Highly Controlled Diffusion Drug Release from UreasilâPoly(ethylene

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Functional Nanostructured Materials (including low-D carbon)

High controlled-diffusion drug release from ureasil-poly(ethylene oxide)-Na-montmorillonite hybrid hydrogel nanocomposites +

Celso Ricardo Jesus, Eduardo Ferreira Molina, Sandra Helena Pulcinelli, and Celso V. Santilli ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b04559 • Publication Date (Web): 11 May 2018 Downloaded from http://pubs.acs.org on May 14, 2018

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ACS Applied Materials & Interfaces

High controlled-diffusion drug release from ureasil-poly(ethylene oxide)-Na+-montmorillonite hybrid hydrogel nanocomposites

Celso R. N. Jesus1, Eduardo F. Molina2*, Sandra H. Pulcinelli1 and Celso V. Santilli1 1

Instituto de Química, UNESP, Rua Professor Francisco Degni 55, Araraquara, SP, 14800-900, Brazil 2

Universidade de Franca, Av. Dr. Armando Salles Oliveira 201, Franca, SP, 14404-600, Brazil *Contact Author e-mail: [email protected]

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ABSTRACT

In this work, we report the effects of incorporation of variable amounts (1-20 wt%) of sodium montmorillonite (MMT) into a siloxane-poly(ethylene oxide) hybrid hydrogel prepared by the sol-gel route. The aim was to control the nanostructural features of the nanocomposite, improve the release profile of the sodium diclofenac (SDCF) drug, and optimize the swelling behavior of the hydrophilic matrix. The nanoscopic characteristics of the siloxane-crosslinked poly(ethylene oxide) network, the semi-crystallinity of the hybrid, and the intercalated or exfoliated structure of the clay were investigated by Xray diffraction (XRD), small-angle X-ray scattering (SAXS), and differential scanning calorimetry (DSC). The correlation between the nanoscopic features of nanocomposites containing different amounts of MMT and the swelling behavior revealed the key role of exfoliated silicate in controlling water uptake by means of a flow barrier effect. The release of the drug from the nanocomposite displayed a stepped pattern kinetically controlled by the diffusion of SDCF molecules through the mass transport barrier created by the exfoliated silicate. The sustained SDCF release provided by the hybrid hydrogel nanocomposite could be useful for the prolonged treatment of painful conditions such as arthritis, sprains and strains, gout, migraine, and pain after surgical procedures. Keywords: Siloxane-polyether, Montmorillonite, Nanocomposite, Drug delivery, Swelling.


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1. Introduction

The combination, at the nanometric level, of clay minerals and polymers is an attractive way to develop new nanocomposites, providing distinct properties or applications that are inherent to these two (polymer and clay) components.1,2 The landmark work on this subject was performed by the Toyota research group,3 who reported the impressive gas barrier and enhanced mechanical and thermal properties achieved by dispersing a small amount (1.9 wt%) of montmorillonite (MMT) into a nylon-6 matrix.3,4 Since this pioneering work, polymer-clay nanocomposites have emerged as a broad research topic, largely due to their wide range of applications in flame retardants,5 gas permeation barriers,6 and food/liquid packaging.7 Since several clays and polymers were classed by US Food and Drug Administration (FDA) as inactive ingredient,8 the drug delivery systems based on polymer-clay nanocomposites have emerged in the last decade.9-11 Clay minerals have long been used as folk remedies for various purposes, such as relief from diarrhea, blood clotting, wound healing, prevention of infections and even treating some allergies.12-15 For example, the sodium montmorillonite (Na-MMT) are effective in laxatives, stimulating the osmosis, while the adsorbent properties of sodium can be exploited as anti-diarrhea agents. Moreover, the cation exchange capacity conjugated with the excellent intercalation ability of MMT have been exploited in the preparation of drug delivery vehicles.16 In the case of orally administered systems the intercalation of drug molecules by cation exchange reaction was used to delay the release and avoid the unpleasant taste of drugs in the buccal cavity.17-19 The MMT carrying DNA was successfully used to prevent the enzymatic degradation of DNA and effective

delivery

into

cells

nucleous.20-23

In

addition,

the

MMT-polymer

nanocomposites with intercalated and/or exfoliated structures have been successfully 3 ACS Paragon Plus Environment


