TRANSDERMAL CONTRACEPTIVE DELIVERY SYSTEM - PRECLINICAL DEVELOPMENT AND CLINICAL-ASSESSMENT

An once-a-week transdermal (monophasic) contraceptive delivery system (TCDS), intended to be marketed in Asian countries, was developed at t he Controlled Drug-Delivery Research Center, Rutgers, College of Pharm acy under the sponsorship of Sintong Chemical Industrial Co. Ltd. in T aiwan, This TCDS was designed to simultaneously deliver a low dose com bination of levonorgestrel (LNG) and 17 beta-estradiol (E2) through th e skin for the fertility regulation in female. In-vitro permeation stu dy using human cadaver skin shows that 60.0 +/- 9.42 mcg/day/10 cm(2) of LNG and 28.8 +/- 4.96 mcg/day/10 cm(2) of E2 can be delivered from this system. The result of the one-week dermal toxicity study on 6 rab bits indicated the minimal potential of this TCDS to cause skin irrita tion. Histopathological examination revealed that this system causes o nly mild to moderate inflammation to the test animal which also showed no significant body weight change and sign of toxicity. A phase I bio availability-dose proportionality clinical study which consists of pre -treatment, treatment and post-treatment cycles was conducted on Ferti le Chinese women. During the pre-treatment cycle, the 48 recruited sub jects were given placebo patches to study the wearability (including s kin irritation and adhesion tests). During the treatment cycle, each o f the 8 subjects in Groups A, B and C received weekly application of 1 , 2 or 3 pieces of 10 cm(2) TCDS patches, respectively, while each sub ject in Group D received one Chinese-made oral contraceptive pill (eac h pill contains 150 mcg of LNG and 35 mcg of ethynyl estradiol) per da y as reference. The TCDS patches were found to be very well accepted b y the subjects as indicated by the results of the wearability study (P DII is less than 1.0 and mean survival rate of the patches = 99.5%). R esidual assay of the used patches indicated that this TCDS has deliver ed LNG and E2 at the rate of about 5.0 mcg/cm(2).day and 4.0 mcg/cm(2) .day, respectively, during the treatment cycle of the study. Radioimmu noassay 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 majo rity of the all 3 groups of subjects receiving TCDS patches. The post- treatment hormonal profiles also indicated that upon the termination o f the administration of TCDS patches, the majority of the subjects ret urn to their normal state of menstrual cycle. It was also reported tha t none of the subjects participated in this phase I study became pregn ant. 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 cycle s 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.