Controlled release of contraceptive steroids from biodegradable and injectable gel formulations: in vivo evaluation.
OBJECTIVE
The purpose of this study was to investigate in vivo biocompatibility, biodegradability and biological effects of contraceptive steroids, such as levonorgestrel and ethinyl estradiol, released from gels prepared with a combination of derivatized vegetable oil (Labrafil 1944 CS) and glyceryl ester of fatty acids (Precirol ATO 5).


METHODS
Biocompatibility, biodegradability, and in vivo effects of levonorgestrel and ethinyl estradiol were studied by histologic evaluation of rat tissue, visual estimate of changes in gel size, and assessment of drug effects on reproductive cyclicity of female rats, respectively, following subcutaneous injection of gel formulations.


RESULTS
Histological evaluation of the tissue samples following an injection of the gel revealed an inflammatory reaction for about 7 days, after which the tissues did not show any inflammatory response. Complete degradation of the gels containing 10% wax was observed between 5 and 6 weeks. Normal rat estrous cycles were completely blocked by the contraceptive steroids released from the gels. Gel formulations containing 0.25% w/w levonorgestrel were more effective in blocking the estrous cycle of female rats compared to the oil formulations containing an identical drug loading. The duration of the biological effect induced by levonorgestrel appears to be dose-related. The gel formulation containing 2.00% ethinyl estradiol was superior to oil formulation containing an identical drug loading in terms of controlling drug release and toxicity.


CONCLUSIONS
These observations suggest that Labrafil-Precirol gels are biocompatible and biodegradable. Moreover, controlled release of steroids is possible in vivo for a prolonged period of time.
Gao
Z H
ZH
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee, Memphis 38163, USA.
Crowley
W R
WR
Shukla
A J
AJ
Johnson
J R
JR
Reger
J F
JF
D000818:Animals; D002626:Chemistry, Pharmaceutical; D003270:Contraceptive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D005260:Female; D005782:Gels; D007279:Injections, Subcutaneous; D016912:Levonorgestrel / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D003270:Contraceptive Agents; D003692:Delayed-Action Preparations; D005782:Gels; D016912:Levonorgestrel