Rapidly degradable konjac glucomannan hydrogels cross-linked with olsalazine for colonic drug release

Abstract

BACKGROUND:

Polysaccharide hydrogel is one of the most important materials for the colon target drug release system. However, the degradation time of polysaccharide hydrogel is much longer than the retention time in the colon. The drugs are expelled from the body before being released.

OBJECTIVE:

In order to match the degradation of drug carriers and their retention time in the colon, a rapidly degradable konjac glucomannan (KGM) hydrogel was designed for colon target drug release.

METHODS:

A crosslinker containing azo bond, olsalazine, was used to prepare the rapidly degradable KGM hydrogel. The degradation and drug release of the hydrogels with different crosslinking densities in the normal buffer and the human fecal medium were studied to evaluate the efficiency of colon drug release.

RESULTS:

More than 50% of the KGM hydrogel by weight was degraded and more than 60% of the 5-fluorouracil (5-Fu) was released within 48 h in 5% w/v human fecal medium.

CONCLUSION:

The drug was released more rapidly in a simulated colon environment than in a normal buffer. Furthermore, the drug release was controlled by the degradation of the hydrogel. The KGM hydrogel containing azo crosslinker has great potential for colon drug release.

Keywords

Konjac glucomannan hydrogel azo bond colon target drug release

1. Introduction

Colon-targeted drug delivery system (OCDDS) is an effective method for bioactive drug delivery, which can overcome the decomposition or absorption of drugs in the stomach and small intestine after oral administration [1–3]. Compared with the traditional drug delivery system, the colon-targeted drug delivery system has the advantages of increasing the bioavailability of the drug, solving the problem of enzyme barrier, increasing the local drug concentration and reducing the systemic side effects [4–6]. It is especially suitable for the treatment of colon diseases such as Crohn’s disease, ulcerative colitis, and colon cancer.

According to the trigger mechanism, colon-targeted drug delivery systems include pH-dependent systems, time-dependent systems, flora-triggered systems and bioadhesive systems. Among them, the flora-triggered type holds great promise, which possesses the virtues of accurate localization, excellent stability, small individual differences, outstanding in vitro and in vivo reproducibility, and low adverse reaction rate. Two kinds of macromolecule materials are often used to prepare the flora-triggered colon-targeted drug delivery carriers, one is natural polysaccharides, such as pectin, guar gum, and konjac glucomannan. These natural macromolecules are not degraded by enzymes in the stomach and small intestinal but are specifically hydrolyzed by β-glucuronidase and hydrolytic enzymes produced by bacteria in the colon [7,8]. The other class of materials is the polymer containing azo bonds. It was reported that the azo bonds on the back chain or side chain can be broken by the action of azoreductase in the colon [9,10]. The matrix tablets manipulated with these macromolecules can protect drugs across the upper digestive tract to the colonic region [11].

Konjac glucomannan (KGM) is a kind of non-ionic water-soluble heteropolysaccharide with β-1,4 linked-β-D-mannopyranose and β-D-glucopyranose residues. In China and Japan, KGM is a very popular healthy food, which has the effect of reducing blood lipid and blood sugar. It is well known that KGM is not degraded by digestive enzymes in the upper gastrointestinal tract, but can be degraded by β-mannanase or β-glucosidases produced by the microbial flora in the colon. This biodegradation characteristic makes it an ideal material for preparing colon-targeted drug carriers [12]. In recent years, many approaches have developed to synthesize KGM hydrogel for colon-targeted drug delivery [13,14]. Xu et al. [15] reported a hydrogel manufactured by an adipic acid dihydrazide modified KGM, which was cross-linked with glutaraldehyde. The medicine for treating colitis 5-aminosalicylic acid loaded in the hydrogel was not destroyed in a low pH value environment, indicating the KGM hydrogel is well suited for OCCDS. Ding et al. [16] reported a hydrogel-loaded berberine prepared by cucurbit [8] urils and phenylalanine modified KGM through host-guest interaction. These KGM hydrogels were successfully used to treat ulcerative colitis. Liu et al. [17] synthesized an azo bond-containing KGM grafted acrylic acid for controlled drug release in the colon. The experimental results show that the drug release kinetics is zero-order release, and the sustained release time exceeds 10 days. Although KGM hydrogels have achieved good results in colon-targeted drug delivery, they generally degrade slowly in the colonic enzymatic environment, even taking several days. As we know, the mean retention time in the colon is generally 12–18 h. Therefore, to match the drug release rate with the colonic residence, the degradation rate of KGM hydrogel carriers should be increased.

