The Influence of Solid Microneedles on the Transdermal Delivery of Selected Antiepileptic Drugs

Emerging micro-scale medical devices are showing promise, whether in delivering drugs or extracting diagnostic biomarkers from skin. In progressing these devices through animal models towards clinical products, understanding the mechanical properties and skin tissue structure with which they interact will be important. Here, through measurement and analytical modelling, we advanced knowledge of these properties for commonly used laboratory animals and humans (~30 g to ~150 kg). We hypothesised that skin’s stiffness is a function of the thickness of its layers through allometric scaling, which could be estimated from knowing a species’ body mass. Results suggest that skin layer thicknesses are proportional to body mass with similar composition ratios, inter- and intra-species. Experimental trends showed elastic moduli increased with body mass, except for human skin. To interpret the relationship between species, we developed a simple analytical model for the bulk elastic moduli of skin, which correlated well with experimental data. Our model suggest that layer thicknesses may be a key driver of structural stiffness, as the skin layer constituents are physically and therefore mechanically similar between species. Our findings help advance the knowledge of mammalian skin mechanical properties, providing a route towards streamlined micro-device research and development onto clinical use.

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“…13 , 14 ), and pigs (e.g. 15 , 16 ). However, how these therapeutic attributes are translated to widespread human testing (e.g.…”

Section: Introductionmentioning

confidence: 99%

Allometric scaling of skin thickness, elasticity, viscoelasticity to mass for micro-medical device translation: from mice, rats, rabbits, pigs to humans

Wei

Edwards

Martin

et al. 2017

Sci Rep

222

124

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“…At present, some physical means, such as microneedles,23 ionophoresis,24 sonophoresis,25 and electroporation,26 have been utilized to enhance transdermal drug delivery. Electroporation has been considered as an efficient physical technique of promoting skin permeability of small molecules and biomacromolecules 18,27.…”

Section: Introductionmentioning

confidence: 99%

Controlled release of optimized electroporation enhances the transdermal efficiency of sinomenine hydrochloride for treating arthritis in vitro and in clinic

Feng¹,

Zhu²,

Huang³

et al. 2017

DDDT

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Sinomenine hydrochloride (SH) is an ideal drug for the treatment of rheumatoid arthritis and osteoarthritis. However, high plasma concentration of systemically administered SH can release histamine, which can cause rash and gastrointestinal side effects. Topical delivery can increase SH concentration in the synovial fluid without high plasma level, thus minimizing systemic side effects. However, passive diffusion of SH was found to be inefficient because of the presence of the stratum corneum layer. Therefore, an effective method is required to compensate for the low efficiency of SH passive diffusion. In this study, transdermal experiments in vitro and clinical tests were utilized to explore the optimized parameters for electroporation of topical delivery for SH. Fluorescence experiment and hematoxylin and eosin staining analysis were performed to reveal the mechanism by which electroporation promoted permeation. In vitro, optimized electroporation parameters were 3 KHz, exponential waveform, and intensity 10. Using these parameters, transdermal permeation of SH was increased by 1.9–10.1 fold in mice skin and by 1.6–47.1 fold in miniature pig skin compared with passive diffusion. After the electroporation stimulation, the intercellular intervals and epidermal cracks in the skin increased. In clinical tests, SH concentration in synovial fluid was 20.84 ng/mL after treatment with electroporation. Therefore, electroporation with optimized parameters could significantly enhance transdermal permeation of SH. The mechanism by which electroporation promoted permeation was that the electronic pulses made the skin structure looser. To summarize, electroporation may be an effective complementary method for transdermal permeation of SH. The controlled release of electroporation may be a promising clinical method for transdermal drug administration.

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“…This approach avoids first-pass metabolism, leads to better patient compliance, and enhances therapeutic action [69]. Currently, the transdermal route of administration is used to deliver about 20 active pharmaceutical ingredients [89] and it is important to use different technologies for transdermal drug delivery enhancement. Our project addresses this challenge by evaluating the effect of microneedle rollers.…”

Section: Discussionmentioning

confidence: 99%

The Influence of Microneedles on the Percutaneous Penetration of Selected Antihypertensive Agents: Diltiazem Hydrochloride and Perindopril Erbumine

Luu

Ita

Morra

et al. 2018

CDD

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Background: It is well documented in the scientific literature that high blood pressure can lead to cardiovascular disease. Untreated hypertension has clinical consequences such as coronary artery dis-ease, stroke or kidney failure. Diltiazem hydrochloride (DH), a calcium-channel blocker, and perindopril erbumine (PE), an inhibitor of the angiotensin converting enzyme are used for the management of hyper-tension.Objective: This project will examine the effect of microneedle rollers on the transport of DH and PE across pig ear skin. The use of the transcutaneous route of administration reduces and in sometimes elimi-nates the trauma and pain associated with injections. Furthermore, there is increased patient compliance. The purpose of this project was to study the effect of stainless steel microneedles on the transdermal de-livery of DH and PE.Method: We utilized vertical Franz diffusion cells to study in vitro transport of DH and PE across mi-croneedle-treated pig ear skin. Confocal laser scanning microscopy (CLSM) was used to characterize microchannel depth. Transdermal flux values were determined from the slope of the linear portion of the cumulative amount versus time curve.Results: There was a 113.59-fold increase in the transdermal permeation of DH following the application of microneedle roller compared to passive diffusion.Conclusion: In the case of PE, there was an 11.99-fold increase in the drug transport across pig skin following the application of microneedle rollers in comparison with passive diffusion. Student’s t-test and Mann-Whitney’s rank sum test were used to determine statistically significant differences between exper-imental and control groups

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The Influence of Solid Microneedles on the Transdermal Delivery of Selected Antiepileptic Drugs

Cited by 36 publications

References 65 publications

Allometric scaling of skin thickness, elasticity, viscoelasticity to mass for micro-medical device translation: from mice, rats, rabbits, pigs to humans

Allometric scaling of skin thickness, elasticity, viscoelasticity to mass for micro-medical device translation: from mice, rats, rabbits, pigs to humans

Controlled release of optimized electroporation enhances the transdermal efficiency of sinomenine hydrochloride for treating arthritis in vitro and in clinic

The Influence of Microneedles on the Percutaneous Penetration of Selected Antihypertensive Agents: Diltiazem Hydrochloride and Perindopril Erbumine

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