Table of Contents Author Guidelines Submit a Manuscript
International Journal of Polymer Science
Volume 2018, Article ID 2071071, 7 pages
https://doi.org/10.1155/2018/2071071
Research Article

Pectin-Coated Curcumin-Chitosan Microparticles Crosslinked with Mg2+ for Delayed Drug Release in the Digestive System

Department of Chemistry, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea

Correspondence should be addressed to Jae Sup Shin; rk.ca.kubgnuhc@nihssj

Received 21 May 2018; Revised 12 August 2018; Accepted 14 August 2018; Published 17 September 2018

Academic Editor: Qinglin Wu

Copyright © 2018 Seung Won Hwang and Jae Sup Shin. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Curcumin-loaded chitosan-pectin microparticles based on polymeric microencapsulation were prepared by two methods to delay the release of curcumin in the digestive system, employing Mg2+ as a pectin-crosslinking agent for the first time. Pectin-coated curcumin-chitosan microparticles (C-g-PMg) and curcumin-loaded chitosan-pectin composite microparticles (C-PMg-g) were formulated, and their release profiles at pH 1.2 and at pH 6.8 were tested. The former (C-g-PMg) showed slower curcumin release profiles than the latter (C-PMg-g) because the C-g-PMg are composed of two layers, a chitosan-glutaraldehyde layer and a pectin-Mg2+ layer, which together hold the curcumin for a longer duration. Of the pectin-coated microparticles, those crosslinked with Mg2+ showed a slower release rate than those crosslinked with Ca2+, but the former showed a faster release rate at pH 6.8 in the presence of pectinase, acting as a promising drug delivery carrier for treating a colonic disease. The pectin layer and the pectin-crosslinking agent play a vital role in prolonging the release of curcumin until pectin is degraded by pectinase.

1. Introduction

Curcumin, 1,7-bis[4-hydroxy-3-methoxyphenyl]-1,6-heptadiene-3,5-dione, which has been used for centuries in traditional Indian medicines, spices, and food colorings, is a polyphenol with conjugated double bonds [1, 2]. Curcumin is safe and nontoxic, exhibiting a broad range of biological activities such as anti-inflammatory, antioxidant, antimicrobial, antitumor, anticoagulant, antiviral, and antiamyloid properties [24]. Preclinical studies on curcumin also found that it inhibits carcinogenesis in a variety of cell lines, including breast, colon, gastric, liver, leukemia, oral epithelial, ovarian, pancreatic, and prostate [1]. The medicinal benefits of curcumin are limited by its extremely low aqueous solubility, rapid metabolism, and instability in the gastric fluid [36]. However, curcumin is soluble in low polar solvents such as ethanol and acetone. Curcumin dissolved in low polar foods can be easily metabolized in the stomach. Thus, relevant formulation strategies based on polymeric nano/microencapsulation have been employed to prevent the metabolism of curcumin at the upper part of the GIT (gastrointestinal tract) for medical use [5].

Encapsulation technologies using polymeric drug delivery systems to improve pharmacological response and to allow time- and distribution-controlled drug delivery have been studied in detail [713]. Various types of polymers have been used, such as nano- and microparticles, micelles, dendrimers, and capsosomes, where drugs can be encapsulated or conjugated in polymer matrices [13]. These drug carriers have been used in a wide range of treatments, including antineoplastic activity, bacterial infections, and inflammatory processes, and vaccines [13]. Polymers used in drug delivery systems play a vital role in providing controlled drug release in which constant dosing, cyclic dosing, and the tunable release of both hydrophilic and hydrophobic drugs can be accomplished over long periods [14]. Such delivery systems retain the structural integrity of a drug, protecting the drug from degradation in the upper GIT [5, 6].

Of the biopolymers derived from natural sources, chitosan is particularly well-suited for mucosal delivery, being relatively nonimmunogenic and nontoxic, as well as having good biodegradability and biocompatibility. Chitosan-based particles have been studied for the effective delivery of many drugs, including anticancer agents, therapeutic proteins, genes, and antigens [1518]. Chitosan is poorly soluble in water, but it easily dissolves in acidic environments such as the gastric fluid in the stomach. Upon protonation in an acidic environment, it stays positively charged and can interact with negatively charged molecules [19], which plays an important role in drug transport and in the reduction of enzymatic drug degradation in the GIT [16]. Moreover, chitosan crosslinked with a hardening agent can impede the degradation of drug molecules in the GIT [20].