In this study, a rapidly degradable KGM hydrogel was designed by using olsalazine as the crosslinking agent. Both the glycosidic bond and the azo bond can be broken in the environment of colonic enzymes. More degradation sites accelerate the degradation rate of the hydrogel. In addition, this hydrogel carrier does not degrade significantly in normal phosphate buffer. The swelling behavior of hydrogels with different crosslink densities was studied, too. To evaluate the biodegradation and drug release in the colon, human fecal extracts which include various colonic bacteria and β-glucuronidase, β-xylosidase, azoreductase and nitroreductase, were used to simulate the colon environment. The approaches designed for the synthesis of olsalazine crosslinked KGM are shown in Fig. 1.

Fig. 1.

Preparation of KGM hydrogels containing azo crosslinker.

2. Methods

2.1. Materials

KGM powder, isophorone diisocyanate (IPDI), N,N’-Dicyclohexyl carbodiimide (DCC), and 5-fluorouracil were purchased from Shanghai Aladdin Reagent Co., Ltd. Olsalazine sodium, glycol, dimethyl sulfoxide, hydrochloric acid, sodium hydroxide, and tetrahydrofuran were obtained from Shanghai Chemical Group, China. All other reagents were of an analytical or higher grade.

2.2. Preparation of crosslinking agent

The crosslinking agent containing an azo bond was synthesized according to the literature [18]. Olsalazine sodium (2.0 g) was dissolved in 30 mL of deionized water to obtain a clear yellow-brown solution. A few drops of concentrated hydrochloric acid were added to the solution, in the process, a large amount of yellow precipitate (olsalazine) was produced immediately, then the pH value was adjusted around to 4. The mixture was filtrated, washed with deionized water several times, and dried at 60 °C. Olsalazine (0.60 g) and ethylene glycol (0.60 g, in excess) were dissolved in 40 mL THF, then, DMAP (0.007 g) and DCC (1.03 g) were added. The reaction was taken at room temperature for 24 h under nitrogen protection. Filtered the mixture and the solution was precipitated with deionized water, filtered again, and washed with deionized water to remove unreacted ethylene glycol. Finally, the yellowish solid (olsalazine glycol ester) was obtained.

IPDI (1 mmol, 0.222 g) and olsalazine glycol ester (0.5 mmol, 0.195 g) were dissolved in 2 mL DMSO, respectively. Then the olsalazine glycol ester solution was added dropwise into the IPDI solution, then, 2 drops of octylene were added as a catalyst, and the mixture was allowed to react at room temperature for 1 h to yield a crosslinking agent solution.

2.3. Preparation of KGM hydrogels

Konjac flour (3.888 g, 24 mmol) was dissolved in 30 mL DMSO, then 2 mL crosslinking agent solution (containing 0.25 mmol crosslinking agent) obtained above was added. After being stirred at room temperature, the mixture was placed in a water bath at 70 °C for 18 h to obtain a yellowish hydrogel, which was named Gel1, then the hydrogel was soaked in deionized water to replace DMSO, and then was cut into 1 cm discs and freeze dried. Gel2 and Gel3 were prepared using the same method with different quantities of crosslinking agents. The molar feed ratio is shown in Table 1.

Table 1
The feeding quantity of konjac, crosslinking agent, and crosslinking degree

Sample Crosslinking agent (mmol) Konjac glucomannan (mmol)* DMSO (mL) Crosslinking degree (%)

Gel1 0.25 24 30 0.92

Gel2 0.375 24 30 1.38

Gel3 0.5 24 30 1.85

Sample	Crosslinking agent (mmol)	Konjac glucomannan (mmol)*	DMSO (mL)	Crosslinking degree (%)
Gel1	0.25	24	30	0.92
Gel2	0.375	24	30	1.38
Gel3	0.5	24	30	1.85

*The molar content of KGM is calculated based on the monosaccharide unit.

2.4. Crosslinking degree of KGM hydrogels

The cross-linking degree of hydrogels was determined according to the method by Wang et al. [9]. The dried hydrogel was weighed and then immersed in NaOH solution (2 mol/L, 20 mL) at 37 °C and constantly shaken at 50 rpm. After the hydrogel was completely degraded in seven days, the final solution was diluted 20-fold with deionized water and the content of olsalazine was determined by UV spectra at 362 nm. The crosslinking degree is obtained by calculating the molar mass of olsalazine divided by that of the monosaccharide unit of the hydrogel.

