Inﬂuence of Polyether Backbone PEO–PPO on the Drug Release Behavior of Polyurea Xerogels

: To evaluate possible structural changes and thermal stability of the polyurea unloaded and loaded with diclofenac sodium, polyurea networks based on polyetheramine containing polypropylene oxide (PPO) or polyethylene oxide (PEO) and hexamethylene diisocyanate trimer-HDI were synthesized. The formation of the network was controlled by sol-gel reactions, and the obtained materials were then characterized by different techniques (FTIR, XRD, TGA). Moreover, the amount of diclofenac released could be modulated as a function of time, studying the water absorption or swelling capacity, the cytotoxicity of the material and the amount of drug released. A choice was therefore made on the hydrophilicity of PEO-or PPO-based polyetheramine (with similar molecular weight), and the release proﬁle was hereafter correlated with the water absorption by the PEO/PPO polyurea matrix. Links could ﬁnally be established between the release of diclofenac and the polyurea matrices properties, such as the nature of polymer (PEO/PPO) and the hydrophilicity (water uptake). Our objective here is to identify challenges and opportunities for the development of innovative functional biomaterials for health applications.


Introduction
Controlled drug delivery involves the strategic administration of dosing bioactive molecules over a certain period [1][2][3]. Thanks to technological advances, the new design of membrane-based devices on a macroscopic scale allows regulation of the rate of release over long periods of time. Sophisticated systems, called nano-transporters, are also available to form controlled drug release systems [3][4][5].
The release of bioactive molecules in polymeric membranes is controlled by mechanisms such as osmosis, diffusion, chemical degradation, swelling and dissolution. Diffusion plays a fundamental and primary role in many controlled drug release systems [6].
Degradable polymeric membranes release drugs by erosion of the polymeric matrix surface, breakage of the polymeric bonds, or diffusion of physically entrapped drugs. Typically, drug release results from a simultaneous combination of all these three mechanisms [7,8].
Diffusion refers to the intricate process of transferring individual molecules of a substance from one part of a system to another, driven by a force arising from a concentration gradient [9]. The diffusion of the active molecules through a carrier can trigger a swelling process upon contact with water, owing to their hydrophilicity. This affinity of the matrix's structural groups with water molecules causes a polymeric structure to swell (expansion of free volume), forming new chemical or physical bonds within its bulk. This process could lead to control of the release/diffusion of bioactive molecules in an aqueous medium [10].
Erosion of the polymeric networks is characterized by a superficial degradation of the matrix, e.g., by hydrolysis and is dependent on the aqueous environment [11]. ular weight of 400 g mol −1 ) and the hexamethylene diisocyanate trimer-HDI (Desmodur N3300 with a molecular weight of~504 g mol −1 ) were donated by Huntsman Performance Products (Brazil) and Bayer Corporation, respectively. Diclofenac sodium salt DCF (C 14 H 10 Cl 2 NNaO 2 ) and acetone (ACS reagent, ≥99.5%) were purchased from Sigma-Aldrich. All reagents were used without further purification.

Synthesis of Polyureas
The polyurea xerogel was obtained by the sol-gel process, as reported in the literature [18,24,33]. The monomers Jeffamine (ED600 or D400) and trimer-HDI were separately dissolved in acetone with the molar ratio of jeffamine: HDI at 1:1. The solutions were sealed and stirred for 2 h at room temperature (RT) to form a homogenous solution. After, the HDI solution was added dropwise to the jeffamine solution until complete dissolution (see details Scheme 1). The resulting solution was poured into Teflon ® mold. During the gelation reaction, to obtain polyurea networks, the acetone solvent is ambient dried (evaporated) before being used for characterization, cytotoxicity and release assays.

