Spray-dried formulations of pyridazinone TRPC5 inhibitors

Abstract

The present invention relates to a spray-dried formulation of a pyridazinone TRPC5 inhibitor. 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) pyridazine-3 (2H)-one, methods and compositions for preparing the same, and solid dosage forms comprising the same. The dosage forms described herein are useful in methods of treating renal diseases or nephropathy associated with a disease or condition as well as methods of treating pain, anxiety, or depression.

Description

[0001] This application is a divisional application of an invention patent with an application date of April 10, 2020, application number 202080042992.8, and invention name “Spray-dried preparation of pyridazinone TRPC5 inhibitor”.

[0002] Related Applications

[0003] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 832,632 filed on April 11, 2019 and U.S. Provisional Application No. 62 / 991,315 filed on March 18, 2020. Background Art

[0004] Proteinuria is a condition in which excess protein in the blood leaks into the urine. Proteinuria can develop from 30 mg of protein loss in the urine in a 24-hour period (called microalbuminuria) to >300 mg / day (called macroalbuminuria), and then reach a level of 3.5 grams of protein or more in a 24-hour period, or 25 times the normal amount. Proteinuria occurs when the glomeruli of the kidney malfunction, causing fluid to accumulate in the body (edema). Long-term protein leakage has been shown to lead to kidney failure. Nephrotic syndrome (NS) disease accounts for about 12% of common end-stage renal disease cases and costs more than $3 billion per year in the United States. About 5 in every 100,000 children are diagnosed with NS each year, and now 15 in every 100,000 children suffer from this disease. For patients who respond positively to treatment, the recurrence frequency is also extremely high. 90% of children with nephrotic syndrome will respond to treatment, however, it is estimated that 75% will relapse. There is a need for more effective methods of treating kidney diseases such as proteinuria or reducing the risk of their development.

[0005] Mammalian TRP channel proteins form six transmembrane cation-permeable channels that can be divided into six subfamilies (TRPC, TRPV, TRPM, TRPA, TRPP, and TRPML) based on amino acid sequence homology. Recent studies of TRP channels have shown that they are involved in many basic cellular functions and are thought to play an important role in the pathophysiology of many diseases. Many TRPs are expressed in the kidney along different parts of the nephron, and increasing evidence indicates that these channels are involved in inherited as well as acquired renal disorders. TRPC6, TRPM6, and TRPP2 are associated with hereditary focal segmental glomerulosclerosis (FSGS), hypomagnesemia with secondary hypocalcemia (HSH), and polycystic kidney disease (PKD), respectively.

[0006] Non-selective Ca 2+-Permeable transient receptor potential (TRP) channels act as sensors to transduce extracellular cues to the intracellular environment in different 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). The dynamic rearrangement of the actin cytoskeleton depends on the spatiotemporally regulated Ca 2+ Influx (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 serve as key regulators of these changes (Etienne-Manneville and Hall, Nature 420, 629-635, 2002); Raftopoulou and Hall, Dev Biol 265, 23-32, 2004). RhoA induces the formation of stress fibers and adhesion plaques, while Rac1 mediates the formation of lamellipodia (Etienne-Manneville and Hall, Nature 420, 629-635, 2002). Transient receptor potential cation channel subfamily C member 5 (TRPC5) works synergistically with TRPC6 to regulate Ca 2+ TRPC5-mediated Ca influx, actin remodeling, and cell motility in renal podocytes and fibroblasts. 2+ Influx increases Rac1 activity, while TRPC6-mediated Ca 2+ Influx promotes RhoA activity. Genetic silencing of TRPC6 channels abolishes stress fibers and reduces focal contacts, presenting a motile, migratory cell phenotype. In contrast, genetic silencing of TRPC5 channels rescues stress fiber formation, presenting a contractile cell phenotype. The results described here reveal a conserved signaling mechanism whereby TRPC5 and TRPC6 channels control the balance of tightly regulated cytoskeletal dynamics through differential coupling with Rac1 and RhoA.

[0007] Ca 2+-dependent remodeling of the actin cytoskeleton is a dynamic process that drives cell migration (Wei et al., Nature 457, 901-905, 2009). RhoA and Racl act as switches responsible for cytoskeletal rearrangement in migrating cells (Etienne-Manneville and Hall, Nature 420, 629-635, 2002); Raftopoulou and Hall, Dev Biol 265, 23-32, 2004). Activation of Rac1 mediates a motile cell phenotype, while RhoA activity promotes a contractile phenotype (Etienne-Manneville and Hall, Nature 420, 629-635, 2002). 2+ It plays an important role in the regulation of small GTPases (Aspenstrom et al., Biochem J 377, 327-337, 2004). 2+ The spatially and temporally restricted flashes of Ca are enriched near the leading edge of migrating cells (Wei et al., Nature 457, 901-905, 2009). 2+ Microdomains engage localized bursts of Rac1 activity (Gardiner et al., Curr Biol 12, 2029-2034, 2002; Machacek et al., Nature 461, 99-103, 2009) as key events at the leading edge. 2+ The source of the influx remains largely elusive. TRP (transient receptor potential) channels generate temporally and spatially restricted Ca2+ influx that is associated with cell migration in fibroblasts and neuronal growth cones. 2+ Signal 0. Specifically, TRPC5 channels are known regulators of neuronal growth cone guidance1, and their activity in neurons depends on the activity of PI3K and Rac1 (Bezzerides et al., Nat Cell Biol 6, 709-720, 2004).

[0008] Podocytes are neuron-like cells that originate from the metanephric mesenchyme of the renal glomeruli and are essential for the formation of the renal filter (Somlo and Mundel, Nat Genet. 24, 333-335, 2000; Fukasawa et al., J Am Soc Nephrol 20, 1491-1503, 2009). Podocytes display a series of extremely precise 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 are characterized by 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 Ca2+. 2+ 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 onset of proteinuria, loss of albumin into the renal capsule and eventual renal failure (Tryggvason and Wartiovaara, N Engl J Med 354, 1387-1401, 2006). The vasoactive hormone angiotensin II induces Ca in podocytes. 2+influx, and long-term treatment leads to stress fiber loss (Hsu et al., J Mol Med 86, 1379-1394, 2008). 2+ There is a well-established association between influx and cytoskeletal reorganization, but the mechanism by which podocytes sense and transduce extracellular cues that regulate cell shape and activity remains elusive. TRP canonical 6 (TRPC6) channel mutations have been associated with 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 little is known about the specific pathways that regulate this process. In addition, TRPC6 shares close homology with six other members of the TRPC channel family (Ramsey et al., Annu Rev Physiol 68, 619-647, 2006; Clapham, Nature 426, 517-524, 2003). TRPC5 channels have an antagonistic effect on TRPC6 channel activity to control the balance of tightly regulated cytoskeletal dynamics through differential coupling to different small GTPases.

[0009] Therefore, additional inhibitors of TRPC5 are needed. Summary of the invention

[0010] One aspect of the present invention is a composition for preparing 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.

[0011] In one aspect, the invention features a method of making a spray-dried dispersion, the method comprising the step of spray-drying a composition of the invention.

[0012] In one aspect, the invention features 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.

[0013] In one aspect, the invention features a solid dosage form comprising a spray-dried dispersion of the invention and one or more of a filler, a disintegrant, a lubricant, a glidant, and a stabilizer.

[0014] In one aspect, the invention features a method of preparing 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 the steps of:

[0015] a. blending the spray-dried dispersion disclosed herein with one or more of: a first filler, a first disintegrant, a first lubricant, a first glidant, and a first stabilizer to form a first solid mixture;

[0016] b. rolling and grinding the first solid mixture; and

[0017] c. optionally blending the roller compacted and milled first solid mixture with one or more of a second filler, a second disintegrant, a second lubricant, a second glidant, and a second stabilizer to form a second solid mixture; and

[0018] 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.

[0019] In one aspect, the invention relates to a method of treating a disease or kidney disease associated with a disease or condition, the method comprising administering to a subject in need thereof a solid dosage form of the invention.

[0020] In some embodiments, the kidney disease or kidney disease associated with the disease or disorder is focal segmental glomerulosclerosis (FSGS), diabetic nephropathy, Alport syndrome, hypertensive kidney disease, nephrotic syndrome, steroid-resistant nephrotic syndrome, minimal change disease, 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), clq nephropathy, rapidly progressive GN, anti-GBM disease, C3 glomerulonephritis, hypertensive nephrosclerosis, I gA 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 kidney disease associated with any of obesity, insulin resistance, type II diabetes, prediabetes, metabolic syndrome, dyslipidemia, pulmonary hypertension, cancer, cholestatic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), or Fabry's disease.

[0021] In one aspect, the 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 invention.

[0022] The method is effective for a variety of subjects, including mammals, e.g., humans and other animals, such as laboratory animals, e.g., mice, rats, rabbits, or monkeys, or domestic and farm animals, e.g., cats, dogs, goats, sheep, pigs, cows, or horses. In some embodiments, the subject is a human.

[0023] The present invention provides several advantages. The preventive and therapeutic methods described herein are effective in treating kidney diseases such as proteinuria with minimal side effects, if any. In addition, the methods described herein are effective in identifying compounds that treat kidney disease, anxiety, depression, or cancer or reduce the risk of developing these diseases.

[0024] Unless otherwise limited, all technical and scientific terms used herein have the same meaning as the commonly understood meaning of the invention to which a person of ordinary skill in the field of the present invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of 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 the event of a conflict, this specification (including definitions) shall prevail. In addition, materials, methods and examples are illustrative only and are not intended to be limiting.

[0025] Other features, objects, and advantages of the invention will be apparent from the detailed description, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1A The thermogram of crystalline Compound 1 free base Form H is shown.

[0027] Figure 1B The thermogram of amorphous Compound 1 is shown.

[0028] Figure 2 Shown is the XRPD diffraction pattern of crystalline Compound 1 free base Form H.

[0029] Figure 3 Shown is a SEM micrograph of crystalline Compound 1 free base Form H at 5000x magnification.

[0030] Figure 4 An XRPD diffraction pattern of a feasible dispersion of Compound 1 is shown.

[0031] Figure 5A is a MDSC thermogram showing the Tg of an amorphous 25% Compound 1 dispersion in HPMCAS-M.

[0032] Figure 5B is a MDSC thermogram showing the Tg of an amorphous 25% Compound 1 dispersion in HPMCAS-L.

[0033] Figure 6 0.1N HCl / FaSSIF non-sedimenting dissolution test of Compound 1 showing feasibility of SDI compared to pure crystalline Compound 1

[0034] Figure 7 The dynamic vapor sorption of compound 1SDI is shown.

[0035] Figure 8 The XRPD diffractogram of a feasible re-spray formulation of Compound 1 is shown.

[0036] Fig. 9XRPD diffractograms of aged SDI after 2 weeks of stabilization are shown. SDI in closed conditions appears to remain amorphous at 40°C / 75% RH and 50°C / 75% RH.

[0037] Fig.10 XRPD diffractograms of aged SDI after 2 weeks of stabilization are shown. SDI in open condition showed crystalline growth at 40°C / 75% RH and 50°C / 75% RH.

[0038] Fig.11 Shown is the XRPD diffractogram of aged SDI after 4 weeks of stabilization (blocking conditions).

[0039] Fig.12 Shown is the XRPD diffractogram of aged SDI after 4 weeks of stabilization (open condition).

[0040] Fig.13 Shown is the Certificate of Test (CoT) for the 25:75 Compound 1:HPMCAS-M SDI test certificate, Batch No: D-17-078.

[0041] FIG. 14A to FIG. 14G Shown are the retention times and relative peak heights of impurities after the spray solution of Compound 1 was kept at 40°C for different times.

[0042] Fig.15A Shown are the assays and related substances for Compound 1 wet SDI when kept at room temperature for up to 15 days.

[0043] Fig. 15B Shown is the chromatogram of Compound 1 wet SDI that is stable over 15 days at room temperature.

[0044] Fig.16 Shown is the diffraction pattern of Compound 1 wet SDI that is stable over 15 days at room temperature.

[0045] Fig.17 Shown are SEM images of Compound 1 wet SDI at room temperature for t=0 (top row) and t=15 days (bottom row).

[0046] Fig.18 .Process flow diagram for preparing Compound 1 prototype tablets.

[0047] Fig.19 Tabletability, compressibility, compactability and disintegration profile of 50 mg Compound 1 prototype tablets.

[0048] Fig. 20 Non-settling dissolution of 50 mg Compound 1 prototype tablets containing lactose and Ac-Di-Sol after 4 weeks of accelerated stabilization.

[0049] Fig.21 Non-settling dissolution of 50 mg Compound 1 prototype tablets containing mannitol and Ac-Di-Sol after 4 weeks of accelerated stabilization.

[0050] Fig. 22 Tabletability, compressibility, compactability and disintegration profiles of 20 mg and 100 mg Compound 1 demonstration batch tablets compared to prototype 50 mg Compound 1 tablets.

[0051] Fig.23 . Dissolution of 100 mg Compound 1 tablets compressed at 200 MPa.

[0052] Fig.24 . Dissolution of 100 mg Compound 1 tablets compressed at 250 MPa.

