title: Cutaneous Penetration-Enhancing Effect of Menthol: Calcium Involvement.
abstract: Menthol is a naturally occurring terpene used as a penetration enhancer in topical and transdermal formulations. Literature shows a growing interest in menthol's interactions with the transient receptor potential melastatin 8. A decrease in extracellular Ca2+due to the activation of the transient receptor potential melastatin 8 receptor produces inhibition of E-cadherin expression that is responsible for cell-cell adhesion. Because calcium is present in the entire epidermis, the purpose of this study is to evaluate whether the aforementioned properties of menthol are also related to its penetration-enhancing effects. We formulated 16 gels: (i) drug-alone (diphenhydramine or lidocaine), (ii) drug with menthol, (iii) drug, menthol, and calcium channel blocker (CCB; verapamil or diltiazem), and (iv) drug and CCB. In vitro studies showed no effect of the CCB on the release of the drugs either with or without menthol. In vivo experiments were performed for each drug/menthol/CCB combination gel by applying 4 formulations on a shaved rabbit's dorsum on the same day. Dermis concentration profiles were assessed with microdialysis. The gels containing menthol showed higher penetration of drugs than those without whereas the addition of the CCB consistently inhibited the penetration-enhancing effects of menthol. In summary, these findings strongly support the involvement of calcium in the penetration-enhancing effect of menthol.
authors.affiliation: Division of Pharmaceutical Sciences, Arnold and Marie Schwartz College of Pharmacy, Long Island University, Brooklyn, New York 11201.
authors.forename: Amit
authors.initials: A
authors.lastname: Joshi
authors.affiliation: Division of Pharmaceutical Sciences, Arnold and Marie Schwartz College of Pharmacy, Long Island University, Brooklyn, New York 11201.
authors.forename: Abhay
authors.initials: A
authors.lastname: Joshi
authors.affiliation: Division of Pharmaceutical Sciences, Arnold and Marie Schwartz College of Pharmacy, Long Island University, Brooklyn, New York 11201.
authors.forename: Hiren
authors.initials: H
authors.lastname: Patel
authors.affiliation: Division of Pharmaceutical Sciences, Arnold and Marie Schwartz College of Pharmacy, Long Island University, Brooklyn, New York 11201.
authors.forename: Dovenia
authors.initials: D
authors.lastname: Ponnoth
authors.affiliation: Division of Pharmaceutical Sciences, Arnold and Marie Schwartz College of Pharmacy, Long Island University, Brooklyn, New York 11201. Electronic address: gstagni@liu.edu.
authors.forename: Grazia
authors.initials: G
authors.lastname: Stagni
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D005260:Female; D005782:Gels / Q000737:chemistry / Q000494:pharmacology*; D008610:Menthol / Q000737:chemistry / Q000494:pharmacology*; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D014677:Pharmaceutical Vehicles / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D012869:Skin Absorption / Q000187:drug effects*; D013552:Swine
chemical_list: D005782:Gels; D004364:Pharmaceutical Preparations; D014677:Pharmaceutical Vehicles; D008610:Menthol; D002118:Calcium
keywords: Diphenhydramine hydrochloride (Pubchem CID: 8980); TRPM8 channel; calcium; cutaneous penetration; diltiazem hydrochloride (Pubchem CID: 62920); l-menthol (Pubchem CID: 16666); lidocaine hydrochloride monohydrate (Pubchem CID: 6314); menthol; microdialysis; transdermal; verapamil hydrochloride (Pubchem CID: 62969)