Targeting tacrolimus to deeper layers of skin with improved safety for treatment of atopic dermatitis—Part II: In vivo assessment of dermatopharmacokinetics, biodistribution and efficacy

Pople, Pallavi V.; Singh, Kamalinder K.

doi:10.1016/j.ijpharm.2012.04.051

Cited by 42 publications

(20 citation statements)

References 58 publications

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“…8,49,50 As we described earlier, FK506-loaded ethosomes, lipid NPs, or modified lipid NPs were reported to enhance FK506 penetration, resulting in an enhanced efficacy for treating AD. 8,49,50 Therefore, the synergistically enhanced penetration of FK506 by the combination of HA-Chol-NPs with NIC also suggests that FK506-HA-Chol-NPs-NIC will exert an enhanced effect on treating skin diseases compared to FK506-HA-CholNPs, FK506-NIC complex, FK506 aqueous suspension, or commercial ointment. In clinic, FK506 has been investigated successfully in the management of AD and psoriasis.…”

mentioning

confidence: 78%

Combination of hydrotropic nicotinamide with nanoparticles for enhancing tacrolimus percutaneous delivery

Pan¹,

Qin²,

Zhang³

et al. 2016

IJN

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Tacrolimus (FK506), an effective immunosuppressant for treating inflammatory skin diseases, hardly penetrates into and through the skin owing to its high hydrophobicity and molecular weight. The aim of this study was to develop a hybrid system based on nicotinamide (NIC) and nanoparticles (NPs) encapsulating FK506, such as FK506–NPs–NIC, for facilitating percutaneous delivery, which exploited virtues of both NIC and NPs to obtain the synergetic effect. Solubility and percutaneous permeation studies were carried out. The results showed that NIC could increase the solubility and permeability of FK506 and that 20% (w/v) NIC presented higher FK506 permeability and was thus chosen as the hydrotropic solution to solubilize FK506 and prepare FK506–NPs–NIC. Hyaluronic acid (HA) was chemically conjugated with cholesterol (Chol) to obtain amphiphilic conjugate of HA–Chol, which self-assembled NPs in 20% NIC solution containing FK506. The particle size, zeta potential, and morphology of NPs were characterized. The encapsulation efficiency and in vitro percutaneous permeation of NPs were evaluated in the presence and absence of NIC. The results demonstrated that hydrotropic solubilizing FK506 was readily encapsulated into NPs with a higher encapsulation efficiency of 79.2%±4.2%, and the combination of NPs with NIC exhibited a significantly synergistic effect on FK506 deposition within the skin (2.39±0.53 μg/cm 2 ) and penetration through the skin (13.38±2.26 μg/cm 2 ). The effect of the combination of NPs with NIC on drug permeation was further visualized by confocal laser scanning microscope through in vivo permeation studies, and the results confirmed that NPs–NIC synergistically enhanced the permeation of the drug into the skin. The cellular uptake performed in HaCaT cells presented a promoting effect of NPs on cellular uptake. These overall results demonstrated that HA–Chol–NPs–NIC can synergistically improve the percutaneous delivery of FK506, and it is a novel potential strategy based on a nano-sized carrier for FK506 to treat skin diseases.

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mentioning

confidence: 78%

Combination of hydrotropic nicotinamide with nanoparticles for enhancing tacrolimus percutaneous delivery

Pan¹,

Qin²,

Zhang³

et al. 2016

IJN

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“…28,29) Whilst there are several reports on the investigation of skin permeation and development of drug delivery systems in AD animal models, [30][31][32] evaluation of pharmacokinetic properties is difficult due to the concurrent inflammatory reactions in AD skin. In order to investigate the drug disposition after topical application on AD skin, it is necessary to understand different influential factors and their individual effects.…”

Section: Discussionmentioning

confidence: 99%

Effect of Physiological Changes in the Skin on Systemic Absorption of Tacrolimus Following Topical Application in Rats

Hazama

Maekawa

Miki

et al. 2016

Biological & Pharmaceutical Bulletin

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Tacrolimus (TL) ointment is a topical treatment for atopic dermatitis, a disease that exhibits various skin conditions. The effect of skin pathologies on the systemic absorption of TL and related side effects remains unknown. This study aimed to investigate factors affecting the cutaneous absorption of TL. We prepared various skin models in hairless rats by tape stripping, injection of prophlogistic material solution (PMS), and continuous subcutaneous adrenaline (Adr) infusion. In vivo absorption studies were conducted, with measurements of transepidermal water loss (TEWL) and skin blood flow as physiological parameters. Very little TL absorption was observed through intact skin. Greater TL absorption was noted in skins with high TEWL values and fully stripped skin with PMS injections. In contrast, Adr infusion, which reduced skin blood flow, resulted in decreased TL absorption through fully stripped skin. Combined use of TL and Adr on skin with PMS injections resulted in suppression of TL absorption. Our results revealed that TL absorption following topical application is affected by alterations in the skin barrier, blood flow, and vascular permeability. We propose an administration plan for TL in a flowchart as a means of preventing systemic side effects.Key words tacrolimus; cutaneous absorption; atopic dermatitis; inflamed skin; transepidermal water loss; skin blood flow Tacrolimus (TL, FK506, molecular weight of 803.5) is a 23-membered macrolide lactone isolated from the bacterium Streptomyces tsukubaensis. For over two decades, TL has been widely used as a calcineurin inhibitor immunosuppressant for organ transplantation, given intravenously and orally. A topical formulation of TL (Protopic ® ointment, available in two TL ointment concentrations: 0.1% for adults and 0.03% for children) has also shown potent immunosuppressive activity and has been used as second line treatment for atopic dermatitis (AD) that cannot be controlled by topical corticosteroids.1,2) In 2006, the U.S. Food and Drug Administration (FDA) issued a black-box warning regarding a potential carcinogenic risk associated with TL ointment. Since then, some cohort studies and case-control studies have been conducted in order to reveal the association between topical use of TL and an increased risk of malignancy. Hui et al. and Arana et al. identified an increased risk of T-cell lymphoma with TL use.3,4) In contrast, other studies revealed no significant differences between TL use and non-use with regard to an increased risk of lymphoma.5,6) Due to short durations and potential study biases in these reports, results have been controversial. Thus, the FDA has advised that monitoring for occurrence of TL-related cancer be continued.AD is a chronically relapsing inflammatory skin disease with severe pruritus and eczema. The skin barrier function in AD patients is disrupted and exhibits an increase in transepidermal water loss (TEWL). [7][8][9] This skin disruption allows TL to permeate the skin despite a large molecular weight. 10,11) TL exerts ...

