An Investigation of Thermogelling Aqueous Systems of Ethyl(HydroxyEthyl)Cellulose and Ionic Surfactants

Sammanfattning: Aqueous solutions of a particular type of the nonionic cellulose derivative ethyl(hydroxyethyl)cellulose (EHEC) may form thermoreversible gels in the presence of ionic surfactants. Low-viscous solutions can be transformed to clear, stiff gels as the temperature is increased. The gelation may occur at temperatures as low as 30-35 °C which could make the systems interesting for applications, e.g. as in situ gelling vehicles for drug delivery. The behavior is restricted to certain compositions, but the polymer concentration can be low, in the order of 1 wt %. EHEC belongs to the class of so-called ”clouding” polymers, which exhibit decreased water solubility with increasing temperature. At a certain temperature, cloud point (CP), the solutions begin to scatter visible light and with time, the systems normally separate into two phases. The CP depends on the polymer type and concentration and it may be changed by cosolutes. The type of EHEC that forms gels with ionic surfactants is rather hydrophobic with a CP at about 30-35 °C in 1 % (aq). Addition of the surfactant will typically increase the polymer solubility and thermal gelation may occur at temperatures below the CP within a certain surfactant concentration interval. The phase and gelling behavior in these systems have been studied. A number of parameters, like the polymer concentration and surfactant type, have been varied, and the effects of addition of cosolutes were investigated. The gelling properties were found at compositions in the vicinity of the phase boundary. Addition of electrolytes can strongly influence the behavior and the gelation may only occur in macroscopically phase separated systems. This effect could be reduced by a proper choice of surfactant and counterions, and/or by increasing the EHEC content. Although the systems are sensitive to the ”internal” salts, gels may readily form under physiological conditions. The formulations can be isotonized with nonionic excipients, e.g. glycerol. The ocular residence time in rabbits of a thermogelling EHEC-surfactant formulation was comparable to another in situ gelling system, Gelrite®, which is a product on the market. The in vitro release of timolol maleate from the two systems was also similar. A lipophilic drug, dexamethasone, could be solubilized to a concentration corresponding to ten times its water solubility in a thermogelling EHEC-surfactant formulation. The in vitro release of this compound was significantly slower than the release of timolol maleate. Thermogelling EHEC-surfactant systems have been studied by small angle neutron scattering (SANS) and high-sensitivity differential scanning calorimetry (HS-DSC). The results are considered to indicate the importance of thermally induced polymer-polymer association for the gel formation in these systems.