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; 11(9). DOI:10.1021/mp400639e · 4.79 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. DOI:10.1016/j.ajps.2013.09.005
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ABSTRACT: Tacrolimus is widely used in the prophylaxis of solid-organ transplant rejection. Several studies have reported that tacrolimus has variable and poor bioavailability after oral administration, apart from adverse effects such as gastrointestinal disorders, hyperglycemia, nephro- and neurotoxicity. The aim of this work was to encapsulate tacrolimus (TAC) in lipid-core nanocapsules (LNC) as an oral strategy to deliver the drug. To validate our hypothesis, the pharmacodynamic effect of TAC-LNC was determined after oral and intraperitoneal (i.p.) administrations to mice. TAC-LNC had z-average diameter of 210 nm (unimodal), and 99.5% of encapsulation efficiency. In vitro sustained release was determined for TAC-LNC fitting an anomalous transport mechanism (n = 0.8). TAC-LNC demonstrated higher immunosuppressive activity after oral and i.p. administrations, when compared to the drug solution. TAC-LNC administered at 6.0 mg kg–1 day–1 showed equivalent percent reduction in lymphocyte when both routes of administration were used. After oral administration, drug nanoencapsulation allows reducing the dose by at least 40%. Furthermore, the nanoencapsulation of TAC in lipid-core nanocapsules showed pharmacodynamic effect similar for the oral and the i.p. routes. In conclusion, the lipid-core nanocapsules were able to improve the TAC deliver across the oral absorption barrier.Journal of Biomedical Nanotechnology 08/2014; 10(8):1599. DOI:10.1166/jbn.2014.1842 · 7.58 Impact Factor