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Abstract

The present research was aimed to design a benign bio-composite hydrogel based on dextran and glucoxylan (a polysaccharide isolated from chia seed, i.e., CSH) using citric acid (CA) as a cross-linking agent for developing a pH-dependent drug delivery system (DDS). The glucoxylan suspension was heated with the aqueous solution of CA and dextran at 80°C for 24 h. High swelling capacity of Dextran-CA-CSH (powder and tablet) was observed in distilled water (DW) and buffer solutions of pH 6.8 and 7.4, while negligible swelling was witnessed at pH 1.2. The swelling capacity of Dextran-CA-CSH (powder and tablet) in aqueous solutions of NaCl and KCl was decreased with increasing concentration. Comparatively, the swelling capacity of Dextran-CA-CSH (powder and tablet) in aqueous solution of NaCl was greater than in aqueous solution of KCl. The swelling-deswelling (on/off switching) properties of Dextran-CA-CSH (powder and tablet) versus different stimuli such as pH 7.4 and pH 1.2, DW and normal saline, and DW and ethanol revealed its stimuli-responsive nature. The release of diclofenac sodium (DFS) from the tablet formulation of Dextran-CA-CSH was pH dependent and followed the first-order kinetic model as well as a non-Fickian diffusion mechanism. Hence, these preliminary studies confirmed the pH-responsive nature of the Dextran-CA-CSH composite and its usefulness for targeted drug delivery at the pH of the distal parts of the gastrointestinal tract.

Keywords

chia seed hydrogel pH-responsiveness dextran citric acid diclofenac sodium

Introduction

Over the last two decades, the hydrogels isolated from plant seed coats have caught the attention of researchers due to their substantial swelling capabilities, stimuli-responsive properties, pharmaceutical applications, diverse pharmacological and functional food attributes, and commercial utilizations. Hydrogels swell/expand when exposed to liquids such as water or biological fluids and shrink/contract when the swollen hydrogels are exposed to low pH, some organic solvents, light, or electrolyte stress.^1–3 Hydrogels have shown their worth as excellent biomaterials in dentistry,⁴ wound care,⁵ tissue engineering,⁶ bone regeneration,⁷ food and healthcare technology,⁸ injectable polymeric systems,⁹ etc.

Hydrogels derived from natural sources have recently been chemically modified through crosslinking to tune their intrinsic properties including swelling, thermal and saline stability, resistance against microbial contamination, hydration rate, mechanical strength, etc.^10,11 To modify hydrogels, many crosslinkers have been utilized with great success. However, most crosslinkers are expensive, toxic, and need particular handling precautions/procedures; hence their use in biomedical fields especially in formulation development is limited. Because of this, it is crucial to utilize economical, easily accessible, water-soluble, biocompatible, and environmentally friendly crosslinking agents to synthesize new cross-linked/modified biomaterials, especially naturally occurring swellable polysaccharides with desirable features.¹² One such diverse crosslinker that has gained much attention recently is citric acid (CA).¹² The CA, which has the chemical formula C₆H₈O₇, a molecular weight of 210.14 g/mol, and various acid dissociation constants (pKa) of 3.4, 4.7, and 6.4, is a biocompatible and historically significant intermediate in the metabolism of all aerobic organisms, particularly in the Krebs cycle. The main source of industrial CA, produced by various fermentation methods, is Aspergillus niger. Because CA has a single hydroxyl (-OH) group and three carboxylic (-COOH) groups, it may actively engage in hydrogen bonding interactions with other polymer networks and enhance their characteristics. Through cross-linking processes, it is frequently employed as a poly-functional modifier to convert -OH polymers into reactive functional polymers or citrate-based biomaterials.¹³ For this reason, CA as an eco-friendly crosslinker has been used for the cross-linking of carboxymethyl tamarind gum,¹⁴ Salvia spinosa gel,¹⁵ Aloe vera gel,¹⁶, and Mimosa pudica hydrogel.¹⁷

