Spray-dried formulation of pyridazinone TRPC5 inhibitor

Abstract

To provide a TRPC5 inhibitor.SOLUTION: Disclosed are spray-dried formulations of 4-chloro-5-(4-(4-fluoro-2- (trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one, methods for preparing the formulations, and composition for preparing the formulations, and solid dosage forms comprising the formulations. Dosage forms described herein are useful in methods of treating kidney diseases or neuropathies associated with diseases or conditions, and in methods of treating pain, anxiety, or depression.SELECTED DRAWING: Figure 1A

Description

[Technical field]

[0001] Related Applications This application claims the benefit of priority to U.S. Provisional Application No. 62 / 832,632, filed April 11, 2019, and U.S. Provisional Application No. 62 / 991,315, filed March 18, 2020. [Background technology]

[0002] Proteinuria is a condition in which an excessive amount of protein in the blood leaks into the urine. Proteinuria can progress from a loss of 30 mg of protein in the urine in 24 hours (called microalbuminuria) to a loss of more than 300 mg / day (called macroalbuminuria) before reaching levels of more than 3.5 grams of protein in 24 hours, or 25 times the normal amount. Proteinuria occurs when there is dysfunction in the glomeruli of the kidneys, causing fluid accumulation (edema) in the body. Long-term protein leakage has been shown to lead to kidney failure. Nephrotic syndrome (NS) disease accounts for approximately 12% of prevalent end-stage renal disease cases and costs more than $3 billion annually in the United States. Approximately 5 per 100,000 children are diagnosed with NS each year, and 15 per 100,000 children currently suffer from NS. For patients who respond positively to treatment, the frequency of recurrence is extremely high. 90% of children with nephrotic syndrome respond to treatment, but an estimated 75% will relapse. There is a need for more effective methods of treating or reducing the risk of developing kidney disease (eg, proteinuria).

[0003] Mammalian TRP channel proteins form six-transmembrane cation-permeable channels that can be classified into six subfamilies (TRPC, TRPV, TRPM, TRPA, TRPP, and TRPML) based on amino acid sequence homology. Recent studies of TRP channels have shown that they are involved in many fundamental cellular functions and may play important roles in the pathophysiology of many diseases. Many TRPs are expressed in the kidney along different parts of the nephron, and increasing evidence suggests that these channels are involved in inherited as well as acquired kidney disorders. TRPC6, TRPM6, and TRPP2 are thought to be involved in hereditary focal segmental glomerulosclerosis (FSGS), hypomagnesemia with secondary hypocalcemia (HSH), and polycystic kidney disease (PKD), respectively.

[0004] Non-selective Ca 2+ Permeable transient receptor potential (TRP) channels function as sensors that transmit extracellular cues to the intracellular environment in diverse cellular processes, including actin remodeling and cell migration (Greka et al., Nat Neurosci 6, 837-845, 2003; Ramsey et al., Annu Rev Physiol 68, 619-647, 2006; Montell, Pflugers Arch 451, 19-28, 2005; Clapham, Nature 426, 517-524, 2003). Dynamic reorganization of the actin cytoskeleton is a key step in the spatiotemporally regulated Ca 2+These changes depend on the influx of phospholipids (Zheng and Poo, Annu Rev Cell Dev Biol 23, 375-404, 2007; Brandman and Meyer, Science 322, 390-395, 2008; Collins and Meyer, Dev Cell 16, 160-161, 2009), and the small GTPases RhoA and Rac1 function as key modulators of these changes (Etienne-Manneville and Hall, Nature 420, 629-635, 2002; Raftopoulou and Hall, Dev Biol 265, 23-32, 2004). RhoA induces stress fiber and focal adhesion formation, and Rac1 mediates lamellipodia formation (Etienne-Manneville and Hall, Nature 420, 629-635, 2002). Transient receptor potential cation channel subfamily C member 5 (TRPC5) cooperates with TRPC6 to translocate Ca 2+ It acts to regulate Ca influx, actin remodeling, and cell motility in kidney podocytes and fibroblasts. 2+ Whereas TRPC6-mediated Ca influx increases Rac1 activity 2+ Influx promotes RhoA activity. Gene silencing of TRPC6 channels eliminates stress fibers, reduces punctate contacts, and leads to a motile, migratory cell phenotype. In contrast, genetic silencing of TRPC5 channels rescues stress fiber formation and leads to a contractile cell phenotype. The results described herein reveal a conserved signaling mechanism by which TRPC5 and TRPC6 channels control a tightly regulated balance of cytoskeletal dynamics through differential binding to Rac1 and RhoA.

[0005] Ca in the actin cytoskeleton 2+Ca-dependent remodeling is a dynamic process that promotes cell migration (Wei et al., Nature 457, 901-905, 2009). RhoA and Rac1 function as switches involved in cytoskeletal rearrangements in migrating cells (Etienne-Manneville and Hall, Nature 420, 629-635, 2002; Raftopoulou and Hall, Dev Biol 265, 23-32, 2004). Activation of Rac1 mediates a motile cell phenotype, whereas RhoA activity promotes a contractile phenotype (Etienne-Manneville and Hall, Nature 420, 629-635, 2002). 2+ Ca plays a central role in the regulation of small GTPases (Aspenstrom et al., Biochem J 377, 327-337, 2004). 2+ The spatially and temporally restricted flicker of Ca is concentrated near the leading edge of migrating cells (Wei et al., Nature 457, 901-905, 2009). 2+ Microdomains signal the local burst of Rac1 activity as a key event at the leading edge (Gardiner et al., Curr Biol 12, 2029-2034, 2002; Machacek et al., Nature 461, 99-103, 2009). So far, no Ca2+ receptor has been implicated in GTPase regulation. 2+ The source of influx is largely unknown. Transient receptor potential (TRP) channels mediate the temporally and spatially restricted Ca influx that has been linked to cell migration in the growth cones of fibroblasts and neurons. 2+ Specifically, TRPC5 channels are known regulators of neuronal growth cone guidance1, and their activity in neurons is dependent on PI3K and Rac1 activity (Bezzerides et al., Nat Cell Biol 6, 709-720, 2004).

[0006] Podocytes are neuron-like cells derived from the metanephric mesenchyme of the kidney glomerulus and are essential for the formation of the renal filtration apparatus (Somlo and Mundel, Nat Genet. 24, 333-335, 2000; Fukasawa et al., J Am Soc Nephrol 20, 1491-1503, 2009). Podocytes have an exquisitely elaborated repertoire of cytoskeletal adaptations to environmental cues (Somlo and Mundel, Nat Genet 24, 333-335, 2000; Garg et al., Mol Cell Biol 27, 8698-8712, 2007; Verma et al., J Clin Invest 116, 1346-1359, 2006; Verma et al., J Biol Chem 278, 20716-20723, 2003; Barletta et al., J Biol Chem 278, 19266-19271, 2003; Holzman et al., Kidney Int 56, 1481-1491, 1999; Ahola et al., Am J Pathol 155, 907-913, 1999; Tryggvason and Wartiovaara, N Engl J Med 354, 1387-1401, 2006; Schnabel and Farquhar, J Cell Biol 111, 1255-1263, 1990; Kurihara et al., Proc Natl Acad Sci USA 89, 7075-7079, 1992). Early events in podocyte injury include dysregulation of the actin cytoskeleton (Faul et al., Trends Cell Biol 17, 428-437, 2007; Takeda et al., J Clin Invest 108, 289-301, 2001; Asanuma et al., Nat Cell Biol 8, 485-491, 2006) and Ca 2+These changes are characterized by a loss of endothelial homeostasis (Hunt et al., J Am Soc Nephrol 16, 1593-1602, 2005; Faul et al., Nat Med 14, 931-938, 2008). These changes are associated with the development of proteinuria, loss of albumin into the urinary space, and ultimately renal failure (Tryggvason and Wartiovaara, N Engl J Med 354, 1387-1401, 2006). The vasoactive hormone angiotensin II increases podocyte Ca 2+ Ca influx is induced and long-term treatment leads to loss of stress fibers (Hsu et al., J Mol Med 86, 1379-1394, 2008). 2+ Although the link between influx and cytoskeletal reorganization is recognized, the mechanisms by which podocytes sense and transduce extracellular cues that regulate cell shape and motility remain unclear. Mutations in the TRP canonical 6 (TRPC6) channel have been linked to podocyte injury (Winn et al., Science 308, 1801-1804, 2005; Reiser et al., Nat Genet 37, 739-744, 2005; Moller et al., J Am Soc Nephrol 18, 29-36, 2007; Hsu et al., Biochim Biophys Acta 1772, 928-936, 2007), but the specific pathways that regulate this process remain largely unknown. Moreover, TRPC6 shares close similarity with the other six members of the TRPC channel family (Ramsey et al., Annu Rev Physiol 68, 619-647, 2006; Clapham, Nature 426, 517-524, 2003). TRPC5 channels antagonize TRPC6 channel activity and control a tightly regulated balance of cytoskeletal dynamics through differential binding to different small GTPases.

[0007] Therefore, there is a need for additional inhibitors of TRPC5. Summary of the Invention

[0008] One aspect of the invention is a composition for producing a spray-dried dispersion, the composition comprising 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one ("Compound 1"), a solvent, and a polymer, wherein the polymer is dissolved in the solvent.

[0009] In one aspect, the invention features a method of making a spray-dried dispersion, the method includes spray drying a composition of the invention.

[0010] In one aspect, the invention features a spray-dried dispersion that includes 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one, a solvent, and a polymer, where the polymer is dissolved in the solvent.

[0011] In one aspect, the invention features a solid dosage form that includes a spray-dried dispersion of the invention and one or more of an excipient, a disintegrant, a lubricant, a glidant, and a stabilizer.

[0012] In one aspect, the invention features a method of making a solid dosage form of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one, the method comprising: a. mixing a spray dried dispersion disclosed herein with one or more of a first excipient, a first disintegrant, a first lubricant, a first glidant, and a first stabilizer to form a first solid mixture; b. roller compacting and grinding the first solid mixture; and c. optionally mixing the roller compacted and milled first solid mixture with one or more of a second excipient, a second disintegrant, a second lubricant, a second glidant, and a second stabilizer to form a second solid mixture; and d. Converting the first solid mixture or the second solid mixture into a solid dosage form of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one. Includes.

[0013] In one aspect, the invention relates to a method of treating a disease or nephropathy associated with a disease or condition, the method comprising administering to a subject in need thereof a solid dosage form of the invention.

[0014] In some embodiments, the renal disease or nephropathy associated with a disease or condition is focal segmental glomerulosclerosis (FSGS), diabetic nephropathy, Alport syndrome, hypertensive renal disease, nephrotic syndrome, steroid-resistant nephrotic syndrome, minimal change nephrotic syndrome, membranous nephropathy, idiopathic membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated MPGN, complement-mediated MPGN, lupus nephritis, post-infectious glomerulonephritis, thin basement membrane disease, mesangial proliferative glomerulonephritis, amyloidosis (primary), c1q nephropathy, rapidly progressive GN, anti-GBM disease, C3 glomerulonephritis, hypertensive nephrosclerosis, IgA nephropathy, IgG4 nephropathy. , proteinuric kidney disease, microalbuminuria, macroalbuminuric kidney disease, transplant-associated FSGS, transplant-associated nephrotic syndrome, transplant-associated proteinuria, nodular glomerulonephritis, NASR disease (proliferative glomerulonephritis with monoclonal IgG deposits), polycystic kidney disease, autosomal dominant polycystic kidney disease (ADPKD), or nephropathy associated with one of the following: obesity, insulin resistance, type II diabetes mellitus, prediabetes, metabolic syndrome, dyslipidemia, pulmonary arterial hypertension, cancer, cholestatic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), or Fabry disease.

[0015] In one aspect, the invention relates to a method of treating pain, anxiety, or depression comprising administering to a subject in need thereof a solid dosage form of the invention.

[0016] The methods are effective in a variety of subjects, including mammals, e.g., humans, and other animals, e.g., laboratory animals, e.g., mice, rats, rabbits, or monkeys, or pets and livestock, e.g., cats, dogs, goats, sheep, pigs, cows, or horses. In some embodiments, the subject is a human.

[0017] The present invention provides several advantages. The preventive and therapeutic methods described herein are effective in treating kidney disease (e.g., proteinuria) with minimal, if any, side effects. Furthermore, the methods described herein are effective in identifying compounds that treat or reduce the risk of developing kidney disease, anxiety, depression, or cancer.

[0018] Unless otherwise defined, all technical and scientific terms used herein shall have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in carrying out or testing the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, shall control. Additionally, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0019] Other features, objects, and advantages of the invention will be apparent from the detailed description and the claims. [Brief description of the drawings]