A second biopolymer such as pectin which is a water-soluble and linear anionic polysaccharide in the primary cell walls of most plants has been used in conjunction with chitosan, which forms a stable polymer complex [1, 5]. Since chitosan and pectin are oppositely charged, they interact through intermolecular electrostatic attractions to form a polyelectrolyte complex structure. The complex remains stable until its pectin component is degraded by pectinase enzymes produced by the colonic microflora [5, 21]. The microorganisms that ferment pectin exist in the colon and are qualitatively consistent in composition across a diverse human population [22]. However, pectin alone is unsuitable for drug transport as it swells under alkaline conditions, potentially triggering premature release of the drug contents [5]. The complexation of pectin with chitosan or the crosslinking of pectin by divalent metal cations such as Ca2+ decreases the permeability, solubility, and disintegration extent of the polymer structure but increases the density and mechanical strength of the dosage form [23], thereby delaying the release of the drug. The physical crosslinking through electrostatic interactions between Ca2+ and the negatively charged carboxyl groups of pectin strengthens the rigidity of the polymer gel.

This study was designed to prolong and control the release of curcumin by encapsulating it with the biodegradable polymers, chitosan and pectin. Specifically, curcumin-loaded chitosan-pectin microparticles were prepared by two new methods, and their relative abilities to accomplish a delayed release of curcumin in the GIT were measured. A microparticle can encapsulate a higher amount of curcumin than a nanoparticle which may contain little or no curcumin due to its small size. In the first method, curcumin-loaded chitosan microparticles were fabricated using glutaraldehyde as a hardening agent and then coated by pectin which was complexed with Mg2+ cations (called C-g-PMg, referring to chitosan-glutaraldehyde, and pectin crosslinked by Mg2+). Generally, Ca2+ has been used as a pectin-crosslinking agent. In this research, Mg2+ was used for the first time as a pectin-crosslinking agent because it is one of the important electrolytes in the human body. The release rate of curcumin resulting from Mg2+ was compared with that resulting from Ca2+ cations. In the second method, pectin was added to a mixture of chitosan-curcumin solutions to formulate the composite particles which were hardened by glutaraldehyde (called C-PMg-g, referring to chitosan-pectin composite crosslinked by Mg2+, and hardened by glutaraldehyde). The curcumin release profiles of the microparticles were observed to compare the effects of the formulation method, pectinase, and divalent cations on drug release. Thermal analysis on pectin-M2+, where M2+ = Mg2+ or Ca2+ gel, was conducted to identify the release rate of curcumin in relation to the network strength of pectin-M2+.

2. Materials and Methods

2.1. Materials

Chitosan was obtained from Showa Chemical Industry Co. Ltd. (Tokyo, Japan). Curcumin (synthetic, >97.0%) and pectin (from citrus) were purchased from Tokyo Chemical Industry Co. Ltd. (Tokyo, Japan). Pectinase (from Aspergillus aculeatus), glutaraldehyde solution (50% in water), span 80, and MgCl2·6H2O were supplied by Sigma-Aldrich (St. Louis, MO, USA). CaCl2·2H2O, tween 80, NaCl (>99%), HCl (>35%), and toluene (>99.5%) were purchased from Daejung Chemical Co. Ltd. (Shiheung City, South Korea). Na3PO4·12H2O (G.R.) and liquid paraffin were supplied by Junsei Chemical Co. Ltd. (Tokyo, Japan).

2.2. Preparation of Microparticles

Before formulating the microparticles, the glutaraldehyde saturated toluene as a hardening agent for chitosan was prepared as follows.

A glutaraldehyde solution (25 ml, 50% in water) and toluene (25 ml) were placed in a beaker and stirred at 1000 rpm for two hours. Then, the mixture was poured into a separatory funnel and allowed to stabilize. After 15 hours, the upper toluene layer saturated with glutaraldehyde was decanted and used as the glutaraldehyde saturated toluene solution [24].