Synthesis of Polyureas
The polyurea xerogel was obtained by the sol-gel process, as reported in the literature [18,24,33]. The monomers Jeffamine (ED600 or D400) and trimer-HDI were separately dissolved in acetone with the molar ratio of jeffamine: HDI at 1:1. The solutions were sealed and stirred for 2 h at room temperature (RT) to form a homogenous solution. After, the HDI solution was added dropwise to the jeffamine solution until complete dissolution (see details Scheme 1). The resulting solution was poured into Teflon ® mold. During the gelation reaction, to obtain polyurea networks, the acetone solvent is ambient dried (evaporated) before being used for characterization, cytotoxicity and release assays. Scheme 1. Sol-gel route for the preparation of polyurea based on Jeffamine ED-600 (PEO500) and Jeffamine D-400 (PPO400) and schematic network showing urea linkage and polyether backbone.

Synthesis of Polyureas Containing Drug
Polyurea PEO/PPO samples containing DCF were prepared via one-step sol-gel process. The desired drug amount (1 and 10 wt% with respect to the mass of jeffamine) was dissolved in acetone and then mixed with PEO or PPO to obtain a homogeneous solution. The HDI solution was dissolved in a separated beaker and added, as cited above, to form DCF-loaded polyurea samples. The resulting mixture was poured into Teflon ® mold and gelled using the same conditions (temperature and time) as for the pure polyurea. The final materials were named PEO500, PPO400 (polyurea based on Jeffamine ED600 and D400, respectively) and PEO-DCFx or PPO-DCFx (loaded polyurea containing diclofenac DCF and x for the wt% of drug loaded). Since the acetone was evaporated at ambient conditions to form the final polyurea membranes, the mass of loaded DCF used was completely incorporated into PEO or PPO matrixes. Scheme 1. Sol-gel route for the preparation of polyurea based on Jeffamine ED-600 (PEO500) and Jeffamine D-400 (PPO400) and schematic network showing urea linkage and polyether backbone.

Synthesis of Polyureas Containing Drug
Polyurea PEO/PPO samples containing DCF were prepared via one-step sol-gel process. The desired drug amount (1 and 10 wt% with respect to the mass of jeffamine) was dissolved in acetone and then mixed with PEO or PPO to obtain a homogeneous solution. The HDI solution was dissolved in a separated beaker and added, as cited above, to form DCF-loaded polyurea samples. The resulting mixture was poured into Teflon ® mold and gelled using the same conditions (temperature and time) as for the pure polyurea. The final materials were named PEO500, PPO400 (polyurea based on Jeffamine ED600 and D400, respectively) and PEO-DCFx or PPO-DCFx (loaded polyurea containing diclofenac DCF and x for the wt% of drug loaded). Since the acetone was evaporated at ambient conditions to form the final polyurea membranes, the mass of loaded DCF used was completely incorporated into PEO or PPO matrixes.

