Development of hot melt extruded polycaprolactone (PCL) matrices for an oral ultra-long-lasting delivery of galantamine for Alzheimer's disease therapy

Abstract

Galantamine Hydrobromide (GAL) is a tertiary alkaloid, acting as a competitive and reversible cholinesterase inhibitor. It is indicated for the symptomatic treatment of patients from mild to moderate dementia level of the Alzheimer's disease (AD) type. For treatment of mild to moderate AD, GAL is generally combined with other drugs. The purpose of this work was development and characterization of hot melt extruded (HME) matrices based on polycaprolactone (PCL) for GAL oral ultra-long-lasting delivery. PCL is a biodegradable polymer, biocompatible, water-insoluble and excellent for HME process. From HME drug and polymer mixtures arms from 1 % up to 50 wt-% of GAL were obtained. The raw materials and the as-obtained HME arms were characterized by particle size distribution (PSD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), wide angle x-ray scattering (WAXS) and dissolution test. Our findings showed that GAL possesses polymorphic crystalline form I. It is thermodynamically stable, and remains its particle size and crystalline form even after HME process. Crystallization temperature of PCL increases with GAL content, indicating strong heterogeneous nucleating effect of drug on polymer crystallization process. SEM morphological analysis indicates continuous polymeric phase on surface. However, higher amounts of GAL (50/50 wt-%) presented clusters and heterogeneity, especially in extruded cross-section. It may have influenced the drug release property, decreasing the sustained release ability, due to the transport of medium molecules through the bulk extrudates by GAL soluble clusters. The diffractograms (WAXS) showed patterns peaks of GAL and PCL, indicating that GAL remains its crystalline structure and PCL recrystallized. In the dissolution test, PCL/GAL 80/20 and 90/10 achieved 100 % drug release over seven days and profiles that can be tuned by varying GAL concentration. Finally, we demonstrate the feasibility of using HME process based on the mixture of PCL and GAL as proposals for oral therapies for conditions of AD. This is the first report showing PCL-GAL polymer matrices that achieves several-days drug release.