2.2.1. Method A: Pectin-Coated Curcumin-Chitosan Microparticles (C-g-PM, where M = Mg or Ca)

Chitosan (0.35 g) was dissolved in 1% (v/v) aqueous acetic acid solution (15 ml). The solution was stirred at 700 rpm for 15 hours. Under continuous magnetic stirring, a solution of curcumin (3.5 mg) dissolved in ethanol (7 ml) was slowly added. The mixture was incorporated into liquid paraffin (100 ml) containing span 80 (1.5 ml) by dropwise addition, with further stirring at 1500 rpm for 30 minutes. It was homogenized at 5000 rpm for 40 minutes with a homomixer (T.K. Homomixer Mark II 2.5, Primix Co.). Next, glutaraldehyde saturated toluene solution (2 ml) was added dropwise, and the mixture was homogenized at 5000 rpm for one hour to facilitate external crosslinking, where aldehyde groups of a glutaraldehyde molecule crosslink with chitosan chains of the surface of a microparticle. For the internal crosslinking of the microparticles, glutaraldehyde solution (0.4 ml, 50% in water) was added dropwise. The mixture was homogenized at 5000 rpm for an additional hour and centrifuged (Hanil Sci. Ind. Co. MF80) at 4000 rpm for five minutes. Subsequently, the precipitate of curcumin-loaded chitosan particles (called C-g, referring to chitosan-glutaraldehyde) was washed twice with n-hexane. After 0.5% (w/v) pectin solution (70 ml) containing tween 80 (0.7 ml) was homogenized, the dried C-g were poured into the solution, followed by continuous homogenization at 5000 rpm for 30 minutes and the entire mixture was centrifuged. The pectin-coated precipitate (called C-g-P, referring to chitosan-glutaraldehyde-pectin) was added to 5% (w/v) MgCl2·6H2O or CaCl2·2H2O solution (80 ml) to crosslink the pectin layer and was homogenized at 5000 rpm for one hour. The resulting mixture was centrifuged, washed twice with distilled water, and then freeze-dried.

2.2.2. Method B: Curcumin-Loaded Chitosan-Pectin Composite Microparticles (C-PMg-g)

Chitosan (0.35 g) was dissolved in 1% (v/v) aqueous acetic acid solution (15 ml), followed by the addition of MgCl2·6H2O (0.2 g). This solution was stirred at 700 rpm for 15 hours. Under continuous magnetic stirring, a solution of curcumin (3.5 mg) dissolved in ethanol (7 ml) was added slowly. This solution was incorporated into liquid paraffin (100 ml) containing span 80 (1.5 ml) by dropwise addition, stirred at 1500 rpm for 30 minutes, and homogenized at 5000 rpm for 40 minutes. Then, 1% (w/v) pectin solution (2 ml) was dropped into the mixture, with further homogenization for 30 minutes. A saturated solution of glutaraldehyde in toluene (2 ml) was added dropwise into the solution for external crosslinking, and the mixture was homogenized continuously for one hour. Subsequently, glutaraldehyde solution (0.4 ml, 50% in water) was dropped into the mixture for the internal crosslinking of chitosan microparticles, with further homogenization for one hour. The entire solution was centrifuged, and the precipitate of chitosan-pectin composite microparticles was washed twice with n-hexane. Figure 1 describes the fabrication schemes for methods A and B. The morphology of the microparticles dried at room temperature was determined by SEM (Ultra Plus, Carl Zeiss). Figure 2 shows the schematic microparticles formulated by methods A and B.

