Poly (β-Cyclodextrin-co-citric Acid) Functionalized Natural Nanozeolite: An Eco-Friendly Platform for IB Delivery

Abstract

Zeolites, due to their porous nature and inherent pH-sensitive properties, are widely studied as drug delivery systems. However, natural zeolite pores are usually larger than drug molecules, which can cause rapid drug release. Consequently, to solve this problem, the zeolite structure must be modified to achieve controlled drug release. On the other hand, the preparation of nanoscale zeolites enables them to enter the living cell. To achieve these objectives, a natural nanozeolite was modified by poly (β-cyclodextrin-co-citric acid) (PCD-zeolite), and used for the loading and release of IB (IB). The PCD-zeolite was synthesized by heating a mixture of citric acid (CA), cyclodextrin (CD), and Na₂HPO₄; it was characterized by FT-IR, TGA, and TEM analyses. Due to the presence of hydroxyl and carboxyl groups in the PCD-zeolite structure, pH plays a vital role in the adsorbed IB; thus, the maximum adsorbed IB was observed at pH = 7. The in vitro release of IB from PCD-zeolite-IB in a phosphate buffer was examined; the PCD-zeolite containing IB (30 wt%) showed the highest release at pH = 3.6 within the first 3–48 h. As a result, the PCD-zeolite, by trapping IB, can improve its solubility and bioavailability. Moreover, the decrease in the dissolution rate of the polymer matrix in an acidic medium may also lower the toxicity of IB.

1. Introduction

Many studies have been applied to achieve controlled drug delivery systems. Although different drug delivery systems have been developed, the introduction of a new strategy that can achieve the goals of controlled drug delivery is still felt. Zeolites are highly regarded as targeted drug delivery because of their mesoporous structure [1,2,3].

The research for polymeric drug delivery has been developed for the last three decades [4,5,6]. Providing new polymeric drug delivery systems methods are among the significant concerns of pharmaceutical researchers regarding their ability to release active parts for a more extended period without changing the plasma level [7,8,9]. Biodegradable polymers have received much attention for drug delivery recently because of their biocompatible and biodegradable nature [10,11,12]. The primary issue with non-biodegradable polymers is removing this polymer from a body after releasing the drug. Thus, biodegradable polymers are preferred more than non-biodegradable polymers for formulating drug delivery systems [13,14]. Because they break down into small monomers in the body, determining whether their monomers are non-toxic or toxic is essential. As a result, introducing new types of biodegradable drug-delivering formulations is of high necessity to target specific areas of the body, such as tumors and inflammation [15,16,17].

Cyclodextrins (CDs) are cyclic oligosaccharides synthesized from the enzymatic degradation of starch. The three mains, CDs, and many derivatives are produced on a large scale and studied extensively for use as drug carriers. The advantages involved in using CDs in drug delivery include flexibility in cavity size, a chemical structure with many potential chemical modification sites, the ability to preserve the structural integrity of degradable drug molecules, the ability to control the release rate profile of complex drugs, and low toxicity [18,19,20].

Biodegradable polymers (BPs) are broadly used in gene therapy, ocular, tissue engineering, vascular, drug delivery, the promotion of plant growth, and heart valve replacements (Dacron, Teflon, and polyurethane). They may occur in both natural and synthetic forms. Synthetic BPs have several advantages over natural, including their unlimited resources, and being synthesized with different physical and chemical properties. Synthetic BPs can be synthesized from a reported method to give the same polymer [21,22,23].

Citric acid (CA) is a multipurpose chemical compound that plays a crucial role in the Krebs cycle and is used in the food, beverages, pharmaceutical, agriculture, and metal industries. Nowadays, CA is considered an effective multifunctional monomer for biological synthesis. CA plays roles in co-forming ester cross-linking to improve compatibility coordination, balance the hydrophobicity of the polymer network, and provide other hydrogen bonding and binding sites for biocompatibility [24,25].

CA modified β-Cyclodextrin (β-CD) polymers have been used for drug delivery systems. In this regard, the synthesis of a porous silicon-cyclodextrin-based polymer as a carrier for ciprofloxacin and prednisolone delivery [26], CA-γ-cyclodextrin cross-linked oligomers for doxorubicin delivery [27], and citrate-modified β-CD functionalized magnetite nanoparticles as curcumin delivery have been reported [28]. Using nanozeolite (NZ) with a water-insoluble β-CD polymer cross-linked by CA can be an efficient carrier for hydrophobic drugs and the delivery of water-insoluble drugs. The presence of a natural zeolite can be a biological, economically feasible, and eco-friendly means for synthesizing the nanocarrier. The present study reports the synthesis, characterization, and studies on IB loaded on poly (β-cyclodextrin-co-citric acid) entrapped NZ.

