Influence of drug solubility in the vehicle on clinical efficacy of ointments

Abstract

In a bilateral paired comparison (randomized double-blind study) 31 dermatitis patients (atopic and contact dermatitis) were tested with two ointments containing 0.0056% betamethasone-17-benzoate. One ointment was applied on each side of the body. The topical formulations differed in their solution capacities for the drug by a factor of about 50 (solution-type: high mutual affinity between drug and vehicle; suspension-type: low affinity). The different antiinflammatory effects were studied visually by assessing five symptoms: erythema, scaling, infiltration, lichenification, and excoriation. On the 5th day, 73% of the patients showed significant differences between the sides in favor of the suspension-type ointment (Wilcoxon test). Blanching tests on 30 volunteers confirmed the result. The in vitro drug release, however, was faster with the solution-type ointment. The efficacy of an ointment can be increased greatly, if the solution capacity for the drug is low, and thus the partition coefficient between the stratum corneum (barrier of the skin) and the vehicle is high. As long as the barrier is not damaged completely, the difference in drug release is not the determining factor for the effect.

From the Structure of the Skin Barrier and Dermal Formulations to in vitro Transport Models for Skin Absorption: Skin Research in the Netherlands and in Germany

“…Based on these in vivo results, the determining factors for drug penetration into human skin could be identified. For validation of these data in clinical situations, a randomized double-blind study was performed with dermatitis patients [82]. The results of this study confirmed the assumption that the clinical efficiency of a suspension-type ointment is higher than a solution-type ointment for a given drug.…”

Factors to Be Considered in the Evaluation of Bioavailability and Bioequivalence of Topical Formulations

“…Bioequi valence may be established through a wellcontrolled clinical trial or even through mea surement of a pharmacological or pharmaco dynamic end point. For example, skin blanch ing caused by corticosteroids has long been used to establish a dose response relationship and assess bioequivalence [10][11][12] and is now sanctioned for such purposes. Establishing that the concentration of drug within the treated tissue correlates with clinical perfor mance or to some relevant pharmacological end point is another approach to bioequival ence which is currently being debated.…”

Topical Treatment with Glucocorticoids

“…Gibson et al could not confirm significant differences in blanching activity of clobetasol after a tenfold dilution [19]. This finding can only be understood by assuming that a solution-type ointment was used as vehicle [51]. Furthermore, the results of Watson and Findlay revealing nearly identical liberation of clobetasol from a propylene glycol and a paraffin ointment can be interpreted insomuch that clobetasol was most likely suspended in the concentration used [84].…”

“…It is also possible that a dilution of the corticosteroid in certain ointment bases does not reduce its potency equivalently [19,51], and may as a consequence cause unexpected side effects. Gibson et al could not confirm significant differences in blanching activity of clobetasol after a tenfold dilution [19].…”

“…However, this is only correct if the drug is in solution (solution-type ointment). If on the other hand the corticosteroid is suspended in the base preparation -suspension-type ointment -(under the prerequisites that (a) the corticosteroid concentration is sufficient to guarantee a constant flux and (b) there is a fast corticosteroid liberation without changes of the skin barrier), its maximum effect is independent of the base preparation [34,46,47,50,51,60].…”