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Encapsulation of Folic Acid in Zeolite Y for Controlled Release via Electric Field Nophawan Paradee and Anuvat Sirivat* Conductive and Electroactive Polymer Research Unit, The Petroleum and Petrochemical College, Chulalongkorn University, Bangkok 10330, Thailand ABSTRACT: Zeolite Y/alginate hydrogel was used as a drug carrier/matrix for an electrophoresis transdermal drug delivery system. Folic acid (FA) as a model drug was loaded into the zeolite Y/alginate hydrogel via an ion-exchange process. The effects of cross-linking ratio, Si/Al ratio, electric field strength, and electrode polarity were investigated with respect to the release mechanism and diffusion coefficient (D) of FA using a modified Franz-diffusion cell. The FA was released from the matrix through the diffusion-controlled mechanism or Fickian diffusion because the diffusion scaling exponent value of FA was close to the value of 0.5. The D increased with an increasing cross-linking ratio and Si/Al ratio due to the meshsize-promoting and the aluminum-content effects. The electric field strength enhanced the D of FA from the anode−FA electroreplusion. In addition, the D of FA could be varied by the electro-attractive or electro-repulsive force between the positively charged FA and the charged electrode depending on whether cathode or anode was placed on the drug matrix. Thus, the fabricated zeolite/hydrogel is of great potential to be used in an electrically controlled transdermal drug delivery system where drug diffusion can be precisely activated and controlled at the time of application. KEYWORDS: zeolite Y/alginate hydrogel, electrically controlled drug release, diffusion coefficient, Si/Al ratio, electric field introduced in the system at the time of application.16 There are many studies reporting the use of zeolites for loading and releasing drugs such as 5-fluorouracil, 10,17 ibuprofen,17 mitoxantrone,18 and sulfonamide antibiotics.19,20 The drug release rate from zeolite depends on framework type, pore diameter, particle size, and chemical content (Si/Al ratio).11 Zeolites appear to be useful for tailoring drug delivery systems that provide different and precise release profiles,17 based on different molecular architectures (pore diameter, particle size, framework type)11 and molecular hydrophilicity (SiO2/Al2O3 ratio).11,21 However, the aggregation of zeolite particles limits the use of zeolites in powder form in a controlled-release application, and therefore, the incorporation of a zeolite powder into a polymer matrix would make zeolites more practical.22 Hydrogel is a three-dimensional network of a hydrophilic polymer through a physical or chemical cross-linking process, resulting in the ability to swell in water without dissolving. Hydrogel is a well-known material for biomedical applications because of its good biocompatibility and biological inertness.23,24 Hydrogel−zeolite nanocomposites are interesting in many fields because zeolite can improve the hydrogel

1. INTRODUCTION A controlled drug delivery system is a designed system enabling the controlled-rate drug release to a specific target in the body. A controlled-release system increases the therapeutic efficiency by optimizing drug concentration for a specific therapeutic administration.1 The transdermal drug delivery system (TDDS) is one of the methods for controlled drug delivery through the skin into the blood system. However, drug diffusion through the skin is restricted by the drug size and the lipophilic nature of skin, which is unsuitable for a hydrophilic or ionic drug.2−4 The electrical current is used to enhance drug delivery via iontophoresis. However, iontophoresis involves the competition in the transport process between buffer ions and drug ions resulting in a decrease in the effective transport of drug ions. This limitation is eliminated by encapsulating the drug ions in the porous materials5 such as metal organic frameworks,6 mesoporous silica,7−9 and zeolites.10−13 Zeolites are microporous materials which are composed of SiO4 and AlO4 tetrahedral in a crystalline three-dimensional framework.10,14,15 The framework allows the accommodation of drug molecules inside, providing a release rate via an ionexchange process.11,14 The drug-loaded zeolite is a promising means to achieve controlled drug release and to enhance drug stability, especially when the drug is adjacent to an electrode component of an iontophoretic device. Encapsulation of charged drugs into the zeolite has been shown as a method to stabilize active drugs until they are released by mobile ions © XXXX American Chemical Society

