Studies On Sustained Release And Enteric Coated Pellets Of Rhein Acid

Rhein is mainly distributed in the Polygonaceae plants. It is a main constituent of Rhubarb, Polygonum cuspidatum and Polygonum multiflorum. Rhein has strong polarity, redox property and pharmacological activities in many aspects, including anti-tumor, anti-bacterial, anti-inflammation, anti-oxidation, anti-liver fibrosis, and anti-high blood sugar. However, because of its weak water solubility, short half-life, gastrointestinal irritation and other factors, its clinical application has been limited. The rhein sustained release and enteric coated pellets prepared in this experiment can be slowly released in the gut. The self-prepared pellets can not only avoid the side effects on stomach, but also achieve the purpose on slowing down the release and improving the bioavailability.Pellets containing alginate were prepared by the process of gelating reaction of alginate and CaCl2, which formed the hydrophobicity backbone frame in which the drug was embedded. As the calcium alginate skeleton structure could not be swelled in acid environment the drug could not be released in the stomach, thus avoiding the drug to stimulate the stomach. The pellets began to release slowly when they reach the intestine, the purpose of releasing slowly and lasting its effect was achieved.Pectin aqueous solution including rhein at a certain concentration was prepared. This dispersion was added drop-wise, using a dropper, into CaCl2solution of the cross-linking agent, forming the Rhein pellets. The single factor experiment was designed to screen the optimal technique to produce the pellets, and then many tests were made respectively in the dropper diameter, speed of dropping, drying temperature and the drying time points. The orthogonal experiment was designed to screen and get the optimal parameters. Such as the concentration of alginate solution, concentration of CaCl2solution, CaCl2solution pH and the dosage of Rhein, These parameters were taken as four influential factors. At three different levels for each factor, the conformation of prescription was determined with L9(34) orthogonal design table. According to the analysis of range, the optimization of technique was definited with the colligation evaluation of formation and the release rate of pellets.The HPLC analytical method was found upon reference and preliminary data.The studies about drug release were carried out according to the second part of Chinese Pharmacopoeia.The chemical and physical stability of optimal formula was investigated as following circumstances:high humidity, high temperature and strong light. On the fifth day and the tenth day of the study period, the formulation was observed to change in physical appearance, color and drug release characteristics.The rabbits were divided into two groups. Each group was administered Oral gavage Rhein pellets and Rhein suspension via the gastric tube. The Rhein concentrations in plasma were determined by HPLC after administered.The pellets were prepared with optimization artwork:dropper diameter1.2mm; speed of dropping2ml.min-1, temperature of drying40℃, time of drying24h. The results of the study showed that the alginate solution concentration, CaCl2solution concentration, CaCl2solution pH and the dosage of rhein are the major effects on the release rate of the pellets in vitro and in vivo. The decibel analysis of orthogonal experiment showed the optimization prescription:alginate solution concentration2.5%, CaCl2solution concentration3%,CaCl2solution pH4and ratio of1:15(Rhein:ALG) dosage. The results of the system serve experiment of the HPLC method to determine the content of Rhein:the reserve time of Rhein is about6.947min, the recoveries are between92.6%-100.2%, the precision is below1%. The method can determine the content of Rhein accurately and precisely.There is no change in the physical appearance and release rate of the pellets at the end of the high temperature study. The pellets get heavy moisture absorption at the end of the high moisture study. That means the pellets should be reserved aridity. There is no obviously change in the physical appearance of the pellets at the end of the strong light study, while there has been a slight decrease in the release rate. That means the pellets should be reserved without light.In plasma, the maximum plasma (test reagents) drug concentration from the pellets was higher than suspension (reference preparation) obviously. The average peak concentration of the pellets cmax=(3.00±0.81) μg·mL-1, average peak time tmax=(9.73±0.68) h, The area under the curve of plasma AUC0～∞=(59.21±4.35) μg·mL·h-1’and the drug mean residence time MRT=(21.12±1.12) h; The suspension’s average peak concentration cmax=(2.71±0.74) μg·mL-1, average peak time tmax=(4.17±0.12) h, the area under the curve of plasma AUC0～∞=(39.72±3.11) μg·mL·h-1and the drug mean residence time MRT=(9.33±2.08) h; Compared with the reference preparation, the relative bioavailability of the test reagents is (149.07±6.12)%.The pellets have uniform hardness, uniform size and good drug release characteristics in vitro when the alginate as the main accessories. After the rabbits oral gavage the rhein pellets, the peak time in the blood was significantly lags behind the suspension. Both the peak concentration and the relative bioavailability are all higher than the suspension. In conclusion, the experiment took ALG/CaCl2chloride as accessories prepared the pellets which had good effect of sustained-release. It provides a research base for the development of the Rhein’s new formulations.