Two Randomized, Double-Blind, Split-Face Studies to Compare the Irritation Potential of Two Topical Acne Fixed Combinations Over a 21-Day Treatment Period

June 2016 | Volume 15 | Issue 6 | Original Article | 721 | Copyright © June 2016

Neal Bhatia MD,a Varsha Bhatt PhD,b Gina Martin MOT,b Radhakrishnan Pillai PhDb

aTherapeutics Clinical Research, San Diego, CA
bDow Pharmaceutical Sciences, a Division of Valeant Pharmaceuticals North America LLC, Petaluma, CA

Abstract
Topical therapy of acne vulgaris (acne) is very common, however cutaneous tolerability can influence patient adherence, and concerns about skin irritation have lead to a number of comparative split-face studies. Advances in formulation technology have provided new fixed combinations with lower concentrations of potentially irritating ingredients without compromising efficacy. These developments now afford the opportunity to formulate fixed combinations with higher concentrations of active ingredients that may provide the greater efficacy needed in more severe disease with good tolerability.
Here, we compare the tolerability of two such developments, clindamycin-BP 3.75% gel and adapalene 0.3%-BP 2.5% gel, in healthy volunteers with no apparent facial redness or dryness over 21-days, using a split-face methodology.
Clindamycin-BP 3.75% gel was more tolerable than adapalene 0.3%-BP 2.5% gel over the duration of the two studies, with statistically significant differences in cumulative change from baseline starting as early as day 4 (stinging), day 5 (erythema, dryness, and scaling), day 6 (burning), and day 8 (itching); and in composite irritation index (stinging, erythema, dryness, scaling, burning, and itching) from day 4. Transepidermal water loss was less with clindamycin-BP 3.75% gel (statistically significant from day 8). Adverse events were twice as common with adapalene 0.3%-BP 2.5% gel.
These data suggest that clindamycin-BP 3.75% gel is likely to be better tolerated than adapalene 0.3%-BP 2.5% gel in moderate-to-severe acne.

J Drugs Dermatol. 2016;15(6):721-726.

INTRODUCTION

Developing effective and well-tolerated topical dermatologic formulations is a long, often complex process that has provided a number of important products over the years.1 They remain the most common and effective treatment option for mild-to-moderate acne vulgaris (acne), and also for maintenance therapy for all degrees of acne severity.2 In addition, fixed topical combinations have been studied in moderate and severe disease.3,4 Benzoyl peroxide (BP) was first shown to be effective in a case of acne in 1934,5 and over the recent decades has been commonly used in fixed combinations containing an antibiotic or retinoid, providing increased anti-acne efficacy compared to monad formulations.6
While topical treatments have safety advantages over oral agents, adherence can be problematic7-9; the intolerance to local skin reactions, occurrence of side effects and young age being the main reasons.10 One of the problems associated with BP-containing topical formulations is localized application site irritation. This concentration-dependent dryness and irritation may impact patient adherence and limit product use.11 However, it is not limited to BP, being seen with retinoids such as tretinoin and adapalene.12 In fixed combinations the problem can be compounded.
Over the last few years, formulation development has focused on using lower concentrations of potentially irritating active ingredients, but also removing excipients that may be irritants in their own right (such as surfactants, certain preservatives and high levels of alcohol and other organic solvents) with the goal of providing equal efficacy and better tolerability.13 An independent meta-analysis comparing clinical data on fixed combinations of clindamycin-BP 5% and clindamycin-BP 2.5% concluded that their efficacy was comparable, with perhaps more favorable results seen with clindamycin-BP 2.5% in noninflammatory lesions.14 The authors suggested that the better results seen with clindamycin-BP 2.5% gel may have been due to advances in formulation development (the older clindamycin-BP 5% fixed combinations were either not effective or approved in noninflammatory lesions15,16), or better adherence because of decreased irritation, but tolerability was not compared.14
These advances in formulation research have opened up the opportunity to develop higher concentration fixed combinations to treat more moderately severe disease. Normalizing for any vehicle effect efficacy in treating inflammatory lesions appears similar, however there does appear to be a dose-dependent