Yasutaka Igari

One-month release injectable microspheres of leuprolide acetate inhibit steroidogenesis and genital organ growth in rats

Abstract We have prepared one-month release injectable microspheres of leuprolide acetate, a highly potent analog of luteinizing hormone-releasing hormone (LH-RH), to treat endocrine-dependent tumors and endometriosis. The drug was encapsulated with a biocompatible and biodegradable polymer, copoly( dl -lactic/glycolic acid) (PLGA), by a novel in-water drying method through a (w/o)/w emulsion. The effects of this sustained-release preparation on maintaining the serum levels of the analog, on serum testosterone, and on the growth of the genital organs were evaluated in rats of different strains (Sprague-Dawley (SD) and Wistar) and ages (6 and 10 weeks). The results were compared with those obtained by constant infusion or daily pulsatile injections of the analog solution. A single injection of the PLGA microspheres sustained effective serum levels of the analog for at least 4 weeks, and persistently inhibited serum testosterone and growth of the genital organs (testis, seminal vesicle, and prostate) over 6 weeks in both strains at both ages. These antagonistic activities were almost identical to those observed after constant infusion of the analog solution, and equal or superior to those after pulsatile daily injections. A single injection of these sustained release injectable microspheres satisfactorily inhibits steroidogenesis and consequently suppresses genital organ growth; its use may eliminate the inconvenience of daily subcutaneous injections, and elevate compliance and efficacy in patients with prostatic cancer.

Heat-specific drug release of large unilamellar vesicle as hyperthermia-mediated targeting delivery

Abstract The heat-specific 6-CF or CDDP release characteristics and liposomal properties of thermosensitive LUVs which were prepared with DPPC and DSPC have been demonstrated in comparison to a thermosensitive SUV. The entrapped amount of 6-CF or CDDP per lipid in the LUV was about 6 times as high as that in the SUV. The LUV was stable in long-term storage (more than 97% latency at room temperature after 6 months). Unlike the LUV, the SUV was unstable. The LUV showed very sharp release-rate increase between 40° C and 41° C. The amount released at 42° C was about 80%. The release occurred explosively in a short time (a few seconds). Unlike the LUV, the SUV showed only a small release rate increase. The optimum lipid composition of the LUV for HT-mediated drug release was found to be DPPC/DSPC = 9 1 (w/w). Heat-specific drug release from the LUV and the drug permeability of the LUV at the phase transition temperature depended on the ratio of the osmotic pressure of the internal aqueous fluid to the osmotic pressure of the liposomal suspension fluid (release test media). These results indicate that the LUV is more favourable than the SUV for thermosensitive delivery with respect to arug encapsulation capacity, liposome stability and drug release and that the osmotic pressure of the internal aqueous space should be 1.5 or more times as high as the physiological osmotic pressure for heat-specific drug release.

In vitro release test system of (d,l-lactic-glycolic) acid copolymer microcapsules for sustained release of LHRH agonist (leuprorelin)

Release of leuprorelin, an LHRH agonist, from injectable microcapsules and degradation of its biodegradable polymer [(d,l-lactic-glycolic) acid copolymer: PLGA] matrix were investigated to optimize an in vitro release test system and to clarify the difference between the in vivo release and in vitro release test system. Many factors such as pH, salt concentration and osmolarity of dispersion medium changed drug release. Weight loss along with the decrease of the molecular weight of PLGA was delayed in the in vitro release test system that successfully predicted in vivo drug release. Most remarkable difference in the change of the molecular weight of PLGA was shown by accumulation of degraded products of PLGA in in vivo, although the ratio of lactic acid to glycolic acid in the polymer as another indicator of the degradation increased similarly as a function of the PLGA weight loss in both systems. Judging from the fact that resembling drug release was acquired despite the different degradation rate of matrix, distinctive mechanism governs the drug release in the in vitro release test system.