2.5. Fourier transform infrared spectroscopic (FT-IR) analysis

The Fourier transform infrared spectrums of KGM powder, olsalazine glycol ester, and KGM hydrogel were measured on a Nicolet 6700 Fourier transform infrared spectrometer (FT-IR).

2.6. Scanning electron microscopic (SEM) analysis

To analyze the morphologies of the hydrogel, the cross-section of the sample was coated with gold-palladium in an argon atmosphere, then observed by a field emission scanning electron microscope with the model GeminiSEM provided by Carl Zeiss in Germany.

2.7. Swelling studies

The dried hydrogels were weighted accurately (W_d), then were immersed in the swelling medium of pH 1.7 (0.2 M HCl-KCl) and pH 6.8 (0.2 M phosphate buffer solution) respectively at 37 °C. At predetermined time intervals, the swollen hydrogels were taken out and blotted with filter paper to remove the surface water then weighted (W_s) immediately. The swelling ratios (SR) of the hydrogel were calculated according to SR = (W_s − W_d)∕W_d. The equilibrium SR of the hydrogel was obtained when the swollen hydrogel reached a constant weight.

2.8. Preparation of human fecal medium

The human fecal medium was prepared as described by Niranjan et al. [19]. Briefly, the fresh feces were obtained from a healthy human volunteer. The medium at the concentration of 5% w/v was prepared by adding appropriate fresh feces to the phosphate buffer solution (pH 6.8). Then, the solution was centrifugated (800 rpm, 2 min) to remove solid residue. Finally, carbon dioxide gas was purged into the medium to remove oxygen.

2.9. Degradation

The degradation of hydrogel was determined by the weight loss in phosphate buffer solution with (pH 6.8) human fecal medium. Briefly, the hydrogels were incubated in the buffer in a constant temperature shaker at 37 °C. After 24 hours, all hydrogels reached swelling equilibrium, then the hydrogels were taken out and the surface water was wiped off with filter paper, and W_d was weighed. Then hydrogels were put in the buffer with the human fecal medium. The medium was degassed by carbon dioxide to ensure an oxygen-free environment. After a certain time interval, the hydrogels were removed from the solution, and W_s were weighed. $\begin{eqnarray}\displaystyle \text{Weight loss rate}=(\text{W}_{s}-\text{W}_{d})/\text{W}_{d}. & & \displaystyle \nonumber\end{eqnarray}$

2.10. In vitro drug release

2.10.1. The preparation of 5-Fluorouracil (5-FU) encapsulated hydrogel

The dry gel was immersed in 10 mL of the prepared 5-FU solution (10 mg/mL) at 4 °C for 24 h. After taking it out, rinse the surface of the hydrogel with clean water, and calculate the drug loading of the hydrogel by subtracting the remaining 5-FU solution and the amount of 5-FU in the rinse water from the total amount of 5-FU. The loading rate of 5-FU was calculated as (W_total − W_remaining)∕W_hydrogel.

2.10.2. Drug release in the buffer containing human fecal medium

Drug release of hydrogel was performed in a thermostatic rotary shaker at the shaking speed of 45 rpm at 37 °C. 5-FU encapsulated hydrogel was immersed in 20 ml of buffer solution containing human fecal medium in an oxygen-free environment. At predetermined intervals, 2 mL of solution was taken out and replaced with 2 mL of fresh buffer solution. The solution was filtered by using a 0.22 μ membrane filter and 5-FU content was determined by UV-visible spectrophotometer (Beijing General Analysis UV2800) at 265 nm, the release continued until the 5-FU release rate reached a plateau. Drug release in the buffer solution without a human fecal medium was measured as a control.

3. Results

3.1. FT-IR characterization of the hydrogels

The FT-IR spectra of KGM hydrogel, KGM power, and olsalazine glycol ester are shown in Fig. 2A. In curve a of olsalazine glycol ester, the peaks around 1581 cm⁻¹ and 1483 cm⁻¹ are characteristic peaks of the benzene ring of olsalazine; due to the intramolecular hydrogen bond between the ester group and the vicinal phenolic hydroxyl group, the characteristic absorption peak of the C=O stretching vibration of the ester group shifts to a low wavenumber at 1683 cm⁻¹. In the infrared spectrum of KGM, the observed peak at 1646 cm⁻¹ is the intermolecular hydrogen bonds [17]. Compared with the spectrum of KGM, the new band at 1714 cm⁻¹ of KGM hydrogel is the stretching vibration peak of amide carbonyl, which indicates that the crosslinking reaction was successful. The peaks at 1084 cm⁻¹ and 1416 cm⁻¹ are the characteristic absorption of C 6-OH in KGM and the bending vibration absorption peak of -CH₂-, respectively [20].

