EXTENDED-RELEASE DOSAGE FORMS FOR TYROSINE KINASE 2 (TYK2) INHIBITORS

Abstract

Stable and bioavailable extended-release formulations and dosage forms comprising a dispersion (e.g., a spray-dried dispersion) of 6-(cyclopropanoamido)-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.

Description

EXTENDED-RELEASE DOSAGE FORMS FOR TYROSINE KINASE 2 (TYK2) INHIBITORS Field of Invention The present invention relates to dosage forms and formulations of 6-(cyclopropanoamido)-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 the bioavailability of 6-(cyclopropanoamido)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 for the treatment of autoimmune and autoinflammatory diseases such as inflammatory bowel disease (IBD) and psoriasis. Background of the Invention Tyrosine kinase 2 (Tyk2) is a member of the Janus kinase (JAK) family of non-receptor tyrosine kinases and has been shown to be critical in regulating the downstream signal transduction cascade of receptors for IL-12, IL-23, and type I interferons in both mice (Ishizaki, M. et al., Involvement of tyrosine kinase2 in both the IL-12 / Thl and IL-23 / TH17 axes in vivo, J. Immunol., 187:181-189 (2011); Prchal-Murphy, M. et al., TYK2 ai? Lenn / zznz / E / YiAi Ref. 332150 kinase activity is required for functional type I interferon responses in vivo, PLoS One, 7:e39141 (2012)) as in 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 (2006)). Tyk2 mediates receptor-induced phosphorylation of STAT family members of transcription factors, an essential signal leading to STAT protein dimerization 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 autoimmunity and related disorders (Ishizaki, M. et al., Involvement of tyrosine kinase-2 in both the IL-12 / Thl and IL-23 / Thl7 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 autoinmune encephalomyelitis, J. Immunol., 183:7539-7546 (2009)). In humans, individuals expressing an inactive variant of Tyk2 are protected against multiple sclerosis and possibly other autoimmune disorders (Couturier, N. et al., Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple selenosis susceptibility, Brain, 134:693-703 (2011)). Association studies of the ai? Lenn / zznz / E / YiAi genome-wide studies have shown that other Tyk2 variants are 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 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, TYK2in 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)). BMS-986165 se refiere a un compuesto de la siguiente fórmula (I) BMS-986165, which is 6-(cyclopropanoamido)-4-((2-methoxy-3-(1-methyl-1H1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, is under investigation for the treatment of autoimmune and autoinflammatory diseases such as psoriasis, psoriatic arthritis, lupus, lupus nephritis, Sjögren's syndrome, inflammatory bowel diseases (including ulcerative colitis and Crohn's disease), and ankylosing spondylitis. It is a highly selective inhibitor of Tyk2-mediated signal transduction. It selectively binds to the Tyk2 pseudokinase domain (JH2) and blocks receptor-mediated Tyk2 activation by stabilizing the JH2 regulatory domain. BMS-986165 and other amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23, and / or IFN-γ responses, methods for preparing them, and methods for using them, are described in U.S. Patent No. 9,505,748 B2, the contents of which are incorporated herein by reference in their entirety. Other methods for synthesizing BMS-986165 are described in U.S. Provisional Patent Application No. 62 / 478,789 and PCT / US2018 / 025100 (published as WO 2018 / 183649), the contents of which are incorporated herein by reference in their entirety. BMS-986165 has been synthesized in crystalline form, as in crystalline form A as described in U.S. Provisional Patent Application No. 62 / 478,789 and PCT / US2018 / 025114 (published as WO 2018 / 183656), the contents of which are incorporated herein by reference. Lenn / zznz / E / YiAi in its entirety, in crystalline form B as described in U.S. Provisional Patent Application No. 62 / 678451 and PCT / US2019 / 034534 (Published as WO 2019 / 232138), the contents of which are incorporated herein by reference in their entirety, and in crystalline form C and in crystalline form D, as described in U.S. Provisional Patent Application No. 62 / 860439 and PCT / US2020 / 036727, the contents of which are incorporated herein by reference in their entirety. Designing suitable formulations and dosage forms for BMS-986165 has presented several challenges, as efforts to design formulations that provide bioavailability of the compound after oral administration and are also sufficiently stable during storage have not been successful. Therefore, 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 (BMS986165) that provide sufficient bioavailability for BMS-986165 and, at the same time, sufficient stability of BMS986165 during storage. 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). Lenn / zznz / E / YiAi (methyl-d3)pyridazine-3-carboxamide (BMS-986165) when BMS986165 is administered together with drugs that raise gastric pH (e.g., drugs such as antacids, H2 receptor antagonists, and / or proton pump inhibitors).Furthermore, and particularly when prolonged release of BMS-986165 after oral administration is desirable, there is a need for formulations and dosage forms that provide bioavailability of 6-(cyclopropaneamido)-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 tract (GI tract), such as the colon, where water availability is low and / or where there are no bile salts to enhance drug solubility. 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 requirements. Brief Description of the Invention The present invention provides formulations of amorphous solid BMS-986165 that are physically and chemically stable and can be used to prepare oral dosage forms that provide the bioavailability of BMS-986165. The formulations comprise the amorphous free base BMS-986165 and one or more polymers. The formulations provide the bioavailability of BMS-986165, even when administered to patients who have taken agents that raise gastric pH. Under such elevated gastric pH conditions, the dosage forms containing the formulations described herein exhibit bioavailability that is comparable to the bioavailability provided by the crystalline BMS-986165 HCl salt capsule or by the BMS-986165 free base in oral solution.The formulations also demonstrate superior stability; for example, the BMS-986165 HCl salt capsule requires refrigeration to prevent conversion of the salt to the free base form during storage, whereas the BMS-986165 amorphous solid formulations and dosage forms exhibit physical stability during storage at room temperature. The formulations described herein are also suitable for preparing immediate-release and modified-release dosage forms. Therefore, certain embodiments of the present invention provide formulations and dosage forms comprising a solid dispersion 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). The formulations and dosage forms provide the release and dissolution of BMS-986165 to a sufficient degree and at a sufficiently rapid rate in media simulating in vivo conditions of the gastrointestinal tract, so that they are 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. The embodiments of the present invention also provide extended-release formulations that can be dosed to a patient once daily and provide a pharmacokinetic profile for BMS-986165 that is comparable to or better than the pharmacokinetic profile for BMS-986165 provided by the twice-daily immediate-release tablet. The extended-release formulations described herein provide bioavailability of BMS-986165 in regions of the GI tract, such as the colon, where water availability is low and / or where bile salts are absent to enhance drug solubility. Such formulations would be particularly useful, for example, in the treatment of inflammatory bowel diseases such as ulcerative colitis and Crohn's disease.With the extended-release tablet formulations of BMS-986165 as described in this document, patient compliance can be improved and convenience for the patient and / or caregiver is also improved, since only one tablet is dosed daily to the patient. Brief Description of the Figures Figures 1A and IB show PXRD diffractograms for 10%, 15% and 20% of BMS-986165: HPMCAS-H SDD, as described in Example C; Figure 1A - initial; Figure IB after 6 months of open storage at 40°C / 75% RH. Figures 2A-2C are SEM images for BMS-986165 at 10%: HPMCAS-H SDD with a magnification of 1500X: Figure 2A initial; Figure 2B - after 6 months of storage at 40 °C / 75 % RH closed; Figure 2C - after 6 months of storage at 40 °C / 75 % RH open. Figures 3A-3C are SEM images for 15% BMS986165: HPMCAS-H SDD with a magnification of 1500X; Figure 3A initial; Figure 3B - after 6 months of storage at 40°C / 75% RH closed; Figure 3C - after 6 months of storage at 40°C / 75% RH open. Figures 4A-4C are SEM images for 20% BMS986165: HPMCAS-H SDD with a magnification of 1500X; Figure 4A initial; Figure 4B - after 6 months of storage at 40 °C / 75 % RH closed; Figure 4C - after 6 months of storage at 40 °C / 75 % RH open. Figure 5 shows the dissolution profiles for the tested dosage forms as described in Example E. ai? Lenn / zznz / E / YiAi Figure 6 shows the dissolution profiles for extended-release crystalline freebase formulations of BMS-986165. Figure 7 shows the dissolution profiles for BMS-986165 extended-release spray-dried dispersion formulations. Figure 8 shows the dissolution profiles for BMS-986165 extended-release spray-dried dispersion formulations with HPMCAS added outside the SDD. Figure 9 shows the dissolution profiles for BMS-986165 extended-release spray-dried dispersion formulations in which the polymer viscosity, surface area to volume ratio, or both were varied. Figure 10 shows the dissolution profiles for BMS-986165 extended-release spray-dried dispersion formulations developed for further clinical studies. Figure 11A shows the mean plasma concentration versus time curves from a crossover study comparing the BMS-986165 SDD tablet with the BMS-986165 crystalline freebase tablet in fasted dogs treated with famotidine. Figures 11B and 11C provide the individual plasma concentration versus time curves for each treatment group (n=4). ai? Lenn / zznz / E / YiAi Detailed Description of the Invention The features and advantages of the present invention can be more easily understood by those skilled in the art by reading the following detailed description. It should be appreciated that certain features of the invention described above and below in the context of separate embodiments can also be combined to form a single embodiment. Conversely, several features of the invention described in the context of a single embodiment, for the sake of brevity, can also be combined to form subcombinations thereof. Formulations and dosage forms The present invention provides oral dosage forms of 6-(cyclopropanoamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165) prepared from dispersions of amorphous BMS-986165. The dispersions generally comprise amorphous BMS-986165 and one or more polymers. The dispersions are used to make various dosage forms for oral administration, including dosage forms that provide immediate release of BMS-986165 and dosage forms that provide prolonged release of BMS-986165. As used herein, amorphous refers to a solid form of a molecule and / or ion that is not crystalline. An amorphous solid does not exhibit a definite X-ray diffraction pattern with sharp maxima; it is a thermodynamically out-of-equilibrium material that does not exhibit long-range periodicity. Compared to BMS-986165 in crystalline form, amorphous BMS-986165 exists in a higher energy state; amorphous BMS-986165 possesses greater entropy, enthalpy, and Gibbs free energy than crystalline BMS-986165. A solid amorphous dispersion, or amorphous dispersion, refers to a dispersion comprising a drug and a polymer, in which the drug is not crystalline. An amorphous drug dispersion 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 a solid matrix. A spray-dried dispersion can be made by dissolving the drug and a polymer in an organic solvent to produce a solution, followed by spray drying of the solution. Techniques for preparing solid dispersions of an amorphous drug in a polymer are described, for example, in U.S. Patent No. 9,095,585 and U.S. Patent No.9,468,604, the contents of which are incorporated herein by reference in their entirety. Solid dispersions are also described, for example, in U.S. Patent No. 8,263,128. 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 (NIR) spectroscopy, or any other standard analytical technique. For example, mDSC evaluates the thermal properties of a solid dispersion drug (SDD); for an amorphous SDD, mDSC analysis will produce a single glass transition temperature. mDSC can also detect the separation of crystalline phases, as the crystalline phase will exhibit a unique thermal signal. PXRD uses X-rays to identify the crystalline form in solid powders and can be used to analyze SDDs, for example, to confirm that an SDD is a single amorphous phase, with no measurable crystalline material. The crystalline free base of BMS-986165 exhibits pH-dependent solubility with low solubility at pH > 4. Therefore, the crystalline free base of BMS-986165 exhibits pH-dependent absorption in the gastrointestinal tract. For immediate-release formulations, such pH-dependent properties may result in reduced bioavailability when dosed with acid-reducing agents, such as famotidine or omeprazole. Although the use of the salt form of ai? Lenn / zznz / E / YiAi The HCl of BMS-986165 for immediate-release formulations mitigates the effect of pH. It was observed that formulations made with the HCl salt form of BMS-986165 converted to the free-base form of BMS-986165 during stability testing. Although using the higher-energy amorphous free-base form of BMS-986165 helps address the above challenges, the formulation of amorphous BMS-986165 presents other challenges, including ensuring the physical stability of the amorphous form during storage and maintaining the compound's supersaturation during dissolution in the GI tract. The present invention provides amorphous dispersion formulations of BMS-986165 with improved solubility and bioavailability compared to the crystalline freebase form of BMS-986165, while maintaining acceptable physical and chemical stability. For example, a spray-dried dispersion of amorphous BMS-986165 in a polymer matrix exhibits higher kinetic solubility compared to BMS-986165 in its crystalline form. The increased solubility of amorphous BMS-986165 in a spray-dried dispersion is advantageous for maintaining bioavailability when dosed with acid-reducing agents and also for delivery to regions of the GI tract, such as the colon, where water availability is low and / or where bile salts that enhance drug solubility are not present.Furthermore, the polymer ai? Lenn / zznz / E / YiAi in the dispersion limits the precipitation of BMS-986165 once the drug dissolves and thus helps maintain a supersaturated solution after the amorphous form of BMS-986165 dissolves. The amorphous BMS-986165 in a spray-dried dispersion also exhibits physical stability; for example, the compound remains in an amorphous form and shows little or no crystallization during storage. Although dispersing a drug in a polymer can improve the drug's concentration or bioavailability in vivo, the amount of polymer that can be used is limited by the total mass requirements of an oral dosage form. In other words, the bioavailability benefits of decreasing the drug-to-polymer ratio (so that the weight percent of drug is less than the weight percent of polymer in the formulation) may be offset by the disadvantages associated with using more polymer in an oral dosage form. For example, when a particular dose is to be delivered in a single tablet or capsule, 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 percentage must be high enough to allow for the preparation of oral dosage forms of an acceptable size for the desired dosage concentrations. However, at the same time, dosage forms with a relatively high drug loading percentage may be more prone to drug crystallization. The present invention provides formulations and dosage forms comprising dispersions of amorphous BMS986165, wherein the formulations and dosage forms achieve the desirable properties of bioavailability and stability, while also satisfying the physical requirements of oral dosage forms. For example, the increased solubility of amorphous BMS-986165 in a spray-dried dispersion improves the bioavailability of the drug, even when dosed with medications that raise gastric pH; the spray-dried amorphous dispersions of BMS-986165 are also chemically and physically stable during storage and can be formulated in the desired dosage amounts in ingestible dosage forms. Certain embodiments of the present invention provide a dispersion in which the w / w percentage of BMS-986165 (amorphous) relative to the polymer is in the range of approximately 3% to approximately 80% BMS-986165 and approximately 97% to approximately 20% polymer. Further embodiments provide a dispersion in which the w / w percentage of BMS-986165 to the polymer is in the range of approximately 4% to approximately 50% BMS-986165 and approximately 96% to approximately 50% polymer. In still other embodiments, the w / w percentage of BMS-986165 is in the range of approximately 5% to approximately 25% BMS-986165 and approximately 95% to approximately 75% polymer. Accordingly, some embodiments provide a dispersion in which the w / w % of BMS-986165 with respect to the polymer is approximately 25% BMS-986165 and approximately 75% polymer.In other forms, the w / w % of BMS-986165 with respect to the polymer is approximately 15% BMS-986165 and approximately 85% polymer, or approximately 10% BMS-986165 and approximately 90% polymer. Suitable polymeric starting material for forming the polymer matrix of dispersions (e.g., spray-dried dispersions) as described herein includes: hydroxypropyl methylcellulose (HPMC; also called hypromellose) such as HPMC E3; hydroxypropyl cellulose (HPC); methylcellulose (MC); hypromellose phthalate (HPMC-P); cellulose phthalate and acetate; hydroxypropyl methylcellulose succinate and acetate (HPMCAS; also called hypromellose succinate and acetate) such as HPMCAS grades L, M, and H; Eudragit® L100-55; vinylpyrrolidone-vinyl acetate copolymer (copovidone); polyvinylpyrrolidone (PVP); polymethacrylate-based copolymers; and polyvinylcaprolactam-based copolymers. Preferably, the polymer chosen to form the polymer matrix is ​​HPMCAS, and grade H of HPMCAS is a preferred grade of this polymer. In certain embodiments, spray drying is used to produce amorphous BMS-986165 dispersed in a polymer matrix, to make a formulation of 6(cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide. The formulation can then be used for immediate-release formulations and dosage forms or for modified-release or controlled-release formulations and dosage forms. Accordingly, a dispersion according to the present invention can be combined with one or more excipients. When a granulation process is used, an excipient can be added before granulation (and thus intragranular) and / or it can be added after granulation (and thus extragranular). For example, the dispersion formulations of the present invention may comprise crystallization inhibitors. Crystallization inhibitors suitable for the formulations described herein include cellulosic polymers such as HPMC, HPMCAS, and hydroxypropyl cellulose (HPC), and vinyl polymers such as PVP. Examples of crystallization inhibitors particularly suitable for extended-release formulations as described herein include hydroxypropyl methylcellulose (HPMC; also called hypromellose) such as HPMC E3; hypromellose phthalate (HPMC-P); hydroxypropyl methylcellulose succinate and acetate (HPMCAS; also called hypromellose succinate and acetate) such as HPMCAS grades L, M, and H; Eudragit® L100-55; vinylpyrrolidone-vinyl acetate copolymer (copovidone); and polyvinylpyrrolidone (PVP). In the preferred modalities, the crystallization inhibitor is HPMCAS.A crystallization inhibitor can be included in the dispersion or it can be added outside of the dispersion. Other excipients that may be included in the dispersion formulations described herein include release-control materials. For example, a release-control polymer may be blended or coated with an 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) containing the dispersion blended