Design and physicochemical characterisation of novel dissolving polymeric microneedle arrays for transdermal delivery of high dose, low molecular weight drugs

Abstract

We describe formulation and evaluation of novel dissolving polymeric microneedle (MN) arrays for the facilitated delivery of low molecular weight, high dose drugs. Ibuprofen sodium was used as the model here and was successfully formulated at approximately 50% w/w in the dry state using the copolymer poly(methylvinylether/maleic acid). These MNs were robust and effectively penetrated skin in vitro, dissolving rapidly to deliver the incorporated drug. The delivery of 1.5 mg ibuprofen sodium, the theoretical mass of ibuprofen sodium contained within the dry MN alone, was vastly exceeded, indicating extensive delivery of the drug loaded into the baseplates. Indeed in in vitro transdermal delivery studies, approximately 33 mg (90%) of the drug initially loaded into the arrays was delivered over 24 h. Iontophoresis produced no meaningful increase in delivery. Biocompatibility studies and in vivo rat skin tolerance experiments raised no concerns. The blood plasma ibuprofen sodium concentrations achieved in rats (263 μg ml− 1 at the 24 h time point) were approximately 20 times greater than the human therapeutic plasma level. By simplistic extrapolation of average weights from rats to humans, a MN patch design of no greater than 10 cm2 could cautiously be estimated to deliver therapeutically-relevant concentrations of ibuprofen sodium in humans. This work, therefore, represents a significant progression in exploitation of MN for successful transdermal delivery of a much wider range of drugs.

Getting Drugs Across Biological Barriers

“…ibuprofen) can be achieved using needles that are designed to break upon application and stay in skin after application. [164] This high plasma drug concentration was achieved with needle patches of ~2 cm 2 applied to rats weighing ~340g.…”

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“…Approximately 90% of the loaded drug was delivered over a period of 24 hours. Biocompatibility studies and in vivo rat experiments confirmed the safety of the developed system 96 . Ghosh et al, developed a codrug approach to achieve drug delivery across microneedle treated skin.…”

Dissolving microneedles for DNA vaccination: Improving functionality via polymer characterization and RALA complexation

“…Results demonstrated that at concentrations up to 10 mg/mL, none of the polymers caused a significant decrease in cell viability. McCrudden et al (2014) found that exposure of L-132 cells to 5 mg/mL of MN formulation (PMVE/MA) resulted in greater than a 90% drop in cell viability yet this did not translate to significant loss of skin viability in a 3D model or irritation to rat skin in vivo following 24 h exposure to the MN formulation. 51 As such although higher concentrations of PVP-360 (20 mg/mL and 40 mg/mL) did result in a drop in cell viability below 80%, these concentration ranges are much higher than would be used in vivo, and are unlikely to result in damage to healthy skin.…”

“…Currently no guidance has been provided from regulators with regards to the safety and toxicity standards which microneedles shall need to meet for licensure; however, the MTT and MTS viability assays, which measure cells' mitochondrial metabolic rate, have been used previously to determine the biocompatibility of dissolvable microneedle formulations. 29,51 Therefore we also examined the effect of increasing concentrations of polymer on cell viability in NCTC 929 fibroblast cells using the MTS viability assay. Results demonstrated that at concentrations up to 10 mg/mL, none of the polymers caused a significant decrease in cell viability.…”