Fig. 2.

(A) FT-IR spectra of Olsalazine glycol ester (a), KGM power (b), and KGM hydrogel (c). (B) FT-IR spectra of 5-FU (a), KGM hydrogel (b), and KGM hydrogel loaded with 5-FU (c).

The FT-IR spectra of 5-FU, KGM hydrogel, and KGM hydrogel loaded with 5-FU are shown in Fig. 2B. In curve a, the absorption peak at 3135 cm⁻¹ was attributed to the stretching vibration of N–H bounds of 5-FU. This absorption peak was also detected in the FT-IR spectra of KGM hydrogel with 5-FU, indicating that 5-FU was successfully loaded in the hydrogel.

3.2. The morphology of the hydrogels

The macroscopic properties of polymer hydrogels are closely related to their microstructures and are dominated by morphological structures. SEM was used to observe the internal micromorphology of olsalazine-crosslinked KGM hydrogels. To keep the internal structure intact, the hydrogel in the swollen state was prepared by freeze-drying. Figure 3 is the SEM image of the hydrogels. The porous honeycomb structure was observed in all samples. These network structures are composed of continuous membrane-like bands and separated irregular pores. It can be seen that the pore size of the hydrogels is different. Gel1 has the largest pore size, due to its lowest crosslink density of 0.92%. By contrast, Gel3 has the smallest pore size.

Fig. 3.

SEM images of hydrogel Gel1 (a), Gel2 (b), and Gel3 (c).

3.3. Studies of the swelling kinetics of the hydrogels

In order to optimize synthesis conditions and determine the swelling property of hydrogels, three samples of KGM hydrogels with different cross-linking degrees were prepared to achieve swelling equilibrium in two buffer solutions. The feed concentration of KGM, crosslinking agent sand DMSO was listed in Table 1. It can be seen clearly in Fig. 4A that all hydrogels reach swelling equilibrium after 24 h and the swelling ratio of Gel3 is lowest compared with the other hydrogels in the same time interval, whether in the buffer solution with a pH of 1.7 or 6.8.

Fig. 4.

Swelling kinetics for hydrogel in the buffer solution of pH 6.8 (A), pH 1.7 (B) at 37 °C.

3.4. Degradation of the hydrogels

Three hydrogels with different crosslinking densities were employed to estimate the biodegradability in normal buffer and 5% w/v human fecal media. It can be seen from Fig. 5 that the three hydrogels have slight weight loss in the normal buffer solution of pH 6.8 in 72 h, indicating that the hydrogels did not degrade in this environment. In the human fecal media, Gel1 has the maximum weight loss and the fastest degradation rate. It was decomposed into small pieces in 24 h, and the weight loss exceeded 50%. Gel2 and Gel3 reached 50% weight loss in 48 h, then disintegrated. Gel3 degraded most slowly due to its maximum crosslink density.

Fig. 5.

In vitro degradation of hydrogels in normal buffer (Gel1a, Gel2a, Gel3a) and human fecal media (Gel1b, Gel2b, Gel3b).

3.5. The loading of 5-FU in the hydrogels

The drug loading rate is an important parameter for drug carriers. It can be seen from Table 2 that the encapsulation rate of 5-FU is related to the crosslinking density of the hydrogel sample. The drug loading decreased with the increase of the hydrogel crosslinking density. Gel1 has the maximum drug loading rate of 15.3%, because of its lowest crosslinking density. This is consistent with the relationship between crosslink density and equilibrium swelling ratio.

