Arne Brodin

Thermosetting microemulsions and mixed micellar solutions as drug delivery systems for periodontal anesthesia

In the present study, thermosetting microemulsions and mixed micellar solutions were investigated as drug delivery systems for anesthetizing the periodontal pocket. The structure of the systems, consisting of the active ingredients lidocaine and prilocaine, as well as two block copolymers (Lutrol F127 and Lutrol F68), was investigated by NMR spectroscopy and photon correlation spectroscopy (PCS). The results obtained for dilute (1-3% w/w) solutions show discrete micelles with a diameter of 20-30 nm and a critical micellization temperature of 25-35 degrees C. Gel permeation chromatography (GPC) was used to study the distribution of the active ingredients, and indicates a preferential solubilization of the active components in micelles over unimers. Analogous to the Lutrol F127 single component system these formulations display an abrupt gelation on increasing temperature. The gelation temperature was found to depend on both the drug ionization and concentration. These systems have several advantages over emulsion-based formulations including good stability, ease of preparation, increased drug release rate, and improved handling due to the transparency of the formulations.

Micellization and gelation in block copolymer systems containing local anesthetics

A formulation consisting of a eutectic mixture of lidocaine and prilocaine, Lutrol((R)) F68 and Lutrol((R)) F127, suitable for anesthetizing the periodontal pocket has previously been developed. This consists of discrete micelles with a diameter of 20-30 nm and has a suitable gelation temperature, a good release profile and excellent long-term stability. In this study, the unimer/micelle transition and gel formation of the formulation, in its concentrated state, are investigated using differential scanning calorimetry (DSC), dye solubilization, rheology, and nuclear magnetic resonance (NMR) self-diffusion. The critical micellization temperature (cmt) and gelation temperature are found to be interconnected and influenced by cosolutes, such as electrolytes and hydrophobic substances, the latter as found particularly for the eutectic mixture of the local anesthetic agents lidocaine and prilocaine. Both cmt and the gelation temperature decrease with increasing pH of the system, i.e. at reduced solubility of the active ingredients. Moreover, both cmt and the gelation temperature increase upon diluting the system with water. The ratio between the two block copolymers present in the system also has an impact on both cmt and the gelation temperature, resulting in a decrease in onset temperature of both processes with an increase of Lutrol((R)) F127. The amount of the active ingredients present in the micelle phase depends on the pH of the system being approximately 0% w/w at pH 5, 50-60% w/w at pH 7.8 and 80% w/w at pH 9.

Local anaesthetic block copolymer system undergoing phase transition on dilution with water.

The possibility of formulating a local anaesthetic system displaying in situ gelation on dilution with water, as well as its dependence on concentration of active ingredients and pH was investigated. For this purpose Lutrol F68, water, a eutectic mixture of lidocaine and prilocaine and Akoline MCM were mixed in different ratios and investigated using crossed polarisers, small-angle X-ray diffraction, rheology, conductivity and NMR self-diffusion measurements. In particular, an isotropic phase of low viscosity turning into a high viscous hexagonal phase upon dilution with water was found. The increase in viscosity is only weakly dependent on temperature in the temperature range of 20-37 degrees C. The rheology and in vitro drug release of these systems were studied and the elastic modulus was found to be fairly independent of concentration of active ingredients and pH in the investigated region. The in vitro release of lidocaine and prilocaine was found to increase with increasing concentration of the active ingredients and with decreasing pH, the latter as a consequence of the pH-dependent ionisation of these substances. The behaviour of the system is promising from a pharmaceutical point of view, since the isotropic low-viscous phase can be injected into, e.g. a periodontal pocket where the presence of saliva will cause a temporal transition into a rigid hexagonal phase thus making the formulation stay at the application site. At even higher water content, either as a result of longer application time or rinsing with water, the hexagonal phase is effectively dissolved through transformation to a water-rich micellar phase.