Dosage forms of TYK2 inhibitors

Abstract

To provide a stable and bioavailable formulation of a compound (BMS-986165) for the treatment of autoimmune and autoinflammatory diseases, such as inflammatory bowel disease and psoriasis. [Solution] A formulation of 6-(cyclopropanamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165), comprising a dispersion of amorphous BMS-986165 dispersed in a polymer matrix, wherein the ratio of amorphous BMS-986165 to polymer in the dispersion is 3-80% w / w of amorphous BMS-986165 to 97-20% w / w of polymer, and the polymer in the polymer matrix comprises one or more polymers selected from hydroxypropyl methylcellulose (HPMC), hypromellose phthalate (HPMC-P), etc.

Description

Technical Field

[0001] The present invention relates to the 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, an extremely selective inhibitor of Tyk2. The formulations and dosage forms exhibit acceptable physical and chemical stability while providing the 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 and can be used for the treatment of autoimmune and autoinflammatory diseases such as inflammatory bowel disease (IBD) and psoriasis.

Background Art

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

[0003] In humans, individuals expressing an inactive 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 identified other variants of Tyk2 associated with autoimmune disorders, such as Crohn's disease, psoriasis, systemic lupus erythematosus, and rheumatoid arthritis, further highlighting 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," Nat. Genet.). 44:1336-1340 (2012).

[0004] BMS-986165 refers to the compound represented by the following formula (I): [ka] It is 6-(cyclopropanamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide. BMS-986165 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, and is a highly selective inhibitor of Tyk2-mediated signaling. It selectively binds to the Tyk2 pseudokinase (JH2) domain and blocks receptor-mediated Tyk2 activation by stabilizing the regulatory JH2 domain.

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

[0006] BMS-986165 is synthesized from crystalline forms, for example, crystalline form A disclosed in U.S. Provisional Application No. 62 / 478,789 and PCT / US2018 / 025114 (published as WO2018 / 183656) (each of which is incorporated herein by citation); crystalline form B disclosed in U.S. Provisional Application No. 62 / 678451 and PCT / US2019 / 034534 (published as WO2019 / 232138) (each of which is incorporated herein by citation); and crystalline forms C and D disclosed in U.S. Provisional Application No. 62 / 860439 and PCT / US2020 / 036727 (each of which is incorporated herein by citation).

[0007] Because efforts to design a formulation that provides bioavailability of the compound after oral administration and is sufficiently stable during storage have not been successful, designing a suitable formulation and dosage form for BMS-986165 presents several challenges.

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

[0009] The present invention provides a formulation of solid amorphous BMS-986165 that is physically and chemically stable and can be used to create an oral dosage form that provides 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 a patient who has taken a drug that increases the gastric pH. Under such gastric pH-increasing conditions, dosage forms comprising the formulation described herein exhibit bioavailability comparable to that provided by BMS-986165 free base in capsules or oral liquid formulations of crystalline BMS-986165 HCl salt. The formulations exhibit even greater stability; for example, capsules of BMS-986165 HCl salt require refrigeration to prevent the salt from being converted to a free base form during storage, while formulations and dosage forms of solid amorphous BMS-986165 exhibit physical stability when stored under room temperature conditions. The formulations described herein are also suitable for making immediate-release and controlled-release dosage forms.

[0010] Accordingly, certain embodiments of the present invention provide formulations and dosage forms comprising a solid dispersion of amorphous 6-(cyclopropanamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165). These formulations and dosage forms provide sufficient release and dissolution of BMS-986165 in a medium that mimics in vivo conditions of the gastrointestinal tract, making them suitable for use as immediate-release formulations and dosage forms. Such immediate-release formulations can be modified to provide controlled-release oral dosage forms of BMS-986165.