Table 2
The crosslinking degree, SR, and drug loading rate of hydrogels

Sample Crosslinking degree (%) SR (pH 6.8, 25 °C) SR (pH 1.7, 25 °C) Drug loading rate (%)

Gel1 0.25 4.98 4.31 15.3

Gel2 0.375 3.70 4.01 11.6

Gel3 0.5 2.54 3.05 9.3

Sample	Crosslinking degree (%)	SR (pH 6.8, 25 °C)	SR (pH 1.7, 25 °C)	Drug loading rate (%)
Gel1	0.25	4.98	4.31	15.3
Gel2	0.375	3.70	4.01	11.6
Gel3	0.5	2.54	3.05	9.3

3.6. In vitro release of 5-FU

In order to study the colon-targeting properties of olsalazine cross-linked KGM hydrogel, the release experiments were carried out in a phosphate buffer solution containing human fecal media in an anaerobic environment. Figures 6–8 represents the drug release of 5-FU adsorbed hydrogels with different cross-linking degrees in normal buffer and fecal media, respectively.

Fig. 6.

In vitro release profile of 5-FU loaded Gel1 in pH 6.8 buffer solution and fecal media at 37 °C.

Fig. 7.

In vitro release profile of 5-FU loaded Gel2 in pH 6.8 buffer solution and fecal media at 37 °C.

Fig. 8.

In vitro release profile of 5-FU loaded Gel3 in pH 6.8 buffer solution and fecal media at 37 °C.

It can be seen from the figures that for all hydrogels, the release rate of 5-FU in normal buffer and human fecal media is similar at the initial stage of release (<8 h). Less than 10% of the drugs were released. When the release time exceeds 8 h, the release rate in human fecal media increases rapidly. However, the drug release curves in the normal buffer remain stable. The release properties of 5-FU loaded olsalazine cross-linked KGM hydrogels suggest that they can be employed as drug carriers for the colon-targeted specific release.

4. Discussion

The advantages of colon targeted drug delivery system include the drug gathering in the colon, controlling the release rate of the drug, protecting the passage of drugs through the upper digestive tract, enhancing the curative effect, and reducing the side effects. Many physicochemical parameters, such as the swelling and biodegradation behavior of the hydrogel, the medium, the ambient temperature, and the interaction between the drug and the polymer, affect the results of the drug release.

The adsorption mechanism of 5-FU to hydrogen is the formation of hydrogen bonds between them [21,22]. The molecular structure of 5-FU contains carbonyl groups and N-H bonds, which can form hydrogen bonds with the hydroxyl groups in the glucomannan unit and adsorb in the pores of the hydrogel. Infrared spectroscopy can detect the formation of hydrogen bonds. The board peak at 3431 cm⁻¹ in the FT-IR spectra of KGM hydrogen was assigned to the O-H groups stretching vibration. After adsorbing the drug 5-FU, this peak shifted to 3424 cm⁻¹ (curve c in Fig. 2B). This is because the formation of hydrogen bonds causes the O-H stretching vibration peak to shift towards a lower wavenumber.

The swelling process of the cross-linked polymer is an equilibrium process of two opposite trends. The solvent tries to penetrate the network so that the volume swelling leads to the extension of the three-dimensional molecular network, and the extension of the molecular chain between the cross-links reduces its conformational entropy value; the elastic contraction force of the molecular network causes the network to contract. A swelling equilibrium is reached when the two opposing tendencies cancel each other out. The hydrogel with a high cross-linking degree has a large number of cross-linking points, and the elastic shrinkage force of the molecular network is strong, so the swelling rate is low. Considering the different pH values of the stomach and the intestinal tract, we tested the swelling of the hydrogel in the buffer of pH 1.7 and 6.8. It was found that the pH of the solution had little effect on the swelling rate of the hydrogels, so gastric acid will not affect the release of drugs in the hydrogels.

Transmit time is another important factor to be considered in colon-targeted drug delivery systems. Generally, the drug stays in the small intestine of healthy people for 2–4 hours and in the colon for 10–70 hours [23]. Many factors affect the transmission time. For example, for patients with ulcerative colitis, diarrhea is a common symptom, and the drug stays in the colon for less than 10 hours. In addition, the size of the drug carrier is also related to the transmit time. Generally, larger size drug carriers have shorter transit time than smaller size ones [24]. Therefore, in order to match the short delivery time of drugs in patients with colon disease, it is necessary to fabricate rapidly degradable drug carriers. The olsalazine-crosslinked KGM hydrogel we prepared has a fast degradation rate in the human fecal bacteria environment, and the degradation rate is adjustable. It is very suitable for the delivery of colon disease drugs.

