Extended release dosage forms of TYK2 inhibitors

Abstract

Provided are 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); the present invention relates to stable and bioavailable extended release formulations and dosage forms of dispersions (e.g., spray-dried dispersions) of liposomes (e.g., BMS-986165) for use in the treatment of autoimmune and autoinflammatory diseases such as Inflammatory Bowel Disease (IBD) and psoriasis. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese patent application with application number 202080078644.6 (application date: 2020 / 9 / 18, invention name: Extended release dosage form of TYK2 inhibitor). Technical Field

[0002] The present invention relates to dosage forms and formulations of 6-(cyclopropanecarboxamido)-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-(cyclopropanecarboxamido)-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 Art

[0003] Tyrosine kinase 2 (Tyk2) is a member of the Janus kinase (JAK) family of non-receptor tyrosine kinases and has been shown to be involved in both IL-12 / Th1 and IL-23 / Th17 axes in vivo 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); Prachal-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 Tyk2 is an essential protein in the signal transduction cascade downstream of the receptors that regulates IL-12, IL-23 and type I interferon in both immunity and pro-inflammatory cytokines. Tyk2 mediates receptor-induced phosphorylation of members of the STAT family of transcription factors, which is an essential signal leading to dimerization of STAT proteins and transcription of STAT-dependent pro-inflammatory 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-2in both the IL-12 / Th1 andIL-23 / Th17 axes in vivo”, J. Immunol., 187: 181-189 (2011); Oyamada, A. et al., “Tyrosine kinase 2plays critical roles in the pathogenic CD4 T cell responses for the development of experimental autoimmune encephalomyelitis”, J. Immunol., 183: 7539-7546 (2009)).

[0004] In humans, individuals expressing an inactive variant 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 that other variants of Tyk2 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, 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" arthritis", Nat. Genet., 44: 1336-1340 (2012)).

[0005] BMS-986165 refers to a compound of the following formula (I):

[0006]

[0007] It is 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide. BMS-986165 (which is being studied 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) is a highly selective inhibitor of Tyk2-mediated signal transduction. It selectively binds to the Tyk2 pseudokinase (JH2) domain and blocks receptor-mediated Tyk2 activation by stabilizing the regulatory JH2 domain.

[0008] BMS-986165 and other amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and / or IFNα responses, methods for their manufacture and methods for their use are disclosed in U.S. Patent No. 9,505,748B2, which is hereby incorporated herein by reference in its entirety. Other methods for synthesizing BMS-986165 are disclosed in U.S. Provisional Patent Application No. 62 / 478,789 and PCT / US2018 / 025100 (published as WO 2018 / 183649), the contents of each of which are hereby incorporated herein by reference in their entirety.

[0009] BMS-986165 has been synthesized in crystalline forms, such as crystalline Form A (as disclosed in U.S. Provisional Patent Application No. 62 / 478,789 and PCT / US2018 / 025114 (published as WO 2018 / 183656), the contents of each of which are hereby incorporated by reference in their entireties), crystalline Form B (as disclosed in U.S. Provisional Patent Application No. 62 / 678451 and PCT / US2019 / 034534 (published as WO 2019 / 232138), the contents of each of which are hereby incorporated by reference in their entireties), and crystalline Form C and crystalline Form D (as disclosed in U.S. Provisional Patent Application No. 62 / 860439 and PCT / US2020 / 036727, the contents of each of which are hereby incorporated by reference in their entireties).

[0010] Designing a suitable formulation and dosage form for BMS-986165 presents some challenges, as efforts to design a formulation that provides bioavailability of the compound following oral administration and is also sufficiently stable upon storage have not been successful.

[0011] Therefore, there is a need in the art for formulations and dosage forms of 6-(cyclopropanecarboxamido)-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 bioavailability of BMS-986165 while also providing sufficient stability of BMS-986165 upon storage. In particular, there is a need for formulations and dosage forms that provide bioavailability of 6-(cyclopropanecarboxamido)-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 co-administered with drugs that increase gastric pH (e.g., drugs such as antacids, H2 receptor antagonists, and / or proton pump inhibitors). In addition, and particularly when extended release of BMS-986165 following oral administration is desired, there is a need for formulations and dosage forms that provide bioavailability of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165) in areas of the gastrointestinal tract (GI tract) where water availability is low and / or bile salts are absent, which may enhance the solubility of the drug, such as the colon. At the same time, such formulations and dosage forms must provide adequate stability of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide upon storage. The formulations and dosage forms of the present invention address these and other needs. Summary of the invention

[0012] The present invention provides a formulation of solid amorphous BMS-986165 that is physically and chemically stable and can be used to manufacture oral dosage forms that provide bioavailability of BMS-986165. The formulation comprises amorphous BMS-986165 free base and one or more polymers. The formulation provides bioavailability of BMS-986165, including when administered to patients who have taken an agent that increases gastric pH. Under such conditions of elevated gastric pH, dosage forms containing the formulations described herein exhibit bioavailability comparable to that provided by crystalline BMS-986165 HCl salt capsules or by BMS-986165 free base in oral solution. The formulation further exhibits excellent stability; for example, BMS-986165 HCl salt capsules require refrigeration to prevent the salt from converting to the free base form during storage, while solid amorphous BMS-986165 formulations and dosage forms exhibit physical stability when stored under room temperature conditions. The formulations described herein are also suitable for manufacturing immediate release and modified release dosage forms.

[0013] Therefore, certain embodiments of the present invention provide formulations and dosage forms comprising a solid dispersion of amorphous 6-(cyclopropanecarboxamido)-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 in a medium that simulates the in vivo conditions of the gastrointestinal tract to a sufficient extent and at a sufficiently fast rate so that they are suitable for use as immediate release formulations and dosage forms. Such immediate release formulations can then be modified to provide a controlled release oral dosage form of BMS-986165.

[0014] Embodiments of the present invention also provide an extended release formulation that can be administered to a patient once a day and provide a pharmacokinetic curve of BMS-986165 comparable to or better than the pharmacokinetic curve of BMS-986165 provided by an immediate release tablet administered twice a day. Extended release formulations as described herein provide the bioavailability of BMS-986165 in the GI tract region (such as the colon) where water availability is low and / or there is no bile salt that can enhance the solubility of the drug. For example, such formulations will be particularly helpful in treating inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease. Using extended release BMS-986165 tablet formulations as described herein can improve patient compliance, and can also improve the convenience of patients and / or caregivers, because only one tablet is administered to the patient every day. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1A and Figure 1BPXRD diffractograms of 10%, 15% and 20% BMS-986165:HPMCAS-HSDD as described in Example C are shown. Figure 1A -start; Figure 1B - After 6 months storage at 40°C / 75% RH open.

[0016] Figure 2A-2C This is a SEM image of 10% BMS-986165:HPMCAS-H SDD at 1500X magnification: Figure 2A -start; Figure 2B - After 6 months of storage at 40℃ / 75%RH in a sealed container; Figure 2C - After 6 months storage at 40°C / 75% RH open.

[0017] Figure 3A-3C is a SEM image of 15% BMS-986165:HPMCAS-H SDD at 1500X magnification. Figure 3A -start; Figure 3B - After 6 months of storage at 40℃ / 75%RH in a sealed container; Figure 3C - After 6 months storage at 40°C / 75% RH open.

[0018] Figure 4A-4C is a SEM image of 20% BMS-986165:HPMCAS-H SDD at 1500X magnification. Figure 4A -start; Figure 4B - After 6 months of storage at 40℃ / 75%RH in a sealed container; Figure 4C - After 6 months storage at 40°C / 75% RH open.