Received: July 29, 2015 Revised: November 9, 2015 Accepted: November 12, 2015

A

DOI: 10.1021/acs.molpharmaceut.5b00592 Mol. Pharmaceutics XXXX, XXX, XXX−XXX

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Molecular Pharmaceutics

with a linear geometric array connected to a voltage supplier (Keithley, 6517A). The specific electrical conductivities (σ) of zeolite Y and FAY were calculated by following eq 1:

properties such as thermal, mechanical, and swelling− deswelling properties.25,26 In this work, the release and its mechanism of folic acid from a zeolite−hydrogel composite were investigated under applied electrical potential. Zeolite Y was chosen as a drug substrate or host system for blending with an alginate hydrogel. Zeolite Y is a supercage of a three-dimensional structure with 7.4 Å in diameter and a window opening of 13 Å in diameter.14 Alginate was utilized as the biomedical hydrogel matrix because of its biocompatibility, nontoxicity, and transparency.27 The purpose of this work was to investigate the release profile of folic acid from zeolite Y/alginate hydrogel composite films under the effect of Si/Al ratio as the aluminum content in zeolite controls the hydrophobic moieties of zeolite framework.17 In addition, the effects matrix mesh size and electric field were also investigated as other important factors in folic acid release mechanism.

σ=

1 1 I = = ρ Rs × t K×V×t

(1)

where σ is the specific conductivity (S/cm), ρ is the specific resistivity (Ω cm), Rs is the sheet resistivity (Ω), I is the measured current (A), K is the geometric correction factor (3.53 × 10−3), V is the applied voltage (V), and t is the pellet thickness (cm). 2.5. FAY/Alginate Hydrogel (FAY/Alg Hydrogel) Characterization. The correlation between the physical properties of hydrogel and the drug release behavior was studied as a function of the mesh size (ξ). An MES buffer solution (pH 5.5) was used to immerse a hydrogel sample after weighing the sample in air and heptane. After the hydrogel swelling behavior reached equilibrium (5 days), it was weighed in air and heptane again before drying in a vacuum oven at 40 °C for 5 days. Finally, the dry sample was weighed in air and heptane. Then ξ was calculated by eq 229,30

2. EXPERIMENTAL SECTION 2.1. Materials. Various types of zeolite Y in a powder form, namely, CBV400 (cation form H+, Si/Al = 5.1), CBV720 (cation form H+, Si/Al = 30), CBV760 (cation form H+, Si/Al = 60), and CBV780 (cation form H+, Si/Al = 80), were purchased from Zeolyst International (Kansas City, MO). Alginic acid sodium salt (Na-Alg) from brown algae as the hydrogel matrix, folic acid (FA) as the model drug, and 2-(NMorpholino) ethanesulfonic acid (MES) monohydrate for preparing the buffer solution, were purchased from SigmaAldrich. Calcium chloride dehydrate (CaCl2·H2O) used as a cross-linker was purchased from Ajax Finechem. Dimethyl sulfoxide (DMSO) was purchased from Labscan. 2.2. Folic Acid-Loaded Zeolite Y Preparation (FAY). FAY was prepared by mixing zeolite Y (5 g) into a solution that consisted of FA (100 mg) dissolved in 50 mL of water, then it was stirred for 48 h at room temperature. The product was separated from the solution by filtration and washed with deionized water to remove excess FA. 2.3. Preparation of Folic Acid-Loaded Zeolite Y/ Alginate Hydrogel (FAY/Alg Hydrogel). Na-Alg powder (0.4% w/v) was dissolved in deionized water to prepare a NaAlg solution. Under continuous stirring, the FAY powder (50 mg) was added into the solution, and then a CaCl2 solution was added to the solution in order to cross-link (at various crosslinking ratios as moles of cross-linker to moles of uronic acid monomer units of 0.3, 0.5, 0.7, 1.0, and 1.3). Then, the solution (10 mL) was cast onto a mold immediately to obtain a FAY/ Alg film within 48 h with a thickness of ∼0.3 mm.28 2.4. FAY Characterization. The functional groups of FAloaded zeolite Y (FAY) were identified by Fourier-transform infrared (FTIR) spectroscopy (FTIR-Thermo Nicolet, Nexus670) at 64 scans, a resolution of ±4 cm−1, and covering the wavenumber range of 400−4000 cm−1 using KBr as the background material. A thermogravimetric analyzer (TGA; PerkinElmer, TGA7) was used to study the thermal behavior of FAY between 30 and 900 °C under nitrogen atmosphere at a heating rate of 10 °C/min. The crystalline structure of FAY was characterized using a wide-angle X-ray diffractometer (Bruker AXS, D8 Advance) in which a broad-range pattern of the sample was collected at 2θ = 5−55 with a 0.04 step size and 1 s/step.10 The surface and pore volume of zeolite Y and FAY were determined using a surface area analyzer (Sortomatic1990). The specific electrical conductivities (σ) of zeolite Y and FAY were investigated using a custom-made two-point probe

