TYK2 inhibitor dosage forms

Abstract

Provided are stable, bioavailable formulations and dosage forms comprising a dispersion (e.g., a spray-dried dispersion) of solid amorphous 6-(cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (Formula (I); BMS-986165) in a solid polymer matrix for the treatment of autoimmune and autoinflammatory diseases, such as inflammatory bowel disease (IBD) and psoriasis. TIFF2022548687000021.tif5855 formula (I)

Description

[Technical Field]

[0001] The present invention relates to dosage forms and formulations of 6-(cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, a highly selective inhibitor of Tyk2. The formulations and dosage forms provide bioavailability of 6-(cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide while exhibiting acceptable physical and chemical stability, and can be used to treat autoimmune and autoinflammatory diseases, such as inflammatory bowel disease (IBD) and psoriasis. [Background technology]

[0002] Tyrosine kinase 2 (Tyk2) is a member of the Janus kinase (JAK) family of non-receptor tyrosine kinases and has been shown to mediate immune responses in mice (Ishizaki, M. et al., "Involvement of tyrosine kinase-2 in both the IL-12 / Th1 and IL-23 / Th17 axes in vivo," J. Immunol., 187:181-189 (2011); Prchal-Murphy, M. et al., "TYK2 kinase activity is required for functional type I interferon responses in vivo," PLoS One, 7:e39141 (2012)) and humans (Minegishi, Y. et al., "Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity," Immunity, 25:745-755 (2012)). (2006)), Tyk2 has been shown to be important in regulating signaling cascades downstream of the receptors for IL-12, IL-23, and type I interferons. Tyk2 mediates receptor-induced phosphorylation of members of the STAT family of transcription factors, an essential signal that leads to dimerization of STAT proteins and transcription of STAT-dependent proinflammatory genes.Tyk2-deficient mice are resistant to experimental models of colitis, psoriasis, and multiple sclerosis, demonstrating the importance of Tyk2-mediated signaling in autoimmune and related disorders (Ishizaki, M. et al., "Involvement of tyrosine kinase-2 in both the IL-12 / Th1 and IL-23 / Th17 axes in vivo," J. Immunol., 187:181-189 (2011); Oyamada, A. et al., "Tyrosine kinase 2 plays critical roles in the pathogenic CD4 T cell responses for the development of experimental autoimmune encephalomyelitis," J. Immunol., 183:7539-7546 (2009)).

[0003] In humans, individuals expressing an inactive mutant of Tyk2 are protected from multiple sclerosis and possibly other autoimmune disorders (Couturier, N. et al., "Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility," Brain, 134:693-703 (2011)). Genome-wide association studies have shown other variants in Tyk2 associated with autoimmune disorders, such as Crohn's disease, psoriasis, systemic lupus erythematosus, and rheumatoid arthritis, further demonstrating the importance of Tyk2 in autoimmunity (Ellinghaus, D. et al., "Combined Analysis of Genome-Wide Association Studies for Crohn's Disease and Psoriasis Identifies Seven Shared Susceptibility Loci," Am. J. Hum. Genet., 90:636-647 (2012); Graham, D. et al., "Association of polymorphisms across the tyrosine kinase gene, TYK2 in UK SLE families," Rheumatology (Oxford), 46:927-930 (2007); Eyre, S. et al., "High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis," Nat. Genet., 44:1336-1340 (2012)).

[0004] BMS-986165 refers to a compound represented by the following formula (I): [ka] Formula (I) BMS-986165 is a highly selective inhibitor of Tyk2-mediated signaling, and is being investigated for the treatment of autoimmune and autoinflammatory diseases such as psoriasis, psoriatic arthritis, lupus, lupus nephritis, Sjögren's syndrome, inflammatory bowel disease (including ulcerative colitis and Crohn's disease), and ankylosing spondylitis. It selectively binds to the Tyk2 pseudokinase (JH2) domain and blocks receptor-mediated Tyk2 activation by stabilizing the regulatory JH2 domain.

[0005] BMS-986165 and other amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23, and / or IFNα responses, methods of making same, and methods of using same are disclosed in U.S. Patent No. 9,505,748 B2, the contents of which are incorporated herein by reference in their entireties. Other methods for synthesizing BMS-986165 are disclosed in U.S. Provisional Patent Application No. 62 / 478,789 and PCT / US2018 / 025100 (published as WO2018 / 183649), the contents of each of which are incorporated herein by reference in their entireties.

[0006] BMS-986165 has been synthesized in crystalline forms, such as crystalline form A disclosed in U.S. Provisional Application No. 62 / 478,789 and PCT / US2018 / 025114 (published as WO2018 / 183656), the contents of each of which are incorporated herein by reference in their entirety; crystalline form B disclosed in U.S. Provisional Application No. 62 / 678451 and PCT / US2019 / 034534 (published as WO2019 / 232138), the contents of each of which are incorporated herein by reference in their entirety; and crystalline forms C and D disclosed in U.S. Provisional Application Nos. 62 / 860439 and PCT / US2020 / 036727, the contents of each of which are incorporated herein by reference in their entirety.

[0007] Designing a suitable formulation and dosage form for BMS-986165 presented several challenges, as efforts to design a formulation that would provide bioavailability of the compound after oral administration and be sufficiently stable upon storage were unsuccessful.

[0008] Thus, there is a need in the art for formulations and dosage forms of 6-(cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165) that provide sufficient stability of BMS-986165 upon storage, while providing sufficient bioavailability of BMS-986165. In particular, there is a need for formulations and dosage forms that provide bioavailability of 6-(cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165) when BMS-986165 is administered with agents that increase gastric pH (e.g., agents such as antacids, H2 receptor antagonists and / or proton pump inhibitors). There is also a need for formulations and dosage forms that provide bioavailability of 6-(cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165) in regions of the gastrointestinal (GI) tract, e.g., the colon, where water availability and / or bile salts to enhance drug solubility are low, particularly when sustained release of BMS-986165 after oral administration is desired. At the same time, such formulations and dosage forms must provide sufficient stability of 6-(cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide during storage. The formulations and dosage forms of the present invention address these and other needs. Summary of the Invention

[0009] The present invention provides solid amorphous BMS-986165 formulations that are physically and chemically stable and can be used to make oral dosage forms that provide bioavailability of BMS-986165. The formulations include amorphous BMS-986165 free base and one or more polymers. The formulations provide bioavailability of BMS-986165, including when administered to patients taking medications that increase gastric pH. Under such conditions of elevated gastric pH, dosage forms containing the formulations described herein exhibit bioavailability comparable to that provided by BMS-986165 free base in capsules or oral solutions of the crystalline BMS-986165 HCl salt. The formulations also exhibit superior stability; for example, capsules of the BMS-986165 HCl salt require refrigeration to prevent conversion of the salt to the free base form upon storage, while solid amorphous BMS-986165 formulations and dosage forms exhibit physical stability upon storage under room temperature conditions. The formulations described herein are also suitable for making immediate-release and modified-release dosage forms.

[0010] Accordingly, certain embodiments of the present invention provide formulations and dosage forms comprising solid dispersions of amorphous 6-(cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165). The formulations and dosage forms provide release and dissolution of BMS-986165 to a sufficient extent, and at a sufficiently rapid rate, in a medium that mimics the in vivo conditions of the gastrointestinal tract so as to be suitable for use as immediate-release formulations and dosage forms. Such immediate-release formulations may then be modified to provide controlled-release oral dosage forms of BMS-986165.

