Original Research

Stratum Corneum Absorption Kinetics of 2 Potent Topical Corticosteroid Formulations: A Pilot Study

Cutis. 2015 August;96(2):135-141

References

1. Ostrenga J, Haleblian J, Poulsen B, et al. Vehicle design for a new topical steroid, fluocinonide. J Invest Dermatol. 1971;56:392-399.

2. Rathi SK, D’Souza P. Rational and ethical use of topical corticosteroids based on safety and efficacy. Indian J Dermatol. 2012;57:251-259.

3. Housman TS, Mellen BG, Rapp SR, et al. Patients with psoriasis prefer solution and foam vehicles: a quantitative assessment of vehicle preference. Cutis. 2002;70:327-332.

4. Sudilovsky A, Clewe TH. Comparative efficacy of halcin-onide and fluocinonide creams in psoriasis and eczematous dermatoses. J Clin Pharmacol. 1975;15:779-784.

5. Close JE. Double-blind comparison of topical halcinonide and fluocinonide in the treatment of psoriasis. Int J Dermatol. 1976;15:534-537.

6. Lynfield Y, Watsky M. Psoriasis: topical corticosteroid therapy. Cutis. 1976;18:133, 136-137.

7. Draelos ZD. Demonstration of the biphasic release of 0.1% halcinonide cream. J Drugs Dermatol. 2015;14:89-90.

8. Bagatell FK. Halcinonide: a new potent topical anti-inflammatory drug. Cutis. 1974;14:459-462.

9. Ostrenga J, Steinmetz C, Poulsen B. Significance of vehicle composition. I. relationship between topical vehicle composition, skin penetrability, and clinical efficacy. J Pharm Sci. 1971;60:1175-1179.

10. Ayres PJ, Hooper G. Assessment of the skin penetration properties of different carrier vehicles for topically applied cortisol. Br J Dermatol. 1978;99:307-317.

11. Olsen EA. Double-blind controlled comparison of generic and trade-name topical steroids using the vasoconstriction assay. Arch Dermatol. 1991;127:197-201.

12. Stoughton RB. Are generic formulations equivalent to trade name topical glucocorticoids? Arch Dermatol. 1987;123:1312-1314.

13. Poulsen BJ, Young E, Coquilla V, et al. Effect of topical vehicle composition on the in vitro release of fluocinolone acetonide and its acetate ester. J Pharm Sci. 1968;57:928-933.

14. Taheri A, Cantrell J, Feldman SR. Tachyphylaxis to topical glucocorticoids: what is the evidence? Dermatol Online J. 2013;19:18954.

15. Ference JD, Last AR. Choosing topical corticosteroids. Am Fam Physician. 2009;79:135-140.

16. Pershing LK, Nelson JL, Corlett JL, et al. Assessment of dermatopharmacokinetic approach in the bioequivalence determination of topical tretinoin gel products. J Am Acad Dermatol. 2003;48:740-751.

17. Weigmann H, Lademann J, v Pelchrzim R, et al. Bioavailability of clobetasol propionate-quantification of drug concentrations in the stratum corneum by dermatopharmacokinetics using tape stripping. Skin Pharmacol Appl Skin Physiol. 1999;12:46-53.

18. Wiedersberg S, Naik A, Leopold CS, et al. Pharmacodynamics and dermatopharmacokinetics of betamethasone 17-valerate: assessment of topical bioavailability. Br J Dermatol. 2009;160:676-686.

Comment

The release of both fluocinonide and halcinonide into the skin was evaluated using dermal tape stripping on 4 sites on the forearms of healthy individuals. Cream formulations of each corticosteroid were evaluated in 5 participants, with 2 participants receiving both formulations during different study periods. In the prior study with halcinonide, the stratum corneum exhibited the highest concentration of the corticosteroid, with substantial declines beyond strip 6 (ie, strips 7–20).⁷ For this reason, only strips 1 to 6 were evaluated for corticosteroid penetration and absorption.

Results from strip 1 indicated immediate absorption of corticosteroid (fluocinonide and halcinonide) into the skin. Unlike the release of halcinonide, which demonstrated a clear sustained release over 6 hours before decreasing,⁷ fluocinonide concentrations began declining immediately after peaking at hour 1 and continued to decline up to hour 9. Only participant 1 exhibited a second peak of fluocinonide concentration at hour 6; the rest of the participants did not. This second peak is most likely an anomaly due to the small number of participants rather than a true elevation.

Given the rapid decline of fluocinonide concentration over the 9 hours compared with the more gradual decline of halcinonide concentration, there appears to be no evidence of a biphasic sustained release of fluocinonide from its vehicle. This difference in release pattern from each corticosteroid’s respective vehicle may explain in part the different clinical outcomes in comparative studies.^4-6

It is known that vehicle composition affects corticosteroid diffusion from the vehicle to the skin surface and subsequent penetration into the skin.⁹ Either process can determine the overall effectiveness of the product. Ayres and Hooper¹⁰ evaluated the penetration of 4 topical preparations of cortisol. Product 1 delivered 16 times more cortisol to the skin than product 2, 8 times more than product 3, and 3 times more than product 4. Because all the preparations contained cortisol-free alcohol, these differences were attributed to the vehicle in which the cortisol was formulated. Products 1 and 4 both contained 10% urea, but the urea in product 1 was a powder in a cream base and the urea in product 4 was in a stabilizing emulsified base. Product 2 contained a propylene glycol/water base and product 3 was a water-miscible cream.¹⁰