2. Experimental

2.1. Materials

The reagents used in this experiment were β-cyclodextrin (CD), citric acid (CA), disodium phosphate (DSP), and Ibuprofen (IB) (Merck, Darmstadt, Germany). NZ was prepared according to a simple method [29].

2.2. Characterization

Fourier-transform infrared spectroscopy (FT-IR) spectroscopy was performed using a Bruker Tensor 27 FT-IR-spectrophotometer, in the range between 400 and 4000 cm⁻¹ with a resolution of 4 cm⁻¹. An average of 24 scans were carried out for each sample. The samples were prepared on a KBr pellet in vacuum desiccators under a pressure of 0.01 torr. Thermo gravimetric analysis (TGA) of the samples was performed with TGA 951 Dupont device in a nitrogen atmosphere at a 10 °C/min heating rate. The diameter of the nanoparticles was measured with a transmission electron microscope (TEM) with the CM 120 device (multipurpose 100 kV LaB6 TEM, Eindhoven, The Netherlands), Eindhoven, Netherlands. UV–VIS spectroscopy with a 2100 spectrophotometer by Beijing Beifen–Ruili Analytical Instrument (Group) Co. Ltd. (BFRL), Beijing, China, was used to determine the concentration of the solvent in the solution. To maintain the material at the desired temperatures, the EN500 digital incubator was used.

2.3. Experiment

2.3.1. Preparation of Polybetacyclodextrin-co-Citric Acid/NZ Clinoptilolite (PCD-Zeolite)

In a culture dish, CA (1 g), CD (1 g), DSP (0.2 g), and distilled water (15 mL) were added and stirred for 5 min. Then, NZ (0.3 g) was added to the mixture, and increased the reaction temperature from 25 to 120 °C; thus, the water evaporates. The mixture was transferred into a culture dish and heated in an electric thermostatic oven at 200 °C for 1 h. The resulting polymer was washed with distilled water, and methanol 3 times, and dried in an oven at 80 °C for 1 d (Figure 1).

2.3.2. Preparation of PCD-Zeolite-IB

IB (10, 20, 30, and 40% w/w) was dissolved in 10 mL ethanol/water (40:60, v/v); then, different amounts of the PCD-zeolite (0.03 and 0.05 g) were added to any of the above reaction mixtures. The experiments were performed to optimize the PCD-zeolite-IB in various pH conditions (3.7, 7, and 10), temperature (25 and 60 °C), and time (0.5 to 24 h). The reaction mixture was stirred for 24 h at room temperature. The deposits were separated by centrifugation at 5000 rpm, washed five times with a solvent to remove the unreacted IB, and dried at 80 °C under vacuum for 24 h. The initial and the final concentrations of IB were assessed by a UV-visible spectrophotometer at λ_max = 222 nm. The drug loading of the PCD-zeolite was determined by the following equation:

(1)$\mathrm{Drug} \mathrm{loading} \%=\frac{\mathrm{weight} \mathrm{of} \mathrm{IB} \mathrm{incorporated} \left(\mathrm{mg}\right)}{\mathrm{weight} \mathrm{of} \mathrm{PCD}-\mathrm{Zeolite}-\mathrm{IB} \left(\mathrm{mg}\right)}\times 100$

2.3.3. Drug Release Studies

The in vitro drug release profiles of a free CD and PCD-zeolite were performed in the buffer phosphate, acetate, and Tris (pH = 3.6, 7, and 10). The product (0.03 g) was dialyzed and lyophilized in a dialysis membrane (MWCO 4000) with a 10 mL buffer at 37 °C for 24 h in an incubator, and shaking at 50 rpm. After appropriate dilution was analyzed using UV–VIS spectroscopy (UV-2100, SHIMADZU, Beijing, China) at 222 nm, the content of IB was calculated via the standard calibration curve achieved (Figure S1). The released amount was calculated by the following equation [30].

