Assessing the risk of a clinically significant infection from a Microneedle Array Patch (MAP) product

Dul, Maria; Alali, Mohammed; Ameri, Mahmoud; Burke, Melanie Rose; Craig, C.; Creelman, Benjamin Paul; Dick, Lisa; Donnelly, Ryan F.; Eakins, Michael N.; Frivold, Collrane; Forster, Angus; Gilbert, Philippe-Alexandre; Henke, Stefan; Henry, Sébastien; Hunt, Desmond G.; Lewis, Hayley; Maibach, Howard I.; Mistilis, Jessica; Park, Jung Hwan; Prausnitz, Mark R.; Robinson, David J.; Hernández, Cecilia; Ross, Charles W.; Shin, Junghoon; Speaker, Tycho Joseph; Taylor, Kevin; Zehrung, Darin; Birchall, James Caradoc; Jarrahian, Courtney; Coulman, Sion

doi:10.1016/j.jconrel.2023.07.001

Cited by 10 publications

(9 citation statements)

References 110 publications

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“…Varying the pulse energies of the laser also did not affect the outcomes significantly. This is in line with previous studies showing that while higher pulse energies influence the depth of the micropores, the total drug delivery does not necessarily increase. , Both laser ablation and MN have well-documented clinical safety profiles triggering no or minor local reactions such as itching or redness. − The skin barrier function typically regenerates within a few hours , while pore closure occurs within 24–48 h. , Further, phase 3 clinical trials did not show any elevated infection risks following pore induction …”

Section: Results and Discussionsupporting

confidence: 88%

“…63−67 The skin barrier function typically regenerates within a few hours 68,69 while pore closure occurs within 24−48 h. 70,71 Further, phase 3 clinical trials did not show any elevated infection risks following pore induction. 69 Surprisingly, no significant differences were observed between DOPE-LNPs (∼14% editing in KC monolayers) and LNP H (∼71% editing in KC monolayers) in actual skin tissue (Figure 5B,C). We hypothesize that this may be due to the differentiation stages KCs obtain in skin tissue which is associated with decreased LDL receptor expression 72 resulting in less LNP uptake, hence lower editing efficacy.…”

Section: Lnp Composition and Genetic Payload Determinementioning

confidence: 99%

“…61,62 Both laser ablation and MN have welldocumented clinical safety profiles triggering no or minor local reactions such as itching or redness. 63−67 The skin barrier function typically regenerates within a few hours 68,69 while pore closure occurs within 24−48 h. 70,71 Further, phase 3 clinical trials did not show any elevated infection risks following pore induction. 69 Surprisingly, no significant differences were observed between DOPE-LNPs (∼14% editing in KC monolayers) and LNP H (∼71% editing in KC monolayers) in actual skin tissue (Figure 5B,C).…”

Section: Lnp Composition and Genetic Payload Determinementioning

confidence: 99%

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Lipid Nanoparticle-Mediated Hit-and-Run Approaches Yield Efficient and Safe In Situ Gene Editing in Human Skin

Bolsoni,

Liu,

Mohabatpour

et al. 2023

ACS Nano

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Despite exciting advances in gene editing, the efficient delivery of genetic tools to extrahepatic tissues remains challenging. This holds particularly true for the skin, which poses a highly restrictive delivery barrier. In this study, we ran a head-to-head comparison between Cas9 mRNA or ribonucleoprotein (RNP)-loaded lipid nanoparticles (LNPs) to deliver gene editing tools into epidermal layers of human skin, aiming for in situ gene editing. We observed distinct LNP composition and cell-specific effects such as an extended presence of RNP in slow-cycling epithelial cells for up to 72 h. While obtaining similar gene editing rates using Cas9 RNP and mRNA with MC3-based LNPs (10−16%), mRNA-loaded LNPs proved to be more cytotoxic. Interestingly, ionizable lipids with a pK a ∼ 7.1 yielded superior gene editing rates (55%−72%) in two-dimensional (2D) epithelial cells while no single guide RNA-dependent off-target effects were detectable. Unexpectedly, these high 2D editing efficacies did not translate to actual skin tissue where overall gene editing rates between 5%−12% were achieved after a single application and irrespective of the LNP composition. Finally, we successfully base-corrected a disease-causing mutation with an efficacy of ∼5% in autosomal recessive congenital ichthyosis patient cells, showcasing the potential of this strategy for the treatment of monogenic skin diseases. Taken together, this study demonstrates the feasibility of an in situ correction of disease-causing mutations in the skin that could provide effective treatment and potentially even a cure for rare, monogenic, and common skin diseases.

