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Electrospinning coating of nanoporous anodic alumina for controlling the drug release: Drug release study and modeling
Journal of Drug Delivery Science and Technology 54 (2019) 101247
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Electrospinning coating of nanoporous anodic alumina for controlling the drug release: Drug release study and modeling
T
Ruhollah Fazli-Abukheylia, Mahmood Reza Rahimia,∗, Mehrorang Ghaedib a b
Department of Chemical Engineering, Faculty of Engineering, Yasouj University, Yasouj, Iran Department of Chemistry, Faculty of Science, Yasouj University, Yasouj, Iran
A R T I C LE I N FO
A B S T R A C T
Keywords: Electrospinning coating Nanoporous anodic alumina Controlled release Mathematical modeling
Local drug delivery system is a promising alternative to conventional methods. Recently, new implants with ordered nanoporous structure have been recommended to improve the local drug delivery performance, one of the favorites is the nanoporous anodic alumina (NAA). For controlling the drug release from NAA, we introduced a novel method by covering the NAA top surface with electrospinning nanofibers including PVDF/PEG. The film thickness and hydrophobicity properties of nanofibers are exploited to control drug release from NAA. The NAA implants were loaded with indole-3-acetic acid (IAA) as a drug model. Comparison of release characteristics of NAA samples with and without electrospinning coating revealed notable alteration in the IAA release profile. Electrospinning coating method can significantly decrease the burst release and prolong the duration of release from nanoporous structures. The behavior of IAA release from electrospinning coated NAA was described by a two-stage mechanism. The release in the first stage was modeled with the zero-order kinetics model, while in the second stage the release was modeled with the first-order kinetics model. The experimental data were fitted to the new model and an excellent agreement between the experimental data and this model was achieved.
1. Introduction Delivery of effective therapeutic agents to diseased site is important for the treatment of many diseases. Unfortunately, conventional drug delivery approaches have difficulty in supplying maximum efficacy using the lowest drug usage for rapid and effective treatment of patients. The origin of this problem emerges from the hydrophobic nature of most drugs which limit their solubility in the blood [1]. Hence, their easy degradation by metabolism prevents their arrival to the designated targeted sites. Also, conventional drug delivery systems possess other drawbacks such as lack of selectivity, side effects, toxicity and undesired release profiles [2–4] which must be compensated by the development of new protocols or materials. In this regard, local drug delivery system (local implantation) has been considered a promising alternative to conventional methods. The advantage of this method is that it offers higher localized drug concentration which reduces the time required for disease treatment [5]. Local drug delivery systems, at first, were made of biodegradable implants which suffer from burst and uncontrolled drug release and failure to attain prolonged and continuous release. These problems are mostly because of the amorphous nature and the irregular structure of the biomaterials [6]. Accordingly, new implants with ordered
∗
nanoporous and nanotubular structure produced by electrochemical anodization including nanoporous anodic alumina (NAA), titania nanotubes (TNT) and porous silicon (pSi) were recommended to improve the local drug delivery performance [6–9]. NAA, which is emerging as a most outstanding drug releasing implants, consists of ordered and parallel cylindrical nanopores arranged in close-packed hexagonal structures. The particular interest in NAA arises from its unique properties such as high porosity and specific surface area, controllable pore size, resistance to erosion, biodegradability and low fabrication costs [10,11]. The advantage of NAA is that its structural characteristics like pore diameter, pore length and interpore distance which influence its release performance can be easily adjusted by controlling the anodization conditions such as current density, applied potential, temperature, process time and electrolyte type and concentration [12]. The method of drug delivery can significantly affect its performance. In essence, drugs have an optimal concentration range that the maximum effect is achieved in it and concentrations above or below this range can be toxic or have no therapeutic effect. Therefore, to achieve the best performance, controlling the drug release from drug carriers is very important. For NAA drug delivery implants, structural modification as a simple strategy was undertaken [6,13,14] to control
Corresponding author. E-mail address: [email protected] (M.R. Rahimi).
https://doi.org/10.1016/j.jddst.2019.101247 Received 3 April 2019; Received in revised form 27 August 2019; Accepted 28 August 2019 Available online 29 August 2019 1773-2247/ © 2019 Published by Elsevier B.V.
Journal of Drug Delivery Science and Technology 54 (2019) 101247
R. Fazli-Abukheyli, et al.
In the first step, the Al disks were anodized for 30 min in 0.3 M oxalic acid (H2C2O4) aqueous solution at 20 °C and a constant voltage of 100 V. Then, to eliminate the formed oxide layer, the disks were immersed in the aqueous solution of phosphoric acid and chromic acid (CrO3:H3PO4 = 1.8:6) at 60 °C for 60 min. The second anodizing step was performed for 3 h in the same conditions as in the preceding step.
and extend the drug release, but this strategy has some limitations due to the reciprocity between loading capacity and release performance [6]. Another strategy to control drug release from NAA is to modify the surface charge of pores to hydrophobic or hydrophilic for changing the interaction between the drug molecules and pore surface [12]. Although the usefulness of this approach in altering the drug release performance was illustrated in some reports [6,15], there are still limitations to achieving a prolonged drug release. To address this issue, covering the NAA top surface with biopolymer was employed as an alternative strategy. Simovic et al. [16] deposited a thin layer of plasma polymer on the NAA top surface to reduce the pore opening after drug loading. Though an extended drug release was achieved by the plasma deposition method, this method has been limited due to the equipment costs and technical complexity [12]. Gulati et al. [17] used dip coating for depositing a thin layer of degradable biopolymer to enclose the pore openings. Here, the drug release is altered by the degradability and chemical properties of the polymer and also the thickness of the film. Despite the simplicity and low cost of the dip coating method, there is a possibility of drug incorporation into biopolymer layer during the process which affects the drug release kinetics. In this study, we employed a novel method for controlling the drug release from the NAA implant by covering the NAA top surface with electrospun polymeric nanofibers. Nanofibers obtained using electrospinning technique have been attained great interest in recent years in the medical field, especially in the drug delivery applications [18–21]. The electrospinning coating process, contrary to the plasma coating process, is a simpler method and does not require expensive equipment. Also, unlike the dip-coating method, it is a dry process and there is no possibility of drug incorporation into the nanofiber mat during the process. Hence the drug release kinetics cannot be affected. In order to evaluate the ability and performance of the electrospinning coating method for controlling the drug release from NAA, an in-vitro experiment was conducted using indole-3-acetic acid (IAA) as a water-insoluble drug model. IAA is a plant growth regulator of the auxin class and has potentials as a cosmetic or dermatological ingredient [22]. It is also used in the oxidation therapy of cancer, as well as the treatment of Acne Vulgaris [23]. Herein, we described the IAA release characteristics from electrospun coated NAA and evaluated the effect of film thickness and hydrophobicity property of nanofibers on IAA release rate. Then, to estimate the amount of IAA release from these systems, the release profiles were analyzed in detail and a two-stage process was proposed for IAA release from electrospun coated NAA.
