Spray-dried formulations of pyridazinone TRPC5 inhibitors

Abstract

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 compositions for preparing the formulations, as well as solid dosage forms containing the formulations. The dosage forms described herein are useful in methods for treating renal disease or neurological disorders associated with a disease or condition, and in methods for treating pain, anxiety, or depression.

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 excessive amounts of blood protein leak into the urine. Proteinuria can progress from a loss of 30 mg of protein in the urine per 24 hours (called microalbuminuria) to a loss of more than 300 mg / day (called macroalbuminuria), and then reach levels of more than 3.5 grams per 24 hours, or 25 times the normal amount. Proteinuria occurs when the kidney's glomeruli malfunction, causing fluid accumulation (edema) in the body. Long-term protein leakage has been shown to lead to kidney failure. Nephrotic syndrome (NS) accounts for approximately 12% of end-stage renal disease cases and accounts for an annual cost of more than $3 billion 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. Even in patients who respond positively to treatment, recurrence is extremely common. While 90% of children with NS respond to treatment, an estimated 75% experience recurrence. 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 research on TRP channels has demonstrated that they are involved in many fundamental cellular functions and likely play an important role in the pathophysiology of many diseases. Many TRPs are expressed along different parts of the nephron in the kidney, 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+ 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 component of spatiotemporally regulated Ca ions. 2+These changes depend on the influx of ATP (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, while 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 transduce Ca 2+ TRPC5-mediated Ca influx, actin remodeling, and acts to regulate cell motility in kidney podocytes and fibroblasts. 2+ TRPC6-mediated Ca influx increases Rac1 activity, whereas TRPC6-mediated Ca 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, gene 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] Actin cytoskeleton Ca 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 reorganization in migrating cells (Etienne-Manneville and Hall, Nature 420, 629-635, 2002; Raftopoulou and Hall, Dev Biol 265, 23-32, 2004). Rac1 activation mediates a motile cell phenotype, while 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 are key events at the leading edge, triggering local bursts of Rac1 activity (Gardiner et al., Curr Biol 12, 2029-2034, 2002; Machacek et al., Nature 461, 99-103, 2009). So far, no Ca2+ receptors have been identified that are involved in GTPase regulation. 2+ The source of the influx is largely unknown. Transient receptor potential (TRP) channels are a temporally and spatially restricted Ca influx pathway linked to cell migration in fibroblast and neuronal growth cones. 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 kidney 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 urinary albumin 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). Angiotensin II, a vasoactive hormone, increases podocyte Ca levels. 2+ Ca influx is induced, and long-term treatment leads to the 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 regulating this process remain largely unknown. Furthermore, 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 including 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, wherein the polymer is dissolved in the solvent.

[0011] In one aspect, the invention features a solid dosage form including 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 present 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 present 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 any one of the following: obesity, insulin resistance, type 2 diabetes, 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 present invention relates to a method of treating pain, anxiety, or depression, the method comprising administering to a subject in need thereof a solid dosage form of the present 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 prophylactic 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 have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in practicing 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, will control. Furthermore, 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 claims. [Brief explanation 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. [Figure 2] 1 shows an XRPD diffractogram of crystalline Compound 1 free base form H. [Figure 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 working 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 dissolution test under non-sink conditions 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 practical re-spray dried product of Compound 1. [Figure 9] XRPD diffractograms of SDI after a two-week stability test 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 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 the XRPD diffractogram of aged SDI after a 4-week stability test (closed conditions). [Figure 12] 1 shows the XRPD diffractograms of aged SDI after a 4-week stability study (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 holding a nebulized solution of Compound 1 at 40° C. for various times. [Figure 14B] 1 shows the retention times and relative peak heights of impurities after holding a nebulized solution of Compound 1 at 40° C. for various times. [Figure 14C] 1 shows the retention times and relative peak heights of impurities after holding a nebulized solution of Compound 1 at 40° C. for various times. [Figure 14D-1] 1 shows the retention times and relative peak heights of impurities after holding a nebulized solution of Compound 1 at 40° C. for various times. [Figure 14D-2] 1 shows the retention times and relative peak heights of impurities after holding a nebulized solution of Compound 1 at 40° C. for various times. [Figure 14E] 1 shows the retention times and relative peak heights of impurities after holding a nebulized solution of Compound 1 at 40° C. for various times. [Figure 14F] 1 shows the retention times and relative peak heights of impurities after holding a nebulized solution of Compound 1 at 40° C. for various times. [Figure 14G] 1 shows the retention times and relative peak heights of impurities after holding a nebulized solution of Compound 1 at 40° C. for various times. [Figure 15A]1 shows test and related articles in wet SDIs 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] 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 the dissolution under non-sink conditions of a 50 mg prototype tablet of Compound 1 containing lactose and Ac-Di-Sol that underwent a 4-week accelerated stability study. [Figure 20-2] 1 shows the dissolution under non-sink conditions of a 50 mg prototype tablet of Compound 1 containing lactose and Ac-Di-Sol that underwent a 4-week accelerated stability study. [Figure 21-1] 1 shows the dissolution under non-sink conditions of a 50 mg prototype tablet of Compound 1 containing mannitol and Ac-Di-Sol after a 4-week accelerated stability study. [Figure 21-2] 1 shows the dissolution under non-sink conditions of a 50 mg prototype tablet of Compound 1 containing mannitol and Ac-Di-Sol after 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. [Figure 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. [Figure 25] Figure 1 shows the dissolution of 100 mg tablets of Compound 1. Results for all tablet compression force conditions are shown together to assess the robustness of the formulation. [Figure 26] 1 shows the friability profiles 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 20 mg and 100 mg demonstration batch tablets of Compound 1, in which spots can be seen on the tablet surface. [Figure 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. [Figure 31] 1 illustrates a drawing of a 0.3125" SRC tablet tooling according to some embodiments of the present invention. [Figure 32] 1 shows a drawing of a 0.3543" x 0.6890" modified oval tablet tooling according to some embodiments of the present invention. [Figure 33-1] 1 shows the Certificate of Analysis for a batch of 20 mg tablets of Compound 1. [Figure 33-2] 1 shows the Certificate of Analysis for a batch of 20 mg tablets of Compound 1. [Figure 33-3] 1 shows the Certificate of Analysis for a batch of 20 mg tablets of Compound 1. [Figure 34-1] 1 shows the Certificate of Analysis for a batch of 100 mg tablets of Compound 1. [Figure 34-2] 1 shows the Certificate of Analysis for a batch of 100 mg tablets of Compound 1. [Figure 34-3] 1 shows the Certificate of Analysis for a batch of 100 mg tablets of Compound 1. DETAILED DESCRIPTION OF THE INVENTION

