IN-SITU GELATION

Various polymers are capable of prolonging the residence time of drug delivery systems by their in-situ gelling properties. For instance, deacetylated gellan gum is used in eye drops (Timoptic XE; CibaVision) in order to prolong the precorneal residence time of the incorporated drug. Such in-situ gelling properties are also beneficial for numerous other drug delivery systems improving the bioavailability and prolonging the drug action [Park J.S., Oh Y.K., Yoon H., Kim J.M., and Kim C.K. (2002) In situ gelling and mucoadhesive polymer vehicles for controlled intranasal delivery of plasmid DNA. J. Biomed Mater. Res., 59, 144-51; Bromberg, L.E. (2001) Enhanced nasal retention of hydrophobically modified polyelectrolytes. J. Pharm. Pharmacol.. 53, 109-14; Paulsson M., Hagerstrom H., and Edsman K. (1999) Rheological studies of the gelation of deacetylated gellan gum (Gelrite) in physiological conditions. Eur. J. Pharm. Sci., 9, 99-105]. In comparison to so far used in-situ gelling polymers, thiolated polymers are capable of providing a comparatively more pronounced increase in viscosity after application, as an extensive crosslinking process by the formation of disulfide bonds between the polymer chains takes place. For instance, in case of thiolated chitosan a more than 1000-fold increase in viscosity by the formation of disulfide bonds within the polymeric network based on a simple oxidation process was shown [Bernkop-Schnürch, A., Hornof, M. and Zoidl, T. (2003) Thiolated polymers – thiomers: modification of chitosan with 2-iminothiolane, Int. J. Pharm., 260, 229-237]. Being applied in liquid form, they become highly viscous gels for instance in the nasal cavity or in the vagina, which avoids an unintended rapid elimination of the semisolid delivery system.

Correlation between the decrease in thiol groups (graph) because of the formation of disulfide bonds and the increase in viscosity (bars) of thiolated chitosan [Hornof, M.D., Kast, C.E., and Bernkop-Schnürch, A. (2003). In vitro evaluation of the viscoelastic properties of chitosan - thioglycolic acid conjugates. Eur J. Pharm. Biopharm., 55, 185-190].
The formation of inter- and intramolecular disulfide bonds within the polymeric network stabilizes drug delivery systems based on thiomers. Click on the picture.