[0011] Embodiments of the present invention also provide sustained-release formulations that can be administered to patients once daily and provide a pharmacokinetic profile of BMS-986165 comparable to or superior to that provided by immediate-release tablets administered twice daily. The sustained-release formulations described herein provide bioavailability of BMS-986165 in regions of the GI tract, e.g., the colon, where water availability and / or bile salts to enhance drug solubility are low. Such formulations are particularly useful for treating inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease. The sustained-release BMS-986165 tablet formulations described herein may improve patient compliance and improve patient and / or caregiver convenience, as patients only need to receive one tablet per day. [Brief explanation of the drawings]

[0012] [Figure 1] 1A and 1B show PXRD diffractograms of 10%, 15%, and 20% BMS-986165:HPMCAS-H SDDs described in Example C: FIG. 1A - starting; FIG. 1B - after 6 months of storage at 40° C. / 75% RH, open air. [Figure 2] 2A-C are SEM images at 1500x magnification for 10% BMS-986165:HPMCAS-HSDD: FIG. 2A - starting; FIG. 2B - after 6 months of storage at 40°C / 75% RH, closed; FIG. 2C - after 6 months of storage at 40°C / 75% RH, open. [Figure 3] 3A-C are SEM images at 1500x magnification for 15% BMS-986165:HPMCAS-HSDD: FIG. 3A - starting; FIG. 3B - after 6 months of storage at 40°C / 75% RH, closed; FIG. 3C - after 6 months of storage at 40°C / 75% RH, open. [Figure 4] 4A-C are SEM images at 1500x magnification for 20% BMS-986165:HPMCAS-HSDD: FIG. 4A - starting; FIG. 4B - after 6 months of storage at 40°C / 75% RH, closed; FIG. 4C - after 6 months of storage at 40°C / 75% RH, open. [Figure 5] FIG. 5 shows the dissolution profiles for the dosage forms tested as described in Example E. [Figure 6] FIG. 6 shows the dissolution profile for a sustained release formulation of BMS-986165 crystalline free base. [Figure 7] FIG. 7 shows the dissolution profile for a sustained release spray-dried dispersion formulation of BMS-986165. [Figure 8] FIG. 8 shows the dissolution profile for a sustained release spray-dried dispersion formulation of BMS-986165 with HPMCAS added in addition to SDD. [Figure 9] FIG. 9 shows the dissolution profiles for sustained release spray-dried dispersion formulations of BMS-986165 varying polymer viscosity, surface area to volume ratio, or both. [Figure 10] FIG. 10 shows the dissolution profile for a sustained-release spray-dried dispersion formulation of BMS-986165 developed for further clinical trials. [Figure 11] Figure 11A shows the mean plasma concentration versus time curves for a crossover study comparing BMS-986165 SDD tablets with BMS-986165 crystalline free base tablets in fasted dogs treated with famotidine. Figures 11B and 11C provide the individual plasma concentration versus time curves for each treatment group (n=4). DETAILED DESCRIPTION OF THE INVENTION

[0013] The features and advantages of the present invention may be more readily understood by those skilled in the art upon reading the following detailed description. It is to be understood that certain features of the invention that are described above and below in the context of separate embodiments may also be combined to form a single embodiment. Conversely, various features of the invention that are, for reasons of brevity, described in the context of a single embodiment may also be combined to form subcombinations thereof.

[0014] (Drug Formulations and Dosage Forms) The present invention provides oral dosage forms of BMS-986165 made from dispersions of amorphous 6-(cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165). The dispersions typically contain amorphous BMS-986165 and one or more polymers. The dispersions are used to make a variety of dosage forms for oral administration, including dosage forms that provide immediate release of BMS-986165 and dosage forms that provide sustained release of BMS-986165.

[0015] As used herein, "amorphous" refers to a solid form of molecules and / or ions that is not crystalline. Amorphous solids do not exhibit a distinct X-ray diffraction pattern with sharp maxima; they are thermodynamically non-equilibrium substances that do not exhibit long-term periodicity. Compared with crystalline BMS-986165, amorphous BMS-986165 exists in a higher energy state; amorphous BMS-986165 has higher entropy, enthalpy and Gibbs free energy than crystalline BMS-986165.

[0016] A solid amorphous dispersion or amorphous dispersion refers to a dispersion containing a drug and a polymer, wherein the drug is non-crystalline. Amorphous dispersions of drugs can be prepared by various manufacturing processes, such as spray drying, coprecipitation, or hot-melt extrusion. A spray-dried dispersion (SDD) is a single-phase amorphous molecular dispersion of a drug in a polymer matrix; it is an amorphous solid in which the drug is molecularly "dissolved" in the solid matrix. A spray-dried dispersion can be prepared by dissolving a drug and a polymer in an organic solvent to form a solution, followed by spray drying the solution. Techniques for preparing solid dispersions of amorphous drugs in polymers are disclosed, for example, in U.S. Pat. Nos. 9,095,585 and 9,468,604 (the contents of each of which are incorporated herein by reference in their entirety). Solid dispersions are also described, for example, in U.S. Pat. No. 8,263,128.

[0017] The absence of crystalline drug in an amorphous dispersion can be characterized by modulated differential scanning calorimetry (mDSC), powder X-ray diffraction (PXRD), near-infrared spectroscopy (NIR), or other standard analytical techniques. For example, mDSC evaluates the thermal properties of SDD; for amorphous SDD, analysis by mDSC yields a single glass transition temperature. mDSC can also detect crystalline phase separation, as crystalline phases exhibit unique thermal signatures. PXRD, which uses X-rays to identify the crystalline form of a solid powder, can be used to analyze SDD, for example, to confirm that the SDD is a single amorphous phase with no measurable crystalline material.

[0018] BMS-986165 crystalline free base exhibits pH-dependent solubility, with low solubility at pH levels above 4. Therefore, BMS-986165 crystalline free base exhibits pH-dependent absorption in the GI tract. For immediate-release formulations, this pH-dependent property can result in reduced bioavailability when administered with antacids, such as famotidine or omeprazole. Using the HCl salt form of BMS-986165 in immediate-release formulations mitigates the pH effect; however, during stability testing, formulations made with the HCl salt form of BMS-986165 were observed to convert to the free base form of BMS-986165. While using the high-energy amorphous free base form of BMS-986165 helps address the above challenges, formulating amorphous BMS-986165 presents other challenges, including ensuring the physical stability of the amorphous form during storage and maintaining supersaturation of the compound during dissolution in the GI tract.

[0019] The present invention provides a dispersion formulation of amorphous BMS-986165 with acceptable physical and chemical stability and improved solubility and bioavailability compared to the crystalline free base form of BMS-986165. For example, a spray-dried dispersion of amorphous BMS-986165 in a polymer matrix has higher kinetic solubility compared to the crystalline form of BMS-986165. The higher solubility of amorphous BMS-986165 in the spray-dried dispersion is advantageous for maintaining bioavailability when administered as an antacid and for delivery to areas of the GI tract, such as the colon, where water availability and / or bile salts to enhance drug solubility are low. Additionally, the polymer in the dispersion limits precipitation of BMS-986165 as the drug dissolves, thereby helping to maintain a supersaturated solution as the amorphous form of BMS-986165 dissolves. Amorphous BMS-986165 in the spray-dried dispersion also exhibits physical stability, eg, the compound remains in amorphous form and exhibits little or no crystallization upon storage.

[0020] Dispersing a drug in a polymer can improve in vivo drug concentration or bioavailability, but the amount of polymer that can be used is limited by the total mass requirements of the oral dosage form. In other words, the bioavailability benefits of using a low drug-to-polymer ratio (such that the weight percent of drug in the formulation is lower than the weight percent of polymer) may be offset by the disadvantages associated with using more polymer in the oral dosage form. For example, when delivery of a specific dose in a single tablet or capsule is desired, using a low drug-to-polymer ratio may result in a tablet or capsule with a large total mass that is too large to swallow. The drug loading must be high enough to produce an oral dosage form of acceptable size for the desired dosage strength. At the same time, however, dosage forms with relatively high drug loadings may be more prone to drug crystallization.

[0021] The present invention provides formulations and dosage forms comprising dispersions of amorphous BMS-986165 that achieve the desired bioavailability and stability characteristics while also meeting the physical requirements of an oral dosage form. For example, the higher solubility of amorphous BMS-986165 in the spray-dried dispersion improves the bioavailability of the drug, including when administered with a drug that increases gastric pH; the spray-dried dispersion of amorphous BMS-986165 is chemically and physically stable upon storage and can be formulated at desired dosages in a swallowable dosage form.

[0022] Certain embodiments of the present invention provide dispersions in which the w / w % of BMS-986165 (amorphous) to polymer ranges from about 3% to about 80% BMS-986165 and from about 97% to about 20% polymer. Further embodiments provide dispersions in which the w / w % of BMS-986165 to polymer ranges from about 4% to about 50% BMS-986165 and from about 96% to about 50% polymer. In still further embodiments, the w / w % of BMS-986165 ranges from about 5% to about 25% BMS-986165 and from about 95% to about 75% polymer. Accordingly, some embodiments provide dispersions in which the w / w % of BMS-986165 to polymer is about 25% BMS-986165 and about 75% polymer. In other embodiments, the w / w % of BMS-986165 to polymer is about 15% BMS-986165 and about 85% polymer, or about 10% BMS-986165 and about 90% polymer.