2.3. IAA loading into NAA The NAA sheets with 20 mm2 area were washed using deionized water and then placed on a hot plate at 80° for 12 h. Subsequently, the dried NAA sheets were immersed in the ethanolic solution of IAA (50 mg/ml) and sonicated for 2 h. The NAA sheets were remained in the solution for 24 h to allow sufficient time for the penetration of IAA into the NAA pores. The NAA sheets loaded with IAA were dried in air and then wiped using a soft tissue to clean the remaining IAA on the surfaces. To determine the IAA loading in NAA pores, the loaded samples were immersed in 5 ml ethanol and sonicated for 6 h, and subsequently, the drug content was measured by spectrophotometry. The experiments were performed in triplicate. 2.4. Electrospun coating of NAA Before the electrospinning process, different PVDF solutions containing 0, 1 and 2 wt % PEG were prepared. PVDF was dissolved at a concentration of 15 wt % in DMF and stirred overnight at a temperature of 60 °C. The PEG was mixed with the PVDF solution and stirred at 60 °C until the mixture became clear. Using these solutions, the electrospinning was performed in a single home-made apparatus at room temperature (22 ± 2 °C). The electrospinning parameters with a slight modification were adapted from previously published literature [25]. Before electrospinning, the NAA disks were fixed from backside to the collector with sellotape. Each of the prepared solutions was poured into a plastic syringe with the stainless steel needle of 0.7 mm diameter. Then, the needle was fixed at 15 cm in a horizontal direction with respect to the collector and the flow rate was set to 0.4 ml h−1. Subsequently, a constant voltage of 17 kV was applied and electrospinning was performed for 30 and 60 min to obtain nanofiber mat with different thickness on the NAA surface. After the electrospinning process was completed, the electrospun film was carefully cut from the periphery of the NAA disk by a sharp cutter. Afterward, the NAA disk was removed from the collector and kept in the oven overnight at 40 °C for DMF removal from nanofibers.
2. Materials and methods 2.5. IAA release 2.1. Chemicals Generally, the drug release behavior of controlled release systems is studied in vitro under dynamic conditions (with stirring or shaking). But, in this work, the release experiments were performed under static conditions (without stirring or shaking) to prevent damage to the electrospun film and to avoid its detachment from the surface of NAA sheets. The drug release performance of the nanoporous structures is commonly investigated under static conditions [26–28], since it is easily carried out and sufficient enough to obtain drug release profiles [28]. In-vitro release of IAA from electrospun coated NAA was investigated by putting the implants in capped vials containing 3 ml of release media at room temperature (22 ± 2 °C). In order to increase the aqueous solubility of IAA and to achieve a sink condition, the water/ethanol solution with the volume ratio of 9:1 was used as a release medium. The solubility of IAA in this solution was measured 5.3 ± 0.6 mg/ml by experiments. At specified time intervals, the whole volume of the solution was poured into a 3-ml cuvette and the absorbance of IAA was determined by UV–vis spectrophotometer (DR6000, Hach, USA) at 280 nm, while at each stage, IAA content was estimated based on the calibration curve. Afterward, 2.5 ml of the
All chemicals including phosphoric acid (85%), perchloric acid (70%), hydrochloric acid (37%), ethanol (95.5%), oxalic acid, acetone, chromium (VI) oxide, sodium hydroxide, copper (II) chloride, indole-3acetic acid, N,N-dimethylformamide (DMF) (99.8%), and Polyethylene glycol (PEG, Mw = 60000) were provided from Merck (Germany). Polyvinylidene fluoride (PVDF, Kynar 761) was procured from Arkema (USA) and aluminum foil (99.9% purity, 0.3 mm thick) was bought from Kingcheng (China). 2.2. Fabrication of NAA Aluminum foil (99.9%) with a thickness of 0.3 mm was cut into circular disks with a diameter of 10 mm. Then, the Al disks were degreased by ultrasonic rinsing in acetone and water for 3 min and subsequently was etched in 3 M sodium hydroxide (NaOH) solution at 30 °C for 10 min. Afterward, the Al disks electropolished in a perchloric acid and ethanol mixture (HClO4:C2H5OH = 1:4 v/v) for 3 min at 0 °C and a constant voltage of 20 V [24]. Anodizing process was performed by the two-step hard method using a home-made electrochemical cell. 2
Journal of Drug Delivery Science and Technology 54 (2019) 101247
R. Fazli-Abukheyli, et al.
3. Results and discussion
60 min electrospun coating, from left to right, respectively. Typical SEM image from the top surface of a sample is shown in Fig. 2(b). This image confirms the nanofiber formation with a few beads. Beads formation is the consequence of the surface tension forces overcoming the viscoelastic forces [29] and commonly reported when the concentration or viscosity of the polymer solution is low. Fig. 2(c and d) show the SEM images of the top surface and cross-section of electrospun coated NAA. The high-resolution image in Fig. 2(d) demonstrates the adherence of nanofibers onto the NAA top surface. SEM images of PVDF nanofibers prepared using different content of PEG were shown in Fig. 2(e–g). As can be seen, the electrospun nanofibers made of pure PVDF had a non-uniform and irregular morphology. With increasing PEG content, the non-uniformity and irregularity of fibers were reduced. The average diameter of electrospun nanofibers measured from SEM images was obtained 142 ± 58, 154 ± 47 and 159 ± 41 nm for samples with 0, 1 and 2% PEG content, respectively. This enhancement of nanofiber diameter is related to the increase in concentration and viscosity of the polymer solution by increasing the PEG content. Unfortunately, evaluation of the nanofiber mat thickness is very difficult with the SEM images, but as a rough estimation, the values of 60 and 100 μm were estimated for the thickness of thin and thick nanofiber mats, respectively. The contact angle tests were performed in order to determine the hydrophilicity of the electrospun nanofiber films (Fig. 3). The contact angles of nanofiber mats prepared from PVDF solution containing 0%, 1% and 2% PEG were around 131 ± 2, 107 ± 2 and 101 ± 3, respectively. Accordingly, all samples exhibit a high hydrophobicity; however, the value for the sample of pure PVDF differs from two other significantly.
3.1. Morphology and structure of NAA
3.3. IAA loading capacity
The morphology and structure of NAA before IAA loading are shown in Fig. 1. The bottoms and the top surface of NAA are presented in Fig. 1(a) and (b), respectively. Fig. 1(b) demonstrates a near uniformity in the pore size and distribution. Fig. 1(c) indicates the cross-section of the NAA after second anodization and demonstrates straight and parallel growth of the pores. The pore diameter and NAA thickness can be controlled mainly by anodization potential and anodization time, respectively, which were 100 V and 3 h in our experiment. Image analysis results in approximate pore diameter of 190 ± 25 nm, pore length of 50 ± 1 μm and interpore distance of 270 ± 36 nm. According to this measurement, the porosity and the pore density of NAA were estimated at 0.45 and 18/μm2, respectively.
