Formulation and performance characterization of radio-sterilized "progestin-only" microparticles intended for contraception

Abstract

The aim of this study was to formulate and characterize a microparticulate system of progestin-only contraceptive. Another objective was to evaluate the effect of gamma radio-sterilization on in vitro and in vivo drug release characteristics. Levonorgestrel (LNG) microspheres were fabricated using poly(lactide-co-glycolide) (PLGA) by a novel solvent evaporation technique. The formulation was optimized for drug/polymer ratio, emulsifier concentration, and process variables like speed of agitation and evaporation method. The drug to polymer ratio of 1:5 gave the optimum encapsulation efficiency. Speed of agitation influenced the spherical shape of the microparticles, lower speeds yielding less spherical particles. The speed did not have a significant influence on the drug payloads. A combination of stabilizers viz. methyl cellulose and poly vinyl alcohol with in-water solvent evaporation technique yielded microparticles without any free drug crystals on the surface. This aspect significantly eliminated the in vitro dissolution "burst effect". The residual solvent content was well within the regulatory limits. The microparticles passed the test for sterility and absence of pyrogens. In vitro dissolution conducted on the product before and after gamma radiation sterilization at 2.5 Mrad indicated no significant difference in the drug release patterns. The drug release followed zero-order kinetics in both static and agitation conditions of dissolution testing. The in vivo studies conducted in rabbits exhibited LNG release up to 1 month duration with drug levels maintained within the effective therapeutic window.

Fig. 1

In vitro dissolution profiles of LNG–PLGA microspheres before and after gamma sterilization (n  = 6) in static dissolution conditions. Values indicate mean ± SD (for triplicate samples)

Fig. 2

In vitro dissolution profiles of LNG–PLGA microspheres before and after gamma sterilization (n  = 6) in agitation dissolution conditions. Values indicate mean ± SD (for triplicate samples)

Fig. 3

Scanning electron photomicrograph of LNG–PLGA microspheres. There are no free drug crystals on the microsphere surface

Fig. 4

Differential scanning calorimetry. A levonorgestrel, B PLGA, C physical mixture of LNG and PLGA, D LNG–PLGA microparticles

Fig. 5

Plasma concentration–time profile LNG release from the microparticle system after intramuscular injection in female rabbits (n  = 6). Values indicate mean ± SD (value for triplicate samples)