Polysaccharides for Drug Delivery and Pharmaceutical Applications

Chapter 10

Chitosan as a Biomaterial for Preparation of Depot-Based Delivery Systems Downloaded by MICHIGAN STATE UNIV on February 18, 2015 | http://pubs.acs.org Publication Date: June 22, 2006 | doi: 10.1021/bk-2006-0934.ch010

J. Grant and C. Allen* Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5S 2S2, Canada

Chitosan is a natural polysaccharide that has become established as a material with great potential for use in biomedical applications. In addition, the recent success of many polymeric depot delivery systems has encouraged further research to identify new materials and develop new systems for use in regional therapy. Several strategies have been developed for preparation of stable chitosan-based depot systems for drug delivery. Chitosan can be physically or chemically crosslinked to prepare microspheres, films and gels. Chitosan has also been blended with a wide range of polymers to produce mostly two-phase systems, which have unique properties that are required for specific applications. These stable chitosan-based depot systems have been investigated for treatment of various diseases including cancer and bacterial infection. This review includes a summary of the favorable chemical, physical and biological properties of chitosan. In addition, the properties of an ideal depot system for use in drug delivery are outlined. Overall, it is hoped that the reader gains an appreciation for the use of chitosan-based systems for the regional or localized delivery of drugs.

© 2006 American Chemical Society

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In Polysaccharides for Drug Delivery and Pharmaceutical Applications; Marchessault, R., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2006.

Downloaded by MICHIGAN STATE UNIV on February 18, 2015 | http://pubs.acs.org Publication Date: June 22, 2006 | doi: 10.1021/bk-2006-0934.ch010

202 Depot systems include films (wafers), gels and particulates (i.e. microspheres, microparticles) that provide a storage reservoir of drug, which is then released at a specific rate within the body. As outlined in Figure 1, depot systems are often administered via parenteral or local routes. The parenteral mode of administration refers to injection through a needle into the body at various sites and depths. The primary routes of parenteral delivery are intravenous, intramuscular and subcutaneous, although intradermal, intracardiac and intraspinal are also included. Depot systems such as microparticles or gels are commonly administered via a parenteral route. Systems such as films or wafers may be administered locally by surgical implantation at a specific site (1)· As shown in Figure 1, following administration the depot system may provide local and/or systemic delivery of the drug. Systemic delivery refers to a drug that is administered, and reaches the blood stream. By contrast, for local delivery the drug is directly delivered at the site of implantation of the depot system (1). Rational design of a depot system requires consideration of the desired mode of administration of the system and type of drug delivery required. In general, depot systems are designed to: 1) provide sustained drug release in order to extend the duration of treatment, 2) provide a therapeutic concentration of drug to a specific site and 3) improve patient compliance. These systems have been investigated for a wide variety of indications including psychological disorders, wound healing, cancer treatment, periodontal disease, and gene therapy (2-5). The drug delivery devices explored to date have been prepared from synthetic and/or natural polymer materials (6). Indeed, several depot systems based on polymer materials have received F D A approval for the treatment of various diseases (e.g. Atridox®, Decapeptyl®, Gliadel®, Lupron D e p o t ® , Nutropin D e p o t ® , Sandostatin L A R ® , Trelstar D e p o t ® and Z o l a d e x ® ) . These approved systems are mostly formed from the synthetic polyesters poly(dj-lactide) (PLA) and poly(lactide-co-glycolide) (PLGA). Lupron D e p o t ® was the first depot delivery system to be approved for clinical use and includes P L G A microspheres that provide sustained systemic delivery of Leuprolide acetate. This product was approved in 1989 and in 2001 its total annual sales were $833 million (7). Specifically, Lupron D e p o t ® has been approved for treatment of fibroids, prostate cancer, endometriosis, and central precocious puberty. Currently, over 600 patents on drug delivery devices formed from P L G A and P L A have been filed and the annual sales for these products have reached approximately $2.5 billion (7). P L G A and P L A are known to be biocompatible, biodegradable materials that are stable under physiological conditions (8). However, they have also been associated with some limitations including foreign body responses that lead to capsid formation (9, 10). Capsid formation involves the encapsulation of the depot in collagenous tissue and thus may alter both the degradation and drug release profiles of the delivery system (11). Also, the degradation products of these synthetic polyesters may cause an increase in the acidity within the area of implantation