Figure 1: Fabrication schemes for (a) C-g-PMg and (b) C-PMg-g, where C is chitosan, Cur. is curcumin, G is glutaraldehyde, P is pectin, and PPT is precipitate.
Figure 2: Schematic presentation of C-g-PMg and C-PMg-g formulated by methods A and B.
2.3. Preparation of SGF (Simulated Gastric Fluid) and SI/CF (Simulated Intestinal/Colonic Fluid)

Prior to the determination of the encapsulation efficiencies and the in vitro curcumin release test, SGF and SI/CF were prepared to mimic the natural dissolution conditions of a typical human GIT: SGF of pH 1.2 was produced by introducing sodium chloride (2.0 g) into 0.1 M HCl (1 L), and SI/CF of pH 6.8 was made from a mixture of 0.2 M Na3PO4·12H2O (250 ml) and the SGF (750 ml) at a volume ratio of 1 to 3 [25].

2.4. EE (Encapsulation Efficiency)

For the calibration of curcumin, the absorbance intensities of the standard curcumin solutions of pH 1.2 (SGF condition) and of pH 6.8 (SI/CF condition) containing 1% (v/v) tween 80 were measured at 427 nm by a UV-VIS spectrophotometer (Scinco Co., LTD S-3100) [1]. The experiment was carried out in triplicate. The microparticles obtained from methods A and B (about 15 mg) were ground for 30 minutes to break them down completely. Each ground sample was weighed and dissolved in SGF (20 ml) of pH 1.2 containing 1% (v/v) tween 80 at 37 ± 0.5 °C. The solution was stirred at 50 rpm for two hours and then centrifuged. The absorbance of the resulting supernatant was measured at 427 nm to estimate the amount of curcumin released in the SGF. Next, the precipitate sample was taken into SI/CF (20 ml) of pH 6.8 containing 1% (v/v) tween 80 at 37 ± 0.5 °C. The solution was stirred at 50 rpm for three hours, and 1% (v/v) pectinase enzyme (0.2 ml) was added. After stirring the resulting solution for 12 hours followed by centrifugation, the absorbance of the supernatant was measured again to determine the amount of curcumin released in the SI/CF. The encapsulation efficiency is as follows: where is the initial total amount of curcumin used and is the loaded amount of curcumin in the sample, that is, is the released amount of curcumin from the ground sample in the SGF for two hours and in the SI/CF for 15 hours. The experiments were performed three times.

2.5. Measurement of In Vitro Curcumin Release

In vitro curcumin release profiles were investigated by observing the release rates of the encapsulated curcumin, with slight modifications of the USP (United States Pharmacopeia) dissolution procedure [25]. SGF maintained at 37 ± 0.5 °C (20 ml) was added to each sample (15 mg) with stirring at 50 rpm to measure the amount of curcumin released in SGF for two hours. After centrifugation of the SGF solution, 20 ml of SI/CF was transferred to the remaining precipitated sample for the release test until the 12th hour, which was also immersed in a water bath maintained at 37 ± 0.5 °C with a rotation speed of 50 rpm. The detailed procedure for the measurement of the curcumin release is illustrated below.

From the beginning (0 hour) to the 2nd hr, the measurement was performed in the SGF as the gastric dissolution medium. During the 3rd to the 12th hr, the release test was carried out in the SI/CF as the intestinal/colonic dissolution medium. During the 6th to the 12th hr, the measurement was conducted in the absence or in the presence of 1% (v/v) pectinase to study the effects of the enzyme on Mg2+- and Ca2+-pectinates. For the experiment, pectinase was added to the SI/CF medium at the 5th hr to observe the release profile from the 6th hr. Throughout the release studies, 1% (v/v) tween 80 was added to the SGF and the SI/CF to prevent the possible sedimentation of curcumin released. 3 ml of the supernatant was periodically withdrawn from each dissolution medium at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12th hr, followed by keeping the total volume of dissolution medium constant after each sampling. The absorbance of each sample was measured at 427 nm, and the curcumin released from the microparticles was estimated. The experiments were performed in triplicate.

2.6. Thermal Analysis

The strengths of crosslinks between pectin and the divalent metal cations in the surfaces of the microparticles were characterized by thermal analysis (Scinco Co., STA N-1000). Specifically, 5% (w/v) pectin solution (5 ml) was added to a 10% (w/v) solution of MgCl2·6H2O or CaCl2·2H2O (5 ml) under slow stirring. After gelation, the samples were freeze-dried. Each sample (3–6 mg) was accurately weighed and placed into a platinum pan for thermal analysis from 100 °C up to 600 °C. The heating rate was kept at 15 °C/min under the atmospheric condition.