[0053] Fig.25 .Dissolution of 100 mg Compound 1 tablets; all tablet compression forces were superimposed to evaluate formulation robustness.

[0054] Fig.26 .Fragility profiles of 20-mg and 100-mg Compound 1 demonstration batch tablets.

[0055] Fig. 27 Tabletability of a 20-mg Compound 1 demonstration batch of tablets.

[0056] Fig.28 .Strain rate for a 20-mg Compound 1 demonstration batch of tablets. The formulation did not appear to be strain rate sensitive.

[0057] Fig.29 . Images of 20-mg and 100-mg Compound 1 demonstration batch tablets where spots are visible.

[0058] Fig.30 .Weight distribution of 20 mg and 100 mg Compound 1 demonstration batch tablets. Composite samples of 50 tablets were used.

[0059] Fig.31 A diagram of 0.3125" SRC tablet processing according to some embodiments of the present invention is shown.

[0060] Fig.32 A 0.3543" x 0.6890" modified oval tablet process diagram is shown according to some embodiments of the present invention.

[0061] Fig.33 A test certificate for a batch of 20 mg Compound 1 tablets is shown.

[0062] Fig.34 A test certificate for a batch of 100 mg Compound 1 tablets is shown. DETAILED DESCRIPTION

[0063] 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 incidence of the disease, disorder, or condition in treated samples relative to untreated control samples, or delays the onset of or reduces the severity of one or more symptoms of the disorder or condition relative to untreated control samples.

[0064] The term "treatment" includes preventive and / or therapeutic treatment. The term "preventive or therapeutic" treatment is recognized in the art and includes administering one or more subject compositions to the host. If treatment is administered before the clinical manifestation of an unwanted disorder (e.g., a disease or other unwanted state of a host animal), the treatment is preventive (i.e., it protects the host from developing unwanted complications), and if treatment is administered after the manifestation of an unwanted disorder, the treatment is therapeutic (i.e., with the intention of alleviating, improving or stabilizing an existing unwanted disorder or its side effect).

[0065] The phrases "administered in combination" and "administered in combination" refer to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in vivo (e.g., the two compounds take effect simultaneously in the patient, which may include a synergistic effect of the two compounds). For example, different therapeutic compounds may be administered simultaneously or sequentially in the same formulation or in separate formulations. In certain embodiments, different therapeutic compounds may be administered within one hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or a week of each other. Thus, individuals receiving such treatment may benefit from the combined effects of different therapeutic compounds.

[0066] The term "prodrug" is intended to encompass compounds that are converted to therapeutic agents of the present invention under physiological conditions. Common methods for preparing prodrugs include hydrolysis under physiological conditions to display one or more selected parts of 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 represented above may be replaced by corresponding suitable prodrugs, for example, wherein the hydroxyl group in the parent compound is presented as an ester or carbonate, or the carboxylic acid present in the parent compound is presented as an ester.

[0067] An "effective amount" is an amount sufficient to achieve 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 or different from a prophylactic effective amount, which is the amount necessary to prevent the onset of a disease or disease symptoms. An effective amount may be administered in one or more administrations, applications, or dosages. The therapeutically effective amount of a composition depends on the composition selected. The composition may be administered once or more per day to once or more per week; including administration every other day. Those skilled in the art will appreciate that certain factors may affect the dosage and schedule required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatment, the general health and / or age of the subject, and other diseases present. In addition, treating a subject with a therapeutically effective amount of a composition described herein may include a single treatment or a series of treatments.

[0068] Compounds of the present invention

[0069] 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 (a / k / a Compound 1) or a pharmaceutically acceptable salt thereof.

[0070]

[0071] 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.

[0072] Pharmaceutical composition

[0073] The compositions and methods of the present invention can be used to treat subjects in need. In certain embodiments, the subject is a mammal, such as 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 comprising, for example, 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, such as water or physiologically buffered saline; or other solvents or vehicles, such as glycols, glycerol, oils such as olive oil; or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are used for human administration, particularly for invasive administration routes (i.e., routes of transport or diffusion through epithelial barriers, such as injection or implantation), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients may be selected, for example, to achieve delayed release of the agent or selectively target one or more cells, tissues or organs. The pharmaceutical composition may be in dosage unit form, such as tablets, capsules (including spray capsules and gelatin capsules), granules, lyophilized agents for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The composition may also be presented in a transdermal delivery system such as a skin patch.The composition may also be presented in a solution suitable for topical administration such as eye drops.

[0074] A pharmaceutically acceptable carrier may contain a physiologically acceptable agent, the function of which is, for example, to stabilize, increase the solubility or increase the absorption of a compound such as the compound of the present invention. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose or dextran; antioxidants such as ascorbic acid or glutathione; chelating agents; low molecular weight proteins or other stabilizers or excipients. The selection of a pharmaceutically acceptable carrier (including a physiologically acceptable agent) depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) may also be a liposome or other polymer matrix into which, for example, a compound of the present invention may be incorporated. For example, liposomes comprising phospholipids or other lipids are non-toxic, physiologically acceptable and metabolizable carriers that are relatively simple to prepare and administer.

[0075] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0076] "Pharmaceutically acceptable salt" is used herein to refer to acid addition salts or base addition salts that are suitable for or compatible with the treatment of a patient.

[0077] As used herein, the term "pharmaceutically acceptable acid addition salt" means any non-toxic organic or inorganic salt of the disclosed compound. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include monocarboxylic acids, dicarboxylic acids and tricarboxylic acids, such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, bitartrate, 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. Monoacid or diacid salts can be formed, and these salts can exist in hydrated, solvated or substantially anhydrous forms. Generally, the acid addition salts of the compounds disclosed herein are more soluble in water and various hydrophilic organic solvents, and generally show higher melting points than their free base forms. The selection of appropriate salts is known to those skilled in the art. Other non-pharmaceutically acceptable salts (eg, oxalates) may be useful, for example, in isolating the compounds disclosed herein for laboratory use, or for subsequent conversion to pharmaceutically acceptable acid addition salts.

[0078] The term "pharmaceutically acceptable base addition salt" as used herein refers to any non-toxic organic or inorganic base addition salt of any acid compound disclosed herein. Exemplary inorganic bases that form suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or barium hydroxide. Exemplary organic bases that form suitable salts include aliphatic, alicyclic or aromatic organic amines, such as methylamine, trimethylamine and picoline or ammonia. The selection of appropriate salts is known to those skilled in the art.

[0079] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, 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 be used 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, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, 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) ethanol; (20) phosphate buffered saline; (21) surfactants and co-surfactants, such as vitamin E, TPGS, HS15 and various polyethylene glycols; and (21) other non-toxic compatible substances used in pharmaceutical preparations.

[0080] The pharmaceutical composition (preparation) can be administered to a subject by any of a variety of routes of administration, including, for example, oral (e.g., as a drench, tablet, capsule (including spray capsules and gelatin capsules) in an aqueous or non-aqueous solution or suspension, bolus, powder, granules, paste applied to the tongue); absorption through the oral mucosa (e.g., sublingual); anus, rectum or vagina (e.g., as a vaginal suppository, cream or foam); parenteral (including intramuscular, intravenous, subcutaneous or intrathecal, such as, for example, as a sterile solution or suspension); nasal; intraperitoneal; subcutaneous; transdermal (e.g., as a patch applied to the skin); and topical (e.g., applied to the skin as a cream, ointment or spray, or as eye drops). The compound can also be formulated for inhalation. In certain embodiments, the compound can simply be dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions useful therefor can be found, for example, in U.S. Patents 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970, and 4,172,896 (each incorporated by reference) and patents cited therein.

[0081] The preparation can be conveniently present in unit dosage form and can be prepared by any method well known in the pharmaceutical field. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the subject being treated, the specific mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be the amount of the compound that produces the therapeutic effect. Typically, in 100%, the range of this amount is from about 1% to about 99% of the active ingredient, preferably from about 5% to about 70%, and most preferably from about 10% to about 30%.

[0082] The method of preparing these preparations or compositions includes the step of bringing into association the active compound such as the compound of the present invention with the carrier and optionally one or more auxiliary ingredients. In general, the preparations are prepared by uniformly and intimately bringing into association the compound of the present invention with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[0083] Formulations of the present invention suitable for oral administration may be in the form of capsules (including spray capsules, gelatin capsules and HPMC capsules), cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and gum arabic or tragacanth), lyophilizates, powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or 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 gum arabic) and / or as a mouthwash, etc., each containing a predetermined amount of the compound of the present invention as the active ingredient. The composition or compound may also be administered as a bolus, electuary or paste.

[0084] To prepare solid dosage forms for oral administration (capsules (including spray capsules and gelatin capsules), tablets, pills, dragees, powders, granules, etc.), 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) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders, such as carboxymethyl cellulose, hydroxypropyl cellulose gelatin, polyvinyl pyrrolidone and starch; (3) wetting agents, such as glycerol; (4) disintegrants, such as agar, calcium carbonate, potato starch, etc. yam or tapioca starch, alginic acid, certain silicates, microcrystalline cellulose, crospovidone, sodium carboxymethylcellulose and sodium carbonate; (5) solution retardants such as paraffin; (6) absorption promoters such as quaternary ammonium compounds; (7) wetting agents such as cetyl alcohol and glyceryl monostearate; (8) absorbents such as kaolin and bentonite; (9) lubricants such as calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, sodium stearyl fumarate, Compritol and mixtures thereof; (10) complexing agents such as modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including spray capsules and gelatin capsules), tablets and pills, the pharmaceutical composition may also contain a buffer. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0085] Tablets can be prepared by compression or molding optionally with one or more auxiliary ingredients. Compressed tablets can be prepared using a binder (e.g., hydroxypropyl cellulose, povidone or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), a surfactant or a dispersant. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0086] Tablets and other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (including spray capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells such as taste-masking coatings, enteric coatings and other coatings well known in the art of pharmaceutical formulation. Hydroxypropyl methylcellulose, other polymer matrices, liposomes and / or microspheres, for example, in different proportions to provide the desired release profile, may also be prepared to provide a slow or controlled release of the active ingredient therein. They may be sterilized by, for example, filtering through a bacterial retention filter or by incorporating a sterilizing agent in the form of a sterile solid composition, which may be dissolved in sterile water or some other sterile injectable medium before use. These compositions may also optionally contain an opacifier and may be a composition that releases the active ingredient only or preferably in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. If appropriate, the active ingredient may also be in a microencapsulated form with one or more of the above-mentioned excipients.

[0087] Liquid dosage forms that can be used for oral administration include pharmaceutically acceptable emulsions, lyophilized agents 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, such as, for example, water or other solvents, cyclodextrins and their derivatives, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuranol, polyethylene glycol and fatty acid esters of sorbitan, vitamin E TPGS (D-α-tocopherol polyethylene glycol succinate), HS15 (polyethylene glycol (15)-hydroxystearate, polyethylene glycol (15)-hydroxystearate, polyoxyethylated 12-hydroxystearic acid) and mixtures thereof.

[0088] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0089] In addition to the active compound, the suspension may contain a suspending agent such as microcrystalline cellulose, aluminum hydroxide, bentonite, agar, tragacanth, hydroxypropylcellulose, sodium carboxymethylcellulose, povidone, and mixtures thereof. The suspension may also contain surfactants and wetting agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters.

[0090] Formulations of pharmaceutical compositions for rectal, vaginal or urethral administration may be presented as suppositories, which may be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylates, and which are solid at room temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.

[0091] The formulation of the pharmaceutical composition for administration to the oral cavity may be presented as a mouthwash, or an oral spray, or an oral ointment.

[0092] Alternatively or in addition, the composition can be formulated for delivery via a catheter, stent, wire or other intraluminal device. Delivery via such a device may be particularly useful for delivery to the bladder, urethra, ureter, rectum or intestine.

[0093] Formulations 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.

[0094] 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 that may be required.

[0095] Ointments, pastes, creams and gels may contain, in addition to the active compounds, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0096] In addition to the active compound, powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0097] Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms can be prepared by dissolving or dispersing the active compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate of such flux can be controlled by providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0098] Ophthalmic preparations, eye ointments, powders, solutions, etc. are also within the scope of the present invention. Exemplary ophthalmic preparations are disclosed in the U.S. in 2005 / 0080056, 2005 / 0059744, 2005 / 0031697 and 2005 / 004074 and U.S. Patent No. 6,583,124, which are incorporated herein by reference. If desired, liquid ophthalmic preparations have characteristics similar to tears, aqueous humor or vitreous humor or are compatible with these liquids. Preferred routes of administration are topical administration (e.g., topical administration, such as eye drops, or administration via implants).

[0099] 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, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, intraocular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0100] Pharmaceutical compositions suitable for parenteral administration comprise 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 which may be reconstituted into sterile injectable solutions or dispersions prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0101] 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, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. For example, appropriate fluidity can be maintained by using coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants.

[0102] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants. By including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, etc., protection against the action of microorganisms can be ensured. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, etc. in the composition. In addition, by including agents that delay absorption, such as aluminum monostearate and gelatin, the absorption of injectable drug forms can be prolonged.