[0020] [Figure 1A] 1 shows a thermogram of crystalline Compound 1 free base form H. [Figure 1B]1 shows a thermogram of amorphous Compound 1. [Diagram 2] 1 shows an XRPD diffractogram of crystalline Compound 1 free base form H. [Diagram 3] 1 shows an SEM micrograph of crystalline Compound 1 free base form H at 5000x magnification. [Figure 4] 1 shows an XRPD diffractogram of a practical dispersion of Compound 1. [Figure 5A] 1 is an MDSC thermogram showing the Tg of an amorphous dispersion of 25% Compound 1 in HPMCAS-M. [Figure 5B] 1 is an MDSC thermogram showing the Tg of an amorphous dispersion of 25% Compound 1 in HPMCAS-L. [Figure 6] 1 shows a comparison of Compound 1 utility SDI with pure crystalline Compound 1 using a non-sink dissolution test using 0.1 N HCl / FaSSIF. [Figure 7] 1 shows dynamic vapor sorption / desorption measurements of compound 1 SDI. [Figure 8] 1 shows the XRPD diffractogram of the utility re-spray dried product of Compound 1. [Figure 9] XRPD diffractograms of SDI after 2 weeks of stability testing are shown. SDI under sealed conditions appears to remain amorphous at 40° C. / 75% RH and 50° C. / 75% RH. [Figure 10] XRPD diffractograms of aged SDI after a two-week stability test show crystal growth at 40° C. / 75% RH and 50° C. / 75% RH under open conditions. [Figure 11] 1 shows an XRPD diffractogram of aged SDI after 4 weeks of stability testing (closed conditions). [Figure 12] 1 shows XRPD diffractograms of aged SDI after 4 weeks of stability testing (open conditions). [Figure 13-1] 25:75 Certificate of Analysis (CoT) for compound 1: HPMCAS-M SDI (Lot: D-17-078) is shown. [Figure 13-2]25:75 Certificate of Analysis (CoT) for compound 1: HPMCAS-M SDI (Lot: D-17-078) is shown. [Figure 13-3] 25:75 Certificate of Analysis (CoT) for compound 1: HPMCAS-M SDI (Lot: D-17-078) is shown. [Figure 13-4] 25:75 Certificate of Analysis (CoT) for compound 1: HPMCAS-M SDI (Lot: D-17-078) is shown. [Figure 13-5] 25:75 Certificate of Analysis (CoT) for compound 1: HPMCAS-M SDI (Lot: D-17-078) is shown. [Figure 13-6] 25:75 Certificate of Analysis (CoT) for compound 1: HPMCAS-M SDI (Lot: D-17-078) is shown. [Figure 14A] 1 shows the retention times and relative peak heights of impurities after nebulized solutions of Compound 1 were held at 40° C. for various times. [Figure 14B] 1 shows the retention times and relative peak heights of impurities after nebulized solutions of Compound 1 were held at 40° C. for various times. [Figure 14C] 1 shows the retention times and relative peak heights of impurities after nebulized solutions of Compound 1 were held at 40° C. for various times. [Figure 14D-1] 1 shows the retention times and relative peak heights of impurities after nebulized solutions of Compound 1 were held at 40° C. for various times. [Figure 14D-2] 1 shows the retention times and relative peak heights of impurities after nebulized solutions of Compound 1 were held at 40° C. for various times. [Figure 14E] 1 shows the retention times and relative peak heights of impurities after nebulized solutions of Compound 1 were held at 40° C. for various times. [Figure 14F] 1 shows the retention times and relative peak heights of impurities after nebulized solutions of Compound 1 were held at 40° C. for various times. [Figure 14G] 1 shows the retention times and relative peak heights of impurities after nebulized solutions of Compound 1 were held at 40° C. for various times. [Figure 15A]Shown are test and related articles in wet SDI of Compound 1 when held at room temperature for up to 15 days. [Figure 15B] 1 shows a chromatogram of wet SDI of Compound 1 after 15 days of stability testing at room temperature. [Figure 16] 1 shows the diffractogram of wet SDI of Compound 1 after 15 days of stability testing at room temperature. [Figure 17] Shown are SEM images of wet SDI of Compound 1 kept at room temperature at t=0 (top row) and t=15 days (bottom row). [Figure 18] FIG. 1 shows a process flow diagram for manufacturing prototype tablets of Compound 1. [Figure 19-1] 1 shows the tabletability profile, compressibility profile, compactibility profile, and disintegration profile of a 50 mg prototype tablet of Compound 1. [Figure 19-2] 1 shows the tabletability profile, compressibility profile, compactibility profile, and disintegration profile of a 50 mg prototype tablet of Compound 1. [Figure 20-1] 1 shows dissolution under non-sink conditions of 50 mg prototype tablets of Compound 1 containing lactose and Ac-Di-Sol undergoing a 4 week accelerated stability study. [Figure 20-2] 1 shows dissolution under non-sink conditions of 50 mg prototype tablets of Compound 1 containing lactose and Ac-Di-Sol undergoing a 4 week accelerated stability study. [Figure 21-1] 1 shows dissolution under non-sink conditions of 50 mg prototype tablets of Compound 1 containing mannitol and Ac-Di-Sol undergoing a 4 week accelerated stability study. [Figure 21-2] 1 shows dissolution under non-sink conditions of 50 mg prototype tablets of Compound 1 containing mannitol and Ac-Di-Sol undergoing a 4 week accelerated stability study. [Figure 22-1] 1 shows the tabletability profile, compressibility profile, compactibility profile, and disintegration profile of 20 mg and 100 mg demonstration batch tablets of Compound 1 compared to a 50 mg prototype tablet of Compound 1. [Figure 22-2] 1 shows the tabletability profile, compressibility profile, compactibility profile, and disintegration profile of 20 mg and 100 mg demonstration batch tablets of Compound 1 compared to a 50 mg prototype tablet of Compound 1. [Diagram 23] 1 shows the dissolution of 100 mg tablets of Compound 1 compressed at 200 MPa. [Figure 24] 1 shows the dissolution of 100 mg tablets of Compound 1 compressed at 250 MPa. [Diagram 25] Figure 1 shows the dissolution of 100 mg tablets of Compound 1. Results from all tablet compression force conditions are presented together to assess the robustness of the formulation. [Figure 26] 1 shows the friability profile of Compound 1 20 mg and 100 mg demonstration batch tablets. [Figure 27] 1 shows the tabletability of a 20 mg demonstration batch of Compound 1 tablets. [Figure 28] 1 shows the strain rate of a 20 mg demonstration batch tablet of Compound 1. The formulation does not appear to be strain rate sensitive. [Figure 29] 1 shows images of a 20 mg demonstration batch tablet and a 100 mg demonstration batch tablet of Compound 1, in which spots can be seen on the tablet surface. [Diagram 30] 1 shows the weight distribution of 20 mg and 100 mg demonstration batch tablets of Compound 1. A batch of 50 tablets was used. [Diagram 31] 1 illustrates a drawing of a 0.3125″ SRC tablet tooling according to some embodiments of the present invention. [Diagram 32] 1 shows a drawing of a 0.3543″×0.6890″ modified oval tablet tooling according to some embodiments of the present invention. [Figure 33-1] 1 shows a certificate of analysis for a batch of 20 mg tablets of Compound 1. [Figure 33-2] 1 shows a certificate of analysis for a batch of 20 mg tablets of Compound 1. [Figure 33-3] 1 shows a certificate of analysis for a batch of 20 mg tablets of Compound 1. [Figure 34-1] 1 shows a certificate of analysis for a batch of 100 mg tablets of Compound 1. [Figure 34-2] 1 shows a certificate of analysis for a batch of 100 mg tablets of Compound 1. [Figure 34-3] 1 shows a certificate of analysis for a batch of 100 mg tablets of Compound 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] As used herein, a therapeutic agent that "prevents" or "reduces the risk of developing" a disease, disorder, or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disease or condition in a treated sample compared to an untreated control sample, or delays the onset of or reduces the severity of one or more symptoms of the disease, disorder, or condition compared to an untreated control sample.

[0022] The term "treating" includes prophylactic and / or therapeutic treatment. The term "prophylactic or therapeutic treatment" is art-recognized and includes administration of one or more of the subject compositions to a host. If a therapeutic agent is administered prior to the onset of clinical signs of an undesirable condition (e.g., a disease or other undesirable condition in a host animal), the treatment is prophylactic (i.e., protects the host from the occurrence of the undesirable condition), whereas if administered after the appearance of the undesirable condition, the treatment is therapeutic (i.e., is intended to reduce, ameliorate, or stabilize an existing undesirable condition or its side effects).

[0023] The terms "co-administration" and "co-administered" refer to any form of administration of two or more different therapeutic compounds such that a second compound is administered while a previously administered therapeutic compound is still effective in the body (e.g., the two compounds are effective in the patient's body at the same time, which may include a synergistic effect of the two compounds). For example, the different therapeutic compounds can be administered simultaneously or sequentially, in the same formulation or in separate formulations. In certain embodiments, the different therapeutic compounds can be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or 1 week of each other. Thus, an individual receiving such treatment can benefit from the combined effect of the different therapeutic compounds.

[0024] The term "prodrug" is intended to include compounds that are converted to the therapeutically active agents of the present invention under physiological conditions. One common method of making a prodrug is to include one or more selected moieties that are hydrolyzed under physiological conditions to produce the desired molecule. In other embodiments, the prodrug is converted by the enzyme activity of the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the present invention. In certain embodiments, some or all of the compounds of the present invention in the formulations shown above may be replaced with the corresponding suitable prodrugs (e.g., hydroxyls in the parent compound are provided as esters or carboxylates, or carboxylic acids present in the parent compound are provided as esters).

[0025] An "effective amount" is an amount sufficient to produce a beneficial or desired result. For example, a therapeutic amount is an amount that obtains a desired therapeutic effect. This amount may be the same as or different from a prophylactically effective amount, which is an amount required to prevent the onset of a disease or a symptom of a disease. An effective amount can be administered in one or more administrations, applications, or dosages. A therapeutically effective amount of a composition depends on the composition selected. The composition can be administered from once or more times a day to once or more times a week, including once every other day. Those skilled in the art will recognize that certain factors, including but not limited to the severity of the disease or disorder, previous treatments, the overall health and / or age of the subject, and other diseases present, can affect the dosage and timing required to effectively treat a subject. Furthermore, treatment of a subject with a therapeutically effective amount of a composition described herein can include a single treatment or a series of treatments.

[0026] Compounds of the Invention In some embodiments, the compound is 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one (also referred to as Compound 1) or a pharma- ceutically acceptable salt thereof.

[0027] [ka]

[0028] In some embodiments, the present invention relates to a pharmaceutical composition comprising a compound of the present invention, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0029] Pharmaceutical Compositions The compositions and methods of the present invention may be utilized to treat a subject in need of treatment. In certain embodiments, the subject is a mammal, such as a human or non-human mammal. When the composition or compound is administered to a subject, such as a human, it is preferably administered as a pharmaceutical composition, such as comprising the compound of the present invention and a pharma- ceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art, and include, for example, aqueous solutions, such as water or physiologically buffered saline, or other solvents or vehicles, such as glycols, glycerol, oils, such as olive oil, or injectable organic esters. In preferred embodiments, when such pharmaceutical compositions are intended for administration to humans, particularly for invasive routes of administration, i.e., routes that avoid transport or diffusion through epithelial barriers, such as injection or implantation, the aqueous solution is pyrogen-free or substantially pyrogen-free. Pharmaceutical excipients may be selected, for example, to provide delayed release of the drug or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition can be included in a unit dosage form, such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilisates for reconstitution, powders, solutions, syrups, suppositories, injections, or the like. The composition can also be present in a transdermal delivery system (e.g., a skin patch). The composition can also be present in a solution suitable for topical administration (e.g., eye drops).

[0030] A pharma- ceutically acceptable carrier may include a physiologically acceptable agent, which acts, for example, to stabilize, increase the solubility, or enhance the absorption of a compound (such as the compound of the present invention). Such physiologically acceptable agents include, for example, carbohydrates (such as glucose, sucrose, or dextran), antioxidants (such as ascorbic acid or glutathione), chelating agents, low molecular weight proteins, or other stabilizers or excipients. The choice of a pharma- ceutical acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) may also be a liposome or other polymer matrix, in which, for example, the compound of the present invention may be included. Liposomes (e.g., those containing phospholipids or other lipids) are physiologically acceptable, metabolizable, non-toxic carriers that are relatively easy to prepare and administer.

[0031] The phrase "pharmacologically acceptable" is used herein to mean that a compound, material, composition, and / or dosage form is suitable for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic response, or other problem or complication, under the exercise of sound medical judgment, and is commensurate with a reasonable benefit / risk ratio.

[0032] "Pharmaceutically acceptable salt" is used herein to refer to an acid or base addition salt that is suitable or compatible with the treatment of a patient.

[0033] The term "pharmaceutical acceptable acid addition salt" as used herein refers to any non-toxic organic or inorganic salt of the disclosed compound. Examples of inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as metal salts such as disodium hydrogen orthophosphate and potassium hydrogen sulfate. Examples of organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, bitartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, and sulfosalicylic acid, as well as sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid. Mono- or di-acid salts may be formed, and such salts may exist in hydrated, solvated, or substantially anhydrous form. In general, the acid addition salt of the compound disclosed herein is highly soluble in water and various hydrophilic organic solvents, and generally shows a higher melting point compared to its free base form.Those skilled in the art will be able to select suitable salt.Other, non-pharmaceutical salts (e.g., oxalates) may be used, and such salts are used, for example, when the compound disclosed herein is isolated for experimental purposes, or when it is subsequently converted into a pharmaceutical acceptable acid addition salt.

[0034] As used herein, the term "pharmaceutical acceptable base addition salt" refers to any non-toxic organic or inorganic base addition salt of any acidic compound disclosed herein. Examples of inorganic bases that form suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or barium hydroxide. Examples of organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines (such as methylamine, trimethylamine, and picoline) or ammonia. Those skilled in the art will be able to select the appropriate salt.

[0035] The phrase "pharmaceutical acceptable carrier" as used herein means a pharma- ceutically acceptable material, composition, or vehicle (such as a liquid or solid excipient, diluent, pharmaceutical additive, solvent, or encapsulating material). Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the subject. Some examples of materials that can act as pharma-ceutically acceptable carriers include: (1) sugars (such as lactose, glucose, and sucrose); (2) starches (such as corn starch and potato starch); (3) cellulose and its derivatives (such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate); (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) pharmaceutical additives (such as cocoa butter and suppository wax); (9) oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and the like); , and soybean oil), (10) glycols (such as propylene glycol), (11) polyols (such as glycerin, sorbitol, mannitol, and polyethylene glycol), (12) esters (such as ethyl oleate and ethyl laurate), (13) agar, (14) buffers (such as magnesium hydroxide and aluminum hydroxide), (15) alginic acid, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) phosphate buffers, (21) surfactants and co-surfactants (such as vitamin E TPGS, Solutol® HS15, and various polyethylene glycols), and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0036] The pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration. These routes of administration include, for example, oral (e.g., liquid oral preparations (such as aqueous or non-aqueous solutions or suspensions), tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue), absorbed through oral mucosa (e.g., sublingually), anal, rectal, or vaginal (e.g., as a pessary, cream, or foam), parenteral (including intramuscular, intravenous, subcutaneous, or intrathecal (e.g., as a sterile solution or suspension)), intranasal, intraperitoneal, subcutaneous, transdermal (e.g., as a patch applied to the skin), and topical (e.g., as a cream, ointment, or spray applied to the skin, or as eye drops). The compound can also be formulated for inhalation. In certain embodiments, the compound can simply be dissolved or suspended in sterile water. Details regarding suitable routes of administration and compositions suitable for such routes of administration can be found, for example, in U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970, and 4,172,896 (all incorporated by reference), and patents cited therein.

[0037] The formulations may be conveniently presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient that may be combined with a carrier material to produce a single dosage form will vary depending on the subject being treated and the particular mode of administration. The amount of active ingredient that may be combined with a carrier material to produce a single dosage form will generally be that amount of compound that produces a therapeutic effect. Generally, this amount, expressed as a percentage of 100 percent active ingredient, will range from about 1 percent to about 99 percent, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent.

[0038] Methods of preparing such formulations or compositions include the step of bringing into association an active compound (such as a compound of the present invention) with the carriers and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0039] Formulations of the present invention suitable for oral administration may be in the form of a capsule (including sprinkle capsules, gelatin capsules, and HPMC capsules), cachet, pill, tablet, lozenge (using a flavored base, usually sucrose and acacia or tragacanth), lyophilizate, powder, granules, or as a solution or suspension in an aqueous liquid or non-aqueous liquid, or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, or as an elixir or syrup, or as a lozenge (using an inert base, such as gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, each of which contains a predetermined amount of a compound of the present invention as an active ingredient. The composition or compound may also be administered as a bolus, electuary, or paste.

