Claims for Patent: 11,253,523

Summary for Patent: 11,253,523

Title:	Tofacitinib oral sustained release dosage forms
Abstract:	The present invention relates to oral sustained release formulations of tofacitinib and pharmaceutical acceptable salts thereof. The formulations described herein have desirable pharmacokinetic characteristics.
Inventor(s):	Herbig; Scott Max (East Lyme, CT), Krishnaswami; Sriram (East Lyme, CT), Kushner, IV; Joseph (Bradford, RI), Lamba; Manisha (Waterford, CT), Stock; Thomas C. (Chester Springs, PA)
Assignee:	Pfizer Inc. (New York, NY)
Application Number:	16/817,689
Patent Claims:	1. A method of treating an immunological disorder in a subject comprising administering to the subject in need thereof a once daily pharmaceutical dosage form comprising a core comprising 11 mg of tofacitinib, or an equivalent amount of tofacitinib in the form of a pharmaceutically acceptable salt thereof, and an osmagen, and a semi-permeable membrane coating surrounding the core wherein said coating comprises a water-insoluble polymer, wherein said dosage form is a sustained release dosage form, and when added to a test medium comprising 900 mL of 0.05M pH 6.8 potassium phosphate buffer at 37.degree. C. in a standard USP rotating paddle apparatus and the paddles are rotated at 50 rpm, dissolves not more than 30% of the tofacitinib, or pharmaceutically acceptable salt thereof, in 1 hour, and not less than 35% and not more than 75% of the tofacitinib, or pharmaceutically acceptable salt thereof, in 2.5 hours and not less than 75% of the tofacitinib, or pharmaceutically acceptable salt thereof, in 5 hours and wherein said dosage form delivers the tofacitinib, or pharmaceutically acceptable salt thereof, to a subject primarily by osmotic pressure and wherein the water-insoluble polymer is a cellulose derivative that sustains release of the tofacitinib, or pharmaceutically acceptable salt thereof, wherein the immunological disorder is selected from the group consisting of rheumatoid arthritis, psoriasis, psoriatic arthritis, ulcerative colitis, ankylosing spondylitis, and juvenile idiopathic arthritis. 2. The method of claim 1, wherein the immunological disorder is rheumatoid arthritis. 3. The method of claim 1, wherein the immunological disorder is ulcerative colitis. 4. The method of claim 1, further comprising one or more additional agents which modulate a mammalian immune system or anti-inflammatory agents. 5. The method of claim 4, wherein the additional agent is selected from the group consisting of a nonbiologic disease-modifying antirheumatic drug (DMARD), methotrexate, glucocorticoid, glucocorticoid receptor agonist, leflunomide, nonsteroidal anti-inflammatory drugs, 6-mercaptopurine, azathioprine, sulfasalazine, and 5-aminosalicylate drugs. 6. The method of claim 5, wherein the additional agent is selected from the group consisting of a nonbiologic DMARD and glucocorticoid receptor agonist. 7. The method of claim 5, wherein the additional agent is methotrexate. 8. A method of treating an immunological disorder in a subject comprising administering to the subject in need thereof a once daily pharmaceutical dosage form comprising a core comprising 11 mg of tofacitinib, or an equivalent amount of tofacitinib in the form of a pharmaceutically acceptable salt thereof, and an osmagen, and a semi-permeable membrane coating surrounding the core wherein said coating comprises a water-insoluble polymer, wherein the dosage form is a sustained release dosage form and when administered orally to the subject provides an AUC in the range of 80% to 125% of the AUC of 10 mg of tofacitinib or an equivalent amount of tofacitinib in the form of a pharmaceutically acceptable salt thereof administered as an immediate release formulation BID and provides a ratio of geometric mean plasma C.sub.max to C.sub.min from about 10 to about 100 and wherein the dosage form delivers the tofacitinib, or pharmaceutically acceptable salt thereof, to the subject primarily by osmotic pressure and wherein the water-insoluble polymer is a cellulose derivative that sustains release of the tofacitinib or pharmaceutically acceptable salt thereof, wherein the immunological disorder is selected from the group consisting of rheumatoid arthritis, psoriasis, psoriatic arthritis, ulcerative colitis, ankylosing spondylitis, and juvenile idiopathic arthritis. 9. The method of claim 8, wherein the immunological disorder is rheumatoid arthritis. 10. The method of claim 9, wherein the immunological disorder is ulcerative colitis. 