Novel Polymeric Prodrugs of Valproic Acid as Anti- Epilepsy Drugs: Synthesis, Characterization and &lt;i&gt;In-vitro&lt;/i&gt; Evaluation

Sn Amiryaghoubi,M Babazadeh

doi:10.4314/tjpr.v14i7.9

Abstract

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 ( 1 H and 13 C-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 o C. 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

Highlights

Polymeric prodrugs or polymer-drug conjugations are novel technique for drug delivery systems
We reported the synthesis and in-vitro evaluation of some acrylic-type polymeric prodrugs of non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen, ketoprofen, diclofenac, and 5-aminosalicylic acid [21,22,23,24,25,26,27,28]
A solution of sodium valproate as a nucleophilic reagent reacted with benzyl chloride bonds in polymers with replacement of the chlorine atoms to give new polymeric prodrugs and valproic acid (VPA) substituents attached to phenyl rings via methylene spacer

Summary

INTRODUCTION

Polymeric prodrugs or polymer-drug conjugations are novel technique for drug delivery systems In these systems, macromolecular chains act as carriers for drugs in a physically bound state or by true chemical linkages as side groups. The solution was shaken vigorously in a thermostatic water bath at 70 ± 1 oC under argon for 12 h After this time, the resulted yellowish viscous solution was poured into 120 ml of cooled methanol as a non-solvent. A solution of 2 g (12 mmol) of sodium valproate in DMF (30 ml) was added dropwise from dropping funnel with stirring to solution of polymers into flask at room temperature. The CMS was hompolymerized and copolymerized with HEMA and MMA by free radical polymerization technique at 70 ± 1 oC using AIBN to obtain amorphous P1-P3.

Method of hydrolysis

CONCLUSION