Enhanced and Modulated Drug Delivery
To optimize therapy, it is often necessary to overcome various physiological constrains and deliver a drug to the body only when and where it is needed, and in the appropriate dose level required to elicit the desired therapeutic effects. In reality, this requires the rational design of delivery systems which can provide a programmable drug concentration-time profile at the site of action in order to produce optimum therapeutic responses. At present, these goals are only partially achieved with most existing drug delivery systems.
One major issue in drug delivery has been the low oral bioavailability of an increasing number of new chemical entities exhibiting poor solubility characteristics. Therefore, the most attractive approach for enhancing the bioavailability is to improve the drug solubility and the rate of dissolution/release through a rational design of delivery systems. Our research in this area is focused on the formation, characterization, and drug delivery applications of nanostructured drug-polymer composites. On one hand, we are interested in understanding the nucleation and crystallization kinetics in drug loaded hydrogels in both the swollen (rubbery) and dehydrated (glassy) states, as well as their effects on subsequent dissolution and release of the drug from such polymeric carriers. On the other hand, we are investigating physicochemical parameters that effectively retard such crystallization process such that a stable solid solution or amorphous drug-polymer composite can be created in glassy hydrophilic polymer carriers. Such stabilized amorphous drug-polymer composites would increase the transient solubility and provide enhanced bioavailability of poorly soluble drugs. Additionally, we are interested in modulating the release of poorly soluble drugs from such nanostructured drug-polymer composites through direct modification of the spatial distribution of either the drug or the polymer structure.
Another major effort of our research is directed towards achieving enhanced and modulated delivery of nitric oxide (NO) for wound healing applications, particularly for diabetic ulcers. NO is a critical mediator for normal tissue repair. Essential wound repair processes such as granulation tissue formation, epidermal migration, collagen deposition and angiogenesis are all regulated by NO bioactivity. Several studies have linked impaired wound healing in diabetic ulcer patients to NO deficiencies at the wound site. Topical administration of NO or NO donors appears to be beneficial in promoting tissue repair and healing of diabetic ulcers in animal models. However, this approach is limited by the short duration of NO release, short half-life of NO in physiological fluid, and the intrinsic instability of available NO donors. Currently, materials that can provide prolonged release of NO to extend its activity duration at the wound site are still lacking. To overcome these deficiencies, we are developing novel, stable and biocompatible systems for generating a durable release of NO based on a new class of S-nitrosoglutathione (GSNO)-conjugated supramacromolecular complexes. In addition to demonstrating enhanced wound healing in diabetic animal models, we are also characterizing the mechanism of NO release and investigating physicochemical parameters for optimizing such delivery systems in terms of desired NO loading levels and NO release rates.
P.I. Lee and Y. Li. Supramacromolecular Polymer Complexes Providing Controlled Nitric Oxide Release for Healing Wounds, US Patent No. 8,992,945, March 31, 2015.
P.I. Lee and Y. Li. Controlled Nitric Oxide Delivery from Aqueous S-Nitrosothiol Conjugated Polymers and their Complexes, PCT International Publication No. WO 2011/003172, January 13, 2011.
L.Y. Fang, P.K. Bradley and P.I. Lee. Pharmaceutical Compositions, US Patent Application No. US2009/0111831, April 30, 2009.
Z. Wang, S.A. Sangekar and P.I. Lee. Pharmaceutical Formulations, US Patent Application No. US2009/0074869, March 19, 2009.
S.A. Sangekar, P.I. Lee and A.A. Nomeir. Molecular Dispersion Composition with Enhanced Bioavailability, Canadian Patent No. 2,315,685, February 5, 2008.
S.A. Sangekar, W.A. Vadino and P.I. Lee. Oral Composition Comprising a Triazole Antifungal Compound, Canadian Patent No. 2,258,683, July 31, 2007.
S.A. Sangekar, W.A. Vadino and P.I. Lee. Solid Solution of an Antifungal Agent with Enhanced Bioavailability, Canadian Patent No. 2,258,679, May 29, 2007.
S.A. Sangekar, P.I. Lee and A.A. Nomeir. Molecular Dispersion Composition with Enhanced Bioavailability, US Patent No. 6,632,455, October 14, 2003.
S.A. Sangekar, P.I. Lee and W.A. Vadino. Solid Solution of an Antifungal Agent with Enhanced Bioavailability, US Patent No. 5,972,381, October 26, 1999.