Characterization
X-ray diffraction XRD patterns were recorded on a Rigaku MiniFlex II Desktop X-ray Diffractometer using Cu Kα (λ = 1.54 Å) radiation at a scan speed of 0.04 • ·s −1 . Fourier Transform Infrared Spectroscopy FTIR spectra were recorded at 3100-700 cm −1 with ATR mode using a Perkin Elmer Frontier spectrometer, with a resolution of 2 cm −1 and an average of 32 scans. Thermogravimetric analysis TGA was carried out applying SDTQ600 TA Instruments. The polyurea samples were cut into small pieces (~10 mg). Measurements were carried out under a nitrogen atmosphere and typical heating rate of 10 • C/min to 25 • C to 700 • C.
The swelling behavior (water uptake) of the PEO-and PPO-based polyurea membranes was studied gravimetrically. A fraction of the samples (2 cm × 2 cm) was immersed in distilled water. The swollen samples were removed from the water at a preset time (5,10,20,30,40,50,60,90,120,150,180, 240 and 300 min), then lightly squeezed with filter papers to remove any excess water on the surface before being weighed in an electronic analytical balance. The swelling ratio (Sr) was determined using the equation: where W s and W d are the mass of swollen and dry polyurea samples, respectively. The in vitro temporal release of DCF was assayed in distilled water (100 mL, pH 6.5) using~0.3 g of loaded PEO or PPO containing different amounts of DCF drug (1 and 10% wt). The release trials were carried out at a controlled temperature of 37 • C under constant stirring (100 rpm). Spectroscopic analysis of the in vitro release was conducted on the UV-Vis band using a Cary60 dual-beam spectrophotometer (Agilent Technologies Brasil Ltda, Barueri, São Paulo, Brazil) connected to an immersion probe (with a 2 mm optical path length). The quantitative determination of the cumulative DCF release was based on a calibration curve compiled from the maximum absorbance values at λ max = 275 nm of drug solutions at different concentrations. The in vitro release and swelling tests were all performed with three independent samples, and the results presented are mean data. Regarding the release mechanism, two well-known approaches were used for the analysis of drug release data (see details in results and discussion Section 3.5).
The cell viability assay XTT was conducted using the cell line GM07492-A obtained from Coriell Cell Repositories (Camden, NJ, USA). Cultivated in DMEM + HAM F10 (1:1, v/v) (Sigma, St Louis, MO, USA), it was supplemented with 10% fetal calf serum (Sigma, St Louis, MO, USA) and 1% of penicillin/streptomycin stabilized solution (Sigma, St Louis, MO, USA,). To determine the cell viability, 1.5 × 105 cells/well were seeded on a 24-well plate. After 24 h, the cell culture was exposed to a 0.04 cm 2 of PEO 500 and PPO 400 membranes and incubated for an additional 24 h. The plates were washed twice in phosphate buffer saline (PBS 1X) and incubated for 4 h at 37 • C with DMEM without phenol red and supplemented with the reagents of the Cell Proliferation Kit (Roche, Mannhein, Germany) as recommended by the manufacturer [34]. Afterwards, the culture media solution was placed on a 96-well plate. Total absorbance was measured at 492 and 690 nm (reference energy) using a microplate reader (ASYS, Eugendorf, Salzburg, Austria). With the results of total absorbance being considered directly proportional to the number of viable cells as a percentage of the negative control (100% of cell viability), a statistical analysis of experimental data was run through the software GraphPad Prism 5.0. The comparative analysis of the experimental groups, based on the Analysis of Variance (ANOVA), was followed by the Tukey test when significant differences among treatments were found. The significance was set at p < 0.05, and the results were reported as means and standard deviations (SD) of three independent experimental samples assayed in triplicate.

Structural Characterization
The synthesis of polyurea is a straightforward method for encapsulating an active pharmaceutical ingredient (API). To prepare the loaded samples, DCF drug was dissolved in acetone and then blended with PEO to create a homogeneous solution (see details in experimental section). It is noteworthy to mention that after gelation, samples began to shrink (acetone extraction). This was due to the drying process at room temperature, and this led to the formation of a homogeneous and transparent polyurea xerogel containing the amount of drug initially dissolved. Thus, 100% encapsulation efficiency is recorded for the drug concentration used in this work (1 and 10% wt), with no precipitation of diclofenac after the gelation process. The structural elucidation of unloaded and loaded polyureas was carried out by FTIR spectroscopy. The FTIR spectra plots of PEO500 and PPO400, without and with DCF drug (1 and 10 wt%), are depicted in Figure 1. A superposition of characteristic bands of unloaded PEO/PPO matrices and the DCF drug was revealed in the region of the FT-IR spectrum studied, and the analysis of potential peak displacements was discussed in relation to the characteristic vibrations of polyurea. The absorption bands at 765, 949 and 1104 cm −1 are attributed to the ethylene rocking vibrations (CH 2 ) and stretching vibrations of the polyether backbone (C-O-C) present in PEO and PPO structure [35]. Three bands centered at approximately 1560, 1641 and 1686 cm −1 , characteristic of CO-N-H amide II, C=O amide I and free C=O group, respectively, can be noticed. The presence of these bands ascribed to amide II and amide I evidence the successful obtention of polyurea matrices based on PEO or PPO (Figure 1, black line and pink line, respectively) with the formation of urea groups. By comparing the spectrum of unloaded polyureas (PEO500 and PPO400) with the spectrum of DCF loaded PEO500-DCF and PPO400-DCF containing 1 and 10% wt of the drug, it can clearly be seen that the polyether characteristic absorption bands do not show changes in peak position (without displacement) after incorporation of the DCF. These results indicate good solvation of DCF molecules through the polyurea matrices. The amount of drug release by PEO/PPO polyureas evidences the DCF encapsulation and excellent solvation of the drug by these matrices, as reported in the release studies.  The X-ray diffraction results of PEO500 and PPO400 xerogels, both unloaded a loaded with 10% wt content of DCF drug, are presented in Figure 2. Interestingly, t diffractograms of all samples, whether loaded or not, exhibit a sole broad Gaussia shaped peak centered at 2θ = 11°, which can be attributed to the amorphous lattice. Ho ever, when crystalline DCF (10% wt) was blended into the polyurea PEO/PPO, its cryst line diffraction peaks disappeared, indicating that the DCF was highly soluble in the m trices. These results highlight the remarkable solubility of DCF in PEO/PPO matric which could have significant implications for drug delivery applications. The X-ray diffraction results of PEO500 and PPO400 xerogels, both unloaded and loaded with 10% wt content of DCF drug, are presented in Figure 2. Interestingly, the diffractograms of all samples, whether loaded or not, exhibit a sole broad Gaussian-shaped peak centered at 2θ = 11 • , which can be attributed to the amorphous lattice. However, when crystalline DCF (10% wt) was blended into the polyurea PEO/PPO, its crystalline diffraction peaks disappeared, indicating that the DCF was highly soluble in the matrices. These results highlight the remarkable solubility of DCF in PEO/PPO matrices, which could have significant implications for drug delivery applications.

