Yayoi Inoue

Drug delivery using biodegradable microspheres

Abstract Rational delivery systems for leuprorelin acetate, a potent LHRH agonist, have been achieved by developing a microsphere system using biodegradable polymers, poly(lactic/glycolic acid) (PLGA) and polylactic acid, which sustainedly release the drug depending on the biodegradation of polymer used and persistently suppress steroidogenesis for over one and 3 months, respectively, following a single injection. To produce these systems we established a novel microencapsulation technique, the in-water drying method, and microspheres with a high trap ratio and small initial burst were obtained. A microsphere system of TRH prepared using PLGA could also continuously release the drug for 2 or 4 weeks. Using these systems effectively reduced the required dose compared with that needed with daily injection due to more continuous receptor hits on the target organs and could improve patient compliance. Chemoembolization using PLGA microspheres containing an angiogenesis inhibitor, TNP-470, resulted in dramatic regression of VX-2 carcinoma in rabbits. The microsphere system using biod-egradable polymers is very useful in designing controlled release delivery and targeted delivery to attain potent and rational therapy.

Pharmacokinetics of once-a-month injectable microspheres of leuprolide acetate.

The pharmacokinetic parameters of leuprolide acetate, a potent analogue of LH-RH, were determined in rats and dogs after i.v. and s.c. dosing with leuprolide solution. The effective human dose of once-a-month injectable microspheres of leuprolide was estimated to be about 3.2 to 8.1 mg analogue/month using these parameters. After microsphere injection at three different doses in rat serum leuprolide concentrations were sustained for over 4 weeks, and the AUCs and mean serum levels were linearly correlated with the dose. The serum levels and urinary excretion of the analogue in rats after repeated s.c. injection of the microspheres every 4 weeks exhibited similar profiles after each injection; no changes of the absorption and excretion of the analogue after the repeated injection could be demonstrated. The serum levels of the analogue metabolite (M-I) were 21% of the intact form 3 hr after injection of the microspheres but very low at the steady state after 1 to 4 weeks.

New method for analysis of biodegradable polyesters by high-performance liquid chromatography after alkali hydrolysis

A new method was developed for analysis of biodegradable polyesters, which involves alkali hydrolysis of polyesters to the corresponding hydroxyacids and determination of the hydroxyacids by high-performance liquid chromatography. It can be used to monitor weight change in polyesters and change in molecular ratio of the hydroxyacid constituents of polyesters during in vitro and in vivo degradation.

Anticancer Effects of an Angiogenesis Inhibitor (TNP-470) After Arterial Injection in Rabbits Bearing VX-2 Carcinoma

TNP-470, an angiogenesis inhibitor, is a new type of anticancer drug that inhibits tumor neovascularization which is critical to tumor growth. Chemoembolization using TNP-470 microspheres prepared with a biodegradable polymer provided striking regression of the tumor, but growth was again observed 1 week after injection. TNP-470 dissolved in Lipiodol (a liquid lymphography agent) or MIGLYOL 812 (medium-chain triglycerides) caused persistent suppression of the tumor growth for 2 or 3 weeks after a single intraarterial injection due to sustained drug release from the preparation. Coadministration of TNP-470 and a conventional chemotherapeutic agent resulted in enhanced antitumor effects.