Drug release characteristics from chitosan–alginate matrix tablets based on the theory of self-assembled film

Abstract

The aim of this study was to better understand the underlying drug release characteristics from chitosan–alginate matrix tablets containing different types of drugs. Theophylline, paracetamol, metformin hydrochloride and trimetazidine hydrochloride were used as model drugs exhibiting significantly different solubilities (12, 16, 346 and >1000 mg/ml at 37 °C in water). A novel concept raised was that drugs were released from chitosan–alginate matrix tablets based on the theory of a self-assembled film-controlled release system. The film was only formed on the surface of tablets in gastrointestinal environment and originated from chitosan–alginate polyelectrolyte complex, confirmed by differential scanning calorimetry characterization. The formed film could decrease the rate of polymer swelling to a degree, also greatly limit the erosion of tablets. Drugs were all released through diffusion in the hydrated matrix and polymer relaxation, irrespective of the drug solubility. The effects of polymer level and initial drug loading on release depended on drug properties. Drug release was influenced by the change of pH. In contrast, the impact of ionic strength of the release medium within the physiological range was negligible. Importantly, hydrodynamic conditions showed a key factor determining the superiority of the self-assembled film in controlling drug release compared with conventional matrix tablets. The new insight into chitosan–alginate matrix tablets can help to broaden the application of this type of dosage forms.

Introduction

Hydrogels are three-dimensional, hydrophilic, polymeric networks capable of imbibing large amounts of water or biological fluids (Peppas et al., 2000). In recent years, a number of studies have greatly contributed to the understanding of polysaccharide hydrogel networks, with numerous systems of this unique class of materials being proposed. Polysaccharide hydrogels that swell in an aqueous medium have been widely used to formulate extended-release tablets (Coviello et al., 2007). The release of drugs from swellable systems usually depends on one or more of the following processes: wetting of the polymer matrix by the solvent, swelling of the polymer, diffusion of drug through the hydrated polymer, dissolution of drug in the solvent and erosion of polymer (Gupta et al., 2001).

Among the polysaccharide hydrogels reported so far, anionic alginate has been employed to control the release of drugs. Sodium alginate (SA) is a naturally occurring anionic polymer typically obtained from brown seaweed, and is known to be a whole family of linear copolymers containing blocks of (1,4)-linked β-D-mannuronate (M) and α-L-guluronate (G) residues. Alginate has been extensively investigated and used for many biomedical applications due to its biocompatibility, low toxicity, relatively low cost, and mild gelation by addition of divalent cations such as Ca²⁺. The conventional role of alginate in pharmaceutics includes serving as thickening, gel forming and stabilizing agents. In addition, alginate also plays a significant role in controlled release drug products, especially in oral dosage forms (Lee and Mooney, 2012). However, based on its swelling and erosion characteristics, alginate can only control the release of drug for 8–10 h (Liew et al., 2006, Sriamornsak et al., 2007). Meanwhile, in a matrix tablet, pH-sensitivity of alginate could affect the characteristics of the diffusion barrier, which regulates drug release from such delivery systems. At pH below the pK_a of M (3.38) and G (3.65) monomers, soluble sodium alginate is converted to insoluble alginic acid, which induces crack formation or lamination of alginate matrix tablet, leading to burst release of drug in gastric environment. This compromises the integrity of drug diffusion barrier and results in loss of controlled drug release. These problems potentially limit the use of alginate as a single matrix in tablets for oral drug delivery (Ching et al., 2008). Therefore, matrix mixture based on alginate and other polymers are being investigated. Alginate has already been widely exploited in many drug delivery applications in combination with chitosan (George and Abraham, 2006).

Chitosan (CS) is a cationic polymer and has already been the subject of interest for its use as polymeric drug carriers in dosage form design due to its appealing properties such as biocompatibility, biodegradability, low toxicity and relatively low production cost from abundant natural sources (Mao et al., 2010, Rinaudo, 2006). Polyelectrolyte complexation between chitosan and alginate was previously reported and the corresponding polyelectrolyte complex was synthesized by reacting the two polymers in solutions (George and Abraham, 2006). Although polyelectrolyte complex as the matrix of controlled release has some obvious advantages, such as increasing the controlled-release ability, reducing the pH dependence, preparation of polyelectrolyte complex was a lengthy process (Park et al., 2008). The polyelectrolyte complex was freeze-dried for over a 24 h period before utilized as a matrix for controlled drug release (Li et al., 2009). As an alternative for this lengthy process, here we propose in situ chitosan–alginate polyelectrolyte complexation in simulated gastrointestinal fluid as a tool for controlling drug release. Our previous study demonstrated that in situ chitosan–alginate polyelectrolyte complexation happened in gastrointestinal environment when physical mixtures of chitosan–alginate were employed as tablet matrix (Zhang et al., 2010).

However, although in situ polyelectrolyte complex of CS–SA as the matrix of tablets has already been mentioned in our early report, knowledge on the applicability of this approach to different types of drugs is absent. Moreover, the effects of polymer level, drug loading in the formulation on the resulting drug release patterns are still unknown, which are critical in the release of drugs (Maderuelo et al., 2011). In addition, since polyelectrolyte complex was formed upon processing CS–SA matrix tablets in the simulated gastrointestinal fluid, factors affecting polyelectrolyte complex formation should be considered (Sun et al., 2008). Meanwhile, most previous reports about CS–SA as the tablets matrix still treated this system with conventional mechanisms (water uptake, swelling and erosion) (Tapia et al., 2005). Thus, further analysis of drug release mechanisms from CS–SA based systems is required.

Therefore, the main objectives of this study are (i) to better understand the importance of in situ polyelectrolyte complex film for the control of drug release from chitosan–alginate matrix tablets, and (ii) to evaluate the release characteristics and mechanisms based on various factors (type of drugs, polymer level, drug loading, pH).