Long-Chain Esters Of Unsaturated Menthol Analogues As Amphiphilic Permeation Enhancers For Transdermal Drug Delivery

Transdermal drug delivery system (TDDS) is designed to effectively delivery the active pharmaceutical ingredient via the skin into the systemic circulation. Since its introduction, TDDS has been a validated technology contributing significantly to global pharmaceutical care. However, development of TDDS products is severely limited by the inability of most drugs to cross the skin at therapeutic rates due to the great barrier imposed by the outmost skin layer, i.e. stratum corneum. Therefore, various strategies based on chemical, physical and pharmaceutical technologies have emerged over recent years to optimize the drug delivery through the skin, among which the chemical permeation enhancers have been most extensively investigated.Menthol is one kind of cyclic terpenes, and has shown to be effective and safe in promoting the drug permeation through the skin. In the present study, a series of unsaturated menthol analogues were synthesized by introduction of a double bond onto its four molecular positions. The enhancement effect of these compounds on the transdermal permeability of a lipophilic drug (flurbiprofen) and a hydrophilic drug (5-fluorouracil) were studied in isopropyl myristate (TPM) solutions. The results indicated that although menthol and its unsaturated analogues were ineffective in the permeation of flurbiprofen, their acitivty towards5-fluorouracil was significantly observed. Especially, the menthol analogue that possessed an exocyclic double bond at C-4showed the greatest enhancing effect, which was significantly higher than that of menthol. Using attenuated total reflection-Fourier transform infrared spectroscopy, transepidermal water loss and molecular modeling investigations, it was suggested that the studied compounds enhanced the5-fluorouracil transport mainly via the interaction with the polar domain of the skin lipid, thereby pulling the drug5-fluorouracil free of H-bonds and increasing its diffusivity through the skin. In addition, this interaction was found closely associated with the position of the double bond in these unsaturated menthol analogues.To identify more potent permeation enhancers, especially for those lipophilic drugs, a series of saturated long-chain esters of isopulegol were then synthesized and their activities were studied in IPM solutions using amlodipine and flurbiprofen as two lipophilic model drugs. As references, the saturated fatty acids and isopulegol were also investigated for their individual and combined ettect on the transdermal drug permeation. The in vitro permeation experiments and confocal laser scanning microscopy both demonstrated that the synthesized esters have significant promoting effect on the drug permeation through the skin, whereas saturated fatty acids and isopulegol had no such effect and even decreased the drug permeation when they were used alone or in combination. The attenuated total reflection Fourier transform infrared spectroscopy revealed that saturated fatty acids and their esters had converse effect on the intercelluar lipid organization in the stratum corneum, and only the esters could significantly decrease the order of the alkyl chains in the skin lipids. In addition, with the in vitro cytotoxicity test and in vivo erythema model, almost no skin irritation and cytotoxicity were observed for the saturated fatty ester of isopulegol.To investigate the in vivo activity of the enhancers, a drug-in-adhensive flurbiprofen patch was prepared using isopuleogl decanoate (ISO-C10) as a preferred permeation enhancer, and its in vitro permeation and pharmacokinetic profiles were determined after transdermal application in the rabbits. The results revealed that ISO-C10enhanced the drug permeation both in vitro and in vivo, and a linear correlation was observed between these data. In addition, the developed flurbiprofen patch with ISO-C10exhibited enhanced analgesic and anti-inflammatory effects by comparison with the control patch without any enhancers. Meanwhile, the drug concentration in the bilaterial synovial fluid was also increased by ISO-C10after topical application of the patches to one knee of the rabbits. In conclusion, the compounds in our present study would be one kind of promising permeation enhancers for transdermal drug delivery.The paper provided a comprehensive investigation on the design of potential permeation enhancers, as well as the evaluation of their activity both in vitro and in vivo. It was expected to be helpful for further study in the investigation of novel permeation enhancers for percutaneous use.