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developed in order to: i) lower the drug diffusion thought the biodegradable polyurethane matrix24, ii) reduce the ‘initial burst’ of the drug in the polymer blend hydrogel formed by polyacrylamide/sodium carboxymethyl25, and iii) increase the sustained chemotherapeutic efficacy of bio-adhesive formulated by the poly(D,Llactide-co-glycolide) and polylactide blending.26 Nowadays, organic-inorganic hybrid (OIH) materials have emerged as a new platform for biological application because they can easily be produced, with controlled structural features, using soft chemistry routes like the sol-gel process. 27 This is a great advantage allowing the incorporation of thermo-unstable drug molecules, which were already explored in the development of commercial biomaterials applied to the treatment of skin diseases, body care and protection.27 In this context the organic modified mesoporous silica was used in the majority of OIH system studied as drug delivery platform.27,28 On opposite, there was a few studies focusing the drug delivery systems based on soft OIH material, like the hydrogel formed by the hydrophilic polymer chains cross linked by sol-gel reaction.29-31 An example is the siloxanepolyether network composed of PEO (poly(ethylene oxide)) macromer grafted at both ends to siloxane cross-linked nodes via urea bridges (–NH(C=O)NH–), known as ureasil and labeled as UPEO.32 These semi-crystalline, transparent and flexible elastomeric hybrid materials are insoluble in water and present hydrogel behavior, characterized by water uptake and swelling, due to the essentially hydrophilic nature of the organic framework. A number of recent publications on the drug delivery potentiality of UPEO show that i) the multifunctional polar network are capable to dissolve several drug molecules,32 ii) the transparency, the skin adhesion and the water permeation properties can be used as semi-occlusive adhesive for topical drug delivery,33 iii) the drug delivery can be triggered by the fusion of semi-crystalline PEO


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induced by the magnetic hyperthermia properties of the super paramagnetic of γ-Fe2O3 nanoparticles dispersed in UPEO,34 and iv) the rate of both the swelling caused by the water uptake and the drug release can be reduced by blending the hydrophilic UPEO with the hydrophobic UPPO (ureasil-poly(propylene oxide).35,36 Considering the importance of the water permeation on the UPEO hydrogel properties and the diffusion barrier role of MMT (discussed below), our hypothesis in this study was that the dispersion of MMT nanoplatelets into UPEO matrix might easily control the water uptake and the drug release rate, improving the sustained release time of the nanocomposites formed by the conjugation of these materials. In order to demonstrate this hypothesis and prove the concept illustrated in the graphical abstract, the UPEO and UPEO-MMT nanocomposites with different amounts of sodium montmorillonite (Cloisite-Na+) were prepared from sol-gel route. The effect of the MMT content on the nanostructure, drug release profile, and swelling properties of nanocomposites was systematically studied using X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), small-angle X-ray scattering (SAXS), and UVVis spectrometry.

2. Experimental Materials: O,O’-bis-(2-aminopropyl) polypropylene glycol-block-polyethylene glycol-block-polypropylene, with PEO block molecular weight of 1900 g mol-1 (Jeffamine

ED-2003),

3-isocyanatopropyltriethoxysilane

(ICPTES),

ethanol

(CH3CH2OH), tetrahydrofuran (THF), and sodium diclofenac (SDCF) were purchased from Sigma-Aldrich. Sodium montmorillonite (Cloisite-Na+) was purchased from Southern Clay Products. Synthesis of the hybrid precursor: A well kwon two step procedure37,38 was adopted to prepare the ureasil-poly(ethylene oxide), see Scheme 1. In a first step, the 5 ACS Paragon Plus Environment


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ureasil cross-linking agent was covalently bonded to both ends of the PEO macromer by the quantitative reaction between the terminal amino-propyl groups of the Jeffamine ED-2003 and ICPTES.38 In brief, 10,4 mL of ICPTES were mixed with 40 g of Jeffamine ED-2003 in 150 ml of tetrahydrofuran solvent. The mixture was refluxed for 24 h at 78 °C and then the solvent was removed by rotary evaporation at 60 °C. According to quantitative NMR analysis this functionalization reaction resulted in 100% yield.39 Synthesis of OIH nanocomposites: A desired mass of 0.015, 0.075, 0.15 or 0.30 g of sodium montmorillonite (Cloisite-Na+) was mixed with 3.0 mL of anhydrous ethanol in order to prepare the nanocomposites with 1, 5, 10 and 20 wt% of MMT, respectively. For a better dispersion of clay, the mixture was kept in a 30 kHz sonicator (vibracel VC 501) for 5 min. After that, 1.0 mL of each MMT suspension was transferred to different beaker containing 1.5 g of the hybrid precursor. In the case of 5 wt% drug loaded samples, 0.075 g of SDCF were added to the MMT dispersion containing precursor. These mixtures were left under mechanical stirring for 4 h at room temperature (≈25 oC) and, after this time the acid catalysed sol-gel reactions were promoted by addition of 36 µL of HCl (2M) and 100 µL of distilled water, leading to formation of a gel. Rubber-like monolithic discs were obtained after drying in desiccators under vacuum at 70 °C for 24 h. For each UPEO-MMT/SDCF composition three monolithic disk-shaped tablets were prepared, with average thickness and diameter of 1.2±0.1 mm, and 18±1.5 mm, respectively. The border of the disc presented systematically a higher thickness, while the disk diameter increases with amount of MMT in the samples. In order to minimize this size effect on the drug deliver and water uptake swelling kinetics, the border of the tablet was cut out using a cork borer with inner diameter of 11 mm. 6 ACS Paragon Plus Environment

