The objective of this study was to prepare floating theophylline microspheres with zero order release profiles for use as buoyant reservoirs with increased retention time in the stomach. The microspheres were prepared by a modified emulsion-solvent evaporation method using a polymer mixture of cellulose acetate butyrate and Eudragit RL 100 (1:1). The drug-polymer dispersions were pressurized under carbon dioxide gas which dissolved in the drug-polymer dispersions and formed bubbles upon the release of the pressure. Some of the bubbles were entrapped in the dispersed drug-polymer droplets and eventually formed internal cavities in the microspheres. The resulting microspheres were characterized for size distribution, morphology, density, drug-polymer content, buoyant capacity and drug release behaviour. The microspheres were spherical with relatively smooth surfaces with round hollow cavities. The microspheres and low densities (less than 1 g/cm3) and remained floating for more than 24 h in pH 1.2 and 7.5 buffers. The dissolution profiles of the floating theophylline microspheres showed near zero order kinetics and sustained release in both pH 1.2 and 7.5 buffers. Modified microspheres processed with the addition of 2% w/v polysorbate 80 to the internal phase had smaller sizes, lower densities and faster drug release compared with those without the addition of the surfactant.
Carboplatin is a potent anticancer agent that has shown efficacy in clinical trials against malignant glioma, one of the most deadly cancers in humans. However, a high systemic dose is required to achieve an effective concentration in the brain because of the presence of the blood-brain barrier (BBB). Such a high dose can cause many side effects. Local delivery of antitumor agents to the brain using injectable and biodegradable microspheres is a new strategy for the treatment of malignant glioma. This method is able to bypass the BBB and allows maximal local exposure and minimal systemic exposure to avoid the severe side effects of carboplatin. Delivering sustained-release microspheres directly to the tumor site could also control local tumor recurrence and improve survival. In the present studies, carboplatin-loaded microspheres were delivered intracerebrally in rats. No signs of systemic or neurologic toxicity associated with the microspheres implanted in the rat brain were observed. The in vivo release of carboplatin followed apparently zero-order release kinetics up to 30 days. The surface characteristics of the microspheres retrieved from the rat brains changed with the progress of polymer biodegradation. Implantation of the microspheres evoked a transient and localized inflammatory reaction that was well tolerated by the animals.
There has been an increasing interest in intracerebral delivery of anticancer agents using biodegradable polymers for the treatment of malignant glioma. This approach circumvents the blood-brain barrier (BBB) to achieve a high local drug concentration in the brain tumor sites and minimize side effects associated with a high systemic dose. It could also control local tumor recurrence and improve survival. In order to deliver anticancer drugs intracerebrally from polymers to tumor sites with minimal surgery, injectable poly(d,l-lactic-coglycolic acid) (PLGA) microspheres impregnated with carboplatin have been prepared. In the current studies, the brain tissue reaction to blank or carboplatin-loaded PLGA microspheres was investigated in rats. The PLGA micro-spheres were well tolerated by all of the rats. The brain tissue reaction to the blank microspheres was accompanied by mild edema, and macrophage/astrocyte/microglia proliferation. The tissue reaction to the carboplatin microspheres was characterized as edema, necrosis, and a more pronounced phagocytic inflammatory reaction. The observed inflammatory reactions decreased remarkably after 1 month. Carboplatin microspheres were then implanted intracerebrally in the rat glioma models. Higher drug concentrations were achieved in the brain tumor than in normal tissues. The survival and weight loss of the rats receiving carboplatin microspheres were compared with those of the rats receiving systemic doses. The local treatment was more effective in controlling the weight loss of the tumor-bearing rats, and was as effective as the systemic treatment in prolonging survival.
The purpose of this work was to develop a computer program that assists optimization of controlled-release devices, both visually and mathematically, using response surface methodology (RSM). A Windows-based computer program, Optima, which interactively implemented a number of subroutines for the optimization procedure, was developed. Optima is an integrated, user-friendly, and graphically oriented program for pharmaceutical dosage form optimization. Central composite design is implemented in the program. First- and second-order models containing up to five variables can be fitted to the data. The user can also choose between linear and exponential individual desirability functions, and use them to construct an overall desirability function that combines all the response variables in a single response. The program can predict the optimum levels of experimental variables, with respect to individual responses and/or the overall desirability. Optima has been successfully used in the development of sustained-release AZT-loaded microspheres. During the optimization process, three experimental variables were investigated and four responses were measured. The experimental design was a central composite design that was generated by the program. The response values were used by the program to calculate the individual desirability functions, which were then combined into an overall desirability function. The individual responses as well as the overall desirability function were optimized by fitting to a second-order polynomial equation. The response surfaces were generated and optimum levels of the experimental variables were predicted. The observed responses of the optimized formulation were very close to those predicted by Optima. The program proved to be a very useful, integrated tool for optimization of the controlled-release microspheres.
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