Interaction of liposome formulations with human skin in vitro.

The interaction of liposome formulations consisting of Phospholipon 80 and sphingomyelin with human skin was investigated. These formulations were shown previously to have a composition-dependent effect on the penetration of Heparin into the skin. Fluorescence labelled phosphatidylethanolamine (PE-NBD) was incorporated in the liposomes and the depth in which the fluorescent phospholipid label enters into epidermal membrane and full thickness skin was studied by confocal laser scanning microscopy (CLSM). Confocal sections parallel to the surface of the skin were recorded in heat separated epidermis. An even distribution of phospholipid in the lipid matrix of the stratum corneum surrounding the corneocytes was observed with Phospholipon 80 but not when sphingomyelin was included in the formulation. The addition of Heparin which formed a coating around the liposomes, caused a strong localization of fluorescence within the epidermis. For full thickness skin, mechanical cross sections of skin were made and optical sections were recorded parallel to the plane of cut. Phospholipid penetrated and was distributed fairly homogeneously in the lower dermis layers within 30 min of application regardless of liposome composition and the presence of Heparin. This rather quick penetration process seemed to follow distinct pathways along the epidermis and the upper dermis, notably the hair follicle route. Thus, a strong and in some respects composition-dependent interaction of phospholipids with skin is evident. These observations, however, are limited to the level of phospholipid molecules, rather than of entire liposomes interacting with skin.

Heparin penetration into and permeation through human skin from aqueous and liposomal formulations in vitro.

The transport of unfractionated (UH) and low molecular weight Heparin (LMWH) in human skin was investigated in vitro using heat separated epidermal membrane and dermis and the effect of liposomal formulations with Phospholipon(R) 80 (PL80) and Sphingomyelin (SM) was assessed. The distribution of Heparin within skin tissue was studied by the tape stripping method. Heparin concentrations were measured with a biological assay. Transepidermal water loss was determined to characterize barrier properties of skin. No consistent permeation of Heparin through epidermal membrane was detected. Penetration into the epidermal membrane was for LMWH significantly greater than for UH. Accumulation of UH was largely restricted to the outermost layers of the stratum corneum while LMWH penetrated into deeper epidermal layers. UH penetration into epidermis was detected for the PL80 liposomal formulation only. The extent of LMWH penetration was independent of the formulation, LMWH, however, showed a trend to accumulate in deeper epidermal layers for the PL80 compared to the aqueous formulation. Thus, molecular weight and liposomal formulations influenced the penetration pattern of Heparin in the epidermis. It can not be concluded whether the concentration of LMWH achieved at the blood capillaries is sufficient to exert a pharmacological effect. UH permeated readily through dermis irrespectively of formulation and its accumulation in the dermis was significantly enhanced and its lag time of permeation increased in the presence of SM liposomes.

Utilizing vehicle imbibition by a microporous membrane and vehicle viscosity to control release rate of salbutamol.

The possibility to control the release rate of salbutamol through the hydrophobic Celgard 2500 polypropylene membrane by varying the composition and the viscosity of hydrophilic drug vehicles was investigated. The use of the polypropylene membrane as a control membrane for reservoir-type drug delivery systems was envisaged and water, glycerol, isopropyl alcohol and ethanol, pure or as binary mixtures were studied as vehicles. With varying composition of the vehicle, a sharp change of its imbibition by the membrane from practically none to a complete filling of the membrane pores occurred, which coincided with a steep rise of the drug permeability for the membrane. From this was inferred that the vehicle-filled pores were the dominant permeation pathway, while when no vehicle was imbibed, transport took place by way of the polymer domain of the membrane. In case of imbibition, the permeation rate could be modulated in a predictable fashion by adjusting the viscosity of the vehicle. This demonstrated that drug release could be controlled by utilizing the in situ interaction of the vehicles with this membrane, leading to imbibition and establishment of a permeation pathway with pre-determined viscosity in the pores of the membrane.

Effect of the amphoteric properties of salbutamol on its release rate through a polypropylene control membrane.

The permeation of salbutamol from aqueous vehicles with different pH values through the Celgard 2500 polypropylene membrane was studied, the goal being to assess the effect of the amphoteric properties of the drug on its release by the membrane. Permeation rates were generally low, which was related to the fact that purely aqueous vehicles were not imbibed into the pores of the membrane and therefore permeation took place through the amorphous polypropylene domains. Permeability coefficients were not proportional to the fraction of uncharged drug at different bulk pH values, indicating that either a pH gradient between the bulk and the membrane surface exists and/or charged drug species can permeate the hydrophobic membrane. Calculated hypothetical pH values of the membrane surface, assuming permeation of the uncharged drug only, failed to provide a consistent explanation of the experimental permeabilities. Permeability coefficients of the different ionization forms of the drug assuming no pH gradient were calculated from a system of linear equations, each one of them corresponding to a specific bulk pH. These were for the anionic and the cationic species one to two orders of magnitude smaller than for the combined uncharged and zwitterionic species. It is possible that both, a pH difference between bulk and membrane surface and permeation of ionized molecules were simultaneously responsible for the observed permeation rates.

Vehicle-dependent in situ modification of membrane-controlled drug release.

The possibility of utilizing the interaction between the drug vehicle and the polymeric control membrane of reservoir-type drug delivery systems to modulate the release rate of these systems was investigated. Lipid vehicles common in dermal formulations, with varying composition and viscosity and the Celgard polypropylene membrane were used to study the release of a model drug (salicylic acid). The release kinetics were investigated taking into account two consecutive transport processes, diffusion within the donor reservoir and permeation through the membrane. Membrane permeation was found to be the rate determining step for mass transport and convection appeared to play a significant role in the donor compartment, even though this compartment was not mechanically stirred. The lipid vehicles were imbibed by the membrane, quantitatively replacing the air from its pores. Drug permeation through the membrane was dominated by the vehicle-filled pore pathway, the pathway of the amorphous polymer domain of the membrane generally contributing a small fraction to the total permeation. Permeability coefficients for different vehicles varied within one order of magnitude. This effect was chiefly accounted for by the differences in viscosity of the vehicles occupying the pores of the membrane. Thus, based on the in situ imbibition of the lipid vehicles by the membrane, a controlled variation of the drug release rate could be achieved.