with a release-control polymer (and other excipients). Accordingly, the present invention also provides a formulation for the prolonged 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), the formulation 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 may 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. Despite the advantages of amorphous drug over crystalline drug as described above, there are at least two substantial challenges involved in designing a sustained-release formulation containing an amorphous SDD (BMS-986165) mixed with a release-control polymer (and other excipients). First, incomplete drug release from the sustained-release formulation may occur due to the release-control polymer in the formulation; such incomplete release may lead, for example, to the administration of an insufficient amount of 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 per se (external phase); and / or after release from the sustained-release formulation.The present invention addresses the first challenge by providing sustained-release formulations in which a suitable polymeric material is chosen as the release-control polymer, and the viscosity of the polymeric material is selected to provide a desired drug release rate. Regarding the second challenge, to maintain the benefits of the amorphous form, the present invention provides a crystallization inhibitor in the sustained-release formulation, but separate from the spray-dried dispersion itself, to reduce or prevent drug crystallization. With the present invention, formulations containing amorphous BMS-986165 with adjustable release rates, while maintaining the benefits of the amorphous form, can be provided to clinicians. The release-controlling polymers that can be used in the sustained-release formulations described herein include natural polymers, biodegradable synthetic polymers, and non-biodegradable synthetic polymers, as would be evident to a person skilled in the art from the present description. Examples of release-controlling polymers include methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, sodium alginate, chitosan, gelatin, tragacanth, xanthan gum, 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 with several different viscometers known in the art. In certain formulations, extended-release dispersion formulations include one or more crystallization inhibitors. For extended-release formulations with an internal and an external phase, the crystallization inhibitor may be provided in the internal and / or external phases. Suitable crystallization inhibitors were described previously. Any of the immediate-release and extended-release formulations of 6-(cyclopropanoamido)4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide as described herein may include pharmaceutically acceptable excipients for the preparation of pills, capsules, tablets, films, syrups, powders, etc. For example, the formulations may include conventional matrix materials, fillers, diluents, binders, lubricants, and / or preservatives. Examples of matrix materials, fillers, or diluents include lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, dicalcium phosphate, and starch.Examples of binders include methylcellulose, microcrystalline 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 sweeteners, and tragacanth or sodium alginate, polyethylene glycol, and similar substances. Examples of lubricants include magnesium stearate, calcium stearate, stearic acid, sodium oleate, and similar substances. Examples of preservatives include sulfites (an antioxidant), benzalkonium chloride, methylparaben, propylparaben, benzyl alcohol, and sodium benzoate. Coloring agents may also be used. In certain embodiments, a dispersion of the present invention is formed into a tablet comprising the dispersion in a weight percentage range of 10 to 50%, such as, for example, 10% w / w, 15% w / w, 20% w / w, or 25% w / w. In some embodiments, at least 15% of the tablet's weight is the dispersion. In certain embodiments, 20% of the tablet's weight is the dispersion. In additional embodiments, the tablet comprises one or more fillers, for example, lactose and / or microcrystalline cellulose, in a total weight percentage range of 50 to 80% of the formulation. In some embodiments, the total amount of fillers is at least 60% w / w, and in other embodiments at least 70% w / w of the formulation. In particular embodiments, the dispersion formulation comprises lactose and microcrystalline cellulose which together constitute at least 70% w / w of the formulation. In additional embodiments, the microcrystalline cellulose:lactose filler ratio is 50:50; in other embodiments, the microcrystalline cellulose:lactose filler ratio is 70:30. In certain embodiments, the tablet dosage form of the invention comprises a disintegrant (e.g., crospovidone, croscarmellose, etc.) in a weight percentage range of 3 to 10%, such as, for example, 5%. In some embodiments, the disintegrant is croscarmellose. When a granulation process is used, the disintegrant can be positioned to be intragranular, extragranular, or both. For example, a tablet may contain 5% w / w croscarmellose (50:50 intragranular:extragranular). In additional embodiments, the tablet dosage form comprises a lubricant, for example, magnesium stearate, in a weight percent range of 0.25 to 2.0%, such as, for example, 0.25%, 0.5% or 0.75%. The phrase "pharmaceutically acceptable," as used herein, refers to those compounds, materials, compositions, and / or dosage forms that, to the best of medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications, consistent with a reasonable risk / benefit ratio. The formulations and dosage forms according to the present invention may contain from approximately 1 mg to approximately 100 mg of BMS-986165, or from approximately 1 mg to approximately 40 mg of BMS-986165, for example, 3 mg, 6 mg, 12 mg, 15 mg, or 36 mg of BMS-986165. In some embodiments, the formulations and dosage forms contain from 12 mg to 36 mg of BMS-986165. In some embodiments, a 100 mg tablet contains approximately 3 mg of BMS-986165, a 200 mg tablet contains approximately 6 mg of BMS-986165, and a 400 mg tablet contains approximately 12 mg of BMS-986165. In some formulations, a 300 mg extended-release tablet contains 15 mg of BMS-986165, and such a tablet may be administered once daily to a patient. Synthesis and Manufacturing BMS-986165 and other amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23, and / or IFN-γ responses, methods for preparing them, and methods for using them are described in U.S. Patent No. 9,505,748 B2, the contents of which are incorporated herein by reference in their entirety. Other methods for synthesizing BMS-986165 are described in U.S. Provisional Patent Application No. 62 / 478,789 and PCT / US2018 / 025100 (published as WO 2018 / 183649), the contents of which are incorporated herein by reference in their entirety. The amorphous dispersions of the present invention can be prepared by hot melt extrusion, freeze-drying, or spray drying. In certain embodiments, spray drying procedures are used. In general, a spray-dried dispersion (SDD) of molecularly dissolved amorphous solid BMS-986165 in a solid polymer matrix can be prepared by dissolving BMS-986165 and a polymer (such as HPMCAS) in an organic solvent (or a mixture of solvents, such as a mixture of acetone and water) to produce a solution or suspension, followed by spray-drying of the solution or suspension. A further description of suitable SDD synthesis steps according to the present invention is set forth in the Examples section of this document. Other manufacturing techniques, such as those described in U.S. Patent No. 9,468,604, may be used to produce a spray-dried dispersion of BMS-986165 in a polymer matrix, and this would be readily apparent to a person skilled in the art from the present description. ai? Lenn / zznz / E / YiAi Accordingly, in some embodiments, a process for making a solid dispersion comprises: (1) adding at least the drug and a polymer to form a solution or suspension, (2) directing the solution or suspension to a spray-drying apparatus and atomizing the solution or suspension into droplets in the spray-drying apparatus, (3) contacting the droplets with a drying gas, resulting in solidification of the particles, and (4) collecting the particles. The dispersions described herein can be formed into tablets using equipment and procedures available in the art. The tablets can be manufactured, for example, by preparing a powder mixture, granulating or grinding, adding a filler, lubricant, and disintegrant, and pressing the mixture into tablets. In certain embodiments, the tablets of the present invention are manufactured by a dry granulation process. Direct compression processes can also be used to form tablets as described herein. Several manufacturing parameters can affect the properties of a tablet dosage form. These parameters include compaction pressure, solids fraction, and target tensile strength. Compaction pressure refers to the applied compaction force divided by the area over which the force is applied. The solids fraction (ai) of a tablet indicates what portion of the tablet is solid and non-porous. The solids fraction (which can be expressed as solids fraction = 1 - porosity) can be calculated by dividing the apparent or shell density of a tablet by the actual density of the material. Generally, applying higher compaction pressure results in higher solids fractions, and a higher solids fraction generally corresponds to greater tablet strength. The tablet's breaking strength refers to the force required to cause the tablet to break or fracture.The tensile strength of a tablet is calculated from the tablet's breaking strength and dimensions. A tablet dosage form according to the present invention exhibits suitable friability and tensile strength, while also providing desirable dissolution characteristics. The description of the manufacture of tablet formulations, including extended-release tablet formulations, containing a spray-dried dispersion of amorphous BMS-986165 in a polymer matrix is ​​set forth in the examples section of this document. Other synthesis techniques, such as those described in U.S. Patent No. 9,713,594, may be used to produce extended-release tablet formulations containing