[0040] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules, and the like), the active ingredient is mixed with one or more pharma- ceutically acceptable carriers (such as sodium citrate or dicalcium phosphate), and / or any of the following: (1) excipients or fillers (such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid), (2) binders (such as, for example, carboxymethylcellulose, hydroxypropylcellulose gelatin, polyvinylpyrrolidone, and starch), (3) humectants (such as glycerol), (4) disintegrants (such as agar-agar, calcium carbonate, potato starch, or tapioca starch), and / or (5) glycerol (such as glycerol, ... (5) solution flow retardants (such as paraffin), (6) absorption enhancers (such as quaternary ammonium compounds), (7) wetting agents (such as cetyl alcohol and glycerol monostearate), (8) adsorbents (such as kaolin and bentonite clay), (9) lubricants (such as calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, sodium stearyl fumarate, compritol, and mixtures thereof), (10) complexing agents (such as modified and unmodified cyclodextrins), and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets, and pills, the pharmaceutical composition may also include buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0041] Tablets can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., hydroxypropylcellulose, povidone, or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be prepared by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0042] Tablets and other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills, and granules, can be optionally scored or prepared with coatings and shells, such as taste-masking coatings, enteric coatings, and other coatings well known in the pharmaceutical formulation art. They can also be formulated to cause delayed or controlled release of the active ingredient contained therein. This formulation is carried out, for example, using hydroxypropylmethylcellulose (used in various ratios to obtain the desired release profile), other polymer matrices, liposomes, and / or microspheres. They can be sterilized, for example, by filtration through a bacteria-retaining filter, or by including a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions can also optionally contain opacifying agents and can be compositions that release the active ingredient(s) only, or preferentially, in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0043] Liquid dosage forms useful for oral administration include pharma- ceutically acceptable emulsions, lyophilizates for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. Liquid dosage forms may contain, in addition to the active ingredient, inert diluents commonly used in the art (such as, for example, water or other solvents), cyclodextrin and its derivatives, solubilizers and emulsifiers (such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, vitamin E TPGS (D-α-tocopherol polyethylene glycol succinate), Solutol® HS15 (macrogol (15) hydroxystearate, polyethylene glycol (15)-hydroxystearate, polyoxyethylated 12-hydroxystearic acid), and the like), and mixtures thereof.

[0044] Besides inert diluents, the oral compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.

[0045] In addition to the active compound, the suspension may also contain suspending agents (e.g., microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth, hydroxypropylcellulose, sodium carboxymethylcellulose, povidone, and mixtures thereof). The suspension may also contain surfactants and wetting agents (such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters).

[0046] The formulation of pharmaceutical composition for rectal, vaginal or urethral administration can be provided as suppository.These suppositories can be prepared by mixing one or more active compounds with one or more suitable non-irritating pharmaceutical excipients or carriers (e.g., those containing cocoa butter, polyethylene glycol, suppository wax or salicylic acid), and these suppositories are solid at room temperature but liquid at body temperature, and therefore melt in the rectal or vaginal cavity and release the active compounds.

[0047] Formulations of the pharmaceutical composition for administration to the mouth may be provided as a mouthwash or mouth spray or mouth ointment.

[0048] Alternatively or additionally, the compositions may be formulated for delivery via a catheter, stent, wire, or other intraluminal device, which may be particularly useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

[0049] Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such carriers as are known in the art.

[0050] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharma- ceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0051] The ointments, pastes, creams, and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0052] Powders and sprays can contain, in addition to the active compounds, pharmaceutical excipients, such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0053] Transdermal patch has the additional advantage that the delivery of the compound of the present invention to the body is controlled.Such dosage forms can be prepared by dissolving or dispersing active compound in suitable medium.Absorption enhancers can also be used to promote the flux of compound across the skin.The rate of such flux can be controlled by using a rate-controlling membrane or dispersing compound in a polymer matrix or gel.

[0054] Ophthalmic preparations, eye ointments, powders, solutions, and the like are also contemplated as being within the scope of the present invention. Examples of ophthalmic preparations are described in U.S. Patent Publication Nos. 2005 / 0080056, 2005 / 0059744, 2005 / 0031697, and 2005 / 004074, and U.S. Patent No. 6,583,124, the contents of which are incorporated herein by reference. If desired, liquid ophthalmic preparations have properties similar to those of tears, aqueous humor, or vitreous humor, or are compatible with such body fluids. The preferred route of administration is topical administration (e.g., external administration (such as eye drops) or administration via implants).

[0055] The phrases "parenteral administration" and "administered parenterally" as used herein mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, intraocular, subcapsular, subarachnoid, intrathecal, and intrasternal injection and infusion.

[0056] Pharmaceutical compositions suitable for parenteral administration may contain one or more active compounds in combination with one or more pharma- ceutically acceptable sterile, isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use (which may contain antioxidants, buffers, bacterial growth inhibitors, solutes that equilibrate the osmolarity of the formulation with the blood of the intended recipient, or suspending or thickening agents).

[0057] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate).Proper fluidity can be maintained, for example, by using coating materials (such as lecithin), by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0058] Such compositions may also contain auxiliary agents, such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial action may be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like, in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0059] In some cases, in order to prolong the effect of a drug, it is desirable to delay the absorption of the drug from subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of poorly water-soluble crystalline or amorphous material.In this case, the absorption rate of the drug depends on its dissolution rate, which in turn can depend on the crystal size and crystalline form.Alternatively, the delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0060] Injectable depot forms are prepared by forming microencapsulated matrices of the subject compounds in biodegradable polymers, such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0061] For use in the methods of the invention, the active compound may be provided alone or as a pharmaceutical composition (e.g., containing from about 0.1 to about 99.5% (more preferably, from about 0.5 to about 90%) of the active ingredient in combination with a pharma- ceutically acceptable carrier).

[0062] Rechargeable or biodegradable devices may also provide a method of introduction. A variety of sustained release polymeric devices have been developed and recently tested in vivo for controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers, including hydrogels, including both biodegradable and non-degradable polymers, can be used to form implants for sustained release of compounds at specific target sites.

[0063] Actual dosage levels of the active ingredients in the pharmaceutical compositions can be varied to provide for a particular patient, composition, and mode of administration, an amount of the active ingredient effective to achieve the desired therapeutic response without causing toxicity to the patient.

[0064] The selected dose level will depend on a variety of factors, including the activity of the particular compound or combination of compounds, or esters, salts, or amides thereof, used, the route of administration, the time of administration, the rate of excretion of the particular compound(s) used, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular compound(s) used, the age, sex, weight, condition, general health, and prior medical history of the subject being treated, and similar factors well known in the medical arts.

[0065] A physician or veterinarian skilled in the art can easily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, such a physician or veterinarian can establish an initial dose of the pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved. A "therapeutically effective amount" refers to a concentration of the compound sufficient to induce the desired therapeutic effect. It is generally understood that the effective amount of the compound varies according to the subject's weight, sex, age, and medical history. Other factors that affect the effective amount may include, but are not limited to, the severity of the subject's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent administered together with the compound of the present invention. The total dose delivered can be increased by administering the agent multiple times. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, incorporated herein by reference).

[0066] In general, a suitable daily dose of an active compound used in the compositions and methods of the present invention will be that amount of the compound that is the minimum dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0067] If desired, the effective daily dose of active compound can be administered as 1, 2, 3, 4, 5, 6 or more divided doses that are administered separately at appropriate intervals throughout the day, and this administration is optionally carried out in unit dosage form.In certain embodiments of the present invention, active compound can be administered 2 or 3 times a day.In certain embodiments, active compound will be administered once a day.

[0068] In certain embodiments, the compound of the present invention can be used alone or co-administered with another type of therapeutic agent. The phrase "co-administration" as used herein refers to any form of administration of two or more different therapeutic compounds, such that the administration of the second compound occurs while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are effective in the subject at the same time, which may include the synergistic effect of the two compounds). For example, the different therapeutic compounds can be administered simultaneously or sequentially in the same formulation or separate formulations. In certain embodiments, the different therapeutic compounds can be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or within 1 week of each other. Thus, the subject who undergoes such treatment can benefit from the combined effect of the different therapeutic compounds.

[0069] In certain embodiments, co-administration of a compound of the invention with one or more additional therapeutic agent(s) results in improved efficacy compared to administration of either the compound of the invention or the one or more additional therapeutic agent(s) individually. In certain such embodiments, co-administration results in an additive effect, where additive effect refers to the sum of the respective effects obtained by administering the compound of the invention and the one or more additional therapeutic agent(s) individually.

[0070] Wetting agents, emulsifying agents, and lubricants (such as sodium lauryl sulfate and magnesium stearate), as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0071] Examples of pharma- ceutically acceptable antioxidants include: (1) water-soluble antioxidants (such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like); (2) oil-soluble antioxidants (such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like); and (3) metal chelators (such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like).

[0072] In some embodiments, the pharmaceutical composition is a spray dried dispersion.

[0073] In some embodiments, the present invention is directed to a composition for producing a spray dried dispersion, the composition comprising 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one, a solvent, and a polymer, wherein the polymer is dissolved in the solvent.

[0074] In some embodiments, the 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one is in an amorphous form.

[0075] Polymers suitable for use in the compositions of the present invention include, but are not limited to, hypromellose acetate succinate, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone / vinyl acetate copolymer (PVP-VA, PVP-VA64), Eudragit®, hydroxypropyl methylcellulose (HPMC), Methocel, hypromellose phthalate, and soluplus.Suitable Eudragit polymers include those for immediate release (e.g., Eudragit E 10, Eudragit E 12.5, Eudragit E PO, Eudragit E PO ReadyMix), those for delayed release (such as for small intestinal delivery (e.g., Eudragit L30 D-55, Eudragit L 100-55, Eudragit FL 30 D-55, Eudragit L 100, Eudragit L 12.5, optionally in combination with PlasACRYL HTP20) or for colonic delivery (e.g., Eudragit S 100, Eudragit S 12.5, Eudragit FS 30 D, Eudragit FS 100, optionally in combination with PlasACRYL T20)), those for sustained release (e.g., Eudragit RL PO, Eudragit RL 100, Eudragit RL 30 D, Eudragit RL 12.5, Eudragit RS PO, Eudragit RS 100, Eudragit RS 30 D, Eudragit RS 12.5, Eudragit NM 30 D), as well as those for enhancing solubility and bioavailability (e.g., Eudragit E 100, Eudragit E PO, Eudragit E 12.5, Eudragit FS 100, Eudragit S 100, Eudragit L 100, Eudragit L 100-55, Eudragit L 12.5), the release profile can be customized by combining Eudragit polymers in different ratios, as would be known to one of skill in the art (see, for example, https: / / healthcare.evonik.com / product / health-care / downloads / evonik-eudragit-brochure.pdf). In some embodiments, the polymer is hypromellose acetate succinate, HPMCAS, PVP-VA64, or Eudragit. In some embodiments, the polymer is hypromellose acetate succinate.

[0076] In some embodiments, the ratio of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one to hypromellose acetate succinate is about 1:9 to about 2:1. In some embodiments, the ratio of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one to hypromellose acetate succinate is about 1:3.

[0077] Hypromellose acetate succinate (HPMCAS) products suitable for use in embodiments of the present invention include, but are not limited to, AquaSolve™ products, such as Grade L, Grade M, and Grade H.

[0078] [Table 1]

[0079] In some embodiments, the hypromellose acetate succinate has an acetyl content of about 5-14%, a succinoyl content of about 4-18%, a methoxyl content of about 20-26%, and a hydroxypropoxy content of about 5-10%. In some embodiments, the hypromellose acetate succinate has an acetyl content of about 7-12%, a succinoyl content of about 7-15%, a methoxyl content of about 21-25%, and a hydroxypropoxy content of about 5-9%.

[0080] In some embodiments, the solvent is acetone, methyl ethyl ketone, ethyl acetate, isopropyl alcohol, dioxane, acetonitrile, ethanol, water, methanol, dichloromethane, tetrahydrofuran, or any combination thereof. In some embodiments, the solvent is a combination of methanol and dichloromethane. In some embodiments, the ratio of dichloromethane to methanol is about 30:70 to about 60:40. In some embodiments, the ratio of dichloromethane to methanol is about 60:40.

[0081] In one aspect, the present invention is directed to a method of making a spray-dried dispersion, the method comprising spray drying a composition of the present invention.

[0082] In some embodiments, the temperature of the nozzle through which the composition passes to be spray dried is from about 20° C. to about 60° C. In some embodiments, the temperature of the nozzle is from about 35° C. to about 40° C.

[0083] In some embodiments, the spray drying step is carried out at a spray pressure of about 1.0 to about 10.0 bar. In some embodiments, the spray drying step is carried out at a spray pressure of about 2.0 to about 4.0 bar.

[0084] In one aspect, the present invention relates to a spray-dried dispersion comprising 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one, a solvent, and a polymer, wherein the polymer is dissolved in the solvent.

[0085] In some embodiments, the 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one is in an amorphous form.

[0086] In some embodiments, the polymer is hypromellose acetate succinate.

[0087] In some embodiments, the ratio of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one to hypromellose acetate succinate is about 1:9 to about 2:1. In some embodiments, the ratio of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one to hypromellose acetate succinate is about 1:3.

[0088] In some embodiments, the hypromellose acetate succinate has an acetyl content of about 5-14%, a succinoyl content of about 4-18%, a methoxyl content of about 20-26%, and a hydroxypropoxy content of about 5-10%. In some embodiments, the hypromellose acetate succinate has an acetyl content of about 5-11%, a succinoyl content of about 10-18%, a methoxyl content of about 20-25%, and a hydroxypropoxy content of about 5-9%. In some embodiments, the hypromellose acetate succinate has an acetyl content of about 7-12%, a succinoyl content of about 7-15%, a methoxyl content of about 21-25%, and a hydroxypropoxy content of about 5-9%. Hypromellose acetate succinate is commercially available in different grades, for example, AquaSolve™ hydroxypropyl methylcellulose acetate succinate grades L, M, and H available from Ashland.

[0089] In some embodiments, the solvent is acetone, methyl ethyl ketone, ethyl acetate, isopropyl alcohol, dioxane, acetonitrile, ethanol, water, methanol, dichloromethane, tetrahydrofuran, or any combination thereof. In some embodiments, the solvent is a combination of methanol and dichloromethane. In some embodiments, the ratio of dichloromethane to methanol is about 30:70 to about 60:40. In some embodiments, the ratio of dichloromethane to methanol is about 60:40.

[0090] In one aspect, the invention relates to a solid dosage form comprising the spray dried dispersion of the invention and one or more of an excipient, a disintegrant, a lubricant, a glidant, and a stabilizer.

[0091] In some embodiments, the excipient comprises one or more of mannitol, lactose, or crystalline cellulose. In some embodiments, the excipient comprises mannitol and crystalline cellulose. In some embodiments, the ratio of mannitol to crystalline cellulose is about 1:3 to about 3:1. In some embodiments, the ratio of mannitol to crystalline cellulose is about 1:1.3, about 1:1.25, or about 1:1. In some embodiments, the ratio of mannitol to crystalline cellulose is about 1:1.3 to about 1:1. In some embodiments, the ratio of mannitol to crystalline cellulose is about 1:1 to about 1:3. In some embodiments, the ratio of mannitol to crystalline cellulose is about 1:1 to about 1:1.3. In some embodiments, the ratio of mannitol to crystalline cellulose is about 1:1 or about 1:1.3. In some embodiments, the ratio of mannitol to crystalline cellulose is about 1:1, about 1:1.3, or about 1:3.

[0092] In some embodiments, the average particle size of the crystalline cellulose is about 5 μm to about 80 μm. In some embodiments, the average particle size of the crystalline cellulose is about 10 μm to about 50 μm.

[0093] In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the croscarmellose sodium is present in an amount of about 3% to about 15% w / w. In some embodiments, the croscarmellose sodium is present in an amount of about 6% w / w.

[0094] In some embodiments, the lubricant is sodium stearyl fumarate. In some embodiments, the sodium stearyl fumarate is present in an amount of about 0.5 to about 5% w / w. In some embodiments, the sodium stearyl fumarate is present in an amount of about 1% w / w. In some embodiments, the sodium stearyl fumarate is present in an amount of about 0.95% w / w.

[0095] In some embodiments, the glidant is colloidal silicon dioxide. In some embodiments, the silicon dioxide is present at about 0.1 to about 5% w / w. In some embodiments, the silicon dioxide is present at about 1% w / w.

