Studies On Preparation Of Acyclovir Controlled Release Pellets

Acyclovir(ACV),an antiviral agent of nucleoside, has highly selective activity against virus infective cells and virtually non-toxic to human normal cells. It can effectively suppress the duplication of various DNA in host cells. Acyclovir has been widely used clinically as the first picked medicine to restrain the herpes simplex virus Type-I, Type-II (HSV-I, II) and varicella-zoster virus infections. However, because of its poor solubility in water, incomplete gastrointestinal absorption and distinct individual differences have been found after oral dosing of acyclovir. The estimated absolute bioavailability of acyclovir in man is between 15% and 30%. On the other hand, with the dose increasing, the average bioavailability becomes lower. Therefore, it can be practiced technically by providing low dose for patients in a more frequent pattern, yet the results of this method indicated the patients did not acclimatize themselves to this methodology. The purpose of the present study was designed to develop a kind of ACV controlled release capsule which would enhance the absorption of acyclovir in gastrointestinal tract and improve its bioavailability, and which would be more convenient for patients to use.HPLC method was utilized to determine the acyclovir content in pellets, UV method for assaying release of acyclovir controlled release capsules. HPLC and UV methods were developed to analyze the intestinal absorption of acyclovir in rats. The HPLC fluorescence method was established to monitor the plasma level in vivo.The preformulation results showed that acyclovir is not soluble in water orvarious physiological pH fluids and the octanol/water partition coefficient is very small(0.02).The absorption sites and the absorption kinetics were studied from various intestinal segments ligation using in situ perfusion method in rats. The research demonstrated that acyclovir was poorly absorbed in intestine in general and mostly absorbed in the upper and middle small intestine. The absorption fraction and absorption rate constant were gradually decreased from the upper small intestine to the large intestine segments. The mechanism of the gastrointestinal absorption of acyclovir is transferred to cell via passive diffusion.Acyclovir pellets were prepared by means of power accumulation with the centrifugal granulation technology. Through the formulation filtration and process observation, it was discovered that the yield of the objective pellets(20/24 mesh cut) was above 50% and the average acyclovir content was 23%. The results suggested the centrifugal granulation technology for acyclovir may not reach the expected goals.Acyclovir pellets were prepared by another method of extrusion -spheronization. Investigation of process parameters and formulation variables and orthogonal design were used to optimize the experiment conditions. The results have revealed that the process variables including spheronization disk speed, spheronization residence time and wetting fluids were the most critical factors in influencing the physical characteristics of the resulting products; and that the excipient of MCC/HPMC and lactose at various ratios was the key in determining the properties of the particles produced; meanwhile, lactose and fumaric acid in the formulation were adjusters to increasing drug release rate. The method of extrusion-spheronization for preparing acyclovir pellets was reliable and repeatable. Release of acyclovir pellets was described as a hydrogel matrix system. The mechanism of release results from the matrix rode and drug diffusion of matrix by describing the drug release curve using Ringer-Peppas model.A fluid bed spray processor was adopted for coating the pellets prepared byextrusion-spheronization. The coating process variables were determined and controlled. A similar pH-independent delayed release pellet system was produced by coating with EudragitNE 30D and Eudragit L 30D-55 at a ration of 10:1, and by filtration of a series of plasticizer TEC, HPMC, talc, static electricity-proo...