Nanoparticle and Gel Based Formulations for Enhanced Drug Delivery

Abstract

Nanogel and hydrogel formulations have shown promising advantages for topical and trans-mucosal routes of administration. The nanoparticle drug within the gel matrix showed significant enhancement in the permeation of drugs in the topical and transdermal drug delivery. On the other hand, the clear hydrogel with the completely solubilized drug showed attractive results as a suitable vehicle for delivering drugs via buccal mucosa to the systemic circulation. In this dissertation, research data has been presented on a nanogel and hydrogel as drug delivery platforms. In addition, research has been presented on siRNA polyplex nanoparticles as a platform for incorporation of therapeutic siRNA molecules in the treatment of melanoma. We developed and evaluated siRNA- polyethyleneimine (PEI) polyplex nanoparticles with varied molecular weights of PEI (low, moderate and high). The polyplex formation was optimized at different N/P ratios (gel retardation assay) and studied their cytotoxicity, and cellular uptake on B16BL6 melanoma cell line. Optimal polyplexes were achieved at 50:1. 10:1, 5:1 N/P ratios for PEI 1.8 KDa, PEI 10 KDa, and PEI 25 KDa, respectively. Based on these results, it was concluded that 1.8 KDa PEI-siRNA polyplex at 50:1 ratio is optimum for siRNA delivery due to its safety and efficacy in the cellular uptake of B16BL6 melanoma cell lines. A nanogel formulation for enhancing the topical delivery of acyclovir was investigated. Since the topical efficacy of acyclovir is hampered by poor skin penetration, the goal was to enhance the percutaneous permeation of acyclovir via nanoparticles based gel formulation with or without penetration enhancers. Acyclovir nanogel (F1) formulation showed an enhanced skin permeation by 2-folds higher flux compared to Zovirax® commercial product. Incorporating 10 % ethanol (F3) in the formulation showed a synergistic permeation enhancement with 24-folds higher flux compared to Zovirax®. Inclusion of propylene glycol (F5), or oleic acid (F4) showed negligible penetration enhancement. To understand if the permeation barrier exists in the stratum corneum or dermal layers, the permeation data were generated on the microneedle-treated skin; which showed a significant enhancement in the skin permeation as compared to passive diffusion, Again the highest enhancement was achieved for the F3 (10% ethanol). Acyclovir nanogel formulations with ethanol as a penetration enhancer demonstrated a pronounced effect on enhancing acyclovir skin permeability and skin content upon topical application. A novel buccal midazolam gel formulation was developed and evaluated for efficacy in comparison to an intravenous solution in healthy dogs. The formulations T19 and T29 (HPMC K100M) with significantly higher release rates than T18 (Pluronic F127) were also effectively absorbed through buccal administration in dogs. At a dose of 0.3mg/kg, T19 and T29 produced a Cmax of 98.3±26.5 and 106.3±35.2 ng/ml respectively, which are approximately two-fold higher as compared to T18 (47.7±38.5 ng/ml). Furthermore, T29 at higher dose (0.6mg/kg) produced a Cmax of (187.0±104.3ng/ml). Results of this study show promise in the treatment of seizures in dogs by buccal midazolam gel. Resveratrol has potent anti-oxidant properties and is believed to be beneficial in treating several diseases. Resveratrol as nanoparticles based gel formulation was developed and evaluated for percutaneous permeation enhancement. The skin permeation studies showed 12-folds higher flux as compared to its conventional gel (suspended resveratrol microparticles). An enhancement of resveratrol skin levels was observed when nanogel formulation was compared to microparticles incorporated in a gel formulation.