Figure 1. A schematic illustrating the concept ofsystemic and localized drug delivery. For systemic delivery, microparticles encapsulated with drug are injected subcutaneously, drug is released and able to reach the blood stream. For localized drug delivery, afilmloaded with drug is directly placed in a tumor resection site using surgicalforceps and drug is released locally.


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resulting in local irritation and accelerated hydrolysis or degradation of some drugs (12). In this way, there is a need to develop and explore new materials for preparation of depot or implantable drug delivery systems. In addition, it is known that the degree of compatibility or interaction between a drug and the material employed to prepare the delivery system may influence many of the performance related parameters of the system including stability, drug loading efficiency and drug release profile. In this way, it is unlikely that any one system prepared from a specific material will universally serve as a universal delivery system for all drugs. Recently, there has been increased interest in the use of natural polymers such as polysaccharides for biomedical applications. This class of polymers includes: alginates, amylose, carrageenans, cellulose, chitin, chitosan, dextran, glycogen, inulin, pectin, pullulan and starch. Cellulose, chitin and chitosan are the most naturally abundant polysaccharides in the world. Many of these biopolymers, especially chitosan, have been shown to have good biological and film-forming properties. Chitosan was first described in the literature in 1811 and has been traditionally used in America for the treatment of machete gashes and in the Orient for the treatment of abrasions. Due to many of chitosan's favorable properties it has been explored for commercial use in nutrition, foods, cosmetics as well as environmental and biomedical applications (13, 14). The potential biomedical applications for chitosan, as summarized by Sanford and Skaugrud, includes: sutures, haemostatic, fungistatic, spermicidal, anti-carcinogen, anticholesterolimic, contact lenses, wound healing, eye bandages, dentalbioadhesives and orthopaedic materials (15, 16). The focus of the present review is the design and use of chitosan-based depot systems for sustained drug delivery. Special attention is given to these systems, as they have shown great potential for treatment of a range of diseases. It is our hope that the reader will gain an appreciation for the exploitable properties of chitosan, the interactions involved in preparing stable chitosan-based systems and the potential of localized drug delivery. Furthermore, this review may serve as a useful tool for preparation of novel chitosan-based depot systems for drug delivery.

Chitosan: Chemical, Physical, and Biological Properties Chitosan is naturally present in crustacean shells, such as shrimp, crab and lobster, some insects, microorganisms and fungi but can also be derived from the deacetylation of chitin (17). Chitosan is one of nature's most versatile biomaterials as it can be prepared as a powder, film, fiber, gel, beads, paste or solution (13). Chitosan is a cationic copolymer that consists mainly of β-(1,4)2-deoxy-2-amino-D-glucopyranose and partially of p-(l,4)-2-deoxy-2acetamido-D-glucopyranose units. Its properties, such as molecular weight, degree of deacetylation, viscosity and purity can be made to vary over a wide



205 range. For example, chitosan can be prepared to have a molecular weight of 50 to 2000 kDa, its degree of deacetylation can be varied from 40-98% and its viscosity, which is concentration and temperature dependent, can be increased to 2000 M P a (18). Chitosan has been more commonly explored for pharmaceutical applications rather than chitin as the former is more readily dissolved in various solvents. The solubility of chitosan is dependent on both the degree of deacetylation of the material and the pH of the medium. For example, 85% deacetylated chitosan is soluble in water at pH

Polysaccharides for Drug Delivery and Pharmaceutical Applications

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