Research paper
pH- and temperature-sensitive release behaviors from polyelectrolyte complex films composed of chitosan and PAOMA copolymer

https://doi.org/10.1016/j.ejpb.2004.08.002Get rights and content

Abstract

This paper describes the pH and temperature effects on drug release from polyelectrolyte complex (PEC) films composed of a cationic polymer, chitosan, and an anionic polymer, polyalkyleneoxide–maleic acid copolymer (PAOMA). In this study, we prepared and investigated PEC films in terms of the drug release properties as pH- and temperature-sensitive drug carriers. Drug release rates were tested at pH 3.8 and 7.2, and at 25 and 50 °C. Salicylic acid and phenol were selected as model drugs. An increase in pH from 3.8 to 7.2 resulted in an increase in the rate of drug release because of the repulsive forces between carboxyl groups in PAOMA and anionic groups in model drugs. When the hydrophobic PAOMA was used as a polyanion, the drug release rate increased at 50 °C. This is attributed to the increase of release area due to the phase transition of PAOMA and the increase of repulsive forces between carboxyl groups in PAOMA and anionic groups in model drugs.

Introduction

Much interest has been focused on polymer systems that show a phase transition in response to external stimuli such as temperature, pH, ionic strength and electric potential. Stimuli-sensitive biodegradable and biocompatible films and hydrogels have recently shown enormous potential in controlled release drug delivery applications [1], [2], [3]. Temperature-sensitive hydrogels are one of the most commonly studied classes of stimuli-sensitive systems [4], [5]. Poly(N-isopropylacrylamide) (PNIPAAm) is a typical polymer among the temperature-sensitive polymers investigated to date because it has a lower critical solution temperature (LCST) in the range of 25–32 °C [6], [7], [8]. However, the clinical applications of PNIPAAm hydrogels are limited due to the carcinogenic or teratogenic toxicity of the monomer and crosslinkers used in PNIPAAm synthesis [1]. In addition, PNIPAAm and its derivatives are not biodegradable [1].

Chitosan (CS), poly-β-(1-4)-2-amino-2-deoxy-d-glucose, is a naturally occurring biodegradable and biocompatible cationic polysaccharide derived from the N-deacetylation of chitin. CS has found wide utility in applications ranging from tissue engineering to drug delivery [9], [10], [11], [12], [13], [14]. At acidic pH ranges, the ionizable amino groups in CS molecules are protonated. Therefore, the formation of polyelectrolyte complexes (PEC) with polyanionic molecules have been widely reported [13], [14]. Polyalkylenoxide–maleic acid copolymer (PAOMA) is an anionic polymer with excellent biocompatibility and unique amphiphilic properties. Especially, a series of PAOMA have various LCST with changing the alkyleneoxide (AO) chain composition. Using these unique polymeric materials, enzyme modification [15], [16] and protein separation [17] have been conducted.

Electrostatic interactions between the cationic CS and the anionic PAOMA result in the formation of a PEC [2]. The swelling, drug permeation and release properties of PEC can be controlled by pH- and temperature-changes. The high biocompatibility of PEC films provides potential for therapeutic applications as a stimuli-sensitive drug delivery carrier.

In previous study [18], we prepared PEC films composed of CS and PAOMA and investigated the pH- and temperature-responsive permeation from the films using model drugs. As a result, we confirmed that those PEC films have pH- and temperature-sensitivity for equilibrium swelling. In addition, the increase in temperature from 25 to 50 °C and the decrease in pH from 7.2 to 3.8 yielded an increase in the rate of drug permeation.

In this study, we prepared the model drug-loaded CS/PAOMA films and investigated the effect of pH and temperature on drugs release. The model drugs used were salicylic acid and phenol. In addition we observed the surface morphology of the films by SEM to correlate the drug release mechanism with the microstructure of the films.

Section snippets

Materials

CS (degree of acetylation, 0.085; average molecular weight, 106) was provided from Kyowa Tecnos Co. Ltd, Japan. PAOMA (AEM-0530, AKM-0530) were supplied from Nippon Oil and Fats Co., Japan. The structures of the polymers used are shown in Fig. 1, Fig. 2. Table 1 shows the PAOMA copolymer composition, molecular weight and cloud point. Cloud point was measured as follows: PAOMA aqueous solution (2 g dm−3, 7 cm3) was prepared and settled in a temperature-constant bath. Temperature of the bath was

Results and discussion

Both dried PEC films and model drug-loaded films were easily peeled off from petri dishes. Those freshly prepared films were transparent and had a thickness of ca. 60 μm. The surface morphology of dried film was quite smooth and uniform, and the cross-sectional morphology was equally dense and homogeneous.

Conclusion

Drug release characteristics of PEC films prepared from CS and PAOMA were studied. Salicylic acid and phenol were used as model drugs. These PEC films were shown to change drug release rate in response to changes in environmental pH and temperature. The drug release was higher in pH 7.2 media compared to pH 3.8 because of the increase of repulsive force between carboxyl groups in PAOMA and anionic groups in model drugs and the increase of effective diffusion area. Temperature-sensitive drug

Acknowledgements

We wish to thank Nippon Oil and Fats Co. and Kyowa Tecnos Co. Ltd for providing PAOMA and chitosan, respectively. We are grateful to Prof. S. Hirose at International Student Center, Tokyo Institute of Technology, for his helpful discussion.

References (26)

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