Chia (Salvia hispanica L.) is a famous crop of the mint (Lamiaceae) family. Due to their high nutritional values, the chia seeds have been utilized for the control of diabetes and cardiovascular disorders.¹⁸ The mucilage from chia seeds (CSH) mainly contains xylan polysaccharides which are famous for their high swelling index and pH-responsive behavior.¹⁹ The CSH is a thermally stable, superporous, biocompatible, and pH-dependent drug delivery carrier.²⁰

In light of the need for innovative drug carriers for pH-responsive and sustained-release oral formulations, the current study reports on the modification and use of naturally occurring hydrogel, i.e., CSH as a smart drug delivery system (DDS). This study aims to synthesize a first-order sustained-release DDS by crosslinking CSH and dextran using a green and commercially available agent, i.e., citric acid. The aim is to investigate the swelling properties of bio-composite hydrogel (Dextran-CA-CSH) and its tablets in various biomimetic media, like DW, and different pHs of the gastrointestinal tract (GIT), and salt solutions containing different molar concentrations of NaCl and KCl. The on/off switching capabilities of Dextran-CA-CSH and Dextran-CA-CSH-based tablet formulations will be tested at pH 7.4 and 1.2, DW and normal saline, and DW and ethanol. Additionally, the potential of Dextran-CA-CSH as a sustained release material will be evaluated by conducting the in vitro diclofenac sodium (DFS) release studies.

Materials and methods

Materials

Seeds of S. hispanica were procured from the local market of District Sargodha, Sargodha, Pakistan. Ethanol and methanol were obtained from Riedel-de Haen. CA, potassium hydrogen phosphate, and n-hexane were obtained from Sigma Aldrich, USA. NaCl, HCl, KCl, and NaOH were purchased from BDH Chemicals, England. Dextran was obtained from Bio Basic INC. diclofenac sodium (DFS) was obtained from Sigma Aldrich, USA. In all the experiments, DW was used to extract the CSH and for the preparation of the solutions. For the isolation of hydrogel from chia seeds, nylon woven gauze was used. Tea bags were used to perform the swelling experiments.

Methods

Extraction of hydrogel

Chia seeds were cleaned and soaked in DW for 24 h. Then soaked seeds were rubbed in nylon wire gauze to isolate the hydrogel. The hydrogel (CSH) was extracted according to the already reported procedure¹⁶ and washed in n-hexane and DW to remove the lipophilic and hydrophilic impurities, respectively. Later, the CSH was dried in an oven at 50°C, milled to get powder, and stored in a desiccator for further use.

Synthesis of bio-composite hydrogel

Dextran (1 g) was dissolved in DMAc (20 mL) in a round bottom flask and heated for 30 min at 80°C under stirring. After that, LiCl (1.5 g) was added to the reaction mixture and heated until the mixture became transparent and named solution “A”. The dried CSH (1 g) was taken in another round bottom flask, DW (20 mL) was added to it, and heated for 1 h at 80°C to make a suspension named solution “B”. Both the “A” and “B” solutions were mixed and heated at 80°C for 1 h. A 2% (w/v) aqueous solution of CA was prepared and added to the reaction mixture of solutions “A” and “B” followed by constant stirring and heating for a further 24 h at 80°C. After the completion of the reaction, the product was precipitated by adding methanol, separated through filtration, and kept in a vacuum oven for 24 h at 60°C for drying. Finally, the dried bio-composite hydrogel (Dextran-CA-CSH) was stored in a desiccator until further use in the experimentations.

Measurement

The formation of Dextran-CA-CSH was confirmed by recording FTIR spectra of CSH, CA, Dextran, and Dextran-CA-CSH using the KBr pellet disc method. In this method, discs of the samples were prepared with KBr under hydraulic pressure. The glassy pellets were dried in a vacuum oven at 50°C before analysis to eliminate any surface moisture. The FTIR spectra were recorded in the range of 4000-400 cm^-1 on an IR prestige-20 spectrophotometer (Shimadzu, Japan).