[0096] In some embodiments, the spray dried dispersion is present at about 3% to about 60% w / w. In some embodiments, the spray dried dispersion is present at about 50% w / w. In some embodiments, the spray dried dispersion is present at about 16.7% w / w. In some embodiments, the spray dried dispersion is present at about 3.33% w / w.

[0097] In some embodiments, the abundance of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one is about 0.75% to 15% w / w. For example, the abundance of the compound is about 0.75% w / w, about 0.8% w / w, about 0.85% w / w, about 0.9% w / w, about 1% w / w, about 1.5% w / w, about 2% w / w, about 2.5% w / w, about 3% w / w, about 3.5% w / w, about 4% w / w, about 4.5% w / w, about 5% w / w, about 5.5% w / w, about 6% w / w, about 6.5% w / w, about 7% The composition may be about 10% w / w, about 7.5% w / w, about 8% w / w, about 8.5% w / w, about 9% w / w, about 9.5% w / w, about 10% w / w, about 10.5% w / w, about 11% w / w, about 11.5% w / w, about 12% w / w, about 12.5% ​​w / w, about 13% w / w, about 13.5% w / w, about 14% w / w, about 14.5% w / w, or about 15% w / w.

[0098] In some embodiments, the solid dosage form comprises: a. 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one, b. Hypromellose acetate succinate, C. mannitol, D. crystalline cellulose, e. Croscarmellose sodium, f. sodium stearyl fumarate, and g. Colloidal silicon dioxide It essentially consists of:

[0099] In some embodiments, the solid dosage form comprises: 0.75% to 40.0% (w / w) of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one; b. 2.0% to 54.0% (w / w) of hypromellose acetate succinate; c. 3.75% to 42.3% (w / w) mannitol; d. 3.75% to 50.0% (w / w) crystalline cellulose; e. 3.0% to 15% (w / w) croscarmellose sodium; f. 0.5% to 5.0% (w / w) sodium stearyl fumarate, and g. 0.1% to 5.0% (w / w) colloidal silicon dioxide It essentially consists of The ratio of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one to hypromellose acetate succinate is 1:9 to 2:1; The total amount of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one and hypromellose acetate succinate in the solid dosage form is 3% to 60% w / w; The ratio of mannitol to crystalline cellulose is 1:3 to 3:1. The total amount of mannitol and microcrystalline cellulose in the solid dosage form is 15.0% to 90% w / w.

[0100] In some embodiments, the solid dosage form comprises: a. 20 mg of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one, b. 60 mg of hypromellose acetate succinate, c. 33.6 mg of mannitol, d. 33.6 mg of crystalline cellulose, e. 9.6 mg of croscarmellose sodium, f. 1.6 mg sodium stearyl fumarate, and g. 1.6 mg colloidal silicon dioxide It essentially consists of:

[0101] In some embodiments, the solid dosage form comprises: a. 100 mg of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one, b. 300 mg of hypromellose acetate succinate, c. 168 mg of mannitol, d. 168 mg of crystalline cellulose, e. 48 mg of croscarmellose sodium, f. 8 mg of sodium stearyl fumarate, and g.8 mg colloidal silicon dioxide It essentially consists of:

[0102] In some embodiments, the solid dosage form comprises: a.5 mg of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one, b. 15 mg of hypromellose acetate succinate, c. 39.2 mg of mannitol, d. 51.2 mg of crystalline cellulose; e. 7.2 mg of croscarmellose sodium, f. 1.1 mg sodium stearyl fumarate, and g. 1.2 mg colloidal silicon dioxide It essentially consists of:

[0103] In some embodiments, the solid dosage form comprises: a. 1 mg of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one, b. 3 mg of hypromellose acetate succinate, c. 47.2 mg of mannitol, d. 59.2 mg of crystalline cellulose, e. 7.2 mg of croscarmellose sodium, f. 1.1 mg sodium stearyl fumarate, and g. 1.2 mg colloidal silicon dioxide It consists of:

[0104] In some embodiments, the solid dosage form is a tablet. In some embodiments, the solid dosage form is a capsule. In some embodiments, the amount of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one in the tablet or capsule is about 1 to 200 mg.

[0105] In some embodiments, the amount of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one in the tablet or capsule is about 5 mg.

[0106] In some embodiments, the amount of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one in the tablet or capsule is about 20 mg.

[0107] In some embodiments, the amount of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one in the tablet or capsule is about 100 mg.

[0108] In some embodiments, the amount of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one in the tablet or capsule is about 1 mg.

[0109] In one aspect, the present invention relates to a method for producing a solid dosage form of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one, the method comprising: a. mixing the spray dried dispersion of any one of claims 17 to 27 with one or more of a first excipient, a first disintegrant, a first lubricant, a first glidant, and a first stabilizer to form a first solid mixture. b. roller compacting and grinding the first solid mixture; and c. optionally mixing the roller compacted and milled first solid mixture with one or more of a second excipient, a second disintegrant, a second lubricant, a second glidant, and a second stabilizer to form a second solid mixture; and d. Converting the first solid mixture or the second solid mixture into a solid dosage form of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one. Includes.

[0110] In some embodiments, the first excipient and the second excipient are selected from mannitol, microcrystalline cellulose, or a combination thereof, the first disintegrant and the second disintegrant are croscarmellose sodium, the first lubricant and the second lubricant are sodium stearyl fumarate, and the first glidant and the second glidant are silicon dioxide.

[0111] In some embodiments, in step c, the roller compacted and milled solid mixture is mixed with a second excipient, a second disintegrant, and a second lubricant.

[0112] In some embodiments, the solid dosage form is a tablet formed by compressing the first solid mixture or the second solid mixture. In some embodiments, the solid dosage form is a filled capsule formed by filling the first solid mixture or the second solid mixture into a capsule.

[0113] Treatment method Proteinuria Proteinuria is a pathological condition in which protein is present in the urine. Albuminuria is a type of proteinuria. Microalbuminuria occurs when the kidneys leak small amounts of albumin into the urine. In a properly functioning body, albumin is not normally present in the urine because it is retained in the bloodstream by the kidneys. Microalbuminuria is diagnosed from a 24-hour urine collection (20-200 μg / min) or, more commonly, from at least two elevated concentrations (30-300 mg / L). Microalbuminuria can be a precursor to diabetic nephropathy. Albumin levels higher than these values ​​are called macroalbuminuria. For example, subjects with certain diseases (e.g., diabetic nephropathy) progress from microalbuminuria to macroalbuminuria and into the nephropathic range (>3.5 g / 24 hours) as the kidney disease reaches advanced stages.

[0114] Causes of Proteinuria Proteinuria can be associated with several conditions, including focal segmental glomerulosclerosis, IgA nephropathy, diabetic nephropathy, lupus nephritis, membranoproliferative glomerulonephritis, progressive (crescentic) glomerulonephritis, and membranous glomerulonephritis.

[0115] A. Focal segmental glomerulosclerosis (FSGS) Focal segmental glomerulosclerosis (FSGS) is a disease that attacks the kidney's filtering system (glomeruli), causing severe scarring. FSGS is one of many causes of a condition known as nephrotic syndrome, which occurs when blood protein leaks into the urine (proteinuria). Primary FSGS usually presents as nephrotic syndrome when no underlying disease cause is found. Secondary FSGS usually presents as kidney failure and proteinuria when an underlying disease cause is identified. FSGS can be genetic, and there are currently several known genetic causes for the inherited form of FSGS.

[0116] There are very few treatments available for FSGS patients. Many patients are treated with steroid regimens, many of which have very harsh side effects. Some patients have been shown to respond positively to blood pressure medications in addition to immunosuppressants, and these drugs have been shown to reduce protein levels in the urine. Thus far, there is no universally accepted effective treatment or therapy, and there are no FDA-approved drugs to treat FSGS. Therefore, more effective methods to reduce or inhibit proteinuria are desirable.

[0117] B. IgA nephropathy IgA nephropathy (also called IgA nephritis, IgAN, Berger's disease, or glomerulonephritis with pharyngitis) is a form of glomerulonephritis (inflammation of the glomeruli of the kidney). IgA nephropathy is the most common glomerulonephritis worldwide. Primary IgA nephropathy is characterized by the deposition of IgA antibodies in the glomeruli. There are other diseases with IgA deposition in the glomeruli, the most common being Henoch-Schönlein purpura (HSP), which is considered a systemic form of IgA nephropathy. Henoch-Schönlein purpura presents with a characteristic purpuric skin rash, arthritis, and abdominal pain and occurs more commonly in young adults (16-35 years of age). HSP is associated with a more benign prognosis than IgA nephropathy. IgA nephropathy has a slow progression to chronic renal failure in 25-30% of cases over a 20-year period.

[0118] C. Diabetic nephropathy Diabetic nephropathy, also known as Kimmel-Stiel-Wilson syndrome and intracapillary glomerulonephritis, is a progressive kidney disease caused by angiopathy of the capillaries of the renal glomeruli. Diabetic nephropathy is characterized by nephrotic syndrome and diffuse glomerulosclerosis. Diabetic nephropathy results from years of diabetes and is the main cause of dialysis. The earliest detectable change in the course of diabetic nephropathy is thickening of the glomeruli. At this stage, the kidneys may begin to leak more serum albumin than normal into the urine. As diabetic nephropathy progresses, an increasing number of glomeruli are destroyed by nodular glomerulosclerosis, and an increasing amount of albumin is excreted in the urine.

[0119] D. Lupus nephritis Lupus nephritis is a kidney disorder that is a complication of systemic lupus erythematosus. It occurs when antibodies and complement build up in the kidneys, causing inflammation. Lupus nephritis often causes proteinuria and can rapidly progress to kidney failure. Nitrogenous waste products build up in the bloodstream. Systemic lupus erythematosus causes a variety of disorders of the internal structure of the kidney, including interstitial nephritis. Lupus nephritis affects approximately 3 in 10,000 people.

[0120] E. Membranoproliferative glomerulonephritis I / II / III Membranoproliferative glomerulonephritis is a type of glomerulonephritis caused by the deposition of mesangial deposits and thickening of the basement membrane in the kidney, activating complement and damaging the glomeruli. There are three types of membranoproliferative glomerulonephritis. Type I is caused by immune complexes deposited in the kidney and is thought to be related to the classical complement pathway. Type II is similar to type I but is thought to be related to the alternative complement pathway. Type III is extremely rare and is characterized by a mixture of subepithelial deposits and typical pathology of type I disease.

[0121] There are two major types of MPGN based on immunofluorescence microscopy: immune complex-mediated and complement-mediated. Hypocomplementemia is common in all types of MPGN. In immune complex-mediated MPGN, complement activation occurs via the classical pathway and typically manifests as normal or mildly low serum C3 and low serum C4 concentrations. Complement-mediated MPGN usually has low serum C3 and normal C4 levels due to activation of the alternative pathway. However, complement-mediated MPGN is not excluded by normal serum C3 concentrations, and it is not uncommon to find normal C3 concentrations in adults with dense deposit disease (DDD) or C3 glomerulonephritis (C3GN).

[0122] C3 glomerulonephritis (C3GN) shows glomerulonephritis by light microscopy (LM), bright C3 staining by immunofluorescence microscopy (IF) but no C1q, C4, or immunoglobulins (Ig), and mesangial and / or subendothelial electron-dense deposits by electron microscopy (EM). Scattered intramembranous and subepithelial deposits are also frequently seen. The term "C3 glomerulonephropathy" is often used to include C3GN and dense deposit disease (DDD), both of which result from dysregulation of the alternative complement pathway (AP). C3GN and DDD are difficult to distinguish from each other when studied by LM and IF. However, EM shows mesangial and / or subendothelial, intramembranous, and subepithelial deposits in C3GN and dense osmiophilic deposits in the glomerular basement membrane (GBM) and mesangium in DDD. Both C3GN and DDD are distinguished from immune complex-mediated glomerulonephritis by the lack of immunoglobulin staining on IF (Sethi et al., Kidney Int. (2012) 82(4):465-473).

[0123] F. Progressive (crescentic) glomerulonephritis Progressive (crescentic) glomerulonephritis (PG) is a renal syndrome that, if left untreated, rapidly progresses to acute renal failure and death within a few months. PG is associated with an underlying condition such as Goodpasture's syndrome, systemic lupus erythematosus, or Wegener's granulomatosis in 50% of cases, with the remaining cases being idiopathic. Regardless of the underlying cause, PG involves significant injury to the renal glomeruli, many of which have characteristic crescent-shaped scars. Patients with PG have hematuria, proteinuria, and occasionally elevated blood pressure and edema. Although the clinical picture is consistent with nephrotic syndrome, the degree of proteinuria may exceed the 3 g / 24 h range associated with nephrotic syndrome. If the disease is untreated, it may progress to decreased urine output (oliguria) with declining renal function.

[0124] G. Membranous glomerulonephritis Membranous glomerulonephritis (MGN) is a slowly progressive kidney disease that affects mainly patients between the ages of 30 and 50, usually Caucasians. Membranous glomerulonephritis can progress to nephrotic syndrome. MGN is caused by circulating immune complexes. Current research shows that the majority of immune complexes are formed by binding of antibodies to antigens in situ against the glomerular basement membrane. These antigens may be endogenous to the basement membrane or may be deposited from the systemic circulation.

[0125] H. Alport syndrome Alport syndrome is a genetic disorder that affects approximately 1 in 5,000-10,000 children and is characterized by glomerulonephritis, end-stage renal disease, and hearing loss. Alport syndrome can also affect the eyes, but vision is not usually affected unless changes occur later in the lens. Hematuria is common. Proteinuria is one of the features that appears as kidney disease progresses.

[0126] I. Hypertensive kidney disease Hypertensive kidney disease (hypertensive nephrosclerosis (HN or HNS) or hypertensive nephropathy (HN)) is a medical condition that refers to damage to the kidneys caused by chronic high blood pressure. HN is classified into two types: benign and malignant. Benign nephrosclerosis is common in people over 60 years of age, while malignant nephrosclerosis is rare, affecting 1-5% of hypertensive patients with diastolic blood pressure above 130 mmHg. Signs and symptoms of chronic kidney disease may occur, including loss of appetite, nausea, vomiting, pruritus, drowsiness or confusion, weight loss, and an unpleasant taste in the mouth. Chronic hypertension causes damage to kidney tissue, which includes small blood vessels, glomeruli, renal tubules, and interstitial tissue. The tissue hardens and thickens (this is known as nephrosclerosis). Narrowing of blood vessels means that less blood is delivered to the tissues, and therefore less oxygen reaches the tissues, resulting in tissue death (ischemia).

[0127] J. Nephrotic syndrome Nephrotic syndrome is a set of symptoms resulting from kidney damage. It includes proteinuria, low blood albumin levels, high blood lipids, and significant swelling. Other symptoms can include weight gain, fatigue, and foamy urine. Complications can include blood clots, infections, and high blood pressure. Causes include multiple kidney diseases, such as focal segmental glomerulosclerosis, membranous nephropathy, and minimal change nephrotic syndrome. It can also occur as a complication of diabetes or lupus. The underlying mechanism typically involves damage to the glomeruli of the kidney. Diagnosis is typically based on a urine test and possibly a kidney biopsy. Nephrotic syndrome differs from nephritic syndrome in that red blood cells are not found in the urine. Nephrotic syndrome is characterized by massive proteinuria (>3.5 g per 1.73 m2 of body surface area per day, or >40 mg per square meter of body surface area per hour in children), hypoalbuminemia (<2.5 g / dL), hyperlipidemia, and edema beginning in the face. Lipiduria (lipids in the urine) may also occur but is not required for the diagnosis of nephrotic syndrome. Hyponatremia also occurs when sodium excretion is low. Genetic forms of nephrotic syndrome are typically resistant to steroids and other immunosuppressive treatments. The goals of treatment are to control urinary protein loss and swelling, provide adequate nutrition to allow the child to grow, and prevent complications. Early and aggressive treatment is used to control the disorder.

