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 solid pharmaceutical composition comprising:
(a) tacrolimus;
(b) hydroxypropyl methylcellulose;
(c) lactose;
(d) polyethylene glycol 6000;
(e) poloxamer 188; and
(f) magnesium stearate.
2. The solid pharmaceutical composition of claim 1 , wherein less than 20% w/w of the tacrolimus is released from the solid pharmaceutical composition 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.
3. The solid pharmaceutical composition of claim 1 , wherein less than 20% w/w of the tacrolimus is released from the solid pharmaceutical composition within 3 hours, when subjected to an in vitro dissolution test using USP Paddle method and using 0.1 N HCl as dissolution medium.
4. The solid pharmaceutical composition of claim 2 , wherein the weight ratio of polyethylene glycol 6000 to poloxamer 188 is between 1:3 and 10:1.
5. The solid pharmaceutical composition of claim 2 , wherein the dosage form is a tablet.
6. The solid pharmaceutical composition 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.
7. The solid pharmaceutical composition of claim 1 , wherein the dosage form is a tablet.
8. The solid pharmaceutical composition of claim 3 , wherein the dosage form is a tablet.