| The incidence of hypertension Increased year by year with the change of people’s life style. Furthermore, among the patients those are more than65years old, the risk of Stroke, congestive heart failure, coronary artery disease, hypertrophy of left ventricular, kidney disease of end-stage and dementia that results from hypertension increased significantly. The vascular compliance of old patients declined, so the antihypertensive measures of improving arterial compliance should be taken. Nowadays, the antihypertensive drugs in clinical act mainly by expansion of blood vessels and lowering the peripheral resistance. However, they seldom improve the vascular compliance, especially the arterial compliance. Gastrodin extracted from traditional chinese medicine Gastrodia was observed to reduce the blood pressure and lower the peripheral resistance except the effect of anticonvulsant, antiepileptic, sedative and hypnotic. In this paper, gasrtodin was selected as the model drug to prepare sustained-release matrix tablets. Oral administration2times a day can effectively prevent and treat the senile hypertension.As a formulation of sustained and controlled release, sustained release matrix tablets have been extensively studied. Gastrodin sustained release tablets were prepared with HPMC which can form a gel layer by water-swelling, and sustained-release can be obtained accordingly. HPMC, nontoxic and harmless, was approved by FDA as a kind of pharmaceutical excipient. Hydrophilic matrix tablets can release the drug slowly, reduce the frequency of administration and avoid the phenomenon of "peak and valley" Furthermore, the drug was less exposure to the gastrointestinal mucosa, so the irritation to the gastrointestinal tract and the side effects such as nausea and vomiting can prevented or minimized. Different drug release mechanisms can be obtained by applying different skeletal material and different preparation technology to improve bioavailability, drug efficacy and the compliance of patients.In this research, gasrtodin was selected as the model drug to prepare sustained release matrix tablets by the method of wet granulation with the main skeletal material HPMC. Analytical method, physicochemical properties, prescription design, preparation technology, release mechanisms, quality standards as well as stability were investigated.1. Analytical method and physicochemical properties studyThe equilibrium solubility of gasrtodin in water, hydrochloric acid of O.1mol/L and phosphate buffer of pH6.8was investigated, respectively. The drug content of gasrtodin was determined by the method of ultraviolet spectrophotometry and the methodology was inspected. The results indicated that the equilibrium solubility of gasrtodin in the three kind of solvent mentioned above was312mg/ml,415mg/ml and351mg/ml, respectively. The related substances were determined by the method of HPLC. Hydrochloric acid of O.1mol/L and phosphate buffer of pH6.8was selected as the release medium to simulate the environment of the gastrointestinal tract. The determination method of in vitro drug release was established, which provides the basis for the optimization of prescription and preparation technology.2. Optimization of prescription and preparation technologyThe method of wet granulation was selected to prepare the sustained-release matrix tablets due to the solubility of granulation in different solvent and the requirements of clinical application. The optimal prescription and preparation technology was determined by single factor and orthogonal experiments using release percentage in vitro as index. Repeated experiment was done to verify the feasibility of prescription and the stability of preparation technology. The results show that the releasing rate of sustained-release tablets reduced with the increasement of content and the viscosity of HPMC in prescription. Furthermore, granulation released more slowly with the addition of the hydrophobic polymer materials, EC, as blocker. Besides, the releasing rate was also affected by the preparation processes such as the granulating adhesives, granulating method, tablet weight, tabletting pressure. On the contrary, the release medium and rotation speed have no significant effect on the releasing rate. The in vitro release profile of the sustained-release matrix tablets of granulation made with the mixture of HPMC and EC showed significant sustained-release property and followed Higuchi equation. The results of three batches of sample showed the preparation technology was simple, stable, reproducible and suitable for industrial production.3. Release mechanisms, quality standard and stability researchOn the basis of single factor, the formulation and technology parameters were optimized by orthogonal experiments. The results of in vitro release were in accordance with Higuchi equation. The fitting results and release results demonstrated that the sustained-release matrix tablets of granulation released drug by the diffusion of drug and the dissolution of skeletal material.The in vitro release results of three batches of sample indicated the reasonable formulation and stable preparation technology. The study of preliminary stability showed that the sustained-release tablets had light stability and notably absorbed moisture on the condition of high humidity. The tablet weight increased7.83%on10days and the drug contents reduced4.39%. The related substances increased at high temperatures. So the sustained-release tablets should be preserved at dry and cool place. The accelerated test in6months and the study of retained samples in12months revealed the good stability of the sustained-release tablets. |
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