Chitosan–alginate multilayer beads for controlled release of ampicillin

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Abstract

The aim of this study is to develop multilayer beads with improved properties for controlled delivery of the antibiotic ampicillin. Ionotropic gelation was applied to prepare single and multilayer beads using various combinations of chitosan and Ca2+ as cationic components and alginate and polyphosphate as anions. Beads prepared with higher concentrations of chitosan entrapped more ampicillin. During incubation in simulated gastric fluid, the beads swelled and started to float but did not show any sign of erosion. Single layer chitosan–alginate beads released 70% of the drug within 4 h. Multilayer beads released only 20–30% in the same period of time. During subsequent incubation in simulated intestinal fluid, both single and multilayer beads continued to release drug. At least part of this release is due to disintegration of the beads. The rate of release both in gastric and intestinal fluid and the kinetics of disintegration in intestinal fluid can be controlled by changing the chitosan concentration in the coagulation fluid. The release of the drug can also be controlled by the degree of cross-linking using polyphosphate. Cross-linked multilayer beads were prepared that released only 40% of the entrapped drug during 24 h. It is concluded that chitosan–alginate multilayer beads, cross-linked with polyphosphate offer an opportunity for controlled gastrointestinal passage of compounds with low molecular weight like ampicillin.

Introduction

Ideally, a drug delivery system releases the drug in the right body compartment at the rate required for a specific treatment. Most available drug delivery systems use biodegradable, biocompatible and natural biopolymers and are capable of rate and/or time controlled drug release. Considerable research efforts are being spent on oral sustained drug delivery systems, with the majority of these systems being solid dosage forms. They distribute their drug load more uniformly in the gastrointestinal tract with the aim to reduce local irritation (Lauwo et al., 1990, Bodmeier et al., 1991).

Beads loaded with antibiotics would be useful for oral delivery to treat gastric diseases such as peptic ulcer (Shu and Zhu, 2000, Remuñañ-Lỏpez et al., 2000, Orienti et al., 2002) and for ulcerative colitis, carcinomas and infections in the intestine (Shah et al., 1999, Tozaki et al., 2002). In addition, sustained systemic absorption specifically in the intestinal region offers interesting possibilities for the treatment of diseases susceptible to the diurnal rhythm, such as asthma, arthritis or inflammation (Yeh et al., 1995, Tozer et al., 1995, Lorenzo-Lamosa et al., 1998). Ampicillin, being a broad spectrum antibiotic, is commonly used for systemic therapy as well as locally for gastric or intestinal infections. It is acid resistant and therefore can be given orally. It has a short biological half-life of 0.75–1.5 h. In order to make the application of ampicillin more effective, research has been directed to design formulations for its sustained and controlled release.

The biopolymer, chitosan, the N-deacetylated product of the polysaccharide chitin, is gaining importance in the pharmaceutical field owing to its unique polymeric cationic character, good biocompatibility, non-toxicity and biodegradability. Chitosan has been proposed as a useful excipient for either sustained release of water-soluble drugs and for enhancing the bioavailability of poorly water-soluble compounds. Large chitosan microspheres and beads (with diameter up to a few millimeters) have been proposed for the controlled release of drugs (Sezer and Akbûga, 1995, Remuñan-Lỏpez et al., 1998, Mi et al., 1999a, Mi et al., 1999b). In order to achieve sufficient stability, chitosan gel beads and microspheres are often chemically cross-linked with glutaraldehyde (Jameela and Jayakrishnan, 1995, Berthold et al., 1996, Genta et al., 1997) and ethylene glycol diglycidyl ether (Mi et al., 1999a, Mi et al., 1999b). However, residues of these compounds in the chitosan beads can cause damage or irritation to mucosal membranes and may induce undesirable side effects (Bodmeier et al., 1991, Jameela and Jayakrishnan, 1995, He et al., 1999). Recently, polyelectrolyte complexes have been proposed for the design of drug delivery systems. Cationic chitosan can form gels with non-toxic multivalent anionic counterions such as polyphosphate (Bodmeier et al., 1989, Lin and Lin, 1992, Mi et al., 1999a, Mi et al., 1999b) and sodium alginate (Aral and Akbûga, 1998, Anal et al., 2003) by ionic cross-linking.

In this study, we prepared chitosan–alginate multilayer beads cross-linked with polyphosphate to develop a stable, non-toxic, interpolymer complex of ionic-cross-linked chitosan–alginate–tripolyphosphate (TPP) beads with improved drug release properties. TPP is a non-toxic and multivalent anionic compound. It can form a gel by ionic interaction with the positively charged amino groups of chitosan. These reinforced beads have been investigated for sustained release under conditions representative for the gastro-intestinal system. This report shows the drug entrapment and drug release behavior in the case of model drug, ampicillin for various single and multilayer chitosan–alginate beads. Drug release was studied in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF).

Section snippets

Materials

Alginic acid (sodium salt) extracted from brown algae (molecular weight 200 kD) with a glucuronic:manuronic acid (G:M) ratio of 2:1, and calcium chloride dihydrate were obtained from Fluka Chemika, ampicillin and tripolyphosphate (TPP) from Sigma Chemicals, USA. The 2% (w/v) aqueous solution of sodium alginate exhibits a viscosity of 220 cp at 25 °C. Chitosan (85% degree of deacetylation, molecular weight 103 kD) was prepared in author's laboratory from shrimp shell (Penaeus monodon) after

Results and discussion

Single chitosan–alginate beads (Table 1, A0–A3) were obtained by dropping aqueous solution of sodium alginate into the coagulation fluid containing (0–0.8%, w/v) chitosan and 3% CaCl2 (w/v). Beads were also obtained by post-coagulation treatment of calcium-alginate beads with chitosan (A4). Multilayer beads (A5 and A6) were obtained by treating the beads more times in a coagulation fluid. The beads after additional treatment with chitosan were intact and compact. The beads, additionally treated

Conclusions

Experiments were done to establish the optimum conditions for the preparation of homogenous and spherical chitosan–alginate single and multilayer beads with a smooth surface. The beads were prepared by dropping an alginate–ampicillin mixture in calcium-chitosan and also by dropping of a chitosan–ampicillin mixture in a mixture of TPP and alginate. Chitosan beads are more efficient in the entrapment of the drug. Chitosan drops loose less of their drug content during ionotropic gelation. Chitosan

Acknowledgement

The authors are grateful to the late Prince Leo de Lignac for his financial support and to Prof. Hans E. Junginger, Department of Pharmaceutical Technology, Leiden University, The Netherlands for review. Due thanks to Prof. Suwalee Chandrkrachang, Dr. Korbtham Sathirakul, Dr. M.S. Rao and Mr. Deepak Bhopatkar for their valuable suggestions and help.

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