a spray-dried dispersion of amorphous BMS-986165 in a polymer matrix, and would be readily apparent to a person skilled in the art in view of the present description. In some embodiments, a dispersion containing a given w / w percentage of drug is used to prepare tablets of various dosage strengths. For example, a dispersion containing 15% w / w amorphous BMS-986165 in a polymer matrix can be used to manufacture tablets containing 1 mg, 3 mg, 6 mg, and / or 12 mg of BMS-986165. The corresponding exemplary tablet weights for each of these 1 mg, 3 mg, 6 mg, and 12 mg doses of BMS-986165 are 50 mg, 100 mg, 200 mg, and 400 mg, respectively. Dissolution Dispersal formulations and dosage forms made from them can be used to provide immediate and / or modified release of BMS-986165 in the gastrointestinal tract. Such release can be examined using in vitro dissolution assays. Such assays include the gastric-to-intestinal buffer transfer microcentrifuge test, which can be used to measure the enhancement of drug concentration provided by the dispersion containing amorphous BMS-986165 relative to the saturation solubility of the crystalline form of the drug. In the microcentrifuge test, the drug is dosed into a microcentrifuge tube containing a medium with a pH that reflects the pH of a fasting stomach. After 30 minutes of exposure to the gastric medium, the sample is transferred to a higher pH medium that reflects the pH of the intestine.Next, the drug concentration is measured at a desired time point or points (e.g., 90 minutes after the first drug dosage in the gastric medium). The measured drug may consist of free drug, drug in micelles, and / or drug suspended in solution as drug / polymer colloids. The ultracentrifuge test can also be performed at various times during the microcentrifuge test to determine the dissolved drug species present. The ultracentrifuge test involves a centrifugation step at 300,000 x g to remove any colloidal species that may be present, leaving only the free drug and the drug in micelles. Another dissolution test is the Pion dissolution test, which involves transferring the drug from a gastric to an intestinal buffer solution.Other dissolution tests can also be used, such as the USP method tests and biorelevant dissolution tests that have been described in the literature. In certain formulations, immediate release refers to the release of at least approximately 80% of the labeled dose within approximately 60 minutes under conditions simulating an empty stomach. In some formulations, at least approximately 80% of the labeled dose is released within approximately 30 minutes under conditions simulating an empty stomach; in additional formulations, at least approximately 80% of the labeled dose is released within approximately 15 minutes (e.g., within approximately 5 minutes, within approximately 10 minutes) under conditions simulating an empty stomach. In additional formulations, such release is achieved under conditions simulating elevated gastric pH.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 forms may release the drug over a period of time ranging from 2 to 8 hours after oral administration. In some embodiments, the dosage forms may release the drug for up to approximately 24 hours after oral administration. The release rate provided by such dosage forms may be relatively uniform or constant over time, or it may vary over time. In additional embodiments, the dosage forms provide delayed release (for example, 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, can be evaluated in dissolution tests such as the tests described above and in the examples. Stability The formulations and dosage forms of the present invention provide physical and chemical stability of amorphous BMS-986165 during processing and storage. For example, in certain embodiments, the dispersion formulations and dosage forms of the invention exhibit approximately 10% or less crystallization of the total BMS-986165 after the formulations and dosage forms are stored for at least approximately one month (e.g., for three months, or for six months) at 40°C / 75% RH in an open container (or alternatively in a closed container).In certain embodiments, the dispersion formulations and dosage forms of the invention exhibit less than 10% crystallization, such as, for example, less than 5% crystallization, less than 2% crystallization, or less than 1% crystallization of BMS-986165 when stored at 40°C / 75% RH in an open (or alternatively, closed) container for at least one month. In further embodiments, the dispersion formulations and dosage forms exhibit less than 10% crystallization, such as, for example, less than 5% crystallization, less than 2% crystallization, or less than 1% crystallization of BMS-986165 when stored at 40°C / 75% RH in an open (or alternatively, a closed) container for at least three months, or in some embodiments for at least six months.The present invention also provides formulations and dosage forms comprising amorphous BMS-986165, wherein the amorphous form exhibits less than 10% crystallization, such as, for example, less than 5% crystallization, less than 2% crystallization, or less than 1% crystallization: when the formulations and dosage forms are stored at 50-40°C / 75% RH in an open container (or alternatively in a closed container) for at least one month, for at least three months, or for at least about six months.In additional embodiments, the dispersion formulations and dosage forms of the invention exhibit less than 10% crystallization, such as, for example, less than 5% crystallization, less than 2% crystallization, or less than 1% crystallization of BMS-986165 when stored at 40°C / 75% RH (relative humidity) in an open (or alternatively closed) container for at least one month, at least three months, or at least six months. The percentage of crystallization can be evaluated using techniques known in the art and described herein (e.g., PXRD, among others). For example, certain embodiments of the invention provide a dispersion comprising 15% amorphous BMS-986165: 85% HPMCAS-H, wherein the amorphous BMS-986165 remains non-crystalline for six months of storage at 40°C and 75% relative humidity (in an open container or a closed container), as determined by PXRD and / or SEM. Furthermore, in certain forms, BMS-986165 in the dispersions provided herein exhibits degradation of less than 5%, degradation of less than 3%, degradation of less than 2%, or degradation of less than 1% when the dispersions, or dosage forms containing the dispersions, are stored under any of the above-described conditions for a period of time of at least approximately one month to at least approximately six months. Bioavailability For an orally administered drug, drug absorption generally depends on the rate and extent of drug release from the pharmaceutical product, the dissolution or solubilization of the drug substance under physiological conditions in the gastrointestinal tract, and the permeation of the drug across the gastrointestinal membrane. A conventional or standard formulation containing a drug with poor solubility is unlikely to achieve sufficient drug solubilization for adequate absorption into the bloodstream to reach therapeutic levels in the bloodstream and target tissue.Although BMS-986165 exhibits low solubility, the formulations and dosage forms of the present invention achieve desirable levels of solubilization and, therefore, drug absorption, while also providing other desirable attributes (e.g., stability during storage, ingestion capacity of the dosage forms, etc.). In some formulations, administration of a dosage form comprising a solid amorphous dispersion of BMS-986165 results in improved bioavailability of BMS-986165 compared to administration of the same dose of BMS-986165 in a dosage form containing a crystalline formulation of the drug. The relative bioavailability of the drug can be tested in vivo in animals or humans using conventional methods for such determination. For example, an in vivo test, such as a crossover study, 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 a group of test subjects (animals or humans), and after an appropriate washout period (e.g., one week), the same subjects are administered a control composition comprising an amount of drug equivalent to that contained in the test composition. The other half of the group is then administered the control composition first, followed by the test composition. Relative bioavailability is measured as the concentration in the blood (serum or plasma) versus time of the area under the curve (AUC) determined for the test composition divided by the AUC in the blood provided by the control composition.Preferably, this test-to-control ratio is determined for each subject, and then the ratios are averaged across all subjects in the study. AUC determinations can be performed by plotting the serum or plasma concentration of the drug along the ordinate (y-axis) against time along the abscissa (x-axis). AUC determination is a well-established procedure and is described, for example, in Welling, Pharmacokineties Processes and Mathematics, ACS Monograph 185 (1986). In some embodiments, the relative bioavailability of the test composition (e.g., a dosage form comprising an amorphous dispersion of BMS986165 as described herein) is at least 1.25 relative to a control composition as described above (the AUC provided by the test composition is at least 1.25 times the AUC provided by the control composition). In additional embodiments, the relative bioavailability of the test composition is at least 2.0 relative to a control composition containing a crystalline form of the drug. The bioavailability of two formulations or dosage forms can also be compared using in vitro dissolution tests as an indicator of in vivo bioavailability. For example, a gastric-to-intestinal media transfer dissolution test can be used to simulate in vivo conditions in 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. In certain formulations, the bioavailability of BMS-986165 provided by the dosage forms described herein is not significantly affected by drugs that raise gastric pH, such as antacids, H2 receptor antagonists, and proton pump inhibitors. For example, although the administration of a proton pump inhibitor (or other gastric pH-raising