PHARMACOKINETIC EVALUATION OF PLGA & PLA BASED LONG ACTING RELEASE (LAR) MICROSPHERE FORMULATIONS OF CETRORELIX IN RATS

Cetrorelix is one of the potent luteinizing hormone?releasing hormone (LH-RH) antagonist which is indicated in the treatment of preventing premature ovulation in IVF (in vitro fertilization) procedures. The objective of the study was to prepare different poly-lactic-coglycolic acid (PLGA) and Polylactic acid (PLA) based long acting release (LAR) microsphere formulations and to further evaluate the pharmacokinetics, invitro and invivo release of cetrorelix from these formulations. Microsphere 1 (MS1) and Microsphere 2 (MS2) formulations prepared with PLGA 50:50 and PLGA75:25 copolymers could sustain the release of drug for 14-28 days, whereas microsphere 3 (MS3) and microsphere 4 (MS4) formulations prepared with PLGA 85:15 copolymer and PLA could extend the release for 120days. On comparing the invitro and invivo release of the microsphere formulations it was observed that release under invivo conditions release was faster than under invitro conditions. It was observed that increase in the drug loading lead to higher rise in the initial cetrorelix plasma levels and further lead to shorter duration of release. On SC injection of MS1, MS2, MS3 & MS4 microspheres formulation to adult male Sprague Dawley rats at 0.25mg/kg lead to an initial rise in plasma cetrorelix levels which is of 23.812 ± 8.554 ng/mL, 150.701 ± 51.772 ng/mL, 57.581 ± 19.781 ng/mL and 164.466 ± 56.512 ng/mL at the median Tmax of 6hr for MS1-4 formulations respectively, where as a single subcutaneous (SC) administration of cetrorelix injection to rats at 0.25 mg/kg provided peak maximum concentration (Cmax) of 79.274 ± 17.734 ng/mL at 1.5 hr (Tmax). The exposure (AUC0-t) achieved by the microsphere formulations are of the order 628.059±127.706, 4814.86 ± 1729.582, 8324.062 ± 2859.633, 10414.69 ± 3577.844 and 15579.68 ± 5352.216 hr.ng/mL for Cetrotide® , MS1, MS2, MS3 and MS4 formulations respectively. When compared with Cetrotide® SC injection the exposures achieved by the microsphere formulations are of the order MS4 > MS3 > MS2 > MS1 formulations. Therefore based on the results of the study it can be concluded that PLGA and PLA microsphere formulations of cetrorelix can be of clinical relevance helping the patients to avoid multiple injections during their therapy. Keywords: Cetrorelix; Poly-lactic-coglycolic acid (PLGA); Polylactic acid (PLA); Subcutaneous; Pharmacokinetics; Long acting release (LAR)