$\mathrm{Release}=\frac{\mathrm{Release} \mathrm{IB}}{\mathrm{Total} \mathrm{IB}}$

3. Results and Discussion

3.1. Nanostructure Characterizations

3.1.1. FTIR Analysis

The FT–IR spectra of NZ show messages related to the tensile and flexural vibrations of the OH groups in the region (3444 cm⁻¹) and (1645 cm⁻¹), respectively [31]. Tensile vibrations of moderate and wide Si-O, and Al-O bonds are observed in the region (1187 cm⁻¹); in addition, flexural vibrations of O-Si-O and O-Al-O are seen in the region (1470 cm⁻¹) (Figure S2) [32,33,34]. The spectrum of the PCD-zeolite shows (Figure S4), in addition to the mentioned messages related to NZ, the tensile vibration of OH (3437 cm⁻¹), tensile vibration of CH (2929 cm⁻¹), and tensile vibration of C=O (1742 cm⁻¹); these confirm the presence of the surrounding polymer coating zeolite [35,36]. The FT–IR spectra of PCD-zeolite-IB contain messages (675, 1215, 1452, 1742, and 2925 cm⁻¹) that confirm the presence of IB in the structure of the PCD-zeolite (Figure S6). Moreover, reducing the intensity of the messages (1032, 1215, 1452, 1632, and 1742 cm⁻¹) confirms the presence of IB in the structure of PCD-zeolite-IB.

3.1.2. TGA Analysis

The NZ TGA curve shows (Figure 2) a weight loss of about 8.03% at temperatures below 260 °C, which is related to the physical adsorption of water molecules with hydroxyl groups on the surface of the substrate; in addition, another weight loss at below 600 °C of about 6.33% is related to intermolecular hydrogen bonds in the zeolite structure [34]. The TGA curve of the PCD-zeolite (Figure 3) shows two weight reductions: the first reduction is about 6.99% at temperatures below 160 °C, which is related to the water adsorbed on the surface and the internal structure of the composite; and the second decrease is observed at 190 to 420 °C, which is related to the polymer structure around the zeolite. These results show that about 52.5% of the organic composition deposited on the zeolite is related to the polymer. The PCD-zeolite-IB TGA curve shows (Figure 4) weight reductions that are similar to the polymer NZ TGA curve. From the DTG curve of the PCD-zeolite, two significant peaks can be observed in the temperature range of 240 to 260 °C; this is related to the degradation of CA components and the temperature range of 260 to 400 °C, which, in turn, is related to the degradation of CD components. According to the DTG curve of PCD-zeolite-IB, the third weight loss in the range of 25 to 160 °C, 160 to 460 °C, and 460 to 600 °C can be observed; herein, the range of 25 to 160 °C is related to the water adsorbed on the surface, and the range of 160 to 600 °C is related to the organic compound on the surface of NZ. The DTG curve of NZ is observed in the temperature range from zero to 150 °C, which is related to water removal.

3.1.3. TEM Analysis

The morphology of PCD-zeolite-IB shows that the nanozeolite particles are fully dispersed in the PCD matrix, and no agglomeration was observed. In addition, the particle size of the nanozeolite is between 70 and 150 nm (Figure 5).

3.2. Studies on the Uptake and Release of IB

3.2.1. General Method to Optimize the Amount of the PCD-Zeolite for the Preparation of PCD-Zeolite-IB

According to the method of preparation of PCD-zeolite-IB, different weights of the PCD-zeolite (0.03 g, and 0.05 g) were added to a mixture of IB (10% w/w) in 10 mL of ethanol/water (40:60, v/v) as a solvent for 24 h. The IB loading (28.71% and 26.91%) was obtained, respectively, by using Equation (1) (Figure 6). These results indicate that the PCD-zeolite (0.03 g) shows the highest percentage of IB absorption.

3.2.2. General Method to Optimization of pH

The PCD-zeolite (0.03 g) and IB (10% by weight) were added into ethanol/water (40:60, v/v) with pH (3.6, 7, and 10) after 24 h (Figure 7). Using the slope equations of the line obtained (Figure S1), absorptions (18.94, 28.71, and 13.75%) are obtained; this indicates that pH = 7 has the highest adsorption (28.71%). These results show that in an acidic environment: the oxygen attached to BCD is protonated; in addition, it is repulsed with oxygen attached to the carbonyl group of IB, which is also protonated; and less oxygen is attached to the oxygen-bound hydrogen in BCD. This is created by a negative charge that is repelled by hydrogen separated from oxygen, which causes negatively charged oxygen to form in IB; in turn, this prevents the further absorption of IB. Probably in an acidic medium, the oxygens bonded to BCD and the carbonyl groups of IB are protonated; thus, they have positive charges and repel each other. In a basic medium, the hydroxyl groups of BCD and IB have negative charges that prevent the absorption of IB.

3.2.3. General Method for the Optimization of Temperature

The PCD-zeolite (0.03 g) and IB (10% by weight) were added into ethanol/water (40:60, v/v) with pH = 7 at 25 and 50 °C (Figure 8). Absorptions of 28.71 and 21.01% are obtained using the standard calibration curve achieved, respectively. These results show that the best IB absorption is obtained at room temperature.