ξ=

⎡ ⎛ 2M̅ ⎞⎤1/2 −1/3 υ2,s ⎢Cn⎜ c ⎟⎥ l ⎢⎣ ⎝ M r ⎠⎥⎦

(2)

where Cn is the Flory characteristic ratio (Cn = 27.33),29 l is the carbon−carbon bond length of the monomer unit (l = 5.15 Å),29 Mr is the monomer molecular weight (Mr = 198 g/mol),29 and M̅ c is the molecular weight between cross-links calculated by the Flory−Rehner equation as shown in Equation 3 3:31,32 1 2 = − M̅ c M̅ n

( )[ln(1 − υ υ̅ V1

2,s)

+ υ2,s + χ1 (υ2,s)2 ]

υ2,r[(υ2,s /υ2,r)1/3 − 0.5(υ2,s /υ2,r)]

(3)

where M̅ n is the number-averaged molecular weight of the polymer before cross-linking (M̅ n = 450 000 g/mol calculated from viscosity measurement using a Ubbelohde capillary viscometer), υ̅ is the specific volume of Alg (υ̅ = 0.60 cm3/g of Alg)32, V1 is the molar volume of the water (V1 = 18 mol/ cm3),32 υ2,r is the volume fraction of the polymer in a relaxed state, υ2,s is the volume fraction of the polymer in a swollen state, and the Flory polymer−solvent interaction parameter (χ1) for Alg is 0.473.32 2.6. Preparation of MES Buffer pH 5.5. A MES buffer solution (0.1 M) was prepared in order to simulate the human skin in the receptor chamber of a modified Franz-diffusion cell.28 2.7. Spectrophotometric Analysis of FA. A UV−visible spectrophotometer (UV-TECAN infinite M200) was used to investigate the maximum absorption wavelength of FA and to create the calibration curve between the absorbance peak value and FA concentration.28 2.8. Actual Drug Content. FAY/Alg hydrogel (sample area as ∼2.51 cm2) was dissolved in DMSO (4 mL), then the solution (0.5 mL) was added into the MES buffer solution (0.8 mL). The amount of FA in the solution was determined using the UV−visible spectroscopy at the wavelengths of 280 nm, which was associated with the actual FA content.28 2.9. FA Release Studies. The release behavior and the diffusion of FA from FAY/Alg hydrogel were studied using the modified Franz-diffusion cell, which has two chambers receptor and donor chambers. The receptor chamber contained B

DOI: 10.1021/acs.molpharmaceut.5b00592 Mol. Pharmaceutics XXXX, XXX, XXX−XXX

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Molecular Pharmaceutics the MES buffer solution (pH 5.5) at 37 ± 2 °C, which was kept in a water circulated bath circulation. The donor chamber was exposed to ambient conditions. On the top of the receptor chamber, the FAY/Alg hydrogel sample (thickness ∼0.30 ± 0.01 mm) with an active area of 2.51 cm2 was placed over a nylon net (mesh size ∼2.25 mm2 and thickness ∼0.2 mm). The MES buffer solution was stirred during the experiment for 48 h. An electric field was applied by placing an aluminum electrode connected to a power supply (KEITHLEY 1100 V Source Meter) on the hydrogel surface at various electrical voltages (0, 0.1, 0.5, 1.0, 2.0, and 3.0 V or electric field strengths of 0, 200, 1000, 2000, 4000, 6000 V/m). At specific times, 0.1 mL of the sample was taken out from the receptor chamber and a fresh buffer solution (0.1 mL) was replaced into the receptor chamber. The amount of FA was examined using the UV− visible spectrophotometer.28 2.10. Release Characteristics of FA from FAY/Alg Hydrogel. The Korsmeyer−Peppas model (Equation 4) was used to determine the release mechanism of FA from FAY/Alg hydrogel by fitting the amount of FA release with this model (a power law in time).33,34 Mt = kHt n M∝