[0011] Embodiments of the present invention also provide a sustained-release formulation that can be administered to a patient once daily and provides a pharmacokinetic profile of BMS-986165 that is comparable to or better than that of immediate-release tablets administered twice daily. The sustained-release formulation described herein provides bioavailability of BMS-986165 in regions of the GI tubule, such as the colon, where water availability for enhancing drug solubility is low and / or bile salts are absent. Such formulations are particularly useful for the treatment of inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease. Because the sustained-release BMS-986165 tablet formulation described herein requires only one tablet per day, patient compliance may be improved and convenience for patients and / or caregivers may also be improved. [Brief explanation of the drawing]

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

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

[0014] (Formulations and Dosage Forms) The present invention provides an oral dosage form of BMS-986165 made from a 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 dispersion typically comprises amorphous BMS-986165 and one or more polymers. The dispersion is used to make various dosage forms for oral administration, including dosage forms that provide immediate release of BMS-986165 and dosage forms that provide sustained release of BMS-986165.

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

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

[0017] The absence of crystalline drug in the amorphous dispersion can be characterized by modulated differential scanning calorimetry (mDSC), powder X-ray diffraction (PXRD), near-infrared spectroscopy (NIR), or other standard analytical techniques. For example, mDSC evaluates the thermal properties of the SDD; for an amorphous SDD, a single glass transition temperature is obtained by mDSC analysis. mDSC can also detect crystalline phase separation because the crystalline phase exhibits a distinct thermal signal. PXRD uses X-rays to identify the crystal form of a solid powder and can be used for the analysis of SDD. For example, it can confirm that the SDD is a single amorphous phase and there is no measurable crystalline substance.

[0018] The crystalline free base of BMS-986165 exhibits pH-dependent solubility, with low solubility at pH values above 4. Therefore, the crystalline free base of BMS-986165 shows pH-dependent absorption in the GI tract. For immediate-release formulations, such pH-dependent properties can lead to a decrease in bioavailability when antacids, such as famotidine or omeprazole, are administered. Using the HCl salt form of BMS-986165 in immediate-release formulations alleviates the effect of pH, but during stability testing, it was observed that formulations made with the HCl salt form of BMS-986165 convert to the free base form of BMS-986165. Using the high-energy amorphous free base form of BMS-986165 helps address the above issues, but formulating amorphous BMS-986165 presents other challenges, including ensuring the physical stability of the amorphous form during storage and maintaining supersaturation of the compound during dissolution in the GI tract.

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

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

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

[0022] In particular embodiments of the present invention, a dispersion is provided in which the w / w% of BMS-986165 (amorphous) relative to the polymer is in the range of about 3% to about 80% BMS-986165 and about 97% to about 20% polymer. Further embodiments provide a dispersion in which the w / w% of BMS-986165 relative to the polymer is in the range of about 4% to about 50% BMS-986165 and about 96% to about 50% polymer. In yet another embodiment, the w / w% of BMS-986165 is in the range of about 5% to about 25% BMS-986165 and about 95% to about 75% polymer. Thus, some embodiments provide a dispersion in which the w / w% of BMS-986165 relative to the polymer is in the range of about 25% BMS-986165 and about 75% polymer. In other embodiments, the w / w% of BMS-986165 relative to the polymer is approximately 15% BMS-986165 and approximately 85% polymer, or approximately 10% BMS-986165 and approximately 90% polymer.

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

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

[0025] Therefore, the dispersion according to the present invention can be combined with one or more other additives. When using a granulation process, the additive may be added before granulation (thus intragranularly) and / or after granulation (thus extragranularly).

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

[0027] Other additives that may be included in the dispersion formulations described herein include release-controlled materials. For example, a release-controlled polymer may be mixed with 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 a dispersion mixed with a release-controlled polymer (and other additives).

[0028] Accordingly, the present invention also provides a formulation for sustained release of 6-(cyclopropanamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165), comprising an internal phase containing a dispersion (e.g., spray-dried dispersion) of amorphous BMS-986165 in a polymer matrix; and an external phase containing a release-controlled 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.