The scanning electron microscope (SEM) equipped with an Everhardt-Thornley detector (ETD) (FEI-NOVA, NanoSEM-450) was used to capture the SEM micrographs of Dextran-CA-CSH to analyze morphological changes in it. To prepare the sample for SEM analysis, Dextran-CA-CSH was first vacuum dried and then 0.2 g was soaked in DW (100 mL). The swollen Dextran-CA-CSH was sonicated for 1/2 h and then freeze-dried. Using a sharp blade, the freeze-dried sample of Dextran-CA-CSH was cut into transverse and longitudinal cross-sections. Before recording the SEM images of Dextran-CA-CSH, gold coating of the cross-sections was done with the help of a sputter coater (Denton, Desk V HP). The images of Dextran-CA-CSH were recorded at different magnifications. To determine the pore size of the transverse and longitudinal cross-sections of Dextran-CA-CSH, the histograms were drawn.

Stimuli-responsive swelling

To check the pH-responsive swelling of Dextran-CA-CSH, a tea bag method was used.²⁰ The Dextran-CA-CSH (100 mg) was packed into the tea bags. The tea bags containing Dextran-CA-CSH were dipped in the beakers having swelling medium, i.e., DW and buffer of pH 7.4, 6.8, and 1.2. After 15 min, the tea bags containing swollen Dextran-CA-CSH were picked out from the beakers and weighed to note the swelling capacity of Dextran-CA-CSH using equation (1). The tea bags were dipped again in all respective swelling media and the swelling process was continued till equilibrium swelling was achieved, i.e., for 480 min.

S w e l l i n g c a p a c i t y (g / g) = \frac{W_{1} - W_{2} - W_{3}}{W_{3}}

(1)

where, W₃ indicates the weight of Dextran-CA-CSH in dry powdered form, W₁ is the weight of the wet tea bag containing Dextran-CA-CSH in swollen form, and W₂ denotes the wet tea bag weight.

Saline-responsive swelling

The saline-responsive swelling of Dextran-CA-CSH was assessed in aqueous solutions of NaCl and KCl having different molar concentrations (0.1 to 2 M). The Dextran-CA-CSH (100 mg) in powder form was packed in tea bags and dipped in each salt solution for 24 h and swelling capacity was measured using equation (1).

Stimuli-responsive swelling-deswelling (on/off switching)

Dextran-CA-CSH (100 mg) was packed in a tea bag and soaked in a 100 mL beaker containing DW (50 mL). The weight of the tea bag containing swollen Dextran-CA-CSH was recorded after 15 min on an analytical balance. The tea bag was dipped again in a beaker containing DW and this process was repeated four times with a time interval of 15 min till 1 h. Then, the same tea bag was transferred to ethanol (50 mL) and deswelling was observed for 1 h. Four cycles of swelling-deswelling were recorded and then calculated the swelling capacity using equation (1). Using the same procedure, the swelling-deswelling of Dextran-CA-CSH was also observed in DW and normal saline as well as at pH 7.4 and 1.2, respectively.

Preparation of tablets

DFS was used as a model drug to evaluate the sustained release potential of Dextran-CA-CSH. A direct compression method was employed to prepare the tablets.²¹ The composition of the tablet was: polymer (Dextran-CA-CSH, 300 mg), DFS (100 mg), and magnesium stearate (10 mg). The powder mixture of polymer, DFS, and magnesium stearate was compressed through a single punch machine using a 9 mm flat surface punch at a hardness of 7.0 ± 0.5 kg/cm².

