Stratum Corneum Absorption Kinetics of 2 Potent Topical Corticosteroid Formulations: a Pilot Study
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therapeutiCs for the CliniCian Close enCounters With the environment Stratum Corneum Absorption Kinetics of 2 Potent Topical Corticosteroid Formulations: A Pilot Study Zoe Diana Draelos, MD PraCtice Points • Fluocinonideconcentrationinthestratumcorneumpeakswithinthefirsthourofapplicationandthen beginsasteadydecline. • Halcinonideconcentrationalsopeakswithinthefirsthourofapplicationandremainselevatedfor6hours afterapplication. copy • Halcinonide,ratherthanfluocinonide,mayprovideclinicalbenefitsinbetweendosesbecauseofits sustainedreleasehoursafterapplication. not Fluocinonide and halcinonide are class II topical he active ingredient of any pharmaceutical corticosteroids that are indicated for the reliefDo product is responsible for the agent’s efficacy of inflammatory and pruritic manifestations of Tand safety profile. This ingredient is exten- corticosteroid-responsive dermatoses and gen- sively studied in clinical trials and evaluated by the erally are applied to affected skin at least twice US Food and Drug Administration before the product daily. This pilot study compared the absorption is commercially available. In dermatologic products, kinetics of cream formulations of fluocinonide especially those for treating dermatoses, the vehicle in and halcinonide in the stratum corneum within which the active ingredient is formulated also plays a a 9-hour period following application. A dermal role in drug delivery and indirectly impacts therapeu- tape-stripping protocol wasCUTIS used to quantify cor- tic outcomes, unlike excipients in oral medications. ticosteroid concentration at 6 sequential depths Topical vehicles must be stable, provide a suitable envi- in the skin of 4 sites on the forearm. Halcinonide ronment that will not degrade the active ingredient or and fluocinonide were extracted from the strips affect its efficacy, and be cosmetically acceptable.1 and concentrations were measured using liquid Topical vehicles are formulated to maintain the chromatography–mass spectrometry. Results stability of the active ingredient and allow it to demonstrated the immediate absorption of fluo- readily penetrate the skin and reach its target area cinonide and halcinonide into the stratum cor- with minimal absorption into the bloodstream, neum within 1 hour of application followed by a thus avoiding systemic adverse events. A variety of sustained release of halcinonide and a steady vehicles can exist for a single active ingredient to decline of fluocinonide after peaking. accommodate different phases of disease and differ- Cutis. 2015;96:135-141. ent anatomical sites where the disease may occur.2 For example, alcohol-based vehicles, sprays, and foams are preferred for the scalp where evaporation From Dermatology Consulting Services, High Point, North Carolina. of the vehicle is beneficial to prevent greasiness of Dr. Draelos received a research grant from Sun Pharmaceutical Industries Ltd to conduct the study. the hair, while ointments may be preferred due to Correspondence: Zoe Diana Draelos, MD, 2444 N Main St, their occlusive nature for areas with xerotic or thick High Point, NC 27262 ([email protected]). skin from dermatoses. WWW.CUTIS.COM VOLUME 96, AUGUST 2015 135 Copyright Cutis 2015. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. Therapeutics for the Clinician Cosmetic acceptability of the vehicle may influ- solution phase for immediate release into the skin and ence patient adherence to therapy. Housman et al3 in a suspension phase that allows a sustained release assessed a variety of products formulated in differ- after equilibrium is reached between the solution and ent vehicles (ie, solutions, foams, emollients, gels, suspension phases.8 Fluocinonide is not known to be creams, ointments) for the treatment of psoriasis. formulated in a similar way. Its vehicle composition Patients with psoriasis applied each test product to and penetration into the skin could explain the supe- a quarter-sized area of normal skin on the forearm rior efficacy of halcinonide versus fluocinonide. using a cotton swab and completed a preference The current pilot study was conducted to com- questionnaire. By far, respondents significantly pare the release pattern of fluocinonide cream versus preferred solutions and foams over creams, gels, halcinonide cream into the stratum corneum using and ointments (P<.01). Side effects were rated an in vivo, noninvasive method. Results for halcin- to be the most important characteristics of topical onide have been previously published.7 therapy, followed by time needed for application, ease of application, and messiness.3 Presumably, Methods