[0029] Despite the advantages of amorphous drugs over crystalline drugs as described above, there are at least two substantial challenges in designing sustained-release formulations containing amorphous BMS-986165 SDDs mixed with release-controlled polymers (and other additives). First, the release-controlled polymer in the formulation may result in incomplete drug release from the sustained-release formulation; such incomplete release may lead, for example, to insufficient delivery of the drug to the patient. Second, crystallization of the drug may occur within the spray-dried dispersion itself (internal phase); within the sustained-release formulation but outside the SDD itself (external phase); and / or after release from the sustained-release formulation. The present invention addresses the first challenge by providing a sustained-release formulation in which a suitable polymer material is selected as the release-controlled polymer and the viscosity of the polymer material is selected to provide a desired release rate of the drug. With respect to the second challenge, in order to maintain the advantages of the amorphous form, the present invention stipulates that a crystallization inhibitor is present in the sustained-release formulation but outside the spray-dried dispersion itself in order to reduce or prevent drug crystallization. The present invention makes it possible to provide clinically available formulations containing amorphous BMS-986165 that have an adjustable release rate and maintain the advantages of an amorphous form.

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

[0031] In certain embodiments, the sustained-release dispersion formulation comprises one or more crystallization inhibitors. In a sustained-release formulation having an inner phase and an outer phase, the crystallization inhibitor may be provided in the inner phase and / or outer phase of the formulation. Suitable crystallization inhibitors are described above.

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

[0033] In certain embodiments, the dispersion of the present invention is made into a tablet containing 10 to 50% by weight, for example, in the weight percentage range of 10% w / w, 15% w / w, 20% w / w, or 25% w / w. In some embodiments, at least 15% by weight of the tablet is the dispersion. In certain embodiments, 20% by weight of the tablet is the dispersion.

[0034] In further embodiments, the tablets contain one or more excipients, 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 excipients is at least 60% w / w, and in further embodiments, at least 70% w / w of the formulation. In certain embodiments, the dispersed formulation contains lactose and crystalline cellulose, together at least 70% w / w of the formulation. In further embodiments, the ratio of crystalline cellulose to lactose excipients is 50:50. In other embodiments, the ratio of crystalline cellulose to lactose excipients is 70:30.

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

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

[0037] As used herein, the term “medically acceptable” means a compound, material, composition and / or dosage form suitable for use in contact with human and animal tissues, within the bounds of sound medical judgment, without excessive toxicity, irritation, allergic reactions or other problems or complications commensurate with a reasonable benefit / risk ratio. That is the case.

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

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

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

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

[0042] Therefore, in some embodiments, the process for making a solid dispersion includes (1) adding at least a drug and a polymer to form a solution or suspension, (2) introducing the solution or suspension into a spray dryer and spraying the solution or suspension into droplets within the spray dryer, (3) bringing the droplets into contact with a drying gas to solidify the particles, and (4) collecting the particles.

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

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

[0045] A description of the manufacture of a tablet formulation, including a sustained-release tablet formulation containing a spray-dried dispersion of amorphous BMS-986165 in a polymer matrix, is provided in the Examples section of this specification. Other synthetic techniques, such as those disclosed in U.S. Patent No. 9,713,594, can be used to manufacture a sustained-release tablet formulation containing a spray-dried dispersion of BMS-986165 in a polymer matrix and will be readily apparent to those skilled in the art in light of this disclosure.

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

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

[0048] In certain embodiments, immediate release refers to the release of at least about 80% of the indicated dose within about 60 minutes under conditions that mimic a fasted stomach. In some embodiments, at least about 80% of the indicated dose is released within about 30 minutes under conditions that mimic a fasted stomach; in further embodiments, at least about 80% of the indicated dose is released within about 15 minutes (e.g., within about 5 minutes, within about 10 minutes) under conditions that mimic a fasted stomach. In further embodiments, such release is achieved under conditions that mimic an elevated pH state in the stomach.