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Scheme 1. Schematic representation of the synthesis route of UPEO and UPEOMMT-SDCF, R1= -CH2-CH3.

2.1. Characterization Differential scanning calorimetry (DSC) measurements were carried out using a TA Instruments Model Q100 system. A disk section weighing approximately 15 mg was removed from the monolithic xerogel and placed into a 40 mL aluminum can. The sample was heated from -90 to 350 °C, at 10 °C min-1, using high purity nitrogen as the purge gas, supplied at a constant flow rate of 70 cm3 min-1. 7 ACS Paragon Plus Environment


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The X-ray diffraction (XRD) technique was used to study the crystallinity of the OIH matrix and the intercalation or exfoliation of the MMT layers in the nanocomposite. Diffraction patterns were acquired with a Siemens D5000 powder diffractometer operated at 40 kV and 30 mA, equipped with a curved graphite monochromator that generated a CuKα X-ray beam (λ = 1.54056 Å). Data were collected in the 2θ range between 2 and 70°, with a scan step of 0.02° s-1. The nanoscopic structures of the samples, before and during the swelling, were analyzed by small-angle X-ray scattering (SAXS) at the SAXS1 beamline of the LNLS synchrotron (Campinas, Brazil), which is equipped with an asymmetrically cut and bent Si(111) monochromator that yields a horizontally focused beam (λ = 0.1608 nm). A two dimensional position-sensitive X-ray detector was used to record the SAXS intensity, I(q), as a function of the modulus of the scattering vector q = (4π/ λ )sin(θ/2), where θ is the scattering angle and λ is the radiation wavelength. The SAXS patterns of dried samples were recorded at 25oC, and the reproducibility of SAXS pattern of samples produced and measured in different runs is evident in Figure S1 of the Supporting Information. For the in situ monitoring of the swelling process a liquid cell thermostated at 37oC was used. The monolithic samples were immersed in deionized water maintained under constant flow (≈0.5 cm3 min-1) and SAXS patterns were recorded every 30 s. The data were normalized considering the varying intensity of the direct Xray beam, detector sensitivity, and sample transmission. The parasitic scattering was subtracted from the total scattering intensity. The temporal evolution of the in vitro drug release was monitored by UV-Vis spectrometry, using about 0.5 g of UPEO-MMT monolithic disc immersed in 100 mL of deionized water at a controlled temperature of 37 °C. UV-Vis absorption data were recorded in the range 190-490 nm, using a Varian Cary 50 dual beam spectrophotometer


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fitted with a fiber optic coupler equipped with an immersion probe with optical path length of 5 mm. The acquisition scan rate was 300 nm min-1, allowing a full spectrum to be recorded each 60 s. Aqueous SDCF standard solutions, at different concentrations, were used to construct a calibration curve for quantitative determination of the cumulative SDCF release.

