Polymer emulsion or polymer mesh technology is based on the utilization of a crosslinked polymer to structure an aqueous vehicle and provide a homogenous dispersion of microparticles. Polymer mesh technology allows for the utilization of a minimum quantity of structuring agent in an aqueous phase and allows the elimination of emulsifiers, waxes, and other inactive ingredients that may interfere with the delivery of active to the skin. It is combined with the use of micronized active ingredients. Drug-active micronization is a unique formulation process that is often confused with microspheres and microencapsulation. It is distinct in that it is a consistent manufacturing of a designated size range of smaller particles of active ingredient.17 Micronization therefore creates uniformly small enough particle sizes that allows for enhanced cutaneous and follicular penetration with a more even distribution upon topical application when incorporated into a vehicle.
Synergism in Topical Acne Combination Products: Decades of Dyads Before a Triad
While numerous single-agent topical antimicrobials and retinoids exist, antibiotic resistance, poor active delivery, and poor treatment adherence (sometimes due to irritation) are major contributors to treatment failures.11 With the advancement of vehicle formulation technologies, topical fixed-dose combination products have been developed that allow for increased adherence given their once-daily application as a single treatment bypassing the need for multiple topicals with multiple applications. Fixed-dose combination products have also allowed for a combination of agents that were initially prohibitive (eg, BPO and tretinoin due to oxidation) and further provide synergy in efficacy.18 The currently approved fixed-dose combination products are discussed next.
BPO-Clindamycin Combinations
Formulations combining clindamycin with BPO have been developed to reduce antibiotic resistance due to clindamycin while maximizing antimicrobial and anti-inflammatory effects. The initial combination products were clindamycin phosphate 1% and BPO 5% (CDP 1%/BPO 5%) gels. Several clinical trials assessed the efficacies of these gel formulations compared to clindamycin, BPO, and vehicle monotherapies alone.19 Xu et al also found CDP 1%/BPO 5% to be superior to clindamycin 1% gel monotherapy in a single-blind randomized comparison trial of 1016 subjects with mild-to-moderate acne over 12 weeks.20 More recently, a gel formulation containing CDP 1.2%/BPO 3.75% was developed. Pariser et al investigated the efficacy of once-daily CDP 1.2%/BPO 3.75% in 498 subjects with moderate-to-severe acne over 12 weeks compared to vehicle.21 34.3% and 15.6% of subjects in the CDP 1.2%/BPO 3.75% and vehicle groups, respectively, achieved treatment success (at least 2-grade improvement in Evaluator's Global Severity Score EGSS) at week 12. Post-hoc analyses found superior reductions in lesion count in the CDP 1.2%/BPO 3.75% group compared to the vehicle as early as week 4 and that Hispanics tolerated treatment well and were not found to be more susceptible to irritation.22,23 Lastly, there is also a CDP 1.2%/BPO 2.5% gel formulation.24 Eichenfield et al showed the superiority of CDP 1.2%/BPO 2.5% gel to the vehicle over 12 weeks in adolescents with skin of color with a favorable cutaneous tolerability profile.25
BPO-Retinoid Dyads
The first fixed-dose combination BPO-retinoid approved for once-daily treatment of acne is adapalene 0.1%/benzoyl peroxide 2.5% (0.1% ADA/BPO) gel.26 A randomized double-blind controlled trial of 1670 subjects showed synergism of once-daily application of 0.1% ADA/BPO gel over each monad (adapalene 0.1%, BPO 2.5% monotherapies) and vehicle gel over 12 weeks of treatment.26 A pooled assessment from 3 randomized, double-blind, controlled studies showed 0.1% ADA/BPO gel to be significantly more effective than adapalene, BPO, and gel vehicle monotherapies despite acne lesion counts with the relative benefit of the combination gel increasing with higher lesion counts at baseline.27,28 One study also demonstrated a 97% reduction in antibiotic-resistant and antibiotic-susceptible C. acnes strains after four weeks of once-daily application.29
As topical treatments alone have not traditionally been seen as suitable for severe non-nodulocystic papulopustular acne, a higher concentration of adapalene in fixed combination with BPO was developed. Stein Gold et al assessed the efficacy of once-daily adapalene 0.3%/benzoyl peroxide 2.5% (0.3% ADA/BPO) gel compared to vehicle in a randomized, double-blind, parallel-group controlled study comprising 503 subjects.30 0.3% ADA/BPO was superior in the co-primary endpoints of Investigatory Global Assessment (IGA) success rate (clear/almost clear, at least a 2-grade change) and change in inflammatory and non-inflammatory lesion counts at week 12. An early onset of action was noted as early as week 1. Notably, this trial also focused on the severe acne population (IGA 4) and utilized a stricter secondary endpoint of a 3-point IGA reduction. 0.3% ADA/BPO demonstrated superiority over vehicle for this secondary endpoint. A post-hoc analysis stratifying subjects based on age and gender further found 0.3% ADA/BPO to be equally effective and safe regardless of age and gender.31 0.3% ADA/BPO is also effective in all skin phototypes and is effective, tolerable, and improves post-inflammatory hyperpigmentation in patients with skin of color.32,33
