Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Gradauer, K.
New Oral Drug Carriers based on Thiomer Coated Liposomes
PhD-Studium (Doctor rerum naturalium); DS Molekularbiologie und Biochemie; [ Dissertation ] NAWI Graz; 2013. pp.148.
- Autor*innen der Med Uni Graz:
- Gradauer Kerstin
- Betreuer*innen:
- Leitinger Gerd
- Prassl Ruth
- Altmetrics:
- Abstract:
- There is a great need for new oral drug delivery systems, as many recently developed drugs are sensitive towards enzymes and a harsh pH and/or are poorly absorbed from the intestine. To protect encapsulated drugs and to enhance their absorption, we designed drug carriers based on the coating of liposomes with thiolated polymers (=thiomers). Liposomes, containing a small amount of a maleimide-functionalized lipid, were incubated with thiomers, leading to the formation of a covalent bond between free SH-groups of the polymer and maleimide groups of the liposome. After this incubation, the liposomes showed a concentration-dependent increase in their size and zeta potential, clearly indicating an effective coupling. The formulations have a storage stability of at least two weeks without releasing any encapsulated compounds. In simulated gastric fluid, the system was shown to be stable over 24 hours, while in simulated intestinal fluid, a slow, sustained release of encapsulated compounds was observed. In vitro studies on porcine small intestine revealed a 2-fold increase in mucoadhesion of coupled liposomes respective uncoupled ones. To evaluate their permeation enhancing- and efflux pump inhibiting properties we monitored the transport of fluoresceinisothiocyanate-dextran (FD4) and rhodamine-123 (Rho-123), respectively, through rat small intestine. Compared to the buffer control, we found a 4-fold higher permeation of FD4 and Rho-123, proving coated liposomes to be permeation enhancing and efflux pump inhibiting, respectively. For an in vivo proof on concept, we orally applied coated and uncoated liposomes to rats, using salmon calcitonin as model drug. Monitoring the blood calcium level, the impact of coated liposomes was 8-fold higher than that of the free drug giving as a solution. Finally, freeze drying and nano spray drying were used to convert the liquid formulation into a more stable powder.