Phloretin, Ketocholestanol as dermal Penetration Enhancers

The aim of this project is to enhance the dermal permeation of various on skin used drugs with phloretin, 6- ketocholestanol and derivatives and to investigate the mechanism of action of these substances. Phloretin is the aglycone of phlorizin, a polyphenolic substance occurring in the root bark of apple trees and 6-ketocholestanol is a steroidal substance. In order to reach the goal several techniques will be applied. Standard in vitro skin permeation methods, using excised human skin or porcine skin will be used to characterise the percutaneous absorption of different drugs in combination with phloretin or 6-ketocholestanol. The data from the diffuion studies will be used to calculate the permeation enhancing effect. The pathway of fluorescently labeled drugs under the influence of phloretin and or 6-ketocholestanol through the skin will be visualised by Confocal Laser Scanning microscopy. A possible interaction of phloretin and 6-ketocholestanol with skin lipids will be investigated by differential scanning calorimetry (DSC) and IR-spectroscopy (ATR-FTIR). Novel permeation enhancers for dermal application would be of great interest for the pharma- as well as for the cosmetic industry.

One of the goals in pharmaceutical science is the development and investigation of untoxic penetration enhancers with a reversible mechanism. The aim of the project was to determine the penetration enhancing effects of phloretin, occurring in apples, and 6-ketocholestanol, a steroid derivative, on human skin and because of the similarity on porcine skin and subsequently to develop dermal formulations which fulfil the technical demands of the daily clinical routine. The first used pre-impregnation of the skin with phloretin or 6-ketocholestanol respectively did not correspond to normal clinical practice and therefore a practicable and simple to use` application form was developed containing the penetration enhancer as well as the drug in order to display their effects together. It could be shown, that 6- ketocholestanol in a suitable preparation had a penetration enhancing effect on the skin permeation of the pro drug` 5-aminolaevulinic acid. In contrast to this phloretin exhibited a positive influence on the permeation of the local anaesthetic lidocain. Additional studies confirmed that phloretin had no cytotoxic- and no haemolytic activity but an antioxidative effect. All these features of phloretin together with literature data showing additionally anti-inflammatory effects and its penetration enhancing activity indicate an interesting application of phloretin. It could be used as a multifunctional additive in skin preparations. Phloretin posses a high potential for the practical use in dermal applied medicaments as well as in cosmetics because of the results of the present studies. Because of the findings it can be assumed that the skin permeation of other drugs maybe also positively influenced by phloretin and 6-ketocholestanol.