[0023] Suitable polymeric starting materials for forming the polymer matrix of the dispersions (e.g., spray-dried dispersions) described herein include hydroxypropyl methylcellulose (HPMC; also known as hypromellose), such as HPMC E3; hydroxypropyl cellulose (HPC); methylcellulose (MC); hypromellose phthalate (HPMC-P); cellulose acetate phthalate; hydroxypropyl methylcellulose acetate succinate (HPMCAS; also known as hypromellose acetate succinate), such as HPMCAS L, M, and H grades; Eudragit® L100-55; vinylpyrrolidone-vinyl acetate copolymer (copovidone); polyvinylpyrrolidone (PVP); polymethacrylate-based copolymers; and polyvinylcaprolactam-based copolymers. Preferably, the polymer selected to form the polymer matrix is ​​HPMCAS, with HPMCAS H grade being the preferred grade of this polymer.

[0024] In certain embodiments, spray drying is used to produce amorphous BMS-986165 dispersed in a polymer matrix to produce a formulation of 6-(cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide. The formulation can then be used in immediate-release formulations and dosage forms, or to produce modified or controlled-release formulations and dosage forms.

[0025] Thus, the dispersion according to the present invention may be combined with one or more other additives. When a granulation process is used, the additives may be added before granulation (thereby being intragranular) and / or after granulation (thereby being extragranular).

[0026] For example, the dispersion formulation of the present invention may contain a crystallization inhibitor. Crystallization inhibitors suitable for the formulations described herein include cellulose-based polymers, such as HPMC, HPMCAS, and hydroxypropyl cellulose (HPC), and vinyl polymers, such as PVP. Examples of crystallization inhibitors particularly suitable for the sustained-release formulations described herein include hydroxypropyl methylcellulose (HPMC; also known as hypromellose), such as HPMC E3; hypromellose phthalate (HPMC-P); hydroxypropyl methylcellulose acetate succinate (HPMCAS; also known as hypromellose acetate succinate), such as HPMCAS L, M, and H grades; Eudragit® L100-55; vinylpyrrolidone-vinyl acetate copolymer (copovidone); and polyvinylpyrrolidone (PVP). In a preferred embodiment, the crystallization inhibitor is HPMCAS. The crystallization inhibitor may be included in the dispersion or added outside the dispersion.

[0027] Other additives that can be included in the dispersion formulations described herein include release-controlling materials.For example, a release-controlling polymer can be mixed with or coated on the amorphous dispersion of BMS-986165 to produce a sustained-release formulation.One type of sustained-release dosage form is an oral dosage form (such as a tablet) that includes a dispersion mixed with a release-controlling polymer (and other additives).

[0028] Accordingly, the present invention also provides a formulation for the sustained release of 6-(cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165), comprising an internal phase comprising a dispersion (e.g., a spray-dried dispersion) of amorphous BMS-986165 in a polymer matrix; and an external phase comprising a release-controlling polymer. The formulation can be in a form suitable for oral administration to a patient, including pills, capsules, tablets, films, syrups, and powders. Preferably, the formulation is in the form of a tablet.

[0029] Despite the advantages of amorphous drugs over crystalline drugs, as described above, there are at least two substantial challenges involved in designing sustained-release formulations that include an SDD of amorphous BMS-986165 mixed with a release-controlling polymer (and other additives). First, the release-controlling polymer in the formulation may result in incomplete release of the drug from the sustained-release formulation; such incomplete release may lead, for example, to insufficient delivery of the drug to the patient. Second, crystallization of the drug may occur within the spray-dried dispersion itself (internal phase); within the sustained-release formulation but outside the SDD itself (external phase); and / or after release from the sustained-release formulation. The present invention addresses the first challenge by providing a sustained-release formulation in which an appropriate polymeric material is selected as the release-controlling polymer, and the viscosity of the polymeric material is selected to provide a desired release rate of the drug. Regarding the second challenge, to maintain the advantages of the amorphous form, the present invention provides for a crystallization inhibitor to be present in the sustained-release formulation but outside the spray-dried dispersion itself to reduce or prevent drug crystallization. The present invention provides a clinically feasible formulation containing amorphous BMS-986165 that provides tunable release rates and maintains the benefits of the amorphous form.

[0030] Release-controlling polymers that can be used in the sustained-release formulations described herein include natural polymers, synthetic biodegradable polymers, and synthetic non-biodegradable polymers, as will be readily apparent to those skilled in the art in light of this disclosure. Examples of release-controlling polymers include methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, sodium alginate, chitosan, gelatin, tragacanth, xanthan, and mixtures thereof. HPMC is a preferred release-controlling polymer for the sustained-release formulations described herein. When HPMC is selected as the release-controlling polymer, it preferably has a viscosity in the range of 80 cP to 120,000 cP. The viscosity of the polymer can be measured using a variety of viscometers known in the art.

[0031] In certain embodiments, the sustained-release dispersion formulation comprises one or more crystallization inhibitors.In the sustained-release formulation having internal phase and external phase, crystallization inhibitors can be provided in the internal phase and / or external phase of the formulation.Suitable crystallization inhibitors are described above.

[0032] Any of the immediate-release and sustained-release formulations of 6-(cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide described herein may contain pharmaceutically acceptable excipients to make pills, capsules, tablets, films, syrups, powders, and the like. For example, conventional matrix materials, excipients, diluents, binders, lubricants, and / or preservatives may be included in the formulation. Examples of matrix materials, excipients, or diluents include lactose, mannitol, xylitol, microcrystalline cellulose, calcium phosphate, dicalcium phosphate, and starch. Examples of binders include methylcellulose, crystalline cellulose, carboxymethylcellulose, gelatin, starch, gums such as guar gum, natural and synthetic gums such as acacia, natural sugars such as glucose or beta-lactose, corn syrup, and tragacanth or sodium alginate, polyethylene glycol, etc. Examples of lubricants include magnesium stearate, calcium stearate, stearic acid, sodium oleate, etc. Examples of preservatives include sulfites (antioxidants), benzalkonium chloride, methylparaben, propylparaben, benzyl alcohol, and sodium benzoate. Coloring agents may also be used.

[0033] In certain embodiments, the dispersions of the present invention are made into tablets containing the dispersion in a weight percent range of 10-50% by weight, e.g., 10% w / w, 15% w / w, 20% w / w, or 25% w / w. In some embodiments, at least 15% by weight of the tablet is the dispersion. In certain embodiments, 20% by weight of the tablet is the dispersion.

[0034] In further embodiments, the tablet comprises one or more excipients, such as lactose and / or microcrystalline cellulose, in a total weight percent range of 50-80% of the formulation. In some embodiments, the total amount of excipients is at least 60% w / w, and in further embodiments, at least 70% w / w of the formulation. In certain embodiments, the dispersion formulation comprises lactose and microcrystalline cellulose, which together comprise at least 70% w / w of the formulation. In further embodiments, the ratio of excipients, microcrystalline cellulose:lactose, is 50:50. In other embodiments, the ratio of excipients, microcrystalline cellulose:lactose, is 70:30.

[0035] In certain embodiments, the tablet dosage form of the present invention contains a disintegrant (e.g., crospovidone, croscarmellose, etc.) in the weight percent range of 3 to 10%, for example, 5%. In one embodiment, the disintegrant is croscarmellose. When using a granulation process, the disintegrant can be arranged so as to be intragranular, extragranular, or both. For example, a tablet can contain 5% w / w croscarmellose (50:50 intragranular:extragranular).

[0036] In a further embodiment, the dosage form may comprise a lubricant, such as magnesium stearate, in the weight percentage range of 0.25 to 2.0%, for example 0.25%, 0.5% or 0.75%.

[0037] As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio. is.

[0038] Formulations and dosage forms according to the present invention may contain about 1 mg to about 100 mg of BMS-986165, or about 1 mg to about 40 mg of BMS-986165, e.g., 3 mg, 6 mg, 12 mg, 15 mg, or 36 mg of BMS-986165. In one embodiment, formulations and dosage forms contain 12 mg to 36 mg of BMS-986165. In one embodiment, a 100 mg tablet contains about 3 mg of BMS-986165, a 200 mg tablet contains about 6 mg of BMS-986165, and a 400 mg tablet contains about 12 mg of BMS-986165. In one embodiment, a 300 mg extended-release tablet contains 15 mg of BMS-986165, and such tablets may be administered to a patient once daily.

[0039] (Synthesis and Manufacturing) BMS-986165 and other amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23, and / or IFNα responses, methods of making same, and methods of using same are disclosed in U.S. Patent No. 9,505,748 B2, the contents of which are incorporated herein by reference in their entireties. Other methods for synthesizing BMS-986165 are disclosed in U.S. Provisional Patent Application No. 62 / 478,789 and PCT / US2018 / 025100 (published as WO2018 / 183649), the contents of each of which are incorporated herein by reference in their entireties.