[0103] In some cases, in order to prolong the effect of the drug, it is desirable to slow down the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. The absorption rate of the drug depends on its dissolution rate, which in turn can depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenteral drug form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0104] Injectable depot forms are prepared by forming a microencapsulated matrix of the subject compound in a biodegradable polymer such as polylactide-polyglycolide. The drug release rate can be controlled according to the ratio of the drug to the polymer and the characteristics of the specific polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by embedding the drug in liposomes or microemulsions compatible with body tissues.

[0105] For use in the methods of the invention, the active compound may be administered per se or as a pharmaceutical composition containing, for example, about 0.1% to about 99.5% (more preferably about 0.5% to about 90%) active ingredient in combination with a pharmaceutically acceptable carrier.

[0106] The introduction method can also be provided by a rechargeable or biodegradable device. In recent years, various slow-release polymer devices for controlled delivery of drugs, including protein biopharmaceuticals, have been developed and tested in vivo. A variety of biocompatible polymers, including hydrogels, including both biodegradable and non-degradable polymers, can be used to form implants that continuously release compounds at specific target sites.

[0107] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0108] The selected dosage level will depend upon a variety of factors including the activity of the specific compound or combination of compounds employed, or their esters, salts or amides, the route of administration, the time of administration, the rate of excretion of the specific compound employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the specific compound employed, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and like factors well known in the medical arts.

[0109] A physician or veterinarian with ordinary skills in the art can easily determine and prescribe the therapeutically effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian can start the dosage of the pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. "Therapeutically effective amount" refers to the concentration of the compound sufficient to cause the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the subject's weight, sex, age and medical history. Other factors affecting the effective amount may include, but are not limited to, the severity of the subject's condition, the condition being treated, the stability of the compound, and, if necessary, another type of therapeutic agent administered with the compound of the present invention. Larger total doses can be delivered by multiple administrations of the agent. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al., (1996) Harrison's Principles of Internal Medicine, 13th edition, 1814-1882, incorporated herein by reference).

[0110] In general, a suitable daily dose of an active compound for use in the compositions and methods of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0111] If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses divided at appropriate intervals throughout the day, optionally in unit dosage form. In certain embodiments of the invention, the active compound may be administered twice or three times a day. In certain embodiments, the active compound will be administered once a day.

[0112] In certain embodiments, the compounds of the present invention can be used alone or in combination with another type of therapeutic agent. As used herein, the phrase "combined administration" refers to any form of administration of two or more different therapeutic compounds, so that the second compound is administered when the previously administered therapeutic compound is still effective in vivo (for example, 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 continuously with the same preparation or with a separate preparation. In certain embodiments, different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours or a week from each other. Therefore, the subject receiving such treatment can benefit from the combined effect of different therapeutic compounds.

[0113] In certain embodiments, the combined administration of a compound of the invention and one or more additional therapeutic agents provides improved efficacy relative to each separate administration of a compound of the invention or the one or more additional therapeutic agents. In certain such embodiments, the combined administration provides an additive effect, wherein the additive effect refers to the sum of each effect of the separate administration of a compound of the invention and the one or more additional therapeutic agents.

[0114] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0115] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0116] In some embodiments, the pharmaceutical composition is a spray-dried dispersion.

[0117] In some embodiments, the present invention is directed to a composition for preparing 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.

[0118] In some embodiments, 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.

[0119] Suitable polymers for use in the compositions of the present invention include, but are not limited to, hydroxypropylmethylcellulose acetate succinate, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone / vinyl acetate copolymer (PVP-VA, PVP-VA64), Hydroxypropyl methylcellulose (HPMC), Methocel, Hydroxypropyl methylcellulose 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), delayed release (such as for small intestinal delivery (e.g., Eudragit L 30D-55, Eudragit L 100-55, Eudragit FL 30D-55, Eudragit L 100, Eudragit L 12.5; optionally in combination with PlasACRYL HTP20) or for colonic delivery (e.g., Eudragit S100, Eudragit S12.5, Eudragit FS 30D, Eudragit FS100; optionally in combination with PlasACRYL T20)), sustained release (e.g., Eudragit RL PO, Eudragit RL 100, Eudragit RL 30D, Eudragit RL 12.5, Eudragit RS PO, Eudragit RS100, Eudragit RS 30D, Eudragit RS12.5, Eudragit NM 30D) and for solubility and bioavailability enhancement (e.g., Eudragit E 100, Eudragit E PO, Eudragit E 12.5, Eudragit FS100, Eudragit S100, Eudragit L 100, Eu dragit L 100-55, Eudragit L12.5); as known to those skilled in the art, the release profile can be customized by combining Eudragit polymers in different ratios (see, e.g., https: / / healthcare.evonik.com / product / health-care / downloads / evonik-eudrag it-brochure.pdf). In some embodiments, the polymer is hydroxypropylmethylcellulose acetate succinate, HPMCAS, PVP-VA64 or Eudragit. In some embodiments, the polymer is hydroxypropylmethylcellulose acetate succinate.

[0120] 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 hydroxypropylmethylcellulose acetate succinate is between about 1:9 and 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 hydroxypropylmethylcellulose acetate succinate is about 1:3.

[0121] Hydroxypropyl methylcellulose acetate succinate (HPMCAS) products suitable for use with embodiments of the present invention include, but are not limited to, AquaSolve TM Products, such as those of L, M and H grades:

[0122]

[0123] In some embodiments, hydroxypropylmethylcellulose acetate succinate has an acetyl content of about 5%-14%, a succinyl content of about 4%-18%, a methoxy content of about 20%-26%, and a hydroxypropoxy content of about 5%-10%. In some embodiments, hydroxypropylmethylcellulose acetate succinate has an acetyl content of about 7%-12%, a succinyl content of about 7%-15%, a methoxy content of about 21%-25%, and a hydroxypropoxy content of about 5%-9%.

[0124] In some embodiments, the solvent is acetone, methyl ethyl ketone, ethyl acetate, isopropanol, 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.

[0125] In one aspect, the present invention relates to a method for preparing a spray-dried dispersion, the method comprising the step of spray-drying a composition of the present invention.

[0126] In some embodiments, the temperature of the nozzle through which the spray-dried composition passes is between about 20° C. and about 60° C. In some embodiments, the temperature of the nozzle is between about 35° C. and about 40° C.

[0127] In some embodiments, the spray drying step is performed at an atomization pressure between about 1.0 bar and about 10.0 bar. In some embodiments, the spray drying step is performed at an atomization pressure between about 2.0 bar and about 4.0 bar.

[0128] In one aspect, the present invention is directed 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.

[0129] In some embodiments, 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.

[0130] In some embodiments, the polymer is hydroxypropylmethylcellulose acetate succinate.

[0131] 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 hydroxypropylmethylcellulose acetate succinate is between about 1:9 and 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 hydroxypropylmethylcellulose acetate succinate is about 1:3.

[0132] In some embodiments, hydroxypropylmethylcellulose acetate succinate has an acetyl content of about 5%-14%, a succinyl content of about 4%-18%, a methoxy content of about 20%-26%, and a hydroxypropoxy content of about 5%-10%. In some embodiments, hydroxypropylmethylcellulose acetate succinate has an acetyl content of about 5%-11%, a succinyl content of about 10%-18%, a methoxy content of about 20%-25%, and a hydroxypropoxy content of about 5%-9%. In some embodiments, hydroxypropylmethylcellulose acetate succinate has an acetyl content of about 7%-12%, a succinyl content of about 7%-15%, a methoxy content of about 21%-25%, and a hydroxypropoxy content of about 5%-9%. Different grades of hydroxypropylmethylcellulose acetate succinate are commercially available, such as AquaSolve from Ashland. TM Hydroxypropyl methylcellulose acetate succinate L, M and H grades.

[0133] In some embodiments, the solvent is acetone, methyl ethyl ketone, ethyl acetate, isopropanol, 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.

[0134] In one aspect, the invention relates to a solid dosage form comprising the spray-dried dispersion of the invention and one or more of a filler, a disintegrant, a lubricant, a glidant and a stabilizer.

[0135] In some embodiments, the filler comprises one or more of mannitol, lactose or microcrystalline cellulose. In some embodiments, the filler comprises mannitol and microcrystalline cellulose. In some embodiments, the ratio of mannitol to microcrystalline cellulose is between about 1:3 and 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 between about 1:1.3 and 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.

[0136] In some embodiments, the average particle size of the microcrystalline cellulose is between about 5 μm and about 80 μm. In some embodiments, the average particle size of the microcrystalline cellulose is between about 10 μm and about 50 μm.

[0137] In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, croscarmellose sodium is present at between about 3% w / w and about 15% w / w. In some embodiments, croscarmellose sodium is present at about 6% w / w.

[0138] In some embodiments, the lubricant is sodium stearyl fumarate. In some embodiments, sodium stearyl fumarate is present at between about 0.5% w / w and about 5% w / w. In some embodiments, sodium stearyl fumarate is present at about 1% w / w. In some embodiments, sodium stearyl fumarate is present at about 0.95% w / w.

[0139] In some embodiments, the glidant is colloidal silicon dioxide. In some embodiments, the silicon dioxide is present at between about 0.1% w / w to about 5% w / w. In some embodiments, the silicon dioxide is present at about 1% w / w.

[0140] In some embodiments, the spray dried dispersion is present at between about 3% w / w to about 60% w / w. In some embodiments, the spray dried dispersion is present at about 50% w / w. In some embodiments, the spray dried dispersion is present at about 16.7% w / w. In some embodiments, the spray dried dispersion is present at about 3.33% w / w.

[0141] In some embodiments, 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 at about 0.75% w / w-15% w / w. For example, the compound can be present at 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, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, about 21% w / w, about 23% w / w, about 24% w / w, about 25% w / w, about 26% w / w, about 27% w / w, about 28% w / w, about 29% w / w, about 30% w / w, about 31% w / w, about 32% w / w, about 34% w / w, about 35% w / w, about 36% w / w, about 37% w / w, about 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 Present at 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.

[0142] In some embodiments, the solid dosage form consists essentially of:

[0143] a. 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one;

[0144] b. Hydroxypropyl methylcellulose acetate succinate;

[0145] c. Mannitol;

[0146] d. microcrystalline cellulose;

[0147] e. Cross-linked sodium carboxymethyl cellulose;

[0148] f. Sodium stearyl fumarate; and

[0149] g. Colloidal silicon dioxide.

[0150] In some embodiments, the solid dosage form consists essentially of:

[0151] a. 0.75%-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;

[0152] b. 2.0%-54.0% (w / w) hydroxypropylmethylcellulose acetate succinate;

[0153] c. 3.75%-42.3% (w / w) mannitol;

[0154] d. 3.75%-50.0% (w / w) microcrystalline cellulose;

[0155] e. 3.0%-15% (w / w) cross-linked sodium carboxymethyl cellulose;

[0156] f. 0.5%-5.0% (w / w) sodium stearyl fumarate; and

[0157] g. 0.1%-5.0% (w / w) colloidal silicon dioxide,

[0158] in:

[0159] 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 hydroxypropylmethylcellulose acetate succinate is between 1:9 and 2:1;

[0160] The sum of the amounts 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 hydroxypropylmethylcellulose acetate succinate is between 3% w / w and 60% w / w of the solid dosage form;

[0161] The ratio of mannitol to microcrystalline cellulose is between 1:3 and 3:1; and

[0162] The sum of the amounts of mannitol and microcrystalline cellulose is between 15.0% w / w and 90% w / w of the solid dosage form.

[0163] In some embodiments, the solid dosage form consists essentially of:

[0164] a. 20 mg 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one;

[0165] b. 60 mg hydroxypropylmethylcellulose acetate succinate;

[0166] c.33.6 mg mannitol;

[0167] d. 33.6 mg microcrystalline cellulose;

[0168] e. 9.6 mg cross-linked carboxymethyl cellulose sodium;

[0169] f. 1.6 mg sodium stearyl fumarate; and

[0170] g.1.6mg colloidal silicon dioxide.

[0171] In some embodiments, the solid dosage form consists essentially of:

[0172] a. 100 mg 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one;

[0173] b. 300 mg hydroxypropylmethylcellulose acetate succinate;

[0174] c. 168 mg mannitol;

[0175] d. 168 mg microcrystalline cellulose;

[0176] e.48mg cross-linked carboxymethyl cellulose sodium;

[0177] f. 8mg sodium stearyl fumarate; and

[0178] g.8mg colloidal silicon dioxide.

[0179] In some embodiments, the solid dosage form consists essentially of:

[0180] a. 5 mg 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one;

[0181] b. 15 mg hydroxypropylmethylcellulose acetate succinate;

[0182] c.39.2 mg mannitol;

[0183] d. 51.2 mg microcrystalline cellulose;

[0184] e. 7.2 mg cross-linked carboxymethyl cellulose sodium;

[0185] f. 1.1 mg sodium stearyl fumarate; and

[0186] g.1.2mg colloidal silicon dioxide.