11. The method of claim 8, further comprising one or more additional agents which modulate a mammalian immune system or anti-inflammatory agents. 12. The method of claim 11, wherein the additional agent is selected from the group consisting of a nonbiologic disease-modifying antirheumatic drug (DMARD), methotrexate, glucocorticoid, glucocorticoid receptor agonist, leflunomide, nonsteroidal anti-inflammatory drugs, 6-mercaptopurine, azathioprine, sulfasalazine, and 5-aminosalicylate drugs. 13. The method of claim 12, wherein the additional agent is selected from the group consisting of a nonbiologic DMARD and a glucocorticoid receptor agonist. 14. The method of claim 12, wherein the additional agent is methotrexate. 15. The method of claim 8, wherein the AUC range is 90% to 110% and the geometric mean plasma concentration C.sub.max to C.sub.min from about 20 to about 40. 16. The method of claim 15, wherein the geometric mean plasma concentration C.sub.max to C.sub.min from about 20 to about 30. 17. The method of claim 8, wherein when the dosage form is administered orally to the subject and provides a mean plasma C.sub.max in the range of 70% to 125% of the mean plasma C.sub.max of tofacitinib administered as the immediate release formulation BID at steady state. 18. The method of claim 8, wherein when the dosage form is administered orally to the subject and provides a drug holiday in the range of 80% to 110% of the drug holiday of tofacitinib administered as the immediate release formulation BID over a 24 hour period. 19. The method of claim 8, having a drug holiday from about 15 to about 18 hours over the 24 hour period. 20. A method of treating an immunological disorder in a subject comprising administering to the subject in need thereof a once daily pharmaceutical dosage form comprising a core comprising 11 mg of tofacitinib, or an equivalent amount of tofacitinib in the form of a pharmaceutically acceptable salt thereof, and an osmagen, and a semi-permeable membrane coating surrounding the core wherein said coating comprises a water-insoluble polymer, wherein said dosage form is a sustained release dosage form, and when administered to a subject has a mean area under the plasma concentration versus time curve following administration from about 17 ng-hr/mL per mg of tofacitinib dosed to about 42 ng-hr/mL per mg of tofacitinib dosed and a ratio of geometric mean plasma C.sub.max to C.sub.min from about 10 to about 100 and wherein said dosage form delivers the tofacitinib, or pharmaceutically acceptable salt thereof, to the subject primarily by osmotic pressure and wherein the water-insoluble polymer is a cellulose derivative that sustains release of the tofacitinib, or pharmaceutically acceptable salt thereof, wherein the immunological disorder is selected from the group consisting of rheumatoid arthritis, psoriasis, psoriatic arthritis, ulcerative colitis, ankylosing spondylitis, and juvenile idiopathic arthritis. 21. The method of claim 20, wherein the immunological disorder is rheumatoid arthritis. 22. The method of claim 20, wherein the immunological disorder ulcerative colitis. 23. The method of claim 20, further comprising one or more additional agents which modulate a mammalian immune system or anti-inflammatory agents. 24. The method of claim 23, wherein the additional agent is selected from the group consisting of a nonbiologic disease-modifying antirheumatic drug (DMARD), methotrexate, glucocorticoid, glucocorticoid receptor agonist, leflunomide, nonsteroidal anti-inflammatory drugs, 6-mercaptopurine, azathioprine, sulfasalazine, and 5-aminosalicylate drugs. 25. The method of claim 24, wherein the additional agent is selected from the group consisting of a nonbiologic DMARD and a glucocorticoid receptor agonist. 26. The method of claim 24, wherein the additional agent is methotrexate. 27. The method of claim 20, wherein the ratio of geometric mean plasma C.sub.max to C.sub.min from about 20 to about 40. 28. The method of claim 27, wherein the ratio of geometric mean plasma C.sub.max to C.sub.min from about 20 to about 30. 29. The method of claim 20, wherein the subject has a single, continuous time above about 17 ng/ml from about 6 to about 15 hours and a single, continuous time below about 17 ng/ml from about 9 to about 18 hours over a dosing 24 hours interval. 30. The method of claim 29, wherein the subject has a single, continuous time above about 17 ng/ml from about 6 to about 9 hours. 