agent) may affect gastric pH, the solubility of amorphous BMS-986165 in the dispersions described herein is less susceptible to a pH effect compared to the solubility of crystalline free base BMS-986165. Therefore, administering a dosage form comprising an amorphous BMS-986165 dispersion may provide the bioavailability of BMS-986165 for patients who are also being administered a proton pump inhibitor (or other pH-raising agent).Accordingly, certain embodiments of the invention provide an oral dosage form comprising amorphous BMS-986165 dispersed in a polymeric matrix, wherein the bioavailability of BMS-986165 of the oral dosage form changes by no more than 25%, no more than 20%, no more than 15%, or no more than 10%, when administered concurrently with the dosage form with a gastric pH-raising agent (e.g., a proton pump inhibitor). Concurrent administration in this context refers to a subject receiving both a gastric pH-raising agent (e.g., a proton pump inhibitor) and a dosage form of amorphous dispersed BMS-986165. The agent (e.g., the proton pump inhibitor) and the BMS-986165 dosage form may be administered on the same day or, for example, three days apart.For example, the agent (e.g., proton pump inhibitor) could be administered within 3 days, 2 days, or 1 day of, or on the same days as, the administration of the BMS-986165 dosage form. Concurrent administration includes all times for administration of the gastric pH-raising agent (e.g., proton pump inhibitor) and the BMS-986165 solid dispersion dosage form. The effect of an acid-reducing or gastric pH-raising agent (e.g., a proton pump inhibitor) on bioavailability can be assessed by a study in which the dosage form of BMS-986165 is administered to a first group of test subjects (animals or humans) who are also not administered the pH-raising agent, while the same dosage form of BMS-986165 is administered to a second group of test subjects, where the subjects in this second group are simultaneously administered the pH-raising agent; after an appropriate washout period, the first group is administered the dosage form of BMS-986165 together with the pH-raising agent, while the second group is administered the dosage form of BMS-986165 without the simultaneous administration of the pH-raising agent.Therefore, each subject will have two AUC values ​​(one AUC obtained when taking the pH-raising or acid-reducing agent, and the other AUC obtained when not taking the agent), and these AUC values ​​can be compared for each subject. For example, the ratio of AUCs for each subject can be obtained, and then the ratios for all subjects in the study can be averaged. In certain modalities, the average ratio obtained by such a method is within the range of 0.75 to 1.25. The present invention also provides extended-release formulations and dosage forms in which a single administration can provide bioavailability similar to that provided by an immediate-release formulation or dosage form administered multiple times a day to deliver the same total amount of drug as in the extended-release formulation or dosage form. For example, an extended-release tablet containing a specific dose of BMS-986165 can be administered to a patient once daily to provide a pharmacokinetic profile of the drug that is comparable to the pharmacokinetic profile of the drug provided by the immediate-release tablet administered twice daily. Treatment methods Autoimmune or autoinflammatory diseases that may be treated using the dosage forms or formulations described in this document include psoriasis (e.g., plaque psoriasis), psoriatic arthritis, lupus, lupus nephritis, Sjogren's syndrome, inflammatory bowel diseases (including ulcerative colitis and Crohn's disease), and ankylosing spondylitis. The dosage forms can be administered orally. Preferably, the dosage form is a tablet. Tablets may contain from approximately 1 mg to approximately 100 mg of the drug (BMS-986165), or from approximately 1 mg to approximately 40 mg of the drug, for example, 6 mg, 12 mg, 15 mg, or 36 mg. For example, in certain formulations, a 300 mg tablet is an extended-release dosage form containing 15 mg of the drug and is administered once daily for the treatment of psoriasis. The present invention further provides for the use of a spray-dried dispersion of amorphous BMS-986165 in a polymeric matrix, in the preparation of a medicament for treating an autoimmune or autoinflammatory disease such as inflammatory bowel diseases (including ulcerative colitis and Crohn's disease) and psoriasis. In certain modalities, methods for treating an autoimmune or autoinflammatory disease (e.g., inflammatory bowel diseases (including ulcerative colitis and Crohn's disease) and psoriasis) in a patient comprise: administering to a patient a sustained-release formulation of 6-(cyclopropanoamido)-4-((2 ai? Lenn / zznz / E / YiAi methoxy-3-(1-methyl-lH-l,2,4-triazol-3-yl)phenyl)amino)-N(methyl-d3)pyridazine-3-carboxamide (BMS-986165) comprising (i) an internal phase comprising a spray-dried dispersion of amorphous BMS-986165 in a polymeric matrix, and (ii) an external phase comprising a release-controlling polymer. The invention also provides methods for treating inflammatory bowel disease or psoriasis in a patient, comprising: administering once daily to a patient a sustained-release formulation of 6(cyclopropanoamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS986165) comprising (i) an internal phase comprising a dispersion of amorphous BMS-986165 in a polymer matrix, and (ii) an external phase comprising a release-control polymer. The inflammatory bowel disease may be ulcerative colitis or Crohn's disease. The psoriasis may be plaque psoriasis. The formulation is preferably in tablet form. The invention further provides methods for treating inflammatory bowel disease or psoriasis in a patient, comprising: administering orally once daily to a patient a sustained-release formulation of 6-(cyclopropanoamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3 ai? Lenn / zznz / E / YiAi carboxamide (BMS-986165) comprising (i) an internal phase comprising a spray-dried dispersion of amorphous BMS-986165 in a polymer matrix, and (ii) an external phase comprising a release-controlling polymer. The inflammatory bowel disease may be ulcerative colitis or Crohn's disease. The psoriasis may be plaque psoriasis. The formulation is preferably in tablet form. The following examples serve only to illustrate the invention and its practice. The examples should not be construed as limitations on the scope or spirit of the invention. EXAMPLES Example A The pharmaceutical substance 6-(cyclopropanoamido)4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide and HPMCAS are added to a mixture of acetone and water in a suitable tank and mixed to produce a solution. The solution is spray-dried in 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. To make dispersion formulations and dosage forms with a prolonged-release profile, are ai? Lenn / zznz / E / YiAi mixed SDD, anhydrous lactose, microcrystalline cellulose, and HPMCAS are analyzed by sieving the mixture. The sieved mixture and magnesium stearate are blended, and the resulting product is subjected to dry granulation (roller compaction / crushing) followed by milling. This further product is blended with additional magnesium stearate, followed by tablet formation to produce a 6-(cyclopropaneamido)4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide extended-release tablet. Example B The composition of a spray-drying solution for the production of a spray-dried dispersion of BMS-986165 molecularly dispersed amorphous solid in a solid matrix of HPMCAS-H (15% w / w: 85% w / w) is set out below in Table B1. Table B1. Compositions of a spray-dried solution and SDD ai? Lenn / zznz / E / YiAi Component Grade Spray-Dried Solution Composition (% wt) SDD Composition (mg / g) BMS-986165 Pharmaceutical 0.95 150 HPMCAS-H NF (National Formulary) 5.36 850 Acetone NF 79.64 0 (volatile; not present in final dosage form) Purified water NF 14.05 0 (volatile; not present in the final dosage form) Nitrogen NF 0 0 (used to provide an inert atmosphere during the manufacturing process) qh Lenn / zznz / E / YiAi Table B-2 below sets out a general process description for the manufacture of a spray-dried dispersion of amorphous BMS-986165:HPMCAS-H (15% w / w : 85% w / w) using a laboratory-scale spray dryer with a drying gas capacity of 150 kg / h. Table B-2. Manufacturing of BMS-986165:HPMCAS-H SDD Action Details Considerations 1. Addition of Solvent Acetone Purified Water Add acetone / water 85 / 15 to the appropriate solution preparation vessel and associated components. Begin stirring. 2. Addition of Polymer HPMCAS-H Add HPMCAS-H to the solution preparation vessel, using stirring. Mix the solution according to the parameters in Table B3 below. 3. Addition of Active Substance BMS-986165 Add BMS-986165 to the solution preparation vessel, using stirring. 4. Heating Vessel Heater Heat the solvent to 45°C while stirring using a jacketed vessel. Follow the mixing time parameters shown in Table B3 below. 5. Spray Drying • Laboratory-scale spray dryer with a drying gas flow rate of 150 kg / h and a spray length of 1.83 m (6 ft) • DPH gas dispenser • Nozzle centering device • Pressure nozzle: SK 78-16 (Pencil Point) • Product collection: 15.24 cm (6 in) outside diameter (OD) cyclone • Solution feed filter: 230 µm filter size using a Mott filter housing • Isolate the lines from the solution tank to the nozzle. Use acetone / water 85 / 15 for starting and stopping the spray dryer. Spray dry under the specified conditions described in Table B4 below. 