Cladribine formulations for improved oral and transmucosal delivery

Abstract

Provided are compositions of cladribine and cyclodextrin which are especially suited for the oral and buccal administration of cladribine.

1 . A pharmaceutical composition comprising a saturated cladribine-cyclodextrin complex formulated into a solid oral dosage form or a transmucosal dosage form, said composition being substantially free of cyclodextrin in excess of the minimum amount required to maximize the amount of cladribine in the complex.  
     
     
         2 . A pharmaceutical composition comprising a saturated cladribine-cyclodextrin complex formulated into a solid oral dosage form or a transmucosal dosage form, said composition being substantially free of cyclodextrin in excess of the minimum amount required to maintain substantially all of the cladribine in the complex.  
     
     
         3 . The composition according to  claim 1 , wherein the saturated cladribine-cyclodextrin complex is formulated into a solid oral dosage form.  
     
     
         4 . The composition according to  claim 1 , wherein the cyclodextrin is γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dimethyl-β-cyclodextrin, randomly methylated β-cyclodextrin, carboxymethyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin.  
     
     
         5 . The composition according to  claim 1 , wherein the cyclodextrin is γ-cyclodextrin.  
     
     
         6 . The composition according to  claim 1 , wherein the cyclodextrin is hydroxypropyl-β-cyclodextrin.  
     
     
         7 . The composition according to  claim 5 , wherein the complex comprises a 1:2 cladribine:γ-cyclodextrin complex.  
     
     
         8 . The composition according to  claim 4 , wherein the weight ratio of cladribine to cyclodextrin is from about 1:35 to about 1:50.  
     
     
         9 . The composition according to  claim 5 , wherein the weight ratio of cladribine to γ-cyclodextrin is about 1:46.  
     
     
         10 . The composition according to  claim 6 , wherein the weight ratio of cladribine to hydroxypropyl-β-cyclodextrin is about 1:42.  
     
     
         11 . The composition according to any one of  claim 2 , wherein the approximate molar ratio of cladribine to cyclodextrin corresponds to a point located on a phase solubility diagram for saturated complexes of cladribine in varying concentrations of the cyclodextrin.  
     
     
         12 . The composition according to  claim 11 , wherein the cyclodextrin is γ-cyclodextrin and the point is taken from the portion of the phase solubility diagram indicative of formation of a 1:2 complex of cladribine:γ-cyclodextrin.  
     
     
         13 . A method for enhancing the oral or transmucosal bioavailability of cladribine comprising administering to a subject in need thereof a pharmaceutical composition comprising a saturated cladribine-cyclodextrin complex formulated into a solid oral dosage form or a transmucosal dosage form, said composition being substantially free of cyclodextrin in excess of the minimum amount required to maximize the amount of cladribine in the complex.  
     
     
         14 . A method for enhancing the oral or transmucosal bioavailability of cladribine comprising administering to a subject in need thereof a pharmaceutical composition comprising a saturated cladribine-cyclodextrin complex formulated into a solid oral dosage form or a transmucosal dosage form, said composition being substantially free of cyclodextrin in excess of the minimum amount required to maintain substantially all of the cladribine in the complex.  
     
     
         15 . The method according to  claim 13 , wherein the saturated cladribine-cyclodextrin complex is formulated into a solid oral dosage form.  
     
     
         16 . The method according to  claim 13 , wherein the cyclodextrin is γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dimethyl-β-cyclodextrin, randomly methylated β-cyclodextrin, carboxymethyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin.  
     
     
         17 . The method according to  claim 13 , wherein the cyclodextrin is γ-cyclodextrin.  
     
     
         18 . The method according to  claim 13 , wherein the cyclodextrin is hydroxypropyl-β-cyclodextrin.  
     
     
         19 . The method according to  claim 17 , wherein the complex comprises a 1:2 cladribine:γ-cyclodextrin complex.  
     
     
         20 . The method according to  claim 16 , wherein the weight ratio of cladribine to cyclodextrin is from about 1:35 to about 1:50.  
     
     
         21 . The method according to  claim 17 , wherein the weight ratio of cladribine to γ-cyclodextrin is about 1:46.  
     