Figure 1. Schematic illustration of FA-loaded zeolite Y and FA-loaded zeolite incubated inside the alginate gel.

of the carboxyl group, 1600 cm−1 for the CO bond stretching vibration of the −CONH2 group.37 The zeolite HY spectrum showed the peaks at 3700−3600 cm−1 for the silanol group and the −OH group, and 1080 and 790 cm−1 for the asymmetric stretching of the SiO4 tetrahedra.38 The FTIR spectra of zeolite FAY was similar to the spectrum of zeolite HY except the peak at 1640 cm−1, which was referred to the hydrogen interaction of the −CO and the −N−H group of FA and zeolite hydroxyl group.39,40 The hydrogen bonding between FA and the zeolite depends on Si/Al ratio which affects the amount of FA loaded into the zeolite as shown in Table 1. The amount of drug loaded in zeolite slightly decreases with increasing Si/Al ratio because the zeolite with a higher Si/Al ratio contains a lower aluminum content which provides a weaker hydrogen bonding with FA resulting in a lower amount of FA that can be loaded into the zeolite,17 “FA−zeolite interaction”. Moreover, the FA loaded into zeolite was investigated using TGA, as shown in Figure 2. The thermogram of FA exhibited the weight loss around 100 °C from the loss of adsorbed water, and the three loss stages for the decomposition of FA at 215, 376, and 647 °C.41 The weight loss of zeolite HY and FAY was at ∼170−200 °C, which could be referred to the decomposition of zeolite structure. The onset decomposition temperature and the char residue of zeolite FAY were higher than that of zeolite HY implying the existing FA in the zeolite structure and the FA−zeolite interaction. The structure of FA consists of the aromatic ring that enhances the thermal stability of zeolite resulting in increasing the onset decomposition temperature of FAY.42 Furthermore, the higher thermal resistance of FAY is a result from the hydrogen interaction between FA and zeolite as shown by FT-IT at 1640 cm−1.43 The XRD pattern of zeolite FAY is similar to the parent zeolite HY (Figure 3), indicating that the zeolite framework is not destroyed by loading FA into zeolite.10,11,21 However, the intensity of zeolite FAY diffraction peak is slightly increased due to the presence of FA crystalline structure in the zeolite pore or on the surface.11 The surface area and the pore volume of zeolite HY before and after FA loading were examined using nitrogen adsorption−desorption isotherms as the isotherms are shown in Figure 4 and of which complete results are tabulated in Table 1. The surface area and the pore volumes of the zeolite FAY decrease after FA loading which confirm that the FA is physically loaded into the pore of zeolite.10,21 The zeolite HY and zeolite FAY with different Si/Al ratios exhibit nearly the same surface areas and pore volumes.44 In addition, Table 1 also shows the electrical conductivity of the zeolite HY and zeolite FAY. The electrical conductivity decreases with increasing Si/Al ratio. The zeolite with a higher Si/Al ratio possesses a lower number of mobile cations present and thus a

(4)

where Mt/Mα is the fraction of the drug released at time t, k is the kinetic constant (unit of T−n), and n is the diffusion scaling exponent for drug release, which is used to characterize different release mechanisms. Moreover, Higuchi’s equation (eq 5) indicates that the fraction of FA release from FAY/Alg hydrogel is proportional to the square root of time.34,35 Mt = kHt 1/2 M∝

(5)

where Mt and Mα are the masses of drug released at the times equal to t and infinite time, respectively, and kH is the Higuchi constant (unit of T−1/2). The Higuchi equation corresponds to a particular case of eq 5 when n is precisely equal to 0.5. If the Higuchi drug release (i.e., Fickian diffusion) is obeyed, then a plot of Mt/Mα versus t1/2 will be a straight line with a slope of kH. The slope of plot between amount of FA and the square root of time according to the Higuchi equation (eq 6) was used to calculate the diffusion coefficient of the FA from the FAY/Alg hydrogels:36 ⎛ Dt ⎞1/2 M t = 2CoA⎜ ⎟ ⎝π ⎠

(6)

where Mt is the amount of drug released (g), A is the diffusion area (∼2.51 cm2), Co is the initial drug concentration in the hydrogel (g/cm3), and D is the diffusion coefficient of the drug (cm2/s).

