for 5 h to obtain compound I (130 g, 68% yield, purity by HPLC: >99%) as an off-white solid. 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.11 (d, J=1.96 Hz, 1H); 8.66 (s, 1H); 8.37 (d, J=3.13 Hz, 1H); 8.11 (t, J=5.87 Hz, 1H); 7.48 (s, 1H); 7.30-7.37 (m, 1H); 7.17-7.24 (m, 1H); 7.21 (d, J=1.7 Hz, 1H); 7.06-7.13 (m, 1H); 7.00-7.06 (m, 1H); 5.87 (s, 2H); 4.11 (d, J=5.87 Hz, 2H).

[0188] Example 2: Spray drying of Compound I alone and Compound I with polymers. Spray drying as a dispersant and physical stability of the powders. Materials used:

[0168] Cellulose acetate phthalate (CAP) (Fluka); HPMCAS- MG(HPMCAS-M) (Shin-Etsu Chemical); Compound I.

[0189] procedure:

[0169] 10 g of Compound I was weighed into a 250 mL Pyrex bottle. Then, 100 mL of tetrahydrofuran (THF) was added and the mixture was stirred until Compound I was completely dissolved. This solution was used to prepare a spray-dried dispersion of pure Compound I.

[0190] 5 g of Compound I was placed into each of three 250 mL Pyrex bottles. 5 g of each polymer was then added, with each polymer being added to a different Pyrex bottle, and 100 mL of THF was then added to each bottle and stirred until the contents were dissolved.

[0191] Each of the solutions prepared above was spray dried under the following conditions: inlet temperature Degree: 100℃; Outlet temperature: Approximately 35-40℃, based on inlet temperature; Aspirator: 100%; Pump: 35%; High efficiency cyclone was used.

[0192]

[0172] The spray dried product obtained from each batch was then sampled and analyzed by XRPD. Three spray-dried solid dispersions of Compound I were evaluated: Dispersant 1: Spray dried pure compound I Dispersion 2: Spray-dried dispersion of Compound I:CAP (50:50) Dispersion 4: Spray-dried dispersion of Compound I:HPMCAS-M (50:50) The following XRPD methods were used to analyze this dispersant: Scan 5- 45° 2θ, 0.02° step size, 1 s each step on a low background holder.

[0193]

[0174] After the initial spray dried solid dispersion was evaluated by XRPD, These were placed in vials in stability chambers and evaluated again by XRPD after one month. Two different stability chambers were used: 25°C / 60% relative humidity (RH) (Stability Chamber 1) and 40°C / 75% RH (Stability Chamber 2). The containers were not sealed and no desiccant was used.

[0194]

[0175] XRPD of pure spray-dried Compound I alone was performed immediately after preparation (2 h After 2 h, the crystallization was performed again, but it showed some crystalline peaks, suggesting that the pure amorphous form of compound I is not stable.

[0195]

[0176] XRPD of the dispersant with polymer was measured after 1 month under stability conditions. However, they showed no crystalline peaks, suggesting that they were stable for at least one month under the given conditions.

[0196]

[0177] Cellulose acetate phthalate (CAP) and hydroxypropyl methyl cellulose Spray-dried dispersions of Compound I with cellulose acetate succinate (HPMCAS-M) were stable after 1 month at 25 °C / 60% RH (stability chamber 1) and 40 °C / 75% RH (stability chamber 2) as measured by XRPD.

[0197]

[0178] The XRPD graphs for each of the above dispersants are shown in Figures 1, 2, and 3. Illustratively, Figure 1 shows XRPD results for crystalline Compound I (thick line) and pure spray-dried Compound I (light line) 2 hours after preparation. Figure 2 shows XRPD results for a solid dispersion of amorphous Compound I with CAP (50:50) at "time 0" versus "after 1 month in stability chamber 1 or stability chamber 2 (unsealed, no desiccant)". The XRPD lines are, in order, from top to bottom on the left side of the graph: Compound I; Compound I:CAP (50:50), time 0; Compound I:CAP (50:50), after 1 month in stability chamber 1; and Compound I:CAP (50:50), after 1 month in stability chamber 2. Figure 3 shows XRPD results for a solid dispersion of amorphous Compound I with HPMCAS-M (50:50) at "time 0" versus "after 1 month in stability chamber 1 or stability chamber 2 (unsealed, no desiccant)". The XRPD lines are, in order from top to bottom on the left side of the graph: Compound I; Compound I:HPMCAS-M (50:50), time 0; Compound I:HPMCAS-M (50:50), after 1 month in stability chamber 1; and Compound I:HPMCAS-M (50:50), after 1 month in stability chamber 2.

[0198] Example 3: Stability of the spray-dried dispersions prepared in Example 2

[0179] In Example 2, a dispersant of cellulose acetate phthalate (CAP) and hyaluronic acid were used. Dispersions with hydroxypropyl methylcellulose acetate succinate (HPMCAS-M) (Dispersion 2 and Dispersion 4, respectively) were prepared and placed in a stability chamber to evaluate their physical stability after one month. In this study, the stability evaluation was continued.

[0199] The two dispersions placed in the stability chamber were not protected from moisture (i.e. When stored in containers (neither induction sealed nor stored with a desiccant), all showed at least a small amount of recrystallization after 4 months at 40°C / 75% RH (Stability Chamber 2). The dispersion with CAP appeared to show the least amount of recrystallization as shown by microscopy.

[0200] material

[0181] Dispersant 2 and Dispersant 4 prepared in Example 2 were subjected to three different techniques. : Analyzed using XRPD, DSC and microscopy.

[0201] procedure

[0182] The conditions described above in Example 2 were used for the XRPD analysis. DSC method: modulated DSC (mDSC); Pan: hermetically sealed pan with pinhole ; equilibration at 0.00°C; modulation of ±1.00°C every 60 seconds; isothermal for 5.00 minutes; temperature ramp 1.50°C / min to 200.00°C.

[0202] Microscopy: performed using a 20X objective under non-polarized light. Images were obtained for each dispersion from stability conditions (Stability Chamber 1 and Stability Chamber 2).

[0203] result Dispersion with CAP (Dispersion 2) or with HPMCAS-M after 4 months For (Dispersant 4), no clear crystallization peak was confirmed by XRPD. The results are shown in Figure 5 (Solid Dispersant 2, produced in Example 2) and Figure 6 (Solid Dispersant 4, produced in Example 2).

[0204]

[0186] mDSC showed the following: Dispersant 2: After 4 months in stability chamber 1, the Tg (glass transition temperature) was 91° C.; after 4 months in stability chamber 2, an exothermic peak was present at approximately 100° C., suggesting possible recrystallization of Compound I under stability chamber 2 conditions.

[0205] Dispersant 4: After 4 months at 25° C. / 60% RH, the Tg was 72° C.; after 4 months at 40° C. / 75% RH, an exothermic peak was present at approximately 100° C., suggesting possible recrystallization of Compound I under the conditions of Stability Chamber 2.

[0206] Microscopy showed the following: Dispersion 2: No morphology change is observed after 4 months at any stability condition. Dispersant 4: No morphological changes observed after storage at 25°C / 60% RH; 40°C / 75% After storage at RH, the formation of some small needles / rods (the crystalline form of Compound I) was visible, suggesting that recrystallization had occurred.

[0207] Example 4: Spray drying of Compound I with additional polymers In Example 2, the spray-dried dispersion of amorphous Compound I was mixed with 50:50 Compound I:polymer ratios were prepared and their stability was evaluated after one month in Example 2 and after four months in Example 3. In this example, dispersions with the same polymer were prepared at a Compound I:polymer ratio of 25:75. In addition, spray-dried solid dispersions of amorphous Compound I were prepared at a 25:75 Compound I:polymer ratio with three additional polymers: hydroxypropyl methylcellulose phthalate (HPMCP), PVP K29 / 32 (a polyvinylpyrrolidone polymer), and Plasdone S630 (a copolymer of polyvinylpyrrolidone and polyvinyl acetate).

[0208] The resulting solid dispersion was subjected to stability chamber 1 and stability chamber 2 conditions. The stability at various time points after being placed in was assessed by XRPD. material: Compound I; cellulose acetate phthalate (CAP) from Fluka; hydroxypropyl methylcellulose acetate succinate (HPMCAS-M) (MG grade) from Shin-Etsu Chemical; hydroxypropyl methylcellulose phthalate (HPMCP) (HP-50 grade) from Shin-Etsu Chemical; hydroxypropyl methylcellulose (HPMC), Methocel E5 Premium LV from Dow; hydroxypropyl cellulose (HPC) (LH-21 grade) from Shin-Etsu Chemical; Eudragit L100-55 from Evonik; polyvinylpyrrolidone (PVP), Plasdone K29 / 32 from Ashland; copolymer of polyvinylpyrrolidone and polyvinyl acetate (Plasdone), Plasdone S630 from Ashland; desiccant (Sorb-IT).

