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. An oral extended release pharmaceutical composition comprising a therapeutically effective amount of tacrolimus and one or more modifying release agents 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 900mL aqueous dissolution medium with 0.005% hydroxypropylcellulose which has been adjusted to pH 4.5.
2. The oral extended release pharmaceutical composition of claim 1 , wherein at most 60% w/w of the tacrolimus in the composition is released within 15 hours.
3. The oral extended release pharmaceutical composition of claim 1 , wherein at most 50% w/w of the tacrolimus in the composition is released within 15 hours.
4. The oral extended release pharmaceutical composition of claim 1 , wherein the pharmaceutical composition provides an AUC fed /AUC fasted of at least 0.9.
5. The oral extended release pharmaceutical composition of claim 1 , wherein the pharmaceutical composition provides pH independent release.
6. The oral extended release pharmaceutical composition of claim 1 , wherein the tacrolimus is dispersed or dissolved in a hydrophilic or water-miscible vehicle.
7. The oral extended release pharmaceutical composition of claim 6 , wherein the hydrophilic or water-miscible vehicle is selected from polyethylene glycol, polyoxyethylene oxide, poloxamer, polyoxyethylene stearate, poly-epsilon caprolactone, polyglycolized glyceride, and mixtures thereof.
8. The oral extended release pharmaceutical composition of claim 7 , wherein the vehicle comprises poloxamer.
9. The oral extended release pharmaceutical composition of claim 7 , wherein the vehicle comprises poloxamer and polyethylene glycol.
10. The oral extended release pharmaceutical composition of claim 9 , wherein the polyethylene glycol and poloxamer are in a proportion by weight of between about 1:3 and about 10:1.
11. The oral extended release pharmaceutical composition of claim 1 , further comprising a solid carrier.
12. The oral extended release pharmaceutical composition of claim 11 , wherein the solid carrier is lactose.
13. The oral extended release pharmaceutical composition of claim 1 , 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 oral extended release pharmaceutical composition of claim 1 , wherein the composition comprises tacrolimus-containing particles.
15. The oral extended release pharmaceutical composition of claim 1 , in the form of a compressed tablet.
16. An oral extended release pharmaceutical composition comprising (a) a therapeutically effective amount of tacrolimus dispersed or dissolved in a vehicle, and (b) one or more modifying release agents, wherein
(i) the vehicle comprises a poloxamer, and
(ii) 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 900mL aqueous dissolution medium with 0.005% hydroxypropylcellulose which has been adjusted to pH 4.5.
17. The oral extended release pharmaceutical composition of claim 16 , wherein at most 60% w/w of the tacrolimus in the composition is released within 15 hours.
18. An oral extended release pharmaceutical composition comprising (a) a therapeutically effective amount of tacrolimus dispersed or dissolved in a vehicle, (b) one or more modifying release agents, and (c) a solid carrier, wherein
(i) the vehicle comprises polyethylene glycol having a molecular weight of from about 1,000 to about 35,000 and a poloxamer, and
(ii) 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 900mL aqueous dissolution medium with 0.005% hydroxypropylcellulose which has been adjusted to pH 4.5.
19. The oral extended release pharmaceutical composition of claim 18 , wherein at most 60% w/w of the tacrolimus in the composition is released within 15 hours.