3. RESULTS AND DISCUSSION 3.1. Characterization of Zeolite HY and FAY. Figure 1 shows the schematic of FA loaded into zeolite Y by ionexchange process with hydrogen cation where the zeolite FAY was embedded into the alginate hydrogel to produce the zeolite FAY/alginate (FAY/Alg) hydrogel.11,14 The interaction between FA and zeolite was confirmed by FTIR spectra. The peaks of FA appeared between 3000 and 3600 cm−1 for the −OH stretching and the NH− stretching vibrations, 1700 cm−1 for the CO bond stretching vibration C

DOI: 10.1021/acs.molpharmaceut.5b00592 Mol. Pharmaceutics XXXX, XXX, XXX−XXX

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Molecular Pharmaceutics Table 1. Surface Area, Pore Size, and Electrical Conductivity of Zeolite (HY) and FA-Loaded Zeolite (FAY) surface area (m2/g) Si/Al ratio 5.1 30 60 80

HY 620 725 695 754

± ± ± ±

FAY 13 12 26 22

511 645 615 484

± ± ± ±

15 20 22 25

pore volume (cm3/g)

electrical conductivity (S/cm)

HY

HY

0.394 0.544 0.562 0.547

± ± ± ±

FAY 0.01 0.01 0.03 0.03

0.300 0.500 0.524 0.400

± ± ± ±

0.01 0.02 0.03 0.03

7.82 4.17 2.56 1.58

× × × ×

10−4 10−4 10−4 10−4

± ± ± ±

amount of FA loaded in 1 mg of zeolite (mg)

FAY 0.00011 0.00052 0.00012 0.00009

8.57 8.79 8.96 9.03

× × × ×

10−5 10−5 10−5 10−5

± ± ± ±

0.00007 0.00010 0.00002 0.00004

0.78 0.76 0.75 0.72

± ± ± ±

0.01 0.02 0.03 0.04

Figure 5. Mesh size of zeolite HY/Alg hydrogels at various crosslinking ratios under electrical potential.

Figure 2. Thermogravimetric thermograms of FA, HY80, and FAY80.

Alg strands between cross-links and a lower swelling behavior.28 Moreover, the electrical potential (1 V) with the anode electrode in contact with the hydrogel also provides a decrease in ξ. Figure 6 shows porous structures and pore sizes of zeolite Figure 3. X-ray diffraction patterns of HY80 and FAY80.

Figure 4. Nitrogen adsorption−desorption isotherms for HY80 and FA-loaded HY80 (FAY80).

Figure 6. Mesh size of zeolite Y/alginate hydrogel at: (a) E = 0 V and (b) E = 1 V (anode electrode placed on hydrogel).

longer distance between the accessible hopping sites between one another.45 The electrical conductivity of zeolite FAY is lower than that of zeolite HY approximately 1 order of magnitude because the structure of FA retards the electron mobility leading to the reduced electrical conductivity. Moreover, the electrical conductivity of FAY slightly decreases with increasing aluminum content (lower Si/Al ratio). The large amount of aluminum content provides a higher FA− zeolite interaction,10 resulting in a higher amount of FA that can be loaded into the zeolite structure, as shown in Table 1 which reduces electrical conductivity. 3.2. Characterization of Zeolite HY/Alginate (HY/Alg) Hydrogel. The ξ values of zeolite HY/Alg hydrogels corresponding to the porous structure of hydrogels at various cross-linking ratios (defined as cross-linker: monomer mole ratios of 0.3, 0.5, 0.7, 1.0, and 1.3), Si/Al ratios (5.1, 30, 60, and 80), and electrical potentials with an anode electrode in contact (0 and 1 V) are shown in Figure 5. The swelling behavior of the zeolite HY/Alg hydrogel depends on the alginate matrix and zeolite structure.46 The presence of zeolite in the hydrogel causes a decrease in ξ of the hydrogel as the zeolite presence reduces the free volume of Alg hydrogel resulting in a lower swelling ability of the hydrogel.47 However, a lower Si/Al ratio causes an increase in ξ. A lower Si/Al ratio consists of higher aluminum content which provides more hydrophilicity to the zeolite, resulting in a higher swelling behavior.48 The ξ decreases with increasing cross-linking ratio due to shorter