3. Results and Discussion

The SEM image of C-g-PMg is depicted in Figure 3(a). The microparticles prepared by method A have double-layered walls, wherein the pectin coats the surfaces of curcumin-loaded chitosan microparticles. The inner layer is formed by crosslinking the chitosan with glutaraldehyde, which builds the spherically shaped microparticles. The outer layer is formed by the pectin-Mg2+ structural network. Thus, two or more chitosan microparticles are often coated together by a pectin layer as seen in Figure 3(a). The C-g-PMg prepared by method A has a thick pectin layer, and the particle size is 6 ± 2.5 μm. In contrast, the C-PMg-g prepared by method B have a single-layered wall in the form of a chitosan-pectin composite with the particle size being 4 ± 1.5 μm and exhibit more clearly shaped particles than those produced by method A as shown in Figure 3(b). The positively charged chitosan and Mg2+ ion interact with the negatively charged pectin in the composite that is hardened again with glutaraldehyde, building spherically shaped microparticles. Figure 3(c) depicts the SEM image of C-g-PCa microparticles prepared by method A. They also show double-layered walls, where the outer layer is formed by the pectin-Ca2+ structural network.

Figure 3: SEM images of (a) C-g-PMg, (b) C-PMg-g, and (c) C-g-PCa.

The EE (%) of the microparticles, C-g-PMg, C-PMg-g, C-g-PCa, C-g-P, and C-g, is listed in Table 1. The EE (%) value is relatively low for C-g prepared in the absence of pectin, indicating that the incomplete structural network of chitosan is not strong enough to encapsulate the curcumin.

Table 1: Encapsulation efficiencies (%) of curcumin-loaded chitosan-pectin microparticles.

Figure 4 reveals the cumulative curcumin release (%) at pH 1.2 and at pH 6.8 in the absence of pectinase and in the presence of pectinase for the two samples prepared by methods A (C-g-PMg) and B (C-PMg-g). The slope at each time in the figure reflects the release rate of curcumin. The microparticles synthesized by method B are enclosed with a single-layered wall and show a faster release rate than those produced by method A, holding the curcumin inside the microparticles less strongly than the C-g-PMg. In contrast, microparticles prepared by method A have double-layered surface membranes, due to chitosan-glutaraldehyde crosslinks and pectin-Mg2+, holding curcumin for a longer duration, thereby prolonging the release of curcumin in a simulated digestive system. Specifically, the curcumin release is below 10% in SGF for the first two hours, which is about four times lower in value than the release from the C-PMg-g in SGF. However, the curcumin release from the C-g-PMg increases abruptly from the 6th hr in the presence of pectinase. This demonstrates that curcumin is readily released from the microparticles after the outer pectin-Mg2+ surfaces of C-g-PMg particles are degraded by pectinase. Degradation of the pectin layer on a C-g-PMg particle is accelerated by pectinase. Then, the inner layer which becomes exposed to the SI/CF begins to release curcumin more rapidly. Hence, C-g-PMg formulated by method A are very effective in treating a colonic disease because they prolong the release of curcumin over the longest period of time in the GIT but release it quickly in the colon where pectinase is present.

Figure 4: Curcumin release (%) profiles of C-g-PMg (filled circle) prepared by method A and C-PMg-g (filled square) prepared by method B in the absence of pectinase. The release profiles of C-g-PMg (open circle) and C-PMg-g (crossed square) in the presence of pectinase from the 6th hour.

The plots for both C-g-PMg and C-g-PCa in the absence of pectinase and in the presence of pectinase are presented in Figure 5 to compare the effect of the pectin-crosslinking agent on the release of curcumin, where Mg2+ is newly employed in this study and Ca2+ has been generally used as a pectin-crosslinking agent. The C-g-PMg sustain the release of curcumin for a longer period of time than C-g-PCa in the absence of pectinase, but they release curcumin more quickly than C-g-PCa microparticles when pectinase is present, which reconfirms that C-g-PMg are highly effective in treating a colonic disease compared with C-g-PCa microparticles. This demonstrates that the drug release profile of pectin-based dosage forms strongly depends on the nature of the divalent cations used.