The amount of loaded IAA in NAA was determined from experiment to be 0.076 ± 0.008 mg. The amount of drug loading in NAA is directly depended on the pore diameter and pore length. The larger pore diameter and the longer pore provide more volume for drug loading and consequently cause a higher amount of drug stored inside the NAA pores. However, the drug loading capacity of NAA is often low (< 25%) due to boundary limits from geometrical confinement of nanopores and possible air entrapment occupying the bottom of the pores [6]. In this work, the loading capacity of NAA was estimated to be about 12%.
solution was pipetted and returned into the vial and then 0.5 ml of fresh solution was added to the vial to maintain the sink conditions. All release experiments were carried out in triplicate and the data reported as the mean value. 2.6. Structural characterizations The morphology of the prepared NAA implants and the microstructure of electrospun nanofiber were analyzed using a field emission scanning electron microscope (FE-SEM: MIRA3, TESCAN, Czech Republic). All samples were sputtered with gold before SEM imaging. An accelerating voltage of 15 kV, working distance of 11 mm and the magnification rates of 1, 25, 50 and 200 kx were used for the structural analysis of samples. The pore diameter, pore length and interpore distance of NAA and also the diameter of nanofibers were determined by analyzing the SEM images with ImageJ v1.51 software. To obtain an average value, 20 measurements for each parameter were carried out from a single SEM image. 2.7. Contact angle tests The hydrophilicity of nanofiber mats was assessed by measuring the contact angle. The tests were performed using a high resolution camera (Nikon, D5200, Japan) and a software (ImageJ v1.51) with a droplet of release medium at ambient temperature. The contact angle was measured two times on three separate locations of each sample and reported as an average.
3.4. In-vitro release of the model drug The idea of the presented method is covering the NAA pore with a thin nanofiber film, and employing the wettability of nanofibers and also the film thickness for controlling the drug release from NAA. Different polymers such as PVA, PVP, PCL, PVDF, PEO, PLGA, etc. have
3.2. Characterization of electrospun film Fig. 2 (a) is a digital image of NAA disks before and after 30 and
Fig. 1. SEM images of NAA disks. (a) The bottoms surface of the specimen; (b) the top surface of the specimen; (c) the cross-sectional of the specimen after second anodization. 3
Journal of Drug Delivery Science and Technology 54 (2019) 101247
R. Fazli-Abukheyli, et al.
Fig. 2. (a) From left to right: NAA disks before electrospun coating and after 30 and 60 min electrospun coating. (b,c) SEM images from the top surface of a sample. SEM images of electrospun nanofibers prepared from PVDF solution containing (d) 0%, (e) 1% and (g) 2% PEG.
The profiles of IAA release from NAA for samples with and without electrospinning coating on top are presented in Fig. 4. It must be noted that the results for electrospun coated NAAs with 0% PEG content had no release. As seen in Fig. 4, for uncoated NAA implant, 90% of IAA was released during the initial 5 h and in the following, a slow release takes placed till 24 h. The burst release may arise from the accumulation of drug on the top of pores and also the wide pores (190 nm) which causes a fast drug release. For NAA samples with electrospinning coating on top, a biphasic release can be seen again, but in comparison with the uncoated sample, the burst release was significantly reduced and the overall release considerably prolonged. As seen, both electrospun film thickness and PEG content affect the release rate. For example, in the sample of PVDF/PEG1%-thin, the burst release for 0–5 h decreased to 43% and the total release time lasted to 120 h. Such a trend is also observed in the case of PVDF/PEG2%-thin, but only the burst release was decreased to 60%. The drug release characteristics of NAA samples coated with thick electrospun films are like the samples with thin electrospun films, except that the decrease in the burst release for the thick samples (40 and 45% for samples with 1 and 2% PEG content, respectively) is more than that for thin samples. The molecular transport of drug through electrospun nanofibers films depends on the film thickness and its diffusivity. In these
Fig. 3. Contact angles of electrospun nanofiber mats prepared from PVDF solution containing (a) 0%, (b) 1% and (c) 2% PEG.
been electrospuned to fabricate nanofiber mat for drug delivery applications [30]. Since drug release from electrospun hydrophilic polymer mats is usually fast, hydrophobic polymer mats are preferred. In this paper, PVDF, a synthetic polymer, is used as a base polymer for electrospinning coating due to its excellent biocompatibility. PVDF nanofibers are extensively used in filtration application because of their good mechanical and thermal properties, as well as, their intrinsically hydrophobic nature which leads to a water contact angle of 130 ± 1° [31]. The application of this polymer in the medical area has been studied in the literatures [32–35] but its practical application in biomedicine is limited due to the inherent hydrophobicity of PVDF. This limitation can be solved by blending PVDF with PEG which is a synthetic, biocompatible and uncharged water-soluble polymer. PEG extensively used as a modifier to enhance the hydrophilicity property of various industrial membranes [35]. 4
Journal of Drug Delivery Science and Technology 54 (2019) 101247
R. Fazli-Abukheyli, et al.
Fig. 4. IAA release profile from uncoated and coated NAA implants: (a) overall and (b) burst release.
experiments, the IAA release from NAA with thin electrospun film showed faster release than thick electrospun films. It was expected because by increasing in the electrospun film thickness, the diffusion path for drug molecules is increased and as a result, the driving force is decreased. The diffusivity of drug through nanofiber mats is related to the several factors including the nature of polymer (charge, degradability, and hydrophilicity/hydrophobicity), the polymer concentration in the electrospinning solution, the polymer molecular weight, nanofiber morphology, drug-polymer interactions and medium used for the preparation of polymer solution. In the case of hydrophobic nanofiber mats, the air captured between the nanofibers is the main factor affecting the permeability. In these materials, the entrapped air decreases the area of contact of the water at the solid nanofiber surface and consequently causes an increase in the hydrophobicity [36]. The displacement of air to control the drug release has already been reported for superhydrophobic electrospun nanofibers combining PCL and PGCC18 as a hydrophobic polymer dopant [37]. Recently, it has been shown that this theory can also be employed to hydrophobic, not only to superhydrophobic nanofiber mats [36]. Given that the contact angle between nanofiber mats and release medium is in range of 101–107° in this study, air entrapment may be a reliable explanation for the prolonged drug release. Another point to be noted here is that the formation of beads in the electrospun nanofiber reduces its porosity, and consequently, the effective diffusion coefficient decreases. Therefore, the presence of a relatively large number of beads in the nanofibers fabricated in this work may also be another reason for the prolonged release process.
