RESUMEN
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.
Asunto(s)
Mestranol/administración & dosificación , Noretindrona/administración & dosificación , Preparaciones de Acción Retardada , Evaluación de Medicamentos , Femenino , Hormonas Esteroides Gonadales/sangre , Humanos , Inyecciones Intramusculares , Cinética , Mestranol/sangre , Mestranol/farmacología , Noretindrona/sangre , Noretindrona/farmacología , Folículo Ovárico/efectos de los fármacos , Ovulación/efectos de los fármacosRESUMEN
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 intramuscular injection maintained NET serum levels above 1 ng/ml for at least 25 days. The system is considered suitable for one month contraceptive protection.
PIP: This study was aimed at assessing a new low dose combined estrogen-progestogen sustained release system in which the steroids were formulated as a microcrystalline aqueous suspension and injected throug a 19-gauge needle. The control of crystal size of norethisterone (NET) and ethinyl estradiol (EE2) produced sustained dissolution in both in vitro and in vivo studies. In vitro dissolution profiles revealed an inverse relationship between the percentage of NET and EE2 dissolved and size range of crystals, with complete dissolution of the miconized steroid achieved at 1 hour. A dose-response experiment carried out in healthy women indicated that intramuscular injection of 10 mg of NET with 1 mg of EE2 maintained NET serum levels above 1 ng/ml for at least 25 days. Systemic side effects such as nausea and vomiting were experienced by all 7 volunteers after the injection, suggesting that EE2 was rapidly absorbed. A less soluble system such as mestranol could be used instead of EE2 to improve the performance of the present system. There were no signs of local irritation. These findings indicate that the dosages of currently available injectable contraceptive compounds can be substantially reduced without loss of anovulatory potency. Clinical studies to assess the pharmacokinetics and pharmacodynamics of 10 mg of NET with 1 mg of EE2 or mestranol as monthly injectable are currently under way.