[0128] K. Minimal change nephrotic syndrome Minimal change nephrotic syndrome (also known as MCD, minimal change glomerulopathy, and Nill disease) is a disease that affects the kidneys and causes nephrotic syndrome. The clinical signs of minimal change nephrotic syndrome are proteinuria (abnormal urinary excretion of protein, mainly albumin), edema (swelling of soft tissues as a result of fluid retention), weight gain, and hypoalbuminemia (low serum albumin). Collectively, these signs are referred to as nephrotic syndrome. The first clinical sign of minimal change nephrotic syndrome is usually edema and associated weight gain. Although swelling may be mild, patients may present with lower body edema, periorbital edema, scrotal / labial area swelling, and in severe cases, generalized edema. In elderly patients, patients may also present with acute kidney injury (20-25% of affected adults) and hypertension. Due to the disease process, patients with minimal change nephrotic syndrome are also at risk for blood clots and infections.

[0129] L. Membranous nephropathy Membranous nephropathy refers to the deposition of immune complexes on the glomerular basement membrane (GBM), associated with thickening of the GBM. The cause is usually unknown (idiopathic), but secondary causes include drugs, infections, autoimmune disorders, and cancer. Findings include insidious onset of edema and heavy proteinuria with benign urinary sediment, normal renal function, and normal or elevated blood pressure. Membranous nephropathy is diagnosed by kidney biopsy. Spontaneous remission is common. Patients at high risk of progression are usually treated with corticosteroids and cyclophosphamide or chlorambucil.

[0130] M. Postinfectious glomerulonephritis Acute proliferative glomerulonephritis is damage to the glomeruli (glomerulonephritis), i.e., the small blood vessels of the kidney. It is a common complication of bacterial infection, typically skin infection with Streptococcus bacteria types 12, 4, and 1 (impetigo), but also after streptococcal pharyngitis, also known as postinfectious or poststreptococcal glomerulonephritis. This nephritis may be a risk factor for future albuminuria. In adults, signs and symptoms of infection may still be present at the time of kidney problems, and the terms infection-associated glomerulonephritis or bacterial infection-associated glomerulonephritis are also used. Deaths from acute glomerulonephritis have declined from 24,000 cases worldwide in 1990 to 19,000 in 2013. Acute proliferative glomerulonephritis (poststreptococcal glomerulonephritis) is caused by streptococci infecting the kidney (usually in the throat or skin), usually three weeks after infection, which takes time for antibodies and complement proteins to be produced. The infection causes inflammation of the kidney's blood vessels, which interferes with the kidney's ability to filter urine.[citation needed] Acute proliferative glomerulonephritis is most commonly seen in children.

[0131] N. Thin basement membrane disease Thin basement membrane disease (TBMD, also known as benign familial hematuria and thin basement membrane nephropathy (or TBMN)) is the most common cause of asymptomatic hematuria, along with IgA nephropathy. The only abnormal finding in this disease is a thinning of the glomerular basement membrane of the kidney. Its importance lies in the fact that patients maintain normal renal function throughout their lives and have a good prognosis. Most patients with thin basement membrane disease have microscopic hematuria that is found incidentally on urinalysis. Blood pressure, renal function, and urinary protein excretion are usually normal, with a minority of patients having mild proteinuria (<1.5 g / day) and elevated blood pressure. The presence of obvious hematuria and lumbar pain should prompt investigation for other causes such as kidney stones or lumbar pain-hematuria syndrome. Also, because there are no systemic symptoms, the presence of hearing or vision problems should prompt investigation for hereditary nephropathy such as Alport syndrome. A proportion of people with TBMD are thought to be carriers of the gene that causes Alport syndrome.

[0132] O. Mesangial proliferative glomerulonephritis Mesangial proliferative glomerulonephritis is a form of glomerulonephritis that is primarily mesangium-related. There is some evidence that interleukin-10 inhibits it in animal models [2]. It is classified by the World Health Organization (WHO) as type II lupus nephritis. Mesangial cells in the renal glomeruli use endocytosis to take up and degrade circulating immunoglobulin. This normal process promotes mesangial cell proliferation and matrix deposition. Therefore, when circulating immunoglobulin concentrations are elevated (i.e., lupus and IgA nephropathy), the number of mesangial cells and matrix in the glomerulus is expected to increase. This is characteristic of nephritic syndromes.

[0133] P. Amyloidosis (primary) Amyloidosis is a group of diseases in which abnormal proteins known as amyloid fibrils accumulate in tissues.[4] Symptoms depend on the type and often vary,[2] but may include diarrhea, weight loss, fatigue, swollen tongue, bleeding, numbness, fainting when standing, swollen feet, or an enlarged spleen.[2] There are approximately 30 different types of amyloidosis, each resulting from the misfolding of a specific protein.[5] Some are hereditary, while others are acquired.[3] They are classified into localized and systemic forms.[2] The four most common types of systemic disease are light chain (AL), inflammatory (AA), dialysis (Aβ2M), hereditary, and elderly (ATTR). Primary amyloidosis refers to amyloidosis without an associated clinical condition identified.

[0134] Q. c1q nephropathy C1q nephropathy is a rare glomerular disease characterized by characteristic mesangial C1q deposits on immunofluorescence microscopy. This nephropathy is histologically defined and poorly understood. Light microscopic features are heterogeneous and include minimal change nephrotic syndrome (MCD), focal segmental glomerulosclerosis (FSGS), and proliferative glomerulonephritis. Clinical presentation is also diverse, ranging from asymptomatic hematuria or proteinuria to frank nephritis or nephrotic syndrome in both children and adults. Elevated blood pressure and renal insufficiency at the time of diagnosis are common findings. Optimal treatment is unclear and is usually guided by the underlying light microscopic lesion. Corticosteroids are the mainstay of treatment, with immunosuppressants reserved for steroid-refractory cases. The presence of nephrotic syndrome and FSGS appears to predict adverse outcome in contrast to the favorable outcome in MCD patients. (Devasahayam, et al., “C1q Nephropathy: The Unique Underrecognized Pathological Entity,” Analytical Cellular Pathology, vol. 2015, Article ID 490413, 5 pages, 2015. https: / / doi.org / 10.1155 / 2015 / 490413.)

[0135] R. Anti-GBM disease Anti-glomerular basement membrane (GBM) disease, also known as Goodpasture's disease, is a rare condition that causes inflammation of small blood vessels in the kidneys and lungs. Anti-glomerular basement membrane (GBM) antibodies primarily attack the kidneys and lungs, but systemic symptoms such as malaise, weight loss, fatigue, fever, and chills are also common, as well as joint aches and pains. 60-80% of patients with the condition experience pulmonary and renal abnormalities, 20-40% have renal abnormalities only, and less than 10% have pulmonary abnormalities only. Pulmonary symptoms usually precede renal symptoms, and symptoms usually include hemoptysis, chest pain (in less than 50% of all cases), cough, and shortness of breath. Renal symptoms usually include hematuria, proteinuria, unexplained swelling of the limbs or face, large amounts of urea in the blood, and high blood pressure. GPS causes abnormal production of anti-GBM antibodies by plasma cells in the blood. Anti-GBM antibodies attack the alveoli and glomerular basement membrane. These antibodies bind reactive epitopes to the basement membrane and activate the complement cascade, resulting in the killing of targeted cells. T cells are also involved. The disease is generally considered a type II hypersensitivity reaction.

[0136] Measurement of urinary protein levels Urinary protein levels can be measured using methods known in the art. Until recently, accurate protein measurements required a 24-hour urine collection. In a 24-hour collection, the patient urinates into a container and refrigerates it after each toilet visit. The patient is instructed to begin collecting urine after the first toilet visit in the morning. All remaining urine for the day is collected in the container. The next morning, the patient completes the collection with the first urine after waking.

[0137] More recently, researchers have found that a single urine sample can provide the information they need. The newer method compares the amount of albumin in a urine sample to the amount of creatinine, a waste product created by the breakdown of healthy muscle. This measurement is called the urinary albumin-to-creatinine ratio (UACR). If a urine sample contains more than 30 milligrams of albumin per gram of creatinine (30 mg / g), it alerts you to a possible problem. If your lab test is above 30 mg / g, another UACR test should be done in 1 to 2 weeks. If the second test also shows high levels of protein, you have persistent proteinuria, a sign of declining kidney function, and you should undergo additional testing to evaluate your kidney function.

[0138] Tests that measure the amount of creatinine in the blood also show whether a person's kidneys are efficiently removing waste products. Excess creatinine in the blood is a sign of kidney damage. Doctors can use creatinine measurements to estimate how efficiently the kidneys are filtering blood. This calculation is called the estimated glomerular filtration rate (or eGFR). Chronic kidney disease is present when the eGFR is less than 60 milliliters per minute (mL / min).

[0139] Transient receptor potential channel 5 (TRPC5) is a calcium-permeable nonspecific cation channel that is primarily expressed in the brain, where it can form a heterotetrameric complex with TRPC1 and TRPC4 channel subunits. TRPC5 is also expressed in the kidney, more specifically in podocytes, where it is involved in the regulation of the podocyte actin cytoskeleton.

[0140] Thus, in certain embodiments, the present invention provides a method for treating or reducing the risk of developing a renal disease or nephropathy associated with a disease or condition, comprising administering a solid dosage form of the present invention to a subject in need thereof. In some embodiments, the renal disease or nephropathy associated with a disease or condition is focal segmental glomerulosclerosis (FSGS), diabetic nephropathy, Alport syndrome, hypertensive renal disease, nephrotic syndrome, steroid-resistant nephrotic syndrome, minimal change nephrotic syndrome, membranous nephropathy, idiopathic membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated MPGN, complement-mediated MPGN, lupus nephritis, post-infectious glomerulonephritis, thin basement membrane disease, mesangial proliferative glomerulonephritis, amyloidosis (primary), c1q nephropathy, rapidly progressive GN, anti-GBM disease, C3 glomerulonephritis, hypertensive nephrosclerosis, IgA nephropathy, IgG4 nephropathy. , proteinuric kidney disease, microalbuminuria, macroalbuminuric kidney disease, transplant-associated FSGS, transplant-associated nephrotic syndrome, transplant-associated proteinuria, nodular glomerulonephritis, NASR disease (proliferative glomerulonephritis with monoclonal IgG deposits), polycystic kidney disease, autosomal dominant polycystic kidney disease (ADPKD), or nephropathy associated with one of the following: obesity, insulin resistance, type II diabetes mellitus, prediabetes, metabolic syndrome, dyslipidemia, pulmonary arterial hypertension, cancer, cholestatic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), or Fabry disease.

[0141] In some embodiments, the renal disease or nephropathy associated with a disease or condition is renal complications due to focal segmental glomerulosclerosis (FSGS), diabetic nephropathy, Alport syndrome, hypertensive renal disease, obesity-related nephropathy, nephrotic syndrome, steroid-resistant nephrotic syndrome, minimal change nephrotic syndrome, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), lupus nephritis, post-infectious glomerulonephritis, thin basement membrane disease, mesangial proliferative glomerulonephritis, amyloidosis (primary), c1q nephropathy, anti-GBM disease, C3 glomerulonephritis, hypertensive nephrosclerosis, IgA nephropathy, IgG4 nephropathy, dyslipidemia-associated nephropathy, nodular glomerulonephritis, NASR disease (proliferative glomerulonephritis with monoclonal IgG deposits), polycystic kidney disease, or Fabry disease.

[0142] In some embodiments, the renal disease is hypertensive nephropathy, metabolic syndrome-associated nephropathy, obesity-associated nephropathy, dyslipidemia-associated nephropathy, diabetic nephropathy, nephrotic syndrome, FSGS, or minimal change nephrotic syndrome. In some embodiments, the renal disease is diabetic nephropathy, FSGS, or minimal change nephrotic syndrome.

[0143] In one aspect, the invention relates to a method of treating pain, anxiety, or depression comprising administering to a subject in need thereof a solid dosage form of the invention.

[0144] Treatment Targets In one embodiment of the present invention, the subject is selected based on having or being at risk of developing renal disease, pulmonary arterial hypertension, anxiety, depression, cancer, diabetic retinopathy, or pain.In another embodiment, the subject is selected based on having or being at risk of developing renal disease, anxiety, depression, cancer, or diabetic retinopathy.In another embodiment of the present invention, the subject is selected based on having or being at risk of developing pain, neuropathic pain, visceral pain, transplant-associated FSGS, transplant-associated nephrotic syndrome, transplant-associated proteinuria, cholestatic liver disease, polycystic kidney disease, autosomal dominant polycystic kidney disease (ADPKD), obesity, insulin resistance, type II diabetes, prediabetes, metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), or nonalcoholic steatohepatitis (NASH).

[0145] Subjects who have or are at risk of developing proteinuria include those with diabetes, elevated blood pressure, or certain family backgrounds. In the United States, diabetes is the leading cause of end-stage renal disease (ESRD). In both type 1 and type 2 diabetes, albumin in urine is one of the first signs of declining kidney function. As kidney function declines, the amount of albumin in urine increases. Another risk factor for developing proteinuria is elevated blood pressure. Proteinuria in hypertensive patients is an indicator of declining kidney function. If elevated blood pressure is not controlled, the patient may progress to complete kidney failure. African Americans are more likely than Caucasians to have high blood pressure and kidney problems even when blood pressure is only mildly elevated. Other groups at risk for proteinuria are Native Americans, Hispanics / Latinos, Pacific Islanders, the elderly, and overweight subjects.

[0146] In one embodiment of the present invention, a subject is selected based on having or being at risk of developing proteinuria. A subject having or being at risk of developing proteinuria is one who has one or more symptoms of the condition. Symptoms of proteinuria are known in the art and include, but are not limited to, large amounts of protein in urine. Protein in urine causes urine to appear foamy in the toilet. Large amounts of protein loss can result in edema, which can cause swelling of the hands, feet, abdomen, or face. These are signs of large amounts of protein loss and indicate that kidney disease is progressing. Laboratory tests are the only way to determine whether a subject has protein in their urine before extensive kidney damage occurs.

[0147] The method is effective in a variety of subjects, including mammals, e.g., humans, and other animals, e.g., laboratory animals, e.g., mice, rats, rabbits, or monkeys, or pets and livestock, e.g., cats, dogs, goats, sheep, pigs, cows, or horses. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. EXAMPLES

[0148] The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

[0149] All parts and percentages are given on a weight basis unless otherwise specified.

[0150] Example 1 Pharmaceutical Excipients and Equipment Potential excipients for use in the development and manufacture of spray dried solid dispersions and tablets were of fair or USP grade and were selected based on previous experience at Patheon. A complete list of excipients and equipment utilized in this set of development work can be found in Table 1. Throughout this report, percent compositions of solutions or solid dispersions are stated on a weight:weight basis unless otherwise specified.

