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US-12622908-B2 - Topical formulation for a JAK inhibitor

US12622908B2US 12622908 B2US12622908 B2US 12622908B2US-12622908-B2

Abstract

This invention relates to pharmaceutical formulations for topical skin application comprising (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, and use in the treatment of skin disorders.

Inventors

  • BHAVNISH PARIKH
  • Bhavesh Shah
  • Krishnaswamy Yeleswaram

Assignees

  • INCYTE CORPORATION
  • INCYTE HOLDINGS CORPORATION

Dates

Publication Date
20260512
Application Date
20211203

Claims (20)

  1. 1 . A pharmaceutical composition for topical skin application to a human patient with a skin disorder comprising: a therapeutically effective amount of a therapeutic agent present in an amount ranging from about 0.5% to about 1.0% by weight of the composition, wherein the therapeutic agent is (R)-3-cyclopentyl-3-[4 (7H-pyrrolo [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof; and a means for effecting skin permeation of (R)-3-cyclopentyl-3-[4 (7H-pyrrolo [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof to the patient.
  2. 2 . The pharmaceutical composition according to claim 1 , wherein the means for effecting skin permeation comprises water, an oil component, and an emulsifier component.
  3. 3 . The pharmaceutical composition according to claim 2 , wherein the oil component is present in an amount of about 20% to about 27%, by weight of the composition.
  4. 4 . The pharmaceutical composition according to claim 2 , wherein the oil component comprises one or more substances chosen from white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium chain triglycerides, and dimethicone.
  5. 5 . The pharmaceutical composition according to claim 2 , wherein the oil component comprises an occlusive agent component.
  6. 6 . The pharmaceutical composition according to claim 5 , wherein the occlusive agent component is present in an amount of about 5% to about 10% by weight of the composition.
  7. 7 . The pharmaceutical composition according to claim 5 , wherein the occlusive agent component comprises white petroleum.
  8. 8 . The pharmaceutical composition according to claim 2 , wherein the oil component comprises a stiffening agent component.
  9. 9 . The pharmaceutical composition according to claim 8 , wherein the stiffening agent component is present in an amount of about 4% to about 7% by weight of the composition.
  10. 10 . The pharmaceutical composition according to claim 8 , wherein the stiffening agent component comprises one or more substances chosen from C 16-18 fatty alcohols.
  11. 11 . The pharmaceutical composition according to claim 2 , wherein the oil component comprises an emollient component.
  12. 12 . The pharmaceutical composition according to claim 11 , wherein the emollient component is present in an amount of about 7% to about 13% by weight of the composition.
  13. 13 . The pharmaceutical composition according to claim 11 , wherein the emollient component comprises one or more substances chosen from light mineral oil, medium chain triglycerides, and dimethicone.
  14. 14 . The pharmaceutical composition according to claim 2 , wherein the water is present in an amount of about 45% to about 55% by weight of the composition.
  15. 15 . The pharmaceutical composition according to claim 2 , wherein the emulsifier component is present in an amount of about 4% to about 7% by weight of the composition.
  16. 16 . The pharmaceutical composition according to claim 2 , wherein the emulsifier component comprises one or more substances chosen from glyceryl fatty esters and sorbitan fatty esters.
  17. 17 . The pharmaceutical composition according to claim 2 , further comprising a stabilizing agent component.
  18. 18 . The pharmaceutical composition according to claim 17 , wherein the stabilizing agent component is present in an amount of about 0.3% to about 0.5% by weight of the composition.
  19. 19 . The pharmaceutical composition according to claim 17 , wherein the stabilizing agent component comprises xanthan gum.
  20. 20 . The pharmaceutical composition according to claim 2 , further comprising a solvent component.

