Controlled release formulation of 10-hydroxy-camptothecin using hydrophilic matrix system.

摘要

The main objective of these studies was to formulate a controlled-released matrix system using Sodium CarboxymethylcelIulose as a hydrophilic polymeric carrier widely used in various pharmaceutical industries, to improve the performance of the matrix tablet containing the drug 10-hydroxycamptothecin (10HC). Efforts in formulating the drug are directed toward maintaining the lactone form of the drug for its potent antitumor activity which is known to be lost upon hydrolysis of the α-hydroxy-lactone ring of the drug.;In an effort to better understand the factors affecting the stability of the lactone form of 10HC and attain optimum formulation conditions, physicochemical characterization of the drug was conducted and several of the physical properties such as pKa, solubility and pH-depedent stability, were determined. The pKa determined was found to be 1.4.;The formulated solid dosage matrices were prepared by physical method in three forms that is, direct compression, wet granulation and lipid matrix formulation. Weight variance, hardness and disintegration tests were performed on the formulated matrices. Of all the matrices, the pH 1.2 granulation formulated matrix had the highest hardness of about 24 Lb and longest disintegration time >120 minutes.;In vitro studies were performed on the various matrices and their dissolution profiles compared based on the release rate and mechanisms. The pH 1.2 granulation matrix (F-5) and lipid formulation matrices (F-8, F-9 and F-10) release the drug with an almost zero-order release profile, while the rest of the formulated matrices yielded either Fickian or Anomalous drug release profile.;Data analysis indicated that the direct compression and the solvent evaporation method failed to prolong the release of the drug, that is, about 100% of the drug was released within 80 minutes in pH 1.2 dissolution media and 250 minutes in pH 6.8 dissolution media.;Analysis was also performed to predict the time for 80% release (t 80) of the drug as a function of the type of the formulation. More specifically, the drug released from the granulated formulation in pH 1.2 and pH 6.8 media were 50% and 80%, respectively, after 25 hours while about 95% of drug is released from the direct compression matrix system in about 4 hours in pH 6.8 dissolution media.;These results suggest that the most suitable formulation for the sustained release of 10-hydroxy-Camptothecin is the tablet matrix prepared with the method of granulation at pH 1.2 which gave an almost zero-order release profile.