experimental data (except for PVDF/PEG1%-thin) only at the initial of the release process. The Higuchi model is an empirical model which is widely used to describe the drug release from matrix systems [38]. From Table 1, it can be seen that for all samples, the correlation coefficients obtained for this model differ significantly from 1. Therefore, the Higuchi model cannot perfectly explains the IAA release from electrospun coated NAA. Lack of agreement between this model and experimental data is also evident in Fig. 5. Korsmeyer-Peppas model is a semi-empirical equation which has been accepted in the drug release modeling over other equations because of its simple form [38]. This model is useful when the drug release mechanism is unknown or when more than one phenomenon affects the drug release [39]. It must be noted that the Korsmeyer-Peppas model is only valid when Mt/M∞ < 0.6 [40,41]. For the KorsmeyerPeppas model, the correlation coefficients were obtained in ranges 0.888–0.921 for all samples (Table 1). Fig. 5 indicates that this model fits well only to the PVDF/PEG1%-thin. Same as the first-order model, this model fits the experimental data only at the beginning of the release process. Hence, this model cannot describe properly the behavior of IAA release from electrospun coated NAA. Lack of agreement between the models described in the literature and our experimental data motivated us to consider a new model for explaining the release process from electrospun coated NAA. As seen in Fig. 4, there is a significant difference between the slope of release curves at the initial and final of the process, denoting a transition in the release process which can be described by a two-stage model. For the first stage, we suppose that the initial drug concentration inside the NAA pores is higher than the solubility of the drug and a saturated solution of the drug is quickly generated upon penetration of water into the pores. Since dissolving of drug inside the pores is fast compared to drug diffusion through the nanofiber film, the drug concentration in the pores remains constant. If the drug diffusion through the nanofiber film is the rate-limiting step, the following equation can be used until there is an excess solid drug in the pores [42]:
3.5. Drug delivery modeling In order to understand the mechanism of IAA release from electrospun coated NAA, the experimental data of release were fitted to wellknown models such as the first order, Korsmeyer-Peppas and Higuchi models. The correlation coefficient (R2) was considered as the goodness of fit parameter to discriminate the appropriate model. The mathematical formula, the value of model parameters and the correlation coefficients were presented in Table 1 for the considered models. Curves related to the release of IAA from electrospun coated NAA for different models were shown in Fig. 5. The first order model is generally used for describing the release of water-soluble drugs from porous matrices [28]. For the first order model, the obtained correlation coefficients are in ranges 0.803–0.898 which demonstrate this model cannot describe properly the IAA release from electrospun coated NAA. Fig. 5 shows that this model fits the
ADeff Cs ⎞ Mt t =⎛ M∞ ⎝ LM∞ ⎠ ⎜
⎟
(1)
where Mt and M∞ are the amounts of release at time t and infinity, respectively; A is the area of the NAA surface; Deff is the effective diffusivity of the active agent within the nanofiber; Cs is the solubility of the drug in the liquid-filled pores, and L is the thickness of the nanofiber film. At the start of the second stage, it is assumed that the solid drug 5
Journal of Drug Delivery Science and Technology 54 (2019) 101247
R. Fazli-Abukheyli, et al.
Table 1 The mathematical formula, the model parameters and the correlation coefficients (R2) for the different drug delivery models. Model
Mathematical formula
First order
Mt M∞
Higuchi
Mt = K h t ½
Korsmeyer–Peppas
Mt = Kp t n
= 1 − exp [−K1 t ]
Curve fitting data
K1 = R2 = Kh = R2 = Kp = n= R2 =
PVDF/PEG1%-thin
PVDF/PEG1%-thick
PVDF/PEG2%-thin
PVDF/PEG2%-thick
0.089 0.803 0.103 0.854 0.236 0.297 0.921
0.141 0.898 0.107 0.760 0.240 0.359 0.888
0.194 0.883 0.108 0.542 0.318 0.285 0.907
0.143 0.854 0.106 0.746 0.265 0.309 0.921
inside the pores is exhausted. Therefore, released drug molecules cannot be replaced by the dissolution of drug excess and consequently, the drug concentration inside the pores reaches below its solubility. In this stage, the concentration of drug inside the pores is gradually decreased with time by diffusion of the drug out through the nanofiber film. Assuming that there is a perfect sink condition in the release environment, the following equations can be derived [42]:
ADeff ⎤ Mt ⎞t = 1 − exp ⎡−⎛ ⎢ ⎝ VL ⎠ ⎥ M∞ ⎣ ⎦ ⎜
⎟
(2)
where V is the volume of the nano-pores. The general equation for drug release from electrospun coated NAA is given by the summation and simplification of Eqs. (1) and (2) as follows:
Fig. 5. Release profiles of IAA from NAA compared with different drug delivery models. 6
Journal of Drug Delivery Science and Technology 54 (2019) 101247
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Fig. 6. Fitting of experimental data of IAA release with Eq. (3).
Mt = K 0 t + u (t − θ)[1 − K 0 t + (K 0 θ − 1) exp [−K1 (t − θ)]] M∞
Therefore, the concentration gradient, which is the driving force for the mass transfer through the nanofiber film, is maximum and, as a result, the diffusion rate is high in this stage. In the second stage, the drug concentration is gradually decreased inside the pores and, consequently, the driving force for the mass transfer through the nanofiber film is reduced. Accordingly, the diffusion rate is lower in this stage compared to the first stage. Results in Table 2 clearly show that both electrospun film thickness and PEG content affect the release rate in the first and second stage of release. Comparison of the values of K0 reveals that the increase in the electrospun film thickness leads to a decrease in the release rate of the first stage while a reverse trend was found for increasing the PEG content. Such a result can also be deduced by comparing the values of K1 for the release rate in the second stage. Both K0 and K1 are directly dependent on Deff which is strongly influenced by the porosity of the film and the interaction between drug molecules and nanofiber surface. The small values of K0 and K1 for samples with less PEG content can be explained by the smallness of Deff due to higher hydrophobicity of polymer constituting the nanofibers. The value of θ shows the end time of the first stage of release and it depends on the amount of IAA stored on the NAA pores, in addition to the release rate. For this reason, no particular trend is seen in this case.
(3)
where K0=(A Deff Cs/L M∞) is the zero order release constant, K1=(A Deff/V L) is the first order release constant, θ is the end time of the first stage and u(t-θ) is a generalized unit step function. To verify the proposed model, the experimental data have been fitted to Eq. (3) and the results are presented in Fig. 6 and Table 2. The obtained results indicate an excellent agreement between the experimental data and the proposed model which means that the release profile of IAA from electrospun coated NAA obeys zero-order kinetics in the first stage and first-order kinetics in the second stage. In the first stage, the drug concentration in the pores is constant at saturation. Table 2 The fitting parameters of model and correlation coefficients. Sample
K0
K1
θ(h)
R2
PVDF/PEG1%-thin PVDF/PEG1%-thick PVDF/PEG2%-thin PVDF/PEG2%-thick
0.153 0.123 0.169 0.142
0.0225 0.0235 0.0221 0.0229
3.652 3.253 3.260 3.269
0.994 0.995 0.990 0.993
7
Journal of Drug Delivery Science and Technology 54 (2019) 101247
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4. Conclusions [14]
We reported a novel method for controlling the drug release from nanoporous structures by covering the NAA top surface with electrospinning nanofibers. The film thickness and hydrophobicity properties of nanofibers are exploited to control drug release from NAA. PVDF/ PEG was selected for electrospinning as they are biocompatible. The NAA implants were loaded with indole-3-acetic acid (IAA) as a drug model. The release characteristics of NAA samples with and without electrospinning coating was explored and results showed a considerable alteration in the IAA release profile. This method can significantly decrease the burst release and prolong the release time, in comparison with the uncoated sample. To study the mechanism of IAA release from electrospun coated NAA, different release models such as the first order, Korsmeyer-Peppas and Higuchi models were applied. Unfortunately, these models did not fit to the experimental data. Therefore, a new twostage mechanism was proposed. The release in the first stage was modeled by the zero-order kinetics model, while in the second stage it was modeled with the first-order kinetics model. The experimental data were fitted to this two-stage model and an excellent agreement between the experimental data and the proposed model was achieved.