Swelling and on/off switching behavior of dextran-CA-CSH-based tablet formulation

The tablet formulation of Dextran-CA-CSH was evaluated for swelling capacity determination in DW and at pH 1.2, 6.8, and 7.4. The swelling of Dextran-CA-CSH was also determined in different molar concentrations of NaCl and KCl. Moreover, the swelling deswelling (on/off switching) behavior of Dextran-CA-CSH-based tablets was performed in DW and normal saline, DW and ethanol, and at pH 7.4 and 1.2. These studies were performed through the procedures described in previous sections, i.e., stimuli-responsive swelling, salt-responsive swelling, and stimuli-responsive swelling-deswelling (on/off switching).

Drug release study

A drug release study was carried out using a dissolution apparatus. The prepared tablets were placed in dissolution vessels filled with 900 mL dissolution media (buffers of pH 1.2/6.8/7.4) maintained at 37 ± 0.5°C at 50 rpm. After selected time intervals, the sample (5 mL) was withdrawn from the vessels, filtered, and determined the absorbance using a UV-vis spectrophotometer. A fresh media of respective pH was immediately added to the vessels to maintain the sink conditions. A graph was plotted between time and cumulative drug release to express the drug release behavior from Dextran-CA-CSH-based tablets.

Drug release kinetics and mechanism

Zero-order, first-order, Hixson-Crowell, and Higuchi kinetics models were used to analyze the drug release kinetics from the synthesized product using equations (2)–(5). Whereas, the drug release mechanism was determined through the Korsmeyer-Peppas model (equation (6)).

Q_{t} = K_{0} t

(2)

where, Q_t and K₀ are the amount of released drug in time t and zero-order rate constant, respectively.²²

\log Q = \log Q_{0} - (\frac{K_{1} t}{2.303})

(3)

where, Q₀, Q, and K₁ are the initial amount of drug added to the tablet, the remaining amount of drug in the tablet, and the first-order rate constant, respectively. t denotes the time of sampling.²³

Q_{0}^{\frac{1}{3}} - Q_{t}^{\frac{1}{3}} = - K_{H C} t

(4)

where, Q₀ and Q_t are the initial and final amount of drug released from the tablet after time t, respectively and K_HC is the Hixson-Crowell rate constant.²⁴

Q_{t} = K_{H} {(t)}^{1 / 2}

(5)

where, Q_t and K_H are the quantity of the drug released from the tablet after time t and the Higuchi rate constant, respectively.²⁵

\frac{M_{t}}{M_{\infty}} = k_{p} t^{n}

(6)

where, M_t/M_∞ is the fraction of drug released in time t. k_p and n represent the Korsmeyer-Peppas constant and the diffusion exponent, respectively. The drug release mechanism is determined by the value of n, i.e., n = 0.45 (Fickian diffusion), n = 0.45-0.89 (non-Fickian diffusion), and n > 0.89 (super case-II transport).^26–28

Results and discussions

Synthesis of dextran-CA-CSH

During the synthesis of Dextran-CA-CSH, the concentrated solution of CA was heated and as a result, a water molecule was removed from the terminal carboxylic acid (-COOH) group and converted to an unstable cyclic anhydride. Then the dissolved dextran was added and heated to convert into the ester of dextran. On further heating, another molecule of water from the second terminal -COOH of CA was removed and converted to the anhydride of dextran. Finally, the suspension of CSH was added and the esterified bio-composite hydrogel (Dextran-CA-CSH) of dextran, CA, and CSH was obtained as illustrated in Figure 1.

Figure 1.

Illustrated reaction scheme for the synthesis of Dextarn-CA-CSH hydrogel based on dextran, CA, and CSH.