[0151] [Table 2]

[0152] Example 2. Differential Scanning Calorimetry (DSC) MDSC was performed using a TA Instruments Discovery DSC2500 Differential Scanning Calorimeter equipped with a TA instruments Refrigerated Cooling System 90. MDSC was used to measure the thermodynamic events and characteristics of Compound 1 API and the subsequent SDI. Events observed included the glass transition temperature (T g ), cold crystallization (T c (defined as a crystallization event occurring at a temperature below the melting temperature)), and the melting temperature (T m ) were included. The SDI samples were placed in non-sealed aluminum pans and heated over the temperature range of 0-200 °C at a constant rate of 2.0 °C / min. The system was purged with a nitrogen flow of 50 mL / min to ensure an inert atmosphere throughout the measurement process. Compound 1 was successfully heated above its melting point to 258 °C and quenched using liquid N2 to obtain an amorphous API. The resulting amorphous API was analyzed by temperature modulated DSC up to 265 °C. A summary of the MDSC analytical parameters can be seen in Table 2.

[0153] [Table 3]

[0154] Example 3. X-ray powder diffraction (XRPD) Crystallinity of the spray-dried materials was assessed by performing XRPD using a Rigaku Miniflex 6G X-ray diffractometer or a Bruker D2 Phaser X-ray diffractometer. Amorphous materials give an "amorphous halo" diffraction pattern, which lacks the discrete peaks seen in crystalline materials. Samples were irradiated with monochromated Cu Kα radiation and analyzed from 5° to 40° using continuous scan mode. Samples were rotated during analysis to minimize preferred orientation effects. A summary of XRPD analysis parameters can be found in Tables 3 and 4 and vary from instrument to instrument to obtain similar diffraction patterns.

[0155] [Table 4]

[0156] [Table 5]

[0157] Example 4. Particle morphology by scanning electron microscope (SEM) SEM samples were prepared by dispersing the gold-palladium conductive thin-layer-coated powder onto a carbon-taped sample stage using a Cressington 108 Auto. Samples were analyzed using an FEI Quanta 200 SEM in high vacuum mode equipped with an Everhart-Thornley (secondary electron) detector. Micrographs were captured at various magnifications to perform qualitative particle morphology analysis. Experimental parameters were varied from sample to sample to obtain the best imaging conditions, including spot size, working distance, and accelerating voltage. These experimental parameters are indicated in the caption of each SEM micrograph.

[0158] Example 5. Particle size distribution (PSD) by optical diffraction The particle size of the SDI samples was determined by laser diffraction using a Mastersizer 3000 with an Aero S unit (Malvern Instruments). Approximately 100 mg of sample was placed in a standard Venturi disperser with a hopper gap of 1.5 mm and then fed into the dispersion. The sample feed rate was adjusted to 40% to keep the laser attenuation level between 0.1 and 15%. Compressed air at 2 bar was used to transport and suspend the sample particles through the optical cell. The measurement time was 10 seconds and a background measurement was performed using air for 10 seconds. Dv 10 Diameter, Dv 50 Diameter and Dv 90 The particle size distribution of the powders was characterized using the diameter. For example, Dv 50 A diameter is a diameter at which 50% of the sample volume is made up of particles of that diameter or less.

[0159] Example 6. Measurement of water content by Karl Fischer (KF) coulometric titration After secondary drying, SDI samples were taken and their moisture content was analyzed by a Metrohm 831 Karl Fischer Coulometric Titrator equipped with a Metrohm 874 oven processor. After sealing approximately 100 mg of sample in a 6 mL crimp vial, moisture content was measured using the following parameters: Reagent Hydranal Coulomat AG-Oven, oven temperature 150° C., and sample extraction time 300 seconds.

[0160] Example 7. Dynamic Vapor Sorption and Desorption (DVS) Dynamic Vapor Sorption and Desorption (DVS) was used to study the moisture sorption level of crystalline Compound 1. Samples were exposed to different relative humidity (RH) levels from 10% to 90% in 10% increments, followed by 10% RH desorption down to 20% RH. Accurate weight measurements (shown as % H2O uptake by weight) taken at 2 minute intervals are shown as a function of RH%. DVS analysis parameters are shown in Table 5 below.

[0161] [Table 6]

[0162] Example 8. Analysis of test and related substances by HPLC An experimental HPLC method was used to evaluate the test and related substances in the SDI samples (Table 6). The HPLC method utilized was based on the API manufacturing HPLC method used for Compound 1. This method demonstrated linear response, selectivity, and resolution for previously seen impurities.

[0163] Example 9. Residual Solvent After secondary drying, the residual solvent content of the SDI was measured by GC-HS. Measurements were performed using an HP6890 series GC equipped with an Agilent 7697A headspace sampler. A 30 m x 0.32 mm x 1.8 μ capillary column (6% cyanopropylphenyl-94% dimethylpolysiloxane GC column) was used for this study. GC sample preparation was performed by dissolving approximately 100 mg of sample in 4 mL of dimethyl sulfoxide (DMSO). A standard GC-HS method (DM-123) was used and no additional validation / confirmation procedures were performed on the drug product at this stage.

[0164] Example 10. In vitro dissolution capacity The in vitro drug dissolution performance of each SDI is evaluated using a two-stage "gastric transit" no-sink dissolution test at Patheon (Table 8), which mimics the pH and bile salt concentrations of gastric and intestinal exposure in an easy-to-perform assay. Pre-weighed SDI powder is quickly suspended in media (e.g., by vortex mixing with 4.0 mL of media for 10 seconds) and transferred to a pre-heated (37° C.) 0.1 N aqueous HCl solution (volume 50 mL) (simulated gastric fluid without pepsin or bile salts, i.e., SGF (pH approx. 1.0)) in a USP Type 2 container (total container volume 100 mL) with stirring (paddle) at 100 rpm. After 30 min exposure to gastric pH, an equivalent volume of PBS-buffered 2× concentrated fasted simulated intestinal fluid (FaSSIF) was added to the SGF to achieve a final pH of 6.8 in FaSSIF (SIF powder (bulk) (Biorelevant Inc.) at 2.24 mg / mL in 100 mM PBS) and a total volume of 100 mL. Aliquots (1.0 mL) of dissolution medium were removed at selected time points before and after simulated gastric transit, spun down (13000 rpm) to pellet and remove insoluble solids, and the supernatant was collected and further diluted with an appropriate diluent to determine the total API drug concentration (e.g., free drug in solution and colloidal / polymer-bound drug) using an appropriate HPLC method. Additional centrifugation and filtration were performed using a 10K molecular weight cutoff filter to remove polymer-bound aggregates and colloids. The resulting free drug-containing filtrate consisted of drug in solution and micelles. The volume of FaSSIF added is adjusted to account for the sample volume removed prior to gastric transit (typically 4 x 1.0 mL). Initial Compound 1 API measurements and SDI dissolution sample measurements were performed using HPLC.

[0165] [Table 7]

[0166] Example 11. Elution under sink conditions Compound 1 was dissolved in 20 mg and 100 mg tablets in 50 mM phosphate buffer (pH=6.8) containing 2% (w / v) SLS according to USP <711> Analyses were performed using Apparatus 2. Samples were filtered at the time of collection and analyzed by reversed-phase high performance liquid chromatography (HPLC) with ultraviolet (UV) detection (Table 7).

[0167] [Table 8]

[0168] Example 12. Preparation of dissolution medium Simulated Gastric Fluid (SGF): Determine the volume of SGF needed for all dissolution samples. Based on this volume, dilute 1.0 N HCl 10-fold with HO in an appropriate Class A graduated cylinder or volumetric flask. Mix well and measure the approximate pH using pH paper. The observed pH should be 1.0-1.1.

[0169] PBS Buffer (200 mM): Determine the volume of buffer needed for all elution samples. Based on this volume, measure out the equivalent of 200 mMol / L NaCl and the equivalent of 200 mMol / L Na2HPO4 and transfer to an appropriately sized container. To this container, add the appropriate volume of H2O. Sonicate the solution until all salts are completely dissolved. If necessary, adjust the pH to 8.9 ± 0.1 with phosphoric acid or 1.0 N NaOH.

[0170] FaSSIF medium (4.48 mg / mL): To the PBS medium above, add 4.48 mg of SIF powder per mL of 200 mM PBS. Mix well by stirring with a magnetic stir bar until all SIF is dissolved in solution. Allow to stand at room temperature for 2 hours before use, then pre-warm to 37 °C for dissolution testing. If FaSSIF is not used on the day of preparation, store in the refrigerator (2-8 °C) for up to 4 days. Remove from the refrigerator at least 2 hours before use to ensure the temperature of the solution reaches 37 °C before use.

[0171] 50 mM phosphate buffer (pH = 6.8) containing 2% (w / v) SLS: Mix 6 L water with 41.4 g sodium dihydrogen phosphate monohydrate and adjust the pH to 6.8. Add 120 g sodium lauryl sulfate and stir to dissolve.

[0172] Example 13. Collapse Using the Varian VK-100 Disintegration Tester to Test USP <701> Disintegration was evaluated according to "Disintegration". The apparatus consisted of a 1000 mL low form beaker and a basket rack assembly containing six open-ended transparent tubes. The beaker was filled with 750 mL of RO water and the temperature of the beaker was maintained at 37°C (± 2°C). The basket was fully submerged at a frequency of 29-32 cycles per minute and the time when the last visible tablet material passed through the basket was recorded as the tablet disintegration time.

[0173] Example 14. Tablet friability Using the Pharmatron FT2 friability tester, <1216> Friability was determined by the following formula: Drum rotation speed was 25 rpm with a total rotation time of 4 minutes. Acceptable loss in friability by the USP method is 1.0 weight percent or less.

[0174] Example 15. Tablet hardness and tensile strength Using the Natoli hardness tester (S / N 1403029), <1217> Tablet breaking force was tested according to "Tablet breaking force". As it is a breaking process, the thickness and weight of the tablets were measured before evaluating the tablet breaking force. The tablets were placed in an automated breaking device and the tablet breaking force was measured in kilogram force per kilopound (kp). The tablet tensile strength for standard round concave (SRC) tablets and oval tablets was calculated (in MPa) based on the following formula:

[0175]

number

[0176]

number

[0177] Example 16. Particle size distribution by sieve analysis USP <786> The particle size distribution was determined by the same analytical sieve method as in . A RO-TAP RX-29-E sieve shaker (WS Tyler) was used to evaluate the materials. The screens and operating parameters used can be seen in Table 8 below.

[0178] [Table 9]

[0179] Example 17. Compound Analysis and Characterization Thermal properties (melting temperature (T m ), glass transition temperature (T g ), and crystallization temperature (T c ) was measured by MDSC. The T m was first trapped, and melting decomposition was observed with an endothermic melting peak at 257 °C. g A liquid quenching method was used to measure T, in which compound 1 was heated above its melting temperature and then rapidly cooled in liquid nitrogen to capture the molten material in an amorphous state. The resulting sample was analyzed by MDSC and a T of 130 °C was obtained. g was observed (Figure 1A-B / Table 9). At that time, no crystallization peak was observed, and no clear melting event was observed even when the amorphous sample was subsequently heated to 275 °C. The obtained T m / T gThe ratio is 1.32, which indicates moderate physical stability. m / T g The ratio, when taken into account the stability of the amorphous API (up to 200° C.), indicates that it is possible to increase the drug loading of amorphous dispersions with acceptable physical stability.

[0180] [Table 10]

[0181] The diffraction pattern of Compound 1 crystalline form was obtained using XRPD (Figure 2). The diffraction pattern of the API drug substance indicates a crystalline material, which is consistent with the thermal analysis.

[0182] The surface morphology of the API bulk particles was characterized using scanning electron microscopy. The SEM images in Figure 3 show images of Compound 1 API taken at magnifications of 500x, 1500x, and 5000x. The API morphology consists of agglomerates of small API particles with different crystal morphologies.

[0183] The solubility of Compound 1 in organic solvents was determined visually in common spray drying solvents (Table 10) utilizing Compound 1 Lot AC5313-058P1.

[0184] [Table 11]

[0185] Upon heating to 40°C, a 3.0% equivalent concentration of compound 1 dissolved in 60:40 DCM:methanol after approximately 2 hours. Upon removal from the heat source, the API precipitated 5 minutes later. A 2.0% solution (% w / w) of compound 1 was then prepared and heated to 40°C, where the solid dissolved immediately. This 2.0% solution was then removed from the heat source, and precipitation of the API was observed after approximately 2 hours. The heated (40°C) solution of 60:40 DCM:methanol was selected as the lead solvent system that would result in a maximum active loading of compound 1 into solution of 2.0%.

[0186] Example 18. Focused Screening of Solid Dispersion Polymers: Preparation of Spray-Dried Formulations Compound 1 lot AC5313-058P1 was used to prepare the utility dispersion. Five Compound 1 SDI formulations were selected for utility screening. These formulations were selected based on data previously obtained by Goldfinch Bio showing acceptable PK results using 25:75 Compound 1:HPMCAS-L SDI. The selected utility dispersions were designed to determine the maximum loading of Compound 1 and evaluated for the capabilities of HPMCAS-M based dispersions. Below can be seen a summary of the spray drying parameters (Table 11) and the recovered SDI dry yields (Table 12). After API addition, the spray solution had a clear amber appearance.

[0187] [Table 12]

[0188] [Table 13]

[0189] Example 19. Focused Screening of Solid Dispersion Polymers: Characterization of Spray-Dried Formulations The initial SDI formulation was characterized by X-ray powder diffraction (XRPD), scanning electron microscopy (SEM), modulated differential scanning calorimetry (MSDC), headspace gas chromatography (GC-HS), and in vitro dissolution testing under no-sink conditions.

[0190] A secondary drying process in a tray dryer was applied to remove residual solvents after spray drying. In this procedure, the "wet" SDI was heated to 40°C and stored in a convection tray oven for 24 hours. Gas chromatograph (GC) headspace analysis was performed to measure residual solvents remaining in the Compound 1 SDI material after secondary drying. Residual solvents in all formulations were below the DCM (600 ppm) and MeOH (3000 ppm) limits set by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). Table 13 shows the residual solvent results for the practical formulations.

[0191] [Table 14]

[0192] Initial characterization by XRPD showed that the SDI with 50% compound 1 content and the SDI with 66% compound 1 content showed crystalline peaks, while the SDI with 25% compound 1 content was entirely amorphous (Figure 4).

[0193] Thermal analysis by MDSC was carried out on two amorphous dispersions with 25% Compound 1 content. Both dispersions showed a single T g DSC showed that these amorphous solid dispersions had a T (Figures 5A-5B), indicating that they were intimately mixed and had good homogeneity (Table 14). To ensure long-term physical stability, the T should be increased at given storage conditions so that the drug has low mobility in the glass dispersions. g SDI should be stored at temperatures well below .

[0194] [Table 15]

[0195] The dissolution ability of SDI materials and crystalline Compound 1 was tested in a non-sink dissolution test at Patheon (Figure 6 and Table 15). This dissolution test is used to measure drug supersaturation over the solubility of crystalline Compound 1 drug substance in biorelevant intestinal media (FaSSIF) after exposure to a low pH environment for 30 minutes. During the test, samples were dissolved in 0.1 N HCl [theoretical C max =1000μA / mL] to FaSSIF[Theoretical C max = 500 μA / mL. This experiment was designed for sequencing and lead formulation selection.

