Details for Patent: 9,549,918

Title:	Stabilized tacrolimus composition
Abstract:	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.
Inventor(s):	Skak; Nikolaj (Virum, DK), Holm; Per (Vanlose, DK)
Assignee:	VELOXIS PHARMACEUTICALS A/S (Horsholm, DK)
Filing Date:	Feb 17, 2011
Application Number:	13/029,304
Claims:	1. A solid sustained release oral dosage form comprising a solid dispersion of tacrolimus in a mixture of a vehicle and tartaric acid, wherein the vehicle comprises polyethylene glycol and poloxamer. 2. The dosage form according to claim 1, wherein the pH in the dosage form is in the range of 3.0-3.6. 3. The dosage form according to claim 1, wherein the pH in the dosage form is in the range of 2.5-4.0. 4. The dosage form according to claim 1, wherein the tartaric acid is present in a concentration of less than 5% w/w, based on the total amount of tacrolimus, vehicle and tartaric acid. 5. The dosage form according to claim 1, which comprises 8 -epitacrolimus in an amount of less than 5% w/w, based upon the total weight of tacrolimus. vehicle and tartaric acid. 6. The dosage form of claim 1, wherein the dosage form comprises from about 0.5 to about 5% of tacrolimus, based upon 100% total weight of the dosage form. 7. The dosage form of claim 1, wherein the dosage form comprises from about 1 to about 4% tacrolimus, based upon 100% total weight of the dosage form. 8. A tablet comprising a solid dispersion of tacrolimus in a mixture of a vehicle and tartaric acid, wherein (a) the tablet contains 8-epitacrolimus, and the 8epitacrolimus is present at a concentration below 0.2% by weight, based upon the total weight of the tablet, and (b) the vehicle comprises polyethylene glycol and poloxamer. 9. The tablet of claim 8, wherein the solid dispersion is substantially free of organic solvent. 10. A tablet comprising (i) a dispersion of tacrolimus in a mixture of a vehicle and tartaric acid, and (ii) 8-epitacrolimus, wherein (a) the tablet comprises less than 0.5% by weight of the 8-epitacrolimus after 12 weeks of storage at 25.degree. C. and 60% relative humidity, based upon 100% total weight of tacrolimus, and (b) the vehicle comprises polyethylene glycol and poloxamer. 11. A tablet comprising (i) a dispersion of tacrolimus in a mixture of a vehicle and tartaric acid, and (ii) 8-epitacrolimus, wherein (a) the tablet comprises less than 0.5% by weight of the 8-epitacrolimus after 10 months of storage at 25.degree. C. and 60% relative humidity, based upon 100% total weight of tacrolimus, and (b) the vehicle comprises polyethylene glycol and poloxamer. 12. A tablet comprising a solid dispersion of tacrolimus in a mixture of a vehicle and tartaric acid, wherein (i) the tablet contains (a) no more than 0.5% by weight more 8-epitacrolimus after storage at 40.degree. C. at 75% relative humidity for 5 weeks compared to the tablet prior to storage, or (b) no more than 0.2% by weight more 8-epitacrolimus after storage at 25.degree. C. at 60% relative humidity for 5 weeks compared to the dosage form prior to storage, based upon 100% total weight of tacrolimus, (ii) the vehicle comprises polyethylene glycol and poloxamer. 13. A stabilized tablet comprising (a) a solid dispersion of tacrolimus in a mixture of a vehicle and tartaric acid and (b) 8-epitacrolimus, wherein (i) the tablet contains (a) no more than 0.5% by weight of the 8-epitacrolimus, (b) no more than 0.5% by weight of the Diene of tacrolimus, (c) no more than 0.5% by weight of the C4-epimer diene of tacrolimus, and/or (d) no more than 0.5% by weight of Regioisomer A of tacrolimus, after storage at 25.degree. C. at 60% relative humidity for 5 weeks, based upon 100% total weight of tacrolimus, and (ii) the vehicle comprises polyethylene glycol and poloxamer. 14. A tablet comprising tacrolimus in a mixture of vehicle and tartaric acid, wherein (i) the tablet comprises from about 0.05 to about 0.6% by weight of tartaric acid, based on the total amount of tacrolimus, vehicle and tartaric acid, and (ii) the vehicle comprises polyethylene glycol and poloxamer. 15. A tablet comprising tacrolimus in a mixture of a vehicle and tartaric acid, wherein the weight ratio of tacrolimus to tartaric acid is about 19:0.5 to about 20:6 and (ii) the vehicle comprises polyethylene glycol and poloxamer.