a SciTechnol journal Rapid Communication Meier-Davis et al., J Pharm Drug Deliv Res 2012, 1:1 http://dx.doi.org/10.4172/2325-9604.1000102 International Publisher of Science, Technology and Medicine All articles published in Journal of Pharmaceutics & Drug Delivery Research are the property of SciTechnol, and is protected by copyright laws. “Copyright © 2012, SciTechnol, All Rights Reserved. Journal of Pharmaceutics & Drug Delivery Research Enhancing the Skin Flux of Tolnaftate Utilizing the Novel Excipient, Dodecyl-2-N,N- Dimethylaminopropionate (DDAIP) Susan R. Meier-Davis 1 *, Salma Debar 1 , Richard Martin 1 , Mohamed Hachicha 1 and Bassam Damaj 1 Abstract Penetration of drug through the stratum corneum to reach the underlying epidermal and dermal layers is a critical step for effective therapy by the topical route. To enhance permeation, various penetration enhancers have been utilized in combination with active drugs. The novel excipient, dodecyl-2-N,N- dimethylaminopropionate (DDAIP), was utilized to assess the epidermal penetration of tolnaftate. Tolnaftate, an anti-fungal agent, is approved as an over-the-counter (OTC) product for the treatment of superfcial fungal infections including, athlete’s foot, ringworm and jock itch. Utilizing human cadaver skin mounted on Franz cells, tolnaftate skin fux was evaluated with and without the presence of DDAIP. Over a 24-hour period, DDAIP at a concentration of 0.5% enhanced tolnaftate permeation through human cadaver skin relative to the marketed tolnaftate formulation (1%). Increased tolnaftate penetration may decrease the number of applications and treatment duration required for dermatophyte therapy. Keywords: Tolnafate; Permeation; Excipient;, Dermatophyte; DDAIP Introduction Causative organisms responsible for fungal infections of the skin, classifed as dermatophytes include Microsporum, Trichophyton, and Epidermophyton spp [1,2]. Dermatophytosis is generally limited to keratin-producing cells of the skin but may become more invasive due to trauma, moisture, secondary infection or patient status [2-4]. Te superfcial nature of the infection allows the fungus to be easily transmissible on contact. Terefore, early diagnosis and treatment initiation not only limit the primary infection but also transmission [1,2]. Te treatment regimen frequently employed to treat these superfcial epidermal fungal infections is topical application of tolnafate [3]. Tolnafate, a thiocarbamate, is fungicidal at its marketed concentration of 1%. Te customary treatment regimen is topical application of the 1% cream on the afected area, twice daily *Corresponding author: S. Meier-Davis, c/o NexMed Inc., 11975 El Camino Real, Suite 300, San Diego, CA 92130, USA, Tel: 858-222-8041; Fax: 858-587- 2131; E-mail:- smeierdavis@apricusbio.com Received: July 03, 2012 Accepted: August 09, 2012 Published: August 13, 2012 [1,5]. Tolnafate is poorly absorbed and, hence, a good candidate for topical treatment of superfcial infections. However, increased penetration of the anti-fungal may reduce the number of applications and the overall treatment duration necessary to clear the infection [6]. Resistance to anti-fungal therapy increases with duration of therapy [7]. Consequently, development of a tolnafate formulation with increased epidermal penetrance could not only decrease the treatment duration but also decrease the potential for organism resistance. Efcient permeation of pharmaceutical agents through the stratum corneum is dependent upon permeation enhancers. Permeation enhancers are thought to enhance delivery of topically applied drugs by increasing the thermodynamic activity of the stratum corneum or traversing between the intercalated lipid layers [8,9]. A number of permeation enhancers have been used to enhance topical drug delivery including isopropyl myristate, capric acid, lauric acid, myristic acid, oleic acid, Tween 20, Tween 80, sodium lauryl sulfate and Span 80 [10,11]. DDAIP is a novel excipient that also may act as a permeation enhancer in combination with pharmaceutical agents. Te putative mechanism for enhanced permeation by DDAIP is due to the temporary changes of the lipid bi-layer permeation dynamics including loosening of the tight junctions between skin cells [12]. Additionally, at the pH of skin, DDAIP remains stable for >100 hours, potentially allowing prolonged permeation (unpublished data). Te objective of this study was to determine whether DDAIP enhances the permeation of the marketed formulation of tolnafate. Increased permeation of tolnafate may contribute to enhanced cure rates of superfcial dermatophyte infections. Materials and Methods All reagents used in this study were analytical reagent grade or better. Tolnafate was commercially available (Lot 14007) and contains 1% tolnafate, butylated hydroxytoluene, cetanol, liquid parafn, methylparaben, polyoxyethylene cetylether, propylene glycol, propylparaben, purifed water, sorbitan monostearate and stearyl alcohol. A tolnafate formulation was developed with the novel excipient, dodecyl-2-N,N- dimethylaminopropionate (DDAIP, lot number R1050) and evaluated for skin penetration against the OTC product, both consisting of a fnal tolnafate concentration of 1%. Human cadaver skin was obtained from the University of California, San Diego Skin Bank and stored at -80°C. Te skin was thawed by immersing in 0.9% sodium chloride for 30 minutes prior to the experiment. In vitro skin fux was conducted by mounting the human cadaver skin sections (US Tissue & Cells-lots 118122127 and 118235129) onto Franz difusion cells (Permegear, Model # VC9). Each experiment comprised either 6 or 9 samples derived from two cadaver skin donors. Te receptor compartment contained a solution of phosphate-bufered isotonic saline (PBS), pH 7.4 ± 0.1 with 20% ethanol, 0.1% gentamicin sulfate and 0.05% thio-urea, maintained at 32.0 ± 0.5°C. Te test formulations (100 µL) were applied directly onto the cadaver epidermis (0.64 cm 2 ). Samples were collected at specifed times from the receptor compartment and the skin was homogenized for determination of tolnafate levels. Te skin