Claims for Patent: 11,123,331

Summary for Patent: 11,123,331

Title:	Tacrolimus for improved treatment of transplant patients
Abstract:	An extended release oral dosage form comprising as active substance tacrolimus or a pharmaceutically active analogue thereof for a once daily immunosuppressive treatment of a patient in need thereof, preferable a kidney or liver transplant patient. The dosage form releases the active substance over an extended period of time. It also provides improved pharmacokinetic parameters due to an extended and constant in vivo release including substantial decreased peak concentrations, despite increased bioavailability, substantial extended times for maximal concentration, and higher minimal concentrations when compared with conventional immediate release dosage forms and a recent modified release tacrolimus dosage form.
Inventor(s):	Gordon; Robert D. (Sandy Springs, GA), Holm; Per (Vanlose, DK), Lademann; Anne-Marie (Klampenborg, DK), Norling; Tomas (Lyngby, DK)
Assignee:	VELOXIS PHARMACEUTICALS, INC. (Cary, NC)
Application Number:	17/085,379
Patent Claims:	1. A method of suppressing kidney rejection in an African American kidney transplant patient being treated with an immediate release tacrolimus formulation twice per day comprising (a) discontinuing treatment with the immediate release tacrolimus formulation, and (b) initiating treatment of the patient with an effective amount of one or more extended release tacrolimus compositions in which the T.sub.max following administration of the compositions is 4 to 6 hours, wherein the ratio of tacrolimus administered per day with the immediate release tacrolimus formulation before discontinuing such treatment to that with the extended release tacrolimus compositions is 1:0.8. 2. A method of suppressing kidney rejection in a kidney transplant patient being treated with an immediate release tacrolimus formulation twice per day comprising (a) discontinuing treatment with the immediate release tacrolimus formulation, and (b) initiating treatment of the patient with an effective amount of one or more extended release tacrolimus compositions in which the T.sub.max following administration of the compositions is 4 to 6 hours, wherein the ratio of tacrolimus administered per day with the immediate release tacrolimus formulation before discontinuing such treatment to that with the extended release tacrolimus compositions is 1:0.66 to 1:0.8. 3. A method of suppressing kidney rejection in a kidney transplant patient being treated with an immediate release tacrolimus formulation twice per day comprising (a) discontinuing treatment with the immediate release tacrolimus formulation, and (b) initiating treatment of the patient with an effective amount of one or more extended release tacrolimus compositions in which (i) the in vivo release of each compositions takes place substantially in the colon or (ii) at least 8% of the tacrolimus in each composition is released within 4 hours and 40% of the tacrolimus is released within 10 to 14 hours, when tested according to the USP II dissolution test (paddle) or USP I dissolution test (basket) method at a rotation of 50 rpm in a medium at pH 4.5 comprising 0.005% hydroxypropylcellulose, wherein the ratio of tacrolimus administered per day with the immediate release tacrolimus formulation before discontinuing such treatment to that with the extended release tacrolimus compositions is 1:0.66 to 1:0.8. 4. The method of claim 1, wherein at least 8% of the tacrolimus in each composition is released at the 4 hour time point and 40% of the tacrolimus is released within 10 to 14 hours, when tested according to the USP II dissolution test (paddle) or USP I dissolution test (basket) method at a rotation of 50 rpm in a medium at pH 4.5 comprising 0.005% hydroxypropylcellulose. 5. The method of claim 1, wherein the in vivo release of each composition after oral administration takes place substantially in the colon. 6. The method of claim 1, wherein the in vivo release of each composition after oral administration takes place substantially in one or more of the colon ascendens, colon transversum and colon descendens. 7. The method of claim 1, wherein (a) at least 8% of the tacrolimus is released at the 4 hour time point after administration of each composition, (b) less than 25% of the tacrolimus is released at the 5 hour time point, (c) 40% of the tacrolimus is released within 10 to 14 hours, (d) 63.5% or less of the tacrolimus is released at the 12 hour time point, and (e) each composition releases the tacrolimus with a substantial zero order release profile over an extended period of time defined by the release from the 8 hours time point to the 15 hours time point, the substantial zero order release being defined as a linear release profile with a deviation of at the most .+-.15%, when tested according to the USP II dissolution test (paddle) or USP I dissolution test (basket) method at a rotation of 50 rpm in a medium at pH 4.5 comprising 0.005% hydroxypropylcellulose. 8. The method of claim 1, wherein 63.5% or less of the tacrolimus in each composition is released when measured at the 20 hour time point. 9. The method of claim 1, wherein the tacrolimus is present in each composition as a molecular dispersion. 10. The method of claim 1, which when administered once per day in steady state to a healthy subject or a patient, the swing of the blood concentrations of tacrolimus measured as (C.sub.max-C.sub.min)/C.sub.min is less than the swing observed when administering either the tacrolimus dosage form approved by the European Agency for the Evaluation of Medicinal Products (EMEA) on Apr. 23, 2007 or the tacrolimus dosage form approved under U.S. New Drug Application No. 050708 in a once per day regimen and being determined under similar conditions and administered in similar molecular daily dosages of the tacrolimus. 11. The method of claim 1, wherein the tacrolimus is present in each composition in a hydrophilic or water-miscible vehicle, and the vehicle is selected from a polyethylene glycol, a polyoxyethylene oxide, poloxamer, polyoxyethylene stearate, poly-epsilon caprolactone, polyglycolized glycerides, polyvinylpyrrolidone, polyvinyl-polyvinylacetate copolymer, polyvinyl alcohol, polymethacrylic polymer hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose, a pectin, a cyclodextrin, galactomannan, alginate, carragenate, xanthan gum, and mixtures thereof. 