[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 undesired condition (e.g., a disease or other undesired condition in a host animal), the treatment is prophylactic (i.e., protects the host from the occurrence of the undesired condition). On the other hand, if administered after the appearance of an undesired condition, the treatment is therapeutic (i.e., is intended to reduce, ameliorate, or stabilize an existing undesired 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 simultaneously, which may involve 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 effects of the different therapeutic compounds.

[0024] The term "prodrug" is intended to encompass compounds that are converted to the therapeutically active agents of the present invention under physiological conditions. One common method for producing prodrugs is to include one or more selected moieties that are hydrolyzed under physiological conditions to yield the desired molecule. In other embodiments, the prodrug is converted by the enzymatic 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 appropriate prodrug (e.g., providing a hydroxyl in the parent compound as an ester or carboxylate, or providing a carboxylic acid present in the parent compound as an ester).

[0025] An "effective amount" is an amount sufficient to produce a beneficial or desired result. For example, a therapeutic amount is an amount that achieves a desired therapeutic effect. This amount may be the same as or different from a prophylactically effective amount, which is the amount needed 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. The therapeutically effective amount of a composition depends on the composition selected. The composition can be administered once or more times daily to once or more times weekly (including once every other day). One of skill in the art will recognize that certain factors (including, but not limited to, the severity of the disease or disorder, previous treatments, the subject's overall health and / or age, 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 pharmaceutically 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 pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0029] Pharmaceutical Composition The compositions and methods of the present invention can be used to treat a subject in need of treatment. In certain embodiments, the subject is a mammal (e.g., a human or non-human mammal). When administered to a subject (e.g., a human), the composition or compound is preferably administered as a pharmaceutical composition (e.g., comprising a compound of the present invention and a pharmaceutically acceptable carrier). Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions (e.g., water or physiologically buffered saline) or other solvents or vehicles (e.g., glycols, glycerol, oils (e.g., olive oil), or injectable organic esters). In preferred embodiments, when such pharmaceutical compositions are intended for administration to humans, particularly those intended 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 can be selected, for example, to provide delayed release of the drug or to selectively target one or more cells, tissues, or organs. The pharmaceutical compositions can be included in unit dosage forms, such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilized products for reconstitution, powders, solutions, syrups, suppositories, injections, or the like. The compositions can also be present in transdermal delivery systems (e.g., skin patches). The compositions can also be present in solutions suitable for topical administration (e.g., eye drops).

[0030] Pharmaceutically acceptable carriers can include physiologically acceptable agents, such as those that stabilize, improve the solubility, or promote the absorption of a compound (such as a compound of the present invention). Examples of such physiologically acceptable agents include 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 pharmaceutically acceptable carrier, including the physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying or self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) can also be a liposome or other polymer matrix, within which, for example, a compound of the present invention can be contained. 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 "pharmaceutically acceptable" is used herein to mean that a compound, material, composition, and / or dosage form is suitable, under sound medical judgment, for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic response, or other problem or complication, 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] As used herein, the term "pharmaceutically acceptable acid addition salt" refers to any non-toxic organic or inorganic salt of a compound of the present disclosure. 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 monocarboxylic, dicarboxylic, 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), and 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 salts of the compounds disclosed herein are highly soluble in water and various hydrophilic organic solvents, and generally exhibit higher melting points than their free base forms. Those skilled in the art will be able to select appropriate salts. Other non-pharmaceutically acceptable salts (e.g., oxalates) may be used, for example, when isolating the compounds disclosed herein for experimental purposes or when subsequently converting them into pharmaceutically acceptable acid addition salts.

[0034] As used herein, the term "pharmaceutically 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 organic amines, alicyclic organic amines, or aromatic organic amines (such as methylamine, trimethylamine, and picoline) or ammonia. Those skilled in the art will be able to select an appropriate salt.

[0035] As used herein, the phrase "pharmaceutically acceptable carrier" refers to a pharmaceutically 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 serve as pharmaceutically 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, etc.), and (10) cellulose derivatives (such as cellulose acetate, cellulose acetate, etc.). , 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 buffer, (21) surfactants and co-surfactants (such as vitamin E TPGS, Solutol® HS15, and various polyethylene glycols), and (22) other non-toxic compatible substances used in pharmaceutical formulations.

[0036] Pharmaceutical compositions (preparations) can be administered to a subject by any of a number of routes of administration. These routes 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, and pastes for application to the tongue), absorption through the 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)), nasal, 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 compounds can also be formulated for inhalation. In certain embodiments, the compounds 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 the patents cited therein.

