Claims for Patent: 8,785,415

Summary for Patent: 8,785,415

Title:	Oral formulations of cladribine
Abstract:	Provided are compositions of cladribine and cyclodextrin which are especially suited for the oral administration of cladribine.
Inventor(s):	Bodor; Nicholas S. (Bal Harbour, FL), Dandiker; Yogesh (Toronto, CA)
Assignee:	Ares Trading S.A. (Aubonne, CH)
Application Number:	12/986,310
Patent Claims:	1. A complex cladribine-cyclodextrin complex which is an intimate amorphous admixture of (a) an amorphous inclusion complex of cladribine with an amorphous cyclodextrin and (b) amorphous free cladribine associated with amorphous cyclodextrin as a non-inclusion complex. 2. The complex according to claim 1, saturated with cladribine. 3. The complex according to claim 1, wherein the amorphous cyclodextrin is hydroxypropyl-.beta.-cyclodextrin, hydroxypropyl-.gamma.-cyclodextrin, randomly methylated .beta.-cyclodextrin, carboxymethyl-.beta.-cyclodextrin or sulfobutyl-.beta.-cyclodextrin. 4. The complex according to claim 1, wherein the amorphous cyclodextrin is hydroxypropyl-.beta.-cyclodextrin or hydroxypropyl-.gamma.-cyclodextrin. 5. The complex according to claim 1, wherein the weight ratio of cladribine to amorphous cyclodextrin is from about 1:10 to about 1:16. 6. The complex according to claim 5, wherein the amorphous cyclodextrin is hydroxypropyl-.beta.-cyclodextrin or hydroxypropyl-.gamma.-cyclodextrin. 7. The complex according to claim 1, wherein from about 30 to about 40 percent by weight of the cladribine is in the inclusion complex (a) and from about 70 to about 60 percent by weight of the cladribine is in the non-inclusion complex (b). 8. A process for the preparation of a complex cladribine-cyclodextrin complex as claimed in claim 1, which comprises the steps of: (i) combining cladribine and an amorphous cyclodextrin in water at a temperature of from about 40 to about 80.degree. C. and maintaining said temperature for a period of from about 6 to about 24 hours; (ii) cooling the resultant aqueous solution to room temperature; and (iii) lyophilizing the cooled solution to afford an amorphous product. 9. The process according to claim 8, further comprising a filtration step following step (ii). 10. The process according to claim 8, wherein step (i) is performed at a temperature of from about 45 to about 60.degree. C. 11. The process according to claim 8, wherein step (i) is performed at a temperature of from about 45 to about 50.degree. C. 12. The process according to claim 10, wherein step (i) is performed with stirring. 13. The process according to claim 12, wherein step (i) is performed for a period of from about 6 to about 9 hours. 14. The process according to claim 8, wherein step (ii) is performed for a period of from about 6 to about 9 hours. 15. The process according to claim 8, wherein step (iii) comprises an initial freezing stage in which the solution is cooled to from about -40 to about -80.degree. C., and held at said temperature for a period of from about 2 to about 4 hours. 16. The process according to claim 15, wherein, in the initial freezing stage of step (iii), the solution is cooled to about -45.degree. C. 17. The process according to claim 10, wherein 12.00 parts by weight of cladribine and 172.50 parts by weight of hydroxypropyl-.beta.-cyclodextrin are introduced in step (i), or wherein 16.35 parts by weight of cladribine and 172.50 parts by weight of hydroxypropyl-.beta.-cyclodextrin are introduced in step (i). 18. The process according to claim 17, wherein 825 parts by volume of water are introduced in step (i). 19. The process according to claim 8, wherein the lyophilization step (iii) comprises: (a) an initial freezing stage in which the complexation solution is brought to from about -40.degree. C. to about -80.degree. C. for approximately 2 to 4 hours; (b) a primary drying stage at about -25.degree. C. for approximately 80 to 90 hours; and (c) a secondary drying stage at about 30.degree. C. for approximately 15 to 20 hours. 20. The process according to claim 19, wherein stage (a) of the lyophilization is conducted at about -45.degree. C. for approximately 3 to 4 hours. 21. The process according to claim 19, wherein stage (b) of the lyophilization is conducted under a pressure of about 100 mTorr. 