HY/Alg hydrogels with and without applying electrical potential. The pore size of the HY/Alg hydrogel under applied electrical potential is smaller than that without electrical potential. The anode electrode in contact with the hydrogel creates the electro-attractive force between the negatively charged carboxylate groups of the Alg structure and the positively charged electrode called the “electro-induced Alg shrinkage”,28 resulting in a smaller hydrogel mesh size. 3.3. Actual Amount of FA Content in Zeolite FAY/Alg Hydrogel. The actual amounts of FA in the zeolite FAY/Alg hydrogels were 3.86 ± 0.12, 3.88 ± 0.10, 3.87 ± 0.12, and 3.89 ± 0.10 mg for the zeolite FAY5.1/Alg hydrogel (sample area of 2.51 cm2), zeolite FAY30/Alg hydrogel, zeolite FAY60/Alg hydrogel, zeolite FAY80/Alg hydrogel, respectively. 3.4. Release Kinetic of FA from FAY/Alg Hydrogel. The amount of FA released from the zeolite FAY/Alg hydrogel increases steadily up to 4 h, after that it reaches equilibrium as shown in Figure 7. The release kinetic of FA from the FAY/Alg hydrogels, namely, the diffusion scaling exponent (n) as determined by the slope of log−log plot of Mt/Mα and time following Equation 4, is tabulated in Table 2 for electrical potentials of 0 and 1 V. The n values are between 0.31 to 0.83, which are close to 0.5, and thus, the release of FA appears to resemble the diffusion controlled mechanism (Fickian diffusion).28,34 In the previous work,14,49 Ibuprofen as a model drug was studied for its release mechanism from dealiminated faujasites, which was shown to be the Fickian D

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Figure 7. Amounts of folic acid released from FAY/Alg_0.7 hydrogels of various Si/Al ratios at E = 1 V.

Figure 8. Amounts of folic acid released from FAY80/Alg_0.7 hydrogels at various electrical potentials.

diffusion process. Furthermore, they confirmed that the rate of delivery was controlled by the diffusion through the pores of the zeolite.17 In the present work, FA diffuses through the zeolite FA/Alg hydrogel by two processes: the diffusion of FA within the zeolite via ion-exchange and the FA transport through hydrogel.14,49 The ion-exchange process within zeolite occurs between FA+ in the zeolite structure and protons from the MES buffer solution to neutralize charge of the zeolite framework can be represented as + + FA+ Y (z) + H(s) ↔ HY(z) + FA (s)

Figure 9. Diffusion coefficients of folic acid from FAY80/Alg_0.7 of various Si/Al ratios and electrical potentials.

which facilitates the diffusion of FA from the matrix28,52 In addition, a higher electrical conductivity of the zeolite and the Si/Al ratio combine to promote the D. The electrical conductivity of zeolite FAY increases with increasing Si/Al ratio (Table 1), which produces a higher mobility of FA to diffuse from the matrix under applied electric field. Furthermore, the D of FA also depends on Si/Al ratio due to the aluminum-content effect. The higher Si/Al ratio provides the higher D of FA because of lesser FA−zeolite interaction resulting in faster drug release.10,50 3.7. Effect of Cross-Linking Ratio. The amount of FA release increased with decreasing cross-linking ratio. The lower cross-linking ratio has a larger pathway or a hydrogel mesh size enhancing the FA diffusion, called the “mesh-size-promoting effect”.28 3.8. Effect of Electrode Polarity. The electrode polarity also affects the amount of FA released as shown in Figure 10.