[0209] procedure:

[0190] CAP and HPMCAS-M were used to elucidate the cleavage of compound I from tetrahydrofuran (THF). The solubility of these polymers in this solvent was already known, as these polymers had already been used in spray drying by et al. HPMCP, HPMC, HPC, Eudragit, PVP, and Plasdone were added to 20 mL scintillation vials at approximately 1 g. 10 mL of THF was added to each vial, and the vials were vortexed and sonicated for 1 hour to determine whether the polymers were dissolved. HPMCP, PVP, and Plasdone were selected for inclusion in Compound I and spray drying, as they were soluble at this concentration.

[0210] To prepare the 50:50 dispersion, 5 g of Compound I and 5 g of polymer were added to 25 mL of ethanol. The solution was weighed into a 0 mL Pyrex bottle, and then 100 mL of THF was added and stirred until completely dissolved.

[0211] To prepare the 25:75 dispersion, 5 g of compound I and 15 g of polymer were mixed in 2 Weighed into a 50 mL Pyrex bottle. Then 100 mL of THF was added and the mixture was stirred until completely dissolved.

[0212]

[0193] Each of the solutions was spray dried under the conditions described in Example 2. The following spray-dried solid dispersions of amorphous Compound I were prepared: Dispersant 5:50:50 Compound I:CAP Dispersant 6:25:75 Compound I:CAP Dispersant 9:50:50 Compound I:HPMCAS-M Dispersant 10:25:75 Compound I: HPMCAS-M Dispersant 11:25:75 Compound I: HPMCP Dispersant 12:25:75 Compound I: PVP Dispersant 13:25:75 Compound I: Plasdone

[0195] The spray-dried dispersion obtained from each batch was collected and used in Examples 2 and 3. The dispersions were evaluated by XRPD within a maximum of 5 days of preparation using the same method described in. The dispersions were placed in the stability chamber 4 days after the initial XRPD evaluation.

[0213]

[0196] Nineteen days after initial placement in the stability chamber, 30 cc of these dispersions were added to They were then added to HDPE bottles and induction sealed. These samples were placed under stability conditions in both Stability Chamber 1 and Stability Chamber 2.

[0214]

[0197] Thirty-one days after initial placement in the stability chamber, these dispersions were It was then added to a 30 cc HDPE bottle containing a desiccant (Sorb IT) and induction sealed. These samples were placed under the stability conditions of both Stability Chamber 1 and Stability Chamber 2 for subsequent analysis.

[0215]

[0198] Comparing the XRPD from the initial evaluation of the above dispersants with previous analyses of pure Compound I, , did not show any crystalline peaks, suggesting that all of these dispersants were amorphous at time 0 (Figure 4).

[0216] Example 5: Large scale spray-dried dispersion of amorphous Compound I with several polymers in a 25:75 ratio material: Compound I, cellulose acetate phthalate (CAP) (manufactured by Eastman); Polyvinylpyrrolidone polyvinyl acetate (Plasdone S630) (Ashland); Hydroxypropyl methylcellulose acetate succinate (HPMCAS-M), AquaSolve (Ashland) procedure: For each dispersant, 22 g of Compound I was added to a 1 L Pyrex bottle. 66 g of the polymer was then added followed by 880 mL of tetrahydrofuran (THF) and the mixture was stirred until all solids were completely dissolved.

[0217] Each of the solutions was spray dried under the following conditions: Inlet temperature: 100 °C; outlet temperature: approximately 40-45 °C based on inlet temperature; aspirator: 100%; pump: 35%; a standard cyclone and collection vessel were used.

[0218]

[0202] The spray-dried amorphous Compound I produced in each batch was sampled and analyzed by XRPD. The evaluation was carried out by: Dispersant 14:25:75 Compound I:CAP Dispersant 15:25:75 Compound I: Plasdone S630 Dispersant 16:25:75 Compound I: HPMCAS-M

[0203] The spray-dried dispersion of amorphous Compound I prepared above was subjected to LOD (loss of drying). The mixture was further dried at 40°C in a vacuum oven at 10-15Hg for 4 nights until the loss level was sufficiently low (see values ​​below).

[0219]

[0204] The dispersants were analyzed by XRPD, mDSC, and microscopy. For RPD and microscopy, the same conditions as described in Example 3 were used. For mDSC, the following slightly modified conditions were used: Modulated DSC; Pan: Hermetically sealed pan with pinhole; Equilibration at 0.00°C; Modulation ±1.00°C every 60 seconds; Isothermal for 5.00 minutes; Temperature ramp 1.50°C / min to 240.00°C.

[0220]

[0206] Dispersant samples were placed in 30cc HDPE bottles with and without 1g of desiccant. and placed in stability chamber 1 and stability chamber 2.

[0207] Dispersant analysis at time 0: Dispersant 14: LOD: 1.66%, Tg: 129°C, amorphous by XRPD, spherical particles with no signs of crystallization.

[0221] Dispersant 15: LOD: 1.40%, Tg: 101° C., amorphous by XRPD, spherical particles with no signs of crystallization. Dispersant 16: LOD: 1.05%, Tg: 91° C., amorphous by XRPD, spherical particles with no signs of crystallization.

[0222]

[0208] The post-preparation XRPD results for Dispersants 14, 15, and 16 are shown in Figure 7. . Example 6: Stability of Spray-Dried Dispersions of Amorphous Compound I Under Different Conditions and Using Different Polymers

[0209] Stability chamber 2 (4) was previously prepared as shown in Examples 2, 4, and 5. Several dispersions stored at 0° C. / 75%) for different times were analyzed by XRPD, mDSC, and microscopy, and the results are summarized in Table 1 below.

[0223] Table 1. Stability of Dispersants Made in Examples 2, 4, and 5

[0224] [Table 1]

[0225] Example 7: Spray-dried dispersion of Compound I with HPMCAS-H polymer

[0210] In the previous examples, a dispersion of Compound I with HPMCAS-M (mid pH) was prepared. Here, we produced dispersions with HPMCAS-H (high pH, ​​different grades of the same polymer).

[0226]

[0211] 22 g of Compound I was weighed into a 1 L Pyrex bottle and then the polymer 66 g of tetrahydrofuran (THF) was added and stirred until all solids were completely dissolved, which took several hours.

[0227] The solution was spray dried under the following conditions: inlet temperature: 100° C.; outlet temperature: Degrees: Approximately 40-45°C based on inlet temperature; Aspirator: 100%; Pump: 35%; Standard cyclone and collection vessel were used.

[0228]

[0213] A new dispersion was made by the above protocol: Dispersant 17: Spray-dried dispersion of Compound I:HPMCAS-H (25:75)

[0214] The dispersion was subjected to a vacuum oven at 10-15Hg until the LOD was sufficiently low. The dispersion was further dried in a centrifuge at 40° C. for 4 nights. The dispersion was analyzed by XRPD, mDSC, and microscopy at time 0. The following conditions were used: XRPD: scan 5-45° 2θ, 0.02° step size, 1 sec each step on a low background holder; DSC: modulated DSC (mDSC); pan: hermetically sealed pan with pinhole; equilibration at 0.00° C.; ±1.00° C. modulation every 60 sec; isothermal for 5.00 min; temperature ramp 1.50° C. / min to 200.00° C.; microscopy: images were taken using a 20X objective under polarized light.

[0229] Characterization at time 0: LOD: 1.05%, Tg: 91° C. by XRPD If it is, it is amorphous and spherical particles with no signs of crystallization. Example 8A: Spray-dried dispersions of Compound I with HPMCAS-M polymer and a range of ratios for stability evaluation First, the spray-dried dispersion of Compound I was mixed with 25:75 and 50:50 Compound I. Dispersions at the 25:75 level were prepared using HPMCAS-M (Dispersions 10, 4, and 9). Dispersions at the 25:75 level were found to have greater stability. In this study, dispersions using HPMCAS-M were prepared at different ratios and subjected to stability conditions in Stability Chamber 1 and Stability Chamber 2. Additionally, additional dispersions were prepared at the 25:75 level for use in subsequent tabletting experiments.

[0230] material:

[0217] Compound I; Hydroxypropyl methylcellulose acetate succinate ( HPMCAS-M, MG grade) (manufactured by Shin-Etsu Chemical).

[0231] Procedure: Preparation of spray-dried dispersion For each dispersant, Compound I and HPMCAS-M were mixed in a 250 mL pipette. The amount of methanol shown in Table 2 was weighed into an Ilex bottle or a 2 L Pyrex bottle and added. The solution was stirred until Compound I and HPMCAS-M were completely dissolved.

[0232] Table 2. Preparation of Dispersant 18 to Dispersant 24

[0233] [Table 2]

[0234] Each of the solutions was spray dried under the following conditions: Inlet temperature: 100 °C; outlet temperature: approximately 35-45 °C, based on inlet temperature; aspirator: 100%; pump: 35%; for dispersant 18-22, a high-efficiency cyclone and collection vessel were used, and for dispersant 23 and dispersant 24, a standard cyclone and collection vessel were used.

[0235]

[0220] Each of the dispersions was dried in a vacuum oven for four nights. The LOD and Tg values ​​of the batches were measured after manufacture with the results shown in Table 3: Table 3. DSC results for Dispersant 18 to Dispersant 24

[0236] [Table 3]

[0237]

[0221] Each batch of spray dried material was sampled for XRPD, D using the following method: The samples were evaluated by SC and microscopy.

