Claims for Patent: 11,419,823

Summary for Patent: 11,419,823

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, INC. (Cary, NC)
Application Number:	16/188,805
Patent Claims:	1. A sustained release pharmaceutical composition comprising a solid dispersion of tacrolimus in a mixture of a vehicle and a stabilizing agent, wherein (i) the stabilizing agent is a metal chelating agent and provides a pH below 7 in the composition, (ii) a sufficient amount of the stabilizing agent is present in the composition such that the composition comprises less than 0.5% by weight of 8-epitacrolimus after 12 weeks of storage at 25.degree. C. and 60% relative humidity, based upon 100% total weight of tacrolimus, and (iii) the tacrolimus is the sole active ingredient in the composition. 2. A composition according to claim 1, wherein the pH in the composition is in the range of 2.5-4.0. 3. A composition according to claim 1, wherein the pH in the composition is in the range of 3.0-3.6. 4. A composition according to claim 1, wherein the stabilizing agent is an organic acid selected from mono-, di-, oligo- and polycarboxylic acids. 5. A composition according to claim 1, wherein the stabilizing agent is an organic acid selected from the group consisting of succinic acid, citric acid, tartaric acid, acrylic acid, benzoic acid, malic acid, maleic acid, and sorbic acid. 6. A composition according to claim 1, wherein the stabilizing agent is an organic acid present in a concentration of less than 5% w/w, based on the total amount of tacrolimus and vehicle and stabilizing agent. 7. A composition according to claim 1, wherein the vehicle is a mixture of a polyethylene glycol and a poloxamer. 8. A composition according to claim 1, which comprises 8-epitacrolimus in an amount of less than 0.5% w/w. 9. The composition of claim 1, wherein an aqueous composition formed after re-dispersing the composition in water has a pH of 2.5 to 4. 10. The composition of claim 1, wherein the stabilizing agent comprises citric acid. 11. The composition of claim 2, wherein the stabilizing agent comprises citric acid. 12. The composition of claim 3, wherein the stabilizing agent comprises citric acid. 13. The composition of claim 6, wherein the stabilizing agent comprises citric acid. 14. The composition of claim 7, wherein the stabilizing agent comprises citric acid. 15. The composition of claim 8, wherein the stabilizing agent comprises citric acid. 16. The composition of claim 9, wherein the stabilizing agent comprises citric acid. 17. A sustained release pharmaceutical composition comprising a solid dispersion of tacrolimus in a mixture of a vehicle and a stabilizing agent capable of providing a pH below 7 in the composition, wherein a sufficient amount of stabilizing agent is present in the composition such that the composition comprises less than 0.5% by weight of 8-epitacrolimus after 12 weeks of storage at 25.degree. C. and 60% relative humidity, based upon 100% total weight of tacrolimus, and wherein the stabilizing agent is an organic acid selected from the group consisting of oxalic acid, tartaric acid, and citric acid. 18. The composition of claim 17, wherein the stabilizing agent comprises citric acid. 19. A sustained release pharmaceutical composition comprising a solid dispersion of tacrolimus in a mixture of a vehicle and a stabilizing agent, wherein the pharmaceutical composition contains 8-epitacrolimus, and the 8-epitacrolimus is present at a concentration below 0.2% by weight, wherein (i) the stabilizing agent is a metal chelating agent and provides a pH below 7 in the composition, (ii) a sufficient amount of the stabilizing agent is present in the composition such that the composition comprises less than 0.5% by weight of 8-epitacrolimus after 12 weeks of storage at 25.degree. C. and 60% relative humidity, based upon 100% total weight of tacrolimus, and (iii) the tacrolimus is the sole active ingredient in the composition. 20. The pharmaceutical composition of claim 19, wherein the solid dispersion is substantially free of organic solvent. 21. The composition of claim 19, wherein an aqueous composition formed after re-dispersing the composition in water has a pH of 2.5 to 4. 22. The composition of claim 19, wherein the stabilizing agent comprises citric acid. 23. The composition of claim 20, wherein the stabilizing agent comprises citric acid. 24. The composition of claim 21, wherein the stabilizing agent comprises citric acid. 25. A sustained release tablet comprising (i) a dispersion of tacrolimus, (ii) 8-epitacrolimus, and (iii) a sufficient amount of a stabilizing agent such that the tablet comprises less than 0.5% by weight of 8-epitacrolimus after 12 weeks of storage at 25.degree. C. and 60% relative humidity, based upon 100% total weight of tacrolimus, wherein (a) the tacrolimus is the sole active ingredient in the tablet, and (b) the stabilizing agent is a metal chelating agent and provides a pH below 7 in the composition. 26. The tablet of claim 25, wherein an aqueous composition formed after re-dispersing the tablet in water has a pH of 2.5 to 4. 27. The composition of claim 25, wherein the stabilizing agent comprises citric acid. 28. The composition of claim 26, wherein the stabilizing agent comprises citric acid.