[0040] The amorphous dispersions of the present invention may be prepared by hot melt extrusion, freeze drying, or spray drying. In certain embodiments, spray drying is used.

[0041] Generally, a spray-dried dispersion (SDD) of solid amorphous BMS-986165 molecularly dissolved in a solid polymer matrix can be prepared by dissolving BMS-986165 and a polymer (e.g., HPMCAS) in an organic solvent (or mixture of solvents, e.g., a mixture of acetone and water) to form a solution or suspension, and then spray-drying the solution or suspension. Further description of suitable SDD synthesis steps according to the present invention is provided in the Examples section herein. Other manufacturing techniques, such as those disclosed in U.S. Pat. No. 9,468,604, can be used to prepare a spray-dried dispersion of BMS-986165 in a polymer matrix and will be readily apparent to those skilled in the art in light of this disclosure.

[0042] Thus, in some embodiments, a process for making a solid dispersion includes: (1) adding at least a drug and a polymer to form a solution or suspension; (2) conducting the solution or suspension to a spray dryer and atomizing the solution or suspension into droplets in the spray dryer; (3) contacting the droplets with a drying gas to solidify the particles; and (4) collecting the particles.

[0043] The dispersion described herein can be tableted using equipment and procedures available in the art.Tablets can be prepared, for example, by preparing a powder mixture, granulating or slugging, adding excipients, lubricants and disintegrants, and then compressing into tablets.In certain embodiments, the tablets of the present invention are prepared by dry granulation process.As described herein, tablets can also be formed by direct compression process.

[0044] Several manufacturing parameters can affect the properties of a tablet dosage form. Such parameters include compression pressure, solids content, and target tensile strength. Compression pressure is the applied compression force divided by the area over which the force is applied. The solids content of a tablet indicates how much of the tablet is solid and not void. Solids content (which may be expressed as solids content = 1 - porosity) can be calculated by dividing the apparent or bulk density of the tablet by the true density of the material. Generally, applying a greater compression pressure results in a higher solids content, which generally corresponds to a higher tablet strength. Tablet breaking strength refers to the force required to break or fracture a tablet. Tablet tensile strength is calculated from the tablet breaking strength and tablet dimensions. The tablet dosage forms according to the present invention exhibit adequate breaking strength and tensile strength while providing the desired dissolution characteristics.

[0045] Descriptions of the preparation of tablet formulations, including extended-release tablet formulations comprising a spray-dried dispersion of amorphous BMS-986165 in a polymer matrix, are provided in the Examples section herein. Other synthesis techniques, such as those disclosed in U.S. Patent No. 9,713,594, can be used to prepare extended-release tablet formulations comprising a spray-dried dispersion of BMS-986165 in a polymer matrix and will be readily apparent to those skilled in the art in light of this disclosure.

[0046] In some embodiments, tablets of various dosage strengths are prepared using dispersions containing a given w / w% of drug. For example, a dispersion of 15% w / w amorphous BMS-986165 in a polymer matrix can be used to prepare tablets containing 1 mg, 3 mg, 6 mg, and / or 12 mg of BMS-986165. The exemplary tablet weights corresponding to these dosage strengths of 1 mg, 3 mg, 6 mg, and 12 mg of BMS-986165 are 50 mg, 100 mg, 200 mg, and 400 mg, respectively.

[0047] (elution) Dispersion formulations and dosage forms made therefrom can be used to provide immediate and / or modified release of BMS-986165 in the gastrointestinal tract. Such release can be tested using in vitro dissolution assays. Such assays include microcentrifuge studies of buffer transfer from the stomach to the intestine, which can be used to measure the increase in drug concentration provided by dispersions containing amorphous BMS-986165 compared to the saturated solubility of the drug in crystalline form. In the microcentrifuge study, the drug is administered to a microcentrifuge tube containing a medium with a pH reflecting the pH of the fasted stomach. After 30 minutes of exposure to the gastric medium, the sample is transferred to a medium with a higher pH reflecting the intestinal pH. Drug concentration is then measured at one or more desired time points (e.g., 90 minutes after initial administration of the drug to the gastric medium). The drug measured can consist of free drug, drug in micelles, and / or drug suspended in solution as a drug / polymer colloid. Ultracentrifugation testing can also be performed at several points during the microcentrifugation test to determine the species of dissolving drug present; ultracentrifugation testing involves a centrifugation step at 300,000 x g to remove any colloidal species that may be present, leaving only free drug and drug in micelles. Another dissolution test is the Pion meson dissolution test of buffer transfer from the stomach to the intestine. Other dissolution tests, such as USP method tests and biorelevant dissolution tests, as described in the literature, can also be used.

[0048] In certain embodiments, immediate release refers to the release of at least about 80% of the labeled dose within about 60 minutes under conditions that simulate fasted stomach.In some embodiments, at least about 80% of the labeled dose is released by about 30 minutes under conditions that simulate fasted stomach; in further embodiments, at least about 80% of the labeled dose is released by about 15 minutes under conditions that simulate fasted stomach (for example, by about 5 minutes, by about 10 minutes).In further embodiments, this release is achieved under conditions that simulate the elevated pH state of stomach.

[0049] In some embodiments, it may be desirable to provide a modified release of BMS-986165. Accordingly, certain embodiments of the present invention provide dosage forms that exhibit controlled release of BMS-986165 after oral administration. For example, the dosage form may release the drug over a period ranging from about 2 to 8 hours after oral administration. In some embodiments, the dosage form may release the drug for up to about 24 hours after oral administration. The release rate provided by such dosage forms may be relatively uniform or constant over time, or may vary over time. In further embodiments, the dosage form provides delayed release (e.g., enteric release) of the drug. The conditions under which the drug is released and the rate at which the drug is released from such modified-release dosage forms may be evaluated using dissolution tests, such as those described above and in the Examples.

[0050] (stability) The formulations and dosage forms of the present invention provide physical and chemical stability of amorphous BMS-986165 during manufacturing and storage. For example, in certain embodiments, the dispersion formulations and dosage forms of the present invention exhibit less than about 10% crystallization of total BMS-986165 after the formulations and dosage forms are stored in an open (or closed) container at 40°C / 75%RH (relative humidity) for at least about one month (e.g., three months or six months). In certain embodiments, the dispersion formulations and dosage forms of the present invention exhibit less than about 10% crystallization of BMS-986165, for example, less than about 5% crystallization, less than about 2% crystallization, or less than about 1% crystallization, after the formulations and dosage forms are stored in an open (or closed) container at 40°C / 75%RH (relative humidity) for at least about one month. In further embodiments, the dispersion formulations and dosage forms exhibit less than about 10% crystallization of BMS-986165, e.g., less than about 5% crystallization, less than about 2% crystallization, or less than about 1% crystallization, after storage in an open (or closed) container at 40°C / 75% RH (relative humidity) for at least about 3 months, and in some embodiments, at least about 6 months. The invention also provides formulations and dosage forms comprising amorphous BMS-986165, wherein the amorphous form exhibits less than about 10% crystallization, e.g., less than about 5% crystallization, less than about 2% crystallization, or less than about 1% crystallization, after storage of the formulations and dosage forms in an open (or closed) container at 50°C / 75% RH for at least about 1 month, at least about 3 months, or at least about 6 months. In certain embodiments, the dispersion formulations and dosage forms of the invention exhibit less than about 10% crystallization of BMS-986165, e.g., less than about 5% crystallization, less than about 2% crystallization, or less than about 1% crystallization, after storage in an open (or closed) container at 25°C / 60% RH (relative humidity) for at least about 1 month, at least about 3 months, or at least about 6 months. The percentage of crystallization can be assessed by techniques known in the art and described herein (e.g., PXRD, among others).

[0051] For example, certain embodiments of the present invention provide a dispersion comprising 15% amorphous BMS-986165:85% HPMCAS-H, wherein the amorphous BMS-986165 remains amorphous over 6 months of storage at 40° C. and 75% relative humidity (in open or closed containers) as determined by PXRD and / or SEM.

[0052] Furthermore, in certain embodiments, the BMS-986165 in the dispersions provided herein, or dosage forms containing the dispersions, exhibit less than about 5% degradation, less than about 3% degradation, less than about 2% degradation, or less than about 1% degradation when stored under any of the above conditions for a period of at least about 1 month to at least about 6 months.