(7)

where the subscripts z and s denote the zeolite and the solution phase, respectively.14 3.5. Effect of Si/Al Ratio of Zeolite HY. Figure 7 shows a decrease in the amount of FA releases with decreasing Si/Al ratio. The amount of drug release depends on the aluminum content of zeolite as a higher aluminum content (lower Si/Al ratio) provides a greater FA-zeolite interaction, resulting in a smaller amount of drug that can be be released,10,50 called the “aluminum-content effect”. A similar behavior was observed in case of the zeolite−fluorouracil10 and the zeolite−ibuprofen17 interactions with different Si/Al ratios. They reported that the higher aluminum content within the zeolites reduced the release amounts of fluorouracil and ibuprofen.10,17 3.6. Effect of Electric Field. The amount of FA increases with increasing electrical potential when placing the anode on the zeolite FAY/Alg hydrogel in the donor part as shown in Figure 8. The electric field provides the electro-repulsive force between positively charged electrode and positively charged FA to enhance the FA diffusion from zeolite FAY/Alg hydrogel called the “anode−FA electrorepulsion”.51,52 Moreover, the diffusion coefficient (D) of FA from zeolite FAY/Alg hydrogel was calculated from the slope of the Higuchi’s equation following eq 6. Figure 9 shows that D of FA increases with increasing electrical potential (E = 0−3 V) with the anode as a positively charged electrode in the donor part. An increase in electric field provides a greater anode−FA electrorepulsion

Figure 10. Amounts of folic acid released from FAY80/Alg_0.7 hydrogels at electrical potential of 0 and 1 V with hydrogel samples attached to anode or cathode.

Table 2. Release Kinetic Parameters and the Linear Regression Values Obtained from Fitting the Drug Release Experimental Data release kinetics FAY5.1

FAY30

E=0V

a

CRa of Ca-Alg 0.3 0.5 0.7 1.0 1.3

n

kH (h−1/2)

0.47 0.51 0.50 0.53 0.72

0.48 0.55 0.60 1.21 0.89

E=1V n

kH (h−1/2)

0.52 0.59 0.51 0.56 0.54

0.97 0.90 0.34 1.21 0.53

FAY60

E=0V n

kH (h−1/2)

0.54 0.57 0.59 0.56 0.83

0.68 0.60 0.67 1.24 0.57

E=1V n

kH (h−1/2)

0.52 0.56 0.52 0.44 0.51

0.57 0.51 0.45 0.99 0.43

FAY80

E=0V n

kH (h−1/2)

0.43 0.56 0.54 0.31 0.53

0.52 0.82 0.38 0.40 0.70

E=1V n

kH (h−1/2)

0.56 0.58 0.54 0.59 0.56

0.41 0.45 0.53 0.47 0.68

E=0V

E=1V

n

kH (h−1/2)

n

kH (h−1/2)

0.44 0.51 0.54 0.41 0.59

0.51 0.55 0.64 0.94 0.52

0.56 0.52 0.44 0.54 0.55

0.57 0.55 0.63 0.57 0.55

CR is the cross-linking ratio. E

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resins. The nicotine released from the hydrogel was higher than that of the resin-containing hydrogel because the diffusion of nicotine from hydrogel had one process without nicotine−resin interaction. In the previous work, Zhang et al.14studied the release of paraquat from zeolite Y. The paraquat was loaded into zeolite cages and released by ion-exchange with sodium ions of NaCl solutions as a concentration of 1.0, 0.1, and 0.01 M. The release of paraquat from zeolite occurred via an ion-exchange process as the charge neutrality of zeolite framework needed to be maintained. There were two processes in the ion-exchange in zeolite: the diffusion within the zeolite and the diffusional transport through the liquid film surrounding the particle. The D of paraquat varied from 2 × 10−8 cm2/s to 1.1 × 10−7 cm2/s depending on NaCl concentration and ionic strength. The D of paraquat was quite close to that of FA from the Alg hydrogel (D of FA varies from 6.53 × 10−8 cm2/s to 8.53 × 10−8 cm2/s). However, the D of FA under applied electric field (D of FA varies from 8.06 × 10−7 cm2/s to 2.34 × 10−7 cm2/s) is higher than that of paraquat due to the anode−FA electrorepulsion. Therefore, the zeolite Y/hydrogel is shown to be suitable for a slow or prolonged drug release. Moreover, zeolite can be active into controlling drug release under electric field. The D of FA from the zeolite/hydrogel occurs via the ion-exchange process without applied electric field and the iontophoresis of charged drugs under applied electric field based on the effect of drug− zeolite interactions, compositions of matrix, zeolite characteristics, and experiment setup.