12. The method of claim 1, wherein 40% of the tacrolimus in each composition is released within 11 to 13 hours, when tested according to the USP II dissolution test (paddle) or USP I dissolution test (basket) method at a rotation of 50 rpm in a medium at pH 4.5 comprising 0.005% hydroxypropylcellulose. 13. The method of claim 1, wherein 50% of the tacrolimus in each composition is released within 13 to 17 hours, when tested according to the USP II dissolution test (paddle) or USP I dissolution test (basket) method at a rotation of 50 rpm in a medium at pH 4.5 comprising 0.005% hydroxypropylcellulose. 14. The method of claim 1, wherein 50% of the tacrolimus in each composition is released within 14 to 16 hours, when tested according to the USP II dissolution test (paddle) or USP I dissolution test (basket) method at a rotation of 50 rpm in a medium at pH 4.5 comprising 0.005% hydroxypropylcellulose. 15. The method of claim 1, wherein (a) at least 8% of the tacrolimus in each composition is released at the 4 hour time point, (b) less than 25% of the tacrolimus is released at the 5 hour time point, (c) 50% of the tacrolimus is released within 13 to 17 hours, (d) 63.5% or less of the tacrolimus is released at the 12 hour time point, and (e) each composition releases the tacrolimus with a substantial zero order release profile over an extended period of time defined by the release from the 8 hours time point to the 15 hours time point, the substantial zero order release being defined as a linear release profile with a deviation of at the most .+-.15%, when tested according to the USP II dissolution test (paddle) or USP I dissolution test (basket) method at a rotation of 50 rpm in a medium at pH 4.5 comprising 0.005% hydroxypropylcellulose. 16. The method of claim 15, wherein 50% of the tacrolimus in each composition is released within 14 to 16 hours, when tested according to the USP II dissolution test (paddle) or USP I dissolution test (basket) method at a rotation of 50 rpm in a medium at pH 4.5 comprising 0.005% hydroxypropylcellulose. 17. A method of suppressing kidney rejection in an African American kidney transplant patient being treated with an immediate release tacrolimus formulation twice per day comprising (a) discontinuing treatment with the immediate release tacrolimus formulation, and (b) initiating treatment of the patient with an effective amount of one or more extended release tacrolimus compositions in which the T.sub.max following administration of the compositions is 4 to 6 hours, wherein the ratio of tacrolimus administered per day with the immediate release tacrolimus formulation before discontinuing such treatment to that with the extended release tacrolimus compositions is 1:0.8, and wherein the patient is concomitantly treated with mycophenolate mofetil. 18. A method of suppressing kidney rejection in an African American kidney transplant patient being treated with an immediate release tacrolimus formulation twice per day comprising (a) discontinuing treatment with the immediate release tacrolimus formulation, and (b) initiating treatment of the patient with an effective amount of one or more extended release tacrolimus compositions in which the T.sub.max following administration of the compositions is 4 to 6 hours, wherein the ratio of tacrolimus administered per day with the immediate release tacrolimus formulation before discontinuing such treatment to that with the extended release tacrolimus compositions is 1:0.8, and wherein the patient is concomitantly treated with a corticosteroid. 19. The method of claim 1, wherein the plasma concentration of tacrolimus in the patient is maintained at a therapeutically effective amount without inducing nephrotoxicity or neurotoxicity. 20. The method of claim 2, wherein the patient is concomitantly treated with mycophenolate mofetil. 21. The method of claim 2, wherein the patient is concomitantly treated with a corticosteroid. 22. The method of claim 2, wherein the plasma concentration of tacrolimus in the patient is maintained at a therapeutically effective amount without inducing nephrotoxicity or neurotoxicity. 23. A method of suppressing kidney rejection in a kidney transplant patient being treated with an immediate release tacrolimus formulation twice per day comprising (a) discontinuing treatment with the immediate release tacrolimus formulation, and (b) initiating treatment of the patient with an effective amount of one or more extended release tacrolimus compositions in which (i) the in vivo release of each compositions takes place substantially in the colon or (ii) at least 8% of the tacrolimus in each composition is released within 4 hours and 40% of the tacrolimus is released within 10 to 14 hours, wherein the ratio of tacrolimus administered per day with the immediate release tacrolimus formulation before discontinuing such treatment to that with the extended release tacrolimus compositions is 1:0.8, and wherein the patient is concomitantly treated with mycophenolate mofetil. 24. A method of suppressing kidney rejection in a kidney transplant patient being treated with an immediate release tacrolimus formulation twice per day comprising (a) discontinuing treatment with the immediate release tacrolimus formulation, and (b) initiating treatment of the patient with an effective amount of one or more extended release tacrolimus compositions in which (i) the in vivo release of each compositions takes place substantially in the colon or (ii) at least 8% of the tacrolimus in each composition is released within 4 hours and 40% of the tacrolimus is released within 10 to 14 hours, wherein the ratio of tacrolimus administered per day with the immediate release tacrolimus formulation before discontinuing such treatment to that with the extended release tacrolimus compositions is 1:0.8, and wherein the patient is concomitantly treated with a corticosteroid. 25. The method of claim 3, wherein the plasma concentration of tacrolimus in the patient is maintained at a therapeutically effective amount without inducing nephrotoxicity or neurotoxicity.