6. Secondary Drying Convection plate dryer. Perform secondary drying under the specified conditions described in Table B5 below. ai? Lenn / zznz / E / YiAi Although Table B-2 provides for the addition of the polymer to the solution preparation vessel before adding the active substance (BMS-986165), the active substance (BMS-986165) can be added to the solution preparation vessel before adding the polymer. Table B-3 below sets out the solution preparation conditions for 15% BMS-986165:85% HPMCAS-H SDD. The spray drying conditions used to manufacture BMS-986165:HPMCAS-H SDD in a laboratory-scale spray dryer with a drying gas flow rate capacity of 150 kg / h were divided into four sets: (A) preheating, (B) heating, (C) feed solution processing, and (D) stopping. Table B-4 below provides a summary of the respective targets and target ranges for the four sets of conditions. Table B-3. Preparation of the spray solution Minimum mixing time Desired solution temperature Comments and / or considerations HPMCAS-H 30 minutes, after the addition of the last component 15-27 °C The solution may be cloudy due to the polymer, but must be free of undissolved solids. BMS-986165 2 hours, after achieving the desired solution temperature 15-27 °C at addition 45 °C (40-50 °C) after heating The solution may be cloudy due to the polymer, but must be free of undissolved solids after heating. Table B-4. Spray Drying Conditions System gas flow (g / min) Dryer inlet temp. (°C) Dryer outlet temp. (°C) Feed pressure (bar (psig)) Speed Feed Rate (g / min) PREHEATING Target 2000 110 Target Range 1850-2150 90-130 WARM-UP Target 2000 110 45 11.0(160) 136 Target Range 1850-2150 90-130 40-50 6.89-17.9 (100-260) 116-146 SOLUTION Target 2000 110 45 11.0(160) 145 Target Range 1850-2150 90-130 40-50 6.89-17.9 (100-260) 125-155 STOP Target 2000 110 45 11.0(160) 136 Target Range 1850-2150 90-130 40-50 6.89-17.9 (100-260) 116-146 The target level of residual acetone in the SDD was less than 0.5 wt%. Acetone levels below the LOQ (limit of quantification) were achieved in a development batch of 15% BMS-986165:85% HPMCAS-H SDD after drying at 40°C / 15% RH for 20.5 hours. Additionally, a residual acetone versus drying study was conducted on two separate development batches. Table B-5 below specifies the secondary drying conditions. Table B-5. Secondary drying conditions ai? Lenn / zznz / E / YiAi Condition Value Bed depth < 2.5 cm Temperature Relative humidity Drying time 40 °C ± 5 °C 15% ± 10% 4 to 20 hours The preferred storage conditions for the spray solution and SDD are set out in Table B-6 below. Table B-6. Storage conditions Item Conditions Spray solution Up to two weeks at up to 50°C SDD Before secondary drying: Up to two weeks on stainless steel at controlled ambient temperature After secondary drying: Store at controlled temperature with desiccant Example C Stability of BMS-986165 SDD formulations The physical and chemical stability of 25% w / w BMS-986165 SDD batches was evaluated using HPMCAS-H. The HPMCAS SDD was chemically stable under all conditions, but powder X-ray diffraction (PXRD) and modulated differential scanning calorimetry (mDSC) data indicated crystallization after one month of open storage at 50°C / 75% RH and after three months of open storage at 40°C / 75% RH. Dissolution performance in the microcentrifuge test remained unchanged. There was no evidence of physical instability when the dispersion formulation was stored at 40°C / 75% RH (closed) or 25°C / 60% RH (open) for up to six months. Further tests were conducted to determine an API loading level in HPMCAS-H that would provide chemical and physical stability while also delivering a desirable dissolution profile. pH transfer dissolution tests using a Pion UV probe (pH 2 or pH 6 to pH 6.5) showed that gastric phase release / maintenance and intestinal phase maintenance generally improved as the API loading was reduced. A six-month stability study of SDDs containing 10%, 15%, or 20% w / w of BMS-986165 in HPMCAS-H showed that all SDDs were chemically stable (Table C). Impurity levels for each SDD matched the impurity levels of the incoming API, indicating that the spray-drying process did not induce degradation; furthermore, impurity levels did not increase during storage. There was no evidence of PXRD crystallization in any SDD after up to 6 months of open storage at 40°C / 75% RH (Figure 1A and Figure 1B). DSC data indicated slight changes similar to those observed in 25% w / w BMS-986165 SDD after exposure to 50°C / 75% RH or 40°C / 75% RH, but there was no trend with API loading and the results were considered to reflect an aging or annealing effect rather than crystal formation.Scanning electron microscopy (SEM) images confirmed the presence of a homogeneous single-phase scattering (Figures 2A2C, Figures 3A-3C, Figures 4A-3C). Thermal activity monitor (TAM) experiments using SDDs with BMS-986165 loadings of 10%, 15%, 20%, and 25% (including PXRD in post-TAM samples) confirmed that the risk of physical instability was low for HPMCAS-H SDDs containing 20% ​​w / w BMS-986165 or less. Dissolution performance in the microcentrifuge test did not change during storage. A lower API loading in the spray-dried solution (SDD), while improving stability, reduced the spray-drying process yield; however, this reduced yield can be compensated for by increasing the solids concentration of the spray-dried 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. To achieve acceptable yield at the target spray solution concentration of 1% API, and to ensure sufficient API loading in the SDD so that the SDD loading in the tablet still allows for tablets of a suitable size for ingestion, an API loading of 15% w / w was selected. Table C. Related substances of BMS-986165: HPMCAS-H SDD ai? Lrnn / zznz / E / YiAi after 6 months of storage Stability conditions BMS-986165 Retention time (min) 11.65 Total impurities >LOQ Ret. time Relative 1.00 API Standard 99.48 0.52 10% BMS-986165 : HPMCAS-H Initial 99.51 0.49 6 months closed, 5 °C 99.49 0.51 6 months open, 25 °C / 60% RH 99.51 0.49 6 months closed, 40 °C / 75% RH 99.45 0.55 6 months open, 40 °C / 75% RH 99.47 0.53 15% BMS-986165: HPMCAS-H Initial 99.51 0.49 6 months closed, 5 °C 99.53 0.47 6 months open, 25 °C / 60% RH 99.45 0.55 6 months closed, 40 °C / 75% RH 99.52 0.48 6 months open, 40 °C / 75% RH 99.40 0.60 ® ¿ | Initial 99.55 0.45 6 months closed, 5 °C 99.49 0.51 6 months open, 25 °C / 60% RH 99.50 0.50 6 months closed, 40 °C / 75% RH 99.47 0.53 6 months open, 40 °C / 75% RH 99.51 0.49 ai? Lenn / zznz / E / YiAi Example D BMS-986165 SDD tablets The following formulation was used to prepare tablets comprising BMS-986165 SDD. Table D. Composition of 3 mg and 12 mg tablets Ingredient % w / w 3 mg tablet (mg per tablet) 12 mg tablet (mg per tablet) Intragranular BMS-986165-01 : HPMCAS-H SDD 15:85 20.00(a) 20.00(a) 80(a) Microcrystalline cellulose 5L25(b) 51.25(b) 205(b) Anhydrous lactose 22.00 22.00 88 Croscarmellose sodium 2.50 2.50 10 Silicon dioxide 1.00 1.00 4 Magnesium stearate 0.25 0.25 1 Extragranular Croscarmellose sodium 2.50 2.50 10 Magnesium stearate 0.50 0.50 2 Tablet weight 100 mg 400 mg Tablet size 6.35 mm round 10 mm round Film coating Coating A based on poly(vinyl alcohol) 4% of tablet weight 4.00 Coating B based on poly(vinyl alcohol) 3% of tablet weight 12 ai? Lenn / zznz / E / YiAi (a) Assuming SDD is 100% of the label declaration (b) Adjusted amount to offset the SDD amount The tablets were manufactured using an Alexanderwerk WP120 compaction roller. Tablet forming was performed using a Korsch XL press, and film coating was performed using a Thomas Compulab Coater apparatus. The tablets exhibited the desired dissolution / disintegration profiles, appropriate hardness and strength, stability during storage, and an acceptable size for ingestion. Tablets were also prepared for a 6 mg dose using a press weight of 200 mg. For the 6 mg dose, a tablet hardness target of 14 SCU provided adequate friability (500-drop test) and an acceptable disintegration time of < 4 minutes. Example E Biorelevant dissolution of BMS-986165 SDD tablets and BMS-986165 HC1 salt capsules (12 mg concentration) The dissolution of tablets containing BMS-986165:HPMCAS-H SDD 15:85, manufactured by a direct compression process, was compared with the dissolution of capsules containing the HCl salt form of BMS-986165 (12 mg concentration for both dosage forms). Dissolution was examined in biorelevant simulated fasting 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 formulation of such a medium is: pH 6.5; osmolality 270110 mOsm; sodium taurocholate 3 mM; lecithin 0.75 mM; KH2PO4 3.9 g; KCl 7.7 g; NaOH; pH 6.5. Deionized water qs 1 liter. The dissolution test was performed in 250 ml of the medium using paddles, at a temperature of 37 °C and a rotation speed of 75 rpm. Six units were tested for each dosage form. Figure 5 provides the results (mean values ​​(n=6)). As shown in Figure 5, the dissolution rate of the SDD tablets was faster than the dissolution rate of the HC1 salt capsule when the dosage forms were tested as described above. For SDD tablets containing amorphous BMS-986165 in a solid dispersion, 95% dissolution was observed at 5 minutes and 97% dissolution at 10 minutes. For capsules containing the HC1 salt form of BMS-986165, 5% dissolution was observed at 5 minutes; 25% dissolution at 10 minutes; 39% dissolution at 15 minutes; and 45% dissolution at 20 minutes. The dissolution of tablets containing BMS-986165:HPMCAS-H SDD 15:85, prepared by granulation, was compared to the dissolution of capsules containing the HC1 salt form of BMS-986165 (concentration of 12 mg for both dosage forms), using the medium and conditions described above (n=6). The results, provided in Table E below, show that the dissolution rate of the granulated tablets comprising amorphous BMS-986165 in a solid dispersion is faster than the dissolution rate of the capsules containing the HC1 salt form of BMS-986165. ai? Lenn / zznz / E / YiAi Table E Time in minutes % Dissolved Average (Min - Max) [%RSD] n=6 Tablet (granulated) Capsule 10 99 (96-100) [1.7] 27 (23-40) [28.7] 15 100 (98-101) [1.2] 39 (26-50) [20.6] 20 100 (99-102) [1.1] 45 (40-52) [8.7] 30 100 (98-102) [1.4] 48 (46-54) [6.0] 45 100 (96-102) [2.1] 50 (48-55) [5.4] 60 100 (100-102) [0.7] 51 (48 -55) [5.1] Example F Prolonged release test of crystalline free base (15 mg concentration) The tablets from example 1, example 2, and example 3, which had the extended-release formulations shown in Table F below, were tested. The dissolution test parameters were as follows: crystalline freebase formulations BMS-986165 (examples 1, 2, or 3) in a potassium phosphate buffer solution (pH 6.8), 20 mesh basket, 1000 ml at 100 rpm. Table F ai? Lenn / zznz / E / YiAi Material Example 1 Example 2 Example 3 BMS-986165 API Crystalline 5% 5% 5% Methocel K100LV 30% - - Methocel E4M - 30% - Methocel K4M - 30% Anhydrous Lactose 32% 32% 32% Microcrystalline Cellulose 32% 32% 32% Magnesium