[0019] Figure 5 The dissolution profile of the dosage form tested as described in Example E is shown.

[0020] Figure 6 Shown is the dissolution profile of an extended release formulation of BMS-986165 crystalline free base.

[0021] Figure 7 Shown is the dissolution profile of an extended release spray-dried dispersion formulation of BMS-986165.

[0022] Figure 8 Shown is the dissolution profile of an extended release spray dried dispersion formulation of BMS-986165 with added HPMCAS outside of the SDD.

[0023] Fig. 9Shown are dissolution profiles of extended release spray-dried dispersion formulations of BMS-986165 in which polymer viscosity, surface area to volume ratio, or both were varied.

[0024] Fig.10 Shown is the dissolution profile of an extended release spray-dried dispersion formulation of BMS-986165 developed for further clinical studies.

[0025] Fig.11A Shown are mean plasma concentration versus time profiles from a crossover study comparing BMS-986165 SDD tablets to BMS-986165 crystalline free base tablets in fasting dogs treated with famotidine. Fig. 11B and Fig. 11C Individual plasma concentration versus time curves are presented for each treatment group (n=4). DETAILED DESCRIPTION

[0026] When reading the following detailed description, those of ordinary skill in the art can more easily understand the features and advantages of the present invention. It should be understood that certain features of the present invention described in the context of a separate embodiment may also be combined to form a single embodiment. On the contrary, for reasons of brevity, the various features of the present invention described in the context of a separate embodiment may also be combined to form a sub-combination thereof.

[0027] Formulations and dosage forms

[0028] The present invention provides oral dosage forms of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165) made from a dispersion of amorphous BMS-986165. The dispersion generally comprises amorphous BMS-986165 and one or more polymers. The dispersion is 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 extended release of BMS-986165.

[0029] As used herein, "amorphous" refers to a non-crystalline molecular and / or ionic solid form. An amorphous solid does not show a well-defined X-ray diffraction pattern with sharp maxima; it is a thermodynamically non-equilibrium material that does not exhibit long-range periodicity. Amorphous BMS-986165 exists in a higher energy state than BMS-986165 in crystalline form; amorphous BMS-986165 has higher entropy, enthalpy, and Gibbs free energy than crystalline BMS-986165.

[0030] A solid amorphous dispersion or amorphous dispersion refers to a dispersion comprising a drug and a polymer, wherein the drug is non-crystalline. Amorphous dispersions of drugs can be prepared by various manufacturing methods, such as spray drying, coprecipitation or hot melt extrusion. Spray dried dispersions (SDD) are single-phase amorphous molecular dispersions of drugs in a polymer matrix; it is an amorphous solid in which the drug is molecularly "dissolved" in a solid matrix. Spray dried dispersions can be manufactured by the following method: the drug and polymer are dissolved in an organic solvent to produce a solution, and then the solution is spray dried. The technology for preparing a solid dispersion of amorphous drugs in polymers is disclosed in, for example, U.S. Patent No. 9,095,585 and U.S. Patent No. 9,468,604, and the contents of each of which are hereby incorporated herein by reference in their entirety. Solid dispersions are also described in, for example, U.S. Patent No. 8,263,128.

[0031] 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 any other standard analytical technique. For example, mDSC evaluates the thermal properties of the SDD; for an amorphous SDD, analysis by mDSC will yield a single glass transition temperature. mDSC can also detect crystalline phase separation, as the crystalline phase will show a unique thermal signature. PXRD uses x-rays to identify crystalline forms in a solid powder, and can be used to analyze the SDD, for example to confirm that the SDD is a single amorphous phase with no measurable crystalline material.

[0032] BMS-986165 crystalline free alkali exhibits pH-dependent solubility, which has low solubility at pH>4. Therefore, BMS-986165 crystalline free alkali exhibits pH-dependent absorption in the GI tract. For immediate release formulations, such pH-dependent characteristics can lead to reduced bioavailability when administered with an acid reducing agent (e.g., such as famotidine or omeprazole). Although the HCl salt form of BMS-986165 is used for immediate release formulations to alleviate pH effects, it was observed during stability testing that the formulation made with the HCl salt form of BMS-986165 would be converted into the free alkali form of BMS-986165. Although the use of higher energy, amorphous free alkali forms of BMS-986165 helps to solve the above challenges, the preparation of amorphous BMS-986165 is also faced with other challenges, including ensuring the physical stability of the amorphous form during storage, and maintaining the supersaturation of the compound during dissolution in the GI tract.

[0033] The present invention provides such amorphous BMS-986165 dispersion formulations, which have improved solubility and bioavailability and acceptable physical and chemical stability relative to the crystalline free base form of BMS-986165. For example, compared with BMS-986165 in crystalline form, the spray-dried dispersion of amorphous BMS-986165 in a polymer matrix has a higher kinetic solubility. The higher solubility of amorphous BMS-986165 in the spray-dried dispersion is conducive to maintaining bioavailability when administered with an acid reducing agent, and is also conducive to delivery to GI tract areas (such as the colon) where water availability is low and / or there is no bile salt that can enhance the solubility of the drug. In addition, once the drug dissolves, the polymer in the dispersion limits the precipitation of BMS-986165, and thereby helps to maintain a supersaturated solution after the amorphous form of BMS-986165 is dissolved. Amorphous BMS-986165 in the spray-dried dispersion also exhibited physical stability—eg, the compound maintained an amorphous form upon storage and exhibited little or no crystallization.

[0034] Although dispersing the drug in a polymer can increase the drug concentration or bioavailability in vivo, the amount of polymer that can be used is limited by the total mass requirement of the oral dosage form. In other words, the bioavailability benefits of reducing the ratio of drug to polymer (making the wt% of the drug lower than the wt% of the polymer in the formulation) may be offset by the disadvantages associated with using more polymers in the oral dosage form. For example, when it is necessary to deliver a specific dose in a single tablet or capsule, using a low drug to polymer ratio may cause the total mass of the tablet or capsule to be too large to swallow. The percentage of drug loading must be high enough so that an oral dosage form of acceptable size can be manufactured to obtain the desired dosage strength. At the same time, however, dosage forms with relatively high percentage drug loading may be more prone to drug crystallization.

[0035] The present invention provides formulations and dosage forms comprising amorphous BMS-986165 dispersions, wherein the formulations and dosage forms achieve the desired properties of bioavailability and stability while also meeting the physical requirements of oral dosage forms. For example, the higher solubility of amorphous BMS-986165 in the spray-dried dispersions improves the bioavailability of the drug, including when administered with drugs that increase gastric pH; amorphous BMS-986165 spray-dried dispersions are also chemically and physically stable during storage, and they can be formulated into swallowable dosage forms at the desired dose.

[0036] Certain embodiments of the present invention provide a dispersion in which the w / w % of BMS-986165 (amorphous) to polymer is in the range of from about 3% to about 80% BMS-986165 and from about 97% to about 20% polymer. Further embodiments provide a dispersion in which the w / w % of BMS-986165 to polymer is in the range of 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 is in the range of from about 5% to about 25% BMS-986165 and from about 95% to about 75% polymer. Thus, some embodiments provide a dispersion 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.