The amount of FA released when the anode electrode (positively charged electrode) was placed on the hydrogel was higher than that with no applied electric field and when cathode electrode (negatively charged electrode) was placed on the hydrogel. The amount of FA released is enhanced under anode electrode placed on hydrogel due to the anode−FA electrorepulsion.51,52 On the other hand, the amount of FA released with the cathode in contact with the hydrogel is obstructed because the cathode generates an electro-attractive force between the negatively charged electrode and the positively charged FA resulting in the reduced FA diffusion.28,52 Figure 11 shows the log−log plot of diffusion coefficient as a function of the ratio of drug size over mesh size of zeolite/Alg

Figure 11. Diffusion coefficient of folic acid from FAY/Alg hydrogel at electrical potentials of 0 and 1 V.

hydrogel. The D increases with decreasing ad/ξ because of the mesh-size-promoting effect. Moreover, the electric field (E = 1 V under placed anode in the donor part) helps to increase the D of FA from zeolite FAY/Alg hydrogel by approximately 2 orders of magnitude due to the anode−FA electrorepulsion. Moreover, the zeolite which consists of a lesser amount of alminium content (higher Si/Al ratio) promotes an increase in the D of FA because of the aluminum-content effect. Nevertheless, a higher FA diffusion was obtained when FA directly diffused from the pure alginate hydrogel (D of FA from alginate hydrogel at E = 1 V was 1 × 10−5 cm2/s) (Paradee et al., 2012) because the interaction between FA and alginate network was an ionic interaction which was relatively weak in comparison with the zeolite which holds FA by adsorption.53 Moreover, there are two processes of the FA diffusion from zeolite FAY/Alg hydrogel: the FA diffusion within zeolite and the transport through hydrogel14,49 as shown in Figure 12. The

4. CONCLUSIONS Zeolite HY/alginate hydrogel was used as a drug carrier/matrix for the controlled release of folic acid (FA). The FA was encapsulated and released from zeolite/alginate matrix by the ion-exchange process. With the diffusion scaling exponent close to 0.5, the release mechanism of FA was the diffusioncontrolled mechanism or the Fickian diffusion. The D of FA depended on the cross-linking ratio and Si/Al ratio because of the mesh size-promoting effect and the aluminum-content effect. The electric field applied under placed anode on the matrix effectively enhanced the D of FA. The D with the anode in contact with the matrix was greater than that without electric field because the electric field induced the anode−FA electrorepulsion. Moreover, the D of FA also depended on electrode polarity; with the anode in contact with the hydrogel, the D of FA was higher than those without electric field and with the cathode in contact with the hydrogel because of the anode−FA electrorepulsion. Thus, the fabricated zeolite/ hydrogel is a potential drug matrix suitable for the slow or prolonged drug release in an electrical stimuli transdermal drug delivery system, and in addition preventing drug diffusion before the application time.

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Figure 12. Proposed mechanism of FA released from zeolite FAY/ alginate hydrogel.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel.: 662 218 4131. Fax: 662 611 7221.

FA diffuses from the zeolite toward the hydrogel via the ionexchange and the anode−FA electrorepulsion. In the alginate hydrogel, the FA also reacts with the alginate matrix via the ionic interaction between positively charged FA and negatively charged carboxylate group on the alginate structure.28 These are the reasons to explain the lower D and slower release of FA from the zeolite FAY/Alg hydrogel. Conaghey et al.49 studied the release of nicotine from a hydrogel containing ion exchange

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to acknowledge the financial support provided by the Thailand Research Fund (TRF, TRF-RGJ F

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Molecular Pharmaceutics

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PHD/0285/2551); the Royal Thai Government; the Conductive and Electroactive Polymer Research Unit; Petroleum and Petrochemical College, Chulalongkorn University; the 90th Anniversary of Chulalong University Fund (Ratchadaphiseksomphot Endownment Fund); and the Ratchadaphiseksomphot Endownment Fund of Chulalongkorn University.

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DOI: 10.1021/acs.molpharmaceut.5b00592 Mol. Pharmaceutics XXXX, XXX, XXX−XXX