In Vitro and In Silico Analyses of Nicotine Release from a Gelisphere-Loaded Compressed Polymeric Matrix for Potential Parkinson's Disease Interventions

Abstract

This study aimed to develop a prolonged-release device for the potential site-specific delivery of a neuroprotective agent (nicotine). The device was formulated as a novel reinforced crosslinked composite polymeric system with the potential for intrastriatal implantation in Parkinson's disease interventions. Polymers with biocompatible and bioerodible characteristics were selected to incorporate nicotine within electrolyte-crosslinked alginate-hydroxyethylcellulose gelispheres compressed within a release rate-modulating external polymeric matrix, comprising either hydroxypropylmethylcellulose (HPMC), polyethylene oxide (PEO), or poly(lactic-co-glycolic) acid (PLGA) to prolong nicotine release. The degradation and erosion studies showed that the produced device had desirable robustness with the essential attributes for entrapping drug molecules and retarding their release. Zero-order drug release was observed over 50 days from the device comprising PLGA as the external matrix. Furthermore, the alginate-nicotine interaction, the effects of crosslinking on the alginate-hydroxyethycellulose (HEC) blend, and the effects of blending PLGA, HPMC, and PEO on device performance were mechanistically elucidated using molecular modelling simulations of the 3D structure of the respective molecular complexes to predict the molecular interactions and possible geometrical orientation of the polymer morphologies affecting the geometrical preferences. The compressed polymeric matrices successfully retarded the release of nicotine over several days. PLGA matrices offered minimal rates of matrix degradation and successfully retarded nicotine release, leading to the achieved zero-order release for 50 days following exposure to simulated cerebrospinal fluid (CSF).

Keywords: PLGA discs; alginate gelispheres; crosslinked matrices; powder flow properties; prolonged release; textural analysis.

Figure 1

Physical properties of compressed polymeric discs following exposure to simulated CSF over a period of 30 days: (a) Changes in the Brinell Hardness Number (N/mm²; N = 3; SD < 23.67 N/mm²); (b) Matrix erosion (%; N = 3; SD < 0.05%); and (c) Changes in conductivity (µSiemens; N = 3; SD < 16.34 µS).

Figure 2

Scanning electron micrographs (Magnification 65×) of compressed: (a) PLGA, (b) HPMC–PLGA, and (c) PEO-PLGA discs following exposure to simulated cerebrospinal fluid (CSF) after 21 days.

Figure 3

Drug released (%) from: (a) nicotine-loaded reinforced alginate gelispheres, and (b) nicotine-loaded reinforced alginate gelispheres compressed into polymeric discs following exposure to simulated cerebrospinal fluid (CSF) over a period of 50 hours (N = 3; SD < 0.53) and 50 days (N = 3; SD < 0.59%) respectively.

Figure 4

Visualization of geometrical preferences of nicotine in complexation with alginate after molecular mechanics simulations. Color codes: C (cyan), O (red), N (blue), and H (white).

Figure 5

Visualization of geometrical preference of (a) Hydroxyethyl cellulose in complexation with alginate; (b) oligosaccharide–Ca²⁺ complex, and (c) oligosaccharide–Ba²⁺ complex derived after molecular mechanics simulations. Color codes: C (cyan), O (red), N (blue), Ca (yellow), Ba (brown), and H (white).

Figure 6

Visualization of geometrical preference of (a) PLGA in complexation with HPMC; (b) PEO in complexation with HPMC; (c) PLGA–HPMC–PEO tripolymeric comples with PEO H-bonded to HPMC; and (d) PLGA–HPMC–PEO tripolymeric complex with PLGA H-bonded to HPMC after molecular mechanics simulations. Color codes: C (cyan), O (red), N (blue), and H (white).