Effect of Nerolidol and/or Levulinic Acid on the Thermotropic Behavior of Lipid Lamellar Structures in the Stratum Corneum

Abstract

Permeation enhancers are required to deliver drugs through the skin efficiently and maintain effective blood concentrations. Studies of the barrier function of the stratum corneum using l-menthol, a monocyclic monoterpene widely used in medicines and foods, have revealed an interaction between characteristic intercellular lipid structures in the stratum corneum and permeation enhancers. The variety of permeation enhancers that can be used to contribute to transdermal delivery systems beyond l-menthol is increasing. In this study, we focused on nerolidol and levulinic acid and investigated their influence on stratum corneum lipid structures. Nerolidol, a sesquiterpene, has been reported to enhance the permeation of various drugs. Levulinic acid is reported to enhance the permeability of buprenorphine and is used as a component of the buprenorphine ® patch. Synchrotron X-ray diffraction and attenuated total reflectance Fourier transform IR spectroscopy measurements revealed that nerolidol disturbs the rigidly arranged lipid structure and increases lipid fluidity. Levulinic acid had a smaller effect on stratum corneum lipid structures, but did increase lipid fluidity when co-administered with nerolidol or heat. We found that nerolidol has an effect on stratum corneum lipids similar to that of l-menthol, and levulinic acid had an effect similar to that of oleic acid.Key words nerolidol; levulinic acid; stratum corneum; synchrotron X-ray diffraction; attenuated total reflectance Fourier transform IR spectroscopy Chemical penetration enhancers are useful in transdermal delivery systems. These enhancers act on intercellular lipid structures in the stratum corneum, reversibly decreasing its barrier function and increasing drug permeability. Many types of enhancers have been investigated, including alcohols, [1][2][3] pyrrolidones, 4,5) surfactants, 6,7) fatty acids, 8,9) and terpenes.10,11)The modes of action of penetration enhancers include increasing lipid partitioning or diffusion, disturbing lipid structure, and extracting lipids. 11) Chemical absorption enhancers must not only have high permeation effects but also a margin of safety for administration to live organisms, and thus many compounds are restricted from practical use. Based on their safety and efficacy, terpenes 10-12) and fatty acids 8,9) have been studied extensively as permeation enhancers. Terpenes increase the diffusion of drugs in the intercellular lipids of the stratum corneum, and fatty acids increase the distribution of drugs to the surface. 11) Combining enhancers with different actions can have a synergistic effect on drug permeability.13) The compatibility of the principal agent and the effect of permeation enhancers on drug permeability has been investigated. 14) Intercellular lipid structures in the stratum corneum of skin act as a barrier to drug permeability.15) These lipids have been shown to form hexagonal and orthorhombic structures. [15][16][17] The observation of hydrocarbon chain packing by wide-angle X-ray diffraction has revealed h...

Effect of Terpenes on the Enhancement of Skin Permeation of Lipophilic Drugs: A Systematic Review

“…The 2.8-fold higher ER observed in nerolidol over limonene and other terpenes is consistent with the lipid probe studies where the interaction of nerolidol with SC intercellular membranes resulted in greater membrane fluidity. 47 Similarly, menthol disrupts the same orthorhombic and hexagonal lipid structures by crystallization. The application of menthol as CPE promotes the fluidity of the SC’s intercellular lipids.…”

“…These steps include (1) the partial disordering that terpenes cause in the lipid alkyl chains of the SC; (2) the disruption of the hydrogen bonds by preferential binding of terpenes with the ceramide head groups of the SC; and (3) the excessive hydration of ceramides brought about by the previous steps thus establishing new polar pathways. [44][45][46][47] The mechanism behind the permeation enhancement capacity of the terpenes is thought to be dependent on their structures or lipophilicity. Hydrocarbon and nonpolar terpenes are postulated to mainly act on step one of the processes, while oxygen-containing and relatively polar terpenes influence the second and third steps of the process.…”

Sustainable process development for the recovery of biobased levulinic acid through reactive extraction

“…4 LA also has applications in the drug industry as a model permeation enhancer to clarify the temperature change mechanism in the stratum corneum's intercellular lipid structures. 5 Cellulosic grass, sugarcane bagasse, rice straw, rice husk, corn straw, wheat straw, and wood chips are only some of the materials being used to produce LA by bio-routes. 6 GF Biochemicals Ltd. Italy is leading the industry in LA production.…”

“…LA is used as a raw material to make different compounds, like fuel additive methyl tetrahydrofuran, broad‐spectrum pesticide delta‐aminolevulinic acid, diphenolic acid, and bisphenol alternatives used in the polymer sector 4 . LA also has applications in the drug industry as a model permeation enhancer to clarify the temperature change mechanism in the stratum corneum's intercellular lipid structures 5 …”

Amino Acids and Their <i>N</i>-Acetylated Derivatives Maintain the Skin’s Barrier Function

“…Some chemical agents were previously determined to be transdermal absorption enhancers that affect the intercellular lipid barrier by promoting fluidity and decreasing the Orth ratio. [7][8][9][10] However, agents that can restore the intercellular lipid packing structures directly have thus far not been identified except for CER [11][12][13][14] and FFA, 11) which are known intercellular lipids.…”