[15]
[16]
[17]
[18]
[19]
[20]
[21]
5. Declarations of interest
[22]
None. [23]
Acknowledgment We are grateful to Dr. Mohammad Mehdi Sabzehmeidani for excellent support and helpful guidance on the electrospinning process.
[24]
[25]
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Contents lists available at ScienceDirect
Journal of Drug Delivery Science and Technology journal homepage: www.elsevier.com/locate/jddst
Electrospinning coating of nanoporous anodic alumina for controlling the drug release: Drug release study and modeling
T
Ruhollah Fazli-Abukheylia, Mahmood Reza Rahimia,∗, Mehrorang Ghaedib a b
Department of Chemical Engineering, Faculty of Engineering, Yasouj University, Yasouj, Iran Department of Chemistry, Faculty of Science, Yasouj University, Yasouj, Iran
A R T I C LE I N FO
A B S T R A C T
Keywords: Electrospinning coating Nanoporous anodic alumina Controlled release Mathematical modeling
Local drug delivery system is a promising alternative to conventional methods. Recently, new implants with ordered nanoporous structure have been recommended to improve the local drug delivery performance, one of the favorites is the nanoporous anodic alumina (NAA). For controlling the drug release from NAA, we introduced a novel method by covering the NAA top surface with electrospinning nanofibers including PVDF/PEG. The film thickness and hydrophobicity properties of nanofibers are exploited to control drug release from NAA. The NAA implants were loaded with indole-3-acetic acid (IAA) as a drug model. Comparison of release characteristics of NAA samples with and without electrospinning coating revealed notable alteration in the IAA release profile. Electrospinning coating method can significantly decrease the burst release and prolong the duration of release from nanoporous structures. The behavior of IAA release from electrospinning coated NAA was described by a two-stage mechanism. The release in the first stage was modeled with the zero-order kinetics model, while in the second stage the release was modeled with the first-order kinetics model. The experimental data were fitted to the new model and an excellent agreement between the experimental data and this model was achieved.
1. Introduction Delivery of effective therapeutic agents to diseased site is important for the treatment of many diseases. Unfortunately, conventional drug delivery approaches have difficulty in supplying maximum efficacy using the lowest drug usage for rapid and effective treatment of patients. The origin of this problem emerges from the hydrophobic nature of most drugs which limit their solubility in the blood [1]. Hence, their easy degradation by metabolism prevents their arrival to the designated targeted sites. Also, conventional drug delivery systems possess other drawbacks such as lack of selectivity, side effects, toxicity and undesired release profiles [2–4] which must be compensated by the development of new protocols or materials. In this regard, local drug delivery system (local implantation) has been considered a promising alternative to conventional methods. The advantage of this method is that it offers higher localized drug concentration which reduces the time required for disease treatment [5]. Local drug delivery systems, at first, were made of biodegradable implants which suffer from burst and uncontrolled drug release and failure to attain prolonged and continuous release. These problems are mostly because of the amorphous nature and the irregular structure of the biomaterials [6]. Accordingly, new implants with ordered
∗
nanoporous and nanotubular structure produced by electrochemical anodization including nanoporous anodic alumina (NAA), titania nanotubes (TNT) and porous silicon (pSi) were recommended to improve the local drug delivery performance [6–9]. NAA, which is emerging as a most outstanding drug releasing implants, consists of ordered and parallel cylindrical nanopores arranged in close-packed hexagonal structures. The particular interest in NAA arises from its unique properties such as high porosity and specific surface area, controllable pore size, resistance to erosion, biodegradability and low fabrication costs [10,11]. The advantage of NAA is that its structural characteristics like pore diameter, pore length and interpore distance which influence its release performance can be easily adjusted by controlling the anodization conditions such as current density, applied potential, temperature, process time and electrolyte type and concentration [12]. The method of drug delivery can significantly affect its performance. In essence, drugs have an optimal concentration range that the maximum effect is achieved in it and concentrations above or below this range can be toxic or have no therapeutic effect. Therefore, to achieve the best performance, controlling the drug release from drug carriers is very important. For NAA drug delivery implants, structural modification as a simple strategy was undertaken [6,13,14] to control
Corresponding author. E-mail address: [email protected] (M.R. Rahimi).
https://doi.org/10.1016/j.jddst.2019.101247 Received 3 April 2019; Received in revised form 27 August 2019; Accepted 28 August 2019 Available online 29 August 2019 1773-2247/ © 2019 Published by Elsevier B.V.
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In the first step, the Al disks were anodized for 30 min in 0.3 M oxalic acid (H2C2O4) aqueous solution at 20 °C and a constant voltage of 100 V. Then, to eliminate the formed oxide layer, the disks were immersed in the aqueous solution of phosphoric acid and chromic acid (CrO3:H3PO4 = 1.8:6) at 60 °C for 60 min. The second anodizing step was performed for 3 h in the same conditions as in the preceding step.
and extend the drug release, but this strategy has some limitations due to the reciprocity between loading capacity and release performance [6]. Another strategy to control drug release from NAA is to modify the surface charge of pores to hydrophobic or hydrophilic for changing the interaction between the drug molecules and pore surface [12]. Although the usefulness of this approach in altering the drug release performance was illustrated in some reports [6,15], there are still limitations to achieving a prolonged drug release. To address this issue, covering the NAA top surface with biopolymer was employed as an alternative strategy. Simovic et al. [16] deposited a thin layer of plasma polymer on the NAA top surface to reduce the pore opening after drug loading. Though an extended drug release was achieved by the plasma deposition method, this method has been limited due to the equipment costs and technical complexity [12]. Gulati et al. [17] used dip coating for depositing a thin layer of degradable biopolymer to enclose the pore openings. Here, the drug release is altered by the degradability and chemical properties of the polymer and also the thickness of the film. Despite the simplicity and low cost of the dip coating method, there is a possibility of drug incorporation into biopolymer layer during the process which affects the drug release kinetics. In this study, we employed a novel method for controlling the drug release from the NAA implant by covering the NAA top surface with electrospun polymeric nanofibers. Nanofibers obtained using electrospinning technique have been attained great interest in recent years in the medical field, especially in the drug delivery applications [18–21]. The electrospinning coating process, contrary to the plasma coating process, is a simpler method and does not require expensive equipment. Also, unlike the dip-coating method, it is a dry process and there is no possibility of drug incorporation into the nanofiber mat during the process. Hence the drug release kinetics cannot be affected. In order to evaluate the ability and performance of the electrospinning coating method for controlling the drug release from NAA, an in-vitro experiment was conducted using indole-3-acetic acid (IAA) as a water-insoluble drug model. IAA is a plant growth regulator of the auxin class and has potentials as a cosmetic or dermatological ingredient [22]. It is also used in the oxidation therapy of cancer, as well as the treatment of Acne Vulgaris [23]. Herein, we described the IAA release characteristics from electrospun coated NAA and evaluated the effect of film thickness and hydrophobicity property of nanofibers on IAA release rate. Then, to estimate the amount of IAA release from these systems, the release profiles were analyzed in detail and a two-stage process was proposed for IAA release from electrospun coated NAA.
