ABSTRACT
Scientific disciplines not normally associated with pharmaceutical development have been employed to enhance the effectiveness and attractiveness of two approaches to steroidal contraception. The use of a bioerodible polymeric carrier for predictable systemic steroidal administration has removed the largest hurdle to the development of a subcutaneous contraceptive implant. A polymeric progesterone delivery system has provided a method for localizing hormonal contraception in the uterine cavity. Extensions of these technologies may provide two useful tools in limiting fertility in an already overcrowded world.
Subject(s)
Contraception/methods , Contraceptive Devices, Female/methods , Progesterone Congeners/pharmacology , Progesterone/pharmacology , Biocompatible Materials , Drug Implants , Female , Humans , Intrauterine DevicesABSTRACT
The object of this program is to prepare a bioerodable naltrexone delivery system which can be implanted subcutaneously in humans and which can relieve the narcotic antagonist over 1-6 months at relatively constant and sufficient rates to block the euphoric effect of morphine based drugs. The system is composed of naltrexone uniformly dispered in a solid hydropholic CHRONOMER TM matrix which undergoes predictable surface erosion when exposed to an aqueous medium. Kinetic studies in vitro have been carried out during the course of the program to determine the best composition for the system. Toxilogical studies conducted at ALZA during the past 2 years have not revealed limiting adverse effects of either the CHRONOMER TM materials or their hydrolysis products. The tail-flick test procedure was used to measure the effectiveness of naltrexone to antagonize the analgesis of morphine in rats. Naltrexone infused intravenously at doses of 4 and 16 ug/kg/hr resulted in, after 6 hours, 54 and 89% antagonism, respectively, against a 63.5% effective dose of morphine. Perliminary sterilization studies showed that no adverse effects to CHRONOMER TM/naltrexone systems occurred after exposure to 2.5 or 5.0 mrads of 60CO irradiation.
Subject(s)
Drug Implants , Narcotic Antagonists/administration & dosage , Polymers , Animals , Biodegradation, Environmental , Injections, Subcutaneous , Kinetics , Mice , Morphine/antagonists & inhibitors , Naltrexone/administration & dosage , Naltrexone/metabolism , Naltrexone/pharmacology , Rats , Reaction Time/drug effectsABSTRACT
We compared the patterns of pilocarpine distribution in the rabbit eye during two regimens that were comparably efficacious in human clinical use: an administration of 2% pilocarpine nitrate eyedrops, every six hours, for four and eight days, and a continuous delivery of pilocarpine for as long as eight days, at 20 mug/hr, from a membrane-controlled delivery system in the inferior cul-de-sac. Pilocarpine labeled with radioactive carbon (14C) was used as a tracer. With administration of eyedrops, 14C levels in ocular tissues rose and fell within each six-hour interval between eyedrops, but with the delivery system, 14C levels remained constant over the two- to eight-day period. In each tissue, the 14C level within the first hour after the most recently administered eyedrop always exceeded the constant level maintained by the delivery system. Three to six hours after eyedrop administration, the 14C levels in cornea, iris, and sclera were approximately equal to those maintained by the delivery system. However, in lens, vitreous humor, and conjunctiva, the 14C levels were always two to five times higher with eyedrop administration than with the delivery system. Only aqueous humor showed a significantly lower 14C level with eyedrops than with the delivery system, occurring late in the interval between eyedrops. Compared to eyedrop administration, the membrane-controlled delivery system produced drug levels in ocular tissues that were constant rather than variable with time, and appreciably lower in tissues where the drug made no known contribution to the reduction of pressure.
Subject(s)
Eye/metabolism , Pilocarpine/administration & dosage , Administration, Topical , Animals , Aqueous Humor/analysis , Carbon Radioisotopes , Conjunctiva/metabolism , Cornea/metabolism , Drug Implants , Iris/metabolism , Lens, Crystalline/metabolism , Ophthalmic Solutions , Pilocarpine/metabolism , Rabbits , Sclera/metabolism , Time Factors , Vitreous Body/metabolismABSTRACT
The object of this program is to prepare a bioerodable naltrexone delivery system which can be implanted subcataneously in human and which can relieve the narcotic antagonist over 1-6 months at relatively constant and sufficient rates to block the euphoric effect of morphine based drugs. The system is composed of naltrexone uniformly dispersed in a solid hydropholic CHRONOMER matrix which undergoes predictable surface erosion when exposed to an aqueous medium. Kinetic studies in vitro have been carried out during the course of the program to determine the best composition for the system. Toxilogical studies conducted at ALZA during the past 2 years have not revealed limiting adverse effects of either the CHRONOMER materials or their hydrolysis products. The tail-flick test procedure was used to measure the effectiveness of naltrexone to antagonize the analgesis of morphine in rats. Naltrexone infused intravenously at doses of 4 and 16 ug/kg/hr resulted in, after 6 hours, 54 and 89 per cent antagonism, respectively, against a 63.5 per cent effective dose of morphine. Preliminary sterilization studies showed that no adverse effects to CHRONOMER/naltrexone systems occurred after exposure to 2.5 or 5.0 mrads of 60Co irradiation.