31. The method of claim 29, wherein the subject has a single, continuous time below about 17 ng/ml from about 15 to about 18 hours. 32. The method of claim 29, wherein the subject has a single, continuous time above about 17 ng/ml from about 11 to about 15 hours. 33. The method of claim 29, wherein the subject has a single, continuous time below about 17 ng/ml from about 9 to about 13 hours. 34. The method of claim 20, wherein the subject has a mean maximum plasma concentration (C.sub.max) from about 3 ng/mL per mg to about 6 ng/mL per mg of tofacitinib dosed. 35. The method of claim 20, wherein said dosage form delivers the tofacitinib, or pharmaceutically acceptable salt thereof, by a system selected from the group consisting of an extrudable core system, a swellable core system, and an asymmetric membrane technology. 36. The method of claim 20, wherein said cellulose derivative is cellulose acetate. 37. The method of claim 20, wherein said coating further comprising a water soluble polymer having an average molecular weight between 2000 and 100,000 daltons. 38. The method of claim 20, wherein said water soluble polymer is selected from the group consisting of water soluble cellulose derivatives, acacia, dextrin, guar gum, maltodextrin, sodium alginate, starch, polyacrylates, and polyvinyl alcohols. 39. The method of claim 38, wherein said water soluble cellulose derivatives comprises hydroxypropylcellulose, hydroxypropylmethylcellulose or hydroxyethylcellulose. 40. The method of claim 20, wherein the osmagen is a sugar. 41. The method of claim 40, wherein the sugar is sorbitol. 42. The method of claim 20, wherein the subject has a mean steady-state minimum plasma concentration (C.sub.min) less than about 0.3 ng/mL per mg of tofacitinib dosed. 43. The method of claim 20, wherein the subject has a mean fed/fasted ratio of the area under the plasma concentration versus time curve from about 0.7 to about 1.4 and a mean fed/fasted ratio of the maximum plasma concentration (C.sub.max) from about 0.7 to about 1.4. 44. The method of claim 1, wherein the immunological disorder is psoriatic arthritis. 45. The method of claim 1, wherein the immunological disorder is ankylosing spondylitis. 46. The method of claim 8, wherein the immunological disorder is psoriatic arthritis. 47. The method of claim 8, wherein the immunological disorder is ankylosing spondylitis. 48. The method of claim 20, wherein the immunological disorder is psoriatic arthritis. 49. The method of claim 20, wherein the immunological disorder is ankylosing spondylitis. 50. A method of treating an immunological disorder in a subject comprising administering to the subject in need thereof a once daily pharmaceutical dosage form comprising a core comprising 22 mg of tofacitinib, or an equivalent amount of tofacitinib in the form of a pharmaceutically acceptable salt thereof, and an osmagen, and a semi-permeable membrane coating surrounding the core wherein said coating comprises a water-insoluble polymer, wherein said dosage form is a sustained release dosage form, and when added to a test medium comprising 900 mL of 0.05M pH 6.8 potassium phosphate buffer at 37.degree. C. in a standard USP rotating paddle apparatus and the paddles are rotated at 50 rpm, dissolves not more than 30% of the tofacitinib, or pharmaceutically acceptable salt thereof, in 1 hour, and not less than 35% and not more than 75% of the tofacitinib, or pharmaceutically acceptable salt thereof, in 2.5 hours and not less than 75% of the tofacitinib, or pharmaceutically acceptable salt thereof, in 5 hours and wherein said dosage form delivers the tofacitinib, or pharmaceutically acceptable salt thereof, to a subject primarily by osmotic pressure and wherein the water-insoluble polymer is a cellulose derivative that sustains release of the tofacitinib, or pharmaceutically acceptable salt thereof, wherein the immunological disorder is selected from the group consisting of rheumatoid arthritis, psoriasis, psoriatic arthritis, ulcerative colitis, ankylosing spondylitis, and juvenile idiopathic arthritis. 51. The method of claim 50, wherein the immunological disorder is rheumatoid arthritis. 52. The method of claim 50, wherein the immunological disorder is ulcerative colitis. 53. The method of claim 50, wherein the immunological disorder is psoriatic arthritis. 54. The method of claim 50, wherein the immunological disorder is ankylosing spondylitis. 55. The method of claim 50, further comprising one or more additional agents which modulate a mammalian immune system or anti-inflammatory agents. 