Claims for Patent: 7,888,328

Summary for Patent: 7,888,328

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:	10/551,205
Patent Claims:	1. A complex cladribine-cyclodextrin complex which is an intimate amorphous admixture consisting of (a) an amorphous inclusion complex of cladribine with the amorphous cyclodextrin hydroxypropyl-.beta.-cyclodextrin and (b) amorphous free cladribine associated with said amorphous cyclodextrin as a non-inclusion complex, said complex cladribine-cyclodextrin complex having a weight ratio of cladribine to said amorphous cyclodextrin of from about 1:10 to about 1:16. 2. The complex cladribine-cyclodextrin complex according to claim 1, saturated with cladribine. 3. The complex cladribine-cyclodextrin complex according to claim 1, wherein the weight ratio of cladribine to hydroxypropyl-.beta.-cyclodextrin is about 1:14. 4. The complex cladribine-cyclodextrin complex according to claim 1, wherein the weight ratio of cladribine to hydroxypropyl-.beta.-cyclodextrin is about 1:11. 5. The complex cladribine-cyclodextrin 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). 6. A pharmaceutical composition comprising a complex cladribine-cyclodextrin complex which is an intimate amorphous admixture consisting of (a) an amorphous inclusion complex of cladribine with the amorphous cyclodextrin hydroxypropyl-.beta.-cyclodextrin and (b) amorphous free cladribine associated with said 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, said composition having a weight ratio of cladribine to said amorphous cyclodextrin of from about 1:10 to about 1:16. 7. The pharmaceutical composition according to claim 6, wherein the complex cladribine-cyclodextrin complex is saturated with cladribine. 8. The composition according to claim 6, wherein the weight ratio of cladribine to hydroxypropyl-.beta.-cyclodextrin is about 1:14. 9. The composition according to claim 6, wherein the weight ratio of cladribine to hydroxypropyl-.beta.-cyclodextrin is about 1:11. 10. The composition according to claim 7, wherein the approximate molar ratio of cladribine to said amorphous cyclodextrin corresponds to a point located on the curve of a phase solubility diagram for saturated complex cladribine-cyclodextrin complexes, said curve defining complex saturated complexes of cladribine in varying concentrations of the cyclodextrin. 11. The composition according to claim 6, 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). 12. A pharmaceutical composition according to claim 6 obtainable by a process comprising the steps of: (i) combining cladribine and the amorphous cyclodextrin hydroxypropyl-.beta.-cyclodextrin in water at a temperature of from about 45 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. 13. A pharmaceutical composition according to claim 12, wherein the process further comprises a filtration step following step (i) or (ii). 14. A pharmaceutical composition according to claim 12, wherein step (i) of the process is performed at a temperature of from about 45 to about 60.degree. C. 15. A pharmaceutical composition according to claim 12, wherein step (i) of the process is performed at a temperature of from about 45 to about 50.degree. C. 16. A pharmaceutical composition according to claim 14, wherein step (i) of the process is performed with stirring. 17. A pharmaceutical composition according to claim 16, wherein step (i) of the process is performed for a period of from about 6 to about 9 hours. 18. A pharmaceutical composition according to claim 12, wherein step (ii) of the process is performed for a period of from about 6 to about 9 hours. 19. A pharmaceutical composition according to claim 12, 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. 20. A pharmaceutical composition according to claim 19, wherein, in the initial freezing stage of step (iii), the solution is cooled to about -45.degree. C. 21. A pharmaceutical composition according to claim 12, 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. 22. A pharmaceutical composition according to claim 12, 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. 23. A pharmaceutical composition according to claim 21, wherein 825 parts by volume of water are introduced in step (i) of the process. 24. A pharmaceutical composition according to claim 12, 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. 25. A pharmaceutical composition according to claim 24, wherein stage (a) of the lyophilization is conducted at about -45.degree. C. for approximately 3 to 4 hours. 26. A pharmaceutical composition according to claim 24, wherein stage (b) of the lyophilization is conducted under a pressure of about 100 mTorr. 