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. 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 %.
2. The solid pharmaceutical composition of claim 1 , wherein the hydrophilic or water-miscible vehicles have a melting point between 40° C. and the melting point of tacrolimus.
3. The solid pharmaceutical composition of claim 1 , wherein the hydrophilic or water-miscible vehicles have a melting point between 50° C. and the melting point of tacrolimus.
4. The solid pharmaceutical composition of claim 1 , wherein one hydrophilic or water-miscible vehicle is a poloxamer.
5. The solid pharmaceutical composition of claim 4 , wherein the poloxamer is poloxamer 188.
6. The solid pharmaceutical composition of claim 1 , wherein one hydrophilic or water-miscible vehicle is polyethylene glycol.
7. The solid pharmaceutical composition of claim 6 , wherein the polyethylene glycol has an average molecular weight of at least 1500.
8. The solid pharmaceutical composition of claim 1 , wherein the composition further comprises a release-modifying agent.
9. The solid pharmaceutical composition of claim 8 , 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.
10. The solid pharmaceutical composition of claim 9 , 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.
11. 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.
12. The solid pharmaceutical composition of claim 11 , wherein the hydrophilic or water-miscible vehicles have a melting point between 40° C. and the melting point of tacrolimus.
13. The solid pharmaceutical composition of claim 11 , wherein the hydrophilic or water-miscible vehicles have a melting point between 50° C. and the melting point of tacrolimus.
14. The solid pharmaceutical composition of claim 11 , wherein one hydrophilic or water-miscible vehicle is a poloxamer.
15. The solid pharmaceutical composition of claim 14 , wherein the poloxamer is poloxamer 188.
16. The solid pharmaceutical composition of claim 11 , wherein one hydrophilic or water-miscible vehicle is polyethylene glycol.
17. The solid pharmaceutical composition of claim 16 , wherein the polyethylene glycol has an average molecular weight of at least 1500.
18. The solid pharmaceutical composition of claim 11 , wherein the composition further comprises a release-modifying agent.
19. The solid pharmaceutical composition of claim 18 , 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.
20. The solid pharmaceutical composition of claim 19 , 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.
21. 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 %.
22. The solid pharmaceutical composition of claim 21 , wherein the hydrophilic or water-miscible vehicles have a melting point between 40° C. and the melting point of tacrolimus.
23. The solid pharmaceutical composition of claim 21 , wherein the hydrophilic or water-miscible vehicles have a melting point between 50° C. and the melting point of tacrolimus.
24. The solid pharmaceutical composition of claim 21 , wherein one hydrophilic or water-miscible vehicle is a poloxamer.
25. The solid pharmaceutical composition of claim 24 , wherein the poloxamer is poloxamer 188.
26. The solid pharmaceutical composition of claim 21 , wherein one hydrophilic or water-miscible vehicle is polyethylene glycol.
27. The solid pharmaceutical composition of claim 26 , wherein the polyethylene glycol has an average molecular weight of at least 1500.
28. The solid pharmaceutical composition of claim 21 , wherein the composition further comprises a release-modifying agent.
29. The solid pharmaceutical composition of claim 28 , 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.
30. The solid pharmaceutical composition of claim 29 , 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.