if patients are frustrated with the topical product Participants were sequestered in a controlled envi- that they are using, adherence to the prescribed ronment for the entire day to allow the skin to dosage and application instructions will diminish equilibrate prior to product application. The meth- over time, leading to suboptimal steady-state levels odology for the application and quantification of of the product. If appropriate levels of the drug halcinonide cream 0.1% into the stratum corneum are not present at the target site, treatment will not of 5 participants using a tape-stripping protocol be successful. has been described elsewhere.7 Concordia Clinical Steady-state levels of a topical drug at the site of Research institutional review board (Cedar Knolls, action also are maintained via appropriate applica- New Jersey) approvedcopy this study, which was con- tion frequency, most commonly once to 4 times ducted at Dermatology Consulting Services (High daily for dermatologic products. Fluocinonide and Point, North Carolina). halcinonide are class II (potent) corticosteroids A 0.1-g dose of generic fluocinonide cream 0.05% indicated for the relief of inflammatory and pru- wasnot applied to four 2.5-cm circular sites on the ritic manifestations of corticosteroid-responsive forearm in 5 participants with normal skin until dermatoses and usually are administered at least completely absorbed. Circular tape strips were sub- twice daily. In double-blind clinical studies com- sequently placed on the application site at 1, 3, paring both products in the treatment of psoriasis,Do 6, and 9 hours posttreatment and were held for halcinonide resulted in more improved outcomes 10 seconds with a controlled pressure plunger to than fluocinonide.4-6 Sudilovsky and Clewe4 studied ensure adequate and consistent contact between the 140 patients with moderate to severe psoriasis. After tape strip and the skin. The tape strip was removed 3 weeks of treatment, 44% showed superior results with forceps, rolled with the skin scale inside, and with halcinonide, 27% showed superior results with placed in a glass vial. This procedure was repeated fluocinonide, 26% showed equal results with both 6 times at 1 of 4 sites with a new tape strip at each time products, and 3% showed noCUTIS relief.4 Similarly, Close 5 point to obtain samples from deeper skin layers. A total reported that 61% of patients showed superior results of 24 tape strips were collected from each participant. with halcinonide, 25% showed superior results with All vials were frozen at –20°C and were shipped fluocinonide, 10% showed equal results with both overnight to Robert Kellar, PhD, at the Center for products, and 4% showed no relief (N=50). Lynfield Bioengineering Innovation at Northern Arizona and Watsky6 reported that 56% of patients with University (Flagstaff, Arizona) for mass spectroscopy severe psoriasis who were treated with halcinonide evaluation. Once received at the outside facility, the for 2 weeks showed improvement to normal or slight vials were stored at –20ºC until analysis. Each sam- inflammation compared to 44% of patients treated ple was spiked with a known quantity of an appro- with fluocinonide (N=59). All 3 studies used cream priate reference standard and extracted with 1 mL formulations of halcinonide and fluocinonide. acetonitrile at room temperature for 1 minute with Recently, halcinonide cream was shown to agitation. New unused tape strips were spiked with a have an immediate release into the stratum cor- small amount of fluocinonide reference standard for neum that peaked within 1 hour of application and extraction efficiency. remained elevated for 6 hours before beginning to Extracts were evaporated to dryness under nitro- decline.7 These results support a biphasic release gen gas, resuspended in 200 µL chromatography of halcinonide, which is in agreement with its solvent, and quantified using liquid chromatography– formulation—that halcinonide exists in both a mass spectrometry. To remove the skin scale from 136 CUTIS® WWW.CUTIS.COM Copyright Cutis 2015. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. Therapeutics for the Clinician the tape strips, 10 mL of a solvent solution of a slight increase of 25 ng/mL at hour 6 (Figure 2B, 0.1 mg/mL fludrocortisone acetate in acetonitrile blue line). This increase is due to the measure- was dispensed into a 4 dram vial containing the ments obtained from participant 1; however, if partici- tape strip. The vials were ultrasonicated and shaken pant 1 is removed from the analysis, a constant decline for 10 to 15 minutes, and the samples were further is observed from hour 1 to hour 9 (Figure 2B, red line). diluted to 100-fold and were inverted several times A prior study evaluated the penetration