True supersaturation states induced by polymeric micelles and liposomes: the mechanistic explanation of drug permeability enhancments

Purpose: The objective of this study was to investigate if the increase in apparent solubility induced by liposomalization or micellization of poorly soluble drug hydrocortisone (HC) would lead to an enhancement of its permeability through nasal mucosa. Methods: Phosphatidylcholine liposome formulations as well as d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) micelle dispersions and polyvinylpyrrolidone (PVP) supersaturated solutions were prepared in order to increase the apparent solubility of HC. Both the apparent solubility of hydrocortisone (i.e. amount of drug entrapped plus non-entrapped in the carriers) as well as the concentration of molecularly dissolved drug (i.e. fraction non-entrapped into carriers) were determined. Subsequently, the permeability of hydrocortisone was assessed for each type of formulation using in-vitro sheep nasal mucosa permeability assay. Results: In all formulations where solubilizing agents were present, an enhanced flux of HC (compared to the pure drug powder suspension) was observed. The expected linear correlation between apparent solubilities and fluxes was not found. Whereas, the concentrations of molecularly dissolved HC (“true supersaturation”), were found surprisingly different in each formulation, and directly proportional to the respective fluxes. Conclusion: We have proven that the amount of HC incorporated in micelles and liposomes does not influence the permeation process in the same way as the drug in crystalline from. On the contrary, only the freely dissolved drug molecules take part in the concentration gradient for the permeation process.