Preparation And Evaluation In Vivo And In Vitro Of Granisetron Hydrocloride Cataplasm

Granisetron hydrocloride (GRA) is a potent and highly selective 5-HT3 receptor antagonist of peripheral and centralnervous system. It is used clinically to prevent or treat nausea and vomiting induced by chemotherapy and radiotherapy. Its domestic injection and tablet had come into the market and been used in clinics in china already, but no report of transdermal delivery system (TDDS).Intravenous administration of GRA is not convenient because it needs special environment and will cause some injury to patients. Oral administration has fairly strong first-pass metabolism and makes operation and cancer patients difficult in taking medicine due to surgical operation or gastrointestinal dysfunction.Therefore, the developments of GRA transdermal delivery systems are necessary to allow well-controlled sustained release of the drug into the blood circulation and achieve a high bioavailability via bypassing gastrointestinal or hepatic first-pass metabolism. GRA cataplasm might be a convenient regimen to alleviate or prevent nausea and vomiting in patientsTDDS is a new system of administration, which has many advantages such as reducing the advers effects, increasing patient compliance, releasing the amount of drug at a constant rate and so on. Cataplasm is a kind of transdermal delivery system. It has not only all advantages of TDDS, but also its own superiority. Its hydrophilic material can be consistent with medicines very well and can be carried more medicines. It can make dermal keratose layer intenerated easily. It has good gas permeability and has no skin irritation and sensitization. In addition, as a result of no using organic solvent, there is no pollution in the process of production.The optimal prescription was selected to produce GRA cataplasm, then we evaluated it in vitro and researched its pharmacokinetics and pharmacodynamics.Part One Research on permeability of GRA in vitroA sensitive high-performance liquid chromatography (HPLC) assay was established to measure the content of GRA in vitro. The conditions as follows: Kromosil ODS C₁₈ colum(4.6mm×150mm,5μm), UV detective wavelength 302nm, Methanol-0.05mol·L^-1 sodium acetate buffer (pH4.6) contained 0.3% (v/v) triethylamine (45:55) was used as mobile phase at flow rate of l.Omlmin^-1.The permeation of GRA across excised rat skin was performed with various concerntration GRA solutions. The results indiated that permeability of GRA increased accompany concerntration increasing.To study the effect of eight different penetration enhancers on the permeation of GRA across skin with Valia-Chien diffusion cell in vitro. Excised SD-rat abdominal skin was pretreated with penetration enhancers. Compared with blank skin, all the enhancers showed significant enhancement effect on the permeability of GRA (p<0.05), and the azone was the best. Part Two Preparation of GRA cataplasmTo optimize the matrix formulation of GRA cataplasma by means of orthogonal design. To choose four important materials affecting the physical property of cataplasm as investigating factors, adhesive force and cohesive force of matrix of cataplasma as the quantitative index. The optimum proportion of partial neutralization sodium polyacrylate, calcium hydroxide, polyvinylpyrrolidone, glycerin is 1: 0.15: 4: 4. The penetration enhancement of azone in cataplasm with various proportions was evaluated. Then the optimal prescription was selected to produce GRA cataplasm, which was of moderate viscosity with good spreadable and humectant properties. Part Three Evaluation in vitro of GRA cataplasmIn this part, we established a rapid and sensitive high-performance liquid chromatography (HPLC) assay to measure the content of GRA in the GRA cataplasm, the release and permeation in vitro.The release pattern of GRA cataplasm followed Higuchi equation. Thepermeation tests through rat skin in vitro demonstrated that the GRA cataplasm exhibited zero-order kinetics. The accelerated test showed that the stability of GRA cataplasm was iea, the drug content and the weight difference of the GRA cataplasm accorded with Pharmacopoeia of the People's Republic of China of 2005 edition. The study on the human skin irriation and allergia of GRA cataplasm were conducted, it was shown that GRA cataplasm had no irriation and allergia. Part Four Research on the pharmacodynamics of GRA cataplasmThe antiemetic effects of GRA cataplasm were assessed via the inhibitory activity on the anticancer agent (cisplatin)-induced kaolin-consuming behavior, a pica model representing vomiting in emesis-resistant rodents, in comparison with the effect of granisetron intraperitoneal injection in rats.Such cisplatin-induced increases in the kaolin consumption were remarkably attenuated by GRA cataplasm. The results showed that GRA cataplasm possessed antiemetic effects and could be a promising regimen for the relief of emesis. Part Five Research on the pharmacokinetics of GRA cataplasmA sensitive high-performance liquid chromatography (HPLC) assay was established to measure the content of GRA in the rat plasma. The mobile phase consisted of methanol-O.OSmol-L"1 sodium acetate buffer (pH4.6, contained 0.3% (v/v) triethylamine) (45:55, v/v). A fluorescence detector of 305 nm for excitation and 360nm for emission was used. In this part, we also used SD rat as experiment animal, and studied the pharmacokinetics and absolute bioavailability after a single dose of intravenous or cataplasm administration.We concluded the curve of the GRA concentration in rat plasma and the time, calculated the parameters of pharmacokinetic. The results showed that GRA cataplasm could decrease the maximum serum concentration, prolong the peak time and extend the MRT. The absolute bioavailability was 64.16%.