A novel foam vehicle for delivery of topical corticosteroids.

Skin, particularly the uppermost layer--the stratum corneum--presents a formidable, largely impassable barrier to the entry of most compounds. Recently, a novel thermolabile, low-residue foam vehicle, VersaFoam (Connetics Corp, Palo Alto, Calif), has emerged that offers a number of clinical and cosmetic advantages for the delivery of therapeutic agents through the skin. Two corticosteroids--mid-potency betamethasone valerate and ultra-high-potency clobetasol propionate--are now available in this formulation, and other products are in development to deliver clindamycin and ketoconazole in the foam vehicle. A series of in vitro studies have demonstrated that the new foam has the ability to deliver the active drug at an increased rate compared with other vehicles. These findings suggest that the new foam utilizes a nontraditional "rapid-permeation" pathway for the delivery of drugs. It is likely that components within the foam (probably the alcohols) act as penetration enhancers, and reversibly alter the barrier properties of the outer stratum corneum, thus driving the delivered drug across the skin membrane via the intracellular route. This is in contrast to traditional topical delivery vehicles, which must first rely on hydration of the intercellular spaces in the stratum corneum to achieve drug delivery. The latter mechanism reflects a hydration-dependent process, which may result in comparatively slower drug permeation.

PBPK modeling of the percutaneous absorption of perchloroethylene from a soil matrix in rats and humans.

Perchloroethylene (PCE) is a widely used volatile organic chemical. Exposures to PCE are primarily through inhalation and dermal contact. The dermal absorption of PCE from a soil matrix was compared in rats and humans using real-time MS/MS exhaled breath technology and physiologically based pharmacokinetic (PBPK) modeling. Studies with rats were performed to compare the effects of loading volume, concentration, and occlusion. In rats, the percutaneous permeability coefficient (K(P)) for PCE was 0.102 +/- 0.017, and was independent of loading volume, concentration, or occlusion. Exhaled breath concentrations peaked within 1 h in nonoccluded exposures, but were maintained over the 5 h exposure period when the system was occluded. Three human volunteers submerged a hand in a container of PCE-laden soil for 2 h and their exhaled breath was continually monitored during and for 2.5 h following exposure. The absorption and elimination kinetics of PCE were slower in these subjects than initially predicted based upon the PBPK model developed from rat dermal kinetic data. The resulting K(P) for humans was over 100-fold lower than for the rat utilizing a single, well-stirred dermal compartment. Therefore, two additional PBPK skin compartment models were evaluated: a parallel model to simulate follicular uptake and a layered model to portray a stratum corneum barrier. The parallel dual dermal compartment model was not capable of describing the exhaled breath kinetics, whereas the layered model substantially improved the fit of the model to the complex kinetics of dermal absorption through the hand. In real-world situations, percutaneous absorption of PCE is likely to be minimal.

Enhanced human nail drug delivery: nail inner drug content assayed by new unique method.

The purpose of this study was to develop an assay method of the human inner nail plate and to compare nail drug penetration by a penetrating enhancing formulation (the test carrier formulation). The test carrier and saline formulations were tested using radiolabeled urea, ketoconazole, and salicylic acid. After twice dosing daily for 7 days on human nail plates, the under inner section of the nail plate was assayed for absorbed drug content using a unique drilling/removal system. Results show that the weight-normalized radioactivity contents of three chemicals in the inner intermediate nail plate center in the carrier formulation were two fold higher than those from saline (p < 0.05). Total radioactivity recovery of dosed [(14)C]-salicylic acid was 89 +/- 2% in the carrier formulation and 88 +/- 5% in saline. In saline formulation, salicylic acid showed greater binding to the outer nail, making it less bioavailable for the inner nail area. This didn't occur with carrier formulation. In conclusion, topical treatment of nail diseases such as onychomycosis is not yet sufficiently effective, likely because of minimal drug penetration into the inner nail plate where the disease perpetuates. The assay system has the unique characteristic of being able to assay the inner part of the nail where the disease resides.