TGA Analysis
The thermal degradation of polyureas and the impact of DCF on thermal stability were studied by TGA. Figure 3 displays the DTGA curves for both unloaded and loaded PEO/PPO polyurea samples. The thermal degradation process of the polyurea samples (PEO and PPO) was observed to have two main stages. The first stage of degradation involved the urea bond decomposition, resulting in a dissociation into isocyanate and alcohol. The second stage is characteristic of polyol and isocyanate degradation into amine compounds (primary/secondary amines), terminal olefinic group and CO2 [36,37]. For PEO500 polyurea xerogel (unloaded and loaded), the first stage of polymer degradation started at approximately 165 °C and ended at around 418 °C. According to Figure 3a, increasing the amount of drug loaded into PEO500 leads to an increase in thermal stability during the first stage of degradation. This may be attributed to the possibility of hydrogen bonding between hydrogen atoms from urea groups and oxygen atoms from the diclofenac [24]. In the case of PPO polyurea xerogel (unloaded and loaded), the first stage of polymer degradation started at approximately 200 °C and ended at around 425 °C ( Figure  3b). These findings indicate that the PPO400 polyurea matrix is thermally more stable than PEO500. Table 1 summarizes the parameters of mass loss (%) at the first and second stages and char residue (%) obtained from TGA curves of unloaded and loaded PEO500 and PPO400 polyurea samples.

TGA Analysis
The thermal degradation of polyureas and the impact of DCF on thermal stability were studied by TGA. Figure 3 displays the DTGA curves for both unloaded and loaded PEO/PPO polyurea samples. The thermal degradation process of the polyurea samples (PEO and PPO) was observed to have two main stages. The first stage of degradation involved the urea bond decomposition, resulting in a dissociation into isocyanate and alcohol. The second stage is characteristic of polyol and isocyanate degradation into amine compounds (primary/secondary amines), terminal olefinic group and CO 2 [36,37]. For PEO500 polyurea xerogel (unloaded and loaded), the first stage of polymer degradation started at approximately 165 • C and ended at around 418 • C. According to Figure 3a, increasing the amount of drug loaded into PEO500 leads to an increase in thermal stability during the first stage of degradation. This may be attributed to the possibility of hydrogen bonding between hydrogen atoms from urea groups and oxygen atoms from the diclofenac [24]. In the case of PPO polyurea xerogel (unloaded and loaded), the first stage of polymer degradation started at approximately 200 • C and ended at around 425 • C (Figure 3b). These findings indicate that the PPO400 polyurea matrix is thermally more stable than PEO500. Table 1 summarizes the parameters of mass loss (%) at the first and second stages and char residue (%) obtained from TGA curves of unloaded and loaded PEO500 and PPO400 polyurea samples.