[0053] (bioavailability) For orally administered drug formulations, drug absorption generally depends on the release of the drug substance from the drug formulation, the dissolution or solubilization of the drug substance under physiological conditions in the gastrointestinal tract, and the rate and extent of drug permeation through the gastrointestinal membrane. Conventional or standard formulations containing low-solubility drugs are unlikely to achieve sufficient drug solubilization so that sufficient drug is absorbed into the bloodstream to reach therapeutic drug levels in the bloodstream and target tissues. Although BMS-986165 exhibits low solubility, the formulations and dosage forms of the present invention achieve the desired level of solubilization and thereby drug absorption, while also providing other desirable properties (e.g., stability during storage, ease of swallowing the dosage form, etc.).

[0054] In some embodiments, administration of a dosage form comprising a solid amorphous dispersion of BMS-986165 improves the bioavailability of BMS-986165 compared to administration of the same dose of BMS-986165 in a dosage form comprising a crystalline formulation of the drug. The relative bioavailability of a drug can be tested in vivo in animals or humans using conventional methods for making such determinations.

[0055] For example, in vivo studies, such as crossover studies, can be used to determine whether a dosage form provides improved relative bioavailability compared to a control. In an in vivo crossover study, a "test composition" is administered to half of the test subjects (animals or humans), and after an appropriate washout period (e.g., one week), the same subjects are administered a "control composition" containing an equivalent amount of drug to that contained in the "test composition." The other half of the group is first administered the control composition, followed by the test composition. Relative bioavailability is determined as the area under the blood (serum or plasma) concentration versus time curve (AUC) determined for the test composition divided by the blood AUC provided by the control composition. Preferably, this test / control ratio is determined for each subject, and then the ratio is averaged across all subjects in the study. AUC determination can be performed by plotting the serum or plasma concentration of the drug along the vertical axis (y-axis) against time along the horizontal axis (x-axis). Determining AUC is a well-known technique and is described, for example, in Welling, "Pharmacokinetics Processes and Mathematics," ACS Monograph 185 (1986).

[0056] In some embodiments, the relative bioavailability of a test composition (e.g., a dosage form comprising an amorphous dispersion of BMS-986165 described herein) is at least 1.25 relative to the control composition (the AUC provided by the test composition is at least 1.25-fold that of the control composition). In further embodiments, the relative bioavailability of a test composition is at least 2.0 compared to a control composition comprising a crystalline form of the drug.

[0057] The bioavailability of two formulations or dosage forms can also be compared using in vitro dissolution tests as a surrogate for in vivo bioavailability. For example, a gastric-to-intestinal media transfer dissolution test can be used to mimic the in vivo conditions of the GI tract and can be used to estimate the amount of free drug provided by a given formulation or dosage form. Other dissolution tests, such as the test described in Example E, can also be used.

[0058] In certain embodiments, the bioavailability of BMS-986165 provided by the dosage forms described herein is not significantly affected by agents that increase gastric pH, such as antacids, H2 receptor antagonists, and proton pump inhibitors. For example, while administration of proton pump inhibitors (or other gastric pH-increasing drugs) can affect gastric pH, the solubility of amorphous BMS-986165 in the dispersions described herein is less affected by pH than the solubility of free base crystalline BMS-986165. Thus, administration of a dosage form containing a dispersion of amorphous BMS-986165 can provide bioavailability of BMS-986165 to patients who are also receiving a proton pump inhibitor (or other pH-increasing drug). Thus, certain embodiments of the present invention provide oral dosage forms comprising amorphous BMS-986165 dispersed in a polymer matrix, wherein the bioavailability of BMS-986165 from the oral dosage form changes by no more than 25%, no more than 20%, no more than 15%, or no more than 10% when a gastric pH-elevating drug (e.g., a proton pump inhibitor) is administered concomitantly with the dosage form. Concomitant administration herein refers to a subject receiving both a gastric pH-elevating drug (e.g., a proton pump inhibitor) and a dosage form of dispersed amorphous BMS-986165. The drug (e.g., a proton pump inhibitor) and the BMS-986165 dosage form can be administered on the same day, or, for example, within three days of each other. For example, the drug (e.g., a proton pump inhibitor) can be administered within three days, two days, or one day of administration of the BMS-986165 dosage form, or on the same day. Co-administration includes all such timings for administration of the gastric pH-elevating agent (e.g., a proton pump inhibitor) and the BMS-986165 solid dispersion dosage form.

[0059] The effect of a gastric pH-elevating drug or antacid (e.g., a proton pump inhibitor) on bioavailability can be evaluated by administering a BMS-986165 dosage form to a first group of test subjects (animals or humans) who are not receiving a pH-elevating drug, while administering the same BMS-986165 dosage form to a second group of test subjects who are simultaneously receiving a pH-elevating drug; after an appropriate washout period, the first group is administered the BMS-986165 dosage form together with the pH-elevating drug, and the second group is administered the BMS-986165 dosage form without the pH-elevating drug. Thus, each subject has two AUC values ​​(the AUC obtained when taking a pH-elevating drug or antacid, and the AUC obtained when not taking the drug), and these AUC values ​​can be compared for each subject. For example, the ratio of AUC for each subject can be obtained and the ratios for all subjects in the study can be averaged. In certain embodiments, the average ratio obtained by such a method is in the range of 0.75 to 1.25.

[0060] The present invention also provides sustained-release formulations and dosage forms in which a single administration can provide bioavailability similar to that provided by immediate-release formulations or dosage forms administered multiple times a day to deliver the same total amount of drug as in the sustained-release formulation or dosage form. For example, a sustained-release tablet containing a specific dose of BMS-986165 can be administered to a patient once a day to provide a pharmacokinetic profile of the drug comparable to that provided by an immediate-release tablet administered twice a day.

[0061] (Treatment method) Autoimmune or autoinflammatory diseases that can be treated using the dosage forms or formulations described herein include psoriasis (e.g., plaque psoriasis), psoriatic arthritis, lupus, lupus nephritis, Sjogren's syndrome, inflammatory bowel disease (including ulcerative colitis and Crohn's disease), and ankylosing spondylitis.

[0062] The dosage form can be administered orally. Preferably, the dosage form is a tablet. The tablet can contain about 1 mg to about 100 mg of the drug (BMS-986165), or about 1 mg to about 40 mg of the drug, for example, 6 mg, 12 mg, 15 mg, or 36 mg. For example, in certain embodiments, a 300 mg tablet is a sustained-release dosage form containing 15 mg of the drug and is administered once a day for the treatment of psoriasis.

[0063] The invention further provides the use of a spray-dried dispersion of amorphous BMS-986165 in a polymer matrix in the manufacture of a medicament for treating autoimmune or autoinflammatory diseases, such as inflammatory bowel disease (including ulcerative colitis and Crohn's disease) and psoriasis.

[0064] In certain embodiments, a method of treating an autoimmune or autoinflammatory disease (e.g., inflammatory bowel disease (including ulcerative colitis and Crohn's disease) and psoriasis) in a patient comprises administering to the patient a formulation for the sustained release of BMS-986165, comprising (i) an internal phase comprising a spray-dried dispersion of amorphous 6-(cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165) in a polymer matrix, and (ii) an external phase comprising a release-controlling polymer.

[0065] The present invention also provides a method for treating inflammatory bowel disease or psoriasis in a patient, comprising administering to the patient once daily a formulation for sustained release of BMS-986165, the formulation comprising: (i) an internal phase comprising a spray-dried dispersion of amorphous 6-(cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165) in a polymer matrix; and (ii) an external phase comprising a release-controlling polymer. The inflammatory bowel disease can be ulcerative colitis or Crohn's disease. The psoriasis can be plaque psoriasis. The formulation is preferably in the form of a tablet.

[0066] The present invention further provides a method for treating inflammatory bowel disease or psoriasis in a patient, comprising orally administering to the patient once daily a formulation for sustained release of BMS-986165, the formulation comprising: (i) an internal phase comprising a spray-dried dispersion of amorphous 6-(cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165) in a polymer matrix, and (ii) an external phase comprising a release-controlling polymer. The inflammatory bowel disease can be ulcerative colitis or Crohn's disease. The psoriasis can be plaque psoriasis. The formulation is preferably in the form of a tablet.

[0067] The following examples serve only to illustrate the invention and its practice and should not be construed as limitations on the scope or spirit of the invention. [Example]

[0068] Example A The 6-(cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide drug substance and HPMCAS are added to a mixture of acetone and water in a suitable tank and mixed to form a solution. The solution is spray dried under a nitrogen atmosphere (nitrogen provides an inert atmosphere during manufacturing). The resulting spray-dried mixture is further dried to provide a spray-dried dispersion (SDD), which can be filled and packaged.