22. A pharmaceutical composition comprising a complex cladribine-cyclodextrin complex which is an intimate amorphous admixture of (a) an amorphous inclusion complex of cladribine with an amorphous cyclodextrin and (b) amorphous free cladribine associated with amorphous cyclodextrin as a non-inclusion complex, formulated into a solid oral dosage form, said composition comprising no significant amount of free crystalline cladribine therein. 23. The pharmaceutical composition according to claim 1, wherein the complex is saturated with cladribine. 24. The composition according to claim 1, wherein the amorphous cyclodextrin is hydroxypropyl-.beta.-cyclodextrin, hydroxypropyl-.gamma.-cyclodextrin, randomly methylated .beta.-cyclodextrin, carboxymethyl-.beta.-cyclodextrin or sulfobutyl-.beta.-cyclodextrin. 25. The composition according to claim 1, wherein the amorphous cyclodextrin is hydroxypropyl-.beta.-cyclodextrin or hydroxypropyl-.gamma.-cyclodextrin. 26. The composition according to claim 1, wherein the weight ratio of cladribine to amorphous cyclodextrin is from about 1:10 to about 1:16. 27. The composition according to claim 26, wherein the amorphous cyclodextrin is hydroxypropyl-.beta.-cyclodextrin or hydroxypropyl-.gamma.-cyclodextrin. 28. The composition according to claim 1, wherein the approximate molar ratio of cladribine to amorphous cyclodextrin corresponds to a point located on the curve of a phase solubility diagram for saturated complexes of cladribine in varying concentrations of the cyclodextrin. 29. The composition according to claim 1, wherein from about 30 to about 40 percent by weight of the cladribine is in the inclusion complex (a) and from about 70 to about 60 percent by weight of the cladribine is in the non-inclusion complex (b). 30. A pharmaceutical composition according to claim 1, obtainable by a process comprising the steps of: (i) combining cladribine and an amorphous cyclodextrin in water at a temperature of from about 40 to about 80.degree. C. and maintaining said temperature for a period of from about 6 to about 24 hours; (ii) cooling the resultant aqueous solution to room temperature; (iii) lyophilizing the cooled solution to afford an amorphous product; and (iv) formulating the amorphous product into a solid oral dosage form. 31. The pharmaceutical composition according to claim 30, wherein the process further comprises a filtration step following step (i) or (ii). 32. The pharmaceutical composition according to claim 30, wherein step (i) of the process is performed at a temperature of from about 45 to about 60.degree. C. 33. The pharmaceutical composition according to claim 32, wherein step (i) of the process is performed with stirring. 34. The pharmaceutical composition according to claim 33, wherein step (i) of the process is performed for a period of from about 6 to about 9 hours. 35. The pharmaceutical composition according to claim 3, wherein 12.00 parts by weight of cladribine and 172.50 parts by weight of the hydroxypropyl-.beta.-cyclodextrin are introduced in step (i) of the process, or wherein 16.35 parts by weight of cladribine and 172.50 parts by weight of the hydroxypropyl-.beta.-cyclodextrin are introduced in step (i) of the process. 36. The pharmaceutical composition according to claim 35, wherein 825 parts by volume of water are introduced in step (i) of the process. 37. The pharmaceutical composition according to claim 30, wherein step (i) of the process is performed at a temperature of from about 45 to about 50.degree. C. 38. The pharmaceutical composition according to claim 30, wherein step (ii) of the process is performed for a period of from about 6 to about 9 hours. 39. The pharmaceutical composition according claim 30, wherein step (iii) comprises an initial freezing stage in which the solution is cooled to from about -40 to about -80.degree. C., and held at said temperature for a period of from about 2 to about 4 hours. 