Modified release compositions comprising tacrolimus
A modified release composition comprising tacrolimus releases less than 20% w/w of the active ingredient within 0.5 hours when subjected to an in vitro dissolution test using USP Paddle method and using 0.1 N HCl as dissolution medium and has increased bioavailability by effectively reducing or even avoiding the effects of CYP3A4 metabolism. The modified composition may be coated with an enteric coating; and/or may comprise a solid dispersion or a solid solution of tacrolimus in a hydrophilic or water-miscible vehicle and one or more modifying release agents; and/or may comprise a solid dispersion or a solid solution of tacrolimus in an amphiphilic or hydrophobic vehicle and optionally one or more modifying release agents.
1. A method for suppressing a rejection reaction by transplantation of an organ in a patient, the method comprising orally administering a therapeutically effective amount of one or more solid extended release pharmaceutical compositions, each solid extended release pharmaceutical composition comprising (i) tacrolimus dispersed or dissolved in a vehicle and (ii) one or more modifying release agents, wherein the pharmaceutical composition provides a W 50 (the time where the plasma concentration is 50% or more of C max ) of at least 14 hours in the patient.
2. The method of claim 1 , wherein the transplanted organ is a kidney.
3. The method of claim 1 , wherein the pharmaceutical composition provides an AUC fed /AUC fasted of at least 0.9.
4. The method of claim 1 , wherein the pharmaceutical composition provides pH independent release.
5. The method of claim 1 , wherein the composition releases at most 62% of the tacrolimus in the composition within 15 hours when subjected to an in vitro dissolution test using USP Paddle method at a rotation speed of 50 rpm in a 900 mL aqueous dissolution medium with 0.005% hydroxypropylcellulose which has been adjusted to pH 4.5.
6. The method of claim 5 , wherein at most 60% w/w of the tacrolimus in the composition is released within 15 hours, when subjected to the in vitro dissolution test.
7. The method of claim 5 , wherein at most 50% w/w of the tacrolimus in the composition is released within 15 hours, when subjected to the in vitro dissolution test.
8. The method of claim 1 , wherein the vehicle comprises polyethylene glycol and poloxamer.
9. The solid method of claim 8 , wherein the polyethylene glycol and poloxamer are in a proportion by weight of between about 1:3 and about 10:1.
10. The method of claim 1 , wherein the composition further comprises a solid carrier.
11. The method of claim 10 , wherein the solid carrier is lactose.
12. The method of claim 1 , wherein the composition further comprises a modifying release agent.
13. The method of claim 12 , wherein the modifying release agent is selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose, poloxamers, polyoxyethylene stearates, poly-s-caprolactone, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-polyvinylacetate copolymer PVP-PVA, polymethacrylic polymers, polyvinyl alcohol (PVA), poly(ethylene oxide) (PED), and mixtures thereof.
14. The method of claim 1 , wherein the composition comprises tacrolimus-containing particles.
15. The method of claim 1 , wherein the composition is in the form of a compressed tablet.
16. A method for suppressing a rejection reaction by transplantation of an organ in a patient, the method comprising orally administering to the patient a therapeutically effective amount of one or more extended release pharmaceutical compositions, each extended release pharmaceutical composition comprising tacrolimus particles, wherein (a) the particles contain (i) tacrolimus dispersed or dissolved in a vehicle and (ii) one or more modifying release agents, (b) the particles have a d gw of from about 100 to about 700 μm, and (c) the pharmaceutical composition provides a W 50 (the time where the plasma concentration is 50% or more of C max ) of at least 14 hours.
17. The method of claim 16 , wherein the pharmaceutical composition provides an AUC fed /AUC fasted of at least 0.9.
18. The method of claim 16 , wherein the pharmaceutical composition provides pH independent release.
19. The method of claim 16 , wherein the composition releases at most 62% of the tacrolimus in the composition within 15 hours when subjected to an in vitro dissolution test using USP Paddle method at a rotation speed of 50 rpm in a 900 mL aqueous dissolution medium with 0.005% hydroxypropylcellulose which has been adjusted to pH 4.5.
20. The method of claim 19 , wherein at most 60% w/w of the tacrolimus in the composition is released within 15 hours.
21. A method for suppressing a rejection reaction by transplantation of an organ in a patient, the method comprising orally administering to the patient a therapeutically effective amount of one or more extended release pharmaceutical compositions, each solid extended release pharmaceutical composition comprising (i) tacrolimus particles, wherein the particles contain tacrolimus dispersed or dissolved in a vehicle and (ii) one or more modifying release agents, wherein
the pharmaceutical composition provides pH independent release, and a W 50 (the time where the plasma concentration is 50% or more of C max ) of at least 14 hours in the patient,
the pharmaceutical composition is free of organic solvent, and
the tacrolimus particles have a d gw of from about 100 to about 700 μm.
22. The method of claim 21 , wherein the pharmaceutical composition provides an AUC fed /AUC fasted of at least 0.9.
23. The method of claim 21 , wherein the composition releases at most 62% of the tacrolimus in the composition within 15 hours when subjected to an in vitro dissolution test using USP Paddle method at a rotation speed of 50 rpm in a 900 mL aqueous dissolution medium with 0.005% hydroxypropylcellulose which has been adjusted to pH 4.5.