**1. Introduction**

Parkinson's disease (PD), a central nervous system disorder, is associated with difficulties with respect to movement, typically outlined by the patient's shuffling gait due to unstable posture, bradykinesia, tremor, and rigidity. The progressive neuronal loss in PD is prolonged, requiring clinical neuroprotection and/or disease modification as therapeutic strategies for effectively reducing PD-related disability. The potential application of nicotine as a neuroprotectant in PD was demonstrated as far back as 1926 [1]. Nicotine has previously been shown to protect against the degeneration of nigrostriatal neurons via evoking the release of dopamine from the striatum [2–5]. PD is still an incurable disease. The available therapeutic options only offer symptomatic relief and

primarily aim to improve the functionality of the patient with no intervention towards the progression of the associated neurodegeneration. Additionally, a major challenge is to improve patient compliance to therapy by reducing the side-effects associated with continuous multiple dosing via the oral route subsequently leading to erratic plasma drug levels.

Generally, prolonged parenteral zero-order drug delivery systems have the capacity to minimize dose-related side-effects owing to a constant and sustained drug release profile. This is applicable specifically to drugs with narrow therapeutic indices, wherein such systems can provide a reduction in administered dose, avoidance of fluctuations in plasma drug levels, reduced frequency of administration, and hence the enhancement of patient compliance [6,7]. The use of polymers is a popular means of achieving controlled drug release due to the simplicity, cost-effectiveness, ease of manufacturing, versatility, and the ability to deliver compounds with a wide range of solubilities [8].

Hydroxypropylmethylcellulose (HPMC) and polyethylene oxide (PEO) have been used extensively to formulate controlled-release drug delivery systems. Both polymers are hydrophilic and undergo simultaneous swelling and erosion when exposed to hydration. Depending on the solubility of incorporated drugs within monolithic matrices of such polymers, the actives diffuse out into the bulk medium preceding or following erosion of the polymer [9,10]. The mechanisms relating to the swelling and hydration of hydrophilic polymeric matrices may include, but are not limited to, polymeric chain extension, disentanglement, and solvent accommodation to macroscopic characteristics such as drug release [11,12]. In addition, formulation factors such as the quantity of drug loading, drug-polymer ratio, drug particle size and molecular mass, polymer viscosity and molecular weight, and presence of formulation excipients and release modulators significantly affect the drug release rate from hydro-swelling matrices [13,14]. Poly(lactic-*co*-glycolic acid) (PLGA), a polyhydroxy acid polymeric carrier, is capable of delivering drugs as a controlled-release site-specific system and has the advantage of being moderately aqueous-soluble for controlled drug diffusion [15]. Biocompatibility studies have indicated that PLGA is biodegradable and considerably well tolerated when implanted into the CNS [16]. Consequently, no surgical intervention or procedures are required for removal of implantable devices prepared with PLGA. Fournier and co-workers (2003) established that regardless of the implantation site, PLGA devices initiate only a moderate and non-specific inflammatory reaction, mainly due to mechanical insult during the implantation procedure [16].

The purpose of this study was to incorporate nicotine-loaded alginate-hydroxyethycellulose (HEC) gelispheres into an external polymeric matrix with the aim of modulating drug release to achieve prolonged zero-order release. The alginate-HEC gelispheres were previously developed by the authors and were physically crosslinked using divalent ions [17]. HPMC, PEO, and PLGA were selected as the polymers for formulating the device due to the desirable inherent characteristics of the polymers for implantation into the CNS. The study was further aimed to elucidate the molecular mechanisms inherent to the drug-polymer interactions, formation of the gelispheres, and finally the fabrication and performance of various composite polymeric matrices using static lattice atomistic simulations.

### **2. Materials and Methods**