Swelling Behavior of Polyurea PEO/PPO Matrixes
The swelling behaviors of polyurea xerogels at room temperature were examined by gravimetric method, as displayed in Figure 4. The results indicate that for PEO500 xerogel, the rapid increase of the swelling ratio during the 6 h of assay leading to 80% can be attributed to the hydration of the matrix due to the hydrophilic nature of PEO chains. On

Swelling Behavior of Polyurea PEO/PPO Matrixes
The swelling behaviors of polyurea xerogels at room temperature were examined by gravimetric method, as displayed in Figure 4. The results indicate that for PEO500 xerogel, the rapid increase of the swelling ratio during the 6 h of assay leading to 80% can be attributed to the hydration of the matrix due to the hydrophilic nature of PEO chains. On the other hand, PPO400 xerogel showed a slower water uptake during the swelling assay, at around 10%. This behavior is due to the hydrophobic nature of PPO chains. Considering the differences between PEO500 and PPO400 swelling ratios, these results open perspectives of controlling the water uptake capacity by selecting the appropriate polyether nature and suggest fine-tuning these properties by mixing PEO/PPO amounts during the polyurea preparation.
Future Pharmacol. 2023, 3, FOR PEER REVIEW 9 the other hand, PPO400 xerogel showed a slower water uptake during the swelling assay, at around 10%. This behavior is due to the hydrophobic nature of PPO chains. Considering the differences between PEO500 and PPO400 swelling ratios, these results open perspectives of controlling the water uptake capacity by selecting the appropriate polyether nature and suggest fine-tuning these properties by mixing PEO/PPO amounts during the polyurea preparation.

Cell Viability Assays
The cytotoxicity evaluation of PEO/PPO polyurea membranes involved the GM07492-A cell line exposure to both PEO500 and PPO400 membranes through direct contact with the culture medium ( Figure 5). The XTT studies ( Figure 5A) revealed that PEO500 demonstrates high cell viability (about 98%). While using PPO400, the percentage decreased to approximately 40%. Under the experimental conditions, after 24 h in contact with the culture medium, the PEO500 sample ( Figure 5B) did not demonstrate changes in adherence and morphology of the cells, indicating healthy and living cells with a fibrous characteristic. In contrast, exposure to PPO400 ( Figure 5C) induced a loss of cellular adherence, alteration in morphology (like spherical, in this case, dead cells), and consequently, the inability of cell growth and survival. These cytotoxicity results suggest that the PEO500 matrix is biocompatible (without cytotoxicity when exposed to cell lines) compared to PPO400, which showed lower cell viability when exposed to the culture medium. These results are in agreement with the XTT assays ( Figure 5A).

Cell Viability Assays
The cytotoxicity evaluation of PEO/PPO polyurea membranes involved the GM07492-A cell line exposure to both PEO500 and PPO400 membranes through direct contact with the culture medium ( Figure 5). The XTT studies ( Figure 5A) revealed that PEO500 demonstrates high cell viability (about 98%). While using PPO400, the percentage decreased to approximately 40%. Under the experimental conditions, after 24 h in contact with the culture medium, the PEO500 sample ( Figure 5B) did not demonstrate changes in adherence and morphology of the cells, indicating healthy and living cells with a fibrous characteristic. In contrast, exposure to PPO400 ( Figure 5C) induced a loss of cellular adherence, alteration in morphology (like spherical, in this case, dead cells), and consequently, the inability of cell growth and survival. These cytotoxicity results suggest that the PEO500 matrix is biocompatible (without cytotoxicity when exposed to cell lines) compared to PPO400, which showed lower cell viability when exposed to the culture medium. These results are in agreement with the XTT assays ( Figure 5A). *** p < 0.0001 compared to negative control; and photograph of (B) PEO500 and (C) PPO400 when exposed to the cell line GM07492-A. The white scale bars represent 50 μm (20× magnification).