[0037] Polymer starting materials suitable for forming the polymer matrix of the dispersions (e.g., spray-dried dispersions) as 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 methyl acetate succinate), such as L, M and H grades of HPMCAS; L100-55; vinylpyrrolidone-vinyl acetate copolymer (copovidone); polyvinylpyrrolidone (PVP); copolymers based on polymethacrylate; and copolymers based on polyvinylcaprolactam. Preferably, the polymer selected to form the polymer matrix is ​​HPMCAS, and HPMCAS H grade is the preferred grade of this polymer.

[0038] In certain embodiments, spray drying is used to produce amorphous BMS-986165 dispersed in a polymer matrix to make a formulation of 6-(cyclopropanecarboxamido)-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 can be used to make modified release or controlled release formulations and dosage forms.

[0039] Thus, the dispersion according to the invention may be combined with one or more other excipients.When a granulation process is used, the excipients may be added before granulation (and thus intragranular) and / or may be added after granulation (and thus extragranular).

[0040] For example, the dispersion formulation of the present invention may include a crystallization inhibitor. Suitable crystallization inhibitors for use in the formulations described herein include cellulosic polymers such as HPMC, HPMCAS, and hydroxypropyl cellulose (HPC) and vinyl polymers such as PVP. Crystallization inhibitors particularly suitable for extended release formulations as 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 hydroxypropyl methylcellulose acetate succinate), such as HPMCAS grades L, M, and H; L100-55; vinyl pyrrolidone-vinyl acetate copolymer (copovidone); and polyvinyl pyrrolidone (PVP). In a preferred embodiment, the crystallization inhibitor is HPMCAS. The crystallization inhibitor may be included in the dispersion or may be added outside the dispersion.

[0041] Other excipients that may be included in the dispersion formulations described herein include materials that control release. For example, a polymer that controls release can be mixed with an amorphous dispersion of BMS-986165 or coated thereon to produce an extended release formulation. One type of extended release dosage form is an oral dosage form (such as a tablet) containing a dispersion mixed with a polymer (and other excipients) that controls release.

[0042] Therefore, the present invention also provides a formulation for the extended release of 6-(cyclopropanecarboxamido)-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 containing a dispersion of amorphous BMS-986165 in a polymer matrix (e.g., a spray-dried dispersion); and an external phase containing a controlled release 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.

[0043] Despite the advantages of amorphous drugs over crystalline drugs as described above, there are at least two major challenges in designing extended release formulations containing amorphous BMS-986165SDD mixed with a controlled release polymer (and other excipients). First, due to the controlled release polymer in the formulation, the drug may be incompletely released from the extended release formulation; for example, this incomplete release may result in insufficient drug delivery to the patient. Secondly, the drug may crystallize: within the spray-dried dispersion itself (internal phase); within the extended release formulation but outside the SDD itself (external phase); and / or after release from the extended release formulation. The present invention solves the first challenge by providing an extended release formulation, wherein a suitable polymer material is selected as a controlled release polymer and the viscosity of the polymer material is selected to provide the desired drug release rate. For the second challenge, in order to maintain the benefits of the amorphous form, the present invention provides a crystallization inhibitor in the extended release formulation but outside the spray-dried dispersion itself to reduce or prevent drug crystallization. Through the present invention, a formulation containing amorphous BMS-986165 with an adjustable release rate and maintaining the benefits of the amorphous form can be provided to the clinic.

[0044] The polymer of the controlled release that can be used for extended release preparation as herein described comprises natural polymer, synthetic biodegradable polymer and synthetic non-biodegradable polymer, as will be easily clear to those of ordinary skill in the art according to the present disclosure.The example of the polymer of controlled release comprises methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, sodium alginate, chitosan, gelatin, tragacanth gum, xanthan gum and aforesaid mixture.HPMC is the polymer of the preferred controlled release for extended release preparation as herein described.When HPMC was selected as the polymer of controlled release, it preferably had the viscosity from 80cP to 120000cP scope.Polymer viscosity can be measured with many different viscometers known in the art.

[0045] In certain embodiments, the extended release dispersion formulation comprises one or more crystallization inhibitors. For extended release formulations with an inner phase and an outer phase, the crystallization inhibitor can be provided in the inner phase and / or in the outer phase in the formulation. Suitable crystallization inhibitors are discussed above.

[0046] Any of the immediate and extended release formulations of 6-(cyclopropanecarboxamido)-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 contain pharmaceutically acceptable excipients to make pills, capsules, tablets, films, syrups, powders, and the like. For example, conventional matrix materials, fillers, diluents, binders, lubricants, and / or preservatives may be included in the formulation. Examples of matrix materials, fillers, or diluents include lactose, mannitol, xylitol, microcrystalline cellulose, calcium phosphate, dicalcium phosphate, and starch. Examples of binders include methylcellulose, microcrystalline cellulose, carboxymethyl cellulose, gelatin, starch, gums (such as guar gum, natural and synthetic gums such as gum arabic), natural sugars (such as glucose or β-lactose), corn sweeteners, and tragacanth or sodium alginate, polyethylene glycol, and the like. 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.

[0047] In certain embodiments, the dispersion of the present invention is formulated into a tablet containing a weight percentage range of 10%-50% (e.g., 10% w / w, 15% w / w, 20% w / w, or 25% w / w) of the dispersion. In some embodiments, at least 15% of the tablet by weight is the dispersion. In certain embodiments, 20% of the tablet by weight is the dispersion.

[0048] In further embodiments, the tablet comprises one or more fillers, such as lactose and / or crystalline cellulose, in a total weight percentage range of 50%-80% of the formulation. In some embodiments, the total amount of filler is at least 60% w / w, and in further embodiments at least 70% w / w of the formulation. In a particular embodiment, the dispersion formulation comprises lactose and microcrystalline cellulose in a total of at least 70% w / w of the formulation. In further embodiments, the ratio of microcrystalline cellulose: lactose filler is 50:50; in other embodiments, the ratio of microcrystalline cellulose: lactose filler is 70:30.

[0049] In certain embodiments, the tablet dosage form of the present invention comprises a disintegrant (e.g., crospovidone, cross-linked carboxymethyl cellulose, etc.) in a weight percentage range of 3%-10% (e.g., such as 5%). In an embodiment, the disintegrant is cross-linked carboxymethyl cellulose. When a granulation method is used, the disintegrant can be located intragranularly, extragranularly, or both. For example, a tablet can contain cross-linked carboxymethyl cellulose 5% w / w (50:50 intragranular: extragranular).

[0050] In other embodiments, the tablet dosage form comprises a lubricant, such as magnesium stearate, in the weight percentage range of 0.25%-2.0% (such as, for example, 0.25%, 0.5% or 0.75%).

[0051] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or animals without producing excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0052] The formulations and dosage forms according to the invention may contain from about 1 mg to about 100 mg of BMS-986165, or from about 1 mg to about 40 mg of BMS-986165, for example 3 mg, 6 mg, 12 mg, 15 mg or 36 mg of BMS-986165. In embodiments, the formulations and dosage forms contain from 12 mg to 36 mg of BMS-986165. In embodiments, 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 embodiments, a 300 mg extended release tablet contains 15 mg of BMS-986165, and such tablets may be administered to a patient once a day.

[0053] Synthesis and manufacturing

[0054] BMS-986165 and other amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and / or IFNα responses, methods for their manufacture and methods for their use are disclosed in U.S. Patent No. 9,505,748B2, which is hereby incorporated herein by reference in its entirety. Other methods for synthesizing BMS-986165 are disclosed in U.S. Provisional Patent Application No. 62 / 478,789 and PCT / US2018 / 025100 (published as WO 2018 / 183649), the contents of each of which are hereby incorporated herein by reference in their entirety.