56. The method of claim 55, wherein the additional agent is selected from the group consisting of a nonbiologic disease-modifying antirheumatic drug (DMARD), methotrexate, glucocorticoid, glucocorticoid receptor agonist, leflunomide, nonsteroidal anti-inflammatory drugs, 6-mercaptopurine, azathioprine, sulfasalazine, and 5-aminosalicylate drugs. 57. The method of claim 56, wherein the additional agent is selected from the group consisting of a nonbiologic DMARD and glucocorticoid receptor agonist. 58. The method of claim 56, wherein the additional agent is methotrexate. 59. A method of treating an immunological disorder in a subject comprising administering to the subject in need thereof a once daily pharmaceutical dosage form comprising a core comprising 22 mg of tofacitinib, or an equivalent amount of tofacitinib in the form of a pharmaceutically acceptable salt thereof, and an osmagen, and a semi-permeable membrane coating surrounding the core wherein said coating comprises a water-insoluble polymer, wherein the dosage form is a sustained release dosage form and when administered orally to the subject provides an AUC in the range of 80% to 125% of the AUC of 10 mg of tofacitinib or an equivalent amount of tofacitinib in the form of a pharmaceutically acceptable salt thereof administered as an immediate release formulation BID and provides a ratio of geometric mean plasma C.sub.max to C.sub.min from about 10 to about 100 and wherein the dosage form delivers the tofacitinib, or pharmaceutically acceptable salt thereof, to the subject primarily by osmotic pressure and wherein the water-insoluble polymer is a cellulose derivative that sustains release of the tofacitinib or pharmaceutically acceptable salt thereof, wherein the immunological disorder is selected from the group consisting of rheumatoid arthritis, psoriasis, psoriatic arthritis, ulcerative colitis, ankylosing spondylitis, and juvenile idiopathic arthritis. 60. The method of claim 59, wherein the immunological disorder is rheumatoid arthritis. 61. The method of claim 59, wherein the immunological disorder is ulcerative colitis. 62. The method of claim 59, wherein the immunological disorder is psoriatic arthritis. 63. The method of claim 59, wherein the immunological disorder is ankylosing spondylitis. 64. The method of claim 59, further comprising one or more additional agents which modulate a mammalian immune system or anti-inflammatory agents. 65. The method of claim 64, wherein the additional agent is selected from the group consisting of a nonbiologic disease-modifying antirheumatic drug (DMARD), methotrexate, glucocorticoid, glucocorticoid receptor agonist, leflunomide, nonsteroidal anti-inflammatory drugs, 6-mercaptopurine, azathioprine, sulfasalazine, and 5-aminosalicylate drugs. 66. The method of claim 65, wherein the additional agent is selected from the group consisting of a nonbiologic DMARD and glucocorticoid receptor agonist. 67. The method of claim 65, wherein the additional agent is methotrexate. 68. The method of claim 59, wherein the AUC range is 90% to 110% and the geometric mean plasma concentration C.sub.max to C.sub.min from about 20 to about 40. 69. The method of claim 68, wherein the geometric mean plasma concentration C.sub.max to C.sub.min from about 20 to about 30. 70. The method of claim 59, wherein when the dosage form is administered orally to the subject provides a mean plasma C.sub.max in the range of 70% to 125% of the mean plasma C.sub.max of tofacitinib administered as the immediate release formulation BID at steady state. 71. The method of claim 59, wherein when the dosage form is administered orally to the subject provides a drug holiday in the range of 80% to 110% of the drug holiday of tofacitinib administered as the immediate release formulation BID over a 24 hour period. 72. The method of claim 59, having a drug holiday from about 15 to about 18 hours over the 24 hour period. 