Stearate 1% 1% 1% Tablet Weight 300 mg 300 mg 300 mg As shown in Figure 6, the formulation in Example 3 had the highest release, 67% after 24 hours, as well as a slow release as a result of the relatively high viscosity of the HPMC polymer. Example G BMS-986165 Extended-Release SDD Formulations Following the extended-release testing of the free crystalline form, the extended-release formulations shown in Table G below were developed. Table G ai? Lenn / zznz / E / YiAi Component Function Range studied (%) BMS-986165-01 SDD (15% BMS-986165-01: 85% HPMCAS) Active substance 11-50% Hypromellose (HPMC) (Viscosity range 80-120000 cP) Release-controlling polymer 20-30% Anhydrous lactose Filler 10-60% Microcrystalline cellulose Filler 10-25% Magnesium stearate Lubricant 1.0% BMS-986165-01, as used in this example and throughout this description, specifically refers to 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-ί1)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide in the free base form. BMS-986165-01 SDD, as used in this example and throughout this description, refers to BMS-986165-01 molecularly dispersed amorphous solid in a solid HPMCAS matrix; BMS-986165-01 is present in the SDD in an amount of 15 wt% of the SDD, and HPMCAS is present in the SDD in an amount of 85 wt% of the SDD. Example H Formulation and dissolution profiles for extended-release SDD formulations (15 mg concentration) The tablets from example 4, example 5, and example 6, which had the formulations shown in Table H below, were tested. The dissolution test parameters were as follows: BMS 986165 SDD formulations (examples 4 or 6) in a potassium phosphate buffer solution (pH 6.8), 20 mesh basket, 1000 ml at 100 rpm. Table H Material Example 4 Example 5 Example 6 API 33.34% 33.34% 33.34% Methocel K100LV 20.00% - - Methocel K100M - - 30.00% Methocel K4M - 20.00% - Anhydrous lactose 45.66% 22.83% 35.66% Microcrystalline cellulose - 22.83% - Magnesium stearate 1.00% 1.00% 1.00% Tablet weight 300 mg 300 mg 300 mg By using a formulation of SSD that contained BMS-986165 With the amorphous API, overall drug release was improved at 24 hours (72% for Example 4, as shown in Figure 7) compared to the crystalline API (67% for Example 1). However, incomplete drug release occurred after 24 hours. This test demonstrated that partial or complete crystallization of the drug within or from an SDD formulation can negate the advantages of using an SDD formulation, for example, by reducing the bioavailability benefit. Example I BMS-986165 Extended-Release SDD Formulations with HPMCAS Added Outside of SDD Following the SDD formulation trial described above, the extended-release formulations shown in Table I below were developed. Table I ai? Lenn / zznz / E / YiAi Component Function Range Studied (%) BMS-986165-01 SDD (15% BMS-986165-01: 85% HPMCAS) Active Substance 11-50% Hydroxypropyl Methylcellulose Acetate and Succinate (HPMCAS) Crystallization Inhibitor Up to 16% Hypromellose (HPMC) (Viscosity Range 80-120000 cP) Release-Controlling Polymer 15-30% Anhydrous Lactose Filler 10-20% Microcrystalline Cellulose Filler 10-20% Magnesium Stearate Lubricant 1.0% Example J Formulation and dissolution profile for extended-release SDD tablet formulation with HPMCAS added outside of SDD The tablets from example 7, which had the formulation shown in Table J below, were tested. The dissolution test parameters were as follows: formulation BMS986165 SDD (example 7) in a potassium phosphate buffer solution (pH 6.8), 20 mesh basket, 1000 ml at 100 rpm. Table J ai? Lenn / zznz / E / YiAi Material Example 7 API 33.34% Methocel K100LV 20.00% HPMCAS 15.66% Anhydrous Lactose 15.00% Microcrystalline Cellulose 15.00% Magnesium Stearate 100% Tablet Weight 300 mg The addition of HPMCAS to the formulation—but outside the SDD portion (in the external phase of) the formulation—further increased the overall drug release at 24 hours to 79% (Example 7, as shown in Figure 8) compared to when no additional HPMCAS was part of the formulation (Example 4). This test demonstrated that additional HPMCAS reduced crystallization in the product / system, resulting in increased release of BMS-986165. Example K The tablets in Examples 8, 9, 10, 11, and 12, which had the extended-release formulations specified in Table K below, were developed to study the factors relevant to designing an adaptable extended-release formulation of BMS-986165. Regarding the viscosity of the release-controlling polymer (HPMC in this case), a range of viscosities was studied using either a single polymer or a blend of polymers with different viscosities. The surface area-to-volume ratio and dosage were studied by changing the tablet weight (dose), thereby also changing the surface area-to-volume ratio. Different adjustments can be made to achieve the same surface area-to-volume ratio. ai? Lenn / zznz / E / YiAi Table K Hey. 8 Ej. 9 Ej. 10 Ej. 11 Hey. 12 Ingredient % w / w mg / tab mg / tab % w / w mg / tab mg / tab % w / w mg / tab Intra-granular (IG) BMS-986165 SDD 40.00 80.0 240.0 40.00 80.0 240.0 40.00 160.00 HPMCAS 10.00 20.0 60.0 10.00 20.0 60.0 10.00 40.00 Mcthoccl K100LV 25.00 50 150 - - - 5.00 20.00 Methocel K15M - - 25.00 50.00 150.0 20.00 80.00 Lactosa anhidra 12.00 24.0 72.0 12.00 24.0 72.0 12.00 48.00 Microcrystalline cellulose 12.00 24.0 72.0 12.00 24.0 72.0 12.00 48.00 Magnesium stearate 0.50 1.0 3.0 0.50 1.0 3.0 0.50 2.00 GI total 99.50 99.50 99.50 Extra-granular - - - Magnesium stearate 0.50 1.0 3.0 0.50 1.0 3.0 0.50 2.00 Total 100.00 200 600 100.00 200 600 100.00 400.00 Viscosity of HPMC (cP) 100 15,000 8000 Relation aprox. of the superficial area with respect to the volume (button -1) 27 16.4 27 16.4 ai? Lenn / zznz / E / YiA Figure 9 shows the dissolution profiles when varying viscosity, the surface area-to-volume ratio, or both. The dissolution test parameters were as follows: dissolution of the formulations in a pH 6.8 phosphate buffer solution using 1% Brij USB II in a caged plate, 1000 ml at 75 rpm. As shown in Figure 9, adjustable release (viscosity and surface area-to-volume ratio) was demonstrated through a variety of release profiles, achieving complete drug release for certain formulations. Example L The tablets in Examples 8-1, 9-1, 10-1, and 11-1, which have the extended-release formulations described below in Tables L1 and L2, were developed for further clinical study. Figure 10 shows the dissolution profile of these formulations. The dissolution test parameters were as follows: BMS-986165 SDD formulations (Examples 8-1, 9-1, 10-1, and 11-1) in potassium phosphate buffer (pH 6.8), 1% Brij, in a platinum cage at 1000 mL at 75 rpm. Any combination of viscosities and dosages as described within these four formulations may be used for further clinical studies. Suitable drug dosage ranges include 12 mg (200 mg tablet weight) to 36 mg (600 mg tablet weight). Table Ll Ex. 8-1 Ex. 9-1 Ingredient % w / w mg / tab mg / tab Intra-granular (IG) BMS-986165 SDD 40.00 80.0 240.0 HPMCAS 10.00 20.0 60.0 Methocel K100LV 24.50 49.0 147.0 Methocel K15M 0.50 1.0 3.0 Anhydrous lactose 12.00 24.0 72.0 Microcrystalline cellulose 12.00 24.0 72.0 Magnesium stearate 0.50 1.0 3.0 Total GI 99.50 Extra-granular - Magnesium stearate 0.50 1.0 3.0 Total 100.00 200 600 Table L-2 απ Lenn / zznz / E / YiAi Ex. 10-1 Ex. 11-1 Ingredient % w / w mg / tab mg / tab Intra-granular (IG) BMS-986165 SDD 40.00 80.00 240.00 HPMCAS 10.00 20.00 60.00 Methocel K100LV 0.50 1.00 3.00 Methocel K15M 24.50 49.00 147.00 Anhydrous lactose 12.00 24.00 72.00 Microcrystalline cellulose 12.00 24.00 72.00 Magnesium stearate 0.50 1.00 3.00 Total GI 99.50 Extra-granular - Magnesium stearate 0.50 1.00 3.00 Total 100.00 200 600 Example M The tablets of example 13 and example 14 were prepared with the following formulations for the prolonged release of BMS-986165. Example 13 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 K100 LV Premium CR present in an amount of 0.50% (w / w); hypromellose K15M Premium CR present in an amount of 24.50% (w / w); anhydrous lactose 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). Example 14 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 K100 LV Premium CR present in an amount of 24.50% (w / w); hypromellose K15M Premium CR present in an amount of 0.50% (w / w); anhydrous lactose 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). Other combinations of quantities can be used for hypromellose K100 LV and hypromellose K15M, and other premium versions of these hypromellose components that are not CR grade can be used. ai? Lenn / zznz / E / YiAi Example N Bioavailability of tablets comprising BMS-986165 SDD and tablets comprising BMS-986165 free base (crystalline) in famotidine-treated dogs This study compared the pharmacokinetic profile of tablets containing BMS-986165-01 SDD (15% BMS 986165-01 : 85% HPMCAS) with the pharmacokinetic profile of tablets containing the crystalline freebase of BMS 986165 in famotidine-treated dogs. The study was a crossover study with two treatment groups (4 male dogs in each group). In both groups, dogs were fasted and pretreated with famotidine, which raises gastric pH. Both tablet dosage forms were tested at a concentration of 4 mg (human equivalent dose [HED] of 12 mg). Table 1 and Figures 11A–11C provide the results. LO ai? Lenn / zznz / E / YiAi As shown in Table N1, under elevated gastric pH conditions, tablets containing BMS-986165 in the form of a crystalline free base exhibited a lower Cmax and the same mean Tmax compared to tablets containing the amorphous free base of BMS-986165 in a solid dispersion. The area under the curve (AUC), calculated from 0 to 24 hours, was also lower for the crystalline free base tablets compared to the SDD tablets; this difference in AUC was statistically significant (p < 0.05). The variability of both dosage forms was within the variability typically observed for pharmacokinetic studies in dogs. These results demonstrate that the crystalline freebase tablets of BMS-986165 exhibit a bioavailability of approximately 50% relative to BMS-986165-01 SDD, at a dose of 4 mg (12 mg HED) under elevated gastric pH conditions. It is hereby stated that, as of this date, the best method known to the applicant for putting the aforementioned invention into practice is the one that is clear from the present description of the invention.

