| Experimental design and formulation optimazation are organically parts in pharmaceutical research. Precisive and high performence optimazation method and its reasonable application is very important in the development of new pharmaceutical preparations. Artificial neural network is a biologically inspired mathmatical method designed to simulate the way in which the human brain process information. High precision simulation,learning ability are the result of the non-linear parall neuralcomputation incorprated in it. Using Tetra-methy pyrazine hydrochloride (TMPH) as model drug, computer aided Artificial neural network technology and different statistical optimazation methods were investigated during the design of TMPH sustained release tablet.UV spectrophotometry were developed for in vitro assay during the studies of physicochemical properties, content, release as well as in situ absorption. According to literatures, High-performance liquid chromatography with UV detection was applied to quatitation of plasma concentration in dogs. The extraction recovery of TMPH was 78.44 + 8.41% and the detective limit is 4.0ng.In the preformulation research the physico-chemical properties of TMPH were investigated,which were connected closely with pharmaceutical formulation designs. The studies on solubility showed that the equilibrium solubility in distilled water, 0.1M HC1 aqueous solution, pH7.4 phosphate buffer were 5. 956,11. 275and 6.681mg -ml-1, respectively; The intrinsic dissolution rates were 18.717, 41.332,33.2154 mg -cm-2 -min-1, respectively. Apparant oil/water partition coefficient in basic environment were as high as 46.93 at physicological pH7.4. In addition ,the chemical stability of solid TMPH was observed, the result of which indicated that temperature, moisture, oxygen and illumination had little effect on it.To clarify the absorption of TMPH from intestine, the absorption and intestinal wall permeability were measured by utilizing the rat intestestinal recirculating method in situ. After perfusing at same concentration for 4hr, no significant difference of absorption percentage per 10cm was observed among duodenum, jejunum, ileum and colon, which were 24.48%, 21.73%, 21.27%, 15.17%, respectively. It provided evidence that there is no site specific absorption in the intestines. The mechanism of intestinal absorption was studied by investigating absorption in lumen solutions at different pH and concentrations, which suggested that the intestinal absorption of TMPH was via passive transport mechanism .The sustained release tablets were prepared with HPMC and EC by wetting granulation procedure. The studies of the influence of formulation and manufacture on the release were carried out using the accumulative release during 12hr. It suggested that the way that TMPH release from gel layer could be described as Fickian diffusion.Optimal formulations of TMPH sustained release tablet were developed by othogonal design, uniform design, full factorial design, simplex lattice design and central compsite design which is a new method applied in pharmceutical research overseas in recent years, on the base of the evaluation between different designs, a simple rule on the selecting of experimetal designs were recmmended .Artificial neural network is a biologically inspired mathmetical method designed to simulate the way in which the human brain process information. A optimal formulation of TMPH sustained release tablet were development based on its' outstanding prediction abilities. The comparasion to statistical methods using response surface methodology showed that artificial neural network is a powerful tool in the formulation optimazation of pharmaceutical research.The studies of pharmacokinetics in dogs verified that desired formulation was achieved. The plasma concentration maintained for about12hr. The pharmacokinetic characteristics of TMPH sustained release tablet conformed to one compartment open model. The result showed that the relative bioavailability of TMPH sustaine...
|
PDF Full Text Request