Synthesis of controlled release drug vehicles in a supercritical medium.

摘要

Controlled delivery products have received considerable attention in the last years. These substances prolong the drug's therapeutic effect, keeping the drug concentration between the therapeutic limit and the toxicity limit. The solvent used to dissolve the drug also acts as a swelling agent. The final product, however, must be free of the organic solvent. Removal of the solvent is also necessary to provide constant property for the final product that does not change with natural evaporation of the solvent. One of the major cost items in the synthesis of controlled release drugs is the removal of this solvent to acceptable limits. The purpose of this study is to eliminate the production step involving the organic solvent from the overall process. In order to achieve this goal, the drug is introduced into the polymer matrix using supercritical carbon dioxide (scCO2) as the carrier solvent and the swelling agent.; Supercritical fluids have been a primary focus in research areas concentrating on extraction, impregnation, drying, processing and modification of polymeric materials, which also attracted attention as media for chemical reactions and separations. The interest in supercritical fluids mainly lies in their unique ability to adjust their solvency power simply by varying the temperature and pressure, their excellent mass transfer characteristics and high molecular diffusivities. Therefore in the supercritical phase, the favorable characteristics of the liquid and gas phases coexist. For the last 30 years now, researchers have been exploring application areas of supercritical fluids. It has been accepted that scCO2, in particular, have properties that will make it an ideal media for adsorption processes. The fact that it is inexpensive, readily available and environmentally acceptable makes it an essence for the synthesis of safe human consumables.; To date, no published work has provided evidence that drug loaded controlled delivery products were synthesized. Very few of them report on the production of drug loaded microspheres, but the reproducibility of the data is still under investigation. Specifically, this study focuses on the impregnation of a biodegradable polymer matrix with 5-fluorouracil and β-estradiol, drugs that are used for chemotherapy and estrogen hormone therapy, respectively. The fundamental issues governing this process, namely swelling of the polymer matrix, solubility of the drug components in scCO2 and the adsorption isotherm/partition coefficients in the presence of scCO2 were studied.; To investigate the single component supercritical adsorptive synthesis of controlled delivery products, accurate experimental techniques which can measure both drug component solubilities in supercritical fluids and the adsorption isotherms in the presence of supercritical fluids were developed. Data on the solubilities of these drugs in scCO2 at 35–55°C temperatures and 101–220 bar pressures were reported. The adsorption equilibrium constants/partition coefficients for these drug components on poly-dl-lactide-co-glycolide at the same conditions were presented. To understand the effect of operating variables on the total drug loading and to be able to predict the drug loading breakthroughs, a flow over a flat plate model was developed which accounts for the polymer swelling, the partitioning of the drug component between the supercritical and the polymer phases and the polymer diffusivity. Experimental isotherm data with and without the polymer were incorporated into the model to isolate the system response from the polymer response in order to determine impregnation efficiencies.