Evaluating Tretinoin Formulations in the Treatment of Acne

April 2014 | Volume 13 | Issue 4 | Original Article | 466 | Copyright © April 2014

Leon H. Kircik MD

Indiana University School of Medicine, Indianapolis, IN
Mount Sinai Medical Center, New York, NY
Physicians Skin Care, PLLC, Louisville, KY

Topical tretinoin has been a standard treatment for acne vulgaris for more than 4 decades. While tretinoin has demonstrated proven efficacy in the treatment of acne lesions, it also is associated with the potential for skin irritation. Newer formulations have been designed to optimize both the drug concentration and the delivery vehicle with the aim to enable clinicians to provide increasingly effective acne treatment that minimizes irritation. These therapies include formulations with varying concentrations of tretinoin and vehicles that utilize a microsponge delivery system, hydrogels and micronized tretinoin, or propolymers. The purpose of this review is to evaluate different formulations and combinations of tretinoin in the treatment of acne vulgaris. While these advanced formulations were designed for controlled release of active ingredient, and have the potential to reduce cutaneous irritation relative to standard tretinoin cream and gel formulations, there is a need for comparative studies to evaluate the relative benefits of each of these advanced tretinoin formulations in optimizing acne treatment.

J Drugs Dermatol. 2014;13(4):466-470.


Topical tretinoin (all-trans-retinoic acid), a first-line therapy for acne vulgaris treatment, is recommended as maintenance therapy for acne, primarily due to its ability to reduce comedone formation without inducing bacterial resistance. 1-3 Tretinoin also produces anti-inflammatory effects and normalizes keratinization.3,4 However, like all topical retinoids, it can cause cutaneous irritation, particularly during the first 3-4 weeks of treatment.4,5 Factors that influence cutaneous irritation include individual differences in skin sensitivity, tretinoin concentration,6 and vehicle formulation.3,6 Thus, improvements in cutaneous irritation may be achieved both by optimizing the drug concentration and by changing the delivery vehicle.
Tretinoin products, including generic formulations, were originally formulated with a high concentration of tretinoin solubilized in solutions containing isopropyl myristate or alcohol.4 In these formulations, tretinoin is rapidly released when applied to the epidermis, which can cause cutaneous irritation (ie, skin drying, peeling, erythema, scaling).4 These formulations may therefore be more irritating than newer branded formulations, which are designed with novel delivery vehicles and dispensers. These newer formulations may not only reduce irritation, but also provide dosing flexibility and enhanced patient satisfaction and compliance. With the current availability of multiple concentrations of tretinoin and the development of newer vehicles, physicians may be able to provide customized treatment that provides proven efficacy while minimizing irritation. The aim of this article is to evaluate different formulations and combinations of topical tretinoin in the treatment of acne vulgaris.


Microsphere Gel Formulation

Microsponges are polymeric microspheres designed to deliver active ingredient efficiently with enhanced stability.7 The Microsponge® Delivery System (MDS), which has been utilized across a number of products, optimizes drug penetration and permeation with micro-encapsulation of topical therapy.7 Within acne therapy, the MDS was designed to enhance the amount of time that tretinoin is present on the skin’s surface while minimizing penetration through the dermis.7 This extended-release of active ingredient to the skin’s surface has the potential to improve efficacy while reducing skin irritation/adverse events (AEs).7 The MDS also produces greater sebum absorbance as compared with conventional oil absorbers (eg, talc, kaolin, bentonite 670, and corn starch) and therefore may offer another key benefit in acne therapy: oil control.8
Tretinoin gel microsphere 0.1% and 0.04% (Retin-A Micro®, Valeant Dermatology, Bridgewater, NJ) includes tretinoin encapsulated in a patented methyl methacrylate/glycol dimethacrylate cross-polymer porous microsphere (ie, utilizing an MDS) in an aqueous gel.9 Tretinoin microsphere gel, both 0.04% and 0.1%, has been found to be effective in reducing acne lesions, with only mild cutaneous irritation.10 Tretinoin gel microsphere 0.04% was studied versus 0.1% microsphere gel in adolescents and adults with mild to moderate acne (N=156, aged 12-41 years; 12 weeks, double-blind).10 Both concentrations were associated with a reduction in total inflammatory and non-inflammatory lesions, and there were no significant differences in the 2 doses at baseline or at weeks 2, 4, 8, and 12. However, there was a greater reduction in inflammatory lesions at week 2 in favor of the 0.1% dose relative to the 0.04% dose. The most common (and mild in severity) skin-related AEs were burning (2.6% and 7.7% for 0.04% and 0.1%, respectively) and irritation (6.4% and 3.8%, respectively). There were no significant differences between the 2 concentrations of tretinoin gel microsphere in peeling, burning/stinging, and itching measures, but fewer patients experienced dryness in the 0.04% group compared with the 0.1% group during the early phase of treatment.10 Another study of 12 weeks’ duration exam-