| Benign prostatic hyperplasia (BPH), which is a common and frequent disease to the elderly and wrinkly people, belongs to "uroschesis" and "retention of sperm" category in TCM. According to the clinical investigation, more than 50% of males(aged above 50) are suffering from the disease. With the increase of aging population, its incidence is also getting higher and higher, seriously affecting life quality of the elderly.Then the prevention and treatment is urgen.According to etiology and pathogenesis of BPH, anatomical characteristics of prostate, pathological characteristics of congestion and dialectic in TCM, we selected Catharsius molossus Linnaeus, which has good clinical efficacy and satisfactory effect for blood circulation, as a model drug. We not only investigated material base and action mechanism, but also developed new drug delivery systems adopting new technologies new craft and new standards. Therefore, this reseach will provide effective,high quality and multiple drug selection for clinic.1. Studies of material baseUsing methods,such as systematic solvent extraction,combined acute toxicity test and pharmacodynamic screening tests (benign prostatic hyperplasia model of mouse induced by testosterone and the tensity test of dog's bladder deltoid muscle), chromatographic method, as well as dialysis technique, we traced and separated active ingredient of Catharsius molossus Linnaeus.The results indicated that material base were mainly polypeptide and amino acid. Morover, Beside that, we initially clarified that the action mechanism of Catharsius molossus Linnaeus for BPH treatment, which could inhibit a receptor.2. Preparation and quality control of intermediateCombining determination with physical and chemical parameters, we prepared effective fraction of Catharsius molossus Linnaeus by percolation. When it comes to purified effect for extract, macroporous resin was superior to foam separation. we determined the molecular weight of polypeptide by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). By means of high performance capillary electrophoresis (HPCE), we conducted the fingerprint research. Finally, we determined the type and quantity of amino acids by automatic amino acid analyzer.All of those could control quality of intermediate comprehensively and effectively.3. Studies of new drug delivery systemWith the clear material base of drug efficacy, we studied two new drug delivery systems for stable and controllable intermediate. One is colon drug delivery system(OCDDS), the effective fraction was made into tablet. Then according to the pH changes in digestive tract, we choosed the pH-sensitive polymer Eudragit S100 for preparation of colon-released tablet. And released tests of amino acids and polypeptide in vitro showed that the tablet reached purpose of colon specific delivery. Taking total amino acid content as index, we discussed the release law of the preparation by spectrophotometric method. The result demonstrated that it was in accordance with Weibull model. The other one was bioadhesive drug delivery system (BDDS). We selected bioadhesive polymers, screened prescription by indices of rheology characteristic, bioadhesive character and release rate in vitro, and choosed suitable prescription and parameters of craft. The systematic evaluation showed that the preparation was pseudoplastic fluid and its rheological behavior was correspondent with Ostwald model. The adhesive mechanism was supposed to be that the molecular chain of HPMC, tangled with mucus of tissue surface when it met water, and non-ionized hydroxy linked up with mucin through hydrogen bonds. The stability of preparation was good under highlight, high temperature and low temperature condition.We also did acute and multiple dosing stimulation test of the bioadhesive gel to rats. It was observed there was no hyperemia, edema and degeneration by naked eyes and light microscope, which indicated the preparation were safe and non-irritative.With improved Franz diffusion cell, we investigated release law, which was in accordance with Weibull model. Adopting spontaneous BPH model of old dogs, the pharmacodynamics comparison of two drug delivery system was studied. The result demonstrated that they all could inhibit prostatic hyperplasia and they had significant effect.The study identified the material base of Catharsius molossus Linnaeus for treatment of BPH, clarified action mechanism initially, completed research of two new drug delivery system, proposed the quality control model which associated physico-chemical parameters with determination of component. Finally, we expected to provide a safe, effective, stable and controllable preparation of TCM for clinical treatment of BPH. |
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