[0055] The amorphous dispersions of the present invention can be prepared by hot melt extrusion, freeze drying or spray drying. In certain embodiments, a spray drying procedure is used.

[0056] Typically, 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 (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, and then spray drying the solution or suspension. Further description of suitable SDD synthesis steps according to the present invention is set forth in the Examples section herein. Other manufacturing techniques (such as those disclosed in U.S. Pat. No. 9,468,604) can be used to produce spray-dried dispersions of BMS-986165 in a polymer matrix, and this will be readily apparent to one of ordinary skill in the art in light of this disclosure.

[0057] Thus, in some embodiments, the method for making a solid dispersion comprises: (1) adding at least the drug and the polymer to form a solution or suspension, (2) introducing the solution or suspension into a spray drying device and atomizing the solution or suspension into droplets in the spray drying device, (3) contacting the droplets with a drying gas to cause the particles to solidify, and (4) collecting the particles.

[0058] The dispersions described herein can be tableted using equipment and procedures available in the art. Tablets can be manufactured, for example, by preparing a powder mixture, granulating or slugging, adding fillers, lubricants, and disintegrants, and pressing into tablets. In certain embodiments, the tablets of the present invention are manufactured by a dry granulation process. Direct compression methods can also be used to form tablets as described herein.

[0059] Several manufacturing parameters can affect the properties of tablet dosage forms. Such parameters include compaction pressure, solid fraction, and target tensile strength. Compaction pressure refers to the compaction force applied divided by the area where the force is applied. The solid fraction of a tablet indicates how many tablets are solid rather than porous. The solid fraction (which can be expressed as solid fraction = 1-porosity) can be calculated by dividing the apparent or surrounding density of the tablet by the true density of the material. Typically, applying a greater compaction pressure results in a higher solid fraction, and a higher solid fraction generally corresponds to a higher tablet strength. Tablet breaking strength refers to the force required to cause cracks or fractures in a tablet. The tensile strength of a tablet is calculated by the breaking strength of the tablet and the size of the tablet. The tablet dosage form according to the present invention exhibits suitable brittleness and tensile strength while still providing the desired dissolution characteristics.

[0060] A description of the manufacture of a spray-dried dispersion of amorphous BMS-986165 in a polymer matrix, including an extended release tablet formulation, is described in the Examples section herein. Other synthetic techniques (such as disclosed in U.S. Pat. No. 9,713,594) can be used to produce an extended release tablet formulation containing a spray-dried dispersion of amorphous BMS-986165 in a polymer matrix, and will be readily apparent to those of ordinary skill in the art based on this disclosure.

[0061] In some embodiments, dispersions containing a given percentage w / w of drug are used to make tablets of various dosage strengths. For example, a 15% w / w dispersion of amorphous BMS-986165 in a polymer matrix can be used to make tablets containing 1 mg, 3 mg, 6 mg, and / or 12 mg of BMS-986165. Exemplary tablet weights corresponding to each of these dosage strengths of 1 mg, 3 mg, 6 mg, and 12 mg BMS-986165 are: 50 mg, 100 mg, 200 mg, and 400 mg, respectively.

[0062] Dissolution

[0063] Dispersion formulations and dosage forms manufactured therefrom can be used to provide immediate release and / or modified release of BMS-986165 in the gastrointestinal tract. This release can be checked using an in vitro dissolution assay. Such assays include a gastric to intestinal buffer transfer microcentrifugation test, which can be used to measure the drug concentration enhancement provided by a dispersion containing amorphous BMS-986165 relative to the saturated solubility of the crystalline form of the drug. In the microcentrifugation test, the drug is injected into a microcentrifuge tube containing a medium with a certain pH (reflecting the pH of a fasted stomach). After being exposed to gastric media for 30 minutes, the sample is transferred to a higher pH medium reflecting intestinal pH. The drug concentration is then measured at one or more desired time points (e.g., 90 minutes after administration in gastric media for the first time). The measured drug can be composed of free drug, drug in micelles, and / or drug suspended in solution as a drug / polymer colloid. During the microcentrifugation test, an ultracentrifugation test may also be performed at multiple time points to determine the dissolved drug material present; the ultracentrifugation test involves a centrifugation step at 300,000 x g to remove any colloidal material that may be present, leaving only free drug and drug in micelles. Another dissolution test is the gastric to intestinal buffer transfer Pion dissolution test. Other dissolution tests may also be used, such as USP method tests and biorelevant dissolution tests that have been described in the literature.

[0064] In certain embodiments, immediate release refers to release of at least about 80% of the label claimed dose within about 60 minutes under conditions simulating a fasted stomach. In some embodiments, at least about 80% of the label claimed dose is released within about 30 minutes under conditions simulating a fasted stomach; in further embodiments, at least about 80% of the label claimed dose is released within about 15 minutes (e.g., about 5 minutes, about 10 minutes) under conditions simulating a fasted stomach. In further embodiments, such release is achieved under conditions simulating elevated gastric pH conditions.

[0065] In some embodiments, it may be necessary to provide a modified release of BMS-986165. Therefore, certain embodiments of the present invention provide a dosage form that exhibits a controlled release of BMS-986165 after oral administration. For example, the dosage form can release the drug during a time period extending to about 2-8 hours after oral administration. In some embodiments, the dosage form can release the drug for up to about 24 hours after oral administration. The release rate provided by such dosage forms can be relatively uniform or constant over time, or can vary over time. In other embodiments, the dosage form provides a delayed release of the drug (e.g., enteric release). The conditions for drug release and the rate at which the drug is released from such modified release dosage forms can be evaluated in dissolution tests (such as those described above and in the examples).

[0066] stability

[0067] The formulations and dosage forms of the present invention provide physical and chemical stability of amorphous BMS-986165 during processing and upon storage. For example, in certain embodiments, the dispersion formulations and dosage forms of the present invention exhibit about 10% or less crystallization of the total BMS-986165 after the formulations and dosage forms are stored in an open (or alternatively in a sealed) 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 when stored in an open (or alternatively in a sealed) container at 40°C / 75% RH (relative humidity) for at least about one month, such as, for example, less than about 5% crystallization, less than about 2% crystallization, or less than about 1% crystallization. In further embodiments, the dispersion formulations and dosage forms exhibit less than about 10% crystallinity of BMS-986165, such as, for example, less than about 5% crystallinity, less than about 2% crystallinity, or less than about 1% crystallinity, when stored in an open (or alternatively in a sealed) container at 40°C / 75% RH for at least about three months, or in some embodiments, at least about six months. The present invention also provides formulations and dosage forms comprising amorphous BMS-986165, wherein the amorphous form exhibits less than about 10% crystallinity, such as, for example, less than about 5% crystallinity, less than about 2% crystallinity, or less than about 1% crystallinity, when the formulations and dosage forms are stored in an open (or alternatively in a sealed) container at 50°C / 75% RH for at least about one month, at least about three months, or at least about six months. In further embodiments, the dispersion formulations and dosage forms of the invention exhibit less than about 10% crystallinity of BMS-986165, such as, for example, less than about 5% crystallinity, less than about 2% crystallinity, or less than about 1% crystallinity, when stored in an open (or alternatively, in a sealed) container at 25°C / 60% RH (relative humidity) for at least about one month, at least about three months, or at least about six months. The percent crystallinity can be assessed by techniques known in the art and described herein (e.g., PXRD, etc.).

