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CN-121971396-A - Dosage form comprising a swellable core of a Tyk2 inhibitor

CN121971396ACN 121971396 ACN121971396 ACN 121971396ACN-121971396-A

Abstract

The present invention relates to a dosage form of Tyk2 inhibitor comprising a swellable core, wherein the swellable core dosage form comprises a dispersion of amorphous 6- (cyclopropaneamide) -4- ((2-methoxy-3- (1-methyl-1H-1,2,4-triazole-3-yl) phenyl) amino) - N - (methyl-d3) pyridazin-3-carboxamide.

Inventors

  • U. Costur
  • SIF Badawi
  • D. Kohler King
  • C. A. Sasser
  • K. Keberz

Assignees

  • 百时美施贵宝公司

Dates

Publication Date
20260505
Application Date
20210917
Priority Date
20200918

Claims (8)

  1. 1. A swellable core dosage form comprising a dispersion of amorphous 6- (cyclopropylamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3 ) pyridazine-3-carboxamide (BMS-986165) dispersed in a polymer matrix.
  2. 2. A method of treating an autoimmune disease or an autoinflammatory disease in a subject, the method comprising administering to the subject the swellable core dosage form of claim 1.
  3. 3. A method of treating inflammatory bowel disease in a subject, the method comprising administering to the subject the swellable core dosage form of claim 1.
  4. 4. The method of claim 3, wherein the inflammatory bowel disease is ulcerative colitis.
  5. 5. The method of claim 3, wherein the inflammatory bowel disease is crohn's disease.
  6. 6. A method of treating psoriasis in a subject, comprising administering to the subject the swellable core dosage form of claim 1.
  7. 7. The method of claim 6, wherein the psoriasis is plaque psoriasis.
  8. 8. The method of any one of claims 2-7, wherein the swellable core dosage form is a bilayer tablet.

Description

Dosage form comprising a swellable core of a Tyk2 inhibitor The application is a divisional application of Chinese patent application with the application date of 2021, 9 and 17, chinese application number of 202180074961.5 and the application name of 'dosage form of Tyk2 inhibitor containing swellable core'. Technical Field The dispersions of amorphous 6- (cyclopropylamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (BMS-986165) described herein are useful in controlled release dosage forms comprising a swellable core. The dosage form may be administered to a patient to treat autoimmune and auto-inflammatory diseases, such as Inflammatory Bowel Disease (IBD) and psoriasis. Background Tyrosine kinase 2 (Tyk 2) is a member of the non-receptor tyrosine kinase two-sided kinase (Janus kinase) (JAK) family and has been shown to be critical in regulating the signaling cascade downstream of the receptors for IL-12, IL-23 and type I interferons in mice (Ishizaki, M. , "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 (2006)）), tyk 2-mediated phosphorylation of members of the STAT transcription factor family, an important signal leading to dimerization of STAT proteins and transcription of STAT-dependent pro-inflammatory genes. Tyk 2-deficient mice have resistance to experimental models of colitis, psoriasis and multiple sclerosis, demonstrating the importance of Tyk 2-mediated signaling in autoimmunity 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)）. In humans, individuals expressing inactive variants of Tyk2 are protected from multiple sclerosis and possibly other autoimmune disorders (Couturier, N. , "Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility," Brain, 134:693-703 (2011)）. Whole genome association studies show 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. , "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)）. BMS-986165 refers to a compound having the following formula (I) The compound of formula (I), It is 6- (cyclopropylamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide. BMS-986165, which is being studied for the treatment of autoimmune diseases and autoimmune inflammatory diseases such as psoriasis, psoriatic arthritis, lupus nephritis, sj's syndrome, inflammatory bowel disease (including ulcerative colitis and crohn's disease), and ankylosing spondylitis, is a highly selective inhibitor of Tyk 2-mediated signal transduction. It selectively binds to the Tyk2 pseudokinase (JH 2) domain and blocks receptor-mediated Tyk2 activation by stabilizing the regulatory JH2 domain. BMS-986165 and other amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23, and/or IFNα responses, methods of making the same, and methods of using the same are disclosed in U.S. Pat. No.9,505,748 B2, the contents of which are hereby incorporated by reference in their entirety. Other methods of synthesizing BMS-986165 are disclosed in U.S. provisional patent application Ser. No. 62/478,789 and PCT/US 2018/025100 (published as WO 2018/183649), the respective contents of each of which are hereby incorporated by reference in their entirety. Formulations and dosage forms having swellable cores are described, for example, in U.S. patent No. 6,706,283 and U.S. patent No. 9,028,870. Disclosure of Invention The present invention provides a method of treating autoimmune and auto-inflammatory diseases in a patient comprising orally administering to the patient once daily a swellable core dosage form of 6- (cyclopropylamido) -4- ((2-methoxy-3- (1-methyl