[0196] All of the resulting SDI formulations showed increased AUC compared to the crystalline API, with the 25% loading in HPMCAS-M showing the best performance. As expected, the free drug concentrations were low compared to the corresponding total drug concentrations. Free drug levels were consistently low compared to the total drug samples and were consistent across formulations in terms of percent of total drug. 25% and 50% loading in HPMCAS-M and 25% loading in HPMCAS-L were selected as lead formulations.

[0197] [Table 16]

[0198] Dynamic vapor sorption and desorption measurements of the lead SDI formulations showed that the 50:50 Compound 1:HPMCAS-M dispersion had the lowest water sorption, which was attributed to the low polymer concentration. All samples showed minor hysteresis to water desorption (Figure 7).

[0199] Example 20. Focused Screening of Solid Dispersion Polymers: Practical Re-Spray Dried Materials Compound 1 lot TJ-GDF-9815-0-A-1 was used for the re-spray dried product. Light crystallinity was observed by XRPD at 50% and 66% Compound 1 loading in the dispersion, so three additional working formulations were prepared. The re-spray dried formulations can be seen in Table 16.

[0200] [Table 17]

[0201] The spray solution after addition of the API had an opaque brown appearance, indicating a different solubility than the API lot in the initial utility spray dried. Lots G8-854-13 and G8-854-14 were sprayed at an elevated outlet temperature (60° C.) to reduce the API-rich regions in the SDI particles. Lot G8-854-10 contained Vitamin E TPGS to help reduce crystallinity, and this lot was sprayed at an outlet temperature of 40° C. due to the low melting point of TPGS (a wax at room temperature). In Figure 8, you can see the XPRD traces of the re-spray dried and the original 25:75 Compound 1:HPMCAS-M dispersion. Both the 50% re-spray dried appear to have crystalline peaks similar to the original SDI, and the re-spray dried 25% dispersion appears to have a very slight crystalline peak around 2θ=26°. This data supports the observation that this new API lot may not be completely dissolved in the spray solution.

[0202] Example 21. Focused Screening of Solid Dispersion Polymers: SDI Accelerated Stability Testing To rapidly assess the physical and chemical stability of Compound 1 SDI formulations, lead dispersions (25:75 Compound 1:HPMCAS-M and 25:75 Compound 1:HPMCAS-L) were subjected to 40°C / 75% RH and 50°C / 75% RH in open and closed packages with desiccant for 4 weeks (stability protocol RD-ST-18-940). These SDIs were evaluated for changes in: Amorphous physical state by XRPD Chemical stability by HPLC

[0203] Initial XRPD analysis of aged SDI samples at 2 weeks showed that all SDI formulations placed under closed conditions, including desiccant, remained amorphous, whereas under open conditions, crystals grew in the 50% dispersion at 40 °C / 75% RH and 50 °C / 75% RH (Figures 9-10).

[0204] Additional XRPD testing was performed on these SDIs at 4 weeks, and all closed condition samples remained amorphous. Under accelerated open conditions at 40°C and 50°C, crystalline peaks were observed but no further crystal growth was observed. SDIs under open conditions at 25°C / 60% RH remained amorphous even after 4 weeks (Figures 11-12).

[0205] Purity analysis of 25:75 Compound 1:HPMCAS-M after 4 weeks showed that impurities did not increase under closed conditions and the impurity profile was consistent with that of the starting API. Under open conditions, impurities with RRTs of 0.34, 0.82, 0.91, and 0.96 increased significantly (Tables 17 and 18), indicating that protective packaging would be recommended to protect SDI stored long term.

[0206] [Table 18]

[0207] [Table 19]

[0208] Similar results were observed in the purity analysis of the 25:75 Compound 1:HPMCAS-L SDI after 4 weeks: no increase in impurities was observed in any of them under closed conditions, but all of them under open conditions had significant increases in impurities with RRTs of 0.82, 0.91, and 0.96 (Tables 19 and 20).

[0209] [Table 20]

[0210] [Table 21]

[0211] Accelerated stability data indicates that the increase in impurities in Compound 1 is induced, at least in part, by exposure to moisture. Since there were no significant differences in the impurity profiles, the 25:75 Compound 1:HPMCAS-M SDI was selected as the lead to proceed into tablet development. This selection was made due to the performance of the 25:75 Compound 1:HPMCAS-M SDI in dissolution testing under non-sink conditions.

[0212] Example 22. Spray dried intermediate demonstration batch Compound 1 working lot: TJ-GDF-9815-0-A-1 (crystal form H). Scale-up of selected SDI formulations was performed using an MS-150 pilot scale spray dryer and an Ekato vacuum dryer for secondary drying. The base recipe can be seen in Table 21. The batch size was 200 kg of solution with 14 kg of SDI.

[0213] [Table 22]

[0214] In Table 22 the demonstration batch parameters can be seen.

[0215] [Table 23]

[0216] The final process yield was 81% and the accountability was 85%. In Table 23 the process conditions recommended for a GMP process can be seen.

[0217] [Table 24]

[0218] For GMP manufacturing, it is recommended to use a nozzle that does not cause accumulation of spray at the tip.

[0219] Example 23. Analytical testing of Compound 1 SDI demonstration batches Appearance, Strength / Related Substances, Moisture Content, Residual Solvents, T g The SDI demonstration batch of Compound 1 was tested for amorphous characteristics, particle size distribution, particle morphology, and bulk / tap density. All results are listed in the Certificate of Analysis (CoT) and can be seen in FIG. 13.

[0220] Example 24. Stability of Demonstration Batch Solutions and Wet SDI Spray solution samples from lot D-18-078 were taken prior to spray drying to determine maximum solution hold time. Solution samples were held at 40° C. and tested for test / related substances and appearance at t=0, 1, 5, 9, and 15 days. The spray solution was stable for 5 days with degradation observed at 9 and 15 days. Degradation was observed at RRT=0.85, 0.86, 0.92, 0.94, 0.96, 1.47, 1.52, and 1.56. The solution color remained constant at "clear orange" through the 15 day time point. Spray solution stability was confirmed by repeating duplicate measurements (FIG. 14).

[0221] The degradation profile in the retest was similar to that of the initial spray solution test. Based on the spray solution retest data, a conservative stability of 3 days was assumed for the spray solution at 40°C.

[0222] The wet SDI was tested at room temperature for appearance, test article / related substance, particle morphology, and amorphous characteristics at t=0, 1, 5, 9, and 15 days. The test requirement was to determine the maximum holding time of the wet SDI before secondary drying in an Ekato vacuum dryer. Appearance remained constant throughout the study as a "tan-greyish white powder." The test article / related substance results for the wet SDI can be seen in Figures 15A and 15B.

[0223] Wet SDI was chemically stable at room temperature for at least 15 days: it remained amorphous by XRPD and the particle morphology appearance remained unchanged after 15 days (Figures 16 and 17).

[0224] For the initial wet SDI, crystallinity was observed at approximately 2θ=26° throughout the stability test. The peak at 2θ=26° did not appear to grow.

[0225] SDI typically has a collapsed globular morphology and no crystallinity is observed. After 15 days, the morphology of wet SDI is equivalent to that of dry SDI, and no change in its stability is observed.

[0226] Example 25. Development of Prototype Compound 1 Tablets Four tablet formulations were selected to evaluate excipient compatibility and tablet physical properties. Excipients (mannitol or lactose) and superdisintegrants (croscarmellose sodium or crospovidone) were varied to find the best combination. The formulations can be seen in Table 24.

[0227] [Table 25]

[0228] Tablets were prepared to have a Compound 1 content of 50 mg and a total tablet weight of 400 mg. Prototype formulations were manufactured by slug compression and milling to simulate a dry granulation process. A process flow chart can be found in Figure 18.

[0229] The intragranular blends were slug compressed using 0.875" flat tooling to a solids percentage of approximately 0.70 (the true density of the prototype blends was assumed to be 1.35 g / cc). The compacts were then crushed using a Vector TFC-Micro crusher equipped with a 20 mesh screen. Prototype tablets were produced on a Natoli single station manual tablet press. Tabletability, compressibility, compactibility, and disintegration profiles were obtained for all formulations using 0.2505" x 0.5385" modified oval tooling over a compression range of 50-300 MPa (Figure 19). (See Figures 31-32 for drawings of applicable tooling).

[0230] All formulations had similar compression profiles, which may be dictated by the higher levels of SDI. The tablet formulations achieved high tensile strength at relatively low compression pressures. Ac-Di-Sol is a much more effective disintegrant compared to Kollidon CL. Formulations containing Kollidon CL have a much steeper slope in the disintegration profile. Variation in compression pressure can lead to large differences in disintegration times and potentially affect dissolution. Formulations containing Ac-Di-Sol were selected for accelerated stability studies and cynomolgus monkey PK studies using single 50 mg tablets in fasted animals based on dissolution. The reduction in dissolution rate of tablets containing crospovidone was also seen with an approximately 50% decrease in AUC compared to tablets containing Ac-Di-Sol. No differences were observed between tablets containing lactose and tablets containing mannitol.

[0231] Example 26. Prototype Compound 1 Tablet Accelerated Stability Study Selected prototype tablets (lactose / Ac-Di-Sol and mannitol / Ac-Di-Sol) were subjected to accelerated stability studies and stored at 40C / 75%RH and 25C / 60%RH under open and closed conditions. After 4 weeks, the tablets were tested for test article / related substances, dissolution under non-sink conditions, and disintegration. Test article / related substance data for both tablets can be found in Table 25 and Table 26.

[0232] [Table 26-1]

[0233] [Table 26-2]

[0234] For the lactose / Ac-Di-Sol tablets, only under open conditions at 40C / 75%RH, a small increase in degradants was observed at RRT=0.34, 0.36, and 0.91 compared to API bulk, while under other conditions, a similar impurity profile was obtained compared to API.

[0235] [Table 27]

[0236] Mannitol / Ac-Di-Sol tablets stored open at 40C / 75%RH showed a small increase in degradants similar to lactose / Ac-Di-Sol tablets. Under other conditions, profiles similar to those of API bulk were obtained. All tablets from both formulation designs met the target potency values.

[0237] Dissolution under non-sink conditions was tested for both tablet formulations under all conditions and found to exhibit similar performance for total and free drug (Figures 20 and 21).

[0238] The disintegration times of the tablets were similar, except for the open condition of 40°C / 75%RH, where the disintegration time of the tablets was significantly increased. This increase may be due to Ac-Di-Sol and Avicel in the formulation absorbing moisture and swelling during the stability test, indicating that all the disintegrants have already been activated. Placing these tablets in the disintegration tank does not create any force to swell the tablets and break them apart. Table 27 shows the disintegration time and appearance data.

[0239] [Table 28]

[0240] Both tablet formulations appear to be similar in terms of stability and in vitro potency. Mannitol / Ac-Di-Sol was selected for scale-up as PK studies determined that it produced better exposure. The lactose and mannitol tablet formulations produced exposures similar to those produced by the 25:75 SDD dispersion. Stability studies indicate that inclusion of a desiccant in the packaging will be necessary to protect the tablets from moisture, as demonstrated by the difference in chemical stability at 40C / 75%RH between open and closed conditions in HDPE bottles with desiccant.

[0241] Example 27. Compound 1 tablet demonstration batch: Compound 1 demonstration batch tablet compression A demonstration batch of Compound 1 tablets was produced on a Piccola 10 station rotary tablet press with a turret speed of 20 rpm. Compression and disintegration profiles were obtained and compared to the working Compound 1 tablets (Figure 22).

[0242] Tabletability, compressibility, and compactibility graphs show that the prototype tablets are stronger compared to the demonstration batch tablets. This difference in strength is due to the different compression dwell times between the two processes (the rotary press has a much shorter compression dwell time). The disintegration profiles of the 50 mg prototype and 100 mg demonstration batch tablets appear to overlap, with a steep increase in disintegration time observed at compression pressures of 150-200 MPa. The 20 mg Compound 1 tablets did not show a steep increase in disintegration time over the compression range tested, demonstrating a more robust operating window. Additional dissolution tests (Figures 23-25) were performed on the 100 mg Compound 1 tablets obtained at 200 MPa and 250 MPa to determine whether the steep increase in disintegration time impacted release.

[0243] The extent of release was similar between the 200 MPa and 250 MPa tablets, although the initial rate was slightly faster for tablets compressed at 200 MPa. The release profile is similar to that of the bulk validation batch material at CoT (Appendix E). PK was also studied in cynomolgus monkeys, and no differences in AUC Cmax were observed compared to the selected 175 MPa compression pressure. The friability profile of the validation batch tablets shows that compression pressures above 100 MPa result in lower friability values ​​(Figure 26).

[0244] Strain rate was tested on 20 mg Compound 1 tablets obtained at table speeds of 30 rpm and 40 rpm. Tablet tensile strength remained consistent at all tested speeds. The formulation does not appear to be strain rate sensitive at speeds between 20 and 40 rpm on a 10-station Piccola rotary tablet press (Figures 27-28).

[0245] The target compression force was 225±25 MPa for 20 mg Compound 1 tablets and 175±25 MPa for 100 mg tablets. First / middle / second half samples were collected throughout compression and tested for weight, thickness, breaking force, disintegration, and friability. Consistent values ​​were observed across all samples. Friability and disintegration data can be found in Tables 28 and 29.

[0246] [Table 29]

[0247] [Table 30]

[0248] The appearance of the tablets is speckled on their surface, which is due to the white color of the extragranular components and the off-white color of the SDI (Figure 29). The speckles on the tablet surface can also be reduced by lowering the solids percentage of the roller compacted ribbons.

[0249] All tablet samples disintegrated within approximately 1-4 minutes and passed the friability test. Tablet weights remained consistent and no powder flow issues were observed during compression at both tablet strengths. Weight analysis of a batch of samples (n=50) from each tablet batch revealed a narrow distribution. The average tablet weights were as targeted with only two tablets (both 20 mg Compound 1) outside the 5% weight variation (Figure 30).

[0250] A summary of both batches can be seen in Table 30.

[0251] [Table 31]

[0252] Example 28. Compound 1 Tablet Validation Batch: Analytical Testing of Compound 1 Tablet Validation Batch The 20 mg and 100 mg demonstration batch tablets of Compound 1 were tested for appearance, moisture content, test article / related substance, content uniformity by layer (Table 31), and dissolution. All analytical results are included in the test report, which can be seen in Figures 33-34.

[0253] [Table 32]

[0254] Example 29. Conclusion The feasibility of SDI revealed that 25% Compound 1 content allows for the production of amorphous dispersions, whereas 50% and 66% Compound 1 content partially retained crystals after the spray drying process. The SDI formulations that showed the best in vitro improvement over crystalline Compound 1 were 25% Compound 1 in HPMCAS-M and 25% Compound 1 in HPMCAS-L. Accelerated stability testing of the amorphous dispersions revealed that under open conditions of 40°C / 75% RH and 50°C / 75% RH, crystal growth was observed, whereas under closed conditions with desiccant, the amorphous nature was completely maintained, indicating that exposure to moisture significantly affected the physical stability of the dispersions. Based on PK studies performed by Goldfinch, 25:75 Compound 1:HPMCAS-M was selected as the SDI and its pilot scale production was successfully carried out in MS-150 and residual solvent was removed using an Ekato vacuum dryer. Scale-up of selected prototype tablet formulations was successfully achieved on a Vector TFC-220 dry compression granulator and a Piccola 10 station rotary tablet press. High levels of fines and flowability issues were observed during the discharge of the final blend, so further development of the granulation process is recommended. Improving flowability will be crucial to increasing manufacturing throughput. Milling the ribbons with a lower energy mill could rectify this issue. GMP manufacturing will use the same equipment for spray drying and tabletting, and is expected to be more successful.

