Thiolated Polymers in Peptide Drug Delivery Systems

The aim of this project is to to generate new thiolated polymers (thiomers) exhibiting strongly improved mucoadhesive, permeation enhancing and enzyme inhibitory properties compared to so far established thiomers (I), to develop non-invasive peptide drug delivery systems based on the most promising new thiolated polymers (II) and finally to verify the efficacy of these delivery systems in vitro, ex vivo and in vivo (III). Basic research and development includes the synthesis of various new thiomers thereby pursuing certain strategies, a detailed chemical and physicochemical characterization of them and in vitro and in vivo evaluations of their properties focusing on mucoadhesion and permeation enhancement. The following applied research and development includes the generation of oral particulate delivery system and matrix tablets, which are hydrated only at a pH above 5, both for insulin used as model drug for biofeedback studies in diabetic mice and rats. Furthermore, a mucoadhesive vaginal delivery system based on a novel thiolated polymer with calcitonin as model drug will be generated. The efficacy of the dosage form will subsequently be evaluated by measuring the change in the blood calcium concentration in pigs.

Thiomers (thiolated polymers) have shown in previous studies to be capable of combining most of the strategies commonly used to overcome the low bioavailability following mucosal peptide administration, namely (i) the use of permeation enhancers, (ii) the addition of enzyme inhibitors and (iii) attempts to increase drug local residence time using mucoadhesive polymers. The permeation enhancing effect of thiomers could even be improved by the addition of the permeation mediator glutathione (GSH). Therefore, it was the aim of this project to evaluate the suitability of thiomers as well as the thiomer/GSH system as multifunctional vehicles for systemic peptide delivery via non-invasive routes. The main focus was thereby given on the oral and nasal route of application. Drug delivery systems based on different thiomers containing therapeutic peptides (calcitonin, insulin, human growth hormone) used in daily clinical practice were developed and exhaustively characterised in vitro and in vivo in rats. The oral application of tablets comprising calcitonin resulted in a decrease of the plasma calcium level by more than 10% and an oral delivery system for insulin led to a significant decrease of the blood glucose level for 24 hours. After nasal administration of a microparticulate formulation a relative bioavailability of 8% could be achieved for human growth hormone (hGH). This study also confirmed the superiority of solid over liquid formulations in the field of nasal drug delivery. Furthermore, novel thiomer conjugates were developed and a series of in vitro studies concerning the characterisation of various thiomers contributed to the knowledge of the properties of thiomers as well as their mechanisms of action.