In Situ Diclofenac Release Assays
Diclofenac drug release studies: The cumulative in situ release of pure DCF and DCF from PEO500/PPO400 polyurea samples are displayed in Figure 6. The DCF drug release monitoring was done with UV-vis spectrometry at 275 nm (see Figure 6a). In vitro studies showed that 80% of the DCF (pure from patch) was released over a period of 6 h ( Figure  6b). The PEO500-DCF profiles showed a well-controlled sustained manner, with a release amount of 67% and 69% by PEO500 polyurea containing 1 and 10% wt of drug, respectively (see Figure 6b, blue circles and green squares). On the other hand, the DCF molecules are barely released from polyurea PPO400-DCF10 (containing 10% wt of drug), reaching about 1.8% after 24 h of assay (see Figure 6b, black triangles). For the PPO400-DCF1 (containing 1% wt of drug), no release of the drug was observed. These different release behaviors of DCF by PEO500 and PPO400 polyurea samples were attributed mainly to the hydrophilicity of the matrixes, i.e., the capacity to swell (water uptake) through the polyurea network. Comparing the two matrices, it is worth noting that (i) PEO500 xerogel showed a faster and higher water uptake after 5 h (see Figure 4, blue circles), characteristic of a swollen network due to the hydrophilic nature of polyether chains, and (ii) PPO400 xerogel displayed a slow and lower water uptake (see Figure 4, black circles) that can be correlated to the hydrophobic nature of the polyether. The findings suggest that utilizing polyurea systems designed for controlled drug delivery molecules is promising for achieving a sustained-release profile by using polyurea based on PEO nature. Nevertheless, the possibility to add a small amount of PPO into the PEO system during the polyurea synthesis encourages further development of polymeric blends as a potential candidate for fine-tuning the amount of drug released and could enhance the cellular viability of the PPO characterized above (Figure 5b) for lower cell viability.

