Release kinetics of 3-keto-desogestrel from contraceptive implants (Implanon) in dogs: comparison with in vitro data.

Ethylene-vinyl acetate (EVA) polymeric contraceptive implants (Implanon) containing 3-keto-desogestrel have been prepared aiming at an in vitro initial release rate of 60 micrograms 3-keto-desogestrel/day. These implants are designed to have an intended life-time of 2 years. During a 3-year period, the release of these implants was studied in 4 dogs after subdermal insertion, using plasma clearance of 3-keto-desogestrel assessed after intravenous administration of 3-keto-desogestrel and steady state plasma levels of 3-keto-desogestrel. The mean plasma level of 3-keto-desogestrel decreased gradually during the first year of the study, viz. from 1.64 nmol/1 at 7 days after implantation to 0.69 nmol/l after one year. At the end of the second year, the level had decreased further to 0.45 nmol/l while after 3 years, the mean 3-keto-desogestrel plasma level was 0.42 nmol/l. The calculated mean daily release of 3-keto-desogestrel decreased during the first year from 70 micrograms/day to 30 micrograms/day. During the second and third year, the decrease in release rate was much less, viz. going from 30 micrograms/day to 28 micrograms/day and from 28 micrograms/day to 25 micrograms/day, respectively. This indicates a much more constant release during the second and third year of the study. The calculated cumulative amount of 3-keto-desogestrel released from the implant during the dog study was 34.0 mg. Based on the initial amount of 3-keto-desogestrel in the implant of 68.3 mg, the remaining amount in the implants at termination of the study should be approximately 34.3 mg. Actually, the mean remaining amount of 3-keto-desogestrel was 33.8 mg, which is in very close agreement with the calculated value. Implants from the same batch as used in the in vivo study were also analyzed for the in vitro release at regular times during the 3-year study period. After one year, the in vitro release rate was about 43 micrograms/day whereas this release rate was 33 and 27 micrograms/day after 2 and 3 years, respectively. Although the in vitro set-up constantly gave a somewhat higher release in comparison with the in vivo release, it is apparent that the in vitro procedure is valuable for prediction of the in vivo release characteristics of the implant. There were no indications for 3-keto-desogestrel accumulation at the implantation site. No local irritations were seen and the animals had no discomfort at all.(ABSTRACT TRUNCATED AT 400 WORDS)

A single injection of a biodegradable microsphere formulation of the ACTH-(4-9) analogue ORG 2766 accelerates functional recovery after brain damage.

The functional recovery from impaired motor activity induced by 6-hydroxydopamine lesions in rat nucleus accumbens was accelerated by subcutaneous treatment with the ACTH-(4-9) analogue Met/O2/-Glu-His-Phe-D-Lys-Phe (ORG 2766). Treatment was effective after daily injections of ORG 2766 dissolved in saline during the first 6 days following the lesion (ED50: 28.5 ng kg-1 day-1) or after a single injection of the peptide in a biodegradable microsphere formulation administered after the lesion (ED50: 8.9 ng kg-1 day-1). This study shows that a single injection of a microsphere preparation can replace multiple injections with ORG 2766 in order to facilitate functional recovery after brain damage.

Biodegradable hollow fibres for the controlled release of drugs.

Biodegradable hollow fibres of poly-L-lactic acid (PLLA) filled with a suspension of the contraceptive hormone levonorgestrel in castor oil were implanted subcutaneously in rats to study the rate of drug release, rate of biodegradation and tissue reaction caused by the implant. The in vivo drug release was compared with the release in vitro using different release media. Fibres, disinfected with alcohol showed a zero-order release, both in vitro and in vivo, for over 6 months. Fibres, either gamma-sterilized or disinfected with alcohol were harvested at time intervals ranging from 1 d to 6 months after implantation. Molecular weights of PLLA, tensile strengths, and remaining amounts of drug were determined as a function of time. The tissue reaction can be described as a very moderate foreign body reaction with the initial presence of macrophages, which are gradually replaced by fibroblasts which form a collagen capsule. Molecular weight determinations of PLLA showed a decrease from an initial Mw of 1.59 X 10(5) to 5.5 X 10(4) in 4 months (after alcohol sterilization). A gradual decrease in fibre strength with time was observed which did not significantly impair the release rate of levonorgestrel.