Figure 5: Curcumin release (%) for C-g-PMg (filled circle) and for C-g-PCa (filled rhombus) prepared by method A in the absence of pectinase. Curcumin release for C-g-PMg (circled square) and for C-g-PCa (crossed square) in the presence of pectinase from the 6th hr.

A study on the relative strength of the pectin-M2+ network through thermal analysis in the temperature range from 300 to 600 °C was performed (see Figure 6). The pectin component of the pectin-M2+ network does not decompose at temperatures below 320 °C, except for the dehydration processes such as MgCl2·6H2O → MgCl2·4H2O → MgCl2·2H2O → MgCl2·H2O and CaCl2·2H2O → CaCl2·H2O → CaCl2 [26]. The degradation of the pectin component is mainly observed at temperatures above 350 °C. Of the crosslinked pectin-M2+, the decomposition temperature of calcium pectinate is lower than that of magnesium pectinate as observed in Figure 6, suggesting that magnesium pectinate forms a stronger network than that of calcium pectinate. In other words, the Mg2+ ion has a smaller size and a higher charge density, compared with the Ca2+ ion. Thus, the microparticles crosslinked with Mg2+ show a prolonged release rate due to the structurally stronger pectin-Mg2+ network in the absence of pectinase as described in Figure 5.

Figure 6: Thermal analysis of pectin-Mg2+ and pectin-Ca2+ gels.

Figure 7 depicts the release of curcumin for curcumin-loaded chitosan microparticles (C-g), pectin-coated chitosan microparticles (C-g-P) in the absence of pectin-crosslinking agent, and pectin-coated curcumin-chitosan microparticles (C-g-PMg) crosslinked with Mg2+. From the cumulative release profiles of the three types of microparticles, it can be observed that the roles of the pectin layer and the pectin-crosslinking agent are crucial in delaying the release of curcumin in the digestive system. Thus, the delayed release of curcumin could be achieved in this study by encapsulating it with a pectin-coated chitosan layer, in which Mg2+ acts as a pectin-crosslinking agent.

Figure 7: Cumulative release (%) of curcumin for C-g (filled triangle), C-g-P (crossed square), and C-g-PMg (filled circle) in the absence of pectinase.

4. Conclusions

In order to prolong the medicinal benefits of curcumin by delaying its release in a simulated digestive system, formulation strategies based on chitosan/pectin microencapsulation techniques were used. For this purpose, glutaraldehyde was employed as a hardening agent for chitosan and the newly selected Mg2+ was utilized as a pectin-crosslinking agent. Two new methods were applied to prepare spherically shaped curcumin-loaded chitosan-pectin microparticles in the W/O phase. In method A, the curcumin-loaded chitosan-glutaraldehyde microparticles were coated by pectin, followed by their complexation with Mg2+ (C-g-PMg). In method B, pectin was added to a mixture of Mg2+ chloride and curcumin-loaded chitosan solutions to form a composite, in which pectin and chitosan were crosslinked with Mg2+ and glutaraldehyde (C-PMg-g), respectively. The release profiles of curcumin were investigated to study the effect of its release in the simulated digestive system, that is, in the SGF medium of pH 1.2 for the first two hours and in the SI/CF medium of pH 6.8 from the 3rd to the 12th hr at 37 ± 0.5 °C. The release of curcumin was found to be more prolonged for the pectin-coated microparticles (C-g-PMg), because of their double layer effect, than for the chitosan-pectin composite (C-PMg-g) particles. The microparticles crosslinked with Mg2+ showed a slower release rate in the absence of pectinase, but they showed a faster release rate in the presence of pectinase compared with those crosslinked with Ca2+ which has been used as a conventional pectin-crosslinking agent. The pectin layer and the pectin-crosslinking agent played a very important role in delaying the release of curcumin. The experimental results show that the C-g-PMg are promising drug delivery carriers in treating the colon, where a large amount of curcumin is released.