[0037] The formulations may conveniently be 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 invention) with the carrier and, optionally, one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately bringing into association a compound of the 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 capsules (including sprinkle capsules, gelatin capsules, and HPMC capsules), cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), lyophilisates, powders, granules, or as a solution or suspension in an aqueous liquid or a 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 containing 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 pharmaceutically 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 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) disintegrants (such as sorbitol, ... (4) surfactants, such as cellulose acetate, cellulose acetate copolymer ... 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., hydroxypropyl cellulose, povidone, or hydroxypropyl methylcellulose), 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 optionally be scored or prepared with coatings and shells, such as taste-masking coatings, enteric coatings, and other coatings well known in the pharmaceutical formulating art. They can also be formulated to delay or control the release of the active ingredient contained therein. This is achieved, for example, by using hydroxypropylmethylcellulose (used in various proportions to achieve 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 incorporating a sterilizing agent immediately before use in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium. These compositions, which may optionally also contain opacifying agents, 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 pharmaceutically acceptable emulsions, lyophilisates for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may contain an inert diluent commonly used in the art (e.g., water or other solvents), cyclodextrin and its derivatives, solubilizers and emulsifiers (e.g., 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 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 preservatives.

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

[0046] Pharmaceutical compositions for rectal, vaginal, or urethral administration may be prepared as suppositories. These suppositories can be prepared by mixing one or more active compounds with one or more suitable non-irritating pharmaceutical additives or carriers (e.g., cocoa butter, polyethylene glycol, suppository wax, or salicylic acid). These suppositories are solid at room temperature but liquid at body temperature, and therefore melt in the rectal or vaginal cavity to 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 to be appropriate.

[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 pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0051] 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, 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 absorption patch has the additional advantage that the compound of the present invention is delivered to the body in a controlled manner.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, the liquid ophthalmic preparation has properties similar to those of tears, aqueous humor, or vitreous humor, or is compatible with such body fluids. A preferred route of administration is topical administration (e.g., external administration (such as eye drops) or administration via an implant).

[0055] As used herein, the phrases "parenteral administration" and "administered parenterally" refer to 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 pharmaceutically 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 osmolality 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). The 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 can be ensured by the inclusion of various antibacterial and antifungal agents (e.g., 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. Furthermore, prolonged absorption of the injectable pharmaceutical form can 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 a crystalline or amorphous substance that is poorly water-soluble.In this case, the absorption rate of the drug depends on its dissolution rate, which in turn depends 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 employed. 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 present invention, the active compound may be provided alone or as a pharmaceutical composition (e.g., comprising 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 pharmaceutically acceptable carrier).

[0062] Rechargeable or biodegradable devices may also provide a method of delivery. A variety of slow-release polymeric devices have been developed and recently tested in vivo for the 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 ingredient 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 a compound will vary depending on 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, other types of therapeutic agents 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] Generally, 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 lowest 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 compounds of the present invention can be used alone or co-administered with another type of therapeutic agent. As used herein, the phrase "co-administration" refers to the administration of two or more different therapeutic compounds in any form, such that the first administered therapeutic compound is still effective in the body while the second compound is administered (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, different therapeutic compounds can be administered simultaneously or sequentially in the same formulation or separate formulations. In certain embodiments, 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. Therefore, subjects receiving such treatment can benefit from the combined effect of 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, the co-administration results in an additive effect, where additive effect refers to the sum of the respective effects achieved by administering the compound of the invention and the one or more additional therapeutic agent(s) individually.

[0070] Wetting agents, emulsifying agents, and lubricating agents (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 pharmaceutically 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 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 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 Eudragit polymers include those for enhancing solubility and bioavailability (e.g., Eudragit 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), and release profiles can be customized by combining Eudragit polymers in different ratios, as would be known to one of ordinary 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 and is 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 an atomization pressure of about 1.0 to about 10.0 bar. In some embodiments, the spray drying step is carried out at an atomization 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 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 present invention relates to a solid dosage form comprising the spray-dried dispersion of the present 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 microcrystalline cellulose. In some embodiments, the excipient comprises mannitol and microcrystalline cellulose. In some embodiments, the ratio of mannitol to microcrystalline cellulose is about 1:3 to about 3:1. In some embodiments, the ratio of mannitol to microcrystalline cellulose is about 1:1.3, about 1:1.25, or about 1:1. In some embodiments, the ratio of mannitol to microcrystalline cellulose is about 1:1.3 to about 1:1. In some embodiments, the ratio of mannitol to microcrystalline cellulose is about 1:1 to about 1:3. In some embodiments, the ratio of mannitol to microcrystalline cellulose is about 1:1 to about 1:1.3. In some embodiments, the ratio of mannitol to microcrystalline cellulose is about 1:1 or about 1:1.3. In some embodiments, the ratio of mannitol to microcrystalline cellulose is about 1:1, about 1:1.3, or about 1:3.

[0092] In some embodiments, the average particle size of the microcrystalline cellulose is about 5 μm to about 80 μm, In some embodiments, the average particle size of the microcrystalline 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 in an amount of about 0.1 to about 5% w / w. In some embodiments, the silicon dioxide is present in an amount of about 1% w / w.

[0096] In some embodiments, the spray-dried dispersion has a prevalence of about 3% to about 60% w / w. In some embodiments, the spray-dried dispersion has a prevalence of about 50% w / w. In some embodiments, the spray-dried dispersion has a prevalence of about 16.7% w / w. In some embodiments, the spray-dried dispersion has a prevalence of about 3.33% w / w.

