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      Development and characterization of gastroretentive sustained-release formulation by combination of swelling and mucoadhesive approach: a mechanistic study

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          Acyclovir has pharmacokinetic limitations, including poor oral bioavailability of 15%–30%, high variability, and short elimination half-life of 2.3 hours. These limitations necessitate frequent administration of acyclovir, up to five times daily, leading to poor patient compliance, which in turn leads to a reduction in therapeutic efficacy and development of resistance.


          A gastroretentive sustained-release (GR) formulation of acyclovir, based on a combination of swelling and mucoadhesive mechanisms, has been developed. Composition has been optimized after evaluation of different polymers, carbomer, polyethylene oxide, and sodium alginate alone and/or in combination. GR formulations were characterized for in-process quality-control tests, drug release and release rate kinetics, similarity factor analysis, swelling index, and matrix erosion.


          A formulation containing a combination of carbomer and polyethylene oxide had the highest similarity of drug release compared with a target drug-release profile obtained by pharmacokinetic simulations. The measurement of mucoadhesive strength, carried out with a texture analyzer, showed that the mucoadhesive strength of the GR formulation was significantly higher than that of the immediate-release (IR) tablet. The optimized GR formulation was found to be retained in the upper part of the gastrointestinal tract for 480 minutes; the IR tablet was retained for only 90 minutes as measured using a gastrointestinal retention study in albino rabbits. The GR formulation was also found to maintain more sustained plasma concentrations than the IR tablet. Mean residence time of the GR formulation was 7 hours versus 3.3 hours for the IR formulation. The relative bioavailability of the GR formulation was 261% of the IR formulation.


          The GR formulation of acyclovir, based on swelling and mucoadhesive mechanisms, has prolonged retention in the upper gastrointestinal tract, sustained in vitro drug release, prolonged in vivo absorption, and better bioavailability than the IR formulation. Such a formulation would improve patient compliance and increase the efficacy of therapy.

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          Most cited references 53

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          Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC).

          The objective of this article is to review the spectrum of mathematical models that have been developed to describe drug release from hydroxypropyl methylcellulose (HPMC)-based pharmaceutical devices. The major advantages of these models are: (i) the elucidation of the underlying mass transport mechanisms; and (ii) the possibility to predict the effect of the device design parameters (e.g., shape, size and composition of HPMC-based matrix tablets) on the resulting drug release rate, thus facilitating the development of new pharmaceutical products. Simple empirical or semi-empirical models such as the classical Higuchi equation and the so-called power law, as well as more complex mechanistic theories that consider diffusion, swelling and dissolution processes simultaneously are presented, and their advantages and limitations are discussed. Various examples of practical applications to experimental drug release data are given. The choice of the appropriate mathematical model when developing new pharmaceutical products or elucidating drug release mechanisms strongly depends on the desired or required predictive ability and accuracy of the model. In many cases, the use of a simple empirical or semi-empirical model is fully sufficient. However, when reliable, detailed information are required, more complex, mechanistic theories must be applied. The present article is a comprehensive review of the current state of the art of mathematical modeling drug release from HPMC-based delivery systems and discusses the crucial points of the most important theories.
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            Expandable gastroretentive dosage forms.

            Expandable gastroretentive dosage forms (GRDFs) have been designed for the past 3 decades. They were originally created for possible veterinary use, but later the design was modified for enhanced drug therapy in humans. These GRDFs are easily swallowed and reach a significantly larger size in the stomach due to swelling or unfolding processes that prolong their gastric retention time (GRT). After drug release, their dimensions are minimized with subsequent evacuation from the stomach. Gastroretentivity is enhanced by the combination of substantial dimensions with high rigidity of the dosage form to withstand the peristalsis and mechanical contractility of the stomach. Positive results were obtained in preclinical and clinical studies evaluating GRT of expandable GRDFs. Narrow absorption window drugs compounded in such systems have improved in vivo absorption properties. These findings are an important step towards the implementation of expandable GRDFs in the clinical setting. The current review deals with expandable GRDFs reported in articles and patents, and describes the physiological basis of their design. Using the dog as a preclinical screening model prior to human studies, relevant imaging techniques and pharmacokinetic-pharmacodynamic aspects of such delivery systems are also discussed.
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              Gastric retention properties of superporous hydrogel composites.

              In many applications, usefulness of conventional hydrogels is limited by their slow swelling. To improve the swelling property of the conventional hydrogels, we have synthesized superporous hydrogels (SPHs) which swell fast to equilibrium size in minutes due to water uptake by capillary wetting through numerous interconnected open pores. The swelling ratio was also large in the range of hundreds. The mechanical strength of the highly swollen SPHs was increased by adding a composite material during the synthesis. The composite material used in the synthesis of SPH composites was Ac-Di-Sol((R)) (croscarmellose sodium). The gastric retention property of the prepared SPH composites was tested in dogs both in fasted and fed conditions. The SPH composites were placed in a hard gelatin capsule (size 000) for oral administration. All dogs tested were fasted for 36 h before experiments. Under the fasted condition, the SPH composite remained in the stomach for 2-3 h after before breaking into two pieces and being emptied. When food was given before the experiment just once following 36 h of fasting, the SPH composite remained in the stomach for more than 24 h, even though the fed condition was maintained only for the first few hours. Our study indicated that SPH composites possessed three properties necessary for gastric retention: fast swelling; superswelling; and high mechanical strength. While more improvements need to be made, the SPH composites provide the basis for the development of effective long-term gastric retention devices.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Dove Medical Press
                05 December 2013
                : 7
                : 1455-1469
                [1 ]Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
                [2 ]Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, India
                Author notes
                Correspondence: Subheet Kumar Jain, Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, 143 005, India, Tel +91 183 225 8802, Fax +91 183 225 8819, Email subheetjain@ 123456gmail.com
                © 2013 Sankar and Jain. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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