Formulation of Controlled Release Hydrogel Microspheres using Acrylate Derivatives: In vitro and Invivo Studies

Abstract

The aim of present study was to develop, characterize, in-vitro and in vivo evaluation of copolymeric pH sensitive microgels/hydrogel microspheres for controlled drug delivery of antihypertensive drugs (nifedipine and diltiazem HCl). Itaconic acid which is a highly hydrophilic monomer having two carboxylic acid groups on side chain and able to form hydrogen bonds with corresponding groups. Due to the double ionization of IA at different pH values, stepwise release behavior was observed for specially adsorbed drugs or other adsorbents by controlling the pH of the medium. Butyl acrylate and 2-ethyl hexyl acrylate (EHA) are hydrophobic monomers which are used to make pH responsive microgels through co-polymerisation with itaconic acid. Nifedipine and diltiazem HCl are calcium channel blockers, are used for the treatment of hypertension and angina pectoris. Due to the poor bioavailability of drugs which undergo first pass hepatic metabolism, pH sensitive copolymeric microgels/ hydrogel microspheres of these antihypertensive drugs were developed. Suspension polymerization technique is used to synthesize pH sensitive copolymeric butyl acrylate-co- itaconic acid p (BA- co-IA) and 2-ethyl hexyl acrylate -co- itaconic acid p (EHA- co-IA) hydrogel microspheres or microgels by using different ratios of monomers with the addition of 5% ethylene glycol dimethacrylate (EGDMA) as crosslinker and 1% benzoyl peroxide (BPO) as an initiator. P (BA- co-IA) hydrogel microspheres or microgels were loaded with nifedipine and p (EHA- co-IA) hydrogel microspheres or microgels loaded with diltiazem HCl by equilibrium swelling method after preparation of empty microgels. Prepared hydrogel microspheres or microgels were evaluated by fourier transforms infrared spectroscopy (FTIR), scanning electron microscopy (SEM), x-ray diffractometry (XRD), thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC). FTIR analysis of both p (BA- co-IA) and p (EHA-co-IA) microgels confirmed the formation of copolymer. FTIR, DSC and X-RD techniques were used to confirm the chemical stability of nifedipine and diltiazem HCl after encapsulation into prepared formulations. TGA of both formulations p (BA- co-IA) and p (EHA-co-IA) indicates that prepared microgels showed much better thermal stability than pure drug nifedipine and diltiazem HCl respectively. SEM images showed that both formulations were spherical in shape. The size distribution of p (BA- co-IA) and p (EHA- co-IA) hydrogel microspheres was found between 4.145μm to 10μm and 4.145 μm to 20 μm respectively using the malvern nanosizer ZS instrument. The nifedipine was encapsulated into prepared hydrogel microspheres maximum up to 67% and maximum % yield was about 72 %. p (EHA- co-IA) hydrogel microspheres were loaded with diltiazem HCl up to 96 % and their % yield were up to 76 %. In vitro release studies of both formulations confirmed the pH sensitivity of the prepared hydrogel microspheres. By appling korsmeyer-peppas equation to cumulative drug release data of both formulations to calculate the diffusion exponent (n), this follows non-Fickian diffusion. These pH sensitive hydrogel microspheres loaded with antihypertensive drugs (nifedipine and diltiazem HCl) are validated in rabbit plasma by HPLC analysis and then in vivo studies of these formulations were performed in rabbits.