Dermal targeting of tacrolimus using colloidal carrier systems.
ABSTRACT In the therapy of chronic inflammatory skin diseases, the epicutaneous application of anti-inflammatory drugs in combination with maintenance therapy leads to ideal therapeutic long term effects. In this work, the development of well-tolerated colloidal carrier systems (ME) containing tacrolimus is described. A comprehensive physico-chemical characterization of the novel systems was performed using different techniques. The potential of three ME compared to an ointment as suitable carrier for dermal delivery of tacrolimus was determined. The penetration studies demonstrated that in comparison to the standard vehicle ointment, all three ME resulted in higher concentrations of tacrolimus in the deeper skin layers independent of the time of incubation. Particularly, the percentage of the bioavailable amount of tacrolimus (sum of the amount found in the dermis and acceptor compartment) from the ME with concentrations up to 20.95 ± 12.03% after 1000 min incubation time differed significantly (p<0.01), when compared to the ointment which yielded a concentration of 6.41 ± 0.57%. As a result of these experiments, using colloidal carrier systems, the penetration profile of tacrolimus was enhanced significantly (p<0.01). High drug amounts penetrated the target site in a short period of time after applying the ME.
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ABSTRACT: Tacrolimus (TAC) suffers from poor cutaneous bioavailability when administered topically using conventional vehicles with the consequence that although it is indicated for the treatment of atopic dermatitis, it has poor efficacy against psoriasis. The aim of this work was to formulate TAC loaded polymeric micelles using the biodegradable and biocompatible methoxy-poly(ethylene glycol)-dihexyl substituted polylactide (MPEG-dihexPLA) diblock copolymer and to investigate their potential for targeted delivery of TAC into the epidermis and upper dermis. Micelle formulations were characterized with respect to drug content, stability and size. An optimal 0.1% micelle formulation was developed and shown to be stable over a period of 7 months at 4°C; micelle diameters ranged from 10 to 50 nm. Delivery experiments using human skin and involving quantification by UHPLC-MS/MS demonstrated that this formulation resulted in significantly greater TAC deposition in skin than Protopic® (0.1% w/w; TAC ointment), (1.50 ± 0.59 and 0.47 ± 0.20 µg/cm2, respectively). The cutaneous biodistribution profile of TAC in the upper 400 µm of tissue (at a resolution of 20 µm) demonstrated that the increase in cutaneous drug levels was due to improved TAC deposition in the stratum corneum, viable epidermis and upper dermis. Given that there was no increase in the amount of TAC in deeper skin layers or any transdermal permeation, the results suggested that it would be possible to increase TAC levels selectively in the target tissue without increasing systemic absorption and the risk of side-effects in vivo. Micelle distribution and molecular penetration pathways were subsequently visualized with confocal laser scanning microscopy (CLSM) using fluorescently labeled copolymer and fluorescent dyes. The CLSM study indicated that the copolymer was unable to cross the stratum corneum and that release of the micelle "payload" was dependent on the molecular properties of the "cargo" as evidenced by the different behavior of DiO and fluorescein. A preferential deposition of micelles into the hair follicle was also confirmed by CLSM. Overall, the results indicate that MPEG-dihexPLA micelles are highly efficient nanocarriers for the selective cutaneous delivery of tacrolimus - superior to the marketed formulation (Protopic®). Furthermore, they may also have significant potential for targeted delivery to the hair follicle.Molecular Pharmaceutics 07/2014; · 4.79 Impact Factor
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ABSTRACT: The penetration behavior into human nails and animal hoof membranes of a novel antifungal agent (EV-086K) for the treatment of onychomycosis was investigated in this study. The new drug provides a high lipophilicity which is adverse for penetration into nails. Therefore, four different formulations were developed, with particular focus on a colloidal carrier system (CCS) due to its penetration enhancing properties. On the one hand, ex vivo penetration experiments on human nails were performed. Afterwards the human nail plates were cut by cryomicrotome in order to quantify the drug concentration in the dorsal, intermediate and ventral nail layer using high-performance liquid chromatography (HPLC) with UV detection. On the other hand, equine and bovine hoof membranes were used to determine the in vitro penetration of the drug into the acceptor compartment of an online diffusion cell coupled with Fourier transform infrared attenuated total reflectance (FTIR-ATR) spectroscopy. In combination, both results should exhibit a correlation between the EV-086K penetration behavior in human nail plates and animal hoof membranes. The investigations showed that the developed CCS could increase drug delivery through the human nail most compared to other formulations (nail lacquer, solution and hydrogel). Using animal hooves in the online diffusion cell, we were able to calculate pharmacokinetic data of the penetration process, especially diffusion and permeability coefficients. Finally, a qualitative correlation between the penetration results of human nails and equine hooves was established.Journal of Controlled Release 04/2014; · 7.26 Impact Factor
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ABSTRACT: The aims of this study were to prepare novel transfersomes (TFs) for tacrolimus to treat atopic dermatitis, and to observe the therapeutic effects on mice atopic dermatitis, as compared to commercial tacrolimus ointment (Protopic®) and liposomes-gel. Different kinds of surfactants—sodium cholate, Tween 80 and Span 80 were investigated to prepare TFs respectively. TFs-Tween 80 was selected as the optimal carrier owing to the best deformability and the highest drug retentions. Entrapment efficiency and diameter were also evaluated. The optimized TFs were further made into gel and in vitro drug release of TFs-gel after 24 h was higher than the commercial ointment. Cumulative drug release from TFs-gel after 12 h in vitro was 37.6%. The optimized TFs-gel illustrated remarkably highest drug skin retentions when compared with liposomes-gel and commercial ointment in vivo skin retention experiments. The amounts of tacrolimus in epidermis and dermis from TFs-gel were 3.8 times and 4.2 times respectively as much as ointment, while liposomes-gel was only 1.7 times and 1.4 times respectively as compared to ointment. Topical application of TFs-gel displayed the best therapeutic effect on mice atopic dermatitis induced by repeated topical application of 2,4-dinitrofluorobenzene. Thus TFs displayed superior performance and effective skin target for topical delivery of tacrolimus.Asian Journal of Pharmaceutical Sciences 12/2013; 8(6):336–345.