     
         22 . The method according to  claim 18 , wherein the weight ratio of cladribine to hydroxypropyl-β-cyclodextrin is about 1:42.  
     
     
         23 . The method according to any one of claims  claim 14 , wherein the approximate molar ratio of cladribine to cyclodextrin corresponds to a point located on a phase solubility diagram for saturated complexes of cladribine in varying concentrations of the cyclodextrin.  
     
     
         24 . The method according to  claim 23 , wherein the cyclodextrin is γ-cyclodextrin and the point is taken from the portion of the phase solubility diagram indicative of formation of a 1:2 complex of cladribine:γ-cyclodextrin.  
     
     
         25 . A method for the treatment of symptoms of a cladribine-responsive condition in a subject suffering from said symptoms comprising administering to said subject a pharmaceutical composition comprising a saturated cladribine-cyclodextrin complex formulated into a solid oral dosage form, said composition being substantially free of cyclodextrin in excess of the minimum amount required to maximize the amount of cladribine in the complex.  
     
     
         26 . A method for the treatment of symptoms of a cladribine-responsive condition in a subject suffering from said symptoms comprising administering to said subject a pharmaceutical composition comprising a saturated cladribine-cyclodextrin complex formulated into a solid oral dosage form, said composition being substantially free of cyclodextrin in excess of the minimum amount required to maintain substantially all of the cladribine in the complex.  
     
     
         27 . The method according to  claim 25 , wherein the cladribine-responsive condition is selected from the group consisting of multiple sclerosis, rheumatoid arthritis and leukemia.  
     
     
         28 . The method according to  claim 27 , wherein the cladribine-responsive condition is multiple sclerosis.  
     
     
         29 . The method according to  claim 25 , wherein the saturated cladribine-cyclodextrin complex is formulated into a solid oral dosage form.  
     
     
         30 . The method according to  claim 25 , wherein the cyclodextrin is γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dimethyl-β-cyclodextrin, randomly methylated β-cyclodextrin, carboxymethyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin.  
     
     
         31 . The method according to  claim 25 , wherein the cyclodextrin is γ-cyclodextrin.  
     
     
         32 . The method according to  claim 25 , wherein the cyclodextrin is hydroxypropyl-β-cyclodextrin.  
     
     
         33 . The method according to  claim 30 , wherein the weight ratio of cladribine to cyclodextrin is from about 1:35 to about 1:50.  
     
     
         34 . The method according to  claim 31 , wherein the weight ratio of cladribine to γ-cyclodextrin is about 1:46.  
     
     
         35 . The method according to  claim 32 , wherein the weight ratio of cladribine to hydroxypropyl-β-cyclodextrin is about 1:42.  
     
     
         36 . The method according to  claim 31 , wherein the complex comprises a 1:2 cladribine:γ-cyclodextrin complex.  
     
     
         37 . A method for enhancing the bioavailability of cladribine from a solid oral or transmucosal dosage form administered to a mammal in need of treatment with cladribine, said method comprising: 
 (a) determining the minimum amount of cyclodextrin required to complex with a selected amount of cladribine and to maintain said selected amount of cladribine in the complex;    (b) combining an amount of cladribine in excess of said selected amount with said minimum amount of cyclodextrin in an aqueous medium;    (c) removing uncomplexed cladribine from the aqueous complexation medium;    (d) removing water from the aqueous complexation medium to afford the dry saturated cladribine-cyclodextrin complex;    (e) formulating said dry saturated cladribine-cyclodextrin complex into a solid oral dosage form or a transmucosal dosage form substantially free of cyclodextrin in excess of the minimum amount required to maintain substantially all of the cladribine in the complex; and    (f) administering said dosage form orally or transmucosally to said mammal.    
     
     
         38 .- 59 . (canceled)  
     
     
         60 . A 1:2 cladribine:γ-cyclodextrin complex.  
     
     
         61 . A mixture of a 1:1 cladribine:γ-cyclodextrin complex and a 1:2 cladribine:γ-cyclodextrin complex, wherein the 1:2 complex is predominant.