Abstract
This study focused on elucidating a mechanistic understanding in support of the multiple mechanisms which govern the formation of crosslinked alginate-hydroxyethylcellulose (Alg-HEC) gelispheres intended for the controlled intrastriatal release of nicotine as a neuroprotectant in Parkinson's Disease. HEC was incorporated as a reinforcing "protective" colloidal polymer to induce interactions between the free carboxyl groups of alginate with hydroxylated HEC monomers. Gelispheres were compressed within an external poly(lactic-co-glycolic acid) (PLGA) matrix to further prolong the release of nicotine. Sol-gel interconversion mechanisms, matrix deformability moduli, matrix fracture energies and chemometric models of the associated energy paradigms were analyzed for their influence on the mechanism and extent of nicotine release. Textural profiling demonstrated higher fracture energies (7.94-26.69 x 10(-4) J) and lower deformability moduli (12.24-58.36 N/mm) when gelispheres were cured in 2 MHCl as a postcuring step. Ba2+ crosslinked gelispheres resulted in superiorly compact matrices with an increase in volume of 201-329% as compared to the Ca2+ and Zn2+ crosslinked matrices. The order of matrix compactness was as follows: Zn2+ < Ca2+ < Ba2+. Molecular mechanisms of formation, interaction, conversion, and stability of sol-gel transitions depended on the type of crosslinker, crosslinking time, energy transactions, and interactions with molecules of the hydration medium. Ba2+ crosslinked gelispheres released nicotine slower than Ca2+ and Zn2+ crosslinked gelispheres due to the higher energy requirement for interconversion to sol while the energy requirements for Ca2+ and Zn2+ was at a lower demand. Ba2+ crosslinked gelispheres within PLGA matrices therefore retarded nicotine release in a pseudo-zero-order manner over 21 days. (C) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2059-2072, 2009