73. A method of treating an immunological disorder in a subject comprising administering to the subject in need thereof a once daily pharmaceutical dosage form comprising a core comprising 22 mg of tofacitinib, or an equivalent amount of tofacitinib in the form of a pharmaceutically acceptable salt thereof, and an osmagen, and a semi-permeable membrane coating surrounding the core wherein said coating comprises a water-insoluble polymer, wherein said dosage form is a sustained release dosage form, and when administered to a subject has a mean area under the plasma concentration versus time curve following administration from about 17 ng-hr/mL per mg of tofacitinib dosed to about 42 ng-hr/mL per mg of tofacitinib dosed and a ratio of geometric mean plasma C.sub.max to C.sub.min from about 10 to about 100 and wherein said dosage form delivers the tofacitinib, or pharmaceutically acceptable salt thereof, to the subject primarily by osmotic pressure and wherein the water-insoluble polymer is a cellulose derivative that sustains release of the tofacitinib, or pharmaceutically acceptable salt thereof, wherein the immunological disorder is selected from the group consisting of rheumatoid arthritis, psoriasis, psoriatic arthritis, ulcerative colitis, ankylosing spondylitis, and juvenile idiopathic arthritis. 74. The method of claim 73, wherein the immunological disorder is rheumatoid arthritis. 75. The method of claim 73, wherein the immunological disorder is ulcerative colitis. 76. The method of claim 73, wherein the immunological disorder is psoriatic arthritis. 77. The method of claim 73, wherein the immunological disorder is ankylosing spondylitis. 78. The method of claim 73, further comprising one or more additional agents which modulate a mammalian immune system or anti-inflammatory agents. 79. The method of claim 78, wherein the additional agent is selected from the group consisting of a nonbiologic disease-modifying antirheumatic drug (DMARD), methotrexate, glucocorticoid, glucocorticoid receptor agonist, leflunomide, nonsteroidal anti-inflammatory drugs, 6-mercaptopurine, azathioprine, sulfasalazine, and 5-aminosalicylate drugs. 80. The method of claim 79, wherein the additional agent is selected from the group consisting of a nonbiologic DMARD and glucocorticoid receptor agonist. 81. The method of claim 79, wherein the additional agent is methotrexate. 82. The method of claim 73, wherein the ratio of geometric mean plasma C.sub.max to C.sub.min from about 20 to about 40. 83. The method of claim 82, wherein the ratio of geometric mean plasma C.sub.max to C.sub.min from about 20 to about 30. 84. The method of claim 73, wherein the subject has a single, continuous time above about 17 ng/ml from about 6 to about 15 hours and a single, continuous time below about 17 ng/ml from about 9 to about 18 hours over a dosing 24 hours interval. 85. The method of claim 84, wherein the subject has a single, continuous time above about 17 ng/ml from about 6 to about 9 hours. 86. The method of claim 84, wherein the subject has a single, continuous time below about 17 ng/ml from about 15 to about 18 hours. 87. The method of claim 84, wherein the subject has a single, continuous time above about 17 ng/ml from about 11 to about 15 hours. 88. The method of claim 84, wherein the subject has a single, continuous time below about 17 ng/ml from about 9 to about 13 hours. 89. The method of claim 73, wherein the subject has a mean maximum plasma concentration (C.sub.max) from about 3 ng/mL per mg to about 6 ng/mL per mg of tofacitinib dosed. 90. The method of claim 73, wherein said dosage form delivers the tofacitinib, or pharmaceutically acceptable salt thereof, by a system selected from the group consisting of an extrudable core system, a swellable core system, and an asymmetric membrane technology. 91. The method of claim 73, wherein said cellulose derivative is cellulose acetate. 92. The method of claim 73, wherein said coating further comprising a water soluble polymer having an average molecular weight between 2000 and 100,000 daltons. 93. The method of claim 73, wherein said water soluble polymer is selected from the group consisting of water soluble cellulose derivatives, acacia, dextrin, guar gum, maltodextrin, sodium alginate, starch, polyacrylates, and polyvinyl alcohols. 94. The method of claim 93, wherein said water soluble cellulose derivatives comprises hydroxypropylcellulose, hydroxypropylmethylcellulose or hydroxyethylcellulose. 95. The method of claim 73, wherein the osmagen is a sugar. 96. The method of claim 95, wherein the sugar is sorbitol. 97. The method of claim 73, wherein the subject has a mean steady-state minimum plasma concentration (C.sub.min) less than about 0.3 ng/mL per mg of tofacitinib dosed. 98. The method of claim 73, wherein the subject has a mean fed/fasted ratio of the area under the plasma concentration versus time curve from about 0.7 to about 1.4 and a mean fed/fasted ratio of the maximum plasma concentration (C.sub.max) from about 0.7 to about 1.4.