Transdermal Contraceptive Delivery System: Preclinical Development and Clinical Assessment

Abstract

An once-a-week transdermal (monophasic) contraceptive delivery system (TCDS), intended to be marketed in Asian countries, was developed at the Controlled Drug-Delivery Research Center, Rutgers, College of Pharmacy under the sponsorship of Sintong Chemical Industrial Co. Ltd. in Taiwan. This TCDS was designed to simultaneously deliver a low dose combination of levonorgestrel (LNG) and 17B-estradiol (E2) through the skin for the fertility regulation in female. In-vitro permeation study using human cadaver skin shows that 60.0 ± 9.42 mcg/day/10 cm² of LNG and 28.8 ± 4.96 mcg/day/10 cm² of E2 can be delivered from this system. The result of the one-week dermal toxicity study on 6 rabbits indicated the minimal potential of this TCDS to cause skin irritation. Histopathological examination revealed that this system causes only mild to moderate inflammation to the test animal which also showed no significant body weight change and sign of toxicity.

A phase I bioavailability-dose proportionality clinical study which consists of pre-treatment, treatment and post-treatment cycles was conducted on Fertile Chinese women. During the pre-treatment cycle, the 48 recruited subjects were given placebo patches to study the wearability (including skin irritation and adhesion tests). During the treatment cycle, each of the 8 subjects in Groups A, B and C received weekly application of 1, 2 or 3 pieces of 10 cm² TCDS patches, respectively, while each subject in Group D received one Chinese-made oral contraceptive pill (each pill contains 150 mcg of LNG and 35 mcg of ethynyl estradiol) per day as reference.

The TCDS patches were found to be very well accepted by the subjects as indicated by the results of the wearability study (PDII is less than 1.0 and mean survival rate of the patches = 99.5%). Residual assay of the used patches indicated that this TCDS has delivered LNG and E2 at the rate of about 5.0 mcg/cm².day and 4.0 mcg/cm². day, respectively, during the treatment cycle of the study. Radioimmunoassay of serum samples revealed that therapeutically effective serum concentration of LNG was achieved. Serum profiles of progesterone, LH and FSH also indicated that ovulation inhibition occurred in the majority of the all 3 groups of subjects receiving TCDS patches. The post-treatment hormonal profiles also indicated that upon the termination of the administration of TCDS patches, the majority of the subjects return to their normal state of menstrual cycle. It was also reported that none of the subjects participated in this phase I study became pregnant.

Due to the success of this phase I study, a pilot phase II study has been initiated which involves more than 100 study subjects. Up to the first week of September, 1993, 112 subjects have completed 3 cycles of study with a total of 342 woman-month. During this pilot phase II study, the participated subjects were found to be sexually active and none of the subject has been reported to become pregnant so far.