Diabetes mellitus (DM) is a metabolic disorder that is one of the most common health problems in the world, primarily type 2 DM (T2DM). Metformin (MTF), as the first-line treatment of DMT2, is effective in lowering glucose levels, but its oral administration causes problems, including gastrointestinal side effects, low bioavailability, and the risk of hypoglycemia. In this study, we formulated MTF into microparticles incorporating a glucose-responsive polymer (MP−MTF−GR), which could potentially increase the bioavailability and extend and control the release of MTF according to glucose levels. This system was delivered by dissolving microneedles (MP−MTF−GR−DMN), applied through the skin, thereby preventing gastrointestinal side effects of orally administered MTF. MP−MTF−GR was formulated using various concentrations of gelatin as a polymer combined with phenylboronic acid (PBA) as a glucose-responsive material. MP−MTF−GR was encapsulated in DMN using polyvinyl pyrrolidone (PVP) and polyvinyl alcohol (PVA) as DMN polymers. The physicochemical evaluation of MP−MTF−GR showed that MTF could be completely entrapped in MP with the percentage of MTF trapped increasing with increasing gelatin concentration without changing the chemical structure of MTF and producing stable MP. In addition, the results of the physicochemical evaluation of MP−MTF−GR−DMN showed that DMN had adequate mechanical strength properties and penetration ability and was stable to environmental changes. The results of the in vitro release and ex vivo permeation study on media with various concentrations of glucose showed that the release and permeation of MTF from the formula increased with increasing glucose levels in the media. The MP−MTF−GR−DMN formula successfully delivered MTF through the skin at 11.30 ± 0.29, 23.31 ± 1.64, 36.12 ± 3.77, and 53.09 ± 3.01 μg from PBS, PBS + glucose 1%, PBS + glucose 2%, and PBS + glucose 4%, respectively, at 24 h, which indicates glucose-responsive permeation and release behavior. The formula developed was also proven to be nontoxic based on hemolysis tests. Importantly, the in vivo study on the rat model showed that this combination approach could provide a better glucose reduction compared to other routes, reducing the blood glucose level to normal levels after 3 h and maintaining this level for 8 h. Furthermore, this approach did not change the skin moisture of the rats. This MP−MTF−GR−DMN is a promising alternative to MTF delivery to overcome MTF problems and increase the effectiveness of T2DM therapy.

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