[0222] XRPD method: scan 5-45° 2θ, 0.02° step size, low ba 1 second for each step on the check round holder.

[0238] DSC method: Modulated DSC; Pan: Hermetically sealed pan with pinhole; 0.00°C Equilibrate at 0.5°C; ±1.00°C modulation every 60 seconds; isothermal for 5.00 minutes; temperature ramp 1.50°C / min to 200.00°C.

[0239]

[0224] Microscopy: Images were taken using a 20X objective under polarized light.

[0225] Once prepared, the dispersion samples were stored at 40°C / 75% for stability evaluation. Placed in a HDPE bottle (unsealed) in a RH stability chamber (Stability Chamber 2).

[0240] [Table 4]

[0241] A summary of the LOD and Tg values ​​is shown above in Table 3. XRPD showed that all dispersants Microscopy showed the presence of spherical particles and the absence of crystalline morphology (needles / rods) at time 0, suggesting that the is amorphous.

[0242]

[0227] All of the dispersions prepared above were stored in an unsealed bottle at 40°C / 75% It showed no signs of crystallization after 12 months of storage at RH. Example 8B. Preparation of Dispersant 25 25:75 Compound I: General procedure for large scale production of HPMCAS-M dispersants: A known weight of methanol was transferred to a container. The methanol was stirred. Compound I was added during this time and allowed to dissolve. With continued stirring, HPMCAS-M was slowly added and allowed to dissolve. The total solids concentration used was 10% and 90% of the weight of the solution came from methanol. The solution was spray dried using the appropriate size spray dryer and nozzle with the appropriate inlet temperature and solution flow rate. Once spray drying was complete, the material was transferred to a tray dryer or fluid bed dryer and dried to a loss on drying (LOD) of less than 2%.

[0243] Dispersant 25 specific instructions 1500 mL of methanol was transferred into a 2 L bottle. The methanol was stirred. While stirring, 37.5 g of Compound I was added and allowed to dissolve. With continued stirring, 112.5 g of HPMCAS-M was slowly added and allowed to dissolve. Spray dried using a Buchi B290 spray dryer equipped with a two-fluid nozzle using the following conditions: Inlet temperature: 100°C; Aspirator: 100%; Pump: 35%

[0230] The powder collected in the collection container under the cyclone of the spray dryer is poured into the oven. Transferred inside and tray dried for 4 nights until a loss on drying (LOD) of less than 2% was achieved.

[0244] Example 9. Tablet production from the dispersion prepared in Example 2 using dry granulation with slugging at 20 mg dose material: Dispersant 2 prepared in Example 2; Dispersant 4 prepared in Example 2; Avicel DG (Co-processed MCC with anhydrous dicalcium phosphate) (FMC); Croscarmellose sodium (CCS), Ac-Di-Sol (FMC); Magnesium stearate (Fisher) ).

[0245] procedure:

[0232] Intragranular blend ingredients other than magnesium stearate (see Tables 4 and 5) were added to HD Weighed into a PE bottle and mixed on a Turbula Shaker for 5 minutes. Magnesium stearate was added and mixed for an additional 3 minutes for each dispersion.

[0246]

[0233] An approximately 1150 mg aliquot of the above mixture was weighed out to obtain a pH of 0.6250" They were compressed using round flat tooling at a pressure of 1500 psi targeting a hardness of 12 kP.

[0247]

[0234] The slugs were milled using a 0.040" sieve at 2000 rpm. was crushed.

[0235] Based on yield, the extragranular ingredients except Mg stearate were added and blended for 5 minutes on the Turbula Shaker. Mg stearate was added and blended for an additional 3 minutes for each dispersion.

[0248] A 200 mg aliquot of each mixture (corresponding to a 20 mg dose of Compound I) was It was weighed and compressed into tablets using 0.3125" round tooling at 1300 psi pressure targeting a hardness of 9-10 kP.

[0249] Tablets T2 / 200 / 20 were obtained from Dispersion Agent 2. Tablets T4 / 200 / 20 were obtained from Dispersion Agent 4. Table 4. Production of tablets T2 / 200 / 20

[0250] [Table 5]

[0251] Table 5. Production of tablets T4 / 200 / 20

[0252] [Table 6]

[0253] Example 10. Tablet production from the dispersion prepared in Example 2 using dry granulation with slugging at 40 mg and 80 mg doses material:

[0239] The mixture previously used in Example 9 to prepare tablets from Dispersant 2 It was used again to produce 400 mg tablets with a 40 mg dose and 800 mg tablets with an 80 mg dose.

[0254] procedure:

[0240] Tooling: 0.2677" for a 40 mg dose (tablet weight: 400 mg). x 0.5787" modified oval tooling was used; for the 80 mg dose (tablet weight: 800 mg), 0.4000" x 0.7500" modified oval tooling was used.

[0255]

[0241] The blends were weighed and evaluated for compression setting. These were selected to achieve the following: Target hardness levels were achieved: 40mg tablets-12~13kP; 80mg tablets-15~16kP.

[0256]

[0242] Tablets T2 / 400 / 40 are obtained from dispersion 2 and contain up to 40 mg per tablet. The final dose of Compound I was obtained; tablets were compressed at 1250 psi.

[0243] Tablets T2 / 800 / 80 are obtained from dispersion 2 and contain up to 80 mg per tablet. The final dose of Compound I was obtained; tablets were compressed at 2000 psi.

[0257] Example 11. Dry granulation by roller compaction at 10 mg dose Tablet production from the dispersion prepared in Example 5 material: Dispersant 14 from Example 5, Dispersant 15 from Example 5, Dispersant 16 from Example 5 Powder 16; Avicel DG (MCC co-processed with dicalcium phosphate) (FMC); Croscarmellose sodium (CCS), Ac-Di-Sol (FMC); Magnesium stearate (Fisher); MCC (Avicel PH-102) (FMC); Opadry II, 8518422 White (Colorcon) - WP731466; Milli Q laboratory water; desiccant (Sorb-IT).

[0258] Production of dry granulation (by roller compaction):

[0246] Dispersant 14, Dispersant 15, and Dispersant 16 obtained in Example 5 were weighed. The mixture was then blended in a 1 quart V-shell on a V-blender with Avicel DG and CCS that had been sieved through a 20 mesh sieve for 10 minutes. Magnesium stearate was passed through a 20 mesh sieve and added during an additional 3 minutes of blending.

[0259]

[0247] The mixture was then rolled at a roller pressure of 10 MPa and a roller speed of 1 rpm. The screw rotation speed was varied from 40 rpm to 70 rpm to achieve the desired ribbon.

[0260] Dispersant 14: Screw rotation speed: approx. 50 rpm, ribbon thickness: 1.8-2.0 mm Dispersant 15: Screw rotation speed: approx. 70 rpm, ribbon thickness: 1.2-1.5 mm Dispersant 16: Screw rotation speed: approx. 50 rpm, ribbon thickness: 1.2-1.5 mm

[0248] The ribbons were milled using a CoMil using a 0.062" sieve at a speed of 2000 rpm to produce the final granulation.

[0261] Tablet manufacturing:

[0249] The extragranular components were sieved through a 20 mesh sieve. Based on yield, The extragranular ingredients, except for Mg stearate, were added and blended in a 1 quart V-shell on a V-blender for 10 minutes. The Mg stearate was added and blended for an additional 3 minutes.

[0262]

[0250] Tableting was carried out using a force feeder with an automatic tablet press. Tablet compression was performed using .3150” round tooling and a target hardness of 9-10 kP.

[0263]

[0251] When monitoring the main compression force and extrusion force, the results showed that Dispersant 14 and Dispersant 16 For dispersant 15, the values ​​were 7-8 kN and 80-100 N, respectively.

[0264] Tablet Coating: The target weight gain during coating was 3.0%. Coating solution used for Agent 15: Opadry II coating solution was prepared at 20% solids by weighing 40.03 g into 200 mL of purified water while stirring with an overhead stirrer. The solution was stirred for at least 45 minutes prior to beginning the coating process.

[0265]

[0253] Coating solution used for dispersant 16: 40.06 g was weighed out and Opadry II coating solutions were prepared at 20% solids by adding Opadry II to 200 mL of purified water while stirring with a one-head stirrer. The solutions were stirred for at least 45 minutes prior to beginning the coating process. The ingredients and amounts utilized for each batch are listed below in Tables 6, 7, and 8.

[0266] Table 6. Preparation of tablets T14 / 200 / 10 / coated. From dispersant 14.

[0267] [Table 7]

[0268] Table 7. Preparation of tablets T15 / 200 / 10 / coated. From dispersant 15.

[0269] [Table 8]

[0270] Table 8. Preparation of tablets T16 / 200 / 10 / coated. From dispersant 16.

[0271] [Table 9]

[0272] Tablet Stability:

[0254] For placement in stability chamber 1 and stability chamber 2, tablets from each lot were A portion of the mixture was placed into a 60cc HDPE bottle.

