Diclofenac delays micropore closure following microneedle treatment in human subjects

Abstract

Drugs absorbed poorly through the skin are commonly delivered via injection with a hypodermic needle, which is painful and increases the risk of transmitting infectious diseases. Microneedles (MNs) selectively and painlessly permeabilize the outermost skin layer, allowing otherwise skin-impermeable drugs to cross the skin through micron-sized pores and reach therapeutic concentrations. However, rapid healing of the micropores prevents further drug delivery, blunting the clinical utility of this unique transdermal technique. We present the first human study demonstrating that micropore lifetime can be extended following MN treatment. Subjects received one-time MN treatment and daily topical application of diclofenac sodium. Micropore closure was measured with impedance spectroscopy, and area under the admittance–time curve (AUC) was calculated. AUC was significantly higher at MN + diclofenac sodium sites vs. placebo, suggesting slower rates of micropore healing. Colorimetry measurements confirmed the absence of local erythema and irritation. This mechanistic human proof-of-concept study demonstrates that micropore lifetime can be prolonged with simple topical administration of a non-specific cyclooxygenase inhibitor, suggesting the involvement of subclinical inflammation in micropore healing. These results will allow for longer patch wear time with MN-enhanced delivery, thus increasing patient compliance and expanding the transdermal field to a wider variety of clinical conditions.

Microneedle characterisation: the need for universal acceptance criteria and GMP specifications when moving towards commercialisation

“…Assessing MN piercing of the skin, and the corresponding insertion force required to cause successful penetration, has been investigated by a number of groups through the use of electrical impedance methods [41,44,48,58,59]. In this context, impedance is the phase dependant resistance of the skin to the flow of alternating current.…”

“…Yan et al [6] recognised a linear relationship between acyclovir flux and the inverse of skin electrical resistance. Typically, the method involves a test/measurement electrode measuring electrical resistance at the site of MN penetration, while a counter reference electrode is placed nearby to complete the electrical circuit [58,59].…”

“…In contrast, the sensitivity of the technique was further alluded to by Brogden et al [59], who commented that this method can detect small changes of electrical impedance in hydrated skin thus indicating that the hydration status of the skin can influence the sensitivity of this technique. They then used this method to demonstrate that micropore lifetime can be extended following MN treatment.…”

“…TEWL studies also provide no information on the depth of MN insertion and are highly sensitive to the hydration status of the skin. However, this technique may not be able to detect small changes in water loss in experiments where the skin has been occluded for a number of days [59]. It was also recognised by Yan et al [6] that there was a difference in recovery between in vitro tests involving human cadaver skin and in vivo rat skin, with the resistance of human cadaver skin remaining constant after MN pre-treatment representing the lack of skin recovery in this material.…”

Hydrogel Microneedle Arrays for Transdermal Drug Delivery

“…In order to retard the recovery of skin, some additional drugs are applied to the skin including diclofenac sodium. Brogden et al [20] suggested that the micro-pore lifetime could be prolonged with simple topical administration of a non-specific cyclooxygenase inhibitor. Ghosh et al [5] utilized naltrexone (NTX) with diclofenac co-drugs for systemic delivery of NTX into the treated skin and the results indicated that the co-drug approach could be used for the development of a 7-day transdermal system.…”