[0068] 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 non-crystalline after storage at 40° C. and 75% relative humidity (in an open container or in a closed container) for six months, as determined by PXRD and / or SEM.

[0069] Furthermore, in certain embodiments, when a dispersion provided herein or a dosage form containing the dispersion is stored under any of the conditions described above for a period of at least about one month to at least about six months, the BMS-986165 in the dispersion exhibits less than about 5% degradation, less than about 3% degradation, less than about 2% degradation, or less than about 1% degradation.

[0070] Bioavailability

[0071] For orally administered drug products, drug absorption generally depends on the rate and extent of release of the drug substance from the drug product, the dissolution or solubility of the drug substance under the physiological conditions of the gastrointestinal tract, and the permeability of the drug across the gastrointestinal membrane. Conventional or standard formulations containing drugs that exhibit poor solubility may not be able to achieve sufficient dissolution of the drug to allow sufficient drug to be absorbed into the bloodstream, thereby achieving therapeutic levels of the drug in the bloodstream and target tissues. Although BMS-986165 exhibits poor solubility, the formulations and dosage forms of the present invention achieve the desired solubility level and therefore achieve absorption of the drug while also providing other desired attributes (e.g., stability during storage, swallowability of the dosage form, etc.).

[0072] In some embodiments, administration of a dosage form comprising a solid amorphous dispersion of BMS-986165 results in improved bioavailability of BMS-986165 relative to administration of the same dose of BMS-986165 in a dosage form containing a crystalline formulation of the drug. Such determinations can be made by testing the relative bioavailability of a drug in vivo in animals or humans using conventional methods.

[0073] For example, in vivo testing (such as crossover studies) can be used to determine whether a dosage form provides enhanced relative bioavailability compared to a control. In an in vivo crossover study, a "test composition" is administered to half of the subjects in a test subject (animal or human) group, and after an appropriate clearance period (e.g., one week), a "control composition" containing an equivalent amount of the drug contained in the "test composition" is administered to the same subject. The other half of the group is first administered with a control composition, and then administered with a test composition. Relative bioavailability is measured as the area under the curve (AUC) of the concentration-time relationship in the blood (serum or plasma) determined by the test composition divided by the AUC in the blood provided by the control composition. Preferably, this test / control ratio is determined for each subject, and then the ratios of all subjects in the study are averaged. The determination of AUC can be performed by plotting the serum or plasma concentration of the drug along the ordinate (y-axis) for the time along the abscissa (x-axis). The determination of AUC is a well-known procedure, and is described in, for example, Welling, "Pharmacokinetics Processes and Mathematics," ACS Monograph 185 (1986).

[0074] In some embodiments, the relative bioavailability of the test composition (e.g., a dosage form comprising an amorphous dispersion of BMS-986165 as described herein) relative to a control composition as described above is at least 1.25 (the AUC provided by the test composition is at least 1.25 times the AUC provided by the control composition). In further embodiments, the relative bioavailability of the test composition relative to a control composition containing a crystalline form of the drug is at least 2.0.

[0075] The bioavailability of two formulations or dosage forms can also be compared using an in vitro dissolution test as a surrogate for in vivo bioavailability. For example, a stomach to intestinal media transfer dissolution test can be used to simulate 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 can be used, such as the test described in Example E.

[0076] In certain embodiments, the bioavailability of BMS-986165 provided by the dosage forms described herein is not significantly affected by drugs that increase gastric pH (such as antacids, H2 receptor antagonists, and proton pump inhibitors). For example, although the administration of proton pump inhibitors (or other gastric pH raising agents) can affect gastric pH, the solubility of amorphous BMS-986165 in the dispersions described herein is less susceptible to pH than free base crystalline BMS-986165. Therefore, the administration of a dosage form comprising a dispersion of amorphous BMS-986165 can provide bioavailability of BMS-986165 for patients who are also administered proton pump inhibitors (or other pH raising agents). Therefore, certain embodiments of the present invention provide an oral dosage form comprising amorphous BMS-986165 dispersed in a polymer matrix, wherein when a gastric pH-raising agent (e.g., a proton pump inhibitor) is administered simultaneously with the dosage form, 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%. Simultaneous administration herein refers to the subject receiving both a gastric pH-raising agent (e.g., a proton pump inhibitor) and a dispersed amorphous BMS-986165 dosage form. The agent (e.g., a proton pump inhibitor) and the BMS-986165 dosage form can be administered on the same day or, for example, within 3 days of each other. For example, the agent (e.g., a proton pump inhibitor) can be administered within 3 days, 2 days, or 1 day of the BMS-986165 dosage form or on the same day. All such administration times including gastric pH-raising agents (e.g., proton pump inhibitors) and BMS-986165 solid dispersion dosage forms are administered simultaneously.

[0077] The effect of gastric pH raising agents or acid reducing agents (e.g., proton pump inhibitors) on bioavailability can be evaluated by a study in which a BMS-986165 dosage form is administered to a first group of test subjects (animals or humans) to which a pH raising agent has not yet been administered, while the same BMS-986165 dosage form is administered to a second group of test subjects, wherein the subjects in the second group are simultaneously administered a pH raising agent; after an appropriate washout period, the first group is then administered a BMS-986165 dosage form and a pH raising agent, while the second group is administered a BMS-986165 dosage form without concurrent administration of a pH raising agent. Thus, each subject will have two AUC values ​​(one AUC obtained when taking a pH raising agent or an acid reducing agent, and another AUC obtained when not taking the agent), and these AUC values ​​for each subject can be compared. For example, an AUC ratio for each subject can be obtained, and then the ratios for all subjects in the study can be averaged. In certain embodiments, the average ratio obtained by such methods is in the range of 0.75-1.25.

[0078] The present invention also provides extended release formulations and dosage forms, wherein a single administration can provide a bioavailability similar to that provided by multiple administrations of an immediate release formulation or dosage form on days when the same total amount of drug is delivered 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 comparable to that provided by an immediate release tablet administered twice daily.

[0079] Treatment

[0080] 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, Sjögren's syndrome, inflammatory bowel disease (including ulcerative colitis and Crohn's disease), and ankylosing spondylitis.

[0081] The dosage form can be administered orally. Preferably, the dosage form is a tablet. The tablet can contain from about 1 mg to about 100 mg of the drug (BMS-986165), or about 1 mg to about 40 mg of the drug, such as 6 mg, 12 mg, 15 mg or 36 mg. For example, in certain embodiments, a 300 mg tablet is an extended release dosage form containing 15 mg of the drug and is administered once a day for the treatment of psoriasis.

[0082] The present invention further provides the use of a spray-dried dispersion of amorphous BMS-986165 in a polymer matrix for the preparation of a medicament for treating autoimmune or autoinflammatory diseases such as inflammatory bowel disease (including ulcerative colitis and Crohn's disease) and psoriasis.

[0083] In certain embodiments, the method of treating an autoimmune or autoinflammatory disease in a patient, such as inflammatory bowel disease (including ulcerative colitis and Crohn's disease) and psoriasis, comprises administering to the patient a formulation for extended release of 6-(cyclopropanecarboxamido)-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 (i) an inner phase comprising a spray-dried dispersion of amorphous BMS-986165 in a polymer matrix and (ii) an outer phase comprising a release-controlling polymer.