[0273]

[0255] Coated tablets obtained from Dispersant 14 (Tablets T14 / 200 / 10 / Coated) The 100% RH (100% CO2) was used for the initial testing and placed in stability chamber 1 at 25°C / 60% RH and in stability chamber 2 at 40°C / 75% RH.

[0274]

[0256] Coated tablets (tablets T15 / 200 / 10 / coated) obtained from Dispersant 15 The 100% RH (100% CO2) was used for the initial testing and placed in stability chamber 1 at 25°C / 60% RH and in stability chamber 2 at 40°C / 75% RH.

[0275]

[0257] Coated tablets obtained from Dispersant 16 (Tablets T16 / 200 / 10 / Coated) The 100% RH (100% CO2) was used for the initial testing and placed in stability chamber 1 at 25°C / 60% RH and in stability chamber 2 at 40°C / 75% RH.

[0276]

[0258] 1g of desiccant was added to all bottles before they were induction sealed. The test bottles were placed in a foil pouch with six 1 g desiccants, sealed and placed at 5°C.

[0277] Example 12. Tablet production from the dispersions prepared in Examples 5 and 7 using dry granulation by roller compaction at 20 mg doses material: Dispersant 14 (25:75 Compound I:CAP) obtained in Example 5; Dispersant 16 (25:75 Compound I:HPMCAS-M) obtained in Example 5; Dispersant 17 (25:75 Compound I:HPMCAS-H) obtained in Example 7, MCC / dicalcium phosphate (Avicel DG) (FMC); Croscarmellose sodium (CCS), Ac-Di-Sol (FMC); Magnesium stearate (Fisher); M CC (Avicel PH-102) (manufactured by FMC); desiccant (Sorb-IT).

[0278]

[0260] The mixture previously used in Example 11 was mixed with Dispersant 14 and Dispersant 16. Thus, a 400 mg tablet was produced to achieve a 20 mg dose.

[0279]

[0261] From Dispersant 16, 25:75 Compound I: HPMCAS-M tablet (20 mg Dose) (tablets T16 / 400 / 20) were manufactured using the following protocol:

[0262] An approximately 400 mg aliquot of the final blend for Dispersant 16 was weighed out The molded pieces were then transferred to a molder using a 0.2677" x 0.5787" modified oval tooling setup on a manual press. The target hardness was 12 kP. See Table 10B.

[0280] Table 10B. Preparation of tablets T16 / 400 / 20

[0281] [Table 10]

[0282]

[0263] From Dispersant 14, 25:75 Compound I: CAP tablet (20 mg dose) (tablet A new formulation (T14 / 400 / 20) was prepared using the following protocol:

[0264] An approximately 400 mg aliquot of the final blend for Dispersant 14 was weighed out The molded pieces were then transferred to a molder using a 0.2677" x 0.5787" modified oval tooling setup on a manual press. The target hardness was 12 kP. See Table 10C.

[0283] Table 10C. Preparation of tablets T16 / 400 / 20

[0284] [Table 11]

[0285] Production of dry granulated products from dispersants 17

[0265] The dispersion was weighed and passed through a 20 mesh sieve in a 1 quart V-shell. The mixture was blended for 10 minutes along with Avicel DG and CCS that had been sieved through a 20 mesh sieve. Magnesium stearate was passed through a 20 mesh sieve and added during an additional 3 minutes of blending.

[0286]

[0266] The mixture was then rolled at a roller pressure of 10 MPa and a roller speed of 1 rpm. The screw rotation speed was varied from 40 rpm to 70 rpm to achieve the desired ribbon.

[0287]

[0267] For the production of dry granulation from Dispersant 17, the screw rotation speed is about 70 rp The ribbons were milled using a CoMil with a 0.062" sieve at a speed of 2000 rpm to obtain the final granulation. Manufactured.

[0288] Preparation of 10 mg tablets (tablets 17 / 200 / 10) from dispersion 17: An extragranular blend for 10 mg tablets was prepared. The extragranular ingredients were sieved through a 20 mesh sieve. Based on yield, extragranular ingredients except Mg stearate were added and blended in a 1 quart V-shell on a V blender for 10 minutes. Mg stearate was added and blended for an additional 3 minutes.

[0289]

[0269] Tableting was carried out using a force feeder with an automatic tablet press. Tablet compression was performed using .3150” round tooling and a target hardness of 9-10 kP. Main compression and extrusion forces were monitored using Director software.

[0290] Preparation of tablets of HPMCAS-H and 20 mg dose of Compound I (from Dispersant 17)

[0270] 25:75 Compound I: HPMCAS-H tablet (tablet T17 / 400 / 20 ) was prepared in 20 mg doses.

[0291] Approximately 400% of the final blend already used for the manufacture of the 10 mg dose tablets described above. Aliquots of mg were weighed and transferred to a molder using 0.2677" x 0.5787" modified oval tooling set up on a manual press. The target hardness was 12 kP (tablets 17 / 400 / 20). Details of this formulation are summarized in Table 11.

[0292] Table 11. Production of tablets T17 / 400 / 20

[0293] [Table 12]

[0294] Example 13. Kinetic solubility of solid dispersions in simulated intestinal fluid

[0272] The solubility of some of the spray dried dispersions prepared above in Example 4 was Solubility was evaluated in simulated intestinal fluids to determine if any polymer would inhibit the crystallization of Compound I from solution for a longer period of time. A solution containing Compound I:polymer (25:75) was used in this study. Solubility was determined in simulated intestinal fluids. Two flow fluids were utilized: FeSSIF (fed state simulated intestinal fluid) and FaSSIF (fasted state simulated intestinal fluid).

[0295] Based on the dissolution data in simulated liquids, the most effective stabilization of the amorphous form of Compound I was The ones that appeared to have the most potential were cellulose acetate phthalate (CAP), HPMCAS, and Plasdone S630.

[0296] material: Compound I; Hydroxypropyl methylcellulose, Methocel E5 (Dow); polyvinylpyrrolidone (PVP), Plasdone K29 / 32 (Ashland); copolymer of polyvinylpyrrolidone and polyvinyl acetate (Plasdone), Plasdone S630 (Ashland); 25:75 Compound I: CAP spray-dried dispersion (Dispersion 6); 25:75 Compound I: HPMCAS spray-dried dispersion (Dispersion 10); 25:75 Compound I: HPMCP spray-dried dispersion (Dispersion 11); 25:75 Compound I: PVP spray-dried dispersion (Dispersion 12); 25:75 Compound I: Plasdone S630 spray-dried dispersion (Dispersion 13); sodium taurocholate (Spectrum); lecithin (Spectrum); pepsin (Fisher Scientific); sodium chloride (Sigma-Aldrich); sodium hydroxide (Fisher Scientific maleic acid (Sigma-Aldrich); FaSSIF-V2 powder (Biorelevant); FeSSIF-V2 powder (Biorelevant).

[0297] procedure: One liter of each simulant was prepared. Biorelevant powders and instructions were used for FaSSIF and FeSSIF. Instructions for preparing FaSSIF can be found online at http: / / biorelevant.com / fassf-v2 / how-to-make / . Instructions for preparing FeSSIF can be found online at http: / / biorelevant.com / fessif-v2-dissolution-medium / fed-state-stimulated-intestinal-fluid-version-two-how-to-make / . You can search for it by clicking on the link below.

[0298]

[0276] FaSS was synthesized using maleic acid, sodium hydroxide, and sodium chloride. Maleate buffers were prepared for IF and FeSSIF at pH levels of 6.5 and 5.8, respectively. FaSSIF-V2 and FeSSIF-V2 powders were then added to produce the dissolution media for FaSSIF and FeSSIF. Both preparations were kept refrigerated until the day of use, when they were removed and placed in laboratory conditions for at least 30 minutes to equilibrate to room temperature before being added to the dispersion media.

[0299]

[0277] For each of the 25:75 Compound I:polymer dispersant prepared in Example 4, Approximately 100 mg of dispersion was weighed into each of two 100 mL glass bottles labeled FaSSIF or FeSSIF. 50 mL of FaSSIF or FeSSIF solvent was then added to the bottles.

[0300] Immediately after preparing the above samples, transfer a 1.5 mL aliquot to a centrifuge tube. All bottles were then placed on a shaker set at 37°C and 115 RPM. The tubes were then centrifuged at 13000 RPM for 15 minutes. 0.5 mL aliquots of the supernatant were transferred into HPLC vials. 0.5 mL of acetonitrile was added to each of the vials and the vials were vortexed. This process was repeated for samples at 15, 30, 45, 60, 90, and 120 minutes, and at 4, 6, and 24 hours.

[0301] Preparation of standards A set of standards was prepared as follows and reinjected with each sample set. Approximately 10 mg of Compound I was weighed into a 20 mL scintillation vial. 2.5 mL of acetonitrile was added and dissolved by vortexing and sonication. 2.5 mL of water was added to this solution and vortexed / sonicated. 0.5 mL of this solution was transferred into an HPLC vial labeled (STDH). 0.5 mL of (1:1) acetonitrile:water was added to this vial. A 10-fold dilution was performed to obtain the middle standard (STDM). A 10-fold dilution of the STDM was then performed to obtain the low standard (STDL).

