Teikoku Seiyaku Co. Ltd.

Transdermal patch administration results in a locally high concentration of drug that induce local toxicity, including tumorogenicity. As a worst-case scenario for consequences of repeated application on neoplastic growth, the melanin-binding drug, rasagiline, was used in a transdermal formulation applied directly to a human-derived melanoma to determine the effects on tumor growth.

Rasagiline mesylate was administered either orally or transdermally to athymic mice implanted with human melanoma (SKMEL28) to determine the effects on tumor growth and survival. Over a 21-day period, animals were administered daily oral gavage (15 mg/kg) or one or two rasagiline mesylate transdermal patches every 3 days. After the last dose administration, blood samples were collected to confirm drug exposure.

All animals from the untreated, vehicle and rasagiline groups survived to the end of the study; however, 7 out of the 10 cisplatin-treated animals died before the end of the study. Rasagiline mesylate dosed either via the oral or transdermal routes had comparable plasma exposure and, unexpectedly, significantly reduced absolute tumor volumes and tumor growth rates in the nude mouse SKMEL28 xenograft model.

Transdermal delivery of melanin-binding rasagiline does not increase melanoma growth in the xenograft model. Because rasagiline decreases melanoma growth, it may be candidate for combination therapy for melanoma.

Donepezil hydrochloride formulated in a transdermal patch for weekly administration is an alternative to the approved daily oral tablet. Transdermal delivery has a locally high concentration at the application site causing potential safety issues. To assess the skin exposure for safety evaluation, studies were performed comparing the donepezil transdermal patch with an oral donepezil dose previously tested in a carcinogenicity study, in which no test article-induced tumors were found. Quant. Whole Body Autoradiog. (QWBA) comparison in Long-Evans rats administered ¹⁴C-donepezil either as single oral dose (30 mg/kg) or a 24-h transdermal patch (∼60 mg/kg) revealed similar organ distribution, including skin. Pigmented tissue, namely, skin and eye showed sustained labeling over 7-10 days, suggesting melanin binding. Subsequently, a ¹⁴C-donepezil study in Long-Evans rats comparing seven daily oral doses (10-30 mg/kg) with a seven-day transdermal patch (∼40 mg/kg) again revealed similar tissue distributions between the two delivery methods, however, skin not directly exposed to the transdermal patch had less label as compared to both unpigmented and pigmented skin after oral dosing. Similarly, eye concentrations generally had higher label after oral dosing as compared to the transdermal administration. Upon patch removal, the non-viable stratum corneum under the dose-site contained the majority of the label with the underlying skin layers returning to baseline levels within 5 and 7 days for unpigmented and pigmented skin, resp., illustrating dermal clearance. Skin structures were comparably labeled after oral and transdermal administration, as evidenced by microautoradioagraphy.

Donepezil hydrochloride is a centrally acting, reversible acetyl cholinesterase inhibitor approved for Alzheimer's disease therapy. Donepezil is marketed as an oral tablet but a transdermal patch may have advantages as an alternate therapy. To determine whether the transdermal route alters known donepezil metabolism, this study compared plasma metabolites of donepezil hydrochloride with two routes of drug delivery, transdermal and oral, in three species; rat, mini-pig and human. The utility of a reconstituted human epidermis (RHE) in vitro model for transdermal drug biotransformation was also evaluated. In addition to donepezil, structures from three metabolic pathways were detectable in each matrix: 1) O demethylation (M1/M2; 2) N-dealkylation (M4); 3) N-oxidation (M6) utilizing LC/quadrupole-Ion trap MS/MS. In rats and humans, including RHE, the mean concentration levels of the donepezil and metabolites for both routes were found in the following order: donepezil>M4>M6>isomeric M1/M2 while in the pig, the order was the following: donepezil>M6>isomeric M1/M2>M4. Overall, there were no substantial differences in the plasma profiles between the rat and human. Donepezil metabolites were detectable in mini-pigs after both oral and transdermal administration, however, the concentrations varied from both rat and human. RHE showed quant. and qual. similarities between the metabolites produced in vitro with those found in human plasma after transdermal application. Thus, the data from the present study demonstrate that similar metabolites are found between the three species with rat most closely resembling humans and that the RHE model is a potentially valuable model to predict dermal metabolism