Mucoadhesive Electrospun Patch Delivery of Lidocaine to the Oral Mucosa and Investigation of Spatial Distribution in a Tissue Using MALDI-Mass Spectrometry Imaging.

Katharina H Clitherow,Anna Mette Handler,Christian Janfelt,Hanne Mørck Nielsen,Mai Bay Stie,Jette Jacobsen,Paul V Hatton,Helen E Colley,Craig Murdoch,Sebastian Guy Spain

doi:10.1021/acs.molpharmaceut.9b00535

Katharina H Clitherow, Anna Mette Handler + Show 8 more

Open Access

https://doi.org/10.1021/acs.molpharmaceut.9b00535

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Abstract

Many oral mucosal conditions cause considerable and prolonged pain that to date has been difficult to alleviate via topical delivery, and the use of injection causes many patients dental anxiety and needle-prick pain. Therefore, developing a noninjectable drug delivery system as an alternative administration procedure may vastly improve the health and wellbeing of these patients. Recent advances in the development of mucoadhesive electrospun patches for the direct delivery of therapeutics to the oral mucosa offer a potential solution, but as yet, the release of local anesthetics from this system and their uptake by oral tissue have not been demonstrated. Here, we demonstrate the fabrication of lidocaine-loaded electrospun fiber patches, drug release, and subsequent uptake and permeation through the porcine buccal mucosa. Lidocaine HCl and lidocaine base were incorporated into the electrospun patches to evaluate the difference in drug permeation for the two drug compositions. Lidocaine released from the lidocaine HCl-containing electrospun patches was significantly quicker than from the lidocaine base patches, with double the amount of drug released from the lidocaine HCl patches in the first 15 min (0.16 ± 0.04 mg) compared to that from the lidocaine base patches (0.07 ± 0.01 mg). The permeation of lidocaine from the lidocaine HCl electrospun patches through ex vivo porcine buccal mucosa was also detected in 15 min, whereas permeation of lidocaine from the lidocaine base patch was not detected. Matrix-assisted laser desorption ionization-mass spectrometry imaging was used to investigate localization of lidocaine within the oral tissue. Lidocaine in the solution as well as from the mucoadhesive patch penetrated into the buccal mucosal tissue in a time-dependent manner and was detectable in the lamina propria after only 15 min. Moreover, the lidocaine released from lidocaine HCl electrospun patches retained biological activity, inhibiting veratridine-mediated opening of voltage-gated sodium channels in SH-SY5Y neuroblastoma cells. These data suggest that a mucoadhesive electrospun patch may be used as a vehicle for rapid uptake and sustained anesthetic drug delivery to treat or prevent oral pain.

Highlights

Control of pain is a major unmet clinical need in a range of oral conditions including mucositis, ulceration, and trauma.[1,2] The effects of pain may be so severe as to affect eating, drinking, speech, or sleep.[3]
All patches showed a similar range of fiber diameters with a random alignment, where the drug-free fiber diameters ranged from 2.28 ± 1.35 μm, the lidocaine HClloaded fibers from 1.98 ± 1.50 μm, and the lidocaine baseloaded fibers from 2.42 ± 2.09 μm (∼100 fibers in total measured from n = 3 patches; mean ± standard deviation (SD))
As two different drug compositions are incorporated into the patches and drug release can be dependent on the pH microenvironment of a system, the pH of the patches dissolved in deionized water was measured

Summary

Introduction

Control of pain is a major unmet clinical need in a range of oral conditions including mucositis, ulceration, and trauma.[1,2] The effects of pain may be so severe as to affect eating, drinking, speech, or sleep.[3] Pain is associated with a number of dental procedures and is most commonly alleviated by the injection of a local anesthetic. The use of injection is a major factor in dental anxiety and nonattendance at the clinic.[4] A wide range of technologies to alleviate localized pain in the oral cavity have been investigated, including tablets, films, gels, and mouth washes.[5−10] These are based on topical delivery of drugs, but all current approaches have limitations related to the very challenging conditions found within the oral cavity, where salivary flow and tissue movement contribute to a hostile mechanical and chemical environment. The patch displays good adhesion to oral tissues and is well tolerated with no significant cytotoxicity or irritation in both a porcine model and healthy

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