3.2.4. General Method to Optimize the Amount of IB

The various amounts of IB (10, 20, 30, and 40 wt%) and the PCD-zeolite (0.03 g) were explored in ethanol/water (40:60, v/v) at pH = 7 at 25 °C (Figure 9). After 24 h, the absorptions (28.71, 41.81, 62, and 70.41%, respectively) are obtained. These results show that with increasing the amount of IB, the percentage of absorption increases.

3.3. In Vitro Reduction-Triggered Release of IB from the PCD-Zeolite in a Phosphate Buffer

The release of IB from the PCD-zeolite was studied by a dialysis method. In brief, the PCD-zeolite (0.03 g) containing IB (10, 20, 30, and 40% by weight) was transferred to a dialysis bag (MWCO 40,000 Da), and dialyzed samples were placed in 10 mL of a phosphate buffer with pH = 7 in a shaking incubator at 37 °C (100 rpm). The amount of released IB was determined using UV–VIS spectroscopy at 222 nm, and the content of IB was calculated via the standard calibration curve achieved. Figure 10 shows that when 30 and 40% of IB are loaded into the PCD-zeolite, the majority of drug release is related. According to the results obtained above, the PCD-zeolite containing 30% of IB was selected to investigate the release of IB at pH = 3.6 and 10. The results show that pH = 3.6 has the highest drug release (Figure 11).

4. Conclusions

Poly (β-cyclodextrin-co-citric acid) functionalized natural NZ was successfully synthesized as a new release delivery system. First, the structure of the nanocomposite is characterized using FT-IR, TGA, and TEM techniques. The FT-IR spectra of the nanocomposite confirm the presence of a polymer coating around the zeolite, and the presence of IB in the structure of the PCD-zeolite. The TGA analysis shows that the synthesized nanocomposite is stable at up to 160 °C. The TEM analysis of PCD-zeolite-IB shows that the particle size is less than 200 nm. The best conditions for drug uptake, such as temperature (25 and 50 °C), dose (0.03 and 0.05 g), and pH (3.6, 7, and 10), were studied. The results showed that 0.03 g of the PCD-zeolite, room temperature, and pH = 7 are the best conditions for IB absorption. In addition, the in vitro release of IB from the PCD-zeolite in a phosphate buffer was studied; pH = 3.6 has the highest release rate of IB. This study showed that the PCD-zeolite shows promising results, and could be used in the future for specialized drug delivery platforms.

Author Contributions

Conceptualization, S.M.B. and S.K.; methodology, N.J.; software, S.M.B.; validation, S.M.B. and S.K.; formal analysis, S.M.B. and S.K.; investigation, N.J., S.M.B. and S.K.; resources, N.J., S.M.B. and S.K.; data curation, S.M.B.; writing—original draft preparation, S.M.B. and S.K.; writing—review and editing, S.M.B. and S.K.; visualization, N.J., S.M.B. and S.K.; supervision, S.M.B. and S.K.; project administration, S.M.B.; funding acquisition, N.J. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in the article and Supplementary Materials.

Acknowledgments

This research is supported by the Islamic Azad University, Ayatollah Amoli Branch, I.R. Iran.

Conflicts of Interest

The authors declare that they have no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

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Figure 1. Synthesis approach of polybetacyclodextrin-co-citric acid/NZ clinoptilolite (PCD-Zeolite).

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Figure 2. TGA curve of NZ.

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Figure 3. TGA curve of the PCD-zeolite.

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Figure 4. TGA curve of PCD-zeolite-IB.

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Figure 5. TEM image of PCD-zeolite-IB.

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Figure 6. Optimization of the amount of the PCD-zeolite.

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Figure 7. Optimization of pH for the absorption of IB.

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Figure 8. Optimization of temperature for the absorption of IB.

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Figure 9. Optimization of the amount of IB for the absorption of IB.

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Figure 10. Evaluation of the release of various amounts of IB from the PCD-zeolite.

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Figure 11. Evaluation of the release of IB at pH = 3.6, 7, and 10.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/app12168241/s1, Figure S1: Standard curve of IB for (a) drug loading and drug release calculation in (b) pH = 7, (c) pH = 3.6 and (d) pH = 10. Figure S2: FT-IR of NZ. Figure S3: FT-IR of β-cyclodextrin. Figure S4: FT-IR of polybetacyclodextrin-co-citric acid/NZ clinoptilolite (PCD-Zeolite). Figure S5: FT-IR of ibuprofen. Figure S6: FT-IR of PCD-Zeolite-IB.

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