[0302]

[0280] Relative to the peak area of ​​the closest standard (either STDL or STDM) Concentration estimates were obtained by quantitating relative peak areas or by analysis against a standard curve.

[0303]

[0281] vs. time over a 24 hour period for each dispersant in each simulated medium Plots of the concentration of Compound I relative to the amount of dispersant dissolved in FaSSIF (Example 13) and the amount of dispersant dissolved in FeSSIF (Example 13) are shown in Figure 8 [Kinetic solubility of dispersant in FaSSIF (Example 13)] and Figure 9 [Kinetic solubility of dispersant in FeSSIF (Example 13)].

[0304] UPLC method: Mobile phase A: 0.1% TFA in water Mobile phase B: 0.1% TFA in acetonitrile Column: Acquity BEH Shield RP18, 1.7 μm, 2.1 × 50 mm, Part number: 18 6002853,SN.021439007153 14 Injection volume: 3μL Autosampler temperature: Ambient temperature Column temperature: 25℃ Run Time: 10 minutes Flow rate: 0.45mL / min Collection wavelengths: 220nm, 245nm, 254nm, 280nm, PDA spectrum (190-400nm) Wavelength used for analysis: 254 nm Concentration gradient:

[0305] [Table 13]

[0306] Example 14. Dissolution of tablets prepared in Example 11 in FaSSIF Dissolution of tablets made with the solid dispersion granulation described above in Example 11 Based on the dissolution of these tablets, the dispersions made with CAP or HPMCAS appear to exhibit faster dissolution profiles than the dispersion made with Plasdone S630.

[0307] material:

[0283] Tablet 14 / 200 / 10 / coated, Tablet 15 / 200 / 10 / coated, Tablets 16 / 200 / 10 / coated; Sodium chloride (Sigma-Aldrich); Sodium hydroxide (Fisher Scientific); Maleic acid (Sigma-Aldrich); FaSSIF-V2 powder (Biorelevant) Procedure, dissolution:

[0284] 6 L of FaSSIF was prepared (see previous example).

[0308]

[0285] For 500 mL of FaSSIF, use a USP type II paddle for 50 minutes at 37°C. A rotation speed of 1000 RPM was used and each dosage form was evaluated for its dissolution.

[0286] Samples were taken at 0, 15, 30, 45, and 60 minutes.

[0309] After sampling at 60 minutes, the dissolution apparatus was ramped up to a paddle speed of 200 RPM. The increment was set for 20 minutes and samples were obtained into Eppendorf tubes. The tubes were centrifuged at 13,000 RPM for 15 minutes.

[0310]

[0288] 0.5 mL of each sample was added to 0.5 mL of acetonitrile and analyzed by UPLC. The mixture was vortexed for analysis. Preparation of standards:

[0289] 10.00 mg of Compound I was weighed into a 20 mL vial and added to 5 mL of acetone. Acetonitrile was added to 0.6 mL of 1:1 acetonitrile:water to achieve a concentration of 1 mg / mL. A 20-fold dilution was performed in 2 mL volumes to achieve a concentration of 0.05 mg / mL. 1 mL of this solution was used as standard 1. 0.4 mL of standard 1 was added to 0.6 mL of 1:1 acetonitrile:water to achieve standard 2 at a concentration of 0.02 mg / mL. 0.2 mL of standard 1 was added to 0.8 mL of 1:1 acetonitrile:water to achieve standard 3 at a concentration of 0.01 mg / mL. 0.1 mL of standard 1 was added to 0.9 mL of 1:1 acetonitrile:water to achieve standard 4 at a concentration of 0.005 mg / mL. 0.05 mL of standard 1 was added to 0.95 mL of 1:1 acetonitrile:water to achieve standard 5 at a concentration of 0.0025 mg / mL. 0.1 mL of standard 3 was added to 0.9 mL of 1:1 acetonitrile:water to achieve standard 6 at a concentration of 0.001 mg / mL.

[0311] The standards and samples were analyzed by UPLC using the following method: Ta. Mobile phase A: 0.1% TFA in water Mobile phase B: 0.1% TFA in acetonitrile Column: Acquity BEH Shield RP18, 1.7 μm, 2.1 × 50 mm, Part number: 18 6002853,SN.021439007153 14 Injection volume: 3μL Autosampler temperature: Ambient temperature Column temperature: 25℃ Run Time: 10 minutes Flow rate: 0.45mL / min Collection wavelengths: 220nm, 245nm, 254nm, 280nm, PDA spectrum (190-400nm) Wavelength used for analysis: 254 nm Concentration gradient:

[0312] [Table 14]

[0313]

[0291] A plot of the tablet dissolution rate is shown in Figure 10 [Amorphous spray-dried fraction of Compound I Dissolution of powder tablets in FaSSIF (Example 14)]. Example 15A. Tablet production from the dispersion prepared in Example 5 using dry granulation by roller compaction at 5 mg dose material: Dispersant 16 from Example 5; MCC / dicalcium phosphate (Avicel DG) (FMC); Croscarmellose sodium (CCS), Ac-Di-Sol (FMC); Magnesium stearate (Mallinckrodt); MCC (Avicel PH-102) (FMC); Opadry II, 8518422 White (Colorcon); Milli Q purified laboratory water; Desiccant, molecular sieve (Dessicare).

[0314] Production of dry granulation (by roller compaction): Dispersant 16 obtained in Example 5 was weighed and mixed in a 16 quart V-blender. The mixture was blended in a mixing bowl with Avicel DG and CCS sieved through a 20 mesh sieve for 10 minutes. Magnesium stearate was passed through a 20 mesh sieve and added during an additional 3 minutes of blending. The theoretical batch size was 5 kg.

[0315]

[0294] The mixture was then rolled at a roller pressure of 1400 psi and 0.75 to 1.25 r The roller was compacted at a roller speed of 1000 rpm. The screw rotation speed was varied from 30 rpm to 50 rpm to achieve the desired ribbon.

[0316] Dispersant 16: Screw rotation speed: approx. 30 rpm, ribbon thickness: 1.4-1.6 mm

[0295] A CoMil using a 0.050" sieve and a circular impeller was run at 2000r. The ribbons were milled using a speed of 10000000000000000 pm to produce the final granulation.

[0317] Tablet manufacturing:

[0296] The extragranular components were sieved through a 20 mesh sieve. Based on yield, Add extragranular ingredients except magnesium stearate and mix in a 16-quart V-shell on a V-blender. The mixture was left to stand and mixed for 10 minutes. Magnesium stearate was added and mixed for an additional 3 minutes.

[0318] Tableting was performed using a force feeder with a Piccola tablet press. Tablet compression was performed using 0.3125” round tooling and a target hardness of 8 kP. The main compression force was 10-11 kN. The turret speed of the tablet press was 30 It was rpm.

[0319] Tablet Coating:

[0299] Coating solution used for dispersant 16: Weigh out 800 g and pour into the overhang. A coating solution of Opadry II was prepared at 20% solids by adding to 3200 mL of purified water with stirring on a head stirrer. The solution was stirred for at least 45 minutes prior to beginning the coating process.

[0320]

[0300] The ingredients and amounts used are listed in Table 15 below. Compression details are listed in Table 16. Summary. Tablets were compressed to a target hardness of 12 kP. Main compression and extrusion forces were 7-8 kN and 70-80 N, respectively. Tablets were coated to a target weight gain of 3.0%. Details of the coating process are summarized in Table 16.

[0321] Table 15. Preparation of tablets T16 / 200 / 5 / coated from dispersant 16.

[0322] [Table 15]

[0323] Table 16. Coating process parameters:

[0324] [Table 16]

[0325] Tablet Stability:

[0301] Aliquots of tablets were prepared for placement in stability chamber 1 and stability chamber 2. The samples were transferred into 60cc HDPE bottles. 1g of desiccant was added to all bottles which were then induction sealed.

[0326]

[0302] These tablets were stored at 25°C / 60% RH and 40°C with 1g of desiccant. The stability (presence of crystallinity) was tested at various time points when stored in sealed bottles at 25 °C / 75% RH. Crystallinity was observed by using the techniques described above for up to 12 months of storage. Moisture also increased over time in the presence of desiccant, but increased moisture did not appear to result in increased crystallinity up to 12 months.

[0327] Example 15B. Dissolution of tablets prepared in Example 15A in FaSSIF

[0303] Using the same protocol as described in Example 14 above, we A batch of 5 mg tablets prepared as described in Example 15B was evaluated for dissolution, and the results are summarized in FIG.

[0328] Example 16. Dog PK study

[0304] The following table (Table 17) shows the results of a study in dogs to determine PK parameters. The tablets tested are summarized below.

[0329] Table 17. Dog PK study design

[0330] [Table 17]

[0331] Feeding Requirements:

[0305] Male beagle dogs were used in this study. 1, 2, 3b, 4b, 5, 6, 7 Groups 1, 8, 9, and 10: All dogs were fasted overnight. All dogs were fed their daily food allowance 4 hours after dosing. Groups 3a and 4a: All dogs were fasted overnight and fed a human FDA diet (2 eggs, 2 strips of bacon, and butter / jelly with tomato paste) within 10 minutes prior to dosing. Each dog was force-fed 50 g of homogenate made from 2 slices of toast, hash brown potatoes, and 8 ounces of whole milk. All dogs were fed their daily ration 4 hours after dosing.

