Transdermal Cubic Phases of Metformin Hydrochloride: In Silico and in Vitro Studies of Delivery Mechanisms

Abstract

Transdermal delivery is one of important controlled drug release strategies for drug development. Cubic phases are the assemblies of amphiphilic molecules in water with the hydrophilic-hydrophobic interpenetrating network for transdermal delivery of both hydrophilic and hydrophobic drugs. However, many details about the transdermal delivery of drugs from cubic phases remain unclear. Here, metformin hydrochloride (Met) cubic phases were prepared with glyceryl monooleate (GMO), ethanol, and water. The cubic structure was identified with the polarizing light microscopy and small-angle X-ray scattering method. Dissipative particle dynamics (DPD) was used for building the microstructures of the cubic phases to explore the mechanism of drug release that mainly depended on drug diffusion from the water channels of cubic phases in accordance with the Higuchi equation of in vitro release experiments. The coarse-grained model and molecular docking method showed that GMO could enhance drug permeation through the skin by disturbing the interaction between Met and the skin proteins, and increasing the fluidity of skin lipids, which was confirmed with the Fourier transform infrared spectroscopy, Langmuir monolayer, and immunohistochemistry. Furthermore, in vitro permeation experiments showed the high Met transdermal improvement of cubic phases. Cubic phases are an ideal transdermal delivery system of Met. In silico methods are very useful for analyzing the molecular mechanisms of transdermal formulations.

Transdermal metformin hydrochloride-loaded cubic phases: in silico formulation optimization, preparation, properties, and application for local treatment of melanoma

“…Firstly, Met mainly diffuses from the water channels of cubic phases to the surface of stratum corneum. Next, GMO highly enhances Met permeation through skin by disturbing the interaction between Met and skin proteins, and disordering the arrangement of skin lipid molecules (Yu et al., 2018).…”

“…Moreover, metformin-induced melanoma cell apoptosis is mainly associated with caspase activation, mitochondrial depolarization and oxidative stress (Janjetovic et al., 2011). In addition, the Met cubic phase has too high skin permeation (Yu et al., 2018). Therefore, the Met cubic phases can enhance apoptosis and necrosis of melanoma cells.…”

“…The basic components of Met-loaded cubic phases include Met, GMO, water, and ethanol. These molecules were put into the simulated system in our previous research (Yu et al., 2018). Briefly, the in silico formulation optimization procedure is described as follows.…”

“…DPD simulations were applied to build the microstructures of all Met/GMO/Ethanol/Water systems according to the Flory-Huggins parameters of binary components. The detailed operation process referred to our previous study (Yu et al., 2018). Finally, the optimized formulation can be screened based on the microstructure and water diffusivity of all liquid crystal systems.…”

Near-infrared light activatable hydrogels for metformin delivery

“…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.…”