Description

This is a continuation of U.S. Ser. No. 16/948,408, filed Sep. 17, 2020, now U.S. Pat. No. 11,219,624, issued on Jan. 11, 2022, which is a continuation of U.S. Ser. No. 16/947,735, filed Aug. 14, 2020, now U.S. Pat. No. 10,869,870, issued on Dec. 22, 2020, which is a divisional of U.S. Ser. No. 16/566,625, filed Sep. 10, 2019, now U.S. Pat. No. 10,758,543, issued on Sep. 1, 2020, which is a continuation application of U.S. Ser. No. 14/714,820, filed May 18, 2015, now abandoned, which is a continuation of U.S. Ser. No. 13/112,370, filed May 20, 2011, now abandoned, which claims the benefit and priority of U.S. Provisional Application 61/347,132, filed May 21, 2010, each of which is incorporated herein by reference in its entirety. TECHNICAL FIELD This invention relates to pharmaceutical formulations for topical skin application comprising (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, and use in the treatment of skin disorders. BACKGROUND Protein kinases (PKs) regulate diverse biological processes including cell growth, survival, differentiation, organ formation, morphogenesis, neovascularization, tissue repair, and regeneration, among others. Protein kinases also play specialized roles in a host of human diseases including cancer. Cytokines, low-molecular weight polypeptides or glycoproteins, regulate many pathways involved in the host inflammatory response to sepsis. Cytokines influence cell differentiation, proliferation and activation, and can modulate both pro-inflammatory and anti-inflammatory responses to allow the host to react appropriately to pathogens. Signaling of a wide range of cytokines involves the Janus kinase family (JAKs) of protein tyrosine kinases and Signal Transducers and Activators of Transcription (STATs). There are four known mammalian JAKs: JAK1 (Janus kinase-1), JAK2, JAK3 (also known as Janus kinase, leukocyte; JAKL; and L-JAK), and TYK2 (protein-tyrosine kinase 2). Cytokine-stimulated immune and inflammatory responses contribute to pathogenesis of diseases: pathologies such as severe combined immunodeficiency (SCID) arise from suppression of the immune system, while a hyperactive or inappropriate immune/inflammatory response contributes to the pathology of autoimmune diseases (e.g., asthma, systemic lupus erythematosus, thyroiditis, myocarditis), and illnesses such as scleroderma and osteoarthritis (Ortmann, R. A., T. Cheng, et al. (2000) Arthritis Res 2(1): 16-32). Deficiencies in expression of JAKs are associated with many disease states. For example, Jak1−/− mice are runted at birth, fail to nurse, and die perinatally (Rodig, S. J., M. A. Meraz, et al. (1998) Cell 93(3): 373-83). Jak2−/−mouse embryos are anemic and die around day 12.5 postcoitum due to the absence of definitive erythropoiesis. The JAK/STAT pathway, and in particular all four JAKs, are believed to play a role in the pathogenesis of asthmatic response, chronic obstructive pulmonary disease, bronchitis, and other related inflammatory diseases of the lower respiratory tract. Multiple cytokines that signal through JAKs have been linked to inflammatory diseases/conditions of the upper respiratory tract, such as those affecting the nose and sinuses (e.g., rhinitis and sinusitis) whether classically allergic reactions or not. The JAK/STAT pathway has also been implicated in inflammatory diseases/conditions of the eye and chronic allergic responses. Activation of JAK/STAT in cancers may occur by cytokine stimulation (e.g. IL-6 or GM-CSF) or by a reduction in the endogenous suppressors of JAK signaling such as SOCS (suppressor or cytokine signaling) or PIAS (protein inhibitor of activated STAT) (Boudny, V., and Kovarik, J., Neoplasm. 49:349-355, 2002). Activation of STAT signaling, as well as other pathways downstream of JAKs (e.g., Akt), has been correlated with poor prognosis in many cancer types (Bowman, T., et al. Oncogene 19:2474-2488, 2000). Elevated levels of circulating cytokines that signal through JAK/STAT play a causal role in cachexia and/or chronic fatigue. As such, JAK inhibition may be beneficial to cancer patients for reasons that extend beyond potential anti-tumor activity. Inhibition of the JAK kinases is also envisioned to have therapeutic benefits in patients suffering from skin immune disorders such as psoriasis, and skin sensitization. In psoriasis vulgaris, the most common form of psoriasis, it has been generally accepted that activated T lymphocytes are important for the maintenance of the disease and its associated psoriatic plaques (Gottlieb, A. B., et al, Nat Rev Drug Disc., 4:19-34). Psoriatic plaques contain a significant immune infiltrate, including leukocytes and monocytes, as well as multiple epidermal layers with increased keratinocyte proliferation. While the initial activation of immune cells in psoriasis occurs by an ill defined mechanism, the maintenance is believed to be dependent on a number o