[0084] The present invention also provides a method for treating inflammatory bowel disease or psoriasis in a patient, the method comprising: administering to the patient once a day a formulation for extended release of 6-(cyclopropanecarboxamido)-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 (i) an inner phase comprising a spray-dried dispersion of amorphous BMS-986165 in a polymer matrix and (ii) an outer phase comprising a controlled release 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.

[0085] The present invention further provides a method for treating inflammatory bowel disease or psoriasis in a patient, the method comprising: orally administering to the patient once a day a formulation for extended release of 6-(cyclopropanecarboxamido)-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 (i) an inner phase comprising a spray-dried dispersion of amorphous BMS-986165 in a polymer matrix and (ii) an outer phase comprising a controlled release 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.

[0086] The following examples are only used to illustrate the present invention and its practice. The examples should not be interpreted as limiting the scope or spirit of the present invention.

[0087] Example

[0088] Example A

[0089] 6-(Cyclopropanecarboxamido)-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 produce 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.

[0090] In order to manufacture dispersion formulations and dosage forms with extended release characteristics, SDD, anhydrous lactose, microcrystalline cellulose and HPMCAS are blended together, and the blended combination is screened. The screened composition and magnesium stearate are blended, and the resulting product is subjected to dry granulation (weight compression / roller compression method), then ground. This further result is blended with other magnesium stearate, and then tableting is to produce a tablet for the extended release of 6-(cyclopropaneamide)-4-((2-methoxy-3-(1-methyl isophthalic acid H-1,2,4-triazol-3-yl) phenyl) amino)-N-(methyl-d3) pyridazine-3-carboxamide.

[0091] Example B

[0092] The composition of the spray drying solution used to produce a spray drying dispersion of solid amorphous BMS-986165 (15% w / w: 85% w / w) molecularly dispersed in a solid HPMCAS-H matrix is ​​shown below in Table B-1.

[0093] Table B-1. Composition of spray solution and SDD

[0094]

[0095] Table B-2 below shows an overview of the process for making a spray-dried dispersion of amorphous BMS-986165:HPMCAS-H (15% w / w:85% w / w) using a laboratory-scale spray dryer with a 150-kg / hr drying gas capacity.

[0096] Table B-2. BMS-986165: Manufacturing of HPMCAS-H SDD

[0097]

[0098] Although Table B-2 provides that the polymer is added to the solution preparation vessel prior to the addition of the active (BMS-986165), the active (BMS-986165) may be added to the solution preparation vessel prior to the addition of the polymer.

[0099] Table B-3 below lists the solution preparation conditions for 15% BMS-986165:85% HPMCAS-HSDD. The spray drying conditions for making BMS-986165:HPMCAS-HSDD on a laboratory-scale spray dryer with a 150-kg / hr drying gas flow rate capacity are divided into four groups: (A) preheat, (B) temperature increase, (C) feed solution processing, and (D) shutdown. Table B-4 below provides a summary of the corresponding targets and target ranges for the four groups of conditions.

[0100] Table B-3. Spray solution preparation

[0101]

[0102] Table B-4. Spray drying conditions

[0103]

[0104]

[0105] The target level of residual acetone in the SDD was less than 0.5 wt%. After drying for 20.5 hours at 40°C / 15% RH, acetone levels below LOQ (limit of quantitation) were achieved in a development batch of 15% BMS-986165:85% HPMCAS-H SDD. In addition, residual acetone and drying were studied for two separate development batches. Table B-5 below shows the secondary drying conditions.

[0106] Table B-5. Secondary drying conditions

[0107]

[0108] Preferred storage conditions for the spray solution and SDD are shown below in Table B-6.

[0109] Table B-6. Storage conditions

[0110]

[0111] Example C

[0112] Stability of BMS-986165SDD formulations

[0113] The physical and chemical stability of a number of 25% w / w BMS-986165SDD with HPMCAS-H was evaluated. HPMCAS DDD was chemically stable under all conditions, but powder X-ray diffraction (PXRD) and modulated differential scanning calorimetry (mDSC) data indicated crystallization after 1 month of open storage at 50°C / 75% RH and 3 months of open storage at 40°C / 75% RH. The dissolution performance in the microcentrifuge test was unchanged. There was no evidence of physical instability when the dispersion formulations were stored for up to 6 months at 40°C / 75% RH sealed or 25°C / 60% RH open conditions.

[0114] Additional testing was performed to determine the API loading levels in HPMCAS-H that would provide chemical and physical stability while still providing the desired dissolution profile. pH shift dissolution testing using a Pion UV probe (pH 2 or pH 6 to pH 6.5) showed that release / maintenance in the gastric phase and maintenance in the intestinal phase generally improved as API loading decreased.

[0115] A six-month stability study of SDDs containing 10%, 15%, or 20% w / w BMS-986165 in HPMCAS-H showed that all SDDs were chemically stable (Table C). The impurity levels of each SDD matched the incoming API impurity levels, indicating that the spray drying process did not cause degradation; in addition, the impurity levels did not increase upon storage. There was no evidence of crystallization by PXRD in any of the SDDs after storage at 40°C / 75%RH open for up to 6 months ( Figure 1A and Figure 1B ). DSC data indicated that after exposure to 50°C / 75% RH or 40°C / 75% RH, there was a slight change similar to that observed in 25% w / w BMS-986165SDD, but there was no trend with API loading, and it was considered that the results reflected an "aging" or "annealing" effect rather than crystal formation. Scanning electron microscopy (SEM) images confirmed the presence of a single phase homogeneous dispersion ( Figure 2A-2C , Figure 3A-3C , Figure 4A-4C ).

[0116] TAM (Thermal Activity Monitor) experiments (including PXRD on post-TAM samples) using SDD with BMS-986165 loading of 10%, 15%, 20%, and 25% confirmed that HPMCAS-HSDD containing 20% ​​w / w BMS-986165 or less had a low physical stability risk. The dissolution performance in the microcentrifuge test did not change upon storage.

[0117] Lower API loading in the SDD (while improving stability) reduced the throughput of the spray drying process; however, this reduced flux could be offset by increasing the solids concentration of the spray solution to the limit of 8% w / w HPMCAS in acetone / water (this limit helped to ensure the robustness of the process). The solids concentration was also limited by the solubility of BMS-986165 in acetone / water. In order to obtain acceptable flux at the target spray solution concentration of 1% API, and to ensure sufficient API loading in the SDD so that the loading of the SDD in the tablet would still allow the tablet to be of a size suitable for swallowing, an API loading of 15% w / w was selected.

[0118] Table C. Related substances of BMS-986165:HPMCAS-H SDD after 6 months storage

[0119]

[0120]

[0121] Example D

[0122] BMS-986165SDD Tablet

[0123] The following formulation was used to prepare tablets containing BMS-986165SDD.

[0124] Table D. Composition of 3 mg and 12 mg tablets

[0125]

[0126] (a) Assuming the SDD is 100% of the label claim

[0127] (b) Amount adjusted to compensate for SDD

[0128] Tablets were manufactured using an Alexanderwerk WP 120 roller compactor. Tableting was performed using a Korsch XL tablet press and film coating was performed using a Thomas Compulab coater.

[0129] Tablets exhibit a desired dissolution / disintegration profile, appropriate hardness and strength, stability on storage, and a size acceptable for swallowing.

[0130] Tablets for a 6 mg dose were also prepared using a 200 mg compression weight.For the 6 mg dose, a tablet hardness target of 14 SCU provided adequate friability (500 drop weight test) and an acceptable disintegration time of <4 minutes.