Claims

1. A dosage form for the prolonged release of 6-(cyclopropanoamido)-4-((2-methoxy-3-(1-methyl1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165), characterized in that it comprises: (i) an internal phase comprising a spray-dried dispersion of BMS-986165 in a polymer matrix; and (ii) an external phase comprising a release-controlling polymer.

2. The dosage form according to claim 1, characterized in that the release-controlling polymer is selected from methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethyl cellulose, sodium alginate, chitosan, gelatin, tragacanth, xanthan and mixtures thereof.

3. A dosage form for the prolonged release of 6-(cyclopropanoamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165), characterized in that it comprises: (i) an internal phase comprising a dispersion of BMS-986165 in a polymer matrix; (ii) an external phase comprising a release-controlling polymer; and (iii) a crystallization inhibitor, which is located in the external phase.

4. The dosage form according to claim 3, characterized in that the release-controlling polymer is selected from methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethyl cellulose, sodium alginate, chitosan, gelatin, tragacanth, xanthan and mixtures thereof.

5. The dosage form according to claim 3, characterized in that the crystallization inhibitor is selected from polyvinylpyrrolidone (PVP), vinyl acetate, hydroxypropyl methylcellulose, methylcellulose, cellulose acetate and phthalate, hydroxypropyl cellulose, polymethacrylate-based copolymers, polyvinylcaprolactam-based copolymers, hydroxypropyl methylcellulose succinate and acetate, and mixtures thereof.

6. The dosage form according to claim 3, characterized in that the polymer matrix is ​​hydroxypropyl methylcellulose succinate and acetate (HPMCAS), and the release-controlling polymer is hydroxypropyl methylcellulose (HPMC).

7. The dosage form according to claim 3, characterized in that the crystallization inhibitor is hydroxypropyl methylcellulose acetate and succinate (HPMCAS).

8. The dosage form according to claim 3, characterized in that it is an oral dosage form.

9. The dosage form according to any of claims 1-7, for use in the treatment of an autoimmune disease or an autoinflammatory disease in a subject.

10. The oral dosage form according to claim 8, for use in the treatment of an autoimmune disease or an autoinflammatory disease in a subject.

11. The dosage form to be used in accordance with claim 9, wherein the subject is a human subject.

12. The dosage form for use in accordance with claim 10, wherein the subject is a human subject.

13. The dosage form according to any of claims 1-8, for use in a method of treating an inflammatory bowel disease in a subject, wherein the method comprises administering the dosage form to the subject once a day.

14. The dosage form for use in accordance with claim 13, wherein the dosage form is a tablet containing 12 to 36 mg of BMS986165.

15. The dosage form for use according to claim 13, wherein the dosage form is a tablet containing 15 mg of BMS-986165.

16. The dosage form for use according to claim 13, wherein the inflammatory bowel disease is ulcerative colitis.

17. The dosage form for use according to claim 13, wherein inflammatory bowel disease is Crohn's disease.