Data Availability

The data (figures and a table) that support the findings of this study are available from the corresponding author upon request.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

Acknowledgments

This work was financially supported by the Research Year of Chungbuk National University in 2016.

References

  1. A. T.-B. Nguyen, P. Winckler, P. Loison, Y. Wache, and O. Chambin, “Physico-chemical state influences in vitro release profile of curcumin from pectin beads,” Colloids and Surfaces B: Biointerfaces, vol. 121, pp. 290–298, 2014. View at Publisher · View at Google Scholar · View at Scopus
  2. B. Boruah, P. M. Saikia, and R. K. Dutta, “Binding and stabilization of curcumin by mixed chitosan–surfactant systems: a spectroscopic study,” Journal of Photochemistry and Photobiology A: Chemistry, vol. 245, pp. 18–27, 2012. View at Publisher · View at Google Scholar · View at Scopus
  3. R. Nazari-Vanani, L. Moezi, and H. Heli, “In vivo evaluation of a self-nanoemulsifying drug delivery system for curcumin,” Biomedicine and Pharmacotherapy, vol. 88, pp. 715–720, 2017. View at Publisher · View at Google Scholar · View at Scopus
  4. J. Shaikh, D. D. Ankola, V. Beniwal, D. Singh, and M. N. V. R. Kumar, “Nanoparticle encapsulation improves oral bioavailability of curcumin by at least 9-fold when compared to curcumin administered with piperine as absorption enhancer,” European Journal of Pharmaceutical Sciences, vol. 37, no. 3-4, pp. 223–230, 2009. View at Publisher · View at Google Scholar · View at Scopus
  5. E. Alkhader, N. Billa, and C. J. Roberts, “Mucoadhesive chitosan-pectinate nanoparticles for the delivery of curcumin to the colon,” AAPS PharmSciTech, vol. 18, no. 4, pp. 1009–1018, 2017. View at Publisher · View at Google Scholar · View at Scopus
  6. L. Zhang, F. Cao, B. Ding, Q. Li, Y. Xi, and G. Zhai, “Eudragit® S100 coated calcium pectinate microspheres of curcumin for colon targeting,” Journal of Microencapsulation, vol. 28, no. 7, pp. 659–667, 2011. View at Publisher · View at Google Scholar · View at Scopus
  7. V. H. K. Li, R. W. Wood, J. Kreuter, T. Harmia, and J. R. Robinson, “Ocular drug delivery of progesterone using nanoparticles,” Journal of Microencapsulation, vol. 3, no. 3, pp. 213–218, 1986. View at Publisher · View at Google Scholar · View at Scopus
  8. K. Kazunori, K. Glenn S., Y. Masayuki, O. Teruo, and S. Yasuhisa, “Block copolymer micelles as vehicles for drug delivery,” Journal of Controlled Release, vol. 24, no. 1–3, pp. 119–132, 1993. View at Publisher · View at Google Scholar · View at Scopus
  9. W. R. Gombotz and D. K. Pettit, “Biodegradable polymers for protein and peptide drug delivery,” Bioconjugate Chemistry, vol. 6, no. 4, pp. 332–351, 2002. View at Publisher · View at Google Scholar · View at Scopus
  10. R. Langer, “Drug delivery and targeting,” Nature, vol. 392, no. 6679, pp. 5–10, 1998. View at Google Scholar
  11. D. Peer, J. M. Karp, S. Hong, O. C. Farokhzad, R. Margalit, and R. Langer, “Nanocarriers as an emerging platform for cancer therapy,” Nature Nanotechnology, vol. 2, no. 12, pp. 751–760, 2007. View at Publisher · View at Google Scholar · View at Scopus
  12. S. Mitragotri, P. A. Burke, and R. Langer, “Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies,” Nature Reviews Drug Discovery, vol. 13, no. 9, pp. 655–672, 2014. View at Publisher · View at Google Scholar · View at Scopus
  13. G. Vilar, J. Tulla-Puche, and F. Albericio, “Polymers and drug delivery systems,” Current Drug Delivery, vol. 9, no. 4, pp. 367–394, 2012. View at Publisher · View at Google Scholar · View at Scopus
