Solid dispersions comprising tacrolimus
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.