Clinical Safety and Efficacy Studies of a Novel Formulation Combining 1.2% Clindamycin Phosphate and 0.025% Tretinoin and for the Treatment of Acne Vulgaris

June 2007 | Volume 6 | Issue 6 | Original Article | 607 | Copyright © June 2007


Joel Schlessinger MD, Alan Menter MD, Michael Gold MD, Craig Leonardi MD, Lawrence F. Eichenfield MD, R. Todd Plott PhD, James J. Leyden MD (ZIANA™ Study Group)

Abstract
Clindamycin phosphate 1.2% and tretinoin 0.025% gel (CLIN/RA gel [ZIANA™ Gel]) is a novel topical combination agent approved by the FDA for the treatment of acne vulgaris in patients 12 years of age or older. A solution of clindamycin phosphate 1.2% combined with partially solubilized and crystalline tretinoin 0.025% suspended in an aqueous-based, alcohol-free gel formulation, CLIN/RA gel was studied in 2 randomized, vehicle-controlled trials involving more than 4,500 patients. Efficacy results from these studies showed that treatment with the combination significantly reduced lesion counts and improved patients overall appearance to a greater extent than the individual components. Individual ingredients and the combination were well-tolerated. Among those treated with the combination formulation, discontinuation rates due to adverse events were 1% or less.

INTRODUCTION

The pathogenesis of acne vulgaris depends upon several key factors including keratinization abnormalities, excess sebaceous gland secretion, the presence and activity of the anaerobic bacterium Propionibacterium acnes (P. acnes), and inflammatory immune reactivity.1 Clinical experience has shown that simultaneously targeting one or more of the pathogenic factors using a combination of appropriate drugs is the most effective approach to treating acne vulgaris. Combinations of antibiotics (clindamycin phosphate and erythromycin) with antimicrobial agents (benzoyl peroxide) and topical retinoids have all been shown to improve acne.2-22
Treatment with a combination of a topical retinoid plus an antimicrobial agent is a logical therapeutic approach based upon their different, and additive, mechanisms of action, including suppression of toll-like receptor 2 (TLR-2) activation by topical retinoids.23-25 The combination targets 3 pathogenic factors: abnormal follicular keratinization, proliferation of P. acnes, and inflammation.2-19 This produces a faster and greater resolution of lesions (comedones and inflammatory lesions) compared to monotherapy, improves antimicrobial penetration, and reduces the risk of low concentration-induced antibiotic resistance.2-4
Clindamycin phosphate 1.2% and tretinoin 0.025% gel (CLIN/RA Gel [Ziana™]) is the newest topical combination agent approved by the US FDA for the treatment of acne vulgaris in patients 12 years of age or older. This product uses innovative technology to combine an antimicrobial, clindamycin phosphate (1.2%), and a topical retinoid, tretinoin (0.025%), in a single formulation that is applied once per day.26

Clindamycin Phosphate 1.2% and Tretinoin 0.025% (CLIN/RA Gel)

Description and Mechanism of Action

In this novel product a solution of clindamycin phosphate 1.2% (equivalent to 1% clindamycin) and a suspension of crystalline tretinoin 0.025% are combined in a patented alcohol- free, aqueous-based gel vehicle. In solution, tretinoin is unstable in an aqueous environment; however, this product uses tretinoin in its solid rather than liquid form. Tretinoin is refined to a microcrystalline powder and placed in suspension within the aqueous based gel. Because the solubility of tretinoin in water is low the tretinoin crystals remain in a stable solid form until dissolved on the skin.
Results from a 6-week, phase I dermal safety and sensitization (occlusive patch test) study in 229 healthy subjects highlighted the value of the novel delivery system and vehicle. That study evaluated the cumulative irritation potential and contact sensitization potential of CLIN/RA gel and the CLIN/RA gel vehicle compared to tretinoin 0.025% gel (Retin-A gel), which contains the same amount of tretinoin solubilized in an alcoholic base. Investigators concluded that both the CLIN/RA gel and the CLIN/RA vehicle had a very low potential for causing sensitization reactions and significant irritation. CLIN/RA gel was significantly less irritating than tretinoin gel 0.025% (P<.001). The results showed that a formulation of tretinoin in a crystalline suspension without alcohol makes a significant difference in irritation.27
Certainly the suspension of crystalline tretinoin in the vehicle gel improves the stability of tretinoin, and it may also provide a means of slow or delayed release of tretinoin into the skin. While the exact mechanism is under investigation, the clinical efficacy and effects suggest that tretinoin dissolves slowly and produces a steady delivery of tretinoin over time. This slow release may ensure that the concentration of tretinoin in the skin does not overwhelm retinoid receptors,