FTIR characterization

The FTIR spectra of the reactants (dextran, CA, and CSH) and product (Dextran-CA-CSH) are shown in Figure 2. In the FTIR spectrum of CSH, the broad peaks in the range of 3434-3537 cm^-1 indicated the presence of O-H stretching whereas, a peak at 1703 cm^-1 is due to C = O stretching of the uronic acid component of the CSH (Figure 2(a)).¹⁵ Figure 2(b) presents the FTIR spectrum of dextran, in which the broad peak in the range of 3226-3506 cm^-1 is due to the O-H stretching. The signals for C-H stretching appeared at 2918 cm^-1 and the peaks at 1145 and 1066 cm^-1 represented the signals of C-OH and C-O-C of dextran, respectively. The FTIR spectrum of CA is shown in Figure 2(c). The peak appeared at 3307 cm^-1 is due to O-H stretching of CA, at 1730 cm^-1 is due to C = O, and at 1456 cm^-1 is due to CH₂ of CA. The appearance of a new and prominent signal at 1734 cm^-1 in the FTIR spectrum Figure 2(d) of Dextran-CA-CSH revealed the formation of an ester functional groups.¹⁶

Figure 2.

FTIR spectra of CSH (a), dextran (b), CA (c), and Dextran-CA-CSH (d).

SEM analysis

The SEM images of Dextran-CA-CSH were recorded to observe its surface morphology. Figure 3(a)–(d) indicated the SEM images of Dextran-CA-CSH along transverse cross-sections at a magnification of 100 and 50 µm and along longitudinal cross-sections at a magnification of 100 and 50 µm, respectively. These images indicated that the Dextran-CA-CSH has a rough and porous surface and has uniformly distributed interconnected channels. The pore size of 16 ± 10 and 17 ± 11 µm was found from the histograms of Dextran-CA-CSH (Figure 3(e), along transverse) and Figure 3(f), along longitudinal)), respectively. Therefore, because of its porous nature, the novel material (Dextran-CA-CSH) can absorb an admirable quantity of water and other biological fluids and it could be a potential biomaterial for pharmaceutical applications.

Figure 3.

SEM images of Dextran-CA-CSH (a, b) along transverse and (d, e) along longitudinal cross-sections. Histograms of Dextran-CA-CSH (c) along transverse and (f) along longitudinal cross-sections.

pH-responsiveness

This study evaluated the pH-dependent dynamic swelling of Dextran-CA-CSH mimicking the pH of different regions of the gastrointestinal tract (GIT). The swelling of Dextran-CA-CSH in DW after 480 min was found to be more pronounced as compared to buffers with varying pH values. This high swelling may be attributed to the absence of charge screening effects and the unavailability of the ions in DW. Furthermore, the Dextran-CA-CSH exhibited reduced swelling in buffers of pH 6.8 and 7.4 relative to DW. However, in the buffer of pH 1.2, Dextran-CA-CSH showed insignificant swelling as seen in Figure 4(a). Once the pH of the solution was adjusted to 7.4, the -COOH groups on the polymeric chain of Dextran-CA-CSH were ionized. Consequently, the formation of anions occurred which offered electrostatic repulsion. As a result, the polymeric chains of Dextran-CA-CSH undergo relaxation and uncoiling, facilitating rapid penetration of the swelling medium, hence, swelling increases.²⁹ In addition, it was noted that at pH 1.2, -COOH on the polymeric chains of Dextran-CA-CSH remain un-ionized or in their protonated state. Therefore, the Dextran-CA-CSH exhibited insignificant swelling in the pH 1.2 buffer.³⁰

Figure 4.

Swelling patterns of Dextran-CA-CSH: (a) pH (powder), (b) pH (tablet), (c) salt (powder), and (d) salt (tablet) responsive.

Saline responsive properties

The impact of electrolyte-induced stress on the equilibrium swelling of Dextran-CA-CSH was assessed by exposing it to salt solutions with varying molar concentrations of NaCl and KCl, and measuring the swelling after 24 h. The experiments revealed that there was a reduction in the equilibrium swelling of Dextran-CA-CSH when the molar concentration of salts increased from 0.25 to 1 M (Figure 4(c)). This phenomenon was attributed to the pronounced charge screening effect caused by the increased number of Na⁺ and K⁺ ions in the swelling media.¹⁵ Furthermore, the substantial drop in the swelling in 0.25 to 1 M solution may also be attributed to the rise in the osmotic pressure difference between Dextran-CA-CSH and salt solutions. Nevertheless, an inconsequential variation in the swelling characteristics of Dextran-CA-CSH was seen when the salt content in the solution was increased from 1 to 2 M. It was also observed that Dextran-CA-CSH experienced more swelling in a NaCl solution compared to a KCl solution. This might be attributed to the higher charge density of K⁺ ions in comparison to Na⁺ ions, resulting in stronger attraction between K⁺ ions and carboxylate ions (COO^-) located on the surface of Dextran-CA-CSH.¹⁶