40. The pharmaceutical composition according to claim 39, wherein, in the initial freezing stage of step (iii), the solution is cooled to about -45.degree. C. 41. The pharmaceutical composition according to claim 30, wherein the lyophilization step (iii) of the process comprises: (a) an initial freezing stage in which the complexation solution is brought to from about -40.degree. C. to about -80.degree. C. for approximately 2 to 4 hours; (b) a primary drying stage at about -25.degree. C. for approximately 80 to 90 hours; and (c) a secondary drying stage at about 30.degree. C. for approximately 15 to 20 hours. 42. The pharmaceutical composition according to claim 41, wherein stage (a) of the lyophilization is conducted at about -45.degree. C. for approximately 3 to 4 hours. 43. The pharmaceutical composition according to claim 41, wherein stage (b) of the lyophilization is conducted under a pressure of about 100 mTorr. 44. The pharmaceutical composition according to claim 30, wherein the formulation step (iv) of the process comprises blending the complex with magnesium stearate and compressing into tablets. 45. The pharmaceutical composition according to claim 44, wherein magnesium stearate is pre-mixed with sorbitol powder before blending with the complex. 46. A method for enhancing the oral bioavailability of cladribine comprising orally administering to a subject in need thereof a pharmaceutical composition comprising a complex cladribine-cyclodextrin complex which is an intimate amorphous admixture of (a) an amorphous inclusion complex of cladribine with an amorphous cyclodextrin and (b) amorphous free cladribine associated with amorphous cyclodextrin as a non-inclusion complex, formulated into a solid oral dosage form, said composition comprising no significant amount of free crystalline cladribine therein. 47. The method according to claim 46, wherein the complex is saturated with cladribine. 48. The method according to claim 46, wherein the amorphous cyclodextrin is hydroxypropyl-.beta.-cyclodextrin, hydroxypropyl-.gamma.-cyclodextrin, randomly methylated .beta.-cyclodextrin, carboxymethyl-.beta.-cyclodextrin or sulfobutyl-.beta.-cyclodextrin. 49. The method according to claim 46, wherein the amorphous cyclodextrin is hydroxypropyl-.beta.-cyclodextrin or hydroxypropyl-.gamma.-cyclodextrin. 50. The method according to claim 46, wherein the weight ratio of cladribine to amorphous cyclodextrin is from about 1:10 to about 1:16. 51. The method according to claim 50, wherein the amorphous cyclodextrin is hydroxypropyl-.beta.-cyclodextrin or hydroxypropyl-.gamma.-cyclodextrin. 52. The method according to claim 46, wherein the approximate molar ratio of cladribine to amorphous cyclodextrin corresponds to a point located on the curve of a phase solubility diagram for saturated complexes of cladribine in varying concentrations of the cyclodextrin. 53. The method according to claim 46, wherein from about 30 to about 40 percent by weight of the cladribine is in the inclusion complex (a) and from about 70 to about 60 percent by weight of the cladribine is in the non-inclusion complex (b). 54. A method for the treatment of symptoms of a cladribine-responsive condition selected from the group consisting of multiple sclerosis, rheumatoid arthritis and leukemia in a subject suffering from said symptoms comprising orally administering to said subject a pharmaceutical composition comprising a complex cladribine-cyclodextrin complex which is an intimate amorphous admixture of (a) an amorphous inclusion complex of cladribine with an amorphous cyclodextrin and (b) amorphous free cladribine associated with amorphous cyclodextrin as a non-inclusion complex, formulated into a solid oral dosage form, said composition comprising no significant amount of free crystalline cladribine therein. 55. The method according to claim 54, wherein the complex is saturated with cladribine. 56. The method according to claim 54, wherein the cladribine-responsive condition is multiple sclerosis. 57. The method according to claim 54, wherein the amorphous cyclodextrin is hydroxypropyl-.beta.-cyclodextrin, hydroxypropyl-.gamma.-cyclodextrin, randomly methylated.beta.-cyclodextrin, carboxymethyl-.beta.-cyclodextrin or sulfobutyl-.beta.-cyclodextrin. 58. The method according to claim 54, wherein the weight ratio of cladribine to amorphous cyclodextrin is from about 1:10 to about 1:16. 59. The method according to claim 54, wherein the amorphous cyclodextrin is hydroxypropyl-.beta.