Variables Affecting Delivery of Glycopyrronium Tosylate Through Human Skin In Vitro

November 2020 | Volume 19 | Issue 11 | Original Article | 1080 | Copyright © November 2020


Published online November 1, 2020

Franceso Caserta a, Jon Lenn PhDa, Hans Hofland PhDb

aMedPharm, Durham, NC
bDermira, Inc., a wholly-owned subsidiary of Eli Lilly and Company, Menlo Park, CA

Abstract
Background: Hyperhidrosis is a condition characterized by excessive sweating beyond what is required for normal thermal regulation. It can involve multiple body areas including the axillae, palms, soles, or craniofacial regions. Glycopyrronium tosylate (GT) is a topical anticholinergic approved by the FDA (2018) for treatment of primary axillary hyperhidrosis in patients 9 years and older.

Objective: Gain insight into variables (anatomical sites, occlusion, exposure time) affecting GT delivery into human skin.

Methods: Human skin from different anatomical regions (palmar, plantar, axillary, and abdominal skin) was mounted into flow-through diffusion cells (MedFlux-HT®). GT solution (2.4%) was applied at 10 mg/cm2 and the receiving fluid was collected every 2 hours, for 24 hours. GT penetration was determined using LC/MS/MS. The effect of occlusion was assessed by covering the skin with either parafilm or saran wrap, and the effect of exposure time was assessed by incubating the skin for 5, 15, or 60 minutes before washing off the GT from the surface.

Results: GT delivery through palmar and plantar skin was up to 40-fold lower compared to delivery through axillary or abdominal skin. Occlusion increased GT delivery up to 10-fold. Reducing exposure time from 24 hours to either 5, 15, or 60 minutes, decreased GT flux by 90%. However, occlusion during these varied exposure times was able to restore GT delivery to levels found in the 24-hour exposed, non-occluded control group.

Conclusion: These in vitro skin penetration studies showed that skin thickness, exposure time, and occlusion substantially influenced GT delivery, potentially impacting clinical trial design.

J Drugs Dermatol. 2020;19(11): doi:10.36849/JDD.2020.5062

INTRODUCTION

Hyperhidrosis is a condition of excessive sweating beyond what is physiologically required to maintain normal thermal regulation. Hyperhidrosis affects an estimated 4.8% of the US population, which amounts to approximately 15.3 million people.1,2 The adverse impact of hyperhidrosis on quality of life has been well documented,2,3 and a recent case-control study found that anxiety and depression are >3.5 times more prevalent among patients with hyperhidrosis than those without.4 Hyperhidrosis treatments may work to block sweat from reaching the skin surface (eg, topical antiperspirants), inhibit neuronal transduction to sweat glands (eg, injectable onabotulinumtoxinA or off-label use of oral anticholinergic drugs), destroy the sweat glands (eg, thermal ablation or surgical removal), or via unknown mechanisms (eg, iontophoresis).2,5,6 These treatments vary greatly with respect to effectiveness, invasiveness, and side effects, and only three of these treatments are approved by the U.S. Food and Drug Administration (FDA) for axillary hyperhidrosis, including topical aluminum salts, onabotulinumtoxinA injections, and a microwave device for thermal ablation of sweat glands. Recently, glycopyrronium tosylate (GT), an acetylcholine receptor antagonist, was approved by the U.S. FDA in 2018 as a novel, once daily topical treatment for primary axillary hyperhidrosis in patients 9 years of age and older (QBREXZA® [glycopyrronium] cloth, 2.4%, for topical use). Primary hyperhidrosis (excessive sweating without a known cause) is localized (focal), characteristically symmetric, and can affect the axillae, palms of the hands, soles of the feet, face, and other areas. Skin in other anatomical areas may be different from the axilla and therefore more studies are needed.

In the present studies, delivery of GT through skin from various anatomical sites, including the axillae, abdomen, palms, and soles, was investigated.The effect of occlusion was investigated as a means to increase delivery. Finally, the effect of exposure time (with and without occlusion) was investigated. GT was removed from the skin 5, 15, and 60 minutes after application.

MATERIALS AND METHODS

Analytical Method
A liquid chromatography with tandem mass spectrometry (LC/ MS/MS) detection method was developed for the quantification of GT from the samples generated in this study. Briefly, the concentrations of GT were measured using an ultra- performance liquid chromatographic system (Nexera X2 Series UHPLC, Shimadzu) equipped with a triple quadrupole tandem