[0049] In some embodiments, it may be desirable to provide controlled release of BMS-986165. Therefore, certain embodiments of the present invention provide dosage forms exhibiting controlled release of BMS-986165 after oral administration. For example, a dosage form may release the drug over a period of approximately 2 to 8 hours after oral administration. In some embodiments, a dosage form 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 may vary over time. In further embodiments, a dosage form provides delayed release of the drug (e.g., enteric-coated release). The conditions under which the drug is released, and the rate at which the drug is released from such controlled-release dosage forms, can be evaluated by dissolution tests, such as those described above and in the examples.

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

[0051] For example, a particular embodiment of the present invention provides a dispersion comprising 15% amorphous BMS-986165 and 85% HPMCAS-H, wherein the amorphous BMS-986165 remains amorphous over a 6-month storage period at 40°C and 75% relative humidity (in an open or closed container), as determined by PXRD and / or SEM.

[0052] Furthermore, in certain embodiments, when BMS-986165 in the dispersion provided herein, or a dosage form containing the dispersion, is stored under any of the above conditions for a period of at least about one month to at least about six months, it exhibits degradation of less than about 5%, less than about 3%, less than about 2%, or less than 1%.

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

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

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

[0056] 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) is at least 1.25 compared to the control composition (the AUC provided by the test composition is at least 1.25 times that of the control composition). In further embodiments, the relative bioavailability of the test composition is at least 2.0 compared to a control composition comprising the crystalline form of the drug.

[0057] The bioavailability of two formulations or dosage forms can also be compared using in vitro dissolution tests as a substitute for in vivo bioavailability. For example, a gastric-to-intestinal dissolution test can be used to simulate in vivo conditions in a GI tube and 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, may also be used.

[0058] In certain embodiments, the bioavailability of BMS-986165 provided by the dosage forms described herein is not significantly affected by agents that raise gastric pH, such as antacids, H2 receptor antagonists, and proton pump inhibitors. For example, while the administration of proton pump inhibitors (or other gastric pH-raising agents) may affect gastric pH, the solubility of amorphous BMS-986165 in the dispersions described herein is less affected by pH compared to the solubility of free base crystalline BMS-986165. Therefore, the administration of dosage forms containing a dispersion of amorphous BMS-986165 may provide bioavailability of BMS-986165 to patients who are also being administered proton pump inhibitors (or other pH-raising agents). Accordingly, certain embodiments of the present invention provide an oral dosage form comprising amorphous BMS-986165 dispersed in a polymer matrix, wherein the bioavailability of BMS-986165 from the oral dosage form changes by 25% or less, 20% or less, 15% or less, or 10% or less when a gastric pH-raising agent (e.g., a proton pump inhibitor) is administered simultaneously with the dosage form. Simultaneous administration as used herein refers to a subject receiving both a gastric pH-raising agent (e.g., a proton pump inhibitor) and the dispersed amorphous BMS-986165 dosage form. The agent (e.g., a proton pump inhibitor) and the BMS-986165 dosage form may 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) may be administered within 3 days, 2 days, 1 day, or on the same day as the administration of the BMS-986165 dosage form. Co-administration includes all such timings for the administration of gastric pH-raising agents (e.g., proton pump inhibitors) and the BMS-986165 solid dispersion dosage form.

[0059] The effect of gastric pH-raising agents or antacids (e.g., proton pump inhibitors) on bioavailability can be evaluated by administering the BMS-986165 dosage form to a first group of test subjects (animals or humans) who are not receiving the pH-raising agent, while administering the same BMS-986165 dosage form to a second group of test subjects who are simultaneously receiving the pH-raising agent; then, after an appropriate washout period, administering the BMS-986165 dosage form to the first group along with the pH-raising agent, and administering the BMS-986165 dosage form to the second group without simultaneous administration of the pH-raising agent. Thus, each subject will have two AUC values ​​(the AUC obtained when taking the pH-raising agent or antacid and the AUC obtained when not taking the drug), and these AUC values ​​can be compared for each subject. For example, the ratio of the AUCs for each subject can be obtained, and the ratios of all subjects in the test can be averaged. In a particular embodiment, the average ratio obtained by this method is in the range of 0.75 to 1.25.