[0332] Thirty minutes prior to test article administration, all animals were treated with pentagastrin (6 mg / mL) In some groups, the same animals were dosed several times with at least a 7 day washout period in each case.

[0333] Dose Administration:

[0307] Tablets were placed in the back of the mouth via pill gun or by hand. After administration, each The animals were given 5-10 mL of water to facilitate swallowing of the tablets.

[0334] Blood / plasma:

[0308] From the jugular, cephalic, and saphenous veins at the following times (0.25 hours after dosing, Blood samples (2 mL) were collected at 0.5, 1, 2, 3, 4, 6, 8, 24, 32, and 48 hours. Blood samples were kept on ice until processed for plasma. Within 1 hour of collection, blood samples were centrifuged at 3200 RPM for 10 minutes at approximately 5° C. Plasma was divided into two approximately equal aliquots and transferred directly to 96-well plate tubes (1.1 mL). Plug caps were placed on the tubes. Plasma samples were stored at approximately −70° C. until use. Plasma concentrations of Compound I were assayed using an HPLC assay.

[0335] In fasted dogs, the tablet T2 / 400 / 40 (50:50 CAP: When dogs were administered a 40 mg dose of Compound I dispersion, the mean Cmax / dose (Cmax (ng / mL) divided by dose (mg / kg)) was approximately 93. Dogs administered an equivalent dose of native Compound I as a wet granulation tablet had a Cmax / dose of approximately 48.

[0336] In fed dogs, the tablet T2 / 200 / 20 (50:50 CAP: When dogs were administered a 20 mg dose of Compound I dispersion, the mean Cmax / dose (Cmax (ng / mL) divided by dose (mg / kg)) was approximately 245. The Cmax / dose for dogs administered an equivalent dose of native Compound I as a wet granulation tablet was approximately 145.

[0337] In fasted dogs, the tablet T2 / 200 / 20 (50:50 CAP: When dogs were administered a 20 mg dose of Compound I dispersion, the mean Cmax / dose (Cmax (ng / mL) divided by dose (mg / kg)) was approximately 153. Dogs administered an equivalent dose of native Compound I as a wet granulation tablet had a Cmax / dose of approximately 40.

[0338] In fasted dogs, the tablet T2 / 800 / 80 (50:50 CAP: When dogs were administered an 80 mg dose of Compound I dispersion, the mean Cmax / dose (Cmax (ng / mL) divided by dose (mg / kg)) was approximately 82. Dogs administered an equivalent dose of native Compound I as a wet granulation tablet had a Cmax / dose of approximately 30.

[0339] In fasted dogs, the tablet T2 / 400 / 40 (50:50 CAP: When dogs were administered a 40 mg dose of Compound I dispersion, the mean AUC / dose (AUC((h×ng) / mL) divided by dose (mg / kg)) was approximately 1710. The AUC / dose for dogs administered an equivalent dose of native Compound I as a wet granulation tablet was approximately 950.

[0340] In fed dogs, the tablet T2 / 200 / 20 (50:50 CAP: When dogs were administered a 20 mg dose of Compound I dispersion, the mean AUC / dose (AUC(h×ng) / mL) divided by dose (mg / kg)) was approximately 3392. The AUC / dose for dogs administered an equivalent dose of native Compound I as a wet granulation tablet was approximately 2324.

[0341] In fasted dogs, the tablet T2 / 200 / 20 (50:50 CAP: When dogs were administered a 20 mg dose of Compound I dispersion, the mean AUC / dose (AUC(h×ng) / mL) divided by dose (mg / kg)) was approximately 1869. The AUC / dose for dogs administered an equivalent dose of native Compound I as a wet granulation tablet was approximately 691.

[0342] In fasted dogs, the tablet T2 / 800 / 80 (50:50 CAP: When dogs were administered an 80 mg dose of Compound I dispersion, the mean AUC / dose (AUC(h×ng) / mL) divided by dose (mg / kg)) was approximately 1273. The AUC / dose for dogs administered an equivalent dose of native Compound I as a wet granulation tablet was approximately 486.

[0343] In fasted dogs, the tablet T2 / 400 / 40 (50:50 CAP: When dogs were administered a 40 mg dose of Compound I dispersion, the average estimated bioavailability (% F) was approximately 59. The estimated bioavailability in dogs administered an equivalent dose of native Compound I as a wet granulated tablet was approximately 31.

[0344] In fed dogs, the tablet T2 / 200 / 20 (50:50 CAP: When dogs were administered a 20 mg dose of Compound I dispersion, the mean bioavailability (% F) was approximately 118. The bioavailability in dogs administered an equivalent dose of native Compound I as a wet granulated tablet was approximately 73.

[0345] In fasted dogs, the tablet T2 / 200 / 20 (50:50 CAP: When dogs were administered a 20 mg dose of Compound I dispersion, the average estimated bioavailability (% F) was approximately 60. The bioavailability in dogs administered an equivalent dose of native Compound I as a wet granulated tablet was approximately 22.

[0346] In fasted dogs, the tablet T2 / 800 / 80 (50:50 CAP: When dogs were administered an 80 mg dose of Compound I dispersion, the estimated bioavailability (% F) was approximately 44. The estimated bioavailability in dogs administered an equivalent dose of native Compound I as a wet granulated tablet was approximately 16.

[0347]

[0321] In fasted dogs, the tablet T14 / 400 / 20 (75:25 CAP When a 20 mg dose of Compound I dispersion was administered, the mean Cmax / dose (Cmax (ng / mL) divided by dose (mg / kg)) was approximately 204.

[0348] Tablet T16 / 400 / 20 (75:25 HPM) in fasted dogs When CAS-M:20 mg dose of Compound I dispersion was administered, the mean Cmax / dose (Cmax (ng / mL) divided by dose (mg / kg)) was approximately 244.

[0349] Tablet T17 / 400 / 20 (75:25 HPM) in fasted dogs When CAS-H:20 mg dose of Compound I dispersion was administered, the mean Cmax / dose (Cmax (ng / mL) divided by dose (mg / kg)) was approximately 92.

[0350]

[0324] In fasted dogs, the tablet T14 / 400 / 20 (75:25 CAP When a 20 mg dose of Compound I dispersion was administered, the mean AUC / dose (AUC((h×ng) / mL) divided by dose (mg / kg)) was approximately 2762.

[0351] Tablet T16 / 400 / 20 (75:25 HPM) in fasted dogs When CAS-M:20 mg dose of Compound I dispersion was administered, the mean AUC / dose (AUC((h×ng) / mL) divided by dose (mg / kg)) was approximately 2798.

[0352] Tablet T17 / 400 / 20 (75:25 HPM) in fasted dogs When CAS-H:20 mg dose of Compound I dispersion was administered, the mean AUC / dose (AUC((h×ng) / mL) divided by dose (mg / kg)) was approximately 1416.

[0353]

[0327] In fasted dogs, the tablet T14 / 400 / 20 (50:50 CAP When a 20 mg dose of Compound I dispersion was administered, the mean estimated bioavailability (% F) was approximately 87.

[0354] Tablet T14 / 400 / 20 (75:25 HPM) in fasted dogs When CAS-M:20 mg dose of Compound I dispersion) was administered, the mean estimated bioavailability (% F) was approximately 99.

[0355] Tablet T14 / 400 / 20 (75:25 HPM) in fasted dogs When CAS-H:20 mg dose of Compound I dispersion) was administered, the mean estimated bioavailability (% F) was approximately 44.

[0356] Example 17. Preparation of tablets from dispersant 25

[0330] Using a protocol equivalent to that described in Example 15, but with a slightly different composition, Two other strength tablets (10 mg and 20 mg) were also manufactured, see table below:

[0357] [Table 18]

[0358]

[0331] Various aspects of the present invention can be described in the following text. As such, it should be understood that these embodiments include pharma- ceutically acceptable salts, even if the phrase "pharmaceutically acceptable salts" is not recited.

[0359] [1]. A solid dispersion of amorphous 1,1,1,3,3,3-hexafluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)propan-2-ol (Compound I).

[0360] [2]. A solid dispersion according to [1] above or according to any other aspect of the present invention, comprising Compound I and a polymer carrier. [3]. The solid dispersion according to [1] or [2] above (or any other aspect of the invention), wherein the polymeric carrier is selected from cellulose polymers.

[0361] [4]. The solid dispersion according to [1], [2] or [3] above, or any other aspect of the invention, wherein the polymeric carrier is selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), polyvinylpyrrolidone (PVP), or a copolymer of polyvinylpyrrolidone.

[0362] [5]. The solid dispersion according to [1], [2], [3] or [4] above, or any other aspect of the invention, wherein the polymeric carrier is selected from HPMCAS or CAP. [6]. The solid dispersion according to [1], [2], [3], [4] or [5] above, or any other aspect of the invention, wherein the polymeric carrier is HPMCAS.