[0097] In some embodiments, the presence 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 presence 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% w / w, or about 8% w / w. 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) 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 consists essentially 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 mannitol, d. 33.6 mg of crystalline cellulose, e. 9.6 mg of croscarmellose sodium, f. 1.6 mg sodium stearyl fumarate, and 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 mannitol, d. 168 mg of crystalline cellulose, e. 48 mg of croscarmellose sodium, f.8 mg 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 mannitol, d. 51.2 mg of crystalline cellulose, e. 7.2 mg of croscarmellose sodium, f. 1.1 mg sodium stearyl fumarate, and 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 mannitol, d. 59.2 mg of crystalline cellulose, e. 7.2 mg of croscarmellose sodium, f. 1.1 mg sodium stearyl fumarate, and 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 characterized by the presence of protein 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 normally absent from the urine because it is retained in the bloodstream by the kidneys. Microalbuminuria is diagnosed based on a 24-hour urine collection (20-200 μg / min) or, more commonly, 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, reaching the nephropathic range (>3.5 g / 24 hours) as kidney disease progresses.

[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 filtration system (glomeruli), causing severe scarring. FSGS is one of many causes of a condition known as nephrotic syndrome, which occurs when blood proteins leak into the urine (proteinuria). Primary FSGS usually presents as nephrotic syndrome when no underlying disease cause is identified. Secondary FSGS usually presents as kidney failure and proteinuria when an underlying disease cause is identified. FSGS can be hereditary, and several known genetic causes of hereditary forms of FSGS are currently recognized.

[0116] There are very few treatments available for patients with FSGS. Many patients are treated with steroid regimens, many of which are associated with severe side effects. Some patients have been shown to respond positively to immunosuppressants as well as blood pressure medications, and these medications have been shown to reduce urinary protein levels. To date, there is no universally accepted, effective treatment or therapy, and no FDA-approved medications exist to treat FSGS. Therefore, more effective methods for reducing or inhibiting proteinuria are desirable.

[0117] B. IgA nephropathy IgA nephropathy (also known as IgA nephritis, IgAN, Berger's disease, or glomerulonephritis with pharyngitis) is a form of glomerulonephritis (inflammation of the kidney's glomeruli). IgA nephropathy is the most common form of glomerulonephritis worldwide. Primary IgA nephropathy is characterized by the deposition of IgA antibodies in the glomeruli. There are other diseases associated with glomerular IgA deposition, the most common of which is 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 (ages 16–35). HSP has a more benign prognosis than IgA nephropathy. IgA nephropathy slowly progresses to chronic renal failure over a 20-year period in 25–30% of cases.

[0118] C. Diabetic nephropathy Diabetic nephropathy, also known as Kimmelstell-Wilson syndrome and intracapillary glomerulonephritis, is a progressive kidney disease caused by angiopathy of the glomerular capillaries. It is characterized by nephrotic syndrome and diffuse glomerular sclerosis. Diabetic nephropathy results from long-standing diabetes and is the primary 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, leading to increased amounts of albumin excreted in the urine.

[0119] D. Lupus nephritis Lupus nephritis is a kidney disorder that is a complication of systemic lupus erythematosus (SLE). 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. SLE causes various damage to the internal structures of the kidneys, including interstitial nephritis. Lupus nephritis affects approximately 3 in 10,000 people.

[0120] E. Membranoproliferative glomerulonephritis I / II / III Membranoproliferative glomerulonephritis (MPN) is a type of glomerulonephritis caused by the deposition of mesangial deposits and thickening of the basement membrane in the renal glomeruli, which activates complement and damages the glomeruli. There are three types of MNPN: Type I, which is caused by immune complex deposition in the kidney and is thought to be related to the classical complement pathway; Type II, which is similar to MNPN but is thought to be related to the alternative complement pathway; and Type III, which is extremely rare and is characterized by a combination of subepithelial deposits and the 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 C4 concentrations. Complement-mediated MPGN usually has low serum C3 and normal C4 levels due to activation of the alternative pathway. However, a normal serum C3 concentration does not exclude complement-mediated MPGN; therefore, normal C3 concentrations are not uncommon 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 immunoglobulin (Ig) staining, and mesangial and / or subendothelial electron-dense deposits by electron microscopy (EM). Scattered intramembranous and subepithelial deposits are also common. The term "C3 glomerulonephropathy" is often used to encompass 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 reveals mesangial and / or subendothelial, intramembranous, and subepithelial deposits in C3GN, while 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 several months. PG is associated with an underlying condition, such as Goodpasture's syndrome, systemic lupus erythematosus, or Wegener's granulomatosis, in 50% of cases; the remaining cases are idiopathic. Regardless of the underlying cause, PG involves significant damage 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 can exceed 3 g / 24 hours, the range associated with nephrotic syndrome. If the disease is untreated, it may progress to decreased urine output (oliguria) as renal function declines.

[0124] G. Membranous glomerulonephritis Membranous glomerulonephritis (MGN) is a slowly progressive kidney disease that primarily affects 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 indicates that the majority of immune complexes are formed by in situ binding of antibodies to antigens on the glomerular basement membrane. These antigens may be endogenous to the basement membrane or deposited from the systemic circulation.

[0125] H. Alport syndrome Alport syndrome is a genetic disorder that affects approximately 1 in 5,000 to 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 usually not affected except in later cases when changes to the lens occur. Hematuria is common. Proteinuria is one of the features that develops 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 hypertension. 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 (including loss of appetite, nausea, vomiting, pruritus, drowsiness or confusion, weight loss, and an unpleasant taste in the mouth) may occur. Chronic hypertension causes damage to kidney tissue, including 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 them, resulting in tissue death (ischemia).

