Dermal targeting of tacrolimus using colloidal carrier systems
Faculty of Biosciences/Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Wolfgang-Langenbeck-Straße 4, 06120 Halle, Saale, International Journal of Pharmaceutics
(Impact Factor: 3.65).
02/2011; 404(1-2):159-68. DOI: 10.1016/j.ijpharm.2010.11.029
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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- "However, physicochemical properties of tacrolimus, high molecular weight (822.95 g/mol) and strong lipophilicity (partition coefficient logP ¼ 3.96 AE 0.83), made it difficult to overcome the skin barrier and penetrate into deeper skin layers . What's more, the skin barrier would extend at diseased regions . "
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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.
Available from: Sara Biagiotti
- "Clearly, there is room for improvements in immunosuppressive drugs administration. To this end, several drug delivery systems aimed to improve oral bioavailability, targeting efficiency and reduce toxicity have been extensively explored both for tacrolimus             and for CsA          . However, to our knowledge, no optimal method to deliver immunosuppressant drugs into circulation has been until developed. "
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ABSTRACT: Cyclosporine A (CsA) and tacrolimus (also known as FK506) are natural compounds with immunosuppressive activity that have improved the outcome of organ transplantation. Unfortunately, both drugs are characterised by high pharmacokinetic variability, poor bioavailability and high toxicity. Until now, no optimal method to deliver immunosuppressant drugs into circulation has been developed. Here we propose the use of engineered erythrocytes as a drug delivery system for the release of immunosuppressants in circulation in order to modify their pharmacokinetic and restrain toxic effects. After administration, FK506 and CsA mainly distribute within erythrocytes owing to the presence into these cells of immunophilins that bind the drugs with very high affinity (FKBP12 for FK506 and cyclophilin A for CsA); therefore, a new strategy aimed to increase the amount of FK506/CsA carried by erythrocytes by increasing the intra-erythrocytic concentration of the respective binding proteins has been developed. We manufactured recombinant forms of human FKBP12 and cyclophilin A to be loaded into RBC through a hypotonic dialysis and isotonic resealing procedure. Erythrocytes loaded with 3.5±1.3, 7.5±3.1 and 15.5±0.4nmol FKBP12 were able to bind 3.5±1.5, 6.0±1.9 and 11.4±2.9μg FK506 per millilitre RBC, respectively, while RBC loaded with 4.0±0.6, 5.0±0.8 and 15.9±2.4nmol of cyclophilin A could bind 8.9±3.4, 12.2±3.5 and 17.0±3.2μg CsA. Thus, both engineered RBC were demonstrated able to bind up to an order of magnitude more drug than corresponding native erythrocytes (1.0±0.3μg FK506 and 3.2±0.3μg CsA). Moreover, FK506 released from FKBP12-RBC is able to be up-taken by T lymphocytes and inhibit IL-2 expression in vitro as free administered drug. In summary, our results indicate that diffusible immunosuppressants could be entrapped into red cells (thanks to the loading of the respective target protein) and suggest that immunophilin-loaded RBC could be employed as potential delivery system for immunosuppressive agents.
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ABSTRACT: Tacrolimus ointment being occlusive is known to give higher dermal penetration but offers limited patient acceptance in treatment of atopic dermatitis, especially in tropical countries. Hence, the aim of this study was to develop, characterize, and evaluate a microemulsion-based cream formulation of tacrolimus against ointment in hapten-induced murine model of dermatitis. Tacrolimus-loaded microemulsion having mean globule size below 25 nm was mixed with cetomacrogol cream base. The microemulsion-based cream exhibited a significantly faster drug release through semipermeable cellulose acetate membrane in comparison to commercially available ointment. The drug retention in rodent and human cadaver skin with cream was almost twofold greater in comparison to the commercially available ointment. Further, in vivo evaluation using a fluorescent marker revealed a greater and deeper accumulation of marker in skin with cream. In vivo studies in mice revealed a prompt and significant reduction in ear swelling. The reduction in inflammatory cytokine gene expression as evaluated by semiquantitative reverse transcriptase polymerase chain reaction was also significantly higher with cream. The better efficacy of cream was reflected in histopathology as well as in morphological observations at the site of application. Thus, microemulsion-based cream presents a possibility of development of an efficacious cream vehicle and a scope for dose reduction which needs to be confirmed in clinical studies.
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