[0069] To create a dispersion formulation and dosage form with a sustained-release profile, SDD, lactose anhydrous, microcrystalline cellulose, and HPMCAS are mixed together and the blended mixture is sieved. The sieved blend is mixed with magnesium stearate, and the resultant is subjected to dry granulation (slugging / roller compaction process) and then milled. This further resultant is mixed with additional magnesium stearate and compressed into tablets to produce tablets for the sustained release of 6-(cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0070] Example B The composition of the spray-drying solution to produce a spray-dried dispersion (15% w / w:85% w / w) of solid amorphous BMS-986165 molecularly dispersed in a solid HPMCAS-H matrix is ​​shown in Table B-1 below. [Table 1]

[0071] Table B-2 below shows a process outline for producing a spray-dried dispersion of amorphous BMS-986165:HPMCAS-H (15% w / w:85% w / w) using a laboratory-scale spray dryer equipped with a drying gas capacity of 150 kg / hr. [Table 2]

[0072] Although Table B-2 indicates that the polymer is added to the solution preparation vessel before adding the active agent (BMS-986165), the active agent (BMS-986165) may also be added to the solution preparation vessel before adding the polymer.

[0073] Table B-3 below shows the solution preparation conditions for 15% BMS-986165:85% HPMCAS-HSDD. The spray drying conditions used to produce BMS-986165:HPMCAS-HSDD in a laboratory-scale spray dryer with a drying gas flow rate of 150 kg / hr were divided into four sets: (A) preheat, (B) warm-up, (C) solution feed treatment, and (D) shutdown. Table B-4 below summarizes the targets and target ranges for each of the four sets of conditions. [Table 3] [Table 4]

[0074] The target level of residual acetone in SDD was less than 0.5 wt%. Less than the LOQ (limit of quantification) level of acetone was achieved in a development batch of 15% BMS-986165:85% HPMCAS-HSDD after drying for 20.5 hours at 40°C / 15% RH. Residual acetone versus drying studies were also performed on two separate development batches. Table B-5 below shows the secondary drying conditions. [Table 5]

[0075] Preferred storage conditions for the spray solution and SDD are shown in Table B-6 below. [Table 6]

[0076] Example C Stability of SDD formulation of BMS-986165

[0077] A lot of 25% w / w BMS-986165 SDD with HPMCAS-H was evaluated for physical and chemical stability. HPMCAS SDD was chemically stable under all conditions, although powder X-ray diffraction (PXRD) and modulated differential scanning calorimetry (mDSC) data indicated crystallization after 1 month of storage at 50°C / 75% RH in the open and after 3 months of storage at 40°C / 75% RH in the open. Dissolution properties in microcentrifuge tests were unchanged. There was no evidence of physical instability when the dispersion formulations were stored for up to 6 months at 40°C / 75% RH in the closed state or at 25°C / 60% RH in the open state.

[0078] Further testing was performed to determine the API loading level in HPMCAS-H that provided chemical and physical stability while providing the desired dissolution profile. pH-shift dissolution studies using a Pion UV probe (pH 2 or pH 6 to pH 6.5) showed that gastric release / retention and intestinal retention generally improved as the API loading decreased.

[0079] Six-month stability studies of SDDs containing 10%, 15%, or 20% w / w BMS-986165 in HPMCAS-H demonstrated that all SDDs were chemically stable (Table C). The impurity levels in each SDD were consistent with the input API impurity levels, indicating that the spray-drying process did not cause degradation; furthermore, impurity levels did not increase upon storage. After up to 6 months of storage at 40°C / 75% RH in the open, there was no evidence of crystallization by PXRD in any of the SDDs (Figures 1A and 1B). DSC data showed slight changes similar to those observed for the 25% w / w BMS-986165 SDDs after exposure to 50°C / 75% RH or 40°C / 75% RH, but there was no trend in API loading, which is believed to reflect an "aging" or "annealing" effect rather than crystal formation. Scanning electron microscope (SEM) images confirmed the presence of a single-phase homogeneous dispersion (Figures 2A-C, 3A-C, 4A-C).

[0080] TAM (microcalorimetry) experiments (including PXRD on post-TAM samples) with SDDs loaded with 10%, 15%, 20%, and 25% BMS-986165 confirmed a low physical stability risk for HPMCAS-H SDDs containing 20% ​​w / w BMS-986165 or less. Dissolution in microcentrifuge studies was unchanged.

[0081] Reducing the API loading in the SDD improves stability and reduces the throughput of the spray-drying process; however, this reduction in throughput can be offset by increasing the solids concentration of the spray solution to a limit of 8% w / w HPMCAS in acetone / water (this limit helps ensure process robustness). The solids concentration is also limited by the solubility of BMS-986165 in acetone / water. An API loading of 15% w / w was chosen to obtain acceptable throughput at a target spray solution concentration of 1% API and to ensure sufficient API loading on the SDD to allow for tablet loading with the SDD to produce tablets of a suitable size for swallowing. [Table 7]

[0082] Example D BMS-986165 SDD tablets

[0083] Tablets containing SDD of BMS-986165 were manufactured using the following formulation: [Table 8]

[0084] Tablets were produced using an Alexanderwerk WP120 roller compactor. Tableting was carried out using a Korsch XL press and film coating was carried out using a Thomas Compulab Coater.

[0085] The tablets exhibited desirable dissolution / disintegration profiles, adequate hardness and strength, stability on storage, and acceptable swallowable size.

[0086] Tablets at a 6 mg dose were also produced using a 200 mg press weight. For the 6 mg dose, a tablet hardness target of 14 SCU provided adequate breakability (500 drop tests) and an acceptable disintegration time of less than 4 minutes.

[0087] Example E Biorelevant dissolution of BMS-986165 SDD tablets and BMS-986165 HCl salt capsules (12 mg strength)

[0088] The dissolution of tablets containing the SDD of 15:85 BMS-986165:HPMCAS-H and manufactured by a direct compression process was compared to the dissolution of capsules containing the BMS-986165 HCl salt form (12 mg strength for both dosage forms). Dissolution was examined in Biorelevant fasting simulated intestinal fluid (FaSSIF). Galia et al., Evaluation of Various Dissolution Media for Predicting In Vivo Performance of Class I and II Drugs, Pharm Res. 15:698-705 (1998). The recipe for such a medium was pH 6.5; osmolality 270±10 mOsm; sodium taurocholate 3 mM; lecithin 0.75 mM; KH2PO4 3.9 g; KCl 7.7 g; NaOH qs to pH 6.5; and deionized water qs to 1 L. Dissolution tests were performed in 250 mL of medium using paddles at a temperature of 37° C. and a rotation speed of 75 rpm. Six units of each dosage form were tested. Figure 5 shows the results (average (n=6)).

[0089] As shown in Figure 5, the dissolution rate of the SDD tablets was faster than that of the HCl salt capsules when the dosage forms were tested as described above. For the SDD tablets containing amorphous BMS-986165 in the solid dispersion, 95% dissolution was observed by 5 minutes, and 97% dissolution was observed by 10 minutes. For the capsules containing the BMS-986165 HCl salt form, 5% dissolution was observed by 5 minutes; 25% dissolution was observed by 10 minutes; 39% dissolution was observed by 15 minutes; and 45% dissolution was observed by 20 minutes.

[0090] The dissolution of tablets containing an SDD of 15:85 BMS-986165:HPMCAS-H and produced by the granulation process was compared to the dissolution of capsules containing the BMS-986165 HCl salt form (12 mg strength for both dosage forms) using the above media and conditions (n=6). The results, provided in Table E below, show that the dissolution rate of the granulated tablets containing amorphous BMS-986165 in a solid dispersion is faster than the dissolution rate of the capsules containing the BMS-986165 HCl salt form. [Table 9]

[0091] Example F Sustained-release study of crystalline free base (15 mg strength)

[0092] Tablets of Example 1, Example 2, and Example 3 having the sustained release formulation shown in Table F below were tested. Dissolution test parameters were as follows: potassium phosphate buffer (pH 6.8), 20 mesh basket, 1000 mL, 100 rpm for the crystalline free base formulation of BMS-986165 (Example 1, 2, or 3). [Table 10]

[0093] As shown in Figure 6, the formulation of Example 3 had a maximum release of 67% after 24 hours and a slow release as a result of the relatively high viscosity of the HPMC polymer.

