Wang, J; (2015) Gastrointestinal stability of peptide drugs. Doctoral thesis , UCL (University College London).

Abstract

The successful oral delivery of peptide drugs is an extremely challenging concept owing to the various barriers encountered in the gastrointestinal tract, of which one of the most common is poor luminal drug stability. In this project, the stability of 17 peptide drugs (nafarelin, buserelin, goserelin, histrelin, [Arg8]-vasopressin, [D-Ser4]-gonadorelin, deslorelin, desmopressin, oxytocin, leuprolide, octreotide, ciclosporin, somatostatin, calcitonin, glucagon, secretin and insulin) was determined in simulated gastrointestinal fluids as well as in gastrointestinal fluids from human, pig, rat and dog. Small peptides (<12 amino acids) were shown to be highly stable in gastric fluids, whereas larger peptides (>12 amino acids) degraded rapidly by contrast. However, in the small intestine, the stability of these peptide molecules was shown to vary widely, depending more on the amino acid sequence and structure rather than size. The presence of the disulfide bond linkages resulted in high rigidity and low flexibility, and appeared to provide resistance against enzymatic cleavage of susceptible peptide bonds. The D- conformation of the amino acids may also play a role in increased proteolytic stability. It was also established that acidifying the small intestinal fluids has the potential to increase peptide stability. Furthermore, in the colonic fluids, the logP of the peptide molecules was found to be the most important factor in predicting colonic stability, as a good correlation was observed. Specifically for octreotide and leuprolide, an enteric microparticle formulation was subsequently developed to enhance their stability and delivery to the small intestine. Spherical, uniform, smooth-surfaced microparticles were successfully produced by use of a solvent evaporation method. In dissolution studies, the formulation showed excellent pH-responsive profiles, with minimal peptide release in acidic conditions and rapid drug release in small intestinal conditions. In an in vivo study in rats a 2.5-fold improvement in the oral bioavailability of octreotide was demonstrated from the microparticle formulation compared to a solution of octreotide. These results indicate that encapsulating peptides into microparticles could effectively increase the stability of peptides and enhance oral peptide bioavailability.

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