Poly(2‐Hydroxyethyl Methacrylate) Hydrogel‐Based Microneedles for Metformin Release

Abstract The release of metformin, a drug used in the treatment of cancer and diabetes, from poly(2‐hydroxyethyl methacrylate), pHEMA, hydrogel‐based microneedle patches is demonstrated in vitro. Tuning the composition of the pHEMA hydrogels enables preparation of robust microneedle patches with mechanical properties such that they would penetrate skin (insertion force of a single microneedle to be ≈40 N). Swelling experiments conducted at 20, 35, and 60 °C show temperature‐dependent degrees of swelling and diffusion kinetics. Drug release from the pHEMA hydrogel‐based microneedles is fitted to various models (e.g., zero order, first order, second order). Such pHEMA microneedles have potential application for transdermal delivery of metformin for the treatment of aging, cancer, diabetes, etc.

. Technical drawings of 3D printed templates (Template to produce array design 1).             (Table S1) and hydrogel formulations (Table S2). A) Force-displacement curves obtained from compression test for triangle pyramid PEGDMA-based hydrogel microneedles.

B)
Effect of crosslinking ratio on rigidity. C) Force-displacement curves obtained from compression test for PEGDMA-based hydrogel microneedles with different geometries. D) Effect of microneedle geometry on rigidity of PEGDMA-based hydrogel microneedles.
Where is the % swelling, M is weight of the swollen hydrogel at time , and M is the weight of the original dry hydrogel. [1] Swelling rate was estimated by measurement of gel mass at different time points, where Mt is the swelling content at any time (g/g d.b.) and M(t+∆t ) represents the swelling content based on the dry content at +Δ . [2] = +△ − △ Figure S13. Swelling rate of hydrogels at different temperatures.
The swelling behavior of the hydrogels was fitted to the following equation:

= =
Where, is the swelling fraction, Mt and Me are the amounts of water diffused into the hydrogels at time t, and at equilibrium (e), respectively; k is a kinetic constant and n is the swelling exponent which describes the type of water diffusion in line with Table S4. The diffusion coefficient can be calculated using the following equation: Where " " represents the coefficient of diffusion as "m 2 s −1 " and " " represents the swollen gels radius. The mechanism of water diffusion in the hydrogels was determined from plots of ln versus ln (Figure S14), and the values of , and regression coefficients were calculated from the slopes and the intercepts ( Table 1) Where, A represents the pre-exponent which is a constant, Ea is activation energy, R is the universal gas constant of 8.314×10 −3 (kJ mol −1 K −1 ), K is the rate constant. From the plot A0 (pre-exponential factor of Arrhenius equation) activation energy was calculated. The activation energy (Ea) was found to be 29.88 KJ mol -1 , and the pre-exponential factor (A0) of the Arrhenius equation or frequency factor was found to be 2.66×10 -3 s -1 .

= Ao exp ((-Ea)/(R(T+273.15)))
Where A0 is the preexponential factor of Arrhenius equation (m 2 s −1 ), Ea is the activation energy (kJ mol −1 ), is temperature of water (K −1 ), and is the universal gas constant of 8.314×10 −3 (kJ mol −1 K −1 ). The graph for Arrhenius-type relationship between effective diffusivity coefficient and temperature (In(D) vs (1/K)), indicates Arrhenius dependence. [2] Figure S16. Relaxation of the polymer chains.  All the experiments were in triplicate (n = 3), and data is reported as the mean average ± standard deviation. UV-vis calibration curves for metformin absorption (with an R 2 value of 1) were used for least squares linear regression analysis and correlation analysis. The limit of detection (LoD) was calculated from: Where, S is Slope, Pi is the SD of intercept; the LoD was found to be 36.8 ppm. The limit of quantification (LoQ) was calculated from: The LoQ was found to be 111.4 ppm. Where, Ct is the amount of drug released at time t, C0 is the initial concentration of drug at time t = 0, K0 is the zero order rate constant. Thus, zero order kinetics defines the process of constant drug release from a drug delivery system and drug level in the medium remains constant throughout the delivery. [5] First order model release kinetics: The equation for first order release is: After rearranging and integrating the equation, log C = log C0-K0 t/2.303 K1 is the first order rate equation expressed in t -1 or per hour, C0 is the initial concentration of the drug, C is the percentage of drug remaining at time t. Hence, log % of drug remaining vs.