Stimuli-responsive swelling-deswelling characteristics

pH 7.4 AND 1.2

The study aimed to examine the swelling-deswelling capabilities of Dextran-CA-CSH in response to changes in pH. To do this, a precisely measured quantity of Dextran-CA-CSH (100 mg) was sequentially immersed in a slight basic buffer with a pH of 7.4 (swelling medium) and an acidic buffer with a pH of 1.2 (deswelling medium). Significantly, the Dextran-CA-CSH exhibited fast swelling in the presence of a swelling medium, and upon transferring to a deswelling medium, it showed rapid deswelling, therefore demonstrating pH-responsive swelling-deswelling characteristics. At a pH of 7.4, the -COOH groups on the Dextran-CA-CSH underwent deprotonation, resulting in the formation of their corresponding -COO^-1. Due to the presence of electrostatic repulsion among the anions, the polymeric chains in close proximity experienced repulsive forces. Consequently, the pH 7.4 buffer solution facilitated the movement of the swelling medium inside the polymeric matrix, leading to the fast swelling of Dextran-CA-CSH. When the pH was adjusted to 1.2, the -COO^-1 underwent protonation, leading to the conversion of the anion to the protonated form, i.e., -COOH. This protonation resulted in a decrease in the extent of swelling.¹⁷ As a result, the Dextran-CA-CSH experienced deswelling when exposed to a pH of 1.2. The observed swelling-deswelling behavior of Dextran-CA-CSH was achieved by the repetition of tests across four consecutive cycles, demonstrating reproducibility (Figure 5(a)).

Figure 5.

Swelling-deswelling characteristics of Dextran-CA-CSH: (a) pH 7.4 and 1.2 (powder), (b) pH 7.4 and 1.2 (tablet), (c) DW and normal saline (powder), (d) DW and normal saline (tablet), (e) DW and ethanol (powder), and (f) DW and ethanol (tablet).

Moreover, it was shown that during the deswelling stage at a pH of 1.2, Dextran-CA-CSH did not exhibit full deswelling back to its initial form. This might be attributed to the retention of swelling media (specifically, a buffer of pH 7.4) on shifting of Dextran-CA-CSH to the deswelling media.

DW and normal saline

In DW and normal saline (0.9% aqueous solution of NaCl), the swelling-deswelling characteristics of Dextran-CA-CSH were examined, respectively. The Dextran-CA-CSH exhibited significant swelling upon exposure to DW but underwent deswelling when exposed to normal saline. This deswelling behavior may be attributed to the charge screening effect caused by the high concentrations of cations (Na⁺) present in the salt solution.¹⁶ Furthermore, the decrease in osmotic pressure between DW and Dextran-CA-CSH caused by the presence of NaCl also induced the movement of water molecules out of Dextran-CA-CSH resulting in deswelling in normal saline.¹⁷ Figure 5(c) illustrated the pulsatile swelling-deswelling behavior of Dextran-CA-CSH in both DW and normal saline. Saline-responsive qualities were still evident in Dextran-CA-CSH after the completion of four successive swelling-deswelling cycles. Hence, Dextran-CA-CSH can be regarded as a material that exhibits reversible responsiveness to changes in salinity. Furthermore, it was also found that during the deswelling phase in the salt solution, the Dextran-CA-CSH did not undergo full deswelling to its initial condition due to the presence of some swelling medium in Dextran-CA-CSH.

