Abstract:
The recent advancement of high throughput screening for potential therapeutic agents resulted in a large pool of hydrophobic drug candidates. This scenario challenges the pharmaceutical industries to establish a suitable formulation layout to tackle the highly variable bioavailability and erratic absorption profiles of hydrophobic drugs. The role of polymer as carrier in the drug delivery is no doubt crucial for which biodegradable and biocompatible polymer carriers from renewable resources are looked upon with growing interest in the pharmaceutical industry. In view of that,
hyperbranched poly(glycerol esteramide) (PGEA) with weight average molecular weight (Mw) ranging from 5000 to 12000 Da were synthesised through a solvent-free and catalyst-free condition whereby stearic acid was reacted with diethanolamine to produce diethanolamide; glycerol was reacted with aliphatic dicarboxylic acid to prepare poly(glycerol ester); and diethanolamide was reacted with poly(glycerol ester) to produce PGEA. The physico-chemical properties of the synthesised PGEA were evaluated through wet lab analyses, e.g., acid value, amine value and hydroxyl value.
The Mw distribution and polydispersity index (PDI) of PGEAs were determined by Gel Permeation Chromatography (GPC). Fourier Transform Infrared (FTIR), 1H and 13C-Nuclear Magnetic Resonance (NMR) spectroscopies were used to elucidate the chemical structure of PGEAs. Differential Scanning Calorimetry (DSC) and X-Ray Diffraction (XRD) analyses were used to study the melting points and crystallinity of the synthesised PGEAs, respectively. Selected synthesised PGEAs were used to formulate solid dispersions (SD) to improve the dissolution and solubility of the hydrophobic model drug, lovastatin (LOV). Through extensive optimisation process via in vitro dissolution study, the best ratio of LOV: PGEA used in the formulation of SD is 5%: 95% w/w. The SD illustrated substantial enhancement both in dissolution
and solubility studies in which 2 fold increment in cumulative drug release and 3.7 fold increment in solubility as compared to pure LOV were observed in the respective studies. In addition, the dissolution and solubility performances of SD formulated with PGEA were compared to SDs prepared with commercial pharmaceutical carriers such as poly(ethylene glycol) and poly(vinyl pyrrolidone) as well as a marketed product,
Apo-Lovastatin. The SD formulated with PGEA (T50%= 1.5 hours; solubility= 38.27 μg/mL) was found to be superior than that of the SDs prepared with commercial carriers (T50%= 6 hours; solubility= 15.69 μg/mL) and marketed product (Apo-Lovastatin) (T50% = 5 hours; solubility= 16.97 μg/mL). SD with PGEA was also stable with respect to drug content and solubility at room temperature and accelerated conditions for up to 3 months. The biosafety of the synthesised PGEAs and the
formulated SDs was proven through MTT assay whereby inhibitory concentration of pure LOV (IC50= 55 μg/mL) increased tremendously upon formulating into SD (IC50= 3200 μg/mL) comprising of PGEA as drug carrier.
