Long-term controlled delivery of levonorgestrel in rats by means of small biodegradable cylinders

Abstract

Hormone release rates from biodegradable cylindrical implants consisting of a physical matrix of [¹⁴ C]levonorgestrel and copolymers of [³ H]lactic and glycolic acids have been monitored in rats. Two copolymers were evaluated: one consisted of 90 parts L-lactide/10 parts glycolide (90L/10G) containing 33 or 50% hormone by weight, and the other of 50 parts DL-lactide/50 parts L-lactide (50DL/50L) containing 50% hormone. For each system, 4–6 rods (0·8 times 16 mm) providing 19 mg of steroid per rat were subcutaneously implanted into the scapular regions of 5 rats, and ¹⁴ C and ³ H in faeces and urine were determined weekly for 90–724 days. An initial burst of hormone release, peaking at approximately 90 μg day⁻¹, occurred in the first two weeks. This was followed by an approximately zeroorder release for ¹⁴ C from all systems. Longer-term release rates were approximately 10–30 μg day⁻¹ for the 90L/10G system containing 33% hormone, a more uniform rate of approximately 25 μg day⁻¹ for the 50DL/50L system and the highest rate of approximately 40 μg day⁻¹ for the 90L/10G system containing 50% hormone. ³ H and ¹⁴ C in residual implants of 90L/10G with 33% hormone removed from animals dying of natural causes during the test were assayed. For this system ³ H activity decreased by over 50% within 250 days, compared with < 25 % loss in ¹⁴ C activity. The amounts of ³ H and ¹⁴ C released were similar over much of the subsequent test period. At the end of the test both polymer and drug were essentially depleted. All animals with the 50DL/50L system died late in the test period. Between days 609 and 724 from 13·7-27·2% initial ¹⁴ C and from 10·0-22·1 % initial ³ H was measured in recovered rods. Microscopic inspection of recovered rods showed a loss of core material and tissue encapsulation. There were no signs of local tissue irritation or systemic toxicity.