[0094] Example G Sustained-release SDD formulation of BMS-986165

[0095] Following sustained release testing of the crystalline free base, the sustained release formulations shown in Table G below were developed. [Table 11]

[0096] As used in this example and throughout this disclosure, "BMS-986165-01" refers specifically to the free base form of 6-(cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide. As used in this example and throughout this disclosure, "BMS-986165-01 SDD" refers to solid amorphous BMS-986165-01 molecularly dispersed in a solid HPMCAS matrix; BMS-986165-01 is present in the SDD in an amount of 15% by weight of the SDD and HPMCAS is present in the SDD in an amount of 85% by weight of the SDD.

[0097] Example H Formulation and dissolution profile of sustained-release SDD formulation (15 mg strength)

[0098] Tablets of Example 4, Example 5, and Example 6 having the formulations shown in Table H below were tested. Dissolution test parameters were as follows: SDD formulation of BMS-986165 (Example 4, 5, or 6) in potassium phosphate buffer (pH 6.8), 20 mesh basket, 1000 mL at 100 rpm. [Table 12]

[0099] Using an SDD formulation with amorphous BMS-986165 API improved overall drug release at 24 hours (72% in Example 4, see Figure 7) compared to the crystalline API (67% in Example 1). However, there was incomplete drug release after 24 hours. This study demonstrated that partial or complete crystallization of drug in or from an SDD formulation can negate the benefits of using an SDD formulation, for example, by reducing the bioavailability benefit.

[0100] Example I Sustained-release SDD formulation of BMS-986165 containing HPMCAS in addition to the SDD

[0101] Following the SDD formulation testing described above, the sustained release formulations shown in Table I below were developed. [Table 13]

[0102] Example J Dissolution profiles for formulations and extended-release SDD tablet formulations with HPMCAS added in addition to the SDD

[0103] Tablets of Example 7 having the formulation shown in Table J below were tested. Dissolution test parameters were as follows: SDD formulation of BMS-986165 (Example 7) in potassium phosphate buffer (pH 6.8), 20 mesh basket, 1000 mL, 100 rpm. [Table 14]

[0104] When HPMCAS was added to the formulation but outside of the SDD portion (in the external phase), the overall drug release at 24 hours further increased to 79% (see Example 7, Figure 8) compared to when the HPMCAS addition was not part of the formulation (Example 4). This study showed that the addition of HPMCAS reduced crystallization of the product / system and increased the release of BMS-986165.

[0105] Example K To study factors related to the design of a tunable sustained-release formulation of BMS-986165, tablets were developed in Examples 8, 9, 10, 11, and 12 with the sustained-release formulations shown in Table K below. Regarding the viscosity of the release-controlling polymer (HPMC in this case): various viscosities were investigated by using a single polymer or by mixing polymers of different viscosities. The surface area / volume ratio and dosage were investigated by changing the tablet weight (dosage), which also changed the surface area to volume ratio. Various modifications can be made to achieve the same surface area to volume ratio. [Table 15]

[0106] Figure 9 shows dissolution profiles with varying viscosity, surface area to volume ratio, or both. Dissolution test parameters were as follows: Dissolution of formulations at 75 rpm in 1000 mL of pH 6.8 phosphate buffer containing 1% Brij USP II with a cage sinker. As shown in Figure 9, tunable release (viscosity and surface area / volume) was demonstrated by a range of release profiles, with complete drug release achieved for certain formulations.

[0107] Example L Tablets in Examples 8-1, 9-1, 10-1, and 11-1, each having the sustained-release formulation shown in Tables L-1 and L-2 below, were developed for further clinical trials. Figure 10 shows the dissolution profiles of these formulations. Dissolution test parameters were as follows: SDD formulations of BMS-986165 (Examples 8-1, 9-1, 10-1, and 11-1) in potassium phosphate buffer (pH 6.8), 1% Brij, cage sinker, 1000 mL, 75 rpm. Any combination of viscosity and dose shown in these four formulations can be used for further clinical trials. Suitable drug dose ranges include 12 mg (200 mg tablet weight) to 36 mg (600 mg tablet weight). [Table 16] [Table 17]

[0108] Example M Tablets of Examples 13 and 14 were prepared having the following formulation for sustained release of BMS-986165.

[0109] Example 13 A spray-dried dispersion of amorphous BMS-986165-01:HPMCAS-H (15% w / w:85% w / w) present in an amount of 40.00% (w / w); HPMCAS present in an amount of 10.00% (w / w); Hypromellose K100LV Premium CR present in an amount of 0.50% (w / w); Hypromellose K15M Premium CR present in an amount of 24.50% (w / w); Lactose Anhydrous present in an amount of 12.00% (w / w); Microcrystalline cellulose present in an amount of 12.00% (w / w); and Magnesium stearate present in an amount of 1.00% (w / w).

[0110] Example 14 A spray-dried dispersion of amorphous BMS-986165-01:HPMCAS-H (15% w / w:85% w / w) present in an amount of 40.00% (w / w); HPMCAS present in an amount of 10.00% (w / w); Hypromellose K100LV Premium CR present in an amount of 24.50% (w / w); Hypromellose K15M Premium CR present in an amount of 0.50% (w / w); Lactose Anhydrous present in an amount of 12.00% (w / w); Microcrystalline cellulose present in an amount of 12.00% (w / w); and Magnesium stearate present in an amount of 1.00% (w / w).

[0111] Other combinations of amounts of hypromellose K100LV and hypromellose K15M can be used, and other premium versions of these hypromellose ingredients that are not CR grade can be used.

[0112] (Example N) Bioavailability of tablets containing BMS-986165SDD and BMS-986165 free base (crystalline) in famotidine-treated dogs

[0113] This study compared the pharmacokinetic profile of tablets containing BMS-986165-01 SDD (15% BMS-986165-01:85% HPMCAS) with that of tablets containing BMS-986165 crystalline free base in famotidine-treated dogs. The study was a crossover design with two treatment groups (four male dogs per group). In both groups, dogs were fasted and pretreated with famotidine, which increases gastric pH. Both tablet formulations were tested at 4 mg strength (12 mg human equivalent dose (HED)). Table N-1 and Figures 11A-C show the results. [Table 18]

[0114] As shown in Table N-1, under elevated gastric pH conditions, tablets containing BMS-986165 in the crystalline free base form exhibited a lower C compared to tablets containing amorphous free base BMS-986165 in a solid dispersion. max and the same median T max The area under the curve (AUC) calculated from 0 to 24 hours was also lower for the crystalline free base tablet compared to the SDD tablet; this difference in AUC was statistically significant (p<0.05). Variability for both dosage forms was within the range of variability typically observed in dog pharmacokinetic studies.

[0115] These results demonstrate that crystalline free base BMS-986165 tablets exhibit approximately 50% bioavailability at a 4 mg dose (12 mg HED) compared to BMS-986165-01 SDD under elevated gastric pH conditions.

Claims

1. 1. A formulation of 6-(cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165), comprising a dispersion of amorphous BMS-986165 in a polymer matrix, the polymer matrix comprising hydroxypropyl methylcellulose acetate succinate (HPMCAS), wherein the ratio of amorphous BMS-986165 to HPMCAS in the dispersion is 3-80% w / w amorphous BMS-986165 to 97-20% w / w HPMCAS.

2. 2. The formulation of claim 1, wherein the HPMCAS is HPMCAS H grade.

3. The formulation of claim 1, wherein the HPMCAS is HPMCAS L grade.

4. The formulation of claim 1, wherein the HPMCAS is HPMCAS M grade.

5. 5. The formulation of any one of claims 1 to 4, wherein the ratio of amorphous BMS-986165 to HPMCAS in the dispersion is 4-50% w / w amorphous BMS-986165 to 96-50% w / w HPMCAS.

6. 5. The formulation of any one of claims 1 to 4, wherein the ratio of amorphous BMS-986165 to HPMCAS in the dispersion is 5-25% w / w amorphous BMS-986165 to 95-75% w / w HPMCAS.

7. 7. The formulation of any one of claims 1 to 6, wherein the dispersion of amorphous BMS-986165 in a polymer matrix is ​​a spray-dried dispersion.

8. 8. The formulation of any one of claims 1 to 7, further comprising a crystallization inhibitor.

9. 9. The formulation of claim 8, wherein the crystallization inhibitor is hydroxypropyl methylcellulose acetate succinate (HPMCAS).

10. 10. The formulation of any one of claims 1 to 9, wherein the dispersion of amorphous BMS-986165 dispersed in a polymer matrix comprises amorphous BMS-986165 in an amount of at least 10% w / w of the dispersion and no more than 25% w / w of the dispersion.

