Novel Polymeric Prodrugs of Valproic Acid as Anti- Epilepsy Drugs: Synthesis, Characterization and In-vitro Evaluation

Purpose: To synthesize and evaluate, in-vitro, novel polymeric prodrugs of valproic acid (VPA) for antiepileptic activity.
Methods: Homopolymer of 4-chloromethyl styrene (CMS) and its copolymers with various acrylic-type monomers such as 2-hydroxyethyl methacrylate and methyl methacrylate were prepared by free radical polymerization method. VPA was then covalently linked to the obtained polymers by treating CMS polymers with sodium valproate. All the compounds were characterized by Fourier transform infrared (FT-IR), nuclear magnetic resonance (¹H and ¹³C-NMR), elemental analyses, and gel permeation chromatography (GPC). The release of VPA from polymeric prodrugs was studied using cellophane membrane dialysis bags containing aqueous buffer solutions (pH 1, 7 and 10) at 37 ℃. The quantity of released drug was detected by ultraviolet (UV) spectroscopy.
Results: ¹H-NMR and elemental analyses data for calculating mole composition of CMS polymers were relatively in good agreement. FT-IR and NMR data for the polymeric prodrugs showed attachment of drug substituents to phenyl rings of CMS units via methylene spacer. The drug-release profiles indicated that selective hydrolysis of ester bond between the drug and the polymer backbone is strongly dependent on polymer hydrophilicity and the pH of the hydrolysis solution.
Conclusion: The synthesized VPA polymeric prodrugs may be cost-effective compounds for release of VPA in vivo when formulated as controlled release systems.

Keywords
4-Chloromethyl styrene; Valproic acid; Polymeric prodrugs; Controlled release; Hydrolysis