2.3. IAA loading into NAA The NAA sheets with 20 mm2 area were washed using deionized water and then placed on a hot plate at 80° for 12 h. Subsequently, the dried NAA sheets were immersed in the ethanolic solution of IAA (50 mg/ml) and sonicated for 2 h. The NAA sheets were remained in the solution for 24 h to allow sufficient time for the penetration of IAA into the NAA pores. The NAA sheets loaded with IAA were dried in air and then wiped using a soft tissue to clean the remaining IAA on the surfaces. To determine the IAA loading in NAA pores, the loaded samples were immersed in 5 ml ethanol and sonicated for 6 h, and subsequently, the drug content was measured by spectrophotometry. The experiments were performed in triplicate. 2.4. Electrospun coating of NAA Before the electrospinning process, different PVDF solutions containing 0, 1 and 2 wt % PEG were prepared. PVDF was dissolved at a concentration of 15 wt % in DMF and stirred overnight at a temperature of 60 °C. The PEG was mixed with the PVDF solution and stirred at 60 °C until the mixture became clear. Using these solutions, the electrospinning was performed in a single home-made apparatus at room temperature (22 ± 2 °C). The electrospinning parameters with a slight modification were adapted from previously published literature [25]. Before electrospinning, the NAA disks were fixed from backside to the collector with sellotape. Each of the prepared solutions was poured into a plastic syringe with the stainless steel needle of 0.7 mm diameter. Then, the needle was fixed at 15 cm in a horizontal direction with respect to the collector and the flow rate was set to 0.4 ml h−1. Subsequently, a constant voltage of 17 kV was applied and electrospinning was performed for 30 and 60 min to obtain nanofiber mat with different thickness on the NAA surface. After the electrospinning process was completed, the electrospun film was carefully cut from the periphery of the NAA disk by a sharp cutter. Afterward, the NAA disk was removed from the collector and kept in the oven overnight at 40 °C for DMF removal from nanofibers.
2. Materials and methods 2.5. IAA release 2.1. Chemicals Generally, the drug release behavior of controlled release systems is studied in vitro under dynamic conditions (with stirring or shaking). But, in this work, the release experiments were performed under static conditions (without stirring or shaking) to prevent damage to the electrospun film and to avoid its detachment from the surface of NAA sheets. The drug release performance of the nanoporous structures is commonly investigated under static conditions [26–28], since it is easily carried out and sufficient enough to obtain drug release profiles [28]. In-vitro release of IAA from electrospun coated NAA was investigated by putting the implants in capped vials containing 3 ml of release media at room temperature (22 ± 2 °C). In order to increase the aqueous solubility of IAA and to achieve a sink condition, the water/ethanol solution with the volume ratio of 9:1 was used as a release medium. The solubility of IAA in this solution was measured 5.3 ± 0.6 mg/ml by experiments. At specified time intervals, the whole volume of the solution was poured into a 3-ml cuvette and the absorbance of IAA was determined by UV–vis spectrophotometer (DR6000, Hach, USA) at 280 nm, while at each stage, IAA content was estimated based on the calibration curve. Afterward, 2.5 ml of the
All chemicals including phosphoric acid (85%), perchloric acid (70%), hydrochloric acid (37%), ethanol (95.5%), oxalic acid, acetone, chromium (VI) oxide, sodium hydroxide, copper (II) chloride, indole-3acetic acid, N,N-dimethylformamide (DMF) (99.8%), and Polyethylene glycol (PEG, Mw = 60000) were provided from Merck (Germany). Polyvinylidene fluoride (PVDF, Kynar 761) was procured from Arkema (USA) and aluminum foil (99.9% purity, 0.3 mm thick) was bought from Kingcheng (China). 2.2. Fabrication of NAA Aluminum foil (99.9%) with a thickness of 0.3 mm was cut into circular disks with a diameter of 10 mm. Then, the Al disks were degreased by ultrasonic rinsing in acetone and water for 3 min and subsequently was etched in 3 M sodium hydroxide (NaOH) solution at 30 °C for 10 min. Afterward, the Al disks electropolished in a perchloric acid and ethanol mixture (HClO4:C2H5OH = 1:4 v/v) for 3 min at 0 °C and a constant voltage of 20 V [24]. Anodizing process was performed by the two-step hard method using a home-made electrochemical cell. 2
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3. Results and discussion
60 min electrospun coating, from left to right, respectively. Typical SEM image from the top surface of a sample is shown in Fig. 2(b). This image confirms the nanofiber formation with a few beads. Beads formation is the consequence of the surface tension forces overcoming the viscoelastic forces [29] and commonly reported when the concentration or viscosity of the polymer solution is low. Fig. 2(c and d) show the SEM images of the top surface and cross-section of electrospun coated NAA. The high-resolution image in Fig. 2(d) demonstrates the adherence of nanofibers onto the NAA top surface. SEM images of PVDF nanofibers prepared using different content of PEG were shown in Fig. 2(e–g). As can be seen, the electrospun nanofibers made of pure PVDF had a non-uniform and irregular morphology. With increasing PEG content, the non-uniformity and irregularity of fibers were reduced. The average diameter of electrospun nanofibers measured from SEM images was obtained 142 ± 58, 154 ± 47 and 159 ± 41 nm for samples with 0, 1 and 2% PEG content, respectively. This enhancement of nanofiber diameter is related to the increase in concentration and viscosity of the polymer solution by increasing the PEG content. Unfortunately, evaluation of the nanofiber mat thickness is very difficult with the SEM images, but as a rough estimation, the values of 60 and 100 μm were estimated for the thickness of thin and thick nanofiber mats, respectively. The contact angle tests were performed in order to determine the hydrophilicity of the electrospun nanofiber films (Fig. 3). The contact angles of nanofiber mats prepared from PVDF solution containing 0%, 1% and 2% PEG were around 131 ± 2, 107 ± 2 and 101 ± 3, respectively. Accordingly, all samples exhibit a high hydrophobicity; however, the value for the sample of pure PVDF differs from two other significantly.
3.1. Morphology and structure of NAA
3.3. IAA loading capacity
The morphology and structure of NAA before IAA loading are shown in Fig. 1. The bottoms and the top surface of NAA are presented in Fig. 1(a) and (b), respectively. Fig. 1(b) demonstrates a near uniformity in the pore size and distribution. Fig. 1(c) indicates the cross-section of the NAA after second anodization and demonstrates straight and parallel growth of the pores. The pore diameter and NAA thickness can be controlled mainly by anodization potential and anodization time, respectively, which were 100 V and 3 h in our experiment. Image analysis results in approximate pore diameter of 190 ± 25 nm, pore length of 50 ± 1 μm and interpore distance of 270 ± 36 nm. According to this measurement, the porosity and the pore density of NAA were estimated at 0.45 and 18/μm2, respectively.