[0131] Example E

[0132] Biorelevant Dissolution of BMS-986165 SDD Tablets and BMS-986165 HCl Salt Capsules (12 mg Strength)

[0133] The dissolution of tablets containing 15:85 BMS-986165:HPMCAS-H SDD and manufactured by direct compression method was compared with the dissolution of capsules containing BMS-986165 HCl salt form (both dosage forms were 12 mg strength) in biologically relevant fasted state simulated intestinal fluid (FaSSIF) for dissolution examination. 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 media is: pH 6.5; weight molar osmotic pressure concentration 270±10mosmol; sodium taurocholate 3mM; lecithin 0.75mM; KH2PO4 3.9 grams; KCl 7.7 grams; appropriate NaOH pH 6.5; appropriate deionized water 1 liter. Dissolution testing was performed in 250 mL of medium using a paddle at a temperature of 37°C and a rotation speed of 75 rpm. Six units of each dosage form were tested. Figure 5 Results (mean values ​​(n=6)) are presented.

[0134] like Figure 5 As shown, when the dosage forms were tested as described above, the dissolution rate of the SDD tablets was faster than that of the HCl salt capsules. For the SDD containing amorphous BMS-986165 in the solid dispersion, 95% dissolution was observed at 5 minutes, and 97% dissolution was observed at 10 minutes. For the capsules containing the HCl salt form of BMS-986165, 5% dissolution was observed at 5 minutes; 25% dissolution was observed at 10 minutes; 39% dissolution was observed at 15 minutes; and 45% dissolution was observed at 20 minutes.

[0135] The dissolution of tablets containing 15:85 BMS-986165:HPMCAS-H SDD and manufactured by the granulation process was compared to the dissolution of capsules containing the HCl salt form of BMS-986165 using the above media and conditions (n=6) (both dosage forms were 12 mg strength). The results provided in Table E below show that the dissolution rate of the granulated tablets containing amorphous BMS-986165 in the solid dispersion was faster than the dissolution rate of the capsules containing the HCl salt form of BMS-986165.

[0136] Table E

[0137]

[0138] Example F

[0139] Crystalline Free Base Extended Release Test (15 mg Strength)

[0140] Tablets of Example 1, Example 2 and Example 3 with extended release formulations listed in Table F below were tested. Dissolution test parameters were as follows: BMS-986165 crystalline free base formulation (Example 1, 2 or 3) in potassium phosphate buffer (pH 6.8), 20 mesh basket, 1000 mL, at 100 rpm.

[0141] Table F

[0142] Material Example 1 Example 2 Example 3 Crystalline BMS-986165API 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 300mg 300mg 300mg

[0143] like Figure 6 As shown, the Example 3 formulation had the highest release, 67% after 24 hours, and a slow release due to the relatively high viscosity of the HPMC polymer.

[0144] Example G

[0145] Extended-release SDD formulation of BMS-986165

[0146] Following extended release testing of the crystalline free base, the extended release formulations shown in Table G below were developed.

[0147] Table G

[0148]

[0149]

[0150] As used in this example and throughout this disclosure, "BMS-986165-01" specifically refers to 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide in free base form. 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.

[0151] Example H

[0152] Formulation and dissolution profile of extended release SDD formulation (15 mg strength)

[0153] Example 4, Example 5 and Example 6 tablets with the formulations listed in Table H below were tested. Dissolution test parameters were as follows: BMS-986165SDD formulation (Example 4, 5 or 6) in potassium phosphate buffer (pH 6.8), 20 mesh basket, 1000 mL, at 100 rpm.

[0154] Table H

[0155] 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 300mg 300mg 300mg

[0156] The total drug release at 24 hours was improved by using the SDD formulation containing the amorphous BMS-986165 API (72% in Example 4, 67% in Example 1) compared to the crystalline API. Figure 7 ). However, drug release was incomplete after 24 hours. This test demonstrates that partial or complete crystallization of the drug in or from the SDD formulation may negate the advantages of using the SDD formulation, for example by reducing the bioavailability advantage.

[0157] Embodiment 1

[0158] Extended release SDD formulation of BMS-986165 with HPMCAS added to SDD

[0159] Following the SDD formulation testing described above, the extended release formulations shown in Table I below were developed.

[0160] Table I.

[0161]

[0162]

[0163] Example J

[0164] Formulation and dissolution profile of extended-release SDD tablet formulation with HPMCAS added to SDD

[0165] Tablets of Example 7 with the formulations listed below in Table J were tested. Dissolution test parameters were as follows: BMS-986165SDD formulation (Example 7) in potassium phosphate buffer (pH 6.8), 20 mesh basket, 1000 mL, at 100 rpm.

[0166] Table J

[0167] Material Example 7 API 33.34％ Methocel K100LV 20.00％ HPMCAS 15.66％ Anhydrous lactose 15.00％ Microcrystalline Cellulose 15.00％ Magnesium Stearate 1.00％ Tablet weight 300mg

[0168] Adding HPMCAS to the formulation - but outside the SDD portion (in the external phase of the formulation) - further increased the total drug release to 79% at 24 hours (Example 7, as shown) compared to when no additional HPMCAS was part of the formulation (Example 4). Figure 8 This test demonstrated that additional HPMCAS reduced crystallization in the product / system, thereby increasing the release of BMS-986165.

[0169] Example K

[0170] Developed embodiment 8, embodiment 9, embodiment 10, embodiment 11 and embodiment 12 tablets with extended release formulation shown in the following table K, so as to study the factors relevant to the adjustable extended release formulation of design BMS-986165. About the viscosity of the polymer (HPMC in this case) of controlled release: by using a single polymer or by mixing the polymers of different viscosities to study the viscosity range. Surface area / volume ratio and dosage were studied by changing tablet weight (dosage) (thereby also changing surface area to volume ratio). Different changes can be carried out to realize the same surface area to volume ratio.

[0171] Table K

[0172]

[0173]

[0174] Fig. 9 Dissolution profiles for varying viscosity, surface area to volume ratio, or both are shown. Dissolution test parameters are as follows: Dissolve formulation in pH 6.8 phosphate buffer with 1% brij USPII and caged sedimentation blue, 1000 mL, at 75 rpm. Fig. 9 As shown, tunable release (viscosity and surface area / volume) was demonstrated via a series of release profiles, with complete drug release achieved for certain formulations.

[0175] Example L

[0176] Tablets of Example 8-1, Example 9-1, Example 10-1 and Example 11-1 with extended release formulations shown in Table L-1 and Table L-2 below were developed for further clinical studies. Fig.10The dissolution curves of these formulations are shown. The dissolution test parameters are as follows: BMS-986165SDD formulations (Examples 8-1, 9-1, 10-1, 11-1) in potassium phosphate buffer (pH 6.8), 1% brij, cage sedimentation blue, 1000 mL, at 75 rpm. Any combination of viscosity and dosage listed in these four formulations can be used for additional clinical studies. Suitable drug dosage ranges include the range of 12 mg (200 mg tablet weight) to 36 mg (600 mg tablet weight).

[0177] Table L-1.

[0178]

[0179] Table L-2.

[0180]

[0181] Embodiment M

[0182] Example 13 and Example 14 tablets were manufactured with the following formulation for extended release of BMS-986165.