[0187] In some embodiments, the solid dosage form consists of:

[0188] a. 1 mg 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one;

[0189] b. 3mg hydroxypropylmethylcellulose acetate succinate;

[0190] c.47.2 mg mannitol;

[0191] d. 59.2 mg microcrystalline cellulose;

[0192] e. 7.2 mg cross-linked carboxymethyl cellulose sodium;

[0193] f. 1.1 mg sodium stearyl fumarate; and

[0194] g.1.2mg colloidal silicon dioxide.

[0195] 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 mg-200 mg.

[0196] 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.

[0197] 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.

[0198] 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.

[0199] 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.

[0200] In one aspect, the present invention relates to a method for preparing 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 the following steps:

[0201] a. blending the spray-dried dispersion according to any one of claims 17-27 with one or more of: a first filler, a first disintegrant, a first lubricant, a first glidant, and a first stabilizer to form a first solid mixture;

[0202] b. rolling and grinding the first solid mixture; and

[0203] c. optionally blending the roller compacted and milled first solid mixture with one or more of a second filler, a second disintegrant, a second lubricant, a second glidant, and a second stabilizer to form a second solid mixture; and

[0204] 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.

[0205] In some embodiments, the first filler and the second filler 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.

[0206] In some embodiments, the roller compacted and milled solid mixture is blended with a second filler, a second disintegrant, and a second lubricant in step c.

[0207] 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 a capsule with the first solid mixture or the second solid mixture.

[0208] Treatment

[0209] Proteinuria

[0210] Proteinuria is a pathological condition in which protein is present in urine. Albuminuria is a type of proteinuria. Microalbuminuria occurs when the kidneys leak a small amount of albumin into the urine. In a normally functioning body, albumin is usually absent from the urine because it is held in the bloodstream by the kidneys. Microalbuminuria can be diagnosed from 24-hour urine collections (20 μg / min to 200 μg / min) or more commonly from concentrations (30 mg / L to 300 mg / L) that rise at at least two moments. Microalbuminuria may be a precursor to diabetic nephropathy. Albumin levels exceeding these values ​​are referred to as macroalbuminuria. Subjects suffering from certain conditions such as diabetic nephropathy can develop from microalbuminuria to macroalbuminuria, and reach the nephrotic range (>3.5 g / 24 hours) when kidney disease reaches the late stage.

[0211] Causes of proteinuria

[0212] Proteinuria may be associated with a variety of diseases, including focal segmental glomerulosclerosis, IgA nephropathy, diabetic nephropathy, lupus nephritis, membranoproliferative glomerulonephritis, progressive (crescentic) glomerulonephritis, and membranous glomerulonephritis.

[0213] A. Focal segmental glomerulosclerosis (FSGS)

[0214] 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 disease called nephrotic syndrome, which occurs when protein from the blood leaks into the urine (proteinuria). Primary FSGS, when no underlying cause can be found, usually presents as nephrotic syndrome. Secondary FSGS, when an underlying cause is identified, usually presents as kidney failure and proteinuria. FSGS can be hereditary; there are several known genetic causes of hereditary forms of FSGS.

[0215] There are few treatments available for patients with FSGS. Many patients are treated with steroid regimens, most of which have very severe side effects. Some patients have been shown to respond positively to immunosuppressive drugs, as well as blood pressure medications that have been shown to reduce protein levels in the urine. To date, there is no generally accepted effective treatment or cure, and there are no FDA-approved drugs for the treatment of FSGS. Therefore, more effective methods of reducing or inhibiting proteinuria are needed.

[0216] B. IgA nephropathy

[0217] IgA nephropathy (also known as IgA nephritis, IgAN, Bergey's disease and glomerulonephritis) is a form of glomerulonephritis (inflammation of the glomeruli of the kidney). IgA nephropathy is the most common glomerulonephritis worldwide. Primary IgA nephropathy is characterized by the deposition of IgA antibodies in the glomeruli. There are other diseases associated with glomerular IgA deposition, the most common of which is Henlein-Schönlein purpura (HSP), which is considered by many to be a systemic form of IgA nephropathy. Henlein-Schönlein purpura presents with characteristic purpuric rash, arthritis and abdominal pain and occurs more often in young people (16-35 years old). HSP is associated with a better prognosis than IgA nephropathy. In IgA nephropathy, 25%-30% of cases slowly progress to chronic renal failure over a period of 20 years.

[0218] C. Diabetic nephropathy

[0219] Diabetic nephropathy, also known as Kimmelstiel-Wilson syndrome and intercapillary glomerulonephritis, is a progressive kidney disease caused by vascular changes in the capillaries in the glomeruli of the kidney. It is characterized by nephrotic syndrome and diffuse glomerulosclerosis. It is caused by long-standing diabetes and is the main reason for dialysis. The earliest detectable change in the course of diabetic nephropathy is thickening of the glomeruli. At this stage, the kidneys may begin to allow higher than normal levels of serum albumin in the urine. As diabetic nephropathy progresses, more and more glomeruli are destroyed by nodular glomerulosclerosis and the amount of albumin excreted in the urine increases.

[0220] D. Lupus nephritis

[0221] Lupus nephritis is a kidney disorder that is a complication of systemic lupus erythematosus. Lupus nephritis occurs when antibodies and complement build up in the kidneys, causing inflammation. It often causes proteinuria and can quickly progress to kidney failure. Nitrogen waste products build up in the blood. Systemic lupus erythematosus causes various diseases of the internal structures of the kidneys, including interstitial nephritis. About 3 in every 10,000 people are affected by lupus nephritis.

[0222] E. Membranoproliferative glomerulonephritis I / II / III

[0223] Membranoproliferative glomerulonephritis is a type of glomerulonephritis caused by deposits in the mesangium of the kidney and thickening of the basement membrane, activated complement, and damage to the glomeruli. There are three types of membranoproliferative glomerulonephritis. Type I is caused by the deposition of immune complexes in the kidney and is thought to be related to the classical complement pathway. Type II is similar to type I but is believed to be related to the alternative complement pathway. Type III is very rare and is characterized by subepithelial deposits mixed with the typical pathological findings of type I disease.

[0224] There are two main 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 is typically manifested by normal or mildly decreased serum C3 concentrations and low serum C4 concentrations. In complement-mediated MPGN, low serum C3 and normal C4 levels are typically present due to activation of the alternative pathway. However, a normal serum C3 concentration does not exclude complement-mediated MPGN, and it is not uncommon to find normal C3 concentrations in adults with dense deposit disease (DDD) or C3 glomerulonephritis (C3GN).

[0225] C3 glomerulonephritis (C3GN) shows glomerulonephritis on light microscopy (LM), bright C3 staining and absence of C1q, C4 and immunoglobulins (Ig) on ​​immunofluorescence microscopy (IF), and mesangial and / or subendothelial electron-dense deposits on electron microscopy (EM). Occasionally, intramembranous and subepithelial deposits are often present. The term "C3 glomerulopathy" is generally used to include C3GN and dense deposit disease (DDD), both of which are caused by disorders of the complement alternative pathway (AP). C3GN and DDD may be difficult to distinguish from each other in LM and IF studies. However, EM shows mesangial and / or subendothelial, intramembranous and subepithelial deposits in C3GN, while dense osmiophilic deposits are present along the glomerular basement membrane (GBM) and in the mesangium in DDD. The difference between C3GN and DDD and immune complex-mediated glomerulonephritis is the lack of immunoglobulin staining on IF. (Sethi et al., Kidney Int. (2012) 82(4):465-473).

[0226] F. Progressive (crescentic) glomerulonephritis

[0227] Progressive (crescentic) glomerulonephritis (PG) is a renal syndrome that, if left untreated, rapidly progresses to acute renal failure and death within a few months. In 50% of cases, PG is associated with an underlying disease such as Goodpasture's syndrome, systemic lupus erythematosus, or Wegener granulomatosis; the remaining cases are idiopathic. Regardless of the underlying cause, PG involves severe damage to the glomeruli of the kidney, many of which contain characteristic crescent-shaped scars. Patients with PG have hematuria, proteinuria, and occasionally hypertension and edema. Although the degree of proteinuria may occasionally exceed 3 g / 24 hours, a range associated with nephrotic syndrome, the clinical picture is consistent with renal syndrome. Untreated disease may progress to a decrease in urine volume (oliguria), which is associated with poor renal function.

[0228] G. Membranous glomerulonephritis

[0229] Membranous glomerulonephritis (MGN) is a slowly progressive kidney disease that primarily affects patients aged 30 to 50 years, usually Caucasians. It can progress to nephrotic syndrome. MGN is caused by circulating immune complexes. Current studies have shown that most immune complexes are formed by antibodies binding to antigens in situ on the glomerular basement membrane. The antigens can be endogenous to the basement membrane or deposited from the systemic circulation.

[0230] H.Alport syndrome

[0231] Alport syndrome is a genetic disorder that affects 1 in 5,000-10,000 children and is characterized by glomerulonephritis, end-stage renal disease, and hearing loss. Alport syndrome can also affect the eyes, but these changes do not usually affect vision unless changes to the lens occur later in life. Blood in the urine is common. Proteinuria is characteristic of progressive kidney disease.

[0232] I. Hypertensive kidney disease

[0233] Hypertensive kidney disease (hypertensive nephrosclerosis (HN or HNS) or hypertensive nephropathy (HN)) is a medical condition involving damage to the kidneys caused by chronic high blood pressure. HN can be divided into two types: benign and malignant. Benign nephrosclerosis is common in individuals over the age of 60, while malignant nephrosclerosis is uncommon and affects 1%-5% of individuals with hypertension, who have a diastolic blood pressure of more than 130 mm Hg. Signs and symptoms of chronic kidney disease may occur, including loss of appetite, nausea, vomiting, itching, drowsiness or confusion, weight loss, and bad taste in the mouth. Chronic high blood pressure causes damage to the tissue of the kidneys; this includes the small blood vessels, glomeruli, tubules, and interstitial tissue. The tissue becomes hardened and thickened, which is called nephrosclerosis. The narrowing of the blood vessels means that less blood enters the tissue, and therefore less oxygen reaches the tissue, which leads to tissue death (local ischemia).

[0234] J. Nephrotic syndrome

[0235] Nephrotic syndrome is a series of symptoms caused by kidney damage. This includes protein in the urine, low blood albumin levels, high blood fats and significant swelling. Other symptoms may include weight gain, feeling tired and foamy urine. Complications may include blood clotting, infection and high blood pressure. Causes include many kidney diseases, such as focal segmental glomerulosclerosis, membranous nephropathy and minimal change disease. It may also occur as a complication of diabetes or lupus. The underlying mechanism usually involves damage to the kidney glomeruli. Diagnosis is usually based on urine tests and sometimes on kidney biopsies. It differs from nephritic syndrome in that there are no red blood cells in the urine. Nephrotic syndrome is characterized by a large amount of proteinuria (>3.5g / 1.73m 2 Nephrotic syndrome is characterized by high levels of protein in the urine (<2.5 g / dl), high cholesterol (<2.5 g / dl), and edema that begins in the face. Lipiduria (lipids in the urine) may also occur, but is not necessary for the diagnosis of nephrotic syndrome. Hyponatremia also occurs with low sodium excretion rates. Inherited forms of nephrotic syndrome are often resistant to steroids and other immunosuppressive treatments. The goals of therapy are to control urinary protein loss and swelling, provide good nutrition to allow the child to grow, and prevent complications. Early and aggressive treatment is used to control the condition.

[0236] K. Minimal change disease

[0237] Minimal change disease (also known as MCD, minimal change glomerulopathy, and no disease, among others) is a disease that affects the kidneys, causing nephrotic syndrome. The clinical signs of minimal change disease are proteinuria (abnormal excretion of protein, primarily albumin, into the urine), edema (soft tissue swelling due to water retention), weight gain, and hypoalbuminemia (low serum albumin). These signs are collectively referred to as nephrotic syndrome. The first clinical sign of minimal change disease is usually edema, with associated weight gain. The swelling can be mild, but patients may present with edema of the lower half of the body, periorbital edema, swelling of the scrotum / labial region, and, in more severe cases, generalized edema. In the elderly, patients may also develop acute kidney injury (20%-25% of affected adults) and hypertension. Due to the disease process, patients with minimal change disease are also at risk for blood clotting and infection.

[0238] L. Membranous nephropathy

[0239] Membranous nephropathy is the deposition of immune complexes on the glomerular basement membrane (GBM), with GBM thickening. The cause is usually unknown (idiopathic), but secondary causes include drugs, infection, autoimmune disease, and cancer. Manifestations include insidious onset of edema and heavy proteinuria with benign urine sediment, normal renal function, and normal or elevated blood pressure. Membranous nephropathy is diagnosed by renal biopsy. Spontaneous remission is common. Treatment of patients at high risk of progression is usually with corticosteroids and cyclophosphamide or chlorambucil.