The amount of loaded IAA in NAA was determined from experiment to be 0.076 ± 0.008 mg. The amount of drug loading in NAA is directly depended on the pore diameter and pore length. The larger pore diameter and the longer pore provide more volume for drug loading and consequently cause a higher amount of drug stored inside the NAA pores. However, the drug loading capacity of NAA is often low (< 25%) due to boundary limits from geometrical confinement of nanopores and possible air entrapment occupying the bottom of the pores [6]. In this work, the loading capacity of NAA was estimated to be about 12%.
solution was pipetted and returned into the vial and then 0.5 ml of fresh solution was added to the vial to maintain the sink conditions. All release experiments were carried out in triplicate and the data reported as the mean value. 2.6. Structural characterizations The morphology of the prepared NAA implants and the microstructure of electrospun nanofiber were analyzed using a field emission scanning electron microscope (FE-SEM: MIRA3, TESCAN, Czech Republic). All samples were sputtered with gold before SEM imaging. An accelerating voltage of 15 kV, working distance of 11 mm and the magnification rates of 1, 25, 50 and 200 kx were used for the structural analysis of samples. The pore diameter, pore length and interpore distance of NAA and also the diameter of nanofibers were determined by analyzing the SEM images with ImageJ v1.51 software. To obtain an average value, 20 measurements for each parameter were carried out from a single SEM image. 2.7. Contact angle tests The hydrophilicity of nanofiber mats was assessed by measuring the contact angle. The tests were performed using a high resolution camera (Nikon, D5200, Japan) and a software (ImageJ v1.51) with a droplet of release medium at ambient temperature. The contact angle was measured two times on three separate locations of each sample and reported as an average.
3.4. In-vitro release of the model drug The idea of the presented method is covering the NAA pore with a thin nanofiber film, and employing the wettability of nanofibers and also the film thickness for controlling the drug release from NAA. Different polymers such as PVA, PVP, PCL, PVDF, PEO, PLGA, etc. have
3.2. Characterization of electrospun film Fig. 2 (a) is a digital image of NAA disks before and after 30 and
Fig. 1. SEM images of NAA disks. (a) The bottoms surface of the specimen; (b) the top surface of the specimen; (c) the cross-sectional of the specimen after second anodization. 3
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Fig. 2. (a) From left to right: NAA disks before electrospun coating and after 30 and 60 min electrospun coating. (b,c) SEM images from the top surface of a sample. SEM images of electrospun nanofibers prepared from PVDF solution containing (d) 0%, (e) 1% and (g) 2% PEG.
The profiles of IAA release from NAA for samples with and without electrospinning coating on top are presented in Fig. 4. It must be noted that the results for electrospun coated NAAs with 0% PEG content had no release. As seen in Fig. 4, for uncoated NAA implant, 90% of IAA was released during the initial 5 h and in the following, a slow release takes placed till 24 h. The burst release may arise from the accumulation of drug on the top of pores and also the wide pores (190 nm) which causes a fast drug release. For NAA samples with electrospinning coating on top, a biphasic release can be seen again, but in comparison with the uncoated sample, the burst release was significantly reduced and the overall release considerably prolonged. As seen, both electrospun film thickness and PEG content affect the release rate. For example, in the sample of PVDF/PEG1%-thin, the burst release for 0–5 h decreased to 43% and the total release time lasted to 120 h. Such a trend is also observed in the case of PVDF/PEG2%-thin, but only the burst release was decreased to 60%. The drug release characteristics of NAA samples coated with thick electrospun films are like the samples with thin electrospun films, except that the decrease in the burst release for the thick samples (40 and 45% for samples with 1 and 2% PEG content, respectively) is more than that for thin samples. The molecular transport of drug through electrospun nanofibers films depends on the film thickness and its diffusivity. In these
Fig. 3. Contact angles of electrospun nanofiber mats prepared from PVDF solution containing (a) 0%, (b) 1% and (c) 2% PEG.
been electrospuned to fabricate nanofiber mat for drug delivery applications [30]. Since drug release from electrospun hydrophilic polymer mats is usually fast, hydrophobic polymer mats are preferred. In this paper, PVDF, a synthetic polymer, is used as a base polymer for electrospinning coating due to its excellent biocompatibility. PVDF nanofibers are extensively used in filtration application because of their good mechanical and thermal properties, as well as, their intrinsically hydrophobic nature which leads to a water contact angle of 130 ± 1° [31]. The application of this polymer in the medical area has been studied in the literatures [32–35] but its practical application in biomedicine is limited due to the inherent hydrophobicity of PVDF. This limitation can be solved by blending PVDF with PEG which is a synthetic, biocompatible and uncharged water-soluble polymer. PEG extensively used as a modifier to enhance the hydrophilicity property of various industrial membranes [35]. 4
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Fig. 4. IAA release profile from uncoated and coated NAA implants: (a) overall and (b) burst release.
experiments, the IAA release from NAA with thin electrospun film showed faster release than thick electrospun films. It was expected because by increasing in the electrospun film thickness, the diffusion path for drug molecules is increased and as a result, the driving force is decreased. The diffusivity of drug through nanofiber mats is related to the several factors including the nature of polymer (charge, degradability, and hydrophilicity/hydrophobicity), the polymer concentration in the electrospinning solution, the polymer molecular weight, nanofiber morphology, drug-polymer interactions and medium used for the preparation of polymer solution. In the case of hydrophobic nanofiber mats, the air captured between the nanofibers is the main factor affecting the permeability. In these materials, the entrapped air decreases the area of contact of the water at the solid nanofiber surface and consequently causes an increase in the hydrophobicity [36]. The displacement of air to control the drug release has already been reported for superhydrophobic electrospun nanofibers combining PCL and PGCC18 as a hydrophobic polymer dopant [37]. Recently, it has been shown that this theory can also be employed to hydrophobic, not only to superhydrophobic nanofiber mats [36]. Given that the contact angle between nanofiber mats and release medium is in range of 101–107° in this study, air entrapment may be a reliable explanation for the prolonged drug release. Another point to be noted here is that the formation of beads in the electrospun nanofiber reduces its porosity, and consequently, the effective diffusion coefficient decreases. Therefore, the presence of a relatively large number of beads in the nanofibers fabricated in this work may also be another reason for the prolonged release process.