DW and Ethanol

The swelling behavior of the Dextran-CA-CSH was seen to be more pronounced in DW and exhibited quick deswelling when exposed to ethanol on a comparable pattern as noted for normal saline (Figure 5(e)). The cause for the swelling and deswelling phenomena seen in Dextran-CA-CSH may be attributed to the disparity in polarity and dielectric constant values between DW and ethanol having a dielectric constant of 80.40 and 24.55, respectively. The hydrogen bonding between Dextran-CA-CSH and DW was enhanced because of the higher dielectric constant of DW compared to ethanol. Conversely, the hydrogen bonding between Dextran-CA-CSH and ethanol was decreased. Furthermore, it has been shown that ethanol has a higher affinity for displacing water molecules inside Dextran-CA-CSH, leading to the expulsion of DW and subsequently causing a reduction in the swelling of the Dextran-CA-CSH.¹⁵ The observed phenomenon of swelling-deswelling was seen on four separate occasions, with consistent cycles (Figure 5(e)). Moreover, it can be shown from the findings that Dextran-CA-CSH did not undergo total deswelling, returning to its original condition. Based on the obtained data, it is evident that patients should informed to avoid taking alcoholic beverages and high-salt foods while taking the dosage forms having Dextran-CA-CSH as a sustained release excipient.

Swelling and on/off behavior of dextran-CA-CSH-based tablet formulations

The swelling behavior of Dextran-CA-CSH-based tablet formulations was assessed in DW and buffers with pH values of 1.2, 6.8, and 7.4. Dextran-CA-CSH-based tablet formulations exhibited significant swelling in both DW and the buffers at pH 6.8 and 7.4, while swelling was minimal in the pH 1.2 buffer, showing a similar trend to the powder form of Dextran-CA-CSH. However, the swelling of Dextran-CA-CSH-based tablet formulations was considerably lower than that of the powder form, likely due to the compression, tight packing, and filling of the interparticle spaces within the tablet (Figure 4(b)).²⁰

The impact of salts (NaCl and KCl) on the swelling properties of Dextran-CA-CSH-based tablet formulations was examined in aqueous solutions of these salts, with the results presented in Figure 4(d). The swelling behavior of Dextran-CA-CSH based tablet formulations followed a similar pattern to that of the Dextran-CA-CSH powder, with a slight decrease in swelling capacity. Such a decrease in swelling in tablets can be associated with the compaction of powder material in tablet form which decreases the rate and extent of swelling in tablet form as compared to powder form.

The on-off switching properties of Dextran-CA-CSH-based tablet formulations were studied in different environments: at pH 7.4 and pH 1.2 (Figure 5(b)), DW and normal saline (Figure 5(d)), and DW and ethanol (Figure 5(f)). These experiments showed trends similar to those observed with Dextran-CA-CSH powder. However, the swelling of Dextran-CA-CSH-based tablet formulations was notably less than that of the powder form, likely due to the compaction of the particles in the tablet.³¹ These results demonstrate that the swelling and on/off switching characteristics of the powder material remain intact even after compression or in tablet form.

Drug release studies and kinetics

A drug release study was carried out at pH 6.8 and it was observed that almost 96% drug was released after 6 h. This delayed release of the DFS at the pH of the small intestine, i.e., 6.8, indicates the sustained release potential of a newly designed polymeric material, i.e., Dextran-CA-CSH (Figure 6(a)). After applying the drug release kinetics models on the drug release data, the first-order kinetics model is looking more appropriate in explaining the drug release from Dextran-CA-CSH. A drug release kinetics model having the highest value of R², i.e., ≈ 1 is considered as the most appropriate model to explain the drug release kinetics (Table 1). The first-order kinetics model demonstrates that the drug release from a system is dependent on the concentration of the drug within that system. The Korsmeyer-Peppas model is used to explain the drug release mechanism from a polymeric system, i.e., Fickian diffusion, non-Fickian diffusion, case-II transport, and super case-II transport. The value of “n” calculated from the Korsmeyer-Peppas model is found as 0.592 which revealed that the drug release followed the non-Fickian diffusion (anomalous transport) as the value of n > 0.45.