[0240] M. Postinfectious glomerulonephritis

[0241] Acute proliferative glomerulonephritis is a disorder of the glomeruli (glomerulonephritis) or small blood vessels in the kidneys. It is a common complication of bacterial infection, typically a skin infection caused by type 12, 4 and 1 streptococcal bacteria (impetigo), but also occurs after streptococcal pharyngitis, so it is also called post-infection or post-streptococcal glomerulonephritis. It may be a risk factor for future albuminuria. In adults, signs and symptoms of infection may still be present when kidney problems occur, and terms such as infection-related glomerulonephritis or bacterial infection-related glomerulonephritis are also used. Acute glomerulonephritis caused 19,000 deaths in 2013, down from 24,000 deaths worldwide in 1990. Acute proliferative glomerulonephritis (post-streptococcal glomerulonephritis) is caused by a streptococcal bacterial infection, usually three weeks after infection, usually of the pharynx or skin, given the time required to produce antibodies and complement proteins. The infection causes inflammation of the blood vessels in the kidneys, which impedes the ability of the kidney organ to filter urine. [citation needed] Acute proliferative glomerulonephritis most commonly occurs in children.

[0242] N. Thin basement membrane disease

[0243] Thin basement membrane disease (TBMD, also called benign familial hematuria and thin basement membrane nephropathy or TBMN), along with IgA nephropathy, is the most common cause of hematuria without other symptoms. The only abnormal finding in this disease is thinning of the glomerular basement membrane in the kidney. Its importance lies in the fact that it has a benign prognosis and patients maintain normal kidney function throughout their lives. Most patients with thin basement membrane disease have microscopic hematuria found incidentally on urinalysis. Blood pressure, renal function, and urinary protein excretion are usually normal. Mild proteinuria (less than 1.5 g / day) and hypertension may be seen in a few patients. Frank hematuria and flank pain should prompt a search for other causes, such as kidney stones or flank pain-hematuria syndrome. In addition, there are no systemic manifestations, so the presence of hearing impairment or visual impairment should prompt a search for hereditary nephritis, such as Alport syndrome. Some TBMD patients are thought to be carriers of the gene that causes Alport syndrome.

[0244] O. Mesangial proliferative glomerulonephritis

[0245] Mesangial proliferative glomerulonephritis is a type of glomerulonephritis that is primarily associated with the mesangium. There is some evidence that interleukin-10 may inhibit it in animal models. [2] The World Health Organization (WHO) classifies it as type II lupus nephritis. Mesangial cells in the glomeruli take up and degrade circulating immunoglobulins by endocytosis. This normal process stimulates mesangial cell proliferation and matrix deposition. Therefore, during periods of elevated circulating immunoglobulins (i.e., lupus and IgA nephropathy), one would expect to see an increase in the number of mesangial cells and matrix in the glomeruli. This is characteristic of the nephritic syndrome.

[0246] P. Amyloidosis (primary)

[0247] Amyloidosis is a group of diseases in which abnormal proteins called amyloid fibrils accumulate in tissues. [4] Symptoms depend on the type and are often variable. [2] They can include diarrhea, weight loss, feeling tired, a swollen tongue, bleeding, numbness, feeling weak when standing, leg swelling, or an enlarged spleen. [2] There are about 30 different types of amyloidosis, each caused by a specific protein misfolding. [5] Some are inherited, while others are acquired. [3] They are divided into localized and systemic forms. [2] The four most common systemic types are light chain (AL), inflammatory (AA), dialysis (Aβ2M), and inherited age-related (ATTR). Primary amyloidosis refers to amyloidosis in which no associated clinical condition is identified.

[0248] Q.c1q nephropathy

[0249] C1q nephropathy is a rare glomerular disease with characteristic mesangial C1q deposits observed on immunofluorescence microscopy. It is histologically defined and poorly understood. Light microscopic features are heterogeneous and include minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and proliferative glomerulonephritis. Clinical presentation is also varied, ranging from asymptomatic hematuria or proteinuria in children and adults to Frank nephritis or nephrotic syndrome. Hypertension and renal insufficiency at diagnosis are common findings. Optimal treatment is unclear and is often guided by the underlying light microscopic lesions. Corticosteroids are the mainstay of treatment, with immunosuppressants reserved for steroid-resistant cases. The presence of nephrotic syndrome and FSGS appears to predict a poor outcome, in contrast to the favorable outcome seen in patients with MCD. (Devasahayam et al., “C1qNephropathy: The Unique Underrecognized Pathological Entity,” Analytical Cellular Pathology, volume 2015, article ID 490413, page 5, 2015. https: / / doi.org / 10.1155 / 2015 / 490413.)

[0250] R. Anti-GBM disease

[0251] Anti-glomerular basement membrane (GBM) disease, also known as Goodpasture's disease, is a rare condition that causes inflammation of small blood vessels in the kidneys and lungs. Anti-glomerular basement membrane (GBM) antibodies primarily attack the kidneys and lungs, but systemic symptoms such as malaise, weight loss, fatigue, fever and chills are also common, as are joint aches and pains. 60% to 80% of patients experience both lung and kidney involvement; 20%-40% affect only the kidneys, and less than 10% affect only the lungs. Pulmonary symptoms usually precede kidney symptoms and often include: coughing up blood, chest pain (less than 50% of total cases), cough and shortness of breath. Kidney symptoms often include blood in the urine, protein in the urine, unexplained swelling of the limbs or face, high urea levels in the blood, and high blood pressure. GPS causes abnormal production of anti-GBM antibodies by the plasma cells of the blood. Anti-GBM antibodies attack the alveoli and glomerular basement membranes. These antibodies bind their reactive epitopes to the basement membrane and activate the complement cascade, leading to marked cell death. T cells are also involved. It is generally considered a type II hypersensitivity reaction.

[0252] Measurement of urine protein levels

[0253] Protein levels in urine can be measured using methods known in the art. Until recently, accurate protein measurement required a 24-hour urine collection. During the 24-hour collection, the patient urinates into a container that is kept refrigerated between bathroom visits. The patient is instructed to begin collecting urine after the first bathroom visit in the morning. Every drop of urine for the rest of the day should be collected in the container. The next morning, the patient adds the first urination after waking up and the collection is complete.

[0254] Recently, researchers have discovered that a single urine sample can provide the needed information. In the newer technique, the amount of albumin in the urine sample is compared to the amount of creatinine, a waste product of normal muscle breakdown. The measurement is called the urine albumin-to-creatinine ratio (UACR). A urine sample that contains more than 30 milligrams of albumin per gram of creatinine (30 mg / g) warns that there may be a problem. If the lab test is over 30 mg / g, another UACR test should be done 1 to 2 weeks later. If the second test also shows high levels of protein, the person has persistent proteinuria, a sign of decreased kidney function, and additional tests to evaluate kidney function should be done.

[0255] A test that measures the amount of creatinine in the blood will also show whether the subject's kidneys are effectively removing waste. Too much creatinine in the blood is a sign that a person has kidney damage. Doctors can use creatinine measurements to estimate how effectively the kidneys filter the 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).

[0256] Transient receptor potential channel 5 (TRPC5) is a calcium-permeable nonspecific cation channel expressed primarily in the brain, where it forms a heterotetrameric complex with the TRPC1 and TRPC4 channel subunits. TRPC5 is also expressed in the kidney, more specifically in podocytes, where it is involved in the regulation of the podocyte actin cytoskeleton.

[0257] Thus, in certain embodiments, the present invention provides a method for treating a kidney disease or nephropathy associated with a disease or condition, or reducing the risk of developing the same, the method comprising administering a solid dosage form of the present invention to a subject in need thereof. In some embodiments, the kidney disease or nephropathy associated with the disease or condition is focal segmental glomerulosclerosis (FSGS), diabetic nephropathy, Alport syndrome, hypertensive renal disease, nephrotic syndrome, steroid-resistant nephrotic syndrome, minimal change disease, 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), clq nephropathy, rapidly progressive GN, anti-GBM disease, C3 glomerulonephritis, hypertensive nephrosclerosis, I gA 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 kidney disease associated with any of obesity, insulin resistance, type II diabetes, prediabetes, metabolic syndrome, dyslipidemia, pulmonary hypertension, cancer, cholestatic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), or Fabry's disease.

[0258] In some embodiments, the kidney disease or kidney disease associated with the disease or condition is focal segmental glomerulosclerosis (FSGS), diabetic nephropathy, Alport syndrome, hypertensive kidney disease, obesity-related kidney disease, nephrotic syndrome, steroid-resistant nephrotic syndrome, minimal change disease, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), lupus nephritis, post-infectious glomerulonephritis, thin basement membrane disease, mesangial proliferative glomerulonephritis, amyloidosis (primary), clq nephropathy, anti-GBM disease, C3 glomerulonephritis, hypertensive nephrosclerosis, IgA nephropathy, IgG4 nephropathy, dyslipidemia-related kidney disease, nodular glomerulonephritis, NASR disease (proliferative glomerulonephritis with monoclonal IgG deposits), polycystic kidney disease, or renal complications caused by Fabry disease.

[0259] In some embodiments, the kidney disease is hypertensive nephropathy, nephropathy associated with metabolic syndrome, nephropathy associated with obesity, nephropathy associated with dyslipidemia, diabetic nephropathy, nephrotic syndrome, FSGS, or minimal change disease. In some embodiments, the kidney disease is diabetic nephropathy, FSGS, or minimal change disease.

[0260] In one aspect, the invention relates to a method of treating pain, anxiety or depression, comprising administering to a subject in need thereof a solid dosage form of the invention.

[0261] Subjects to be treated

[0262] In one aspect of the invention, the subject is based on that they suffer from renal disease, pulmonary hypertension, anxiety, depression, cancer, diabetic retinopathy or pain or are in the risk of developing these diseases and select. In another aspect, the subject is based on that they suffer from renal disease, anxiety, depression, cancer or diabetic retinopathy or are in the risk of developing these diseases and select. In another aspect of the invention, the subject is based on that they suffer from pain, neuropathic pain, visceral pain, FSGS related to transplantation, nephrotic syndrome related to transplantation, proteinuria related to transplantation, cholestatic liver disease, polycystic kidney disease, autosomal dominant polycystic kidney disease (ADPKD), obesity, insulin resistance, type II diabetes, prediabetes, metabolic syndrome, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) or are in the risk of developing these diseases and select.

[0263] Subjects who suffer from proteinuria or are at risk of developing proteinuria include subjects with diabetes, hypertension or certain family backgrounds. In the U.S., diabetes is the main cause of end-stage renal disease (ESRD). In type 1 and type 2 diabetes, albumin in urine is one of the first signs of kidney function deterioration. As kidney function declines, the amount of albumin in urine increases. Another risk factor for developing proteinuria is hypertension. Proteinuria in people with hypertension is an indicator of kidney function decline. If hypertension is not controlled, this person may progress to complete renal failure. African Americans are more likely to have hypertension and therefore develop kidney problems than Caucasians, even if their blood pressure is only slightly elevated. Other groups at risk of proteinuria are American Indians, Hispanics / Latin Americans, Pacific Islanders Americans, the elderly and overweight subjects.

[0264] In one aspect of the present invention, the subject is selected based on that they suffer from proteinuria or are in the risk of developing proteinuria. The subject who suffers from proteinuria or is in the risk of developing proteinuria is a subject with one or more symptoms of the disease. The symptoms of proteinuria are well known to those skilled in the art and include but are not limited to a large amount of protein in the urine, which may cause the urine to look foamy in the bathroom. The loss of a large amount of protein may cause edema, wherein swelling of the hands, feet, abdomen or face may occur. These are signs of a large amount of protein loss and indicate that kidney disease has progressed. Laboratory testing is the only way to find out whether there is protein in the subject's urine before extensive kidney damage occurs.

[0265] The method is effective for a variety of subjects, including mammals, e.g., humans and other animals, such as laboratory animals, e.g., mice, rats, rabbits, or monkeys, or domesticated and farm animals, 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.

[0266] Example

[0267] The present invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

[0268] Unless otherwise indicated, all ratios and percentages are presented on a weight basis.

[0269] Example 1 Excipients and Equipment

[0270] Potential excipients for spray-dried solid dispersions and tablet development preparations were pharmacopeia grade or USP grade and were selected based on Patheon's prior experience. A complete list of excipients and equipment used for this body of work can be found in Table 1. Unless otherwise specified, throughout this report, the composition percentages of solutions or solid dispersions are described on a weight:weight basis.

[0271] Table 1: Materials and Equipment

[0272]

[0273]

[0274] Example 2 Differential Scanning Calorimetry (DSC)

[0275] MDSC was performed using a TA Instruments Discovery DSC2500 differential scanning calorimeter equipped with a TA instruments cryocooling system 90. MDSC was used to measure the thermodynamic events and characteristics of Compound 1 API and subsequent SDI. The events observed included the glass transition temperature (T g ), cold crystallization (T c , defined as a crystallization event at a temperature below the melting temperature) and the melting temperature (T m). The SDI sample was placed in a non-sealed aluminum pan and heated at a constant rate of 2.0°C / min in the temperature range of 0°C-200°C. The system was purged with a nitrogen flow at 50 mL / min to ensure an inert atmosphere throughout the measurement. The amorphous API was obtained by successfully heating compound 1 above the melting point to 258°C and rapidly quenching it using liquid N2. The resulting amorphous API was analyzed by modulated DSC at up to 265°C. A summary of the MDSC analysis parameters is shown in Table 2.

