Hydrogel-forming microneedles enhance transdermal delivery of metformin hydrochloride

Abstract

We investigated, for the first time, the potential for a hydrogel-forming microneedle (MN) patch to deliver the high-dose drug metformin HCl transdermally in a sustained manner. This may minimize some gastrointestinal side effects and small intestine absorption variations associated with oral delivery. Patches (two layers) were assembled from a lyophilised drug reservoir layer, with the MN layer made from aqueous blend of 20% w/w poly (methylvinylether-co-maleic acid) crosslinked by esterification with 7.5% w/w poly (ethylene glycol) 10,000 Da. >90% of metformin was recovered from homogeneous drug reservoirs. Drug reservoir dissolution time in PBS (pH 7.4) was <10 min. MN penetrated a validated skin model Parafilm® M consistently. Permeation of metformin HCl across dermatomed neonatal porcine skin in vitro was enhanced by using MN. The combined MN and metformin HCl reservoir patch (containing 75 mg or 50 mg metformin HCl, respectively) delivered 9.71 ± 2.22 mg and 10.04 ± 1.92 mg at 6 h, respectively, and 28.15 ± 2.37 mg and 23.25 ± 3.58 mg at 24 h, respectively.In comparison, 0.34 ± 0.39 mg and 0.85 ± 0.68 mg was delivered at 6 h, respectively, and 0.39 ± 0.39 mg and 1.01 ± 0.84 mg was delivered at 24 h, respectively, from a control set-up employing only the drug reservoirs. In vivo, metformin HCl was detected in rat plasma at 1 h post MN application at a concentration of 0.62 ± 0.51 μg/mL, increasing to 3.76 ± 2.58 μg/ml at 3 h. A maximal concentration of 3.77 ± 2.09 μg/ml was achieved at 24 h. Css was 3.2 μg/mL. Metformin transdermal bioavailability using MNs was estimated as 30%.Hydrogel-forming MN are a promising technology that has demonstrated successful transdermal delivery of metformin HCl. Potential clearly exists for administration of other high-dose drugs using this system.

Near-infrared light activatable hydrogels for metformin delivery

“…Using the metformin based rGO/COOH patch for the delivery of metformin via photothermal activation for 10 min, a maximal plasma concentration was detected after 1h activation where a concentration of 13±2 µg mL -1 was detected, in line with other reports. 24 It decreased thereafter slowly until the 2h endpoint. Figure 8: In vivo plasma profiles of metformin following oral administration with only CMS (black) or CMS+metformin (blue), subcutaneous metformin injection (green) and following application of the rGO/metformin gel and activation for 10 min at 0.7 W cm -2 .…”

“…The efficiency of thermalinduced transdermal metformin delivery of rGO-COOH/metformin gel is competitive with the hydrogel microneedles reported recently by Migdadi et al, reaching a release percentage of 12.94±2.96% and 37.53±3.17% after 6 and 24 h, respectively. 24 About 5-30 µg (5-6%) of metformin was further found to be trapped in the skin (Figure 6C).…”

“…Furthermore, metformin exhibits an unfavorable pharmacokinetics profile, with low and variable oral bioavailability (50-60%) and a biological half-life time in the range of 0.9-2.6 h. 20,21 Therefore, frequent applications of high doses of metformin (0.5-2g twice daily) are required for an effective treatment To overcome these limitations, transdermal delivery of metformin has been identified as an effective alternative. 4,[22][23][24][25][26] The transdermal administration route allows metformin to be delivered into the body bypassing the gastrointestinal tract and avoiding many of the unpleasant side effects. Additionally, the enhanced bioavailability of metformin allows reducing the administered daily dose amount and its frequency.…”

“…The transdermal delivery of metformin is currently limited to the use of thermo-responsive microneedles, where metformin is released upon needle melting, 4,22,25,26 and the use of hydrogel-based microneedles. 24 The advantage of hydrogel-based microneedles over thermo-responsive microneedles is that once applied to the skin they can be withdrawn and remain intact. Onto this microneedles metformin reservoirs were integrated to have access to a sufficient amount of metformin.…”

Polymeric Microneedle Arrays: Versatile Tools for an Innovative Approach to Drug Administration

“…In vivo (human) [24] Melasma Dissolving In vivo (mouse) [25] Acne vulgaris Swelling In vivo (mouse) [26] Ocular infection Dissolving Ex vivo (cornea) [27] Diabetes Swelling In vitro In vivo (mouse) [28] [ 29] Cancer Dissolving In vitro In vivo (mouse) [30] [ 31,43] Immunity (vaccines)…”