  14. W. B. Liechty, D. R. Kryscio, B. V. Slaughter, and N. A. Peppas, “Polymers for drug delivery systems,” Annual Review of Chemical and Biomolecular Engineering, vol. 1, no. 1, pp. 149–173, 2010. View at Publisher · View at Google Scholar · View at Scopus
  15. I. Younes and M. Rinaudo, “Chitin and chitosan preparation from marine sources. Structure, properties and applications,” Marine Drugs, vol. 13, no. 3, pp. 1133–1174, 2015. View at Publisher · View at Google Scholar · View at Scopus
  16. A. R. Dudhani and S. L. Kosaraju, “Bioadhesive chitosan nanoparticles: preparation and characterization,” Carbohydrate Polymers, vol. 81, no. 2, pp. 243–251, 2010. View at Publisher · View at Google Scholar · View at Scopus
  17. L. Qi, Z. Xu, X. Jiang, C. Hu, and X. Zou, “Preparation and antibacterial activity of chitosan nanoparticles,” Carbohydrate Research, vol. 339, no. 16, pp. 2693–2700, 2004. View at Publisher · View at Google Scholar · View at Scopus
  18. W. Fan, W. Yan, Z. Xu, and H. Ni, “Formation mechanism of monodisperse, low molecular weight chitosan nanoparticles by ionic gelation technique,” Colloids and Surfaces B: Biointerfaces, vol. 90, pp. 21–27, 2012. View at Publisher · View at Google Scholar · View at Scopus
  19. Y. Gokce, B. Cengiz, N. Yildiz, A. Calimli, and Z. Aktas, “Ultrasonication of chitosan nanoparticle suspension: influence on particle size,” Colloids and Surfaces A: Physicochemical and Engineering Aspects, vol. 462, pp. 75–81, 2014. View at Publisher · View at Google Scholar · View at Scopus
  20. S. A. Agnihotri, N. N. Mallikarjuna, and T. M. Aminabhavi, “Recent advances on chitosan-based micro- and nanoparticles in drug delivery,” Journal of Controlled Release, vol. 100, no. 1, pp. 5–28, 2004. View at Publisher · View at Google Scholar · View at Scopus
  21. S. Das, A. Chaudhury, and K.-Y. Ng, “Preparation and evaluation of zinc–pectin–chitosan composite particles for drug delivery to the colon: role of chitosan in modifying in vitro and in vivo drug release,” International Journal of Pharmaceutics, vol. 406, no. 1-2, pp. 11–20, 2011. View at Publisher · View at Google Scholar · View at Scopus
  22. L. Liu, M. L. Fishman, J. Kost, and K. B. Hicks, “Pectin-based systems for colon-specific drug delivery via oral route,” Biomaterials, vol. 24, no. 19, pp. 3333–3343, 2003. View at Publisher · View at Google Scholar · View at Scopus
  23. T. W. Wong, G. Colombo, and F. Sonvico, “Pectin matrix as oral drug delivery vehicle for colon cancer treatment,” AAPS PharmSciTech, vol. 12, no. 1, pp. 201–214, 2011. View at Publisher · View at Google Scholar · View at Scopus
  24. K. C. Ofokansi, F. C. Kenechukwu, A. B. Isah, and E. L. Okigbo, “Formulation and evaluation of glutaraldehyde-crosslinked chitosan microparticles for the delivery of ibuprofen,” Tropical Journal of Pharmaceutical Research, vol. 12, no. 1, pp. 19–25, 2013. View at Publisher · View at Google Scholar · View at Scopus
  25. USPNF, United States Pharmacopeia [USP] 35 – National Formulary [NF] 30 (online), Dissolution (Revision Bulletin), United States Pharmacopeial Convention, Inc., Rockville, MD, USA, 2012.
  26. V. M. Van Essen, J. C. Gores, L. P. Bleijendaal et al., “Characterization of salt hydrates for compact seasonal thermochemical storage,” in ASME 2009 3rd International Conference on Energy Sustainability, pp. 825–830, San Francisco, CA, USA, July 2009. View at Publisher · View at Google Scholar · View at Scopus