Pharmaceutical NanotechnologySirolimus solid self-microemulsifying pellets: Formulation development, characterization and bioavailability evaluation

To enhance the dissolution and oral absorption of water insoluble drug sirolimus (SRL), self-microemulsifying pellets of SRL were developed and evaluated. Solubility test, self-emulsifying grading test, ternary phase diagrams and central composite design were adopted to screen and optimize the composition of liquid SRL-SMEDDS. The selected liquid SRL-SMEDDS formulations were prepared into pellets by extrusion-spheronization method and the optimal formulation of 1 mg SRL-SMEDDS pellets capsule (1.0, 22.4, 38.4, 19.2, 121.6, 30.4 and 8.0 mg of SRL, Labrafil M1944CS, Cremophor EL, Transcutol P, MCC, Lactose and CMS-Na, respectively) was finally determinated by the feasibility of the preparing process and redispersibility. The optimal SRL-SMEDDS pellets showed a significant quicker redispersion rate than the dissolution rate of commercial SRL tablets Rapamune® in water. The droplet size and polydispersity index of the reconstituted microemulsion was almost unchanged after solidification, and pellet size and friability were all qualified. Visual observation and scanning electron microscopic analysis confirmed good appearance of the solid pellets. DSC, XRPD, and IR analysis confirmed that there was no crystalline sirolimus in the pellets. Pharmacokinetic study in beagle dogs showed the oral relative bioavailability of SRL-SMEDDS pellets to the commercial SRL tablets Rapamune® was about 136.9%. In conclusion, the solid SMEDDS pellets might be an encouraging strategy to improve the oral absorption of SRL and the extrusion-spheronization method was a feasible technology for the solidification of liquid SMEDDS.

The prepared solid sirolimus self-microemulsifying pellets had a good appearance and in vitro redispersibility. No crystalline sirolimus was observed in the pellets and the oral bioavailability in beagle dogs was significantly improved relative to the commercial sirolimus tablets.217