Julian Blair

Stabilisation and delivery of labile materials by amorphous carbohydrates and their derivatives

The effective stabilisation of labile biological materials, such as proteins and peptides, requires that stabilising excipients should be glass-forming with high glass transition temperatures (Tg) and processing should be performed at low temperatures (i.e., freeze-drying). Below Tg, any pharmaceutically active material in the amorphous matrix is claimed to be stable. Repeatedly, however, degradation has been shown to occur below Tg. A better predictor of stability has been proposed to be the zero mobility temperature (T0) which lies below Tg. Thus, to work most effectively a glass-forming excipient must have not only a high Tg but also a high T0. The importance of Tg, T0 and other properties of carbohydrates that are advantageous for use as excipients in protein stabilisation are discussed. The perceived advantage of the freeze-drying process is that the rate of degradation of a pharmaceutically active material is reduced. This perceived advantage may not be as great as would be expected due freeze-concentration which accelerates many chemical reactions. The paper describes how a consideration of the relationship between temperature, time and degradation of the pharmaceutically active material has allowed a faster, more effective drying process (Q-T4sys®) to be developed. A limitation of all amorphous carbohydrate based systems is that to a greater or lesser degree they are hygroscopic and unable to give controlled release. The paper describes how the SoliDose® system, which utilises non-hygroscopic chemically modified carbohydrates, can offer the potential to stabilise labile biologicals in the glassy state (as in conventional amorphous carbohydrate systems) while allowing for improved bioavailability and controlled release.

Enhanced immunogenicity of a hepatitis B virus peptide vaccine using oligosaccharide ester derivative microparticles

Controlled release microspheres can overcome many of the disadvantages of multiple vaccine delivery such as rate of uptake and cost of administration. Proteins and peptides are difficult to administer using conventional polymers owing to protein degradation, premature release and stability. Here we report the successful development of room temperature stable, controlled release formulations using oligosaccharide ester derivatives (OEDs) of trehalose and a synthetic peptide analogue of hepatitis B surface antigen. Employing a range of different OED preparations, we have optimised the immunogenicity of the peptide formulation such that mice injected with a single preparation of microspheres consisting of trehalose octaacetate (TR101; Group G) produce high titre anti-hepatitis B (anti-HBs) surface antigen antibodies. The kinetics of the immune response could be manipulated with different peptide/OED formulations and correlated with the OED composition of the microspheres. Our data demonstrate the considerable potential of OED microspheres as novel delivery systems for vaccines. The ability to induce strong immune responses, without the requirement for multiple doses or cold-chain storage, could radically improve vaccination programmes in developing countries.