Formulation and Performance Characterization of Radio-Sterilized “Progestin-Only” Microparticles Intended for Contraception

Abstract

Abstract. The aim of this study was to formulate and characterize a microparticulate system of progestinonly 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.

Biodegradable insulin-loaded PLGA microspheres fabricated by three different emulsification techniques: Investigation for cartilage tissue engineering

“…We have no data for the residual solvent content in this study, but for similarly sized PLGA microspheres (14.1 lm diameter) prepared as a w/o/w formulation by solvent evaporation a residual methylene chloride content of 14.4 ppm was found for the dried microspheres [36]. Other groups have also determined a residual methylene chloride content in PLGA microspheres prepared by emulsification and solvent evaporation well below the regulatory limit [37][38][39]. As the HFIP concentration used was in the ratio 1:200 relative to that of methylene chloride, the amount of residual HFIP should be even lower, and, furthermore, HFIP is miscible with the external aqueous phase.…”

“…They also showed that insulin has a minimal reactivity under acidic conditions, as occur during PLGA degradation in the interior of the microsphere and in the release medium [55]. To counteract acid-induced denaturation of insulin a basic excipient such as sodium bicarbonate can be co-encapsulated in the PLGA microspheres [39].…”

Towards the development of a longer-acting injectable contraceptive: past research and current trends

“…In contraceptive research, PLG, PLA and PLGA have shown promise for the controlled release of LNG both in vitro and in vivo [26][27][28][29][30][31]. Additionally, PLGA microspheres have been evaluated in vivo for delivery of Nestorone, a potent contraceptive progestin being developed by the Population Council in a variety of formulations.…”

Biodegradable Polymeric Biomaterials in Different Forms for Long-acting Contraception and Drug Delivery to the Eye and Brain

“…Drug microcrystals have advantages of low cost due to fewer process steps and materials involved, and using water as an administration vehicle, but needs reconstitution and are difficult to achieve sustained release of APIs for more than three months. Microspheres have the advantages of using water as a vehicle, and capability of achieving more than the three-month release of APIs due to the retarding effect of the polymeric matrix [99][100][101][102][103][104][105][106][107][108][109]. However, more often the microencapsulation processes involve the use of high temperature and organic solvents which may affect the stability of the therapeutics, and some toxic organic solvents might be trapped inside.…”

“…In rat studies, LNG-or LNG and ethinylestradiol-loaded PLGA and PCL microspheres were found to maintain constant LNG blood level at 0.2-2 ng/mL for 15 weeks to 5 months [100,101,143]. In rabbit studies, it was found that progesterone was maintained a blood level of 1-2 ng/mL for about 5 months [159], 5 months [160] and 20 days [161] by microspheres made of chitosan, casein and serum albumin, respectively [159,160]; and LNG was maintained a blood level of 0.1-0.5 ng/mL for 28 days by microspheres made of casein [104]. In mouse study, LNG-or LNG and estradiol-loaded poly(ethylene glycol-b-poly(D,L-lactide)) [162], gelatin [163] or poly(3-hydroxy butyrate) [164] microspheres showed 6 month, 50 day, and 1-3 month contraceptive effect, respectively.…”