27. A pharmaceutical composition according to claim 12, wherein the formulation step (iv) of the process comprises blending the complex with magnesium stearate and compressing into tablets. 28. A pharmaceutical composition according to claim 27, wherein magnesium stearate is pre-mixed with sorbitol powder before blending with the complex. 29. 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 consisting of (a) an amorphous inclusion complex of cladribine with the amorphous cyclodextrin hydroxypropyl-.beta.-cyclodextrin and (b) amorphous free cladribine associated with said 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, said composition having a weight ratio of cladribine to said amorphous cyclodextrin of from about 1:10 to about 1:16. 30. The method according to claim 29, wherein the complex cladribine-cyclodextrin complex is saturated with cladribine. 31. The method according to claim 29, wherein the weight ratio of cladribine to hydroxypropyl-.beta.-cyclodextrin is about 1:14. 32. The method according to claim 29, wherein the weight ratio of cladribine to hydroxypropyl-.beta.-cyclodextrin is about 1:11. 33. The method according to claim 30, wherein the approximate molar ratio of cladribine to said amorphous cyclodextrin corresponds to a point located on the curve of a phase solubility diagram for saturated complex cladribine-cyclodextrin complexes, said curve defining complex saturated complexes of cladribine in varying concentrations of the cyclodextrin. 34. The method according to claim 29, 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). 35. A method for the treatment of a condition selected from the group consisting of multiple sclerosis, rheumatoid arthritis and leukemia in a subject suffering from said condition comprising orally administering to said subject a pharmaceutical composition comprising a complex cladribine-cyclodextrin complex which is an intimate amorphous admixture consisting of (a) an amorphous inclusion complex of cladribine with the amorphous cyclodextrin hydroxypropyl-.beta.-cyclodextrin and (b) amorphous free cladribine associated with said 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, said composition having a weight ratio of cladribine to said amorphous cyclodextrin of from about 1:10 to about 1:16. 36. The method according to claim 35, wherein the complex cladribine-cyclodextrin complex is saturated with cladribine. 37. The method according to claim 35, wherein the condition is multiple sclerosis. 38. The method according to claim 35, wherein the weight ratio of cladribine to hydroxypropyl-.beta.-cyclodextrin is about 1:14. 39. The method according to claim 25, wherein the weight ratio of cladribine to hydroxypropyl-.beta.-cyclodextrin is about 1:11. 40. The method according to claim 35, 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). 41. 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 the amorphous cyclodextrin in water at a temperature of from about 45 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. 42. A process according to claim 41, further comprising a filtration step following step (ii). 43. A process according to claim 41, wherein step (i) is performed at a temperature of from about 45 to about 60.degree. C. 44. A process according to claim 41, wherein step (i) is performed at a temperature of from about 45 to about 50.degree. C. 45. A process according to claim 43, wherein step (i) is performed with stirring. 46. A process according to claim 41, wherein step (i) is performed for a period of from about 6 to about 9 hours. 47. A process according to claim 41, wherein step (ii) is performed for a period of from about 6 to about 9 hours. 48. A process according to claim 41, 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. 49. A process according to claim 48, wherein, in the initial freezing stage of step (iii), the solution is cooled to about -45.degree. C. 50. A process according to claim 41, wherein 12.00 parts by weight of cladribine and 172.50 parts by weight of hydroxypropyl-.beta.-cyclodextrin are introduced in step (i). 51. A process according to claim 41, wherein 16.35 parts by weight of cladribine and 172.50 parts by weight of hydroxypropyl-.beta.-cyclodextrin are introduced in step (i). 52. A process according to claim 50, wherein 825 parts by volume of water are introduced in step (i). 53. A process according to claim 41, 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. 54. A process according to claim 53, wherein stage (a) of the lyophilization is conducted at about -45.degree. C. for approximately 3 to 4 hours. 55. A process according to claim 53, wherein stage (b) of the lyophilization is conducted under a pressure of about 100 mTorr.