In order to promote absorption of drugs, vehicles often include penetration enhancing ingredients that temporarily disrupt the skin barrier, fluidize the lipid channels between corneocytes, alter the partitioning of the drug into skin structures, or otherwise enhance delivery into skin. Socalled penetration enhancers are drug substance- and vehicledependent and therefore are not universally effective. Propylene glycol is a multifunctional excipient in topical formulations, having humectant, solvent, and antimicrobial. The mechanism of permeation enhancement by propylene glycol is multiple and varies with concentration and formulation type. Propylene glycol is commonly used as an excipient in topical drug formulations and is found in a majority of formulations of corticosteroids. It is shown to diminish barrier function,13 and often functions as a penetration enhancer. Interestingly, despite its utility and safety in topical formulations, propylene glycol at high doses is toxic to humans.14
Other penetration enhancers, including detergents and emulsifiers, disrupt the barrier to encourage migration of active drug through the stratum corneum. Oleic acid can be a penetration enhancer in certain formulations and its mechanism is thought to be through fluidizing the intercellular lipids of the stratum corneum. Isopropyl myristate (IPM) is a unique penetration enhancer that is thought to provide benefit by fluidizing stratum corneum lipids and partially dissolving them.15 It is used in clobetasol propionate 0.05% spray (Clobex Spray, Galderma) to encourage rapid penetration of corticosteroid into the treated skin.
Most penetration enhancing excipients have the potential to be irritating to the skin, depending upon concentration and the other inactive ingredients in a particular vehicle.
Only relatively recently have formulators focused on modulating the detrimental effects of penetration enhancers by reducing or ameliorating the signs and symptoms of irritation. Review of three modern formulations of benzoyl peroxide (BPO)—an inherently irritating drug —and clindamycin demonstrate how vehicles may be formulated in efforts to reduce the irritation potential.
Benzaclin (clindamycin, 1%, benzoyl peroxide, 5%, Sanofi-Aventis) contains micronized benzoyl peroxide in an aqueous gel with surfactant and no non-volatile solvent. Upon application, the micronized BPO is deposited in the sebum-rich follicle where it exerts it effects.
In Duac (clindamycin, 1%, benzoyl peroxide, 5%, Stiefel) micronized benzoyl peroxide is formulated in an aqueous gel with surfactant, glycerin, a humectant to minimize the desiccating effect of BPO, and the emollient dimethicone to help moisturize the skin.
Acanya gel (clindamycin phosphate 1.2%, benzoyl peroxide 2.5%, Coria Laboratories) contains a 2-fold lower dose of benzoyl peroxide than the other clindamycin/BPO products, yet laboratory evidence suggests delivery of a similar amount of BPO to the skin.16 This may be an effect of low concentration propylene glycol in the formulation that helps to solubilize the BPO microparticles and transports them into the sebum.
The use of micrsopheres represents another approach to minimizing BPO-induced irritation. NeoBenz Micro (Intendis) entraps micronized benzoyl peroxide within polymeric sponges, offering slow release of the drug over time. Slow release of benzoyl peroxide through microspheres is shown to reduce irritation and minimize percutaneous absorption.17,18
Other attempts to minimize the irritancy associated with BPO while enhancing efficacy have focused on solubilizing the drug. A gel and lotion formulation (ClenziDerm, MD, Obagi Medical Products) features chemically micronized, solubilized BPO molecules to ensure even distribution in the vehicle. In clinical trials comparing solubilized BPO gel to a non-solubilized BPO/clindamycin combination formulation, the solubilized gel produced a greater reduction in non-inflammatory lesions at weeks 1 and 2 and an equivalent reduction in inflammatory lesions at week 12. Solubilized BPO is shown to produce a greater reduction of colony forming units of P. acnes compared to combination BPO/clindamycin.19
Ethanolic foam vehicles that dissolve at body temperature (Olux and Luxiq, Stiefel) not only provide good spreadability and cosmetic elegance, but also enhance delivery of corticosteroids compared to other traditional formulations. The mechanism to enhance penetration is the creation of a supersaturated drug solution in the propylene glycolrich secondary formulation remaining on the skin after evaporation of the alcohol and propellants. Supersaturation provides a driving force for drug delivery into the skin. Despite good overall tolerability with original ethanolic foams, a newer foam vehicle (Olux E, Stiefel) features emollients that counter the drying effect of the ethanolic foam, thereby hydrating the skin and providing a lubricant film to counteract sensations of stinging, burning, and dryness related to ethanol.20
In the case of Metro 1 (metronidazole 1%, Galderma), metronidazole is not very soluble in water or oil, so the molecule was formulated inside a dextran ring (Betadex NF or beta cyclodextrin) to which niacinamide was added in order to keep 10mcg/g in solution. Given the physicochemical characteristics of metronidazole, optimal delivery would be predicted from a solution rather than a suspension of the active ingredient. Niacinamide is further shown to improve skin hydration and barrier function.21 Low concentrations of glycerin in the formulation enhance percutaneus absorption and provide humectant effects. Betadex has a polyhydric hydrophilic surface (to enhance solubility and moisturize the skin) and hydrophobic core that encapsulates the metronidazole molecule. This newer formulation enables once-daily dosing of a higher concentration of metronidazole than had previously been available, and with improved tolerability.
Sides Media.