In vitro permeation profile of a local anaesthetic compound from topical formulations with different rheological behaviour--verified by in vivo efficacy data.

The object of this study was to develop a topical cream of suitable consistency, i.e. with a high apparent yield stress, without affecting the in vitro permeation profile and the subsequent in vivo efficacy of the formulation. Different formulations of a model compound were manufactured, an oil-in-water (o/w) emulsion, a cream consisting of the o/w emulsion thickened with various concentrations of neutralised Carbopol934P gel, and a semisolid water-in-oil (w/o) emulsion. Rheological measurements were performed giving the apparent yield stress of the formulations. The in vitro permeation rate of the compound was measured, using static diffusion cells with both guinea pig and human skin as membrane. The o/w emulsion without polymer was used as reference. The in vivo efficacy of the formulations was investigated on guinea pigs by the pinprick method. The apparent yield stress of the w/o emulsion was in the same range as that of the most viscous o/w cream while the o/w emulsion behaved as a Newtonian liquid. Furthermore, the yielding property of the w/o emulsion was not as temperature-sensitive as that of the o/w cream. The permeation rate of the compound from the two emulsions, o/w and w/o, was similar at 6% (w/w), while the o/w cream resulted in a significantly lower permeation rate at the same concentration. The two emulsions produced sufficient and comparable in vivo efficacy, while the o/w cream was less efficient. In conclusion, a reversed-phase emulsion may be used to produce the appropriate apparent yield stress, without affecting the in vivo efficacy of the formulation. The viscosity of a w/o emulsion depends on the amount of the aqueous phase and the degree of dispersity. Thus, the transport of the active compound is not prevented by the excipients present in the formulation, as is the case for the o/w cream.

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.

The effect of rheological behaviour of a topical anaesthetic formulation on the release and permeation rates of the active compound.

The objective of this study was to investigate the possibility of developing a topical cream that allows maximum release rate of the active compound while having suitable consistency, i.e., sufficient apparent plasticity. A submicron (o/w) emulsion containing a model compound was investigated in the presence and absence of different polymers: sodium carboxymethylcellulose (CMC), Carbopol 934P (C934), polyethylene glycol 400 (PEG400) and polyethylene glycol 4000 (PEG4000). Various concentrations of the polymers were used in order to produce different rheological behaviours. The amount of drug passing through the membrane was measured as a function of time, using static diffusion cells with either Silastic sheeting 500-1 or guinea pig skin as membrane. The emulsion without polymer was used as reference. Rheological measurements were performed, giving the viscosity and the apparent yield stress of the formulations. Furthermore, theoretical values for diffusion coefficients and diffusion pathways were estimated and compared with the experimental data to discuss different diffusion models. Gelling polymers have been shown to produce an increase in the macroviscosity, thus inhibiting the diffusion of the oil droplets in the formulation without affecting the molecular diffusion. However, we suggest that when a compound of limited solubility is emulsified, the intact oil droplets contribute to the transport of the compound through the formulation. Thus, both release and permeation rates are decreased as the apparent yield stress, i.e., the macroviscosity of the formulation, is increased sufficiently by addition of gelling polymers.

Inhibition of Ostwald ripening in local anesthetic emulsions by using hydrophobic excipients in the disperse phase.

The stability of submicron emulsions of different local anesthetic/analgesic substances was investigated in the presence and absence of different hydrophobic excipients (ripening inhibitors). Ostwald ripening was believed to be the underlying mechanism for the instability of these emulsions. In the absence of ripening inhibitors, the mean droplet size of the emulsions increased from 100 nm to about 4-5 microm within an hour of manufacture. The addition of a small amount of a second component of lower solubility to the disperse phase decreased the rate of Ostwald ripening, producing good stability of the emulsions. The efficiency of the ripening inhibitors was directly proportional to their solubility in the disperse phase, i.e. the water. The lower the solubility, the more effective the stabilization of the emulsions. The experimentally observed rates of increase in droplet size in the emulsions were closely correlated with those predicted according to the Liftshitz-Slezov-Wagner (LSW) theory.