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

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

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

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

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

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

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

[0067] The following examples are for illustrative purposes only to illustrate the invention and its implementation. The examples should not be construed as limitations on the scope or spirit of the invention. [Examples]

[0068] (Example A) The 6-(cyclopropanamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide API 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 production). The resulting spray-dried mixture is further dried to obtain a spray-dried dispersion (SDD), which can then be filled and packaged.

[0069] To produce a dispersed formulation and dosage form with a sustained-release profile, SDD, lactose anhydride, crystalline cellulose, and HPMCAS are mixed together, and the mixed formulation is sieved. The sieved formulation is mixed with magnesium stearate, and the resulting product is subjected to dry granulation (slugging / roller compaction process) and then pulverized. This further obtained product is mixed with further magnesium stearate and compressed into tablets to produce tablets for sustained release of 6-(cyclopropanamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

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

[0071] Table B-2 below outlines the process for producing 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 / hour. [Table 2]

[0072] Table B-2 shows that the polymer is added to the solution preparation vessel before adding the active substance (BMS-986165), but the active substance (BMS-986165) may be added to the solution preparation vessel before adding the polymer.

[0073] Table B-3 below shows the solution preparation conditions for 15% BMS-986165:85% HPMCAS-HSDD. The spray drying conditions used to produce BMS-986165:HPMCAS-H SDD in a laboratory-scale spray dryer with a dry gas flow rate of 150 kg / hour were divided into four sets: (A) preheating, (B) warm-up, (C) solution feeding process, and (D) shutdown. Table B-4 below shows a summary of the target and target range for each of the four sets of conditions. [Table 3] [Table 4]

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

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

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

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

[0078] Further testing was conducted to determine the API loading level in HPMCAS-H that provides chemical and physical stability while offering the desired elution profile. pH transition elution tests using a Pion UV probe (pH2 or pH6-pH6.5) showed that release / sustain in the gastric phase and persistence in the intestinal phase generally improved as the API loading decreased.

[0079] Six-month stability tests 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 were consistent with the API impurity levels present, indicating that the spray drying process did not cause degradation; furthermore, impurity levels did not increase during storage. After storage at 40°C / 75%RH, open for up to six months, there was no evidence of crystallization by PXRD in any of the SDDs (Figures 1A and 1B). DSC data showed slight changes similar to those observed in 25% w / w BMS-986165 SDDs after exposure to 50°C / 75%RH or 40°C / 75%RH, but there was no trend in API loading and it was thought to reflect an "aging" or "annealing" effect rather than crystal formation. Scanning electron microscope (SEM) images confirmed the presence of a single-phase, uniformly dispersed material (Figures 2A-C, 3A-C, and 4A-C).

[0080] TAM (microcalorimeter) experiments using SDDs loaded with 10%, 15%, 20%, and 25% BMS-986165 (including PXRD in samples after TAM) confirmed that SDDs of HPMCAS-H containing 20% ​​w / w BMS-986165 or less posed a low risk of physical stability. Elution properties in microcentrifugation tests remained unchanged.

[0081] Reducing the API load in the SDD improves stability and lowers the throughput of the spray-drying process; however, this throughput reduction can be offset by increasing the solid concentration of the spray solution to the limit of 8% w / w HPMCAS in acetone / water (this limit helps ensure process robustness). The solid concentration is also limited by the solubility of BMS-986165 in acetone / water. A 15% w / w API load was chosen to obtain an acceptable throughput at a target spray solution concentration of 1% API and to ensure that the SDD is loaded with enough API so that tablets of a swallowable size are possible even when the SDD is loaded onto the tablets. [Table 7]

[0082] (Example D) SDD tablets BMS-986165

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

[0084] The tablets were manufactured using an AlexanderwerkWP120 roller compactor. Tablet compression was performed using a Korsch XL press, and film coating was carried out using a Thomas Compulab Coater.