[0276] Table 2. MDSC analysis parameters

[0277] parameter value instrument TA Discovery DSC2500, RCS 90 Sample tray Tzero Al, non-hermetic Temperature range 5℃-200℃(5℃-265℃ for API) Heating rate 2℃ / min Scan Mode modulation Modulation frequency 60s Modulation Amplitude 1℃

[0278] Example 3 X-ray powder diffraction (XRPD)

[0279] XRPD was performed using a Rigaku Miniflex 6G or a Bruker D2 Phaser X-ray diffractometer to evaluate the crystallinity of the spray dried material. Amorphous materials give an "amorphous halo" diffraction pattern without the discrete peaks that would be found in crystalline materials. The samples were irradiated with monochromatized Cu Kα radiation and analyzed in continuous scan mode between 5° and 40°. The samples were rotated during analysis to minimize preferred orientation effects. A summary of the XRPD analysis parameters can be found in Tables 3 and 4 and are different for each instrument in order to achieve similar diffraction patterns.

[0280] Table 3. XRPD analysis parameters (Rigaku)

[0281]

[0282]

[0283] Table 4. XRPD analysis parameters (Bruker)

[0284]

[0285] Example 4 Particle morphology by scanning electron microscopy (SEM)

[0286] SEM samples were prepared by dispersing the powder onto a sample rod coated with adhesive carbon using a Cressington 108Auto, which was coated with a thin gold-palladium conductive layer. The samples were analyzed using a FEIQuanta 200SEM equipped with an Everhart-Thornley (secondary electron) detector operating in high vacuum mode. Micrographs were taken at different magnifications for qualitative particle morphology analysis. Experimental parameters including spot size, working distance, and accelerating voltage varied from sample to sample to obtain optimal imaging conditions and were recorded in the title of each SEM micrograph.

[0287] Example 5 Particle Size Distribution (PSD) by Light Diffraction

[0288] The particle size of the SDI samples was determined by laser diffraction using a Mastersizer 3000 with an Aero S unit (Malvern Instruments). Approximately 100 mg of sample was added to a standard venture disperser with a hopper gap of 1.5 mm and then fed into the dispersion. The feed rate was adjusted to 40% to maintain the laser obscuration level at 0.1%-15%. Compressed air at 2 bar was used to transport and suspend the sample particles through the optical cell. A measurement time of 10 seconds was used, and a background measurement of 10 seconds was performed using air. Dv 10 、Dv 50 and Dv 90 Diameter is used to characterize the particle size distribution of the powder. For example, Dv 50 The diameter is the diameter at which 50% of the sample volume consists of particles of equal or smaller size.

[0289] Example 6 Water content measurement by coulometric Karl Fischer (KF) titration

[0290] SDI samples were collected after secondary drying and analyzed for water content by a Metrohm 831 Karl Fischer coulometric titrator with a Metrohm 874 oven processor. Approximately 100 mg of sample was sealed in a 6 mL crimp vial and then the water content was measured with the following parameters: reagent Hydranal Coulomat AG-hoven, oven temperature 150°C, and sample extraction time 300 seconds.

[0291] Example 7 Dynamic Vapor Sorption (DVS)

[0292] Dynamic vapor sorption (DVS) was used to study the water adsorption level of crystalline compound 1. The samples were exposed to humidity levels varying from 10%-90% in 10% increments and desorbed to 20% relative humidity (RH). Accurate weight measurements made at 2 minute intervals showed that the weight % uptake of H2O was a function of %RH. The DVS analysis parameters are shown in Table 5 below.

[0293] Table 5. DVS analysis parameters

[0294]

[0295]

[0296] Example 8 Determination by HPLC and analysis of related substances

[0297] An experimental HPLC method was used to evaluate the determination of SDI samples and related substances (Table 6). The HPLC method used was based on the API preparative HPLC method of Compound 1. This method demonstrated linear response, selectivity, and separation of previously seen impurities.

[0298] Example 9 Residual Solvent

[0299] The residual solvent content of SDI was measured by GC headspace analysis (GC-HS) after secondary drying. The measurement was performed using an HP 6890 series GC equipped with an Agilent 7697A headspace sampler. The test was performed using a 30m×0.32mm×1.8μ capillary column with a 6% cyanopropylphenyl 94% dimethylpolysiloxane GC column. The GC sample was prepared by dissolving ~100mg sample in 4mL dimethyl sulfoxide (DMSO). Using a standard GC-HS method (DM-123), no additional verification / confirmation activities were performed on the drug product at this stage.

[0300] Example 10 In vitro dissolution performance

[0301] The in vitro drug dissolution performance of each SDI was evaluated by Patheon's two-stage "gastric transit" non-sedimentation dissolution test (Table 8), which simulates the pH and bile salt concentrations of gastric and intestinal exposure in an easy-to-perform assay. Pre-weighed SDI powder was briefly suspended in the medium (e.g., by vortexing with 4.0 mL of medium for 10 seconds) and transferred to a 50 mL preheated (37° C.) volume of 0.1 N HCl in a USP Type 2 microcontainer (100 mL total container volume). (水溶液)(simulated gastric fluid or SGF, pH ~ 1.0, without pepsin or bile salts) while stirring (paddle) at 100 rpm. After 30 minutes of gastric pH exposure, an equal volume of PBS-buffered 2x concentrated fasted state simulated intestinal fluid (FaSSIF) was added to SGF, resulting in a final pH of 6.8 in FaSSIF (100mM PBS, containing 2.24mg / mL SIF powder (original) (Biorelevant Inc.), total volume of 100mL). Aliquots (1.0mL) of the dissolution medium were taken at selected time points before and after simulated gastric transit, centrifuged (13000rpm) to precipitate undissolved solids, and the supernatant was sampled and further diluted in an appropriate diluent to determine the total drug concentration of the API (e.g., free and colloid / polymer-bound drug in solution) using a suitable HPLC method. Additional centrifugation and filtration were performed using a 10K molecular weight cutoff filter to remove polymer-bound aggregates and colloids. The resulting filtrate of free drug consists of drug and micelles in solution. The volume of FaSSIF added was adjusted to account for the sampling volume removed prior to gastric diversion (typically 4 x 1.0 mL).The initial Compound 1 API measurements and SDI dissolution samples were determined using HPLC.

[0302] Table 6. Non-sedimentation dissolution test parameters

[0303] parameter value Device USP Type 2 (100mL) Gastric media 0.1N HCl (aqueous solution) Intestinal media FaSSIF temperature 37℃±0.5℃ Paddle speed 100RPM dose 1.0→0.5mg compound 1 / mL

[0304] Example 11 Sedimentation and Dissolution

[0305] In 50 mM phosphate buffer (pH = 6.8, containing 2% SLS (w / v)), using USP <711> Compound 1 tablets, 20 mg and 100 mg, were analyzed by apparatus 2. Samples were filtered upon collection and analyzed by reverse phase high performance liquid chromatography (HPLC) with ultraviolet (UV) detection (Table 7).

[0306] Table 7. Summary of dissolution parameters

[0307]

[0308]

[0309] Example 12 Preparation of dissolution medium

[0310] Simulated Gastric Fluid (SGF): Determine the volume of SGF required for all dissolution samples. Based on this volume, dilute 1.0N HCl 10× with H2O in an appropriate Class A graduated cylinder or volumetric flask. Mix well and test the approximate pH using pH paper. The observed pH should be 1.0-1.1.

[0311] PBS Buffer (200 mM): Determine the volume of buffer required for all dissolution samples. Based on this volume, weigh 200 mMol / L NaCl and 200 mMol / L Na2HPO4 and transfer to an appropriately sized container. Add an appropriate volume of H2O to this container. Sonicate the solution until all salts are completely dissolved. If necessary, adjust to pH 8.9 ± 0.1 with phosphoric acid or 1.0 N NaOH.

[0312] FaSSIF Medium (4.48 mg / mL): Add 4.48 mg of SIF powder to each mL of 200 mM PBS in the above PBS medium. Mix well and stir with a magnetic stir bar until all SIF is dissolved. Place at RT for two 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°C-8°C) for up to 4 days. Remove from the refrigerator at least two hours before use, ensuring that the solution reaches 37°C before use.

[0313] 50 mM phosphate buffer, pH = 6.8, containing 2% SLS (w / v): Combine 6 L of water and 41.4 g of sodium dihydrogen phosphate monohydrate, adjust to pH = 6.8. Add 120 g of sodium dodecyl sulfate and stir until dissolved.

[0314] Example 13 Disintegration

[0315] According to USP <701> "Disintegration" Disintegration was assessed using a Varian VK-100 disintegration apparatus. The apparatus consisted of a 1000 mL low profile beaker and a basket assembly with six open ended transparent tubes. The beaker contained 750 mL RO water and was maintained at a temperature of 37°C (±2°C). The basket was fully submerged at a frequency of 29-32 cycles per minute, and the tablet disintegration time was recorded when the last visible tablet material passed through the basket.

[0316] Example 14 Tablet friability

[0317] Friability passes USP <1216> Determined using a Pharmatron FT 2 friability tester. A drum rotation speed of 25 rpm was used with a total rotation time of 4 minutes. According to the USP method, the acceptable friability loss is ≤ 1.0 wt%.

[0318] Example 15 Tablet hardness and tensile strength

[0319] Tablet breaking force according to USP <1217> "Tablet crushing force" was tested using a Natoli hardness tester (S / N 1403029). Tablet thickness and weight were measured prior to evaluating tablet crushing force, as this is a destructive process. Tablets were placed in an automatic crushing device and tablet crushing force was measured in kilogram-force / kilogram-force (kp). Tablet tensile strength (in MPa) was calculated for standard circular concave (SRC) and oval tablets based on the following formula:

[0320] Formula 2:

[0321] Formula 3:

[0322] Where P = breaking load, D = tablet width, t = tablet thickness, W = tape thickness (KG Pitt and MG Heasley. "Determination of the tensile strength of elongated tablets." Powder Technology, Vol. 238 (2013), pp. 169-175.)

[0323] Example 16 Particle size distribution by sieving analysis

[0324] Particle size distribution is determined by a method similar to USP <786> The analytical sieving method was used to determine the material. A RO-TAP RX-29-E sieve shaker (WSTyler) was used to evaluate the material. The sieves used and the operating parameters can be found in Table 8 below:

[0325] Table 8. Equipment and parameters for particle size distribution analysis via analytical sieving method

[0326] parameter value Equipment Manufacturers WS Tyler Vibrating screen machine model RO-TAP RX-29-E Vibration Mode Coarse Operation time 5min Sieve #1 20 mesh (841μm) Sieve #2 30 mesh (595μm) Sieve #3 40 mesh (420μm) Sieve #4 60 mesh (250μm) Sieve #5 120 mesh (125μm) Sieve #6 200 mesh (74μm)

[0327] Example 17 Compound Analysis and Characterization Evaluation

[0328] Thermal properties of Compound 1 crystalline Form H (anhydrous / solvate-free) were measured by MDSC, including the melting temperature (T m ), glass transition temperature (T g ) and crystallization temperature (T c ). T of compound 1 m It was captured under a standard heating rate ramp initially performed at 10°C / min and a melt decomposition was observed with an endothermic melting peak at 257°C. T was measured by a melt quench technique where compound 1 was heated above its melting temperature and rapidly cooled in liquid nitrogen to trap the molten material in an amorphous state. g The resulting sample was analyzed by MDSC and a T of 130 °C was observed. g ( Figure 1A-B / Table 9), no crystallization peak or clear melting event was observed in the subsequent amorphous slope up to 275°C. m / T g The ratio is 1.32, indicating moderate physical stability. The T m / T g Than indicated the possibility of higher drug loading amorphous dispersions with acceptable physical stability.

[0329] Table 9. Summary of Thermal Properties of Crystalline Compound 1 Free Base Form H

[0330] Material batch number <![CDATA[T g ]]> <![CDATA[T m ]]> Compound 1 A05313-058P1 130℃ 257℃

[0331] The diffraction pattern of the crystalline Compound 1 form was determined using XRPD ( Figure 2 ). The diffraction pattern of bulk API indicated crystalline material consistent with thermal analysis.

[0332] Scanning electron microscopy was used to characterize the surface morphology of bulk API particles. Figure 3 The SEM images in show Compound 1 API at 500x, 1500x, and 5000x magnifications. The API morphology consists of agglomerates of smaller API particles of different crystal morphologies.

[0333] The organic solubility of Compound 1 was determined visually in common spray drying solvents (Table 10) and using Compound 1 batch number AC5313-058P1.

[0334] Table 10. Visual determination of the solubility of bulk Compound 1 crystalline form H in organic solvents

[0335]

[0336] 1 A clear solution was obtained upon heating to 40°C.

[0337] 3.0% Compound 1 dissolved in 60:40 DCM: methanol approximately 2 hours after heating to 40°C. When removed from heat, the API collapsed after 5 minutes. A solution was then prepared at 2.0% Compound 1 (% w / w) and heated to 40°C, where the solids dissolved immediately. The 2.0% solution was then removed from heat, where the API collapsed after approximately 2 hours. Heated (40°C) 60:40 DCM: methanol was designated as the lead solvent system, with the maximum active loading of 2.0% Compound 1 in solution.

