Effect of Terpenes on the Skin Permeation of Lomerizine Dihydrochloride

Abstract

-Purpose. Lomerizine dihydrochloride (LOM) is a Ca2+ channel blocker used as an antimigraine drug, which is currently administered orally in Japan. We therefore investigated the effect of terpenes in propylene glycol (PG) solvent on the percutaneous absorption of LOM by hairless mouse skin. Methods. Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR), confocal laser scanning microscopy (CLSM), and small angle X-ray scattering (SAXS) were carried out to analyze the effects of terpene enhancers on the biophysical properties of the stratum corneum (SC) of the skin. Results. Of the terpenes tested, the highest permeation rate of LOM (28.8 g/cm 2 /h) was observed with 1,8-cineole, while nerolidol conferred the lowest enhancement of LOM flux (14.2 g/cm 2 /h). ATR-FTIR studies revealed that terpenes/PG induced higher CH2 stretching frequencies of SC lipids than PG alone. The extent of penetration of the lipophilic fluorescence probes Nile Red and DiI was measured by CLSM in in vitro skin permeation studies, using either PG or terpenes/PG as skin permeation enhancers. With PG alone, both fluorescence dyes were undetectable in the skin. In contrast, when co-administered with terpenes/PG, both probes were distributed into the intercellular space between corneocytes and detected in the deeper layers of the skin. SAXS measurements showed that in SC treated with a combination of 1,8-cineole and PG, the scattering peak of the SC was broad and very weak in intensity compared to untreated SC, whereas pretreatment with PG alone did not alter the peak profile. Conclusion. A combination of terpenes and PG enhance the skin permeation of LOM. Our findings suggest that the mechanism for this effect involves the ability of terpenes to increase the fluidity of SC lipids, thus enhancing the distribution of LOM into the intercellular region of the SC.

Development of essential oils as skin permeation enhancers: penetration enhancement effect and mechanism of action

“…The shift to a higher frequency occurs when methylene groups of the SC lipid alkyl chains change from trans to gauche conformation, suggesting that the SC lipid is disturbed. The magnitude of blue shift in the peak frequency of the asymmetric and symmetric stretching vibration absorbance is correlated with an increased number of gauche conformers in the lipid acyl chain (Furuishi et al 2013). The areas of these two peaks are in proportional to the amount of the lipids present in SC.…”

“…These bands can be attributed to the methylene groups of the SC lipid alkyl chains. It has been demonstrated that PEs which cause a shift to a higher CH 2 stretching frequency improve drug permeation (Casiraghi et al 2010;Furuishi et al 2013). And the decrease of peak area for both CH symmetric and asymmetric stretching absorbance frequency peak caused by PEs also indicated a disruption of the intercellular lipid bilayers (Vaddi et al 2002;Casiraghi et al 2010;Lan et al 2014a).…”

“…Attenuated total reflection-fourier transform infrared spectroscopy (ATR-FTIR) studies ATR-FTIR studies were performed in a similar manner to that reported by Furuishi et al (2013). The skin prepared using the procedure as described above was cut into approximately 1 cm 2 pieces and soaked in 3% w/v EO dissolved in the vehicle of PG:IPA (3:7, v/v), 3% azone or blank vehicle at 32 C for 12 h, respectively.…”

“…Terpenes are the main constituents of EOs and consist of isoprene (C 5 H 8 ) units. They have been suggested as promising nontoxic, nonirritating PEs for both hydrophilic and lipophilic drugs (Furuishi et al 2013;Moghadam et al 2013). Terpenes of natural origin have a 'Generally Regarded As Safe' (GRAS) status with the Food and Drug Administration of the United States of America (Fox et al 2011).…”

“…The penetration enhancement effectiveness of terpenes were investigated and compared. Terpenes mainly acted on the intercellular lipid structure between corneocytes to increase the fluidity of SC lipids (Furuishi et al 2013). For the terpene families, the apparent degree of SC lipid disorder may be related to the overall size and degree of long chain alkyl functionality.…”