Tsugio Shimamoto

Controlled release of LHRH agonist, leuprolide acetate, from microcapsules: serum drug level profiles and pharmacological effects in animals

Abstract— The pharmacokinetic behaviour of leuprolide acetate from a controlled release parenteral dosage form has been studied in rats and dogs. The release of the drug in rats after a single subcutaneous injection exhibited pseudo‐zero‐order kinetics for one month in doses ranging from 0·0135 to 1·35 mg/rat; the release rate at a dose of 1·35 mg/rat was 2·8% of dose/day; after intramuscular injection the response was similar. In rats, the serum leuprolide acetate levels increased sharply immediately after injection by either route as a consequence of the initial release of the drug; subsequently, the levels attained a plateau for two weeks. The serum level profiles in dogs showed essentially the same pattern as those in rats. When the dosage form was injected into rats, the serum testosterone level (a pharmacological index) sharply peaked, abruptly decreased to below the normal level, and then was sustained at a suppressed level for over six weeks at a dose of 1·35 mg/rat (equivalent to 3 mg kg−1) and higher, while the serum testosterone level after an injection of 0·0135 and 0·135 mg/rat was not sufficiently suppressed. The profiles in dogs showed essentially the same pattern as those in rats. With multiple administrations (once every 4 weeks), serum testosterone levels in dogs did not show any sharp rise after the second and third injections. Changes in rat reproductive organ weights agreed well with the serum testosterone profile in the suppression. The results demonstrate that this dosage form releases the drug at a constant rate for one month and has a long‐acting potency.

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.

Estimation of drug absorption rates using a deconvolution method with nonequal sampling times

A method affording direct estimation of the drug absorption rate from blood level data using arbitrary time intervals has been derived based on the staircase input principle. In the derivation, the drug was assumed to follow linear kinetics where the plasma concentration of the drug after an impulse input is expressed by a multiexponential function. Drug absorption was assumed to occur at a constant rate during each subsequent sampling interval. The absorption rate profiles obtained by the method using several numerical examples were expressed as a set of rectangular pulses. Divergence in the profiles reflected blood sampling measurement errors rather than errors due to the deconvolution. Smoothing of the rate profiles by calculating the mean of the absorption rates between adjacent time intervals gave realistic results. Absorption rate profiles for theophylline obtained by the method using published data gave information on the initiation and termination of the absorption as well as the extent of absorption from the dosage form.

Sustained Pharmacological Activities in Rats Following Single and Repeated Administration of Once-a-Month Injectable Microspheres of Leuprolide Acetate

Once-a-month injectable microspheres of leuprolide acetate prepared with copoly(DL-lactic/glycolic acid) using an in-water drying method were assessed for duration of the analogue release and pharmacological effects in rats after a single or repeated injection. The periodic challenge test revealed that a single injection of the microspheres caused a dramatic and persistent suppression of the ability of the pituitary–gonadal system to secrete gonadotropin and testosterone for over 5 weeks. The complete recovery of these functions was observed 10 weeks after the injection. The repeated injection of the microspheres at intervals of 2 or 4 weeks achieved persistent suppression of steroidogenesis after an initial transient flare-up and beneficially avoided the “acute-on-chronic response.” This depot formulation is expected to assure patient compliance and produce stronger therapeutic effects than the daily solution.

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.