Study of Hydrogel based Controlled Release Drug Delivery System for Captopril and its in-vitro, in-vivo Evaluation

Abstract

A foremost step towards controlled and targeted administration of therapeutic agents is development of new drug delivery systems. Oral administration is mostly preferred and desired as a non-invasive mean of providing drug at controlled rate. In present research work, hydrogels were prepared for controlled release of captopril, an angiotensin converting enzyme (ACE) inhibitor, used for the treatment of hypertension. Three types of hydrogel formulations were prepared by different proportions of polymers and monomers. A chemical crosslinking method, free radical polymerization was selected for synthesis of polymeric networks, involving use of thermostatic water bath as well as induction by microwave radiations. A microwave assisted hydrogel synthesis, was used for preparation of hydroxypropyl methylcellulose-graft-poly(vinyl alcohol)-co-poly(acrylic acid) copolymeric network. N,N-methylenebisacrylamide and potassium persulfate (KPS) were used as crosslinking agent and initiator, respectively. Formulations with same combinations of polymers and monomers were also prepared by utilizing conventional thermostatic water bath. The hydrogels obtained by these techniques were compared with each other in terms of morphological properties, swelling ratios, drug loading and drug release behavior. The hydrogel formulations were also prepared by crosslinking of 2-acrylamido-2-methyl-1- propanesulfonic acid (AMPS) and acrylic acid with hydroxypropyl methylcellulose (HPMC). These hydrogels had shown higher ability to absorb and retain aqueous solutions and solute particles. Another type of polymeric network was synthesized under influence of microwaves radiations, with lower initiator concentration, by crosslinking of poly(vinyl alcohol) (PVA) with 2-acrylamido-2-methyl-1-propanesulfonic acid (AMPS). They have ability to exhibit relatively higher swelling behavior at pH 2 in comparison to pH 7.4 and have gastro retentive characteristics. Due to their massive swelling tendencies, these could be retained in stomach and unable to pass through next segment of gastrointestinal tract. Thus, after oral administration of captopril loaded hydrogels, they could have ability to release drug continuously at acidic pH of stomach, in a control manner for longer time periods. The results of drug release are according to swelling powers of formed copolymeric hydrogels. 6 All types of hydrogel formulations prepared were evaluated by in-vitro and in-vivo analytical procedures. The in-vitro characterization was done by Fourier Transform Infrared Spectroscopy (FT-IR), scanning electron microscopy (SEM), X-ray diffraction (XRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), swelling properties, drug loading and release. The drug release was evaluated by the application of zero order kinetics, first order kinetics, Higuchi model, Korsmayer-Peppas model and Weibull model. The hydrogels selected on the basis of their in-vitro evaluation were subjected to in-vivo characterization. High performance liquid chromatography (HPLC) method, with UV detector was utilized for in-vivo characterization. The study was performed on twenty four rabbits and liquid-liquid extraction procedure was used for separation of captopril from plasma samples. The bioavailability and pharmacokinetic parameters were determined by kinetica (version 5.0). The maximum concentration (Cmax) of captopril was reduced while time to reach maximum concentration (Tmax) was increased by hydrogels in comparison to control (free drug enclosed in hard gelatin capsules). The values of area under curve AUC (calculated by trapezoidal rule) and elimination half-life were higher for controlled release hydrogel formulations than control. The drug could be available for longer periods of time after administration of captopril loaded hydrogels, maintaining optimum concentration in blood, exerting its efficacious effects as an antihypertensive therapeutic agent.