Synchronizing the release rates of topotecan and paclitaxel from a self-eroding crosslinked chitosan - PLGA platform.

This study is a continuation of a previous study in which two model drugs, sodium salicylate (highly water-soluble) and indomethacin (low water-soluble) were loaded into an erodible hydrogel, made of ionically crosslinked chitosan (x-Ct). The erosion rate of the x-Ct matrix was controlled by its immersion in calcium chloride solutions (de-crosslinker) of different concentrations, leading to synchronization of the release rates of the two drugs over 2 h. In the present study, a modified platform was developed in order to (a) synchronize the release rates of the two cytotoxic drugs, topotecan (TT, highly water soluble) and paclitaxel (PTX, poorly water soluble); (b) prolong the erosion duration and the derived concomitant release of the two drugs to several days. TT was loaded into a PLGA sphere, which was co-loaded with calcium chloride (CaCl2). The sphere was then placed in an aqueous solution of chitosan (Ct) in which PTX was dispersed. A PLGA core-containing hydrogel was then produced by ionically crosslinking the Ct. The formulation screening section of the study includes a statistically designed Fractional Factorial experiment. It was comprised of the following five experimental factors: (a) the type of Ct and (b) its relative amount in the formulation, (c) the type of ionic crosslinker (citric acid or oxalic acid), (d) the concentration of the ionic crosslinker and (e) the co-loaded amounts of CaCl2 (the constitutional de-crosslinking agent). The difference factor, f1, and the similarity factor, f2, of the TT and PTX release profiles into water, were used as the experimental responses. The computerized prediction models were employed to assess the collective effects of the pre-determined experimental factors on the difference factor, f1, and the similarity factor, f2 (the response factors), by employing a fractional factorial design and multifactorial analysis, without the need to account for the exact mechanisms of the release processes involved. The final composite platform was capable of releasing TT and PTX, at similar (concomitant) rates, over a period of 7 days, a finding which suggests that the novel polymeric platform may serve as a multi-drug implant. An attractive medical application for such a device would be post-operative local treatment that could benefit from localized combination chemotherapy after the removal of malignant tissues, in the surgical treatment of breast cancer, ovarian cancer, glioma and peritoneal carcinomatosis.

Synchronizing the release rates of salicylate and indomethacin from degradable chitosan hydrogel and its optimization by definitive screening design.

Three types of ionically crosslinked (with citric acid) chitosan discs were loaded with the highly water- soluble drug, sodium salicylate (SS) and the poorly water-soluble drug, indomethacin (Ind). In separate experiments the hydrated discs were immersed in a de-crosslinking solution comprising of different concentrations of calcium chloride, which induced a controlled erosion of the discs, a process which was optimized to synchronize the release rates of the two drugs over a predetermined period of time. The optimization was accomplished by manipulating six factors: chitosan MW, its amount in the formulation, the concentration of the crosslinker agent, the concentration of the de-crosslinking agent in the dissolution medium, its pH and its temperature. A computerized multifactorial definitive screening design analysis assisted in minimizing the number of experiments. The quotient of the SS to Ind release rates, the difference factor f1, the similarity factor f2 and the combination of f1 and f2 were determined as the experimental responses. The computerized prediction profilers that were used to simulate the contribution of the experimental factors and their effect on the experimental responses led to a successful erodible formulation with a concomitant release of the two drugs over 150 min.