[0085] The tablets exhibited the desired dissolution / disintegration profile, appropriate hardness and strength, storage stability, and a swallowable, acceptable size.

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

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

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

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

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

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

[0092] Tablets of Examples 1, 2, and 3, which have the sustained-release formulations shown in Table F below, were tested. The dissolution test parameters were as follows: BMS-986165 crystalline free base preparation (Examples 1, 2, or 3) in potassium phosphate buffer (pH 6.8), 20-mesh basket, 1000 mL at 100 rpm. [Table 10]

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

[0094] (Example G) BMS-986165 Sustained-Release SDD Formulation

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

[0096] As used in these embodiments and throughout this disclosure, “BMS-986165-01” refers in particular to 6-(cyclopropanamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide in its free base form. As used in these embodiments 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 at an amount of 15% by weight of the SDD, and HPMCAS is present in the SDD at an amount of 85% by weight of the SDD.

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

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

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

[0100] (Example I) A sustained-release SDD formulation of BMS-986165 with HPMCAS added outside of the SDD.

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

[0102] (Example J) Dissolution profiles for the formulation and for sustained-release SDD tablets with HPMCAS added outside of SDD.

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

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

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

[0106] Figure 9 shows dissolution profiles with varying viscosity, surface area-to-volume ratio, or both. The dissolution test parameters were as follows: dissolution of the formulation at 75 rpm in 1000 mL of pH 6.8 phosphate buffer containing 1% Brij USPII with a cage sinker. As shown in Figure 9, adjustable release (viscosity and surface area / volume) is demonstrated by a series of release profiles, and complete drug release was achieved with specific formulations.

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

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

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

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

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

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

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

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

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

Claims

1. A dosage form of 6-(cyclopropanamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165), comprising a dispersion of amorphous BMS-986165 dispersed in a polymer matrix.

2. The dosage form according to claim 1, wherein the polymer matrix comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS).

3. The dosage form according to claim 1, wherein the dispersion of amorphous BMS-986165 dispersed in a polymer matrix is ​​a spray-dried dispersion.

4. The dosage form according to claim 1, further comprising a crystallization inhibitor.

5. The dosage form according to claim 4, wherein the crystallization inhibitor is hydroxypropyl methylcellulose acetate succinate (HPMCAS).

6. The dosage form according to any one of claims 1 to 5, wherein the dispersion of amorphous BMS-986165 dispersed in a polymer matrix contains an amount of amorphous BMS-986165 such that it constitutes at least about 10% w / w of the dispersion.

7. The dosage form according to any one of claims 1 to 5, wherein the dispersion of amorphous BMS-986165 dispersed in a polymer matrix contains an amount of amorphous BMS-986165 such that it is approximately 15% w / w of the dispersion.

8. The dosage form according to any one of claims 1 to 5, wherein the dispersion of amorphous BMS-986165 dispersed in a polymer matrix contains an amount of amorphous BMS-986165 such that it is more than approximately 25% w / w of the dispersion.

9. The dosage form according to any one of claims 1 to 5, wherein the ratio of amorphous BMS-986165 to polymer in the dispersion is approximately 15% w / w amorphous BMS-986165 to approximately 85% w / w polymer.

10. A dosage form according to any one of claims 1 to 9, which does not contain crystalline BMS-986165 after being stored at 40°C / 75% relative humidity for at least 3 months.

11. A dosage form according to any one of claims 1 to 9, which does not contain crystalline BMS-986165 after being stored at 40°C / 75% relative humidity for at least 6 months.

12. The dosage form according to any one of claims 1 to 11, wherein when the dosage form is stored at 40°C / 75% relative humidity for at least 6 months, the amorphous BMS-986165 in the dosage form shows less than 5% degradation.

13. The dosage form according to any one of claims 1 to 12, wherein, after the dosage form is placed in a medium having a pH of about 1 to about 2, at least about 80% of the amorphous BMS-986165 in the dosage form is released within about 30 minutes.