[0338] Example 18 Focused Screening of Solid Dispersion Polymers: Spray Drying Formulation Preparation

[0339] Feasibility dispersions were prepared using Compound 1 batch number AC5313-058P1. Five Compound 1 SDI formulations were selected for feasibility screening. These formulations were selected based on previous data provided by Goldfinch Bio, where acceptable PK results were obtained using 25:75 Compound 1:HPMCAS-L SDI. The selected feasibility 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 the recovered SDI drying yield (Table 12) can be found below. The spray solution was amber and transparent after adding the API.

[0340] Table 11. Summary of spray drying parameters used for Compound 1 feasibility.

[0341] parameter value Spray Dryer Buchi B290 cyclone High efficiency Solvent system 60:40DCM:Methanol Solution temperature 40℃ Batch size, activity 9g Compound 1 Solution composition 3％-7％ Atomization pressure 25psi Solution feed rate 15mL / min Inlet temperature 77℃-105℃ Outlet temperature 45℃ Secondary drying 24 hours at 40℃

[0342] Table 12. Summary of spray dried formulation yields.

[0343] preparation batch number Drying yield (%) 25:75 Compound 1: HPMCAS-M G8-854-4 80 50:50 Compound 1: HPMCAS-M G8-854-5 66 66:34 Compound 1: HPMCAS-M G8-854-6 76 25:75 Compound 1: HPMCAS-L G8-854-7 60 50:50 Compound 1: HPMCAS-L G8-854-8 66

[0344] Example 19 Focused Screening of Solid Dispersion Polymers: Spray-Dried Formulation Characterization

[0345] The initial SDI formulations were characterized by powder X-ray diffraction (XRPD), scanning electron microscopy (SEM), modulated differential scanning calorimetry (MSDC), headspace gas chromatography (GC-HS), and in vitro non-sedimentation dissolution testing.

[0346] After spray drying, the residual solvent is removed using a secondary tray drying method. In this operation, "wet" SDI is heated to 40 ° C and stored in a convection tray oven for 24 hours. Gas chromatography (GC) headspace analysis is used to measure the residual solvent remaining in the compound 1SDI material after secondary drying. The residual solvent in all preparations is lower than DCM (600ppm) and MeOH (3000ppm) limits specified by the International Conference on Harmonization (ICH). Table 13 shows the residual solvent results of feasibility preparations.

[0347] Table 13. Summary of GC headspace results for Compound 1 SDI after secondary drying.

[0348] preparation batch number Residual solvents (ppm) 25:75 Compound 1: HPMCAS-M G8-854-4 MeOH: <400; DCM: not detected 50:50 Compound 1: HPMCAS-M G8-854-5 MeOH: <400; DCM: not detected 66:34 Compound 1: HPMCAS-M G8-854-6 MeOH: <400; DCM: not detected 25:75 Compound 1: HPMCAS-L G8-854-7 MeOH: <400; DCM: not detected 50:50 Compound 1: HPMCAS-L G8-854-8 MeOH: <400; DCM: not detected

[0349] Initial characterization by XRPD indicated that 50% and 66% of Compound 1 SDI showed crystalline peaks, and all 25% SDI was amorphous ( Figure 4 ).

[0350] Thermal analysis of two amorphous 25% Compound 1 dispersions was performed by MDSC. DSC showed that both dispersions had a single T g ( Figure 5A -B), indicating that the intimately mixed amorphous solid dispersion has good uniformity (Table 14). To ensure long-term physical stability, SDI should be stored at a temperature far below T under given storage conditions. g The temperature makes the mobility of the drug in the glass dispersion low.

[0351] Table 14. MDSC Data for Amorphous 25% Compound 1 Dispersions in HPMCAS-M and HPMCAS-L

[0352] preparation batch number Measured Tg(℃) 25:75 Compound 1: HPMCAS-M G8-854-4 91 25:75 Compound 1: HPMCAS-L G8-854-8 91

[0353] The dissolution performance of SDI materials and crystalline Compound 1 was tested in the Patheon non-sedimentation dissolution test ( Figure 6 and Table 15). The dissolution test was used to measure the supersaturation of drug solubility in a biologically relevant intestinal medium (FaSSIF) above bulk crystalline Compound 1 after exposure to a low pH environment for 30 minutes. During the test, samples were diluted from 0.1N HCl [theoretical C max =1000μA / mL] is converted to FaSSIF [theoretical C max =500 μA / mL]. This experiment was designed to rank and select lead agents.

[0354] All SDI formulations provided an increase in AUC when compared to the crystalline API where the 25% HPMCAS-M solution showed the best performance. As expected, free drug concentrations were lower than the total drug counterparts. Free drug levels were consistently lower than the total drug samples and were constant as a percentage of total drug across the formulations. The selected lead formulations had drug loadings of 25% and 50% in HPMCAS-M and 25% in HPMCAS-L.

[0355] Table 15. 0.1 N HCl / FaSSIF Non-Settling Dissolution Testing of Compound 1 Feasibility SDI Compared to Pure Crystalline Compound 1 Form H

[0356]

[0357] a C max FaSSIF = Maximum drug concentration after transfer to FaSSIF

[0358] b C 210 = drug concentration at 180 minutes after transfer to FaSSIF

[0359] c AUC 35-210 FaSSIF = Area under the curve from 35 to 210 minutes after transfer to FaSSIF

[0360] The lead SDI formulations were tested by dynamic vapor sorption, with the 50:50 Compound 1:HPMCAS-M dispersion showing minimal water sorption due to the lower polymer concentration. All samples showed slight hysteresis upon desorption ( Figure 7 ).

[0361] Example 20 Focused Screening of Solid Dispersion Polymers: Feasibility of Respraying Agents

[0362] The Compound 1 batch number used for the re-spray was TJ-GDF-9815-0-A-1. Due to minor crystallinity observed by XRPD for the 50% and 66% Compound 1 loading dispersions, three additional feasible formulations were prepared. The re-spray formulations can be found in Table 16.

[0363] Table 16. Summary of Feasibility Respray Formulation Yields and Assigned Batch Numbers

[0364] preparation batch number Drying yield (%) 25:75 Compound 1: HPMCAS-M G8-854-13 85 50:50 Compound 1: HPMCAS-M G8-854-14 56 50:40:10 Compound 1: HPMCAS-M: Vitamin E TPSG G8-854-15 59

[0365] The spray solution was brown and opaque after the addition of the API, indicating that the API batch had a different solubility from the first round of feasibility sprays. Batches G8-854-13 and 14 were sprayed at increased outlet temperatures (60°C) to mitigate API-rich areas in the SDI particles. Batch G8-854-10 included Vitamin E TPGS to help mitigate crystallinity and was sprayed at 40°C outlet temperature due to the low melting point of TPGS (a wax at room temperature). XPRD traces for the heavy spray and the original 25:75 Compound 1:HPMCAS-M dispersion can be seen at Figure 8 The two 50% resprays appear to have crystallization peaks similar to the original SDI, with the 25% resprayed dispersion appearing to have a very slight crystallization peak around 26° 2-theta. This data supports the observation that the new API batch may not be fully dissolved in the spray solution.

[0366] Example 21 Focused Screening of Solid Dispersion Polymers: SDI Accelerated Stabilization

[0367] To rapidly evaluate 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 aged for 4 weeks at 40°C / 75% RH and 50°C / 75% RH in open and closed plus desiccant packaging configurations (Stability Protocol RD-ST-18-940). Changes in SDI were evaluated for:

[0368] ●Amorphous physical state by XRPD

[0369] ●Chemical stability by HPLC

[0370] Initial XRPD analysis of aged SDI samples at 2 weeks showed that all SDI formulations remained amorphous under closed conditions with desiccant at 40°C / 75% RH and 50°C / 75% RH, while showing crystalline growth in the 50% dispersion under open conditions ( Figure 9-10 ).

[0371] Additional XRPD testing was performed on the SDI at 4 weeks and all samples in the closed condition remained amorphous. The aggressive 40°C and 50°C open conditions showed crystalline peaks but did not appear to have any further crystalline growth. The SDI in the 25°C / 60%RH open condition was amorphous after 4 weeks ( Figure 11-Figure 12 ).

[0372] Purity analysis of 25:75 Compound 1: HPMCAS-M after 4 weeks showed no impurity growth under closed conditions and the impurity profile matched the starting API. Open conditions showed significant impurity growth at RRT 0.34, 0.82, 0.91 and 0.96 (Tables 17 and 18), indicating that protective packaging would be recommended to protect the long-term storage of SDI.

[0373] Table 17. Purity results for 25:75 Compound 1: HPMCAS-M SDI after 4 weeks accelerated stability.

[0374]

[0375]

[0376] Table 18. Purity results for 25:75 Compound 1: HPMCAS-M SDI after 4 weeks of accelerated stabilization.

[0377]

[0378]

[0379] Similar results were observed with the purity analysis of 25:75 Compound 1:HPMCAS-L SDI after 4 weeks. No impurity growth was observed under any closed condition at RRT 0.82, 0.91, and 0.96, while significant amounts of impurity growth were observed under all open conditions. (Tables 19 and 20).

[0380] Table 19. Purity results for 25:75 Compound 1: HPMCAS-L SDI after 4 weeks accelerated stability.

[0381]

[0382]

[0383] Table 20. Purity results for 25:75 Compound 1: HPMCAS-L SDI after 4 weeks accelerated stability.

[0384]

[0385] Accelerated stability data indicated that Compound 1 impurity growth was driven, at least in part, by moisture exposure. There were no significant differences in the impurity profiles, so the 25:75 Compound 1:HPMCAS-M SDI was selected as the lead to advance to tablet development due to its performance in the non-settling dissolution test.

[0386] Example 22 Spray Drying Intermediate Demonstration Batch

[0387] Compound 1 batch number used; TJ-GDF-9815-0-A-1 (crystalline form H). The specified SDI formulation was placed in proportion in a MS-150 pilot scale spray dryer and an Ekato vacuum dryer for secondary drying. The master formula can be found in Table 21. The batch size was 14 kg SDI, 200 kg solution.

[0388] Table 21.25:75 Master formula of compound 1: HPMCAS-M SDI

[0389]

[0390] Demonstration batch parameters can be found in Table 22.

[0391] Table 22. Spray drying process parameters for the demonstration batch of compound 1SDI on the MS-150 spray dryer

[0392]

[0393]

[0394] The final process yield was 81% and 85% quantifiable. The recommended processing conditions for GMP processing can be found in Table 23.

[0395] Table 23. Recommended spray drying process parameters for 25:75 Compound 1: HPMCAS-M SDI

[0396]

[0397] Anti-bearding nozzle tips are recommended for GMP preparation.

[0398] Example 23 Compound 1SDI Demonstration Batch Analysis Test

[0399] Test the appearance, potency / related substances, water content, residual solvents, T of the demonstration batch of compound 1SDI g, amorphous character, particle size distribution, particle morphology and bulk / tapped density. All results are documented in the Certificate of Test (CoT) and can be found at Fig.13 .

[0400] Example 24 Demonstration of Batch Solution and Wet SDI Stability

[0401] Before spray drying, collect spray solution samples from batch D-18-078 to determine the maximum solution retention time. Solution samples were maintained at 40°C and tested for assay / related substances and appearance at t=0, 1, 5, 9 and 15 days. The spray solution was stabilized for 5 days and degradation was observed at the 9th and 15th day time points. Degradation was observed at RRT=0.85, 0.86, 0.92, 0.94, 0.96, 1.47, 1.52 and 1.56. The solution remained "transparent orange" at the 15-day time point. Repeated measurements of spray solution stability were performed again to confirm the results (Figure 14).

[0402] The degradation profile for the retest was similar to the initial spray solution test.Based on the spray solution retest data, a conservative 3 day stability at 40°C was assigned to the spray solution.

[0403] Wet SDI was tested for appearance, assays / related substances, particle morphology, and amorphous characteristics at room temperature at t=0, 1, 5, 9, and 15 days. Testing was required to determine the maximum retention time of wet SDI prior to secondary drying in an Ekato vacuum dryer. The appearance remained "off-white light brown powder" throughout the test. Assay / related substance results for wet SDI can be found at Fig.15A and Fig. 15B middle.

[0404] Wet SDI was chemically stable at room temperature for at least 15 days. Wet SDI remained amorphous and the particle morphology did not appear to change after 15 days by XRPD. Fig.16 and Fig.17 ).

[0405] Crystallinity is observed at about 26° 2-θ throughout the stable and initial wet SDI. The peak at 26° 2-θ does not appear to grow.

[0406] SDI had a typical collapsed sphere morphology, and no crystallinity was observed. The morphology of wet SDI at 15 days was equivalent to that of dry SDI, and no stability changes were observed.

[0407] Example 25 Development of Prototype Compound 1 Tablets

[0408] Four tablet formulations were selected to evaluate excipient compatibility and tablet physical properties. The filler (mannitol or lactose) and superdisintegrant (croscarmellose sodium or crospovidone) were varied to find the best combination. The formulations can be found in Table 24.

