Studies On Harmine Hydrochloride Bioadhesive Sustained-release Suppository

Objective:Harmine(HM), an effective alkaloid ingredient in nature product, was extracted from Preganum harmala seeds which was used by Uygur and Mongolian as a traditional medicine from very early time.In order to reduce its ADR and enlarge its way of clincal using,so harmine hydrochloride bioadhesive sustained release suppository (HM-BASRS) was prepared in this paper, and a series of experiments of HM-BASRS have been done in the preparation ,properties, drug release character in vitro, characteristics of pharmacokinetics as well as rectal membrane permeability of HM and so on.Methods:In studies on rectal membrane permeability of HM,two methods were improved for this study. We used Magnus'both method to study the rectal membrane permeability effect of different animal rectal membrane, different drug concentration and different solution pH, etc. In studies on preparation technology of HM-BASRS, the pharmaceutical investigation was performed using odd factor design method,including the effect of different PEG and prescription component, etc. Finally, the optimum formulation of HM-BASRS was achieved by employing even design. In the studies on the properties of the HM-BASRS in vitro release, we used rotation basket to study the characteristics of drug release. The influence of the release mediums, their pH, rotation rate and semipermea ble membrane were investigate respectively. In the studies on the adhesive characteristics of the HM-BASRS.,methylene blue instead of HM was included in the suppository to visualize the distribution invivo,we have selected this dye as a marker of distribution because of its hydrophilic nature and poor membrane permeability, the result in vitro was coincidenced with the former. In the studies on rectal irritation of HM-BASRS, the rabbits were anesthetized and decapitated at 12 hr after the administration of suppository and blank excipient, respectively, the rectum was isolated and stained with hematoxylin-eosin (HE), the mucosal irritation was evaluated macroscopically. In the experimental studies on the process of HM-BASRS in vivo, we used HPLC and 3p87, the pharmacokinetics between HM-BASRS and HM capsule in rabbits were compared. The correlation test had been done between accumulate release percent and absorption coefficient in vivo.Results: The results of study on rectal membrane permeability of HM were that transport ways of HM is passive diffision and membrance transport route of HM is transcellular pathway,the results is the basis of preparation HM-BASRS. The pharmaceutical study of HM-BASRS showed light yellow color, apperence with a rough surface, It fit requirement of Ch.P. about suppository in melting time limit and error of weight ,t30 is 2.1 hr. The results of release test showed that drug release speed was much faster in water than in other release mediums. The release rate showed distinctive difference when the pH of BPS increased, rotation rate had no effect on the drug release, and the release profile in vitro could be described by Ritger-pepppas equation, LnQ=1.066Lnt-2.568 (r=0.926). The results of the studies on the adhesive characteristics were that adhesive suppository was found to prevent the upward spread of the dye in the rectum, indicating that the absorption site for HM-BASRS could be limited at the lower part of the rectum. The results of irritating test indicated that the blank was less irritating to the rectal mucosa, but HM-BASRS caused partial degeneration and desquamation in the mucous epithelium and slight cellular infiltration in the lamina propia.The results of pharmacokinetics test indicated that the plasma concentration-timecurves for both HM-BASRS and capsule fit two compartments open model. The AUC is 5.03 ((μ g/ml) h), and the mean residence time (MRT) is 29.59 (h).Meanwhile, there were lower drug plasma concentration after administrated suppository to the rabbits.The results of correlation of accumulate drug release (Q%) in vitro and the obsorption fraction (Fa%) in vivo showed significant line correlation, F=0.5082Q+24.7289 (r=0.9032). P<0.001...