[0255] Example 30. Sample formulation

[0256] [Table 33]

[0257] [Table 34]

[0258] [Table 35]

[0259] Incorporation by Reference All United States patents and published United States and international applications cited herein are hereby incorporated by reference.

[0260] Equivalent The above specification is sufficient to enable those skilled in the art to practice the invention. The scope of the invention should not be limited by the described examples, since each example is intended as a single illustration of one aspect of the invention, and other functionally equivalent embodiments are also included within the scope of the invention. Various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the above description. These modifications are intended to be included within the scope of the appended claims. The advantages and objectives of the invention are not necessarily encompassed by each embodiment of the invention.

Claims

1. 1. A composition for producing a spray dried dispersion, the composition comprising 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one, a solvent, and a polymer, the polymer being dissolved in the solvent.

2. 2. The composition of claim 1, wherein the 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one is in amorphous form.

3. 3. The composition of claim 1 or claim 2, wherein the polymer is hypromellose acetate succinate.

4. 4. The composition of claim 3, wherein the ratio of the 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one to the hypromellose acetate succinate is from about 1:9 to about 2:

1.

5. 5. The composition of claim 4, wherein the ratio of the 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one to the hypromellose acetate succinate is about 1:

3.

6. 6. The composition of claim 4 or claim 5, wherein the hypromellose acetate succinate has an acetyl content of about 5-14%, a succinoyl content of about 4-18%, a methoxyl content of about 20-26%, and a hydroxypropoxy content of about 5-10%.

7. 7. The composition of claim 6, wherein the hypromellose acetate succinate has an acetyl content of about 7-12%, a succinoyl content of about 7-15%, a methoxyl content of about 21-25%, and a hydroxypropoxy content of about 5-9%.

8. 8. The composition of any one of claims 1 to 7, wherein the solvent is acetone, methyl ethyl ketone, ethyl acetate, isopropyl alcohol, dioxane, acetonitrile, ethanol, water, methanol, dichloromethane, tetrahydrofuran, or any combination thereof.

9. 9. The composition of claim 8, wherein the solvent is a combination of methanol and dichloromethane.

10. 10. The composition of claim 9, wherein the ratio of said dichloromethane to said methanol is from about 30:70 to about 60:

40.

11. 11. The composition of claim 10, wherein the ratio of said dichloromethane to said methanol is about 60:

40.

12. A method for producing a spray dried dispersion, said method comprising the step of spray drying a composition according to any one of claims 1 to 11.

13. The method of claim 12, wherein the temperature of the nozzle through which the composition passes to be spray dried is from about 20°C to about 60°C.

14. The method of claim 13, wherein the nozzle has a temperature of about 35°C to about 40°C.

15. The method of any one of claims 12 to 14, wherein the spray drying step is carried out at an atomization pressure of about 1.0 to about 10.0 bar.

16. The method of claim 15, wherein the spray drying step is carried out at an atomization pressure of about 2.0 to about 4.0 bar.

17. A spray dried dispersion comprising 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one, a solvent, and a polymer, wherein the polymer is dissolved in the solvent.

18. 18. The spray dried dispersion of claim 17, wherein the 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one is in amorphous form.

19. 19. The spray dried dispersion of claim 17 or 18, wherein the polymer is hypromellose acetate succinate.

20. 20. The spray dried dispersion of claim 19, wherein the ratio of the 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one to the hypromellose acetate succinate is from about 1:9 to about 2:

1.

21. 21. The spray dried dispersion of claim 20, wherein the ratio of the 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one to the hypromellose acetate succinate is about 1:

3.

22. 22. The spray dried dispersion of claim 20 or 21, wherein the hypromellose acetate succinate has an acetyl content of about 5-14%, a succinoyl content of about 4-18%, a methoxyl content of about 20-26%, and a hydroxypropoxy content of about 5-10%.

23. 23. The spray dried dispersion of claim 22, wherein the hypromellose acetate succinate has an acetyl content of about 5-11%, a succinoyl content of about 10-18%, a methoxyl content of about 20-25%, and a hydroxypropoxy content of about 5-9%.

24. 24. The spray dried dispersion of any one of claims 17 to 23, wherein the solvent is acetone, methyl ethyl ketone, ethyl acetate, isopropyl alcohol, dioxane, acetonitrile, ethanol, water, methanol, dichloromethane, tetrahydrofuran, or any combination thereof.

25. 25. The spray dried dispersion of claim 24, wherein the solvent is a combination of methanol and dichloromethane.

26. 26. The spray dried dispersion of claim 25, wherein the ratio of the dichloromethane to the methanol is from about 30:70 to about 60:

40.

27. 27. The spray dried dispersion of claim 26, wherein the ratio of the dichloromethane to the methanol is about 60:

40.

28. 28. A solid dosage form comprising the spray dried dispersion of any one of claims 17 to 27 and one or more of an excipient, a disintegrant, a lubricant, a glidant, and a stabilizer.

29. 30. The solid dosage form of claim 28, wherein the excipient comprises one or more of mannitol, lactose, or microcrystalline cellulose.

30. 30. The solid dosage form of claim 29, wherein the excipients comprise mannitol and microcrystalline cellulose.

31. 31. The solid dosage form of claim 30, wherein the ratio of mannitol to microcrystalline cellulose is from about 1:3 to about 3:

1.

32. 32. The solid dosage form of claim 31, wherein the ratio of mannitol to microcrystalline cellulose is from about 1:1 to about 1:1.

3.

33. 33. The solid dosage form of any one of claims 28 to 32, wherein the microcrystalline cellulose has an average particle size of from about 5 μm to about 80 μm.

34. The average particle size of the crystalline cellulose is about 10 μm to about 50 μm.

34. The solid dosage form of claim 33.

35. 35. The solid dosage form of any one of claims 28 to 34, wherein the disintegrant is croscarmellose sodium.

36. 36. The solid dosage form of claim 35, wherein the croscarmellose sodium is present in an amount of from about 3% to about 15% w / w.

37. 37. The solid dosage form of claim 36, wherein the croscarmellose sodium is present in an amount of about 6% w / w.

38. 38. The solid dosage form of any one of claims 28 to 37, wherein the lubricant is sodium stearyl fumarate.

39. 39. The solid dosage form of claim 38, wherein the sodium stearyl fumarate is present in an amount of from about 0.5 to about 5% w / w.

40. 40. The solid dosage form of claim 39, wherein the sodium stearyl fumarate is present in an amount of about 1% w / w or about 0.95% w / w.

41. 41. The solid dosage form of any one of claims 28 to 40, wherein the glidant is colloidal silicon dioxide.

42. 42. The solid dosage form of claim 41, wherein the silicon dioxide is present in an amount of from about 0.1 to about 5% w / w.

43. 42. The solid dosage form of claim 41, wherein the silicon dioxide is present in an amount of about 1% w / w.

44. 44. The solid dosage form of any one of claims 28 to 43, wherein the spray dried dispersion is present in an amount of from about 3% to about 60% w / w.

45. 45. The solid dosage form of claim 44, wherein the spray dried dispersion is present at about 50% w / w.

46. 45. The solid dosage form of claim 44, wherein the spray dried dispersion is present at about 16.7% w / w.

47. 45. The solid dosage form of claim 44, wherein the spray dried dispersion is present at about 3.33% w / w.

48. 48. The solid dosage form of any one of claims 28 to 47, wherein the 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one is present in an amount of about 0.75% to 15% w / w.

49. a. 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one, b. Hypromellose acetate succinate, c. mannitol, d. crystalline cellulose, e. Croscarmellose sodium, f. Sodium stearyl fumarate, and g. Colloidal silicon dioxide 30. The solid dosage form of claim 28, consisting essentially of:

50. a. 0.75% to 40.0% (w / w) of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one; b. 2.0% to 54.0% (w / w) of hypromellose acetate succinate; c. 3.75% to 42.3% (w / w) mannitol; d. 3.75% to 50.0% (w / w) microcrystalline cellulose; e. 3.0% to 15% (w / w) of croscarmellose sodium; f. 0.5% to 5.0% (w / w) of Sodium Stearyl Fumarate, and g. 0.1% to 5.0% (w / w) colloidal silicon dioxide; It essentially consists of the ratio of the 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one to the hypromellose acetate succinate is 1:9 to 2:1; the combined amount of the 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one and the hypromellose acetate succinate in the solid dosage form is 3% to 60% w / w; The ratio of the mannitol to the crystalline cellulose is 1:3 to 3:1; 50. The solid dosage form of claim 49, wherein the total amount of the mannitol and the microcrystalline cellulose in the solid dosage form is 15.0 to 90% w / w.

51. a. 20 mg of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one, b. 60 mg hypromellose acetate succinate, c. 33.6 mg mannitol; d. 33.6 mg microcrystalline cellulose; e. 9.6 mg croscarmellose sodium, f. 1.6 mg Sodium Stearyl Fumarate, and g. 1.6 mg colloidal silicon dioxide 51. The solid dosage form of claim 50, consisting essentially of:

52. a. 100 mg of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one, b. 300 mg hypromellose acetate succinate; c. 168 mg mannitol; d. 168 mg microcrystalline cellulose; e. 48 mg croscarmellose sodium, f. 8 mg of sodium stearyl fumarate, and g. 8 mg colloidal silicon dioxide 51. The solid dosage form of claim 50, consisting essentially of:

53. a. 5 mg of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one, b. 15 mg hypromellose acetate succinate, c. 39.2 mg mannitol; d. 51.2 mg microcrystalline cellulose; e. 7.2 mg croscarmellose sodium, f. 1.1 mg of sodium stearyl fumarate, and g. 1.2 mg colloidal silicon dioxide 51. The solid dosage form of claim 50, consisting essentially of:

54. a. 1 mg of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one, b. 3 mg hypromellose acetate succinate, c. 47.2 mg mannitol; d. 59.2 mg microcrystalline cellulose; e. 7.2 mg croscarmellose sodium, f. 1.1 mg of sodium stearyl fumarate, and g. 1.2 mg colloidal silicon dioxide 51. The solid dosage form of claim 50, consisting of:

55. 55. The solid dosage form of any of claims 28 to 54, wherein the solid dosage form is a tablet.

56. 55. The solid dosage form of any of claims 28 to 54, wherein the solid dosage form is a capsule.

57. 57. The solid dosage form of claim 55 or 56, wherein the amount of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one in the tablet or capsule is about 1 to 200 mg.

58. 58. The solid dosage form of claim 57, wherein the amount of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one in the tablet or capsule is about 5 mg.

59. 58. The solid dosage form of claim 57, wherein the amount of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one in the tablet or capsule is about 20 mg.

60. 58. The solid dosage form of claim 57, wherein the amount of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one in the tablet or capsule is about 100 mg.

61. 58. The solid dosage form of claim 57, wherein the amount of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one in the tablet or capsule is about 1 mg.

62. 1. A method for making a solid dosage form of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one, said method comprising: a. mixing the spray dried dispersion of any one of claims 17 to 27 with one or more of a first excipient, a first disintegrant, a first lubricant, a first glidant, and a first stabilizer to form a first solid mixture. b. roller compacting and grinding the first solid mixture; and c. optionally mixing the roller compacted and milled first solid mixture with one or more of a second excipient, a second disintegrant, a second lubricant, a second glidant, and a second stabilizer to form a second solid mixture; d. Converting the first solid mixture or the second solid mixture into the solid dosage form of the 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one. The method comprising:

63. the first excipient and the second excipient are selected from mannitol, microcrystalline cellulose, or a combination thereof; the first disintegrant and the second disintegrant are croscarmellose sodium; the first lubricant and the second lubricant are sodium stearyl fumarate; 63. The method of claim 62, wherein the first glidant and the second glidant are silicon dioxide.

64. 63. The method of claim 62, wherein in step c, the roller compacted and milled solid mixture is mixed with a second excipient, a second disintegrant, and a second lubricant.

65. 65. The method of any one of claims 62-64, wherein the solid dosage form is a tablet formed by compressing the first solid mixture or the second solid mixture.

66. 65. The method of any one of claims 62-64, wherein the solid dosage form is a filled capsule formed by filling the first solid mixture or the second solid mixture into a capsule.

67. 62. A method of treating a renal disease or nephropathy associated with a disease or condition, said method comprising administering to a subject in need thereof a solid dosage form according to any one of claims 28 to 61.

68. The kidney disease or nephropathy associated with the disease or condition is selected from the group consisting of focal segmental glomerulosclerosis (FSGS), diabetic nephropathy, Alport syndrome, hypertensive kidney disease, nephrotic syndrome, steroid-resistant nephrotic syndrome, minimal change nephrotic syndrome, membranous nephropathy, idiopathic membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated MPGN, complement-mediated MPGN, lupus nephritis, post-infectious glomerulonephritis, thin basement membrane disease, mesangial proliferative glomerulonephritis, amyloidosis (primary), c1q nephropathy, rapidly progressive GN, anti-GBM disease, C3 glomerulonephritis, hypertensive nephrosclerosis, IgA nephropathy, IgG4 nephropathy, proteinuric kidney disease, 68. The method of claim 67, wherein the nephropathy is associated with any one of microalbuminuria, macroalbuminuric kidney disease, transplant-associated FSGS, transplant-associated nephrotic syndrome, transplant-associated proteinuria, nodular glomerulonephritis, NASR disease (proliferative glomerulonephritis with monoclonal IgG deposition), polycystic kidney disease, autosomal dominant polycystic kidney disease (ADPKD), or obesity, insulin resistance, type II diabetes, prediabetes, metabolic syndrome, dyslipidemia, pulmonary arterial hypertension, cancer, cholestatic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), or Fabry disease.

69. 69. The method of claim 68, wherein the renal disease or nephropathy associated with the disease or condition is renal complications due to focal segmental glomerulosclerosis (FSGS), diabetic nephropathy, Alport syndrome, hypertensive renal disease, obesity-related nephropathy, nephrotic syndrome, steroid-resistant nephrotic syndrome, minimal change nephrotic syndrome, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), lupus nephritis, post-infectious glomerulonephritis, thin basement membrane disease, mesangial proliferative glomerulonephritis, amyloidosis (primary), c1q nephropathy, anti-GBM disease, C3 glomerulonephritis, hypertensive nephrosclerosis, IgA nephropathy, IgG4 nephropathy, dyslipidemia-associated nephropathy, nodular glomerulonephritis, NASR disease (proliferative glomerulonephritis with monoclonal IgG deposits), polycystic kidney disease, or Fabry disease.

70. 70. The method of claim 69, wherein the renal disease is hypertensive nephropathy, metabolic syndrome-associated nephropathy, obesity-associated nephropathy, dyslipidemia-associated nephropathy, diabetic nephropathy, nephrotic syndrome, FSGS, or minimal change nephrotic syndrome.

71. 71. The method of claim 70, wherein the renal disease is diabetic nephropathy, FSGS, or minimal change nephrotic syndrome.

72. 62. A method of treating pain, anxiety, or depression, the method comprising administering to a subject in need thereof a solid dosage form according to any one of claims 28 to 61.

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