Design of microencapsulated chitosan microspheres for colonic drug delivery

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Abstract

Among the different approaches to achieve colon-selective drug delivery, the use of polymers, specifically biodegraded by colonic bacteria, holds great promise. In this work a new system which combines specific biodegradability and pH-dependent release is presented. The system consists of chitosan (CS) microcores entrapped within acrylic microspheres. Sodium diclofenac (SD), used as a model drug, was efficiently entrapped within CS microcores using spray-drying and then microencapsulated into Eudragit® L-100 and Eudragit S-100 using an oil-in-oil solvent evaporation method. The size of the CS microcores was small (1.8–2.9 μm) and they were efficiently encapsulated within Eudragit microspheres (size between 152 and 223 μm) forming a multireservoir system. Even though CS dissolves very fast in acidic media, at pH 7.4, SD release from CS microcores was delayed, the release rate being adjustable (50% dissolved within 30–120 min) by changing the CS molecular weight (MW) or the type of CS salt. Furthermore, by coating the CS microcores with Eudragit, perfect pH-dependent release profiles were attained. No release was observed at acidic pHs, however, when reaching the Eudragit pH solubility, a continuous release for a variable time (8–12 h) was achieved. A combined mechanism of release is proposed, which considers the dissolution of the Eudragit coating, the swelling of the CS microcores and the dissolution of SD and its further diffusion through the CS gel cores. In addition, infrared (IR) spectra revealed that there was an ionic interaction between the amine groups of CS and the carboxyl groups of Eudragit, which provided the system with a new element for controlling the release. In conclusion, this work presents new approaches for the modification of CS as well as a new system with a great potential for colonic drug delivery.

Introduction

Colon-selective drug delivery systems have been the focus of increasing interest for the last decade. This is mainly due to the recently recognized importance of this region of the gastrointestinal (GI) tract, not only for local but also for systemic therapy. At present, the specific drug delivery to the colon is considered an important alternative for the treatment of serious local diseases such as Crohn's disease, ulcerative colitis, carcinomas and infection. On the other hand, specific systemic absorption in the colonic region offers interesting possibilities for the treatment of diseases susceptible to the diurnal rhythm, such as asthma, arthritis or inflammation 1, 2.

Strategies for specific drug delivery to the various regions of the GI tract and, in particular, to the colon, have been reviewed by Rubinstein [3]. A simple approach has been the use of enteric polymers, as protective drug coatings, which are able to release the drug at a particular pH. The major drawback of this alternative is that, in contrast to what was believed in the past, the pH of the proximal and transverse colon is more acidic than that in the small intestine. Thus, the drug is rapidly released along the upper intestine before reaching the colon. These enteric coating formulations are, despite this limitation, the only commercialized products for the treatment of the ulcerative colitis with 5-aminosalicylic acid (5-ASA) [4]. The timed release systems have been also proposed for colonic drug delivery. These systems deliver drugs after a particular time, which is the time normally required to reach the colon (3–4 h). The only limitation associated to this approach is the enormous variability in the gastric emptying of the dosage form depending on the quantity and kind of food consumed. A more realistic strategy for targeting drugs to the colon uses the ecosystem of the specific microflora in the large intestine. There are two main classes of bacterial enzymes, the azoreductases and the polysaccharidases, which are in a sufficient quantity as to be exploited in colonic drug targeting. Based on this idea, different natural and synthetic polymers have lately been evaluated for their susceptibility of being cleaved by these bacterial enzymes [5]and, thus, for their use as major constituents of colon-specific drug delivery systems [6]. Kopecková et al. have recently reported a crosslinked polymer especially tailored for the colonic delivery of 5-ASA [7]. This polymer combines two specific features: the presence of azo groups susceptible to degradation by bacterial enzymes and the presence of aminosaccharide moieties which enable the polymer to adhere to the colon mucosa. The practical use of these novel polymers is, however, limited by some concerns about their safety and also about the control of their decomposition rate. Promising alternative polymers are natural polysaccharides which suffer hydrolysis of their glycosidic bonds in the colon, such as chitosan (CS), pectin, guar-gum, dextrans, amylose and chondroitin sulphate. The only inconvenience of these polymers is their high solubility in the GI fluids; this implies the need of crosslinking to assess their integrity until they reach the colonic region 8, 9.

In this work, the polysaccharide CS was selected as a drug carrier for colon-selective delivery of drugs based on its specific biodegradability by the enzyme, lysozyme, which is highly concentrated in the mucosa, and by the enzymes secreted by the colonic bacteria 10, 11, and also on its mucoadhesive character [12]. In addition, CS has the advantage of being widely approved as a food ingredient, which suggests its acceptability as a new excipient for oral administration [13]. Despite these promising characteristics, a limitation of CS is its rapid dissolution in the gastric cavity. Chemical crosslinking with aldehydes has been, so far, a way of overcoming this problem 14, 15, 16. Nevertheless, the toxicity of aldehydes enormously limits the exploitation of these crosslinked microcapsules. Furthermore, this crosslinking process is not totally effective in preventing the release of the encapsulated drug.

In this article we present a novel multiparticulate system based on CS core microspheres coated with enteric polymers. With this system we aimed to overcome the problem due to the high solubility of CS in the gastric cavity while avoiding chemical crosslinking with aldehydes. The feasibility of these new microencapsulated cores for colon-selective delivery of drugs was studied using sodium diclofenac (SD) as a model anti-inflammatory drug. We expected that this drug would benefit from the proposed system, first, because SD is particularly well absorbed in the colon [17]and, second, because its release in the gastric cavity is avoided and, hence, its local side effects.

Section snippets

Materials

The following chemicals were obtained from commercial suppliers and used as received: chitosan glutamate (150 and 350 kDa for Sea cure® G110, medium-MW grade; and Sea cure® G210, high-MW grade), chitosan base (50, 150 and 300 kDa for Sea cure® 123, low-MW grade; Sea cure® 223, medium-MW grade; and Sea cure® 320, high-MW grade) (Pronova Lab., Drammer, Norway). The deacetylation degree of chitosan was, according to the specifications from the provider, higher than 80% in all cases. Eudragit®

Results and discussion

As indicated in Section 1, the aim of the work described here was to design a new multiparticulate colonic drug delivery system which combines two approaches previously attempted: pH-sensitive delivery and biodegradation in the colon environment. For the development and evaluation of this system, which consists of CS microcores entrapped within enteric microspheres, we chose the anti-inflammatory drug, SD, as a model compound. The system was developed in two steps: first, SD was entrapped

Conclusions

This work describes a new colonic drug delivery system, consisting of CS core-coated microspheres, which have the special feature of releasing the encapsulated drug, at pH 7.4, continuously over a prolonged and adjustable period of time. Another important finding in this work is that it opens new prospects in the crosslinking of CS using pH-sensitive polymers, thereby making this biopolymer more useful for oral drug delivery.

Acknowledgements

This work was supported by grants from the `Spanish Commission of Sciences and Technology' (CICYT-SAF 94-0579) and `Xunta de Galicia' (Xuga 20304A96). The authors wish to thank Professor Castiñeiras for his help in the interpretation of the IR spectra.

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