Research Of Flutamide Sustained-Release Tablets

Flutamide (FLU) is a kind of non-steroidal androgen antagonist, which was first designed by the American Schering-Plough Company and first sold in1989for prostate cancer treatment in the United States. FLU is acyl aniline medicine and a first-line drug for prostate cancer. FLU does not belong to hormons, so it will not cause side effects like hormone drugs. Flutamide could inhibit cancer cell growth by blocking the binding of androgen and its receptor, which means it does not reduce the body androgen level and does improve the life quality of patients. In addition, FLU can improve urinary symptoms like frequent urination, urgency, dysuria and relieve pain after administrating in one month.The commercial preparation of FLU is only ordinary oral capsules or tablets. Due to the peak and valley effect, high administration frequency and other factors of commercial formulations, we prepared FLU controlled-release formulation, which was only taken twice per day, compared with original3times per day. On one hand, this new formulation could increase the medication compliance of patients and on the other hand it can also reduce the liver toxicity came from drugs.Hydrophilic polymer material poly (ethylene oxide)(PEO) was chosen as matrix material to prepare matrix tablets. Matrix tablets are widely used in controlled release formulations because they are easy to manufacture and inexpensive. PEO is obtained by ring-opening polymerization of ethylene oxide and its structure is (CH2CH2O) n. PEO is water-soluble, easy to form a gel and low toxicity and it has been successfully applied in many hydrophilic matrix tablets. Compared with traditional material hydroxypropyl methyl cellulose (HPMC), sustained-release tablets applied PEO are much easier to achieve zero-order release.In the first part, the determination method of FLU in intestine perfusate by HPLC was established firstly. A circulation method of rat small intestine was used to study the absorption characteristics of FLU in rat intestine. The results showed that:there was FLU absorption in each part of rat intestine, and the absorption was a first-order process with passive diffusion mechanism; drug concentration and Polysorbate-80concentration had no effect on the absorption rate of the drug absorption in the range of experiment; the absorption rate of different intestinal segments of rats:Duodenum≈jejunum≈ileum≈colon, which meant FLU had a good absorption in the whole segments of intestine in rats.In the second part, FLU controlled-release tablets, which are only taken twice per day orally, were prepared by wet granulation technology. In the formulation, PEO was used as matrix and PVPP as adjuvant and the active ingredient content is80%. The central composite design response surface methodology was used in this part to optimize the formulation and the standards were the accumulative drug release percent in1h,4h and8h. The experiment drug release of the optimal formulation obtained by this methodology had the similar release curve as the one forecasted by the model, which is15～30%in1h,50～70%in4h and over80%in8h. The mechanism of FLU released from controlled-release tablets was investigated by fixing to different equations described typical release trend. The results showed that drug release characteristics appeared to be zero level release equation in vitro.The UV spectrophotometry method for determining the concentration for FLU in the tablet was established in the third part. Release medium got the sink conditions. Different batches of tablets prepared by the optimal formulation were detected to investigate if there were discrepancy between their release behaviors in vitro. The commercial tablets were used to compare with the self-made controlled-release tablets.In the last part, HPLC method was established for OHF determination in dog plasma. This method is sensitive and accurate. Two-period and two-crossover experiment with commercial tablets as reference preparation and FLU controlled-release tablets as test preparation was used in the research to study the pharmacokinetics and bioavailability of controlled-release tablets in Beagle dogs by detecting the concentration of OHF in plasma sample. The results showed that the concentration-time curve could be explained well by oral one-compartment model. Compared with commercial tablets, the Tmax and MRT of controlled-release tablets were prolonged and the Cmax was reduced significantly. And the AUCs were equal. The relationship of in vitro absorption and in vivo release could be described as y=1.328x-0.326, r=0.9949. Therefore, the in vivo release could be used to predict the in vitro release.