11. 10. The formulation of any one of claims 1 to 9, wherein the ratio of amorphous BMS-986165 to HPMCAS in the dispersion is 25% w / w amorphous BMS-986165 to 75% w / w HPMCAS.

12. 10. The formulation of any one of claims 1 to 9, wherein the ratio of amorphous BMS-986165 to HPMCAS in the dispersion is 20% w / w amorphous BMS-986165 to 80% w / w HPMCAS.

13. 10. The formulation of any one of claims 1 to 9, wherein the ratio of amorphous BMS-986165 to HPMCAS in the dispersion is 15% w / w amorphous BMS-986165 to 85% w / w HPMCAS.

14. 10. The formulation of any one of claims 1 to 9, wherein the ratio of amorphous BMS-986165 to HPMCAS in the dispersion is 10% w / w amorphous BMS-986165 to 90% w / w HPMCAS.

15. 10. The formulation of any one of claims 1 to 9, wherein the dispersion of amorphous BMS-986165 in a polymer matrix comprises amorphous BMS-986165 in an amount of 15% w / w of the dispersion.

16. 16. The formulation of any one of claims 1 to 15, which is free of crystalline BMS-986165 after storage at 40°C / 75% relative humidity for at least 3 months.

17. 16. The formulation of any one of claims 1 to 15, which is free of crystalline BMS-986165 after storage at 40°C / 75% relative humidity for at least 6 months.

18. 18. The formulation of any one of claims 1 to 17, wherein the amorphous BMS-986165 in the formulation exhibits less than 5% degradation when the formulation is stored at 40°C / 75% relative humidity for at least 6 months.

19. 19. The formulation of any one of claims 1-18, wherein at least 80% of the amorphous BMS-986165 in the formulation is released by 30 minutes after the formulation is placed in a medium having a pH of 1 to 2.

20. 19. The formulation of any one of claims 1-18, wherein at least 80% of the amorphous BMS-986165 in the formulation is released by 30 minutes after the formulation is placed in a medium having a pH of 6 to 7.

21. The formulation of any one of claims 1 to 20, wherein the amount of amorphous BMS-986165 in the formulation is 12 mg.

22. 22. The formulation of claim 21, which is a tablet having a tablet weight of 400 mg or less.

23. The formulation of any one of claims 1 to 20, wherein the amount of amorphous BMS-986165 in the formulation is 6 mg.

24. 24. The formulation of claim 23, which is a tablet having a tablet weight of 200 mg.

25. The formulation of any one of claims 1 to 20, wherein the amount of amorphous BMS-986165 in the formulation is 3 mg.

26. The formulation of claim 25, which is a tablet having a tablet weight of 100 mg.

27. The formulation of any one of claims 1 to 20, wherein the amount of amorphous BMS-986165 in the formulation is 1 mg to 12 mg.

28. 23. The formulation of claim 21 or 22, which exhibits improved bioavailability compared to another formulation comprising 12 mg of crystalline 6-(cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

29. 21. The formulation of any one of claims 1 to 20, further comprising microcrystalline cellulose, lactose, croscarmellose, magnesium stearate and silicon dioxide.

30. 30. The formulation of claim 29, comprising: a 20% w / w dispersion of amorphous BMS-986165 in a polymer matrix, wherein the ratio of amorphous BMS-986165 to HPMCAS in the dispersion is 15% w / w amorphous BMS-986165 to 85% w / w HPMCAS; 51.25% w / w microcrystalline cellulose; 22% w / w lactose anhydrous; 5% w / w croscarmellose sodium; 0.75% w / w magnesium stearate; and 1% w / w silicon dioxide.

31. 31. The formulation of claim 30, wherein the formulation comprises an intragranular portion and an extragranular portion, the 5% w / w croscarmellose sodium being in a 1:1 intragranular:extragranular ratio and the 0.75% w / w magnesium stearate being in a 1:2 intragranular:extragranular ratio.

32. The formulation of claim 29 or 30, which is a tablet.

33. The formulation of any one of claims 29 to 32, wherein the amount of amorphous BMS-986165 in the formulation is 1 mg to 12 mg.

34. The formulation of any one of claims 29 to 32, wherein the amount of amorphous BMS-986165 in the formulation is 6 mg.

35. The formulation of any one of claims 29 to 32, wherein the amount of amorphous BMS-986165 in the formulation is 3 mg.

36. The formulation of any one of claims 1 to 20, which is a tablet.

37. 37. The formulation of any one of claims 1-27 and 29-36, wherein the formulation exhibits improved bioavailability compared to another formulation comprising crystalline BMS-986165, when the two formulations contain the same amount of BMS-986165.

38. 38. The formulation of claim 37, wherein the improved bioavailability is determined by a crossover animal study.

39. 38. The formulation of claim 37, wherein the improved bioavailability is determined by comparing the percent of BMS-986165 dissolved from the formulation to the percent of BMS-986165 dissolved from the other formulation in an in vitro dissolution test in Biolevant fasted simulated intestinal fluid (FaSSIF) (pH 6.5) at a temperature of 37°C using paddles and a rotation speed of 75 rpm.

40. 30. The formulation of any one of claims 1 to 21, 23, 25, and 27 for oral administration, wherein the bioavailability of BMS-986165 from the formulation when administered to a subject concomitantly with a proton pump inhibitor differs by no more than 25% from the bioavailability of BMS-986165 from the formulation when administered to a subject without concomitant administration of a proton pump inhibitor, and wherein the bioavailability of BMS-986165 from the formulation is determined by the area under the plasma concentration versus time curve.

41. 41. The formulation of any one of claims 1 to 40 for treating an autoimmune or autoinflammatory disease in a subject.

42. 42. The formulation of claim 41, wherein the subject is a human subject.

43. 43. The formulation of claim 42, wherein the autoimmune or autoinflammatory disease is inflammatory bowel disease.

44. 44. The formulation of claim 43, wherein the inflammatory bowel disease is ulcerative colitis.

45. 44. The formulation of claim 43, wherein the inflammatory bowel disease is Crohn's disease.

46. 43. The formulation of claim 42, wherein the autoimmune or autoinflammatory disease is psoriasis.

47. 47. The formulation of claim 46, wherein the psoriasis is plaque psoriasis.

48. 43. The formulation of claim 42, wherein the autoimmune or autoinflammatory disease is psoriatic arthritis.

49. 1. Use of a spray-dried dispersion of amorphous 6-(cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165) in a polymer matrix in the manufacture of a medicament for treating an autoimmune or autoinflammatory disease, comprising:

1. Use of a spray-dried dispersion of (cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165) comprising 5-25% w / w amorphous BMS-986165 in 95-75% w / w hydroxypropyl methylcellulose acetate succinate (HPMCAS).

50. 50. The use of claim 49, wherein the spray-dried dispersion of amorphous 6-(cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165) in a polymer matrix comprises 15% w / w amorphous BMS-986165 to 85% w / w HPMCAS.

51. 51. The use according to claim 49 or 50, wherein the medicament is for treating inflammatory bowel disease.

52. 52. The use of claim 51, wherein the inflammatory bowel disease is ulcerative colitis.

53. 52. The use of claim 51, wherein the inflammatory bowel disease is Crohn's disease.

54. 51. The use according to claim 49 or 50, wherein the medicament is a medicament for treating psoriasis.

55. 55. The use according to claim 54, wherein the psoriasis is plaque psoriasis.

56. 51. The use according to claim 49 or 50, wherein the medicament is for treating psoriatic arthritis.

57. A formulation of 6-(cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165), comprising a dispersion of amorphous BMS-986165 dispersed in a polymer matrix, the polymer matrix comprising hydroxypropyl methylcellulose acetate succinate (HPMCAS), the dispersion comprising amorphous BMS-986165 in an amount of at least 10% w / w of the dispersion but not more than 25% w / w of the dispersion.

58. The formulation of claim 57, wherein the HPMCAS is HPMCAS H grade.

59. The formulation of claim 57 or 58, wherein the dispersion is a spray-dried dispersion.

60. A formulation according to any one of claims 57 to 59 for treating psoriasis.

61. The formulation described in claim 60, wherein the psoriasis is plaque psoriasis.

62. A formulation described in any one of claims 57 to 59 for treating psoriatic arthritis.

63. A formulation described in any one of claims 60 to 62, wherein the amount of amorphous BMS-986165 in the formulation is 6 mg.

64. A formulation described in any one of claims 60 to 62, wherein the amount of amorphous BMS-986165 in the formulation is 3 mg.

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