Stabilized tacrolimus composition
The invention relates to a stable pharmaceutical composition comprising comprising a solid dispersion of tacrolimus in a vehicle further comprising a stabilizing agent capable of providing a pH below 7 in the composition, as measured after re-dispersion in water, and preventing or reducing the formation upon storage of major degradation products of tacrolimus, in particular the 8-epitacrolimus.
1. A sustained release tablet comprising (i) a dispersion of tacrolimus, (ii) 8-epitacrolimus, and (iii) a metal chelating agent that is an organic acid, wherein the tacrolimus is the sole active ingredient in the tablet and the tablet comprises a sufficient amount of the metal chelating agent such that the tablet comprises less than 0.5% by weight of the 8-epitacrolimus after 12 weeks of storage at 25° C. and 60% relative humidity, based upon 100% total weight of tacrolimus.
2. A sustained release tablet comprising (i) a dispersion of tacrolimus, (ii) 8-epitacrolimus, and (iii) a metal chelating agent that is an organic acid, wherein the tacrolimus is the sole active ingredient in the tablet and the tablet comprises a sufficient amount of the metal chelating agent such that the tablet comprises less than 0.5% by weight of the 8-epitacrolimus after 10 months of storage at 25° C. and 60% relative humidity, based upon 100% total weight of tacrolimus.
3. A sustained release tablet comprising a solid dispersion of tacrolimus in a mixture of a vehicle and a metal chelating agent that is an organic acid, wherein the tacrolimus is the sole active ingredient in the tablet and the tablet contains a sufficient amount of the metal chelating agent such that the tablet comprises (a) no more than 0.5% by weight 8-epitacrolimus after storage at 40° C. at 75% relative humidity for 5 weeks compared to the tablet prior to storage, or (b) no more than 0.2% by weight 8-epitacrolimus after storage at 25° C. at 60% relative humidity for 5 weeks compared to the tablet prior to storage, based upon 100% total weight of tacrolimus.
4. A stabilized sustained release tablet comprising (A) a solid dispersion of tacrolimus, (B) 8-epitacrolimus, and (C) a metal chelating agent that is an organic acid, wherein (i) the tacrolimus is the sole active ingredient in the tablet and (ii) the tablet contains a sufficient amount of the metal chelating agent such that the tablet comprises no more than 0.5% by weight of the 8-epitacrolimus after storage at 25° C. at 60% relative humidity for 5 weeks, based upon 100% total weight of tacrolimus.
5. The sustained release tablet of claim 1 , wherein the tablet has a pH of 2.5 to 4 as measured after re-dispersing the tablet in water.
6. The sustained release tablet of claim 2 , wherein the tablet has a pH of 2.5 to 4 as measured after re-dispersing the tablet in water.
7. The sustained release tablet of claim 3 , wherein the tablet has a pH of 2.5 to 4 as measured after re-dispersing the tablet in water.
8. The sustained release tablet of claim 4 , wherein the tablet has a pH of 2.5 to 4 as measured after re-dispersing the tablet in water.
9. The sustained release tablet of claim 1 , wherein the dispersion of tacrolimus comprises tacrolimus dispersed in a vehicle, and the metal chelating agent is dissolved in the vehicle.
10. The sustained release tablet of claim 2 , wherein the dispersion of tacrolimus comprises tacrolimus dispersed in a vehicle, and the metal chelating agent is dissolved in the vehicle.
11. The sustained release tablet of claim 3 , wherein the metal chelating agent is dissolved in the vehicle.
12. The sustained release tablet of claim 4 , wherein the dispersion of tacrolimus comprises tacrolimus dispersed in a vehicle, and the metal chelating agent is dissolved in the vehicle.
13. The sustained release tablet of claim 1 , wherein the metal chelating agent is oxalic acid.
14. The sustained release tablet of claim 2 , wherein the metal chelating agent is oxalic acid.
15. The sustained release tablet of claim 3 , wherein the metal chelating agent is oxalic acid.
16. The sustained release tablet of claim 4 , wherein the metal chelating agent is oxalic acid.