FACING THE CHALLENGE OF SKIN PENETRATION - A STUDY ON LIPIDIC LIQUID CRYSTALLINE PHASES FOR DERMAL DRUG DELIVERY

Doctoral thesis, 2013

The skin is a barrier which protects us against daily attacks of foreign substances. From a pharmaceutical perspective it is also an interesting delivery route with its large surface and possibility to reach the blood stream circumventing first passage metabolism. With the varied size, structure etc. of active pharmaceutical substances, as well as the structure and function of the tissue, skin penetration is challenging. The work included in this thesis mainly focus on exploring the lipid based cubic liquid crystalline phases as dermal drug delivery vehicles. Of particular interest has been systems based on glyceryl monooleyl ether (GME), while cubic phase containing glyceryl monooleate (GMO) and water was used as reference system. These lipids and cubic phases are very similar but an important difference is that GME requires a solvent to form a cubic phase in excess water while GMO does not. The cubic phases made of GME, are less studied but have potential to be effective dermal delivery vehicles. The phase behavior of the GME systems has been thoroughly investigated and the dermal delivery of active compounds from the cubic formulations evaluated. Examples of the methods used are small angle X-ray diffraction, in vivo fluorescence spectrophotometry, two photon microscopy, and high performance liquid chromatography. The GME-based formulations showed to be as good as the GMO-based cubic phase for dermal delivery of small molecules. The cubic formulations significantly enhanced the delivery, both in amount and depth, compared to a commercial product. For larger molecules and nanoparticles, however, skin penetration was found only when a GME-based cubic formulation was used as delivery vehicle. Through combining all obtained results, a hypothesis of the dermal delivery mechanism was formed. The skin adherence and the occluding and hydrating effects of the formulations are important for effective delivery. However, the phase behavior of the formulations is also important to explain the mechanism. The GME-based cubic phase turns into a reversed hexagonal phase in excess water, whereas the GMO-based formulation maintains its cubic structure. This small but significant difference may be the reason for the difference in ability to deliver larger molecules and particles into skin.