[0363] [7]. The polymer carrier according to [1], [2], [3] or [4] above, wherein the polymer carrier is HPMCP. A solid dispersion (or according to other aspects of the invention). [8]. The solid dispersion according to [1], [2], [3], [4] or [5] above, or any other aspect of the invention, wherein the polymer carrier is CAP.

[0364] [9]. The solid dispersion according to [1], [2], [3] or [4] above, or any other aspect of the invention, wherein the polymer carrier is PVP.

[10] . The solid dispersion according to [1], [2], [3] or [4] above, or any other aspect of the invention, wherein the polymer carrier is a copolymer of PVP.

[0365]

[11] . A solid dispersion according to any one of [1] to

[10] above, or any other embodiment of the present invention, wherein the polymer is present in an amount between about 40% and about 95% of its total weight.

[12] . A solid dispersion according to any one of [1] to

[11] above, or any other aspect of the present invention, wherein the polymer is present in an amount between 50% and 90% of its total weight.

[0366]

[13] . A solid dispersion according to any one of [1] to

[12] above, or any other aspect of the present invention, wherein the polymer is present in an amount between 60% and 90% of its total weight.

[14] . A solid dispersion according to any one of [1] to

[11] above, or any other aspect of the present invention, wherein the polymer is present in an amount between 60% and 95% of its total weight.

[0367]

[15] . A solid dispersion according to any one of [1] to

[14] above, or any other embodiment of the present invention, wherein the polymer is present in an amount between about 70% and about 90% of its total weight.

[16] . A solid dispersion according to any one of [1] to

[15] above, or any other embodiment of the present invention, wherein the polymer is present in an amount between about 75% and about 90% of its total weight.

[0368]

[17] . The solid dispersion according to any one of [1] to

[11] or

[14] above, or any other embodiment of the invention, wherein the polymer is present in an amount between about 80% and about 95% of its total weight.

[18] . The solid dispersion according to any one of [1] to

[11] ,

[14] or

[17] above, or any other embodiment of the invention, wherein the polymer is present in an amount between about 90% and about 95% of its total weight.

[0369]

[19] . A solid dispersion according to any one of [1] to

[18] above, or according to another aspect of the present invention, obtained by spray drying.

[20] . A solid dispersion according to any one of [1] to

[18] above or another aspect of the present invention, produced by melt extrusion.

[0370]

[21] . The solid dispersion according to any one of the above [1] to

[20] or another embodiment of the present invention, wherein compound I is present in an amount of about 5% by weight to about 50% by weight thereof.

[22] The solid dispersion according to any one of [1] to

[21] above or another embodiment of the present invention, wherein compound I is present in an amount of about 5% by weight to about 40% by weight.

[0371]

[23] . The solid dispersion according to any one of [1] to

[22] above or another embodiment of the present invention, wherein compound I is present in an amount of about 10% by weight to about 30% by weight.

[24] The solid dispersion according to any one of [1] to

[23] above, or another embodiment of the present invention, wherein compound I is present in an amount of about 10% by weight to about 25% by weight.

[0372]

[25] . The solid dispersion according to any one of [1] to

[22] above, or another embodiment of the present invention, wherein compound I is present in an amount of about 15% by weight to about 40% by weight.

[26] . The solid dispersion according to any one of [1] to

[23] or

[25] above, or any other aspect of the present invention, wherein compound I is present in an amount of about 20% by weight to about 30% by weight.

[0373]

[27] A solid dispersion of Compound I according to any one of [1] to

[26] above or another aspect of the present invention, comprising less than 20% crystalline Compound I.

[28] A solid dispersion of Compound I according to any one of [1] to

[27] above or another aspect of the present invention, comprising less than 10% crystalline Compound I.

[0374]

[29] . A solid dispersion of Compound I according to any one of [1] to

[28] above or another aspect of the present invention, comprising less than 5% of crystalline Compound I.

[30] . A solid dispersion according to any one of the above [1] to

[29] or another embodiment of the present invention, which is a stable solid dispersion of Compound I.

[0375]

[31] . The solid dispersion according to any one of the above [1] to

[30] or other embodiments of the present invention, wherein the weight to weight ratio of compound I to polymer is between 10:90 and 50:50.

[32] . The solid dispersion according to any one of the above [1] to

[30] or other embodiments of the present invention, wherein the weight to weight ratio of compound I to polymer is between 20:80 and 40:60.

[0376]

[33] . The solid dispersion according to any one of the above [1] to

[32] or other embodiments of the present invention, wherein the weight to weight ratio of compound I to polymer is 25:75.

[34] . The solid dispersion according to any one of the above [1] to

[31] or other embodiments of the present invention, wherein the weight to weight ratio of compound I to polymer is 50:50.

[0377]

[35] A pharmaceutical composition comprising at least one pharma- ceutically acceptable excipient or carrier and a solid dispersion according to any one of [1] to

[34] above or another aspect of the present invention.

[36] . The pharmaceutical composition according to

[35] above or any other aspect of the invention, wherein the at least one pharma- ceutical acceptable excipient is selected from a filler, a flow agent, a lubricant, or a disintegrant.

[0378]

[37] . A unit dosage form comprising any one of the solid dispersions according to [1] to

[34] above, or any one of the pharmaceutical compositions according to

[35] or

[36] above, or any other aspect of the present invention.

[38] . A unit dosage form suitable for oral administration, comprising any one of the solid dispersions according to [1] to

[34] above, or any one of the pharmaceutical compositions according to

[35] or

[36] above, or any other aspect of the present invention.

[0379]

[39] . A unit dosage form comprising any one of the solid dispersions [1] to

[34] above, or any one of the pharmaceutical compositions

[35] or

[36] above, or according to other aspects of the present invention, selected from a capsule, a suspension, a powder, or a tablet.

[0380]

[40] . A unit dosage form comprising any one of the solid dispersions [1] to

[34] above, or any one of the pharmaceutical compositions

[35] or

[36] above, or another aspect of the present invention, which is a tablet.

[0381]

[41] . A method for treating a disease, condition, or disorder, comprising administering to a subject in need of treatment a therapeutically effective amount of any of the compounds described in [1] to

[34] above, or the pharmaceutical composition described in

[35] or

[36] above, or any of the unit dosage forms described in

[38] to

[40] above, or other aspects of the present invention, wherein the disease, condition, or disorder is selected from diabetic nephropathy, diabetic retinopathy, non-alcoholic steatohepatitis (NASH), hypertension, or heart failure.

[0382]

[42] . A method for treating a disease, condition, or disorder, comprising administering to a subject in need of treatment a therapeutically effective amount of any of the compounds described in [1] to

[34] above, or the pharmaceutical composition described in

[35] or

[36] above, or any of the unit dosage forms described in

[38] to

[40] above, or other aspects of the present invention, wherein the disease, condition, or disorder is diabetic nephropathy.

[0383]

[43] . A method for treating a disease, condition, or disorder, comprising administering to a subject in need of treatment a therapeutically effective amount of any of the compounds described in [1] to

[34] above, or the pharmaceutical composition described in

[35] or

[36] above, or any of the unit dosage forms described in

[38] to

[40] above, or other aspects of the present invention, wherein the disease, condition, or disorder is diabetic retinopathy.

[0384]

[44] . A method for treating a disease, condition, or disorder, comprising administering to a subject in need of treatment a therapeutically effective amount of any of the compounds described in [1]-

[34] above, or the pharmaceutical composition described in

[35] or

[36] above, or any of the unit dosage forms described in

[38] -

[40] above, or other aspects of the present invention, wherein the disease, condition, or disorder is non-alcoholic steatohepatitis.

[0385]

[45] . A method for treating a disease, condition, or disorder, comprising administering to a subject in need of treatment a therapeutically effective amount of any of the compounds described in [1] to

[34] above, or the pharmaceutical composition described in

[35] or

[36] above, or any of the unit dosage forms described in

[38] to

[40] above, or other aspects of the present invention, wherein the disease, condition, or disorder is heart failure.

[0386]

[46] . A method for treating a disease, condition, or disorder, comprising administering to a subject in need of treatment a therapeutically effective amount of any of the compounds described in [1]-

[34] above, or the pharmaceutical composition described in

[35] or

[36] above, or any of the unit dosage forms described in

[38] -

[40] above, or other aspects of the present invention, wherein the disease, condition, or disorder is selected from heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF).

[0387]

[47] . A method for treating a disease, condition, or disorder, comprising administering to a subject in need of treatment a therapeutically effective amount of any of the compounds described in [1] to

[34] above, or the pharmaceutical composition described in

[35] or

[36] above, or any of the unit dosage forms described in

[38] to

[40] above, or other aspects of the present invention, wherein the disease, condition, or disorder is heart failure with preserved ejection fraction (HFpEF).

[0388]

[48] . A method for treating a disease, condition, or disorder, comprising administering to a subject in need of treatment a therapeutically effective amount of any of the compounds described in [1] to

[34] above, or the pharmaceutical composition described in

[35] or

[36] above, or any of the unit dosage forms described in

[38] to

[40] above, or other aspects of the present invention, wherein the disease, condition, or disorder is heart failure with reduced ejection fraction (HFrEF).

