Structure And Biological Effect Of A New Sustain Release Analgesic Delivery System

Objectives:1. To present the preparation of two slow release analgesic systems using Chitosan as carrier with morhphine and butorphanol tartarate as active drugs.2. To evaluate the biocompatibility of these two analgesic delivery systems.3. To evaluate the pharmacological effects of these two analgesic delivery systems.Methods:1. Using emulsion crosslinking chitosan microspheres were prepared and chitosan-morphine microspheres (MM) were constructed with morphine as the analgesic drug and chitosan as the carrier. Then the characteristics of these MM were studied in vitro.2. Using spray-dry method alginate micropsheres and chitosan microspheres were prpared and alginate-butorphanol tartarate micospheres were constructed with alginate as the drug carrier. By self-assembly scaffold a drug delivery system with butorphanol-alginate microsphere-chitosan microspere (BM) is formed and the characteristic of this system is studied in vitro.3. Uisng mouse embryonic fibroblast toxicity test, mouse micronucleus test, rat muscle implantation test, rabbit blood hemolysis test and mice acute systemic reaction test, biocompatibilty of these two drug delivery systems (BM, MM) were studied.4. With nasal drug administration in rabbit, epidural drug administration in guinea pig, subcutaneous drug administration in rat, the pharmacodynamic effect of BM and MM were evaluated with rat tail flick test and rabbit nose thermal pain test.Results:1. The two drug delivery systems so prepared showed good microsphere formation and good drug releasing effect in vitro.2. Both analgesic drug delivery systems showed good biocompatibility and no toxicity with cell toxicity grading from 0 to 1. The micronucleus test was negative and no teratogenic toxicity shown.. Hemolysis rate was less than 5%. Acute systemic reaction test was negative with steady weight gain and no mortality in mice. Muscle implantation test showed no local tissue necrosis, skin ulceration or infection and wound healing was normal. Pathological examination showed some local foreign body reaction which decreased over time with complete subsidence in 6-8 weeks and was actually less severe when compared to local reaction to implanted surgical silk suture.. There was no abnormalities in hepatic, renal or hemopoietic function observed. 3. The analgesic effect of subcutaneously implanted BM and MM showed statistically significant difference (p<0.05) over the subcutaneous administration of normal saline, or the corresponding active drugs (butorphanol or morphine injectable) with BM and MM producing much longer analgesic effects (p<0.05). When administered nasally in rabbits BM showed signficantly prolonged analgesic effect than injectable butorphanol (p<0.05). When administered epidurally in rats MM showed significantly longer analgesic effect than injectable morphine (p<0.05).Conclusion:1.Chitosan can be used as an effective carrier in analgesic drug delivery system.2. Chitosan show good biocompatibility as carrier in analgesic drug delivery system.3. Morphine-Chitosan microsphere drug delivery system can be used for epidural analgesia in rats with prolonged analgesic activity.4. Butorphanol tartarate-alginate microsphere-chitosan microsphere complex can be used for nasal administration in rabbit with signficantly longer duration of analgesia than injectable butorphanol.5. When subcautaneously implanted, morphine-chitosan microspheres produce prolonged analgesia than injectable morphine.6. When implanted subcutaneously butorphanol microsphere preparation provides a much longer analgesic effect than injectable butorphanol tartarate.