Figure 6.

DFS release from tablet formulation at pH 6.8 (a) and at different pH and transit times of gastrointestinal tract (b).

Table 1.

Kinetics modeling and the values of corresponding kinetics parameters.

Zero-order		First-order		Higuchi		Hixson-crowell		Korsmeyer-peppas
R ²	K ₀	R ²	K ₁	R ²	K _H	R ²	K _HC	R ²	K _kp	n
0.7958	20.816	0.9940	0.417	0.9676	38.156	0.9715	0.116	0.9839	34.808	0.592

A drug release study was also carried out mimicking the pH and transit time of the gastrointestinal tract (Figure 6(b)). It was observed that only 11% drug was released at pH 1.2 during the 2 h study. After a 5 h study at pH 6.8, 67% drug was released. After 3 h study at pH 7.4 and at the end of a total 10 h study, up to 98% drug was released (Figure 6(b)). This study indicated that the drug released was hindered at pH 1.2 and increased at the pH of small and large intestine, i.e., pH 6.8 and 7.4, respectively. Therefore, Dextran-CA-CSH can be used as a sustained/controlled release excipient for developing modified or targeted-release drug delivery systems, especially tablet formulation.

Conclusions

The synthesis of crosslinked bio-composite hydrogel (Dextran-CA-CSH) was accomplished by the esterification process, utilizing CA as the cross-linking agent. The Dextran-CA-CSH exhibited a notable increase in its swelling capacity when exposed to DW, as well as at pH 6.8 and 7.4. Dextran-CA-CSH exhibited first-order release kinetics, suggesting concentration-dependent drug-releasing properties. The inability of Dextran-CA-CSH to release the drug at stomach pH is beneficial for the oral delivery of acid-labile pharmaceuticals, such as non-steroidal anti-inflammatory medications (NSAIDs), antibiotics, proteins, amino acids, etc. Consequently, Dextran-CA-CSH has great potential as a suitable bio-material for targeted drug delivery inside different segments of the gastrointestinal tract. Further comprehensive research is still needed to ascertain the suitability of this crosslinked material as an inert and non-toxic excipient for potential application in various drug delivery systems and other biomedical applications.

Footnotes

ORCID iD

Muhammad Ajaz Hussain

Author contributions

M. A. Hussain and A. Ali conceived and designed the research methodologies and reviewed the paper; K. Shehzad performed the experiments; M. T. Haseeb wrote the paper and S. Z. Hussain analyzed the data.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The authors declare that the data supporting the findings of this study are available within the paper.*

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Development of a novel smart bio-composite hydrogel based on dextran,citric acid,and glucoxylan for pH-dependent drug delivery and stimuli-responsive swelling and release

Abstract

Keywords

Introduction

Materials and methods

Materials

Methods

Extraction of hydrogel

Synthesis of bio-composite hydrogel

Measurement

Stimuli-responsive swelling

Saline-responsive swelling

Stimuli-responsive swelling-deswelling (on/off switching)

Preparation of tablets

Swelling and on/off switching behavior of dextran-CA-CSH-based tablet formulation

Drug release study

Drug release kinetics and mechanism

Results and discussions

Synthesis of dextran-CA-CSH

FTIR characterization

SEM analysis

pH-responsiveness

Saline responsive properties

Stimuli-responsive swelling-deswelling characteristics

pH 7.4 AND 1.2

DW and normal saline

DW and Ethanol

Swelling and on/off behavior of dextran-CA-CSH-based tablet formulations

Drug release studies and kinetics

Conclusions

Footnotes

ORCID iD

Author contributions

Funding

Declaration of conflicting interests

Data Availability Statement

References