[0389]

[49] . A method for treating a disease, condition, or disorder, comprising administering to a subject in need of treatment a therapeutically effective amount of any of the compounds described in [1] to

[34] above, or the pharmaceutical composition described in

[35] or

[36] above, or any of the unit dosage forms described in

[38] to

[40] above, or other aspects of the present invention, wherein the disease, condition, or disorder is hypertension.

[0390]

[50] . A method for treating a disease, condition, or disorder, comprising administering to a subject in need of treatment a therapeutically effective amount of any of the compounds described in [1] to

[34] above, or the pharmaceutical composition described in

[35] or

[36] above, or a unit dosage form described in any one of

[38] to

[40] above (or according to another aspect of the present invention), wherein the disease, condition, or disorder is resistant hypertension.

[0391]

[0332] Numerous embodiments have been described. However, the spirit and scope of the present invention It will be understood that various modifications can be made without departing from the scope of the invention. This application includes the following inventions. [Item 1] A solid dispersion of amorphous 1,1,1,3,3,3-hexafluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)propan-2-ol (Compound I). [Item 2] The solid dispersion of item 1, comprising compound I and a polymer carrier. [Item 3] The solid dispersion according to item 1 or 2, wherein the polymer carrier is selected from cellulose polymers. [Item 4] The solid dispersion according to item 2, wherein the polymer carrier is selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), polyvinylpyrrolidone (PVP), or a copolymer of polyvinylpyrrolidone. [Item 5] The solid dispersion according to Item 4, wherein the polymer carrier is selected from HPMCAS or CAP. [Item 6] The solid dispersion according to Item 5, wherein the polymer carrier is HPMCAS. [Item 7] The solid dispersion according to Item 4, wherein the polymer carrier is HPMCP. [Item 8] The solid dispersion according to Item 5, wherein the polymer carrier is CAP. [Item 9] The solid dispersion according to item 4, wherein the polymer carrier is PVP. [Item 10] The solid dispersion according to item 4, wherein the polymer carrier is a copolymer of PVP. [Item 11] The solid dispersion of any one of items 2 to 10, wherein the polymer is present in an amount between about 40% and about 95% by total weight of the solid dispersion. [Item 12] The solid dispersion of item 11, wherein the polymer is present in an amount between 50% and 90% of its total weight. [Item 13] The solid dispersion of item 12, wherein the polymer is present in an amount between 60% and 90% of its total weight. [Item 14] The solid dispersion of item 11, wherein the polymer is present in an amount between 60% and 95% of its total weight. [Item 15] The solid dispersion of any one of Items 11 to 14, wherein the polymer is present in an amount between about 70% and about 90% by total weight of the solid dispersion. [Item 16] The solid dispersion of item 15, wherein the polymer is present in an amount between about 75% and about 90% by total weight of the solid dispersion. [Item 17] The solid dispersion of item 14, wherein the polymer is present in an amount between about 80% and about 95% of its total weight. [Item 18] The solid dispersion of item 17, wherein the polymer is present in an amount between about 90% and about 95% by total weight of the solid dispersion. [Item 19] The solid dispersion according to any one of Items 1 to 18, obtained by spray drying. [Item 20] The solid dispersion according to any one of items 1 to 18, produced by hot-melt extrusion. [Item 21] The solid dispersion according to any one of Items 1 to 20, wherein Compound I is present in an amount of about 5% by weight to about 50% by weight thereof. [Item 22] The solid dispersion of item 21, wherein compound I is present in an amount of about 5% by weight to about 40% by weight. [Item 23] The solid dispersion of item 22, wherein compound I is present in an amount of about 10% by weight to about 30% by weight. [Item 34] The solid composition according to Item 23, wherein Compound I is present in an amount of about 10% by weight to about 25% by weight. Dispersant. [Item 25] The solid dispersion of Item 22, wherein Compound I is present in an amount of about 15% by weight to about 40% by weight. [Item 26] The solid dispersion of Item 25, wherein Compound I is present in an amount of about 20% by weight to about 30% by weight. [Item 27] ​​The solid dispersion of Compound I according to any one of Items 1 to 26, wherein the solid dispersion contains less than 20% of crystalline Compound I. [Item 28] The solid dispersion of Compound I according to Item 27, comprising less than 10% crystalline Compound I. [Item 29] The solid dispersion of Compound I according to Item 28, comprising less than 5% crystalline Compound I. [Item 30] The solid dispersion according to any one of Items 1 to 29, which is a stable solid dispersion of Compound I. [Item 31] The solid dispersion of any one of items 1 to 10, wherein the weight-to-weight ratio of compound I to polymer is between 10:90 and 50:50. [Item 32] The solid dispersion of item 31, wherein the weight-to-weight ratio of compound I to the polymer is between 20:80 and 40:60. [Item 33] The solid dispersion of item 32, wherein the weight-to-weight ratio of compound I to the polymer is 25:75. [Item 34] The solid dispersion of item 31, wherein the weight-to-weight ratio of compound I to the polymer is 50:50. [Item 35] A pharmaceutical composition comprising at least one pharma- ceutically acceptable excipient and the solid dispersion according to any one of Items 1 to 34. [Item 36] The pharmaceutical composition of Item 35, wherein the at least one pharma- ceutical acceptable excipient is selected from a filler, a flow agent, a lubricant, or a disintegrant. [Item 37] A unit dosage form comprising the solid dispersion according to any one of Items 1 to 34, or the pharmaceutical composition according to any one of Items 35 to 36. [Item 38] A unit dosage form of Item 37 suitable for oral administration. [Item 39] The unit dosage form of Item 38 selected from a capsule, a suspension, a powder, or a tablet. [Item 40] The unit dosage form of Item 39 which is a tablet. [Item 41] A method for treating a disease, condition, or disorder in a subject in need of treatment, comprising administering to the subject in need of treatment a therapeutically effective amount of the amorphous solid dispersion according to any one of Items 1 to 34, or the pharmaceutical composition according to Item 35 or Item 36, or the unit dosage form according to any one of Items 38 to 40, wherein the disease, condition, or disorder is selected from diabetic nephropathy, diabetic retinopathy, nonalcoholic steatohepatitis (NASH), hypertension, or heart failure. [Item 42] The method of Item 41, wherein the disease is diabetic nephropathy. [Item 43] The method of Item 41, wherein the disease or disorder is diabetic retinopathy. [Item 44] The method of Item 41, wherein the disease or disorder is non-alcoholic fatty liver disease. [Item 45] The method of Item 41, wherein the disease or disorder is heart failure. [Item 46] The method of Item 45, wherein the heart failure is selected from heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF). [Item 47] The method of Item 46, wherein the heart failure is HFpEF. [Item 48] The method of Item 46, wherein the heart failure is HFrEF. [Item 49] The method of Item 41, wherein the disease or disorder is hypertension. [Item 50] The method of Item 49, wherein the hypertension is resistant hypertension.

Claims

1. 1. A solid dispersion comprising amorphous 1,1,1,3,3,3-hexafluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)propan-2-ol (Compound I) and a polymeric carrier which is hydroxypropyl methylcellulose phthalate (HPMCP), polyvinylpyrrolidone (PVP), or a copolymer of polyvinylpyrrolidone, wherein the polymer is present in an amount of about 60% to about 95% by total weight of the solid dispersion.

2. The solid dispersion of claim 1, wherein the polymer carrier is HPMCP.

3. 3. The solid dispersion of claim 1 or 2, wherein the polymer is present in an amount of about 70% to about 90% or about 75% to about 90% of the total weight of the solid dispersion.

4. 4. The solid dispersion of claim 1, which is spray dried.

5. 5. The solid dispersion of claim 1, wherein Compound I is present in an amount of: (i) about 10% to about 30% by weight; (ii) about 10% to about 25% by weight; or (iii) about 20% to about 30% by weight.

6. The solid dispersion of claim 1, wherein less than 20%, less than 10%, or less than 5% of compound I contained in the solid dispersion is in crystalline form.

7. 7. The solid dispersion of claim 1, wherein the weight to weight ratio of Compound I to polymer is 25:

75.

8. A pharmaceutical composition comprising at least one pharma- ceutical acceptable excipient and the solid dispersion according to any one of claims 1 to 7.

9. 9. The pharmaceutical composition of claim 8 in an oral unit dosage form.

10. 10. The pharmaceutical composition of claim 9, wherein the unit dosage form is a tablet.

11. 11. The pharmaceutical composition of any one of claims 8 to 10, for treating a disease, condition, or disorder selected from renal disease, diabetic nephropathy, diabetic retinopathy, non-alcoholic steatohepatitis (NASH), hypertension, or heart failure.

12. The pharmaceutical composition according to claim 11, wherein the disease or disorder is diabetic nephropathy or diabetic retinopathy.

13. 12. The pharmaceutical composition of claim 11, wherein the renal disease is selected from renal fibrosis, ischemic renal disease, renal failure, renal insufficiency, and chronic renal disease, and the renal failure may be due to accumulation or deposition and tissue damage, progressive sclerosis, or glomerulonephritis.

14. 12. The pharmaceutical composition of claim 11, wherein the disease or disorder is hypertension, which may be resistant hypertension.

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