Topical drug delivery: History, percutaneous absorption, and product development

Roberts, Michael S.; Cheruvu, Hanumanth Srikanth; Mangion, Sean E.; Alinaghi, Azadeh; Benson, Heather A. E.; Mohammed, Yousuf; Holmes, Amy; Hoek, John van der; Pastore, Michael; Grice, Jeffrey E.

doi:10.1016/j.addr.2021.113929

Cited by 93 publications

(52 citation statements)

References 341 publications

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“…On the other hand, some additional factors such as the skin of different populations (pediatric, adult, elderly, different ethnicity, diseased) or different anatomical regions (face, neck, scalp, forehead, upper arm, lower leg, upper leg, inner forearm, outer forearm, back, abdomen, etc.) [64,65] should also be considered when ex vivo models are evaluated.…”

Section: Discussionmentioning

confidence: 99%

Skin-on-a-Chip Technology for Testing Transdermal Drug Delivery—Starting Points and Recent Developments

et al. 2021

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During the last decades, several technologies were developed for testing drug delivery through the dermal barrier. Investigation of drug penetration across the skin can be important in topical pharmaceutical formulations and also in cosmeto-science. The state-of- the-art in the field of skin diffusion measurements, different devices, and diffusion platforms used, are summarized in the introductory part of this review. Then the methodologies applied at Pázmány Péter Catholic University are shown in detail. The main testing platforms (Franz diffusion cells, skin-on-a-chip devices) and the major scientific projects (P-glycoprotein interaction in the skin; new skin equivalents for diffusion purposes) are also presented in one section. The main achievements of our research are briefly summarized: (1) new skin-on-a-chip microfluidic devices were validated as tools for drug penetration studies for the skin; (2) P-glycoprotein transport has an absorptive orientation in the skin; (3) skin samples cannot be used for transporter interaction studies after freezing and thawing; (4) penetration of hydrophilic model drugs is lower in aged than in young skin; (5) mechanical sensitization is needed for excised rodent and pig skins for drug absorption measurements. Our validated skin-on-a-chip platform is available for other research groups to use for testing and for utilizing it for different purposes.

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Section: Discussionmentioning

confidence: 99%

Skin-on-a-Chip Technology for Testing Transdermal Drug Delivery—Starting Points and Recent Developments

et al. 2021

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“…Whilst there has been concern about the general safety of zinc oxide nanoparticle sunscreens in topical products, work to date has focussed on whether nanoparticles can be found in the viable epidermis after permeation through the SC and via furrows and the follicles, including by lateral diffusion [75]. These zinc oxide nanoparticles, in turn, release zinc ions when the skin pH is either neutral or acidic and high zinc ion concentrations have been shown to be toxic in isolated keratinocytes [41].…”

Section: Discussionmentioning

confidence: 99%

Human Epidermal Zinc Concentrations after Topical Application of ZnO Nanoparticles in Sunscreens

Khabir

Holmes

Lai

et al. 2021

IJMS

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Zinc oxide nanoparticle (ZnO NP)-based sunscreens are generally considered safe because the ZnO NPs do not penetrate through the outermost layer of the skin, the stratum corneum (SC). However, cytotoxicity of zinc ions in the viable epidermis (VE) after dissolution from ZnO NP and penetration into the VE is ill-defined. We therefore quantified the relative concentrations of endogenous and exogenous Zn using a rare stable zinc-67 isotope (67Zn) ZnO NP sunscreen applied to excised human skin and the cytotoxicity of human keratinocytes (HaCaT) using multiphoton microscopy, zinc-selective fluorescent sensing, and a laser-ablation inductively coupled plasma–mass spectrometry (LA-ICP-MS) methodology. Multiphoton microscopy with second harmonic generation imaging showed that 67ZnO NPs were retained on the surface or within the superficial layers of the SC. Zn fluorescence sensing revealed higher levels of labile and intracellular zinc in both the SC and VE relative to untreated skin, confirming that dissolved zinc species permeated across the SC into the VE as ionic Zn and significantly not as ZnO NPs. Importantly, the LA-ICP-MS estimated exogenous 67Zn concentrations in the VE of 1.0 ± 0.3 μg/mL are much lower than that estimated for endogenous VE zinc of 4.3 ± 0.7 μg/mL. Furthermore, their combined total zinc concentrations in the VE are much lower than the exogenous zinc concentration of 21 to 31 μg/mL causing VE cytotoxicity, as defined by the half-maximal inhibitory concentration of exogenous 67Zn found in human keratinocytes (HaCaT). This speaks strongly for the safety of ZnO NP sunscreens applied to intact human skin and the associated recent US FDA guidance.

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“…A range of complementary imaging methods have been used over the past 50 years for measuring the delivery of ZnPT after topical application to the skin [56,85,115,[126][127][128][129][130][131][132]. Each modality carries advantages and disadvantages summarized in Table 1.…”

Section: Skin Imaging Methods To Evaluate the Spatial Delivery Of Znptmentioning

confidence: 99%

“…With the methods previously described [131], we have used multiphoton microscopy (MPM, Figure 8A) combined with FLIM (Figure 8B) to map ZnPT delivery within the hair follicles of human skin [132]. ZinPyr-1 is a fluorescent probe used to detect labile zinc within tissue and it has previously been applied to observe relative increases in labile zinc within skin after topical application of zinc species [138][139][140].…”

Section: Fluorescence Lifetime Imaging Microscopymentioning

confidence: 99%

Targeted Delivery of Zinc Pyrithione to Skin Epithelia

Mangion

Holmes

Roberts

2021

IJMS

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Zinc pyrithione (ZnPT) is an anti-fungal drug delivered as a microparticle to skin epithelia. It is one of the most widely used ingredients worldwide in medicated shampoo for treating dandruff and seborrheic dermatitis (SD), a disorder with symptoms that include skin flaking, erythema and pruritus. SD is a multi-factorial disease driven by microbiol dysbiosis, primarily involving Malassezia yeast. Anti-fungal activity of ZnPT depends on the cutaneous availability of bioactive monomeric molecular species, occurring upon particle dissolution. The success of ZnPT as a topical therapeutic is underscored by the way it balances treatment efficacy with formulation safety. This review demonstrates how ZnPT achieves this balance, by integrating the current understanding of SD pathogenesis with an up-to-date analysis of ZnPT pharmacology, therapeutics and toxicology. ZnPT has anti-fungal activity with an average in vitro minimum inhibitory concentration of 10–15 ppm against the most abundant scalp skin Malassezia species (Malassezia globosa and Malassezia restrica). Efficacy is dependent on the targeted delivery of ZnPT to the skin sites where these yeasts reside, including the scalp surface and hair follicle infundibulum. Imaging and quantitative analysis tools have been fundamental for critically evaluating the therapeutic performance and safety of topical ZnPT formulations. Toxicologic investigations have focused on understanding the risk of local and systemic adverse effects following exposure from percutaneous penetration. Future research is expected to yield further advances in ZnPT formulations for SD and also include re-purposing towards a range of other dermatologic applications, which is likely to have significant clinical impact.

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Topical drug delivery: History, percutaneous absorption, and product development

Cited by 93 publications

References 341 publications

Skin-on-a-Chip Technology for Testing Transdermal Drug Delivery—Starting Points and Recent Developments

Skin-on-a-Chip Technology for Testing Transdermal Drug Delivery—Starting Points and Recent Developments

Human Epidermal Zinc Concentrations after Topical Application of ZnO Nanoparticles in Sunscreens

Targeted Delivery of Zinc Pyrithione to Skin Epithelia

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