Martin Malmsten

Physicochemical characterisation of a drug-containing phospholipid-stabilised o/w emulsion for intravenous administration.

Clomethiazole (CMZ) was used as a model drug to be incorporated into an emulsion vehicle. The effects of drug concentration and number of homogenisation steps were evaluated using multiple linear regression. The droplet size, measured as a z-average diameter by photon correlation spectroscopy (PCS), was found to be between 60 and 260 nm in the investigated range of CMZ concentrations, highly dependent on the concentration, but more weakly so on the number of homogenisation steps. Slow-scanning high-sensitivity differential scanning calorimetry (DSC) measurements showed that CMZ depresses the phospholipid chain melting temperature in the emulsion system, whereas (13)C nuclear magnetic resonance (NMR) experiments suggested that the CMZ molecules are to a large extent located in the surface region of the emulsion droplets. This interpretation is compatible with results from NMR self-diffusion measurements, which showed that most of the CMZ molecules are rapidly exchanged between emulsion droplets and the aqueous surrounding. It can be concluded that the surface-active drug CMZ has a significant influence on the characteristics of phospholipid-stabilised emulsions through its ability to interact with the phospholipid interface. Thus, the results underline the importance of characterising drug-lipid interactions for the development of lipid-based formulations.

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.

Adsorption of diblock copolymers of poly(ethylene oxide) and poly(lactide) at hydrophilic silica from aqueous solution

The adsorption of a series of amphiphilic poly(ethylene oxide)-poly(DL-lactide) (PEO-PL) diblock copolymers at the water/silica interface was investigated by ellipsometry and reflectometry. For all copolymers, a much higher saturation adsorption is found compared to that of the PEO homopolymers, indicating the importance of the PL block for the adsorption. The copolymers display a saturation adsorption that increases with increasing hydrophobic content of the polymer, and decreases with increasing hydrophilic content of the polymer. Despite this, however, the layer thickness observed is rather similar for all polymers, regardless of the length and composition of the copolymers. Moreover, the layer thicknesses were significantly higher than what would be expected for the unperturbered copolymer dimensions. The initial adsorption kinetics of the different copolymers are comparable. The initial adsorption rate increases cooperatively with concentration and is slower than that expected for diffusion-controlled adsorption. Moreover, the adsorption increases only slightly over a concentration the range from 20 to 50 degrees C. Furthermore, pH titrations show that all polymers exhibit a critical desorption pH of 8-9, which is lower than the corresponding value of pH 10.5 observed for the PEO homopolymer. These results are discussed in terms of the adsorption mechanism and the adsorbed layer structure and formation. Copyright 2000 Academic Press.

Surfaces coated with ethyl(hydroxyethyl) cellulose: Temperature effects on adsorption and interaction

The temperature dependence of the forces acting between hydrophobic surfaces coated by a layer of ethyl(hydroxyethyl) cellulose, (EHEC), has been studied as a function of separation and temperature. Both the situation where the adsorbed amount is kept constant and where the adsorbed amount is allowed to vary with temperature have been explored. In both cases the surface interaction is very temperature sensitive due to the temperature dependent interactions between ethylene oxide groups and water. The results are discussed and related to the protein repelling properties of EHEC coated surfaces and EHEC as a steric stabilizer.