LIPID PARTICLES AS ADJUVANTS AND DELIVERY SYSTEMS

October 11, 2008 by craig

Liposomes have been used to deliver vaccines and have been observed to have immunostimulant activity. When administered orally liposomes with encapsulated antigens have been claimed to provide protection from the gastric proteolytic enzymes. Liposomes also have potential as mucosal delivery systems since not only are they immunogenic in their own right but physical association of the antigen with the liposomal structure is not a requirement for intranasal immunostimulation. Simple mixtures of liposomes with other agents such as chitosan have potential for nasal delivery and have facilitated enhanced responses to vaccines administered orally.

Cochleate systems consisting of calcium-precipitated protein–phospholipid complexes are stable solid sheets that roll up into a spiral with no internal aqueous space, and the calcium ions bridge adjacent sheets. Oral administration of vaccines in cochlear delivery systems has been shown to induce strong long-lasting circulation and mucosal antibody responses with long-term immunological memory to influenza glycoproteins.

Virosomes are viral glycoproteins encapsulated in lipid vesicles, which have been shown to be effective as experimental vaccines delivered by both mucosal and systemic routes. Viruses and their surface glycoproteins have a high affinity for receptors on mucosal surfaces, especially along the respiratory tract.

CHITOSANS

Chitin is almost as common in nature as cellulose and is a main structural element of Crustacea, molluscs, and insects. Because it has limited solubility in industrial solvents, it has limited use; but when deacetylated under alkaline conditions it is converted to chitosan. Chitosan has terminal free amino groups distributed along its molecular chain, giving it a higher chemical and biochemical reactivity and thereby allowing it to be applied in a number of areas, including cosmetics and drug delivery. While inexpensive and readily available commercially, this material is also claimed to be nontoxic, biodegradable, and biocompatible. One other advantage, less widely recognized, is that it is a mucoadhesive and it also appears to act as an immunoadjuvant which, in the context of vaccine delivery, might provide a considerable advantage. In addition, the adjuvanticity of chitosan can be enhanced by the addition of secondary adjuvants so, overall, this material is seen to be very promising.

Commercially chitosans can have molecular weights varying from 4 to 2000 kDa and vary in the degree of deacetylation from 66% to 95%. Because of the free amino groups chitosan behaves as a weak base, with a pKa of 6.2–7.0 and is insoluble in water or organic solvents. It is a polyamine and therefore dissolves in hydrochloric acid and various organic acids including acetic, oxalic, and lactic acids, thereby forming salts. Chitosan salts are soluble in water, the solubility depending on the type of acid involved. For example, sebasic, phosphoric, and sulfuric salts are all less soluble and this provides a means of making dispersed insoluble particles of chitosan. In one method the chitosan powder is dissolved in a dilute acetic acid solution and poured into a solution of sodium sulfate, forming a fine dispersion of chitosan microparticles that can be collected and dried.

The stability of unmodified chitosan particles in an aqueous environment may be questionable and some authors have made covalent cross-linked chitosan microparticles by taking advantage of the formation of Schiff bases with the free amino groups using a reactive aldehyde such as glutaraldehyde. These cross-linked particles may be less soluble in water and they are more stable physically but need to be loaded with any drug only after the remaining glutaraldehyde is thoroughly washed out and neutralized with sodium metabisulfite.

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