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“…Cyclosporine Liposomes (Freise et al, 1994;Shah et al, 2006); polymeric NP (Gref et al, 2001;Italia et al, 2007;Azzi et al, 2010;Tang et al, 2012); lipid NP (Muller et al, 2008) Preclinical Tacrolimus Lipid NP (Pople and Singh, 2012); polymeric NP (Tammam et al, 2012); liposomes (Erdogan et al, 2002;Zhang et al, 2010) Preclinical Rapamycin/sirolimus Polymeric NP (Yuan et al, 2008;Woo et al, 2012;Shah et al, 2013); micelles (Yanez et al, 2008;Chen et al, 2013); liposomes (Rouf et al, 2009;Ghanbarzadeh et al, 2013) Preclinical Mycophenolic acid Polymeric NP (Shirali et al, 2011); nanogels (Look et al, 2013); dendrimers (Hu et al, 2009) Preclinical Corticosteroids Liposomes Linker et al, 2008;Schweingruber et al, 2011;Ulmansky et al, 2012); polymeric NP (Ishihara et al, 2005;Matsuo et al, 2009); solid lipid NP (Jensen et al, 2010;Zhang and Smith, 2011); dendrimers (Khandare et al, 2005) Preclinical Non-steroidal anti-inflammatory Dendrimers (Chauhan et al, 2004;Na et al, 2006;Chandrasekar et al, 2007;Cheng et al, 2007); nanocolloid (Milkova et al, 2013); lipid NP (Castelli et al, 2005); liposomes (Paavola et al, 2000;Srinath et al, 2000;Turker et al, 2008)…”

Section: Nanocarrier Statusmentioning

confidence: 99%

“…Some of these challenges may be circumvented by formulating the immunosuppressants into nanoparticles (Canadas et al, 2004;Liu et al, 2007;Czogalla, 2009;Shin et al, 2010;Pople and Singh, 2012;Tammam et al, 2012). For example, liposomal and polymeric nanoparticle reformulation of cyclosporine significantly reduced nephrotoxicity of the drug in rats and in a rat ischaemic kidney model (Freise et al, 1994;Italia et al, 2007).…”

Section: Preclinicalmentioning

confidence: 99%

“…For example, liposomal and polymeric nanoparticle reformulation of cyclosporine significantly reduced nephrotoxicity of the drug in rats and in a rat ischaemic kidney model (Freise et al, 1994;Italia et al, 2007). Incorporation of tacrolimus into 75 nm lipid nanoparticles resulted in improved skin penetration and deposition, and reduced side effects in comparison to the traditional formulation Protopic ® (Pople and Singh, 2012). Another example of using nanotechnology to improve delivery of T-cell-specific immunosuppressive drugs is the study by J.…”

Section: Preclinicalmentioning

confidence: 99%

See 1 more Smart Citation

Immunosuppressive and Anti-Inflammatory Properties of Engineered Nanomaterials

Ilinskaya

Dobrovolskaia

2016

Handbook of Immunological Properties of Engineered Nanomaterials

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Nanoparticle interactions with various components of the immune system are determined by their physicochemical properties such as size, charge, hydrophobicity and shape. Nanoparticles can be engineered to either specifically target the immune system or to avoid immune recognition. Nevertheless, identifying their unintended impacts on the immune system and understanding the mechanisms of such accidental effects are essential for establishing a nanoparticle's safety profile. While immunostimulatory properties have been reviewed before, little attention in the literature has been given to immunosuppressive and anti-inflammatory properties. The purpose of this review is to fill this gap. We will discuss intended immunosuppression achieved by either nanoparticle engineering, or the use of nanoparticles to carry immunosuppressive or anti-inflammatory drugs. We will also review unintended immunosuppressive properties of nanoparticles per se and consider how such properties could be either beneficial or adverse. LINKED ARTICLESThis article is part of a themed section on Nanomedicine. To view the other articles in this section visit http://dx

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Targeting tacrolimus to deeper layers of skin with improved safety for treatment of atopic dermatitis—Part II: In vivo assessment of dermatopharmacokinetics, biodistribution and efficacy

Cited by 42 publications

References 58 publications

Combination of hydrotropic nicotinamide with nanoparticles for enhancing tacrolimus percutaneous delivery

Combination of hydrotropic nicotinamide with nanoparticles for enhancing tacrolimus percutaneous delivery

Effect of Physiological Changes in the Skin on Systemic Absorption of Tacrolimus Following Topical Application in Rats

Immunosuppressive and Anti-Inflammatory Properties of Engineered Nanomaterials

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