3. Results and Discussion 3.1 Structural features The influences of the amount of MMT and the SDCF loading on the structural characteristics of the UPEO-MMT nanocomposites were studied by XRD, SAXS, and DSC. Comparison of the XRD patterns of MMT, UPEO hybrid, and UPEO-MMT (Figure 1a) revealed the effects of the addition of MMT on the crystalline phases present in the nanocomposites. The UPEO hybrid presented a broad diffraction peak centered at around 22°, assigned to the amorphous phase, which overlapped two narrow and well-defined peaks at ~19° and ~23°. These features are characteristic of the semicrystalline structure of PEO40 and their evolution allows monitoring of the dependency of the crystallinity of the polymeric phase on the quantity of MMT clay. The diffraction patterns of the nanocomposite showed an antagonistic effect with increasing MMT loading, suggesting the occurrence of concurrent processes. The decreased intensity and greater broadening of the diffraction peak observed with increasing quantity of MMT up to 5% evidenced a decrease of the PEO crystallite size. This behavior could result from the interaction of ether-type oxygen of PEO with Na+ cations present in the MMT gallery. In this Na+-PEO coordination, the polymer chains adopted a crown ether conformation, which deviated from the helical conformation typically found in PEO crystals41 and therefore limited the crystallinity. In contrast, above 5%, the diffraction



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peak intensity increased and the peak became narrower as the amount of MMT increased, evidencing an increase of the PEO crystallite size. This behavior suggested that incorporation of the clay favored the heterogeneous nucleation of PEO, hence promoting greater crystallinity of the polymer phase. Such nucleation eﬀects have been observed for MMT incorporated into polyvinyl alcohol, polypropylene, and nylon-6.42,43 For all the nanocomposites, the MMT (001) diffraction peak at 2θ = 7.5°, corresponding to an interlayer spacing of 11.8 Å, was downshifted to 2θ = 4.9°, showing that the interlayer spacing increased to 18.0 Å. This behavior evidenced that the PEO chains were intercalated in the galleries of silicate lamellae. Irrespective of the amount of clay, the MMT (001) diffraction peaks presented almost the same width and intensity, indicating that the quantity of the intercalated structure remained almost invariant. This feature could be explained by the formation of a greater amount of exfoliated structure as the quantity of MMT in the nanocomposite increased. Considering a d001 spacing of 18.0 Å for MMT embedded in the UPEO matrix and a thickness of the silicate layer of around 9.5 Å, the thickness of the interlayer gallery was approximately 8.5 Å. This thickness would be expected43 for the intercalation of two monolayers of PEO molecules in planar zigzag conformation, or for one PEO monolayer in helical conformation, see Figures 1c and 1d.


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Figure 1. XRD patterns for (a) MMT clay, UPEO, and UPEO-MMT with different amounts of MMT, and (b) SDCF powder, MMT clay, unloaded UPEO, and 5% SDCFloaded UPEO hybrid and UPEO-MMT nanocomposites, (c) intercalation of two monolayers of PEO molecules (red lines) in planar zigzag conformation, or (d) one PEO monolayer in helical conformation. MMT stand for green platelet. 11 ACS Paragon Plus Environment


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Figure 1b shows a comparison of the XRD patterns of SDCF powder, unloaded and 5% SDCF-loaded UPEO hybrid, and UPEO-MMT nanocomposites with different quantities of MMT. The diffraction pattern of the SDCF-loaded UPEO hybrid showed that addition of the SDCF led to substantial decreases of the intensities of the diffraction peaks at 19º and 23º, reflecting decreased crystallinity of the semi-crystalline PEO. This behavior could be explained by coordination of Na+ cations of the SDCF salt by the ether-type oxygen of PEO, concealing the helical conformation present in PEO crystals and favoring ionic dissolution of the drug salt. This was supported by the absence of diffraction peaks characteristic of crystalline SDCF in the drug-loaded UPEO, evidencing the solubility of this salt in the hybrid matrix.44 Accordingly, for the drugloaded UPEO-MMT, the additive contributions of Na+ cations derived from both the MMT and the SDCF salt led to suppression of the heterogeneous nucleation effect. This feature was evidenced by the absence of the diffraction peaks characteristic of semicrystalline PEO in the diffractograms for the nanocomposite samples loaded with 10 and 20% of MMT. Figure 2a shows the SAXS curves for MMT, the UPEO hybrid, and UPEOMMT containing different amounts of MMT. The SAXS curve for the MMT powder displayed three characteristic features: a (001) diffraction peak at q = 5.3 nm-1, decadal linear behavior in the low q range, and a transition zone in the middle q range. The linearity of the curve in the log-log plot could be described by a power law function: I(q) ∝ q-α, where the exponent α gives information about the shape of the particles and the state of agglomeration.45 An α value of 2 is expected for a biphasic system formed by a diluted set of randomly oriented bidimensional nano-objects, such as the exfoliated MMT tactoids.46 This tendency was observed in the middle q range (1.3 - 2.7 nm-1) of the MMT SAXS curve, while a decay of q-3.8 was found in the low q range (

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