In-situ fast gelling formulation for oral sustained drug delivery of paracetamol to dysphagic patients

https://doi.org/10.1016/j.ijbiomac.2019.05.092Get rights and content

Abstract

Evaluation of the potential for oral sustained drug delivery of formulations with in-situ gelling properties is the main objective of the present investigation. Oral administration of aqueous dispersion of sodium alginate (1.5% w/v) containing calcium ions in complex form resulted in the formation of gel matrix as a consequence of the release of the calcium ions in the acidic environment of stomach fluid. Addition of methylcellulose, sodium chloride and polyethylene glycol improved the drug retention efficacy of the gel. In this investigation, the study on the influence of added excipients on the rheological and drug release properties of the formulations has been focused. In-vitro studies demonstrated diffusion-controlled release of paracetamol from the gels. The bioavailability of orally administered paracetamol from the in-situ gel F4 (composed of 1.5% sodium alginate, 1.5% methyl cellulose, 3% CaCO3, 2% NaCl 0.05% polyethylene glycol) administered in the stomach of rabbit, was more sustained as compared to the commercially available suspension Calpol® containing an identical dose of paracetamol.

Introduction

Geriatric and dysphasic patients often have problems with swallowing solid oral delivery systems, but compliance with easily swallowable thickened liquid preparations. Paracetamol is generally administered in tablet or liquid form [[1], [2], [3]]. Several in-situ gelling oral liquid formulations have been developed for sustained drug release. Use of natural and synthetic polymers such as gellan gum, xyloglucan, pectin, chitosan, and sodium alginate (NaAlg) develop the in-situ gel forming drug delivery systems to improve patient compliance [4,5]. NaAlg, a water-soluble polysaccharide having good membrane forming property, can be readily cross-linked with Ca2+ ions [6]. Alginate is a linear chain structure of (1, 4)-linked β-D-mannuronic acid and α-L-glucuronic acid residues. Alginates show characteristic ion binding for multivalent cation [6]. For sustained release of drugs, the Calcium-induced alginate beads have been used in various ways in the gastrointestinal tract. Many investigations have been focused on the use of alginate gels for the sustained release of drugs and Nakano et al. studied on the investigation of the tablets containing sodium alginate for the sustained release of theophylline [7]. Sustained release effects of matrices containing sodium alginate and calcium salt have been investigated [8].

In the present study we investigated the possibility of exploiting the in-situ floating gel characteristics of sodium alginate for oral drug delivery. The formulation adopted is an alginate solution containing methyl cellulose as viscosity enhancer, calcium carbonate (as a source of Ca2+ ions), and sodium chloride, which forms complex with the free Ca2+ ions and releases them only in the highly acidic environment of the stomach [9,10]. Incorporation of polyethylene glycol modified the drug release by instantaneous gelation. In order to increase the length of time available for drug absorption, attempts have been made to extend the gastrointestinal transit times of oral drug delivery systems by prolonging their gastric residence [11]. The gel, formed from in-situ gelling system, being lighter than gastric fluids, floats over the stomach contents in which diffusion mechanism is responsible for drug release [12,13]. Gastroretentive in-situ gelling system helps to increase bioavailability of drug compared to conventional liquid dosage forms [14,15].

The purpose of this study is to evaluate the potential for oral sustained delivery of paracetamol. Paracetamol shows irregular absorption pattern [16] and the elimination half-life is 1–3 h. Hence paracetamol has been chosen as a model drug with an aim to develop a sustained release system for 24 h. This study reveals in-vitro and in-vivo measurements of the release of a model drug paracetamol, and a comparison of the in-vivo release characteristics with those from a commercial oral sustained release formulation.

Section snippets

Materials

Methylcellulose (MC, Metolose SM 4000) was supplied by Shin-Etsu Chemical Co. Ltd., Japan. Polyethylene glycol 6000 (PEG) was purchased from Sisco Research Laboratories Pvt. Ltd., Mumbai, India. Sodium alginate (NaAlg), CaCO3, NaCl, Potassium dihydrogen phosphate, 4-aminophenol, Acetonitrile, Hydrochloric acid was obtained from S. D. Fine-Chem Ltd., Mumbai, India. Paracetamol (PC) was obtained from Yarrow Chem. Products Wadala (E), Mumbai, India. Calpol® (LOT N299, GlaxoSmithKline

In-vitro and In-situ gelation study

The formulations of in-situ gel containing Ca2+ ions in complex form where the release of ions in the acidic medium of the stomach, ensured cross linking of NaAlg molecule resulted in gelation. The ion responsive gel forming properties of solution of 1.5% NaAlg, 1.5% MC, 3% CaCO3, 2% NaCl with/without PEG (0.05 & 5%) were observed visually when these solutions were poured into acidic fluid at pH 1.2 at 37 °C. From Table 3, it is observed that all the formulations gelled instantly when added to

Conclusion

From the present investigation, it has been demonstrated that the oral administration of aqueous dispersions containing sodium alginate, methylcellulose, polyethylene glycol, sodium chloride and calcium in complex form results in the formation of gels in rabbit stomach and it acts as depot for the sustained release of paracetamol over a period of 24 h. Similar tmax is observed for both F4 and Calpol®. The relative bioavailability is 1.29 for F4 in rabbit to those of a commercial suspension

Acknowledgements

Suraj Sharma and Gunjan Sarkar like to thank the Department of Pharmaceutics, Himalayan Pharmacy Institute and the University of Calcutta respectively for providing research facilities.

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