Generic corticosteroid products have been observed in clinical practice and have been shown in vasoconstriction assays to be less and more potent than their brand-name equivalents.^2,11 Vasoconstriction assays are the standard for assessing the potency of topical corticosteroids and predicting their clinical efficacy.² One study reported significant differences in therapeutic effectiveness between generic formulations and their brand-name equivalents.¹² Kenalog cream 0.1% (multiple manufacturers) was significantly more potent than any of the generic triamcinolone creams tested (P<.05); in fact, Kenalog cream 0.025% (multiple manufacturers) was statistically superior to all the generic triamcinolone creams 0.1%. Moreover, Artistocort A ointment 0.1% (Lederele Laboratories) and Valisone cream 0.1% (Schering Corporation) also were more potent than their generics at the same concentration in the same vehicle type.¹² A second study also observed that 2 of 6 generic formulations had significantly less vasoconstriction than their respective brand-name formulations.¹¹ A brand-name betamethasone valerate cream produced significantly greater vasoconstriction than its generic equivalent, and a brand-name betamethasone dipropionate cream produced greater vasoconstriction than one generic and equal vasoconstriction to another generic. Additionally, the vasoconstriction measured with Diprosone was greater than that measured with Diprolene, another brand-name product of betamethasone dipropionate.¹¹ Diprosone and Diprolene differ in their vehicle content. The latter, a class I corticosteroid, contains a modified vehicle high in propylene glycol, whereas the former contains less propylene glycol and thus is classified as a class III corticosteroid. Propylene glycol allows hydrophobic molecules such as corticosteroids to dissolve more fully in the vehicle.¹²

Ostrenga et al¹ studied the solubility of corticosteroids in different vehicles and, as expected, corticosteroids that fully solubilized in the vehicle exhibited better penetration into the skin on assessment with vasoconstriction assays. Corticosteroids in a suspension, on the other hand, showed slower penetration into the skin.^1,13 A balance between the solution and suspension phase would allow a drug to rapidly penetrate the skin upon application, and when this pool of solubilized drug was depleted, additional drug could penetrate into the skin from the suspension phase. Based on the tape strip results from the current study it appears that halcinonide, which is manufactured in a biphasic formulation, follows this pattern of penetration and absorption into the stratum corneum. In contrast, fluocinonide appears to exist in a soluble state without much, if any, amount in a suspension phase because it had no sustained release during the 9 hours after application.

Common belief among dermatologists is that long-term use of corticosteroids leads to tachyphylaxis,¹⁴ which can be attributed to poor patient adherence. If patients skip doses, then the steady state of the product at the target site is not maintained. It is interesting to speculate that using agents with more sustained release beyond the time of application (such as halcinonide) may preserve steady-state levels even when patients are neglectful of the next medication application. Corticosteroids that work in 2 phases such as halcinonide may minimize tachyphylaxis experienced with prolonged use of corticosteroids.

Fluocinonide and halcinonide are both class II high-potency corticosteroids as shown on outcomes from vasoconstrictor assays, which assess the extent to which a corticosteroid causes cutaneous vasoconstriction or blanching in normal healthy individuals.¹⁵ The assay depends on the molecule diffusing from the vehicle, penetrating the skin, and causing a reaction (blanching) that is then evaluated. The assay cannot effectively evaluate the rate of continued diffusion and skin penetration beyond the appearance of blanching. In contrast, the tape-stripping method provides an inside look at the extent of penetration of the corticosteroid beyond the skin surface and the rate of its clearance from different skin layers. In the current study, the levels of fluocinonide declined after peaking at 1 hour after application, but the levels of halcinonide clearly remained elevated after peaking at the same time point. Most likely, vasoconstrictor studies would not be able to differentiate between the concentrations of the 2 products in the stratum corneum beyond the first hour after application.

Tape stripping, or dermatopharmacokinetics, has advantages over vasoconstriction assays in studying corticosteroid penetration and clearance from the stratum corneum. At one point, the US Food and Drug Administration had included tape stripping in its preliminary guidelines for generic topical bioequivalence studies until data from the same formulation generated from 2 different laboratories produced different results.¹⁶ Since that time, much work has been done with tape stripping to ensure its consistency. Weigmann et al¹⁷ demonstrated equivalent results with clobetasol using vasoconstriction and tape stripping, and Wiedersberg et al¹⁸ demonstrated the same with betamethasone. For the current study, the fluocinonide and halcinonide formulations were weighed prior to application so that the same dose was tested in all participants. A plunger was used to produce consistent pressure at all application sites to control for the amount of skin that was stripped off with the tape. Results for both corticosteroids were consistent between the participants. Variability in the data was detected; however, this observation is most likely due to the small number of participants in the studies.

Conclusion

In summary, this pilot study demonstrated that fluocinonide concentration in the stratum corneum peaks within the first hour of application before beginning a steady general decline. There was no evidence of sustained release. In contrast, halcin-onide demonstrated a sustained release for 6 hours after application. Halcinonide is formulated in a cream base in which the corticosteroid is present in a solution and suspension phase that allows for sustained delivery in skin over time. Fluocinonide does not appear to be formulated in the same way, and its concentrations in the stratum corneum begin to decline 1 hour after application.

Acknowledgement

Thank you to Robert Kellar, PhD, at the Center for Bioengineering Innovation at Northern Arizona University, Flagstaff, for conducting the liquid chromatography–mass spectrometry.