[0183] Embodiment 13

[0184] Amorphous BMS-986165-01: HPMCAS-H (15% w / w: 85% w / w) spray-dried dispersion at 40.00%

[0185] (w / w) amount present;

[0186] HPMCAS is present in an amount of 10.00% (w / w);

[0187] Hydroxypropyl methylcellulose K100 LV Premium CR is present in an amount of 0.50% (w / w);

[0188] Hydroxypropyl methylcellulose K15M Premium CR was present in an amount of 24.50% (w / w);

[0189] anhydrous lactose is present in an amount of 12.00% (w / w);

[0190] Microcrystalline cellulose is present in an amount of 12.00% (w / w); and

[0191] Magnesium stearate was present in an amount of 1.00% (w / w).

[0192] Embodiment 14

[0193] Amorphous BMS-986165-01: HPMCAS-H (15% w / w: 85% w / w) spray-dried dispersion at 40.00%

[0194] (w / w) amount present;

[0195] HPMCAS is present in an amount of 10.00% (w / w);

[0196] Hydroxypropyl methylcellulose K100 LV Premium CR is present in an amount of 24.50% (w / w);

[0197] Hydroxypropyl methylcellulose K15M Premium CR is present in an amount of 0.50% (w / w);

[0198] anhydrous lactose is present in an amount of 12.00% (w / w);

[0199] Microcrystalline cellulose is present in an amount of 12.00% (w / w); and

[0200] Magnesium stearate was present in an amount of 1.00% (w / w).

[0201] Other combinations of amounts of hypromellose K100 LV and hypromellose K15M may be used, and other premium versions of these hypromellose components other than CR grade may be used.

[0202] Example N

[0203] Bioavailability of tablets containing BMS-986165 SDD and tablets containing BMS-986165 free base (crystalline) in famotidine-treated dogs

[0204] This study compared the pharmacokinetic profile of tablets containing BMS-986165-01SDD (15% BMS 986165-01:85% HPMCAS) in dogs treated with famotidine with the pharmacokinetic profile of tablets containing BMS 986165 crystalline free base in dogs treated with famotidine. The study was a crossover study with two treatment groups (4 male dogs per group). For both groups, the dogs were fasted and pretreated with famotidine, which raised gastric pH. Both tablet dosage forms were tested at 4 mg strength (12 mg human equivalent dose (HED)). Table N-1 and Figure 11A-11C Results are provided.

[0205] Table N-1. Pharmacokinetic parameters

[0206]

[0207] As shown in Table N-1, under elevated gastric pH conditions, tablets containing BMS-986165 in the form of crystalline free base exhibited lower C 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 with the SDD tablet; this difference in AUC was statistically significant (p<0.05). The variability of both dosage forms was within the range of variability typically observed in dog pharmacokinetic studies.

[0208] These results demonstrate that the crystalline free base BMS-986165 tablets exhibit approximately 50% bioavailability relative to BMS-986165-01 SDD at a 4 mg dose (12 mg HED) under elevated gastric pH conditions.

[0209] In summary, the present invention includes but is not limited to the following items:

[0210] 1. A dosage form for extended release of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165), the dosage form comprising: (i) an inner phase comprising a spray-dried dispersion of BMS-986165 in a polymer matrix; and (ii) an outer phase comprising a release-controlling polymer.

[0211] 2. The dosage form according to claim 1, wherein the release-controlling polymer is selected from methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, sodium alginate, chitosan, gelatin, tragacanth gum, xanthan gum, and mixtures thereof.

[0212] 3. A dosage form for extended release of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165), the dosage form comprising: (i) an inner phase comprising a dispersion of amorphous BMS-986165 in a polymer matrix; (ii) an outer phase comprising a controlled release polymer; and (iii) a crystallization inhibitor in the outer phase.

[0213] 4. The dosage form according to claim 3, wherein the release-controlling polymer is selected from methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, sodium alginate, chitosan, gelatin, tragacanth gum, xanthan gum and mixtures thereof.

[0214] 5. A dosage form according to claim 3, wherein the crystallization inhibitor is selected from polyvinylpyrrolidone (PVP), PVP vinyl acetate, hydroxypropyl methylcellulose, methylcellulose, cellulose acetate phthalate, hydroxypropyl cellulose, polymethacrylate-based copolymers, polyvinyl caprolactam-based copolymers, hydroxypropyl methylcellulose acetate succinate, and mixtures thereof.

[0215] 6. The dosage form according to item 3, wherein the polymer matrix is ​​hydroxypropylmethylcellulose acetate succinate (HPMCAS) and the release-controlling polymer is hydroxypropylmethylcellulose (HPMC).

[0216] 7. The dosage form according to item 3, wherein the crystallization inhibitor is hydroxypropylmethylcellulose acetate succinate (HPMCAS).

[0217] 8. The dosage form according to item 3, which is an oral dosage form.

[0218] 9. A method of treating an autoimmune disease or an autoinflammatory disease in a subject, the method comprising administering to the subject the dosage form according to any one of items 1-7.

[0219] 10. A method of treating an autoimmune disease or an autoinflammatory disease in a subject, the method comprising administering to the subject the oral dosage form according to item 8.

[0220] 11. A method according to claim 9, wherein the subject is a human subject.

[0221] 12. The method of claim 10, wherein the subject is a human subject.

[0222] 13. A method of treating inflammatory bowel disease in a subject, the method comprising administering to the subject once daily the dosage form according to any one of items 1-8.

[0223] 14. The method of claim 13, wherein the dosage form is a tablet containing 12 mg to 36 mg of BMS-986165.

[0224] 15. The method of claim 13, wherein the dosage form is a tablet containing 15 mg of BMS-986165.

[0225] 16. A method according to claim 13, wherein the inflammatory bowel disease is ulcerative colitis.

[0226] 17. A method according to claim 13, wherein the inflammatory bowel disease is Crohn's disease.

Claims

1. A dosage form for extended release of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165), the dosage form comprising: (i) an inner phase comprising a spray-dried dispersion of BMS-986165 in a polymer matrix; and (ii) an outer phase comprising a release-controlling polymer.

2. The dosage form of claim 1, wherein the release-controlling polymer is selected from the group consisting of methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, sodium alginate, chitosan, gelatin, tragacanth gum, xanthan gum, and mixtures thereof.

3. A dosage form for extended release of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165), the dosage form comprising: (i) an inner phase comprising a dispersion of amorphous BMS-986165 in a polymer matrix; (ii) an outer phase comprising a controlled release polymer; and (iii) a crystallization inhibitor in the outer phase.

4. The dosage form of claim 3, wherein the release-controlling polymer is selected from the group consisting of methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, sodium alginate, chitosan, gelatin, tragacanth gum, xanthan gum, and mixtures thereof.

5. The dosage form according to claim 3, wherein the crystallization inhibitor is selected from the group consisting of polyvinylpyrrolidone (PVP), PVP vinyl acetate, hydroxypropyl methylcellulose, methylcellulose, cellulose acetate phthalate, hydroxypropyl cellulose, polymethacrylate-based copolymers, polyvinyl caprolactam-based copolymers, hydroxypropyl methylcellulose acetate succinate, and mixtures thereof.

6. The dosage form of claim 3, wherein the polymer matrix is ​​hydroxypropylmethylcellulose acetate succinate (HPMCAS) and the release-controlling polymer is hydroxypropylmethylcellulose (HPMC).

7. The dosage form of claim 3, wherein the crystallization inhibitor is hydroxypropylmethylcellulose acetate succinate (HPMCAS). The dosage form according to claim 3 , which is an oral dosage form.

9. A method of treating an autoimmune disease or an autoinflammatory disease in a subject, the method comprising administering to the subject the dosage form of any one of claims 1-7.

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