[0127] J. Nephrotic syndrome Nephrotic syndrome is a group of symptoms resulting from kidney damage. Nephrotic syndrome 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 kidney's glomeruli. Diagnosis is typically based on urinalysis and, occasionally, kidney biopsy. Nephrotic syndrome differs from nephritic syndrome in that red blood cells are not present in the urine. Nephrotic syndrome is characterized by massive proteinuria (more than 3.5 g per 1.73 m2 of body surface area per day, or more than 40 mg per square meter of body surface area per hour in children), hypoalbuminemia (less than 2.5 g / dL), hyperlipidemia, and edema, beginning with 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 (MCS), also known as minimal change glomerulopathy (MCG), or Nir disease, is a disease that affects the kidneys and causes nephrotic syndrome. Clinical signs of minimal change nephrotic syndrome include proteinuria (abnormal urinary excretion of protein, primarily 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. While swelling can be mild, patients may also present with lower extremity edema, periorbital edema, and swelling in the scrotal / labial area, and in severe cases, anasarca. 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), accompanied by 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. Treatment for patients at high risk of progression typically involves 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 infections caused by Streptococcus types 12, 4, and 1 (impetigo), but can also occur after streptococcal pharyngitis, also known as postinfectious or poststreptococcal glomerulonephritis. This nephritis can 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 worldwide have decreased from 24,000 in 1990 to 19,000 in 2013. Acute proliferative glomerulonephritis (poststreptococcal glomerulonephritis) occurs when streptococci infect the kidney (usually in the throat or skin), usually three weeks after infection, allowing 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 (TBMN)), along with IgA nephropathy, is the most common cause of asymptomatic hematuria. The only abnormal finding in this disease is thinning of the glomerular basement membrane of the kidney. Its significance lies in the fact that patients maintain normal renal function throughout their lives and have a favorable prognosis. Most patients with thin basement membrane disease have incidental microscopic hematuria detected on urinalysis. Blood pressure, renal function, and urinary protein excretion are usually normal, although a small percentage of patients have mild proteinuria (<1.5 g / day) and elevated blood pressure. The presence of frank hematuria and lumbar pain should prompt investigation for other causes, such as kidney stones or lumbar pain-hematuria syndrome. Furthermore, because there are no systemic symptoms, the presence of hearing or visual impairment should prompt investigation for hereditary nephropathies, such as Alport syndrome. Some 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 primarily involves the mesangium. There is some evidence that interleukin-10 inhibits it in animal models. [2] The World Health Organization (WHO) classifies it as type II lupus nephritis. Mesangial cells in the renal glomerulus use endocytosis to internalize and degrade circulating immunoglobulins. This normal process promotes mesangial cell proliferation and matrix deposition. Therefore, when circulating immunoglobulin concentrations are elevated (i.e., in lupus and IgA nephropathy), the number of mesangial cells and matrix within the glomerulus is expected to increase, which is a hallmark 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 vary depending on the type and often vary.[2] They may include diarrhea, weight loss, fatigue, tongue enlargement, bleeding, numbness, fainting when standing, swelling of the 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 as 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) amyloidosis. Primary amyloidosis refers to amyloidosis without an associated clinical condition.

[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 presentations are 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 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-resistant cases. The presence of nephrotic syndrome and FSGS appears to predict adverse outcomes in contrast to the favorable outcomes 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. Although anti-glomerular basement membrane (GBM) antibodies primarily attack the kidneys and lungs, systemic symptoms such as fatigue, weight loss, tiredness, fever, and chills are also common, as well as joint aches and pains. 60–80% of patients with this condition experience both pulmonary and renal abnormalities, 20–40% have renal abnormalities alone, and less than 10% have pulmonary abnormalities alone. Pulmonary symptoms usually precede renal symptoms and typically include hemoptysis, chest pain (in less than 50% of cases), cough, and shortness of breath. Renal symptoms typically include hematuria, proteinuria, unexplained swelling of the limbs or face, excessive blood urea, and high blood pressure. GPS causes abnormal production of anti-GBM antibodies by blood plasma cells. Anti-GBM antibodies attack the alveoli and glomerular basement membrane. These antibodies bind reactive epitopes to the basement membrane, activating the complement cascade and killing targeted cells. T cells are also involved. The disease is generally considered a type II hypersensitivity reaction.

[0136] Measurement of urine 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, patients urinate into a container and refrigerate it after each toilet visit. Patients are instructed to begin collecting urine after their 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 they urinate upon waking.

[0137] More recently, researchers have found that a single urine sample can provide the necessary information. Newer methods compare the amount of albumin in a urine sample with the amount of creatinine, a waste product formed by the breakdown of normal muscle. This measurement is called the urinary albumin-to-creatinine ratio (UACR). A urine sample containing more than 30 milligrams of albumin per gram of creatinine (30 mg / g) signals a potential problem. If the lab value exceeds 30 mg / g, another UACR test should be performed in 1 to 2 weeks. If the second test also shows high levels of protein, the patient has persistent proteinuria, a sign of declining kidney function, and should undergo additional testing to evaluate kidney function.

[0138] Tests that measure the amount of creatinine in the blood also indicate 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 regulating the podocyte actin cytoskeleton.

[0140] Thus, in certain embodiments, the present invention provides methods for treating or reducing the risk of developing a renal disease or nephropathy associated with a disease or condition, the methods 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 any one of the following: obesity, insulin resistance, type 2 diabetes, 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 present invention relates to a method of treating pain, anxiety, or depression, the method comprising administering to a subject in need thereof a solid dosage form of the present invention.

[0144] Treatment target In one embodiment of the present invention, the subject is selected based on having or being at risk of developing kidney 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 kidney 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 with or at risk of developing proteinuria include those with diabetes, elevated blood pressure, or certain family backgrounds. Diabetes is the leading cause of end-stage renal disease (ESRD) in the United States. In both type 1 and type 2 diabetes, urinary albumin 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. Uncontrolled elevated blood pressure can lead to complete kidney failure. African Americans are more likely than Caucasians to develop high blood pressure and are more likely to experience kidney problems even when blood pressure is only mildly elevated. Other groups at risk for proteinuria include 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 with or 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 the urine. Protein in the urine causes the 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 the progression of kidney disease. Laboratory tests are the only way to determine whether a subject has protein in their urine before extensive kidney damage occurs.

