Norethisterone (NET) in combination with mestranol (ME), in a macrocrystalline aqueous suspension that provides sustained release of steroids, was assessed as a once-a-month injectable contraceptive in ten healthy women of reproductive age. The ovarian function was studied before and after the intramuscular administration of 12mg NET plus 1.2mg ME, delivered as crystals of 150 micron average size. Serial blood samples were taken throughout the injection intervals in all women to measure serum progesterone (P), estradiol (E2), and NET. The NET/ME preparation effectively inhibited ovulation in 23 out of the 25 injection intervals studied. The administration of this formulation induced in some women a small degree of follicular maturation not followed by luteal activity. The endometrial bleeding patterns after each injection showed a bleeding-free period of two to three weeks. The overall data demonstrate that the parenteral administration of a macrocrystalline steroid preparation of NET/ME can bring about a sustained release contraceptive system at a substantially lower dose than those currently employed in once-a-month injectable contraception.

A drug delivery system which provides a sustained release of norethindrone (NET) and mestranol (ME) for one month after a single intramuscular injection was assessed as a long-acting injectable contraceptive. The system is based upon well defined particle size crystals of the synthetic steroids maintained in suspension with saline solution. Eight healthy ovulating women volunteered for the study; they received a combination of 10 mg of NET plus 1 mg of ME in 1 ml of vehicle by intramuscular injection on day five of their menstrual cycle. Blood samples were drawn at 0, 1, 5, 10, 13, 17 and 21 days after drug administration. The immunoreactive serum levels of estradiol, progesterone, NET and ethinylestradiol were measured by specific radioimmunoassay procedures to assess ovarian function and the kinetic parameters of the synthetic steroids. This newly developed contraceptive system proved to be both effective, and long-lasting as well as devoid of side effects.

A low-dose combined estrogen-progestogen sustained release system has been developed. The control of crystal size of the steroids produced sustained dissolution in vitro and in vivo. A dose-response experiment carried out in healthy women indicated that 10 mg of norethisterone (NET) with 1 mg of ethinylestradiol (EE2) when given by intramsucular injection mantained NET serum levels above 1 ng/ml for at least 25 days. The system is considered suitable for one month contraceptive protection.