(225c) Solubility of Timolol Maleate in Supercritical Carbon Dioxide with Water on Extraction from Silicone Hydrogel

Development of ocular drug release system using hydrogel has been demanded toward to the achievement of the high bioavailability and sustainable release on the ocular treatment. The fabrication techniques and process for the ocular drug release system using hydrogel have been reported the fabrication method or process by many research groups, such as the polymerization of the hydrogel with drugs and impregnation of the hydrogel with drugs. Impregnation type method has a merit as simple the fabrication method and process compared with those by the polymerization. For the hydrophilic drug, it is important to reduce the diffusion rate into the ocular surface. The reduction of the ocular drug diffusivity inside the silicone hydrogel release system by addition of vitamin E has been reported. Vitamin E is a fat-soluble compound and not toxic to the human body. Supercritical carbon dioxide has been applied for fabrication of drug / polymer composite as impregnation media because of high solubility and diffusivity, low surface tension and no toxicity of supercritical carbon dioxide. The supercritical carbon dioxide has also a possibility to be an impregnation solvent for loading of vitamin E into the hydrogel. In our previous work, the vitamin E loading process into the silicone hydrogel with timolol maleate using supercritical carbon dioxide has been developed for the fabrication of the timolol maleate release system. However, the loading of vitamin E in supercritical carbon dioxide caused that timolol maleate from the silicone hydrogel was extracted into the supercritical carbon dioxide and then reducing the drug loading amount. Knowledge of the solubility of timolol maleate in supercritical carbon dioxide for the process design of the vitamin E loading. The solubility of timolol maleate in supercritical CO₂ was measured in different three conditions, in pure CO₂, CO₂ saturated with water and CO₂ with water phase in this work. This knowledge would be useful to know how to reduce timolol maleate extraction. In addition, the extraction of timolol maleate from the silicone hydrogel into supercritical carbon dioxide with water was investigated. The silicone hydrogel containing timolol maleate was impregnated with vitamin E in supercritical carbon dioxide with water for the fabrication of the timolol maleate release system. The release of timolol maleate from the hydrogel with vitamin E are studied and the diffusivity of timolol maleate in the hydrogel with vitamin E are also discussed. The solubility of timolol maleate in supercritical carbon dioxide and supercritical carbon dioxide saturated with water, and supercritical carbon dioxide with water phase were experimentally determined at 313 K and 8 to 18 MPa. The solubility in supercritical carbon dioxide saturated with water is slightly higher than those in pure carbon dioxide without because of the molecular interaction between timolol maleate and water in supercritical carbon dioxide. Two phase system of supercritical carbon dioxide water phase gives the reduction of the solubilities of timolol maleate in supercritical carbon dioxide largely due to the ionization of timolol maleate in the water phase. This result of the quite low solubility of timolol maleate would succeed in the restrained extraction during the supercritical impregnation. Consequently, the large amount of timolol maleate is loaded into the silicone hydrogel with vitamin E treated in supercritical CO₂ saturated with water. The silicone hydrogel impregnated with vitamin E in supercritical CO₂ saturated with water results in the diffusivity of timolol maleate lower than that without vitamin E.