[0147] 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 mammal. In some embodiments, the subject is a human. [Example]

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

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

[0150] Example 1 Pharmaceutical Excipients and Devices Potential excipients for use in the development and manufacture of spray-dried solid dispersions and tablets were of standard or USP grade and were selected based on previous experience at Patheon. A complete list of excipients and equipment utilized in this line of development work can be found in Table 1. Throughout this report, percent compositions of solutions or solid dispersions are listed 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 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 sample was placed in a non-sealed aluminum pan and heated at a constant rate of 2.0 °C / min over the temperature range of 0 to 200 °C. 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 the 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 found in Table 2.

[0153] [Table 3]

[0154] Example 3. X-ray powder diffraction (XRPD) The crystallinity of the spray-dried materials was assessed by 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, lacking 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 analytical parameters can be found in Tables 3 and 4 and varied between instruments 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 powder coated with a thin conductive layer of gold-palladium using a Cressington 108 Auto onto a carbon-taped specimen stage. Sample analysis was performed using an FEI Quanta 200 SEM equipped with an Everhart-Thornley (secondary electron) detector in high-vacuum mode. Micrographs were captured at various magnifications for qualitative particle morphology analysis. Experimental parameters, including spot size, working distance, and accelerating voltage, were varied from sample to sample to obtain optimal imaging conditions. These experimental parameters are indicated in the captions of each SEM micrograph.

[0158] Example 5. Particle Size Distribution (PSD) by Light Diffraction The particle size of 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 1.5 mm hopper gap and then fed into the dispersion system. The sample feed rate was adjusted to 40% to maintain laser attenuation levels 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 powder was characterized using the diameter, e.g., Dv 50 The diameter is the diameter at which 50% of the sample volume is made up of particles of that diameter or less.

[0159] Example 6. Determination of Water Content by Karl Fischer (KF) Coulometric Titration After secondary drying, SDI samples were taken and analyzed for moisture content using a Metrohm 831 Karl Fischer Coulometric Titrator equipped with a Metrohm 874 oven processor. Approximately 100 mg of sample was sealed in a 6 mL crimp vial and the 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 / desorption (DVS) was used to study the water adsorption level of crystalline Compound 1. Samples were exposed to different relative humidity (RH) levels from 10% to 90% RH in 10% increments, followed by 10% RH desorption down to 20% RH. Accurate weight measurements (expressed as % HO 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 article 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 observed impurities.

[0163] Example 9. Residual Solvent After secondary drying, the residual solvent content of the SDI was determined by GC-HS (Headspace Analysis by Gas Chromatography). 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 μm 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). This dissolution test 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 vehicle (e.g., by vortex mixing with 4.0 mL of vehicle for 10 seconds) and transferred with paddle stirring at 100 rpm to a 50 mL volume of preheated (37°C) 0.1 N aqueous HCl solution (simulated gastric fluid, i.e., SGF (pH ∼1.0) without pepsin or bile salts) in a USP Type 2 container (total container volume 100 mL). After 30 minutes of exposure to gastric pH, an equivalent volume of PBS-buffered 2x concentrated fasted small intestinal simulated fluid (FaSSIF) was added to the SGF to achieve a final pH of 6.8 and a total volume of 100 mL in FaSSIF (SIF powder (bulk) (Biorelevant Inc.) at 2.24 mg / mL in 100 mM PBS). Aliquots (1.0 mL) of dissolution medium were removed at selected time points before and after simulated gastric transit and spun down (13,000 rpm) to pellet and remove insoluble solids. 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 using a 10K molecular weight cutoff filter removed 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 200 mMol / L equivalent of NaCl and 200 mMol / L equivalent of 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 using phosphoric acid or 1.0 N NaOH.

[0170] FaSSIF medium (4.48 mg / mL): To the PBS medium described 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 the solution. Allow to stand at room temperature for 2 hours before use, then preheat 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 solution reaches a temperature of 37°C before use.

[0171] 50 mM phosphate buffer (pH = 6.8) containing 2% (w / v) SLS: Mix 6 L of water with 41.4 g of sodium dihydrogen phosphate monohydrate and adjust the pH to 6.8. Add 120 g of 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 completely submerged at a frequency of 29 to 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> The friability was determined by the following formula: The drum rotation speed was 25 rpm, with a total rotation time of 4 minutes. The acceptable loss in friability according to 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 Example 1. 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 The liquid quenching method was used to measure T. Compound 1 was heated above its melting temperature and 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 (Figures 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. m / T gThe ratio was 1.32, indicating adequate 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 the Compound 1 crystalline form was obtained using XRPD (Figure 2). The diffraction pattern of this API drug shows 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 crystalline 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, the API precipitated 5 minutes later. Next, a 2.0% solution (% w / w) of compound 1 was prepared and heated to 40°C, where the solid dissolved immediately. This 2.0% solution was then removed from the heat, and precipitation of the API was observed approximately 2 hours later. The heated (40°C) solution of 60:40 DCM:methanol was selected as the lead solvent system, providing a maximum active loading of compound 1 in 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 a utility dispersion. Five Compound 1 SDI formulations were selected for utility screening. These formulations were selected based on data previously obtained by Goldfinch Bio demonstrating acceptable PK results using a 25:75 Compound 1:HPMCAS-L SDI. Selected utility dispersions were designed to determine the maximum Compound 1 loading and evaluate the performance of HPMCAS-M-based dispersions. A summary of the spray drying parameters (Table 11) and recovered SDI dry yields (Table 12) can be seen below. 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 non-sink dissolution testing.

[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 chromatographic (GC) headspace analysis was performed to measure the 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 Harmonisation (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 exhibited 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 was determined under given storage conditions to reduce the drug's mobility in glass dispersions. g SDI should be stored at temperatures well below 100°C.