-cyclodextrin or hydroxypropyl-.gamma.-cyclodextrin. 60. The method according to claim 54, wherein from about 30 to about 40 percent by weight of the cladribine is in the inclusion complex (a) and from about 70 to about 60 percent by weight of the cladribine is in the non-inclusion complex (b). 61. A method for the treatment of symptoms of a cladribine-responsive condition selected from the group consisting of multiple sclerosis, rheumatoid arthritis and leukemia in a subject suffering from said symptoms comprising orally administering to said subject a pharmaceutical composition comprising a complex cladribine-cyclodextrin complex which is an intimate amorphous admixture of (a) an amorphous inclusion complex of cladribine with an amorphous cyclodextrin and (b) amorphous free cladribine associated with amorphous cyclodextrin as a non-inclusion complex, formulated into a solid oral dosage form, said composition comprising no significant amount of free crystalline cladribine therein, wherein administering cladribine is accompanied by administering one or more additional active ingredients for treating the cladribine-responsive condition. 62. The method according to claim 61, wherein the complex is saturated with cladribine. 63. The method according to claim 62, wherein the amorphous cyclodextrin is hydroxypropyl-.beta.-cyclodextrin, hydroxypropyl-.gamma.-cyclodextrin, randomly methylated .beta.-cyclodextrin, carboxymethyl-.beta.-cyclodextrin or sulfobutyl-.beta.-cyclodextrin. 64. The method according to claim 61, wherein the amorphous cyclodextrin is hydroxypropyl-.beta.-cyclodextrin, hydroxypropyl-.gamma.-cyclodextrin, randomly methylated .beta.-cyclodextrin, carboxymethyl-.beta.-cyclodextrin or sulfobutyl-.beta.-cyclodextrin. 65. The method according to claim 64, wherein the weight ratio of cladribine to amorphous cyclodextrin is from about 1:10 to about 1:16. 66. The method according to claim 65, wherein the amorphous cyclodextrin is hydroxypropyl-.gamma.-cyclodextrin. 67. The method according to claim 61, wherein the weight ratio of cladribine to amorphous cyclodextrin is from about 1:10 to about 1:16. 68. The method according to claim 67, wherein the amorphous cyclodextrin is hydroxypropyl-.beta.-cyclodextrin. 69. The method according to claim 68, wherein the cladribine-responsive condition is multiple sclerosis. 70. The method according to claim 69, wherein one or more additional active ingredients for treating multiple sclerosis is/are selected from the group consisting of interferon beta, glatiramer acetate, natalizumab, alemtuzumab, 4-aminopyridine and amantadine. 71. The method according to claim 61, wherein the amorphous cyclodextrin is hydroxypropyl-.beta.-cyclodextrin. 72. The method according to claim 71, wherein the weight ratio of cladribine to hydroxypropyl-.beta.-cyclodextrin is about 1:14. 73. The method according to claim 71, wherein the weight ratio of cladribine to hydroxypropyl-.beta.-cyclodextrin is about 1:11. 74. The method according to claim 71, wherein from about 30 to about 40 percent by weight of the cladribine is in the inclusion complex (a) and from about 70 to about 60 percent by weight of the cladribine is in the non-inclusion complex (b). 75. The method according to claim 71, wherein the cladribine-responsive condition is multiple sclerosis. 76. The method according to claim 75, wherein one or more additional active ingredients for treating multiple sclerosis is/are selected from the group consisting of interferon beta, glatiramer acetate, natalizumab, alemtuzumab, 4-aminopyridine and amantadine. 77. The method according to claim 61, wherein from about 30 to about 40 percent by weight of the cladribine is in the inclusion complex (a) and from about 70 to about 60 percent by weight of the cladribine is in the non-inclusion complex (b). 78. The method according to claim 61, wherein the cladribine-responsive condition is multiple sclerosis. 79. The method according to claim 78, wherein one or more additional active ingredients for treating multiple sclerosis is/are selected from the group consisting of interferon beta, glatiramer acetate, natalizumab, alemtuzumab, 4-aminopyridine and amantadine.