By Dr Michael Dornish, VP research and development, and Dr Are Kristiansen, commercial development manager, at FMC BioPolymer.

The biopolymers alginate, chitosan and hyaluronan are well known and have been used in many pharmaceutical formulations for many years. These polysaccharides play a central role in the development of new drug delivery concepts. Some of the unique properties that these biopolymers can bring to the drug delivery field are:

  • Formation of gels with controlled degradability in physiological conditions
  • Bioadhesiveness
  • Specific cellular interactions that can be used to target drugs to specific cell types

C haracterisation with respect to physical, chemical and biological properties is important, and knowledge of biopolymer properties will affect their successful use in drug delivery applications. S ome novel drug delivery applications of alginate, chitosan and hyaluronan are described below.

Alginate

Alginate is a straight-chain polysaccharide composed of two monomers, mannuronic acid and its C-5 epimer guluronic acid. The unbranched structure of alginate can be described by three block structures: M-block, where there are long sections of mannuronate; G-block, where there are repetitive areas of guluronate; and the MG-block, an alternating structure of mannuronate and guluronate.

Alginate will gel instantaneously on contact with calcium or other divalent cations (except magnesium), and the resulting gel structure will be dependent upon the structure and sequence of the alginate. One application of gelling of alginate is in the immobilisation or encapsulation of living cells in alginate gels to form artificial organs and cell therapy constructs. The porosity of the alginate gel is such that oxygen and nutrients can enter while cell products such as proteins – up to certain molecular weights – can diffuse out of the gel. The gel is, however, not porous to antibodies or immune cells and can act as a continuous production system for substances such as insulin. This kind of biofactory has been implanted into animals and diabetic patients, and has been seen to function for at least one year.

Chitosan

Chitosan is a linear biopolymer that consists of glucosamine and N-acetyl-glucosamine. Chitosan is normally made by deacetylating chitin, which is the structural polymer found in the shells of crabs and shrimp (lobster, squid, some yeast and mould, too). Chitosan contains protonisable amino groups and is a polycationic biopolymer in aqueous solution.

Chitosan has shown promise in the development of non-parenteral delivery systems for challenging drugs. Chitosan is bioadhesive and has the ability to transiently open tight junctions in the nasal epithelia, thereby permitting drugs to diffuse through this barrier. Advantages of the nasal route of administration include: a higher permeability of the nasal mucosa than in the gastrointestinal tract; a low degree of pre-systemic metabolism; and a high level of patient compliance, compared to injectable systems.

Hyaluronan

Sodium hyaluronate, or hyaluronan, is a linear polymer composed of N-acetyl-glucosamine and glucuronic acid. Hyaluronan has found uses in a variety of products in the pharmaceutical and biomedical field. There are two current production methods: animal-derived (hyaluronan extracted from rooster combs, or other animal tissue), and non-animal derived production from fermentation. New research shows that hyaluronan can bind to specific cellular receptors and act as a drug-targeting molecule. Today, this technology is being fully explored in novel drug and gene delivery concepts.

Regulatory issues

The success of these biopolymers in the commercialisation of formulations will be dependent upon the regulatory acceptance of these polymers. T here are EP monographs for sodium alginate (EP 0625), chitosan chloride (EP 1774) and sodium hyaluronate (EP 1472). There is a USP monograph on alginic acid, and the USP is evaluating monographs on chitosan, chitosan chloride and chitosan glutamate.

Manufacture of biopolymers for use in drug delivery systems should be in accordance with current good manufacturing practice (GMP)guidelines. Suppliers should also be compliant with quality assurance systems, such as ISO 9001:2000 and ISO 13485:2003.