experimental data (except for PVDF/PEG1%-thin) only at the initial of the release process. The Higuchi model is an empirical model which is widely used to describe the drug release from matrix systems [38]. From Table 1, it can be seen that for all samples, the correlation coefficients obtained for this model differ significantly from 1. Therefore, the Higuchi model cannot perfectly explains the IAA release from electrospun coated NAA. Lack of agreement between this model and experimental data is also evident in Fig. 5. Korsmeyer-Peppas model is a semi-empirical equation which has been accepted in the drug release modeling over other equations because of its simple form [38]. This model is useful when the drug release mechanism is unknown or when more than one phenomenon affects the drug release [39]. It must be noted that the Korsmeyer-Peppas model is only valid when Mt/M∞ < 0.6 [40,41]. For the KorsmeyerPeppas model, the correlation coefficients were obtained in ranges 0.888–0.921 for all samples (Table 1). Fig. 5 indicates that this model fits well only to the PVDF/PEG1%-thin. Same as the first-order model, this model fits the experimental data only at the beginning of the release process. Hence, this model cannot describe properly the behavior of IAA release from electrospun coated NAA. Lack of agreement between the models described in the literature and our experimental data motivated us to consider a new model for explaining the release process from electrospun coated NAA. As seen in Fig. 4, there is a significant difference between the slope of release curves at the initial and final of the process, denoting a transition in the release process which can be described by a two-stage model. For the first stage, we suppose that the initial drug concentration inside the NAA pores is higher than the solubility of the drug and a saturated solution of the drug is quickly generated upon penetration of water into the pores. Since dissolving of drug inside the pores is fast compared to drug diffusion through the nanofiber film, the drug concentration in the pores remains constant. If the drug diffusion through the nanofiber film is the rate-limiting step, the following equation can be used until there is an excess solid drug in the pores [42]:
3.5. Drug delivery modeling In order to understand the mechanism of IAA release from electrospun coated NAA, the experimental data of release were fitted to wellknown models such as the first order, Korsmeyer-Peppas and Higuchi models. The correlation coefficient (R2) was considered as the goodness of fit parameter to discriminate the appropriate model. The mathematical formula, the value of model parameters and the correlation coefficients were presented in Table 1 for the considered models. Curves related to the release of IAA from electrospun coated NAA for different models were shown in Fig. 5. The first order model is generally used for describing the release of water-soluble drugs from porous matrices [28]. For the first order model, the obtained correlation coefficients are in ranges 0.803–0.898 which demonstrate this model cannot describe properly the IAA release from electrospun coated NAA. Fig. 5 shows that this model fits the
ADeff Cs ⎞ Mt t =⎛ M∞ ⎝ LM∞ ⎠ ⎜
⎟
(1)
where Mt and M∞ are the amounts of release at time t and infinity, respectively; A is the area of the NAA surface; Deff is the effective diffusivity of the active agent within the nanofiber; Cs is the solubility of the drug in the liquid-filled pores, and L is the thickness of the nanofiber film. At the start of the second stage, it is assumed that the solid drug 5
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Table 1 The mathematical formula, the model parameters and the correlation coefficients (R2) for the different drug delivery models. Model
Mathematical formula
First order
Mt M∞
Higuchi
Mt = K h t ½
Korsmeyer–Peppas
Mt = Kp t n
= 1 − exp [−K1 t ]
Curve fitting data
K1 = R2 = Kh = R2 = Kp = n= R2 =
PVDF/PEG1%-thin
PVDF/PEG1%-thick
PVDF/PEG2%-thin
PVDF/PEG2%-thick
0.089 0.803 0.103 0.854 0.236 0.297 0.921
0.141 0.898 0.107 0.760 0.240 0.359 0.888
0.194 0.883 0.108 0.542 0.318 0.285 0.907
0.143 0.854 0.106 0.746 0.265 0.309 0.921
inside the pores is exhausted. Therefore, released drug molecules cannot be replaced by the dissolution of drug excess and consequently, the drug concentration inside the pores reaches below its solubility. In this stage, the concentration of drug inside the pores is gradually decreased with time by diffusion of the drug out through the nanofiber film. Assuming that there is a perfect sink condition in the release environment, the following equations can be derived [42]:
ADeff ⎤ Mt ⎞t = 1 − exp ⎡−⎛ ⎢ ⎝ VL ⎠ ⎥ M∞ ⎣ ⎦ ⎜
⎟
(2)
where V is the volume of the nano-pores. The general equation for drug release from electrospun coated NAA is given by the summation and simplification of Eqs. (1) and (2) as follows:
Fig. 5. Release profiles of IAA from NAA compared with different drug delivery models. 6
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Fig. 6. Fitting of experimental data of IAA release with Eq. (3).
Mt = K 0 t + u (t − θ)[1 − K 0 t + (K 0 θ − 1) exp [−K1 (t − θ)]] M∞
Therefore, the concentration gradient, which is the driving force for the mass transfer through the nanofiber film, is maximum and, as a result, the diffusion rate is high in this stage. In the second stage, the drug concentration is gradually decreased inside the pores and, consequently, the driving force for the mass transfer through the nanofiber film is reduced. Accordingly, the diffusion rate is lower in this stage compared to the first stage. Results in Table 2 clearly show that both electrospun film thickness and PEG content affect the release rate in the first and second stage of release. Comparison of the values of K0 reveals that the increase in the electrospun film thickness leads to a decrease in the release rate of the first stage while a reverse trend was found for increasing the PEG content. Such a result can also be deduced by comparing the values of K1 for the release rate in the second stage. Both K0 and K1 are directly dependent on Deff which is strongly influenced by the porosity of the film and the interaction between drug molecules and nanofiber surface. The small values of K0 and K1 for samples with less PEG content can be explained by the smallness of Deff due to higher hydrophobicity of polymer constituting the nanofibers. The value of θ shows the end time of the first stage of release and it depends on the amount of IAA stored on the NAA pores, in addition to the release rate. For this reason, no particular trend is seen in this case.
(3)
where K0=(A Deff Cs/L M∞) is the zero order release constant, K1=(A Deff/V L) is the first order release constant, θ is the end time of the first stage and u(t-θ) is a generalized unit step function. To verify the proposed model, the experimental data have been fitted to Eq. (3) and the results are presented in Fig. 6 and Table 2. The obtained results indicate an excellent agreement between the experimental data and the proposed model which means that the release profile of IAA from electrospun coated NAA obeys zero-order kinetics in the first stage and first-order kinetics in the second stage. In the first stage, the drug concentration in the pores is constant at saturation. Table 2 The fitting parameters of model and correlation coefficients. Sample
K0
K1
θ(h)
R2
PVDF/PEG1%-thin PVDF/PEG1%-thick PVDF/PEG2%-thin PVDF/PEG2%-thick
0.153 0.123 0.169 0.142
0.0225 0.0235 0.0221 0.0229
3.652 3.253 3.260 3.269
0.994 0.995 0.990 0.993
7
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4. Conclusions [14]
We reported a novel method for controlling the drug release from nanoporous structures by covering the NAA top surface with electrospinning nanofibers. The film thickness and hydrophobicity properties of nanofibers are exploited to control drug release from NAA. PVDF/ PEG was selected for electrospinning as they are biocompatible. The NAA implants were loaded with indole-3-acetic acid (IAA) as a drug model. The release characteristics of NAA samples with and without electrospinning coating was explored and results showed a considerable alteration in the IAA release profile. This method can significantly decrease the burst release and prolong the release time, in comparison with the uncoated sample. To study the mechanism of IAA release from electrospun coated NAA, different release models such as the first order, Korsmeyer-Peppas and Higuchi models were applied. Unfortunately, these models did not fit to the experimental data. Therefore, a new twostage mechanism was proposed. The release in the first stage was modeled by the zero-order kinetics model, while in the second stage it was modeled with the first-order kinetics model. The experimental data were fitted to this two-stage model and an excellent agreement between the experimental data and the proposed model was achieved.
[15]
[16]
[17]
[18]
[19]
[20]
[21]
5. Declarations of interest
[22]
None. [23]
Acknowledgment We are grateful to Dr. Mohammad Mehdi Sabzehmeidani for excellent support and helpful guidance on the electrospinning process.
[24]
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