Solid dispersions comprising tacrolimus

Abstract

A pharmaceutical composition comprising tacrolimus (FK-506) dissolved and/or dispersed in a hydrophilic or water-miscible vehicle to form a solid dispersion or solid solution at ambient temperature have improved bioavailability.

1 - 51 . (canceled) 
     
     
         52 . A solid pharmaceutical composition comprising (i) a solid carrier, and (ii) tacrolimus in a mixture of at least two hydrophilic or water-miscible vehicles having a melting point between 30° C. and the melting point of tacrolimus, wherein the tacrolimus is present in the composition at a concentration of between 0.01 w/w % and 15 w/w %. 
     
     
         53 . The solid pharmaceutical composition of  claim 52 , wherein the hydrophilic or water-miscible vehicles have a melting point between 40° C. and the melting point of tacrolimus. 
     
     
         54 . The solid pharmaceutical composition of  claim 52 , wherein the hydrophilic or water-miscible vehicles have a melting point between 50° C. and the melting point of tacrolimus. 
     
     
         55 . The solid pharmaceutical composition of  claim 52 , wherein one hydrophilic or water-miscible vehicle is poloxamer. 
     
     
         56 . The solid pharmaceutical composition of  claim 55 , wherein the poloxamer is poloxamer 188. 
     
     
         57 . The solid pharmaceutical composition of  claim 52 , wherein one hydrophilic or water-miscible vehicle is polyethylene glycol. 
     
     
         58 . The solid pharmaceutical composition of  claim 57 , wherein the polyethylene glycol has an average molecular weight of at least 1500. 
     
     
         59 . The solid pharmaceutical composition of  claim 52 , wherein the composition further comprises a release-modifying agent. 
     
     
         60 . The solid pharmaceutical composition of  claim 59 , wherein the composition provides a W 50  (the time where the plasma concentration is 50% or more of C max ) of at least 12 hours. 
     
     
         61 . The solid pharmaceutical composition of  claim 60 , wherein the composition provides a W 50  (the time where the plasma concentration is 50% or more of C max ) of at least 14 hours. 
     
     
         62 . A solid pharmaceutical composition comprising agglomerated particles comprising a solid carrier and tacrolimus dispersed or dissolved in a mixture of at least two hydrophilic or water-miscible vehicles having a melting point between 30° C. and the melting point of tacrolimus, wherein (i) the tacrolimus is present in the composition at a concentration of between about 0.01 w/w % and about 15 w/w %, and (ii) the particles have a geometric weight mean diameter d gw  of from 100 to 1000 μm. 
     
     
         63 . The solid pharmaceutical composition of  claim 62 , wherein the hydrophilic or water-miscible vehicles have a melting point between 40° C. and the melting point of tacrolimus. 
     
     
         64 . The solid pharmaceutical composition of  claim 62 , wherein the hydrophilic or water-miscible vehicles have a melting point between 50° C. and the melting point of tacrolimus. 
     
     
         65 . The solid pharmaceutical composition of  claim 62 , wherein one hydrophilic or water-miscible vehicle is poloxamer. 
     
     
         66 . The solid pharmaceutical composition of  claim 65 , wherein the poloxamer is poloxamer 188. 
     
     
         67 . The solid pharmaceutical composition of  claim 62 , wherein one hydrophilic or water-miscible vehicle is polyethylene glycol. 
     
     
         68 . The solid pharmaceutical composition of  claim 67 , wherein the polyethylene glycol has an average molecular weight of at least 1500. 
     
     
         69 . The solid pharmaceutical composition of  claim 62 , wherein the composition further comprises a release-modifying agent. 
     
     
         70 . The solid pharmaceutical composition of  claim 69 , wherein the composition provides a W 50  (the time where the plasma concentration is 50% or more of C max ) of at least 12 hours. 
     
     
         71 . The solid pharmaceutical composition of  claim 70 , wherein the composition provides a W 50  (the time where the plasma concentration is 50% or more of C max ) of at least 14 hours. 
     
     
         72 . A solid pharmaceutical composition prepared by a process comprising the steps of:
 (a) spraying a solid carrier with tacrolimus dispersed or dissolved in a melted mixture of two hydrophilic or water-miscible vehicles, the vehicles having a melting point between 30° C. and the melting point of tacrolimus,   (b) mechanically working the product from step (a) to form agglomerated particles having a geometric weight mean diameter d gw  of from 100 to 1000 μm, and   (c) compressing the agglomerated particles, wherein the tacrolimus is present in the composition at a concentration of between about 0.01 w/w % and about 15 w/w %.   
     
     
         73 . The solid pharmaceutical composition of  claim 72 , wherein the hydrophilic or water-miscible vehicles have a melting point between 40° C. and the melting point of tacrolimus. 
     
     
         74 . The solid pharmaceutical composition of  claim 72 , wherein the hydrophilic or water-miscible vehicles have a melting point between 50° C. and the melting point of tacrolimus. 
     
     
         75 . The solid pharmaceutical composition of  claim 72 , wherein one hydrophilic or water-miscible vehicle is poloxamer. 
     
     
         76 . The solid pharmaceutical composition of  claim 75 , wherein the poloxamer is poloxamer 188. 
     
     
         77 . The solid pharmaceutical composition of  claim 72 , wherein one hydrophilic or water-miscible vehicle is polyethylene glycol. 
     
     
         78 . The solid pharmaceutical composition of  claim 77 , wherein the polyethylene glycol has an average molecular weight of at least 1500. 
     
     
         79 . The solid pharmaceutical composition of  claim 72 , wherein the composition further comprises a release-modifying agent. 
     
     
         80 . The solid pharmaceutical composition of  claim 79 , wherein the composition provides a W 50  (the time where the plasma concentration is 50% or more of C max ) of at least 12 hours. 
     
     
         81 . The solid pharmaceutical composition of  claim 80 , wherein the composition provides a W 50  (the time where the plasma concentration is 50% or more of C max ) of at least 14 hours.