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Section: Results and Discussionsupporting

confidence: 88%

Section: Lnp Composition and Genetic Payload Determinementioning

confidence: 99%

Section: Lnp Composition and Genetic Payload Determinementioning

confidence: 99%

See 1 more Smart Citation

Lipid Nanoparticle-Mediated Hit-and-Run Approaches Yield Efficient and Safe In Situ Gene Editing in Human Skin

Bolsoni,

Liu,

Mohabatpour

et al. 2023

ACS Nano

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“…However, long-term studies on the cytotoxicity and biocompatibility of insulin by the MNs route of delivery are lacking. When promoting the application of MNs, the sterility and bacterial endotoxin should be carefully checked to avoid clinical infection [ 90 ]. Moreover, the frequency of MNs administration should be evaluated carefully for diabetic patients, given the small volume of the moulds and the small amount of insulin loading [ 91 ].…”

Section: Application Of Long-acting Polymeric Microneedlesmentioning

confidence: 99%

Recent progress of polymeric microneedle-assisted long-acting transdermal drug delivery

Meng,

Qiao,

Xin

et al. 2024

J. pharm. pharm. sci.

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Microneedle (MN)-assisted drug delivery technology has gained increasing attention over the past two decades. Its advantages of self-management and being minimally invasive could allow this technology to be an alternative to hypodermic needles. MNs can penetrate the stratum corneum and deliver active ingredients to the body through the dermal tissue in a controlled and sustained release. Long-acting polymeric MNs can reduce administration frequency to improve patient compliance and therapeutic outcomes, especially in the management of chronic diseases. In addition, long-acting MNs could avoid gastrointestinal reactions and reduce side effects, which has potential value for clinical application. In this paper, advances in design strategies and applications of long-acting polymeric MNs are reviewed. We also discuss the challenges in scale manufacture and regulations of polymeric MN systems. These two aspects will accelerate the effective clinical translation of MN products.

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“…The absence of guidelines places a burden on applicants, such as establishing evaluation methods and confirming validity, which is unnecessary for other dosage forms, thereby hindering product development. Recently, a Regulatory Working Group (RWG) was established to collaborate with industry, government, and academia to identify critical quality attributes (CQAs) and standardize test methods for MNs [ 15 , 16 ]. The RWG proposed that the delivered dose, puncture performance, dissolution, physical stability, mechanical strength, and needle morphology were high-priority CQAs [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Mechanical Characterization of Dissolving Microneedles: Factors Affecting Physical Strength of Needles

Ando,

Miyatsuji,

Sakoda

et al. 2024

Pharmaceutics

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Dissolving microneedles (MNs) are novel transdermal drug delivery systems that can be painlessly self-administered. This study investigated the effects of experimental conditions on the mechanical characterization of dissolving MNs for quality evaluation. Micromolding was used to fabricate polyvinyl alcohol (PVA)-based dissolving MN patches with eight different cone-shaped geometries. Axial force mechanical characterization test conditions, in terms of compression speed and the number of compression needles per test, significantly affected the needle fracture force of dissolving MNs. Characterization using selected test conditions clearly showed differences in the needle fracture force of dissolving MNs prepared under various conditions. PVA-based MNs were divided into two groups that showed buckling and unbuckling deformation, which occurred at aspect ratios (needle height/base diameter) of 2.8 and 1.8, respectively. The needle fracture force of PVA-based MNs was negatively correlated with an increase in the needle’s aspect ratio. Higher residual water or higher loading of lidocaine hydrochloride significantly decreased the needle fracture force. Therefore, setting appropriate methods and parameters for characterizing the mechanical properties of dissolving MNs should contribute to the development and supply of appropriate products.

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Assessing the risk of a clinically significant infection from a Microneedle Array Patch (MAP) product

Cited by 10 publications

References 110 publications

Lipid Nanoparticle-Mediated Hit-and-Run Approaches Yield Efficient and Safe In Situ Gene Editing in Human Skin

Lipid Nanoparticle-Mediated Hit-and-Run Approaches Yield Efficient and Safe In Situ Gene Editing in Human Skin

Recent progress of polymeric microneedle-assisted long-acting transdermal drug delivery

Mechanical Characterization of Dissolving Microneedles: Factors Affecting Physical Strength of Needles

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