Water-solubility of drugs is one of the most important properties that determine whether the drugs are clinically useful or not. Thus, a new approach that can increase the water- solubility of poorly soluble drugs by orders of magnitude would help more effective use of existing drugs and new drugs in the development stage. The objective of this project is to develop oral paclitaxel formulations using hydrotropic polymers that can increase the paclitaxel solubility by 2 approximately 4 orders of magnitude in aqueous solution. The central hypothesis of this project is that the increase in paclitaxel solubility results in improved bioavailability after oral administration.
The specific aims of this project are: (1) to identify the structural requirements necessary for increasing water solubilities of paclitaxel using various low molecular weight hydrotropic agents; (2) to synthesize hydrotropic polymers based on the structures of the low molecular weight hydrotropic agents identified in Specific Aim 1; (3) to prepare paclitaxel formulations using hydrotropic polymers for oral administration; (4) to test increased cytotoxicity of paclitaxel in hydrotropic polymer formulations using human tumor cell lines; and (5) to define the bioavailability of paclitaxel in hydrotropic polymer formulations using an in vivo chronically catheterized rat model. The significance of this project is that, upon successful completion, we will be able to dissolve paclitaxel in water as if it is a freely soluble drug with aqueous solubility of 1 approximately 10 mg/ml. The high water solubility of paclitaxel will make it possible to develop more patient-friendly formulations with reduced or no undesirable side effects. In addition, the approach used for paclitaxel can be used for other poorly soluble drugs. This will allow more effective use of existing drugs and development of various new drug candidates that are otherwise eliminated from further consideration due to their poor water-solubilities.
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