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

#### **Pradeep Kumar, Yahya E. Choonara, Lisa C. du Toit, Neha Singh and Viness Pillay \***

Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown 2193, South Africa; pradeep.kumar@wits.ac.za (P.K.); yahya.choonara@wits.ac.za (Y.E.C.); lisa.dutoit@wits.ac.za (L.C.d.T); neni2707@gmail.com (N.S.)

**\*** Correspondence: viness.pillay@wits.ac.za; Tel.: +27-11-717-2274

Received: 13 October 2018; Accepted: 12 November 2018; Published: 15 November 2018

**Abstract:** This study aimed to develop a prolonged-release device for the potential site-specific delivery of a neuroprotective agen<sup>t</sup> (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:** alginate gelispheres; textural analysis; crosslinked matrices; PLGA discs; prolonged release; powder flow properties