[0194] [Table 15]

[0195] The dissolution performance of SDI material 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 30 minutes of exposure to a low pH environment. During the test, samples were dissolved in 0.1 N HCl [theoretical C max = 1000 μA / 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, 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 percentage of total drug. HPMCAS-M loadings of 25% and 50% and HPMCAS-L loadings of 25% were selected as lead formulations.

[0197] [Table 16]

[0198] When the lead SDI formulations were tested by dynamic vapor sorption / desorption measurements, the 50:50 Compound 1:HPMCAS-M dispersion exhibited the lowest water sorption, which was attributed to the low polymer concentration. All samples exhibited minor hysteresis for 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. Because slight crystallinity was observed by XRPD at 50% and 66% Compound 1 loadings in the dispersion, 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 appeared opaque brown, indicating a different solubility than the API lot in the initial practical spray-dried product. Lots G8-854-13 and G8-854-14 were sprayed at an elevated outlet temperature (60°C) to reduce the API-rich region in the SDI particles. Vitamin E TPGS was included in lot G8-854-10 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). Figure 8 shows the XPRD traces of the re-spray dried product and the original 25:75 Compound 1:HPMCAS-M dispersion. Both the 50% re-spray dried product appeared to have crystalline peaks, similar to the original SDI, while the re-spray dried 25% dispersion appeared to have a very slight crystalline peak near 2θ = 26°. This data supports the finding 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 desiccant-containing packages 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 kept 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-condition 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 may 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 the samples under closed conditions, but all of the samples under open conditions showed 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 indicate that the increase in impurities in Compound 1 is induced, at least in part, by exposure to moisture. Due to the lack of significant differences in impurity profiles, the 25:75 Compound 1:HPMCAS-M SDI was selected as the lead for tablet development. This selection was based on 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 (crystalline 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 formula 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 recommended process conditions 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, potency / 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 Figure 13.

[0220] Example 24. Stability of Demonstration Batch Solution and Wet SDI Spray solution samples from lot D-18-078 were collected prior to spray drying to determine the maximum solution hold time. Solution samples were held at 40°C and tested for test / related substance 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 RRTs of 0.85, 0.86, 0.92, 0.94, 0.96, 1.47, 1.52, and 1.56. The solution color remained a consistent "clear orange" through 15 days. Spray solution stability was confirmed by repeating replicate measurements (Figure 14).

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

[0222] The wet SDI was tested at room temperature at t = 0, 1, 5, 9, and 15 days for appearance, test article / related substance, particle morphology, and amorphous characteristics. The testing requirement was to determine the maximum holding time of the wet SDI before secondary drying in an Ekato vacuum dryer. The appearance remained constant throughout the test as a "tan-off-white powder." 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 remained unchanged over the 15-day period (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 spherical 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 a Prototype Compound 1 Tablet Four tablet formulations were selected to evaluate excipient compatibility and tablet physical properties. The 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 contain 50 mg of Compound 1 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 blend was slug compressed using 0.875" flat tooling to a solids fraction of approximately 0.70 (the true density of the prototype blend was assumed to be 1.35 g / cc). The compaction was then milled using a Vector TFC-Micro mill 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 to 300 MPa (Figure 19). (See Figures 31-32 for drawings of the applicable tooling.)

[0230] All formulations had similar compression profiles, which may be dictated by the high level of SDI. The tablet formulations achieved high tensile strength at relatively low compression pressures. Ac-Di-Sol was a much more effective disintegrant than Kollidon CL. Formulations containing Kollidon CL had a much steeper slope in the disintegration profile. Variation in compression pressure could result in significant differences in disintegration time and potentially affect dissolution. Based on 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. The decreased dissolution rate of tablets containing crospovidone was also seen as a decrease in AUC of approximately 50% 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) underwent accelerated stability testing and were stored under open and closed conditions at 40°C / 75% RH and 25°C / 60% RH. After 4 weeks, the tablets were tested for test article / related substance, non-sink dissolution, 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 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 drug substance. Under other conditions, a similar impurity profile was obtained compared to API.

[0235] [Table 27]

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

[0237] Both tablet formulations under all conditions were tested for dissolution under non-sink conditions and were found to perform similarly for total and free drug (Figures 20 and 21).

[0238] The disintegration times of the tablets were similar, with the exception of the 40°C / 75%RH open condition, where the disintegration time of the tablets was significantly longer. This prolongation may be due to the Ac-Di-Sol and Avicel in the formulation absorbing moisture and swelling during the stability test, indicating that all of the disintegrants had already been activated. Placing these tablets in the disintegration tank would not generate enough 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 because 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 indicated that the inclusion of a desiccant in the packaging was necessary to protect the tablets from moisture, as demonstrated by the difference in chemical stability at 40°C / 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 the strength of the prototype tablets compared to the demonstration batch tablets. This difference in strength is due to the difference in compression dwell time between the two processes (the rotary tablet 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 sharp increase in disintegration time observed at compression pressures of 150 to 200 MPa. The 20 mg Compound 1 tablets did not exhibit a sharp increase in disintegration time across the compression range tested, demonstrating a more robust operating range. Additional dissolution tests (Figures 23-25) were performed on 100 mg Compound 1 tablets obtained at 200 MPa and 250 MPa to determine whether the sharp increase in disintegration time affected 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 resulted 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 test speeds. The formulation does not appear to be strain rate sensitive at speeds of 20-40 rpm on a 10-station Piccola rotary tablet press (Figures 27-28).

[0245] The target compression force was 225±25 MPa for the 20 mg Compound 1 tablets and 175±25 MPa for the 100 mg tablets. Pre-, mid-, and post-compression samples were collected 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 gray-white color of the SDI (Figure 29). The speckled surface of the tablets can also be reduced by lowering the solids content 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. Average tablet weights were on target, with only two tablets (both 20 mg Compound 1) outside the 5% weight variation range (Figure 30).

