Dermal Delivery of the High-Molecular-Weight Drug Tacrolimus by Means of Polyglycerol-Based Nanogels

Abstract

Polyglycerol-based thermoresponsive nanogels (tNGs) have been shown to have excellent skin hydration properties and to be valuable delivery systems for sustained release of drugs into skin. In this study, we compared the skin penetration of tacrolimus formulated in tNGs with a commercial 0.1% tacrolimus ointment. The penetration of the drug was investigated in ex vivo abdominal and breast skin, while different methods for skin barrier disruption were investigated to improve skin permeability or simulate inflammatory conditions with compromised skin barrier. The amount of penetrated tacrolimus was measured in skin extracts by liquid chromatography tandem-mass spectrometry (LC-MS/MS), whereas the inflammatory markers IL-6 and IL-8 were detected by enzyme-linked immunosorbent assay (ELISA). Higher amounts of tacrolimus penetrated in breast as compared to abdominal skin or in barrier-disrupted as compared to intact skin, confirming that the stratum corneum is the main barrier for tacrolimus skin penetration. The anti-proliferative effect of the penetrated drug was measured in skin tissue/Jurkat cells co-cultures. Interestingly, tNGs exhibited similar anti-proliferative effects as the 0.1% tacrolimus ointment. We conclude that polyglycerol-based nanogels represent an interesting alternative to paraffin-based formulations for the treatment of inflammatory skin conditions.

Skin Barriers in Dermal Drug Delivery: Which Barriers Have to Be Overcome and How Can We Measure Them?

“…In addition, also radioactively labelled surrogates for hydrophilic (caffeine) or lipophilic (testosterone) molecules are often used [ 140 ]. To this end, the molecular markers/drugs are applied in vitro (reconstructed human epidermis/skin, e.g., [ 141 , 142 ]), ex vivo (e.g., excised skin in horizontal or vertical diffusion cells—e.g., Franz cells—, Saarbrücken penetration model, Hamburg model of penetration, [ 138 , 143 , 144 ]) or in vivo [ 145 , 146 ] onto the skin.…”

Semisolid Dosage

“…Finally, the article of Rancan and coworkers deals with ''Dermal Delivery of the High-Molecular-Weight Drug Tacrolimus by Means of Polyglycerol-Based Nanogels" [7]. The authors show that tacrolimus formulated as ointment or nanogel suspension penetrates skin with different efficiency in dependence on SC thickness and integrity.…”

Topical Delivery of Rapamycin by Means of Microenvironment-Sensitive Core-Multi-Shell Nanocarriers: Assessment of Anti-Inflammatory Activity in an ex vivo Skin/T Cell Co-Culture Model

“…Irritation effects have been observed by topical use of the macrolides like tacrolimus and sirolimus 62 , 63 and the release of pro-inflammatory cytokines by skin cells has been reported in in vitro as well as ex vivo skin experiments. 64 , 65 Therefore, we used the skin/T cell co-culture set-up to monitor eventual local irritation effects of the investigated Rapa formulations. At this purpose, IL-6, IL-8, and IL-1α were measured in skin extracts as well as in culture medium ( Figure 4 and Figures S3 – S4 ).…”

“…These inflammatory mediators, which play a major role in skin inflammatory conditions like psoriasis, 66 , 67 are also considered as markers for skin irritation. 68 In cultured ex vivo human skin, these cytokines are expressed at low levels, 69 , 70 but their release can be boosted by various stimuli like barrier disruption 65 , 69 or stimulation of the protease-activated receptors 2 (PAR-2) signaling pathway. 34–36 In the investigated samples, the expression of pro-inflammatory markers varied widely among the donors, possibly as a result of inter-individual variability but also of different baseline levels of inflammatory cytokines depending on anatomic region (breast vs abdomen), type and extent of surgery, as well as transportation time.…”