Lidocaine carboxymethylcellulose with gelatine co-polymer hydrogel delivery by combined microneedle and ultrasound

Abstract

A study that combines microneedles (MNs) and sonophoresis pre-treatment was explored to determine their combined effects on percutaneous delivery of lidocaine from a polymeric hydrogel formulation. Varying ratios of carboxymethylcellulose and gelatine (NaCMC/gel ranges 1:1.60-1:2.66) loaded with lidocaine were prepared and characterized for zeta potential and particle size. Additionally, variations in the formulation drying techniques were explored during the formulation stage. Ex vivo permeation studies using Franz diffusion cells measured lidocaine permeation through porcine skin after pre-treatment with stainless steel MNs and 20 kHz sonophoresis for 5-and 10-min durations. A stable formulation was related to a lower gelatine mass ratio because of smaller mean particle sizes and high zeta potential. Lidocaine permeability in skin revealed some increases in permeability from combined MN and ultrasound pre-treatment studies. Furthermore, up to 4.8-fold increase in the combined application was observed compared with separate pre-treatments after 30 min. Sonophoresis pre-treatment alone showed insignificant enhancement in lidocaine permeation during the initial 2 h period. MN application increased permeability at a time of 0.5 h for up to ∼17 fold with an average up to 4 fold. The time required to reach therapeutic levels of lidocaine was decreased to less than 7 min. Overall, the attempted approach promises to be a viable alternative to conventional lidocaine delivery methods involving painful injections by hypodermic needles. The mass transfer effects were fairly enhanced and the lowest amount of lidocaine in skin was 99.7% of the delivered amount at a time of 3 h for lidocaine NaCMC/GEL 1:2.66 after low-frequency sonophoresis and MN treatment.

A New Paradigm for Numerical Simulation of Microneedle-Based Drug Delivery Aided by Histology of Microneedle-Pierced Skin

“…The insertion depths of these commercial MNs patches (~ 117 400 -500 µm) are much shorter than the actual lengths of the MN as the insertion depths 118 depend not only the actual MN lengths but also the force of insertion, MN density of the patches 119 and viscoelasticity of the skin. These have been demonstrated in our previous paper [24] and 120 are not discussed here. 121 A MNs patch is pushed with a relatively high thumb pressure to ensure that all the needles are 122 pierced into the skin and then mounted to a pneumatic pump with a constant 1MPa pressure for 123 10min.…”

Lidocaine permeation from a lidocaine NaCMC/gel microgel formulation in microneedle-pierced skin: vertical (depth averaged) and horizontal permeation profiles

“…Normally, the entire length of MNs from base to tip does not penetrate the skin with the needle base touching the skin surface because of the elastic folding effect of skin [9]. A full thickness skin piercing using 1100 µm length MNs and the MNs density resulted in approximately 400 µm deep cavities [12]. However, we controlled the MN cavities to a much smaller length so as to just pierce the SC in this work as discussed below.…”

“…Franz diffusion cell (FDC) is typically adopted to determine the in vitro (IV) mass transport properties of the active molecules passing the SC [10] or the whole skin thickness [11,12]. Depending on the direction of concentration gradient and permeability, an active molecule can however diffuse both vertically and horizontally in skin tissues.…”

“…The characterised percentage loading efficiency (LE) for our lidocaine microgel formulation (equation 2) was calculated as discussed earlier [11,12] %LE = Actual 5% weight of Lidocaine from sample(g) 5% theoretical loaded weight of Lidocaine(g) × 100…”

“…In a number of recent studies, it has been discussed that MN assisted percutaneous delivery of lidocaine may be beneficial in numbing a larger surface area of skin and minimising possible clearance from predominate vertical permeation of the drug [11,12,15,16]. Parenteral administration of lidocaine may increase the chances of clearance resulting in its depleted levels in the systemic circulation [17].…”