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

[0251] [Table 31]

[0252] Example 28. Compound 1 Tablet Demonstration Batch: Analytical Testing of Compound 1 Tablet Demonstration 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 provided in the Certificate of Analysis, which can be seen in Figures 33-34.

[0253] [Table 32]

[0254] Example 29. Conclusion The feasibility of SDIs revealed that a 25% Compound 1 content allowed for the production of amorphous dispersions, while 50% and 66% Compound 1 contents resulted in partial residual 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 crystal growth occurred under open conditions at 40°C / 75% RH and 50°C / 75% RH, whereas complete amorphousness was maintained under closed conditions with a desiccant, indicating that exposure to moisture significantly affected the physical stability of the dispersions. Based on PK studies conducted by Goldfinch, a 25:75 Compound 1:HPMCAS-M SDI was selected, and its pilot-scale production was successfully carried out in an MS-150, with residual solvent 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 upon discharge of the final blend, so further development of the granulation process is recommended. Improving flowability will be crucial for increasing manufacturing throughput. Ribbon milling with a lower energy mill could potentially correct this issue. GMP manufacturing, which will use the same equipment for spray drying and tableting, is expected to be highly 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 foregoing specification is sufficient to enable one skilled in the art to practice the present invention. The scope of the present invention should not be limited by the described examples, as each example is intended as a single illustration of one aspect of the invention, and other functionally equivalent embodiments are also within the scope of the present invention. Various modifications of the present 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 fall within the scope of the appended claims. The advantages and objectives of the present invention are not necessarily encompassed in each and every embodiment of the present 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. The composition described in claim 1, wherein the polymer is hypromellose acetate succinate.

3. The composition described in claim 1, wherein the polymer is Eudragit (registered trademark of EVONIK).

4. The composition of claim 1, wherein the polymer is Eudragit L 100 (registered trademark of EVONIK).

5. 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 4.

6. 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, and a polymer.

7. 7. The spray dried dispersion of claim 6, 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.

8. 8. The spray dried dispersion of claim 6 or 7, wherein the polymer is hypromellose acetate succinate.

9. The spray dried dispersion of claim 6 or 7, wherein the polymer is Eudragit.

10. The spray dried dispersion of claim 6 or 7, wherein the polymer is Eudragit L 100.

11. 11. The spray dried dispersion of any one of claims 6 to 10, 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 polymer is from about 1:9 to about 2:

1.

12. 11. The spray dried dispersion of any one of claims 6 to 10, 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 polymer is about 1:

3.

13. 9. The spray dried dispersion of claim 8, 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%.

14. A solid dosage form comprising the spray dried dispersion of any one of claims 6 to 13 and one or more of an excipient, a disintegrant, a lubricant, a glidant, and a stabilizer.

15. 15. The solid dosage form of claim 14, wherein the excipient comprises one or more of mannitol, lactose, or microcrystalline cellulose.

16. 16. The solid dosage form of claim 15, wherein the excipients include mannitol and microcrystalline cellulose.

17. 17. The solid dosage form of claim 16, wherein the ratio of mannitol to microcrystalline cellulose is from about 1:3 to about 3:

1.

18. The solid dosage form of claim 14, wherein the excipients include lactose and microcrystalline cellulose.

19. The solid dosage form of claim 18, wherein the ratio of lactose to microcrystalline cellulose is from about 1:3 to about 3:

1.

20. 20. The solid dosage form of any one of claims 14 to 19, wherein the disintegrant is croscarmellose sodium.

21. 21. The solid dosage form of claim 20, wherein the croscarmellose sodium is present in an amount of from about 3% to about 15% w / w.

22. 22. The solid dosage form of any one of claims 14 to 21, wherein the lubricant is sodium stearyl fumarate or magnesium stearate.

23. 23. The solid dosage form of claim 22, wherein said lubricant is magnesium stearate and said magnesium stearate is present in an amount of from about 0.5 to about 5% w / w.

24. 24. The solid dosage form of any one of claims 14 to 23, wherein the glidant is colloidal silicon dioxide.

25. 25. The solid dosage form of any one of claims 14 to 24, wherein the spray dried dispersion is present in an amount of from about 3% to about 60% w / w.

26. 26. The solid dosage form of any one of claims 14 to 25, 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.

27. 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 15. The solid dosage form of claim 14 consisting essentially of:

28. 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; 28. The solid dosage form according to claim 27, wherein the total amount of the mannitol and the microcrystalline cellulose in the solid dosage form is 15.0 to 90% w / w.

29. The solid dosage form comprises: (A) 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 a solid dosage form consisting essentially of (B) 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 a solid dosage form consisting essentially of (C) 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 A solid dosage form consisting essentially of: (D) 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 15. The solid dosage form of claim 14, wherein the solid dosage form is one of the solid dosage forms consisting of:

30. 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. Eudragit L 100, d. lactose, e. Microcrystalline cellulose, f. Croscarmellose sodium, g. magnesium stearate, and h. Colloidal silicon dioxide 15. The solid dosage form of claim 14, comprising: 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) lactose; 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) magnesium stearate; g. 0.1% to 5.0% (w / w) colloidal silicon dioxide, and h. Eudragit L 100, Including, 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 lactose to the microcrystalline cellulose is 1:3 to 3:1; 15. The solid dosage form of claim 14, wherein the total amount of said lactose and said microcrystalline cellulose in said solid dosage form is 15.0 to 90% w / w.

32. 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 6 to 13 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:

33. 32. A composition for treating pain, anxiety, or depression, said composition comprising a solid dosage form according to any one of claims 14 to 31.

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