In Situ Diclofenac Release Assays
Diclofenac drug release studies: The cumulative in situ release of pure DCF and DCF from PEO500/PPO400 polyurea samples are displayed in Figure 6. The DCF drug release monitoring was done with UV-vis spectrometry at 275 nm (see Figure 6a). In vitro studies showed that 80% of the DCF (pure from patch) was released over a period of 6 h (Figure 6b). The PEO500-DCF profiles showed a well-controlled sustained manner, with a release amount of 67% and 69% by PEO500 polyurea containing 1 and 10% wt of drug, respectively (see Figure 6b, blue circles and green squares). On the other hand, the DCF molecules are barely released from polyurea PPO400-DCF10 (containing 10% wt of drug), reaching about 1.8% after 24 h of assay (see Figure 6b, black triangles). For the PPO400-DCF1 (containing 1% wt of drug), no release of the drug was observed. These different release behaviors of DCF by PEO500 and PPO400 polyurea samples were attributed mainly to the hydrophilicity of the matrixes, i.e., the capacity to swell (water uptake) through the polyurea network. Comparing the two matrices, it is worth noting that (i) PEO500 xerogel showed a faster and higher water uptake after 5 h (see Figure 4, blue circles), characteristic of a swollen network due to the hydrophilic nature of polyether chains, and (ii) PPO400 xerogel displayed a slow and lower water uptake (see Figure 4, black circles) that can be correlated to the hydrophobic nature of the polyether. The findings suggest that utilizing polyurea systems designed for controlled drug delivery molecules is promising for achieving a sustained-release profile by using polyurea based on PEO nature. Nevertheless, the possibility to add a small amount of PPO into the PEO system during the polyurea synthesis encourages further development of polymeric blends as a potential candidate for fine-tuning the amount of drug released and could enhance the cellular viability of the PPO characterized above ( Figure 5B) for lower cell viability.  (1)), log (M t /M ∞ ) plotted as a function of log t, from PEO500 and PPO400 (red line means fitting to data generated from Equation (2)).
The drug release kinetics of DCF drug in polyurea samples were investigated using the Korsmeyer-Peppas model [38]. This model is based on Fick's law of diffusion, and the equation is given by Equation (2): where M t /M ∞ is the fractional solute release, t is the release time, k is a kinetic constant characteristic of the drug/polymer system, and n is an exponent which characterizes the mechanism of release, where n values of 0.50 and 1 are characterized by Fickian diffusion and Case II transport mechanism, respectively. Values of n between 0.55 and 0.90 can indicate the superposition of both phenomena (anomalous transport). Figure 6c shows the DCF release curves plotted as log (M t /M ∞ ) as a function of log t from loaded PEO500 and PPO400 polyurea samples. The DCF amount released in the final assays (t = 1440 min) and the parameters obtained by the Korsmeyer-Peppas model are displayed in Table 2. The coefficient of determination (R 2 ) for loaded PEO500 samples was 0.99; and for PPO400 containing 10% wt of drug, it was~0.95. The experimental n values obtained for PEO500 containing 1 and 10% wt of DCF were n = 1 and 0.59, respectively.
These n values indicate a Case II transport mechanism (for the PEO500-DCF1 sample) and an anomalous transport (for the PEO500-DCF10 sample) attributed to the diffusion/zeroorder rate of drug controlled by the penetration of the water-swollen, respectively. The PPO400-DCF10 sample showed an n value of 0.62, characteristic of anomalous transport. Higuchi model [39] was used to compare the release mechanism results. In this case, when linear regression of M t /M ∞ versus t 1/2 is applied, the curve does not fit well, presenting the R 2 values < 0.98 for loaded PEO500 containing 1 and 10% wt of the drug, respectively. Thus, we conclude that the Korsmeyer-Peppas model nicely describes all data sets analyzed. Recently, Chen et al. [40] developed an ocular drug delivery system based on miltefosine loaded in a contact lens hydrogel. The authors demonstrate the importance of a slow and steady release of the antiparasitic miltefosine for the treatment of Acanthamoeba keratitis. In this sense, polyurea based PEO-PPO materials could be promising candidates for this scenario since they are (i) easy to obtain by one-pot process, (ii) low in cost, (iii) high in transparency, and have (iv) desired shape and thickness according to needs [24]. Moreover, with a judicious PEO-PPO mixture during the synthesis followed by fabricate process, it is possible to produce microneedle patch-based polyurea devices which could be used, for example, as a sustained release of insulin. Cao et al. used silk fibroin for the purpose that the swelling degree of the needle controls the release of insulin [41].

Conclusions
The influence of the polymeric nature on the physicochemical properties of polyureas using PEO and PPO of similar molecular weight (Mw~500 g mol −1 ), exhibiting sustainedrelease profiles, has been herein evidenced. These xerogels were selected as the carrier for sodium diclofenac DCF at different drug loads. Polyureas based on PEO500 and PPO400 have high thermal stability (onset of degradation above 200 • C), as shown in TGA studies. Therefore, the degree of swelling can be controlled by the nature of the matrix (PEO or PPO), which plays an important role in the profile release of DCF drug. PEO500 matrix was very compatible with the GM07492-A cell, and the fibrous morphology of the cells did not visibly alter after contact with the membrane. After contact with PPO400, on the contrary, the cells changed their morphology to spherical, resulting in low cellular viability. The polyurea xerogels can then be considered a favorable carrier for the sustained release of drug molecules. In our study, commercially available reagents (PEO/PPO and HDI) can be used to produce polyurea membranes with potential applications as transdermal drug delivery systems. This approach is very advantageous owing to the low cost and simplicity of manufacture of the sol-gel synthesis. Thus, basing our conclusion on the properties of polyurea PPO400, this formulation could also be exploited as a matrix for high-performance advanced composite materials, such as membranes for gas separation and as a coating.