[0409] Table 24. Compound 1 prototype tablet formulations were used to evaluate excipient compatibility and tablet physical properties. Tablet strength was 50 mg Compound 1, with a total tablet weight of 400 mg.

[0410]

[0411] Tablets were prepared at a 50 mg concentration of Compound 1 and a total tablet weight of 400 mg. The prototype formulation was prepared by simulating a dry granulation process using a briquetting machine and a mill. The process flow diagram can be found at Fig.18 middle.

[0412] The intragranular blend was compacted to a solid fraction of approximately 0.70 using a 0.875" flat die. (The true density of the prototype blend was assumed to be 1.35 g / cc). The compacts were then ground using a Vector TFC-micromill with a 20 mesh screen. Prototype tablets were prepared on a Natoli single-station manual press. Tabletability, compressibility, compactability, and disintegration profiles for all formulations using a 0.2505" x 0.5385" modified oval die were generated over a compression range of 50 MPa-300 MPa ( Fig.19 ). (See the applicable mold drawing Figure 31-Figure 32 . )

[0413] All formulations have similar compression curves, which may be determined by high levels of SDI. Tablet formulations achieve high tensile strength at relatively low compression pressures. Ac-Di-Sol is a much more effective disintegrant than Kollidon CL. Formulations containing Kollidon CL have steeper slopes on disintegration curves. Fluctuations in compression pressure can cause huge differences in disintegration time and potentially affect dissolution. Formulations containing Ac-Di-Sol were selected for accelerated stability studies and based on dissolution and cyno PK studies using a single 50 mg tablet in fasted animals. It was also observed that the dissolution rate of tablets containing crospovidone was slower, with AUC reduced by about 50% relative to tablets containing Ac-Di-Sol. No differences were observed between tablets containing lactose and tablets containing mannitol.

[0414] Example 26 Accelerated stability of prototype compound 1 tablets

[0415] The selected prototype tablets (lactose / Ac-Di-Sol and mannitol / Ac-Di-Sol) were placed under accelerated stabilization and stored under open and closed conditions at 40°C / 75% RH and 25°C / 60% RH. The tablets were tested for assay / related substances, non-settling dissolution and disintegration after 4 weeks. The assay / related substances data for the two tablets can be found in Tables 25 and 26.

[0416] Table 25. Assays and related substances for Compound 1 prototype tablets containing lactose / Ac-Di-Sol after 4 weeks of accelerated stabilization.

[0417]

[0418]

[0419] Compared to the bulk API opened only at 40°C / 75%RH, the lactose / Ac-Di-Sol tablets showed minor degradant growth at RRT = 0.34, 0.36 and 0.91. The other conditions showed similar impurity profiles compared to the API.

[0420] Table 26. Assays and related substances for Compound 1 prototype tablets containing mannitol / Ac-Di-Sol after 4 weeks of accelerated stabilization.

[0421]

[0422]

[0423] Mannitol / Ac-Di-Sol tablets stored open at 40°C / 75% RH showed little degradant growth, similar to lactose / Ac-Di-Sol tablets. Other conditions showed similar characteristics to the bulk API. All tablets from both formulations matched target potency values.

[0424] Both tablet formulations were tested for non-sedimentation dissolution under all conditions and found to show similar performance for total and free drug ( Fig. 20 and Fig.21 ).

[0425] The tablets showed similar disintegration times, except for the 40°C / 75% RH open condition, which was significantly longer. This may be due to the fact that Ac-Di-Sol and Avicel in the formulation absorbed moisture and swelled during the stabilization period, which means that all disintegrants have been activated. When these tablets were placed in the disintegration bath, there was no force to swell and break the tablets. Table 27 shows the disintegration time and appearance data.

[0426] Table 27. Disintegration and appearance of prototype Compound 1 tablets after 4 weeks of accelerated stabilization.

[0427]

[0428] The two tablet formulations appeared equivalent in terms of stability and in vitro performance. PK testing determined that mannitol / Ac-Di-Sol provided better exposure and was designated for scale-up. Lactose and mannitol tablet formulations were equivalent when exposed to a 25:75 SDD suspension. Stability studies indicated that packaging would require a desiccant to protect the tablets from moisture, as demonstrated by differences in chemical stability in open vs. desiccant-sealed HDPE bottle configurations at 40°C / 75% RH.

[0429] Example 27 Compound 1 Tablet Demonstration Batch: Compound 1 Tablet Demonstration Batch Compression

[0430] A demonstration batch of Compound 1 tablets was prepared on a Piccola 10-station rotary press at a turret speed of 20 rpm. Compression and disintegration profiles were generated and compared to feasibility Compound 1 tablets ( Fig. 22 ).

[0431] Tablet compressibility, compressibility and compactability graphs show that the prototype tablets are stronger than the demonstration batch tablets. This is due to the difference in residence time between the two methods (rotary tablet press has significantly less residence time). The disintegration curves of the 50mg prototype and 100mg demonstration batch tablets appear to overlap, with a sharp increase observed from 150MPa-200MPa compression pressure. The 20mg Compound 1 tablets did not show a sharp increase within the compression range tested and had a more robust operating window. Additional dissolution testing was performed on the 100mg Compound 1 tablets at 200MPa and 250MPa ( Figure 23-Figure 25 ) to determine whether a dramatic increase in disintegration time would affect release.

[0432] The extent of release was the same between the 200 MPa and 250 MPa tablets, however, the initial rate was slightly faster for the 200 MPa compressed tablets. The release profile was similar to the bulk demonstration batch material on CoT (Appendix E). A Cyno PK was also performed where no difference in Cmax for AUC was observed when compared to the specified 175 MPa compression pressure. The demonstration batch tablet friability curve showed low friability values ​​above 100 MPa compression pressure ( Fig.26 ).

[0433] Strain rate of 20 mg Compound 1 tablets was tested at table speeds of 30 rpm and 40 rpm. The tablet tensile strength remained consistent at all tested speeds. On a 10-station Piccola rotary press, the formulation did not appear to be strain rate sensitive at speeds of 20 rpm-40 rpm ( Figure 27-Figure 28 ).

[0434] The target compression for the 20 mg Compound 1 tablet was 225 ± 25 MPa and for the 100 mg tablet was 175 ± 25 MPa. The start / middle / end samples were collected throughout the compression process and tested for weight, thickness, crushing force, disintegration and friability. Consistent values ​​were observed in all samples. Friability and disintegration data are shown in Table 28 and Table 29.

[0435] Table 28. Disintegration time of the start, middle and end samples of the 20 mg and 100 mg Compound 1 demonstration batch tablets

[0436]

[0437] Table 29. Friability of starting, middle, and ending samples of 20 mg and 100 mg Compound 1 demonstration batch tablets.

[0438]

[0439] The tablets have a mottled appearance due to the off-white color of the SDI contrasting with the white color of the extragranular components ( Fig.29 ). Spots can also be reduced by rolling the ribbon to a lower solids fraction.

[0440] All tablet samples disintegrated and passed friability in approximately 1-4 minutes. Tablet weights remained consistent and no powder flow issues were observed during compression for both tablet strengths. The weights of composite samples from each tablet batch (n=50) were analyzed and a tight distribution was found. The average tablet weight was within target and only two tablets differed by weight by more than 5% (both 20 mg Compound 1) ( Fig.30 ).

[0441] A summary of the two batches can be found in Table 30.

[0442] Table 30. Demonstration batch summary of 20 mg and 100 mg Compound 1 tablets.

[0443]

[0444] 4 Mould drawing see Figure 31-Figure 32 .

[0445] 5 Low yield due to material consumption during ranging activities.

[0446] Example 28 Compound 1 Tablet Demonstration Batch: Compound 1 Tablet Demonstration Batch Analysis Test

[0447] The 20 mg and 100 mg Compound 1 demonstration batches of tablets were tested for appearance, water content, assay / related substances, layered content uniformity (Table 31), and dissolution. All analytical results have been compiled in the literature available at Figure 33-Figure 34The test certificate can be viewed in .

[0448] Table 31. Stratified CU data for start, middle, and end samples of 20 mg and 100 mg Compound 1 demonstration batch tablets

[0449]

[0450] Example 29 Conclusion

[0451] SDI feasibility found that amorphous dispersions could be prepared at 25% Compound 1, while 50% and 66% Compound 1 remained partially crystalline after the spray drying process. The SDI formulations that showed the best improvement over crystalline Compound 1 in vitro were 25% Compound 1 in HPMCAS-M and HPMCAS-L. Accelerated stability testing of the amorphous dispersions condemned crystal growth found under open conditions at 40°C / 75% RH and 50°C / 75% RH, where closed conditions with desiccant remained completely amorphous, indicating that moisture exposure had a significant effect on the physical stability of the dispersion. Based on PK testing performed by Goldfinch, 25:75 Compound 1:HPMCAS-M was the designated SDI and was successfully prepared on a pilot scale MS-150, and an Ekato vacuum dryer was used to remove residual solvent. The designated prototype tablet formulation was successfully scaled up to a Vector TFC-220 roller press and a Piccola 10-station rotary press. Due to high levels of fines and flow issues observed during the discharge of the final blend, further development of the granulation process was recommended. Improved flow will be critical for higher throughput production. Grinding the ribbons with a low energy mill may remedy this problem. GMP production will use the same equipment used for spray drying and tableting and is expected to have a high likelihood of success.

[0452] Example 30 Sample Preparation

[0453] 1-mg tablet

[0454]

[0455] a) Active Compound 1 for tablet use is provided as Compound 1 SDD.

[0456] b) The amount of mannitol used was adjusted to compensate for the measured potency of the SDD.

[0457] 5-mg tablet

[0458]

[0459]

[0460] a) Active Compound 1 for tablet use is provided as Compound 1 SDD.

[0461] b) The amount of mannitol used was adjusted to compensate for the measured potency of the SDD.

[0462] 20-mg and 100-mg tablets

[0463]

[0464] Incorporated by Reference

[0465] All U.S. patents and U.S. and PCT published patent applications cited herein are hereby incorporated by reference.

[0466] Equivalent solutions

[0467] The foregoing written description is sufficient to enable those skilled in the art to practice the invention. The scope of the invention is not limited by the examples provided, as these examples are intended to be a single illustration of one aspect of the invention, and other functionally equivalent embodiments are also within the scope of the invention. Based on the foregoing description, various modifications of the invention, in addition to those shown and described herein, will become apparent to those skilled in the art and fall within the scope of the appended claims. The advantages and objects of the invention are not necessarily included in each embodiment of the invention.

Claims

1. A composition for preparing 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.

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

3. A composition as claimed in claim 1 or 2, wherein the polymer is hydroxypropylmethylcellulose acetate succinate.

4. The composition of claim 1 or 2, wherein the polymer is Eudragit.

5. The composition of any one of claims 1-4, wherein the solvent is acetone, methyl ethyl ketone, ethyl acetate, isopropanol, dioxane, acetonitrile, ethanol, water, methanol, dichloromethane, tetrahydrofuran, or any combination thereof.

6. The composition of claim 5, wherein the solvent is a combination of methanol and dichloromethane.

7. The composition of claim 6, wherein the ratio of dichloromethane to methanol is from about 30:70 to about 60:

40.

8. A method for preparing a spray-dried dispersion, the method comprising the step of spray-drying the composition according to any one of claims 1 to 7.

9. 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.

10. The spray-dried dispersion of claim 9, wherein the polymer is hydroxypropylmethylcellulose acetate succinate.

11. The spray-dried dispersion of claim 9, wherein the polymer is Eudragit.

12. The spray-dried dispersion of claim 10, wherein 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 hydroxypropylmethylcellulose acetate succinate is between about 1:9 and about 2:

1.

13. A solid dosage form comprising the spray-dried dispersion according to any one of claims 9 to 12, and one or more of a filler, a disintegrant, a lubricant, a glidant and a stabilizer.

14. The solid dosage form of claim 13, wherein the filler comprises mannitol and microcrystalline cellulose.

15. The solid dosage form of claim 14, wherein the ratio of mannitol to microcrystalline cellulose is between about 1:3 and about 3:

1.

16. The solid dosage form of claim 14, wherein the ratio of mannitol to microcrystalline cellulose is from about 1:1 to about 1:1.

3.

17. The solid dosage form of any one of claims 13-16, wherein the disintegrant is croscarmellose sodium.

18. The solid dosage form of claim 17, wherein the croscarmellose sodium is present at between about 3% w / w and about 15% w / w.

19. A method for preparing 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 the following steps: a. blending the spray-dried dispersion according to any one of claims 9 to 12 with one or more of the following: a first filler, a first disintegrant, a first lubricant, a first glidant and a first stabilizer to form a first solid mixture; b. rolling and grinding the first solid mixture; as well as c. optionally blending the roller compacted and milled first solid mixture with one or more of a second filler, 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.

20. Use of a solid dosage form as claimed in any one of claims 13 to 18 for the preparation of a medicament for treating a kidney disease or nephropathy associated with a disease or condition.

21. Use of the solid dosage form of any one of claims 13 to 18 in the preparation of a medicament for treating pain, anxiety or depression.

Images