The drug release is mainly based on the following two mechanisms: one is diffusion release, that is, the solvent penetrates into the network and the drug is released, and the other one is hydrolysis release. At the initial stage of release, various degrading enzymes did not penetrate into the network structure sufficiently, there is no obvious degradation in hydrogels. The diffusion mechanism dominates the release of 5-FU in normal buffers and human fecal media. Therefore, the drug release rates from the hydrogels are similar in the first 8 h. As the drug release goes on, enough β-glycosidase and azoreductase get into the inside of the hydrogel, the cross-links between the KGM chains are gradually broken, and the network structure is destroyed, which causes the rapid release of 5-FU. Therefore, hydrogel degradation dominates drug release. From the release curves, we can also find that the fastest 5-FU release rate of Gel1 occurs in 8–10 h, while that of Gel2 and Gel3 occurs in 8–24 h. The reason for this phenomenon is that Gel1 has the lowest cross-linking density and the fastest degradation. The drug release characteristics of these hydrogels are consistent with degradation.

To study the effect of gastric acid on drug release from hydrogel, we compared the drug release characteristics of Gel2 in buffer solutions of pH 1.7 and 6.8. The result is shown in Fig. 9. The release seems a diffusion process and the cumulative release of 5-FU in these two buffer solutions had similar trends. About 10% of 5-FU were released in the first 8 h. The release rate was slower in pH 1.7 buffer, because the swelling rate is smaller in this buffer solution, and thus it is difficult to dissolve and diffuse the drug in the hydrogel network. In conclusion, the hydrogel can rapidly degrade and release drugs in intestinal enzyme solution, and it is very suitable for colon-targeted drug release.

Fig. 9.

In vitro release profile of 5-FU loaded Gel2 in the buffer solution of pH 6.8 and pH 1.7 at 37 °C.

5. Conclusion

In this study, olsalazine crosslinked KGM hydrogel was successfully prepared and used to deliver 5-FU. The hydrogel has a porous structure and a high swelling rate. The swelling ratio and the internal network structure are related to the crosslink density of hydrogel. Since the cross-linking agent contains azo bonds, the hydrogel has a faster degradation rate in an intestinal enzyme solution and a faster drug release rate in vitro, which is expected to be used as a drug colon-targeted release carrier.

Footnotes

Acknowledgements

The study was supported by the Natural Science Foundation of China (No. 51503165).

Conflict of interest

The authors declare no conflict of interest.

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Rapidly degradable konjac glucomannan hydrogels cross-linked with olsalazine for colonic drug release

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSION:

Keywords

1. Introduction

2.1. Materials

2.2. Preparation of crosslinking agent

2.3. Preparation of KGM hydrogels

Table 1 The feeding quantity of konjac, crosslinking agent, and crosslinking degree Sample Crosslinking agent (mmol) Konjac glucomannan (mmol)* DMSO (mL) Crosslinking degree (%) Gel1 0.25 24 30 0.92 Gel2 0.375 24 30 1.38 Gel3 0.5 24 30 1.85

2.5. Fourier transform infrared spectroscopic (FT-IR) analysis

2.6. Scanning electron microscopic (SEM) analysis

2.7. Swelling studies

2.8. Preparation of human fecal medium

2.9. Degradation

2.10. In vitro drug release

2.10.1. The preparation of 5-Fluorouracil (5-FU) encapsulated hydrogel

2.10.2. Drug release in the buffer containing human fecal medium

3. Results

3.1. FT-IR characterization of the hydrogels

Table 2 The crosslinking degree, SR, and drug loading rate of hydrogels Sample Crosslinking degree (%) SR (pH 6.8, 25 °C) SR (pH 1.7, 25 °C) Drug loading rate (%) Gel1 0.25 4.98 4.31 15.3 Gel2 0.375 3.70 4.01 11.6 Gel3 0.5 2.54 3.05 9.3

Footnotes

Acknowledgements

Conflict of interest

References

Table 1
The feeding quantity of konjac, crosslinking agent, and crosslinking degree

Sample Crosslinking agent (mmol) Konjac glucomannan (mmol)* DMSO (mL) Crosslinking degree (%)

Gel1 0.25 24 30 0.92

Gel2 0.375 24 30 1.38

Gel3 0.5 24 30 1.85

Table 2
The crosslinking degree, SR, and drug loading rate of hydrogels

Sample Crosslinking degree (%) SR (pH 6.8, 25 °C) SR (pH 1.7, 25 °C) Drug loading rate (%)

Gel1 0.25 4.98 4.31 15.3

Gel2 0.375 3.70 4.01 11.6

Gel3 0.5 2.54 3.05 9.3