14. The dosage form according to any one of claims 1 to 13, wherein, after the dosage form is placed in a medium having a pH of about 6 to about 7, at least about 80% of the amorphous BMS-986165 in the dosage form is released within about 30 minutes.

15. The dosage form according to any one of claims 1 to 14, wherein the dosage form is a tablet containing approximately 12 mg of amorphous BMS-986165.

16. The dosage form according to claim 15, wherein the tablet has a tablet weight of approximately 400 mg or less.

17. The dosage form according to any one of claims 15 and 16, which exhibits improved bioavailability compared to another dosage form containing approximately 12 mg of crystalline 6-(cyclopropanamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

18. A dosage form comprising amorphous 6-(cyclopropanamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165) dispersed in a polymer matrix, crystalline cellulose, lactose, croscarmellose, magnesium stearate, and silicon dioxide.

19. The dosage form according to claim 18, comprising: 20% w / w amorphous BMS-986165 dispersed in a polymer matrix (where the amorphous BMS-986165 dispersed in the polymer matrix is ​​15% w / w amorphous BMS-986165:85% polymer); 51.25% w / w crystalline cellulose; 22% w / w lactose anhydrous; 5% w / w croscarmellose sodium; 0.75% magnesium stearate; and 1% w / w silicon dioxide.

20. The dosage form according to claim 19, wherein the dosage form is manufactured by a process including granulation, and the 5% w / w croscarmellose sodium is in a 1:1 in-granule:out-granule ratio, and the 0.75% magnesium stearate is in a 1:2 in-granule:out-granule ratio.

21. A dosage form according to any one of claims 18 to 19, manufactured by a process including direct compression.

22. A dosage form according to any one of claims 18 to 21, comprising approximately 1 mg to approximately 12 mg of amorphous BMS-986165.

23. A dosage form according to any one of claims 18 to 22, which is a tablet for oral administration.

24. The dosage form according to any one of claims 18 to 23, wherein, when the dosage form and another dosage form containing crystalline BMS-986165 contain the same amount of BMS-986165, the dosage form exhibits improved bioavailability compared to the other dosage form.

25. The dosage form according to claim 24, wherein the improvement in bioavailability is determined by crossover animal studies.

26. The dosage form according to claim 24, wherein the improvement in bioavailability is determined by comparing the percentage of BMS-986165 eluted from the dosage form to the percentage of BMS-986165 eluted from the other dosage form in an in vitro dissolution test of BioRelevant in fasting artificial intestinal fluid (FaSSIF) (pH 6.5) at a temperature of 37°C using a paddle and a rotation speed of 75 rpm.

27. An oral dosage form comprising amorphous 6-(cyclopropanamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165) dispersed in a polymer matrix, wherein the bioavailability of BMS-986165 from the oral dosage form when administered to a target subject simultaneously with a proton pump inhibitor differs from the bioavailability of BMS-986165 from the oral dosage form when not administered to the target subject simultaneously with a proton pump inhibitor by 25% or less, and the bioavailability of BMS-986165 from the oral dosage form is determined by the area under the plasma concentration-time curve.

28. A method for treating an autoimmune disease or autoinflammatory disease in a subject, comprising administering the dosage form described in any one of claims 1 to 26 to the subject.

29. A method for treating an autoimmune disease or autoinflammatory disease in a subject, comprising administering the oral dosage form described in claim 27 to the subject.

30. The method according to claim 28, wherein the target is a human target.

31. The method according to claim 29, wherein the target is a human target.

32. The oral dosage form according to claim 27, wherein the target substance is a human target substance.

33. Use of a spray-dried dispersion of amorphous 6-(cyclopropanamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165) in a polymer matrix in the manufacture of pharmaceuticals for treating autoimmune or autoinflammatory diseases.

34. The use according to claim 33 for manufacturing a pharmaceutical product for inflammatory bowel disease.

35. The use according to claim 34, wherein the inflammatory bowel disease is ulcerative colitis.

36. The use according to claim 34, wherein the inflammatory bowel disease is Crohn's disease.

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