Oxidized konjac glucomannan-cassava starch and sucrose esters as novel excipients for sustained-release matrix tablets

Journal Pre-proof Oxidized konjac glucomannan-cassava starch and sucrose esters as novel excipients for sustained-release matrix tablets

Cancan Liu, Jianbin Li, Kai Li, Caifeng Xie, Jidong Liu PII:

S0141-8130(19)34688-4

DOI:

https://doi.org/10.1016/j.ijbiomac.2019.11.146

Reference:

BIOMAC 13927

To appear in:

International Journal of Biological Macromolecules

Received date:

22 June 2019

Revised date:

13 November 2019

Accepted date:

18 November 2019

Please cite this article as: C. Liu, J. Li, K. Li, et al., Oxidized konjac glucomannancassava starch and sucrose esters as novel excipients for sustained-release matrix tablets, International Journal of Biological Macromolecules(2018), https://doi.org/10.1016/ j.ijbiomac.2019.11.146

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© 2018 Published by Elsevier.

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Oxidized konjac glucomannan-cassava starch and sucrose esters as novel excipients for sustained-release matrix tablets

Cancan Liua, Jianbin Lia,b,*, Kai Lia, Caifeng Xiea, Jidong Liua

College of Light Industry and Food Engineering, Guangxi University, Nanning

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a

Guangxi Key Laboratory of Biorefinery, Nanning 530003, China

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b

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530004, China

*

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Corresponding author

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E-mail addresses: [email protected] (J. Li)

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Postal address: College of Light Industry and Food Engineering, Guangxi University, Nanning 530004, China

1

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ABSTRACT

A novel sustained-release matrix tablet was developed through wet granulation by using oxidized konjac glucomannan-cassava starch (OKGM-CS) and sucrose esters (SE) as excipients. OKGM-CS treated by dry heat exhibited low solubility and swelling power, indicating that it might be a potential adjuvant for sustained-release

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drug formulations. SE incorporation significantly decreased the porosity and swelling

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rates of tablets and retarded drug release. Tablets containing SE with an HLB value of

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5 displayed better sustained-release performance, the cumulative release decreased

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from 94.36% to 83.29% and MDT increased from 4.50 h to 5.79 h. All these findings

matrix tablets.

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suggest the potential of OKGM-CS and SE as novel sustained-release agents for

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Keywords: Oxidized konjac glucomannan; Cassava starch; Sucrose esters

1. Introduction

In oral sustained-release drug delivery systems, matrix tablets have been widely used because of their simple and low-cost preparation processes [1]. In recent years, polysaccharides have gained widespread attention as pharmaceutical carrier materials, because of their nontoxicity, biocompatibility, biodegradability, and ease of modification [2]. Konjac glucomannan (KGM) is an attractive candidate as a colon-targeted drug excipient as it is not degraded in the stomach and small intestine, but can be degraded by β-mannanase produced by colonic flora [3]. However, KGM 2

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has a disadvantage of high water-swelling ability, owing to its high molecular weight and the presence of many hydrogen bonds in the molecule; because there is insufficient free water in the colon, KGM can lead to diarrhea and hinder drug release [4]. Dry heating is a simple and safe physical method, and starches modified by dry heating with ionic gums have been considered to be functionally equivalent to

of

chemically cross-linked starches [5]. Vashisht et al. [6] have found that starch

ro

modified by dry heating with ionic gums shows a decreased swelling power and

-p

releases the drug more slowly. Cassava, an important crop in tropical countries, can

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endure adverse conditions that most crops cannot survive, and it contains more than

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80% starch (dry weight) [7]. Compared with starches from other sources, cassava starch (CS) has a lower price in the world market [8]. CS is deformed primarily

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through plastic flow during compression in a similar manner to corn starch, thus

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indicating that CS may be a suitable substitute for tablet formulations [9]. In the present study, we prepared an OKGM-CS polymer using oxidized KGM (OKGM) containing carboxyl groups and CS by dry heat treatment, which is probably a suitable candidate for sustained-release agent. Sucrose esters (SE) are esters consisting of hydrophilic sucrose heads and lipophilic fatty acid tails [1]. As sucrose has eight free hydroxyl groups, it can be esterified with up to eight fatty acids to form esters. Thus, SE provides various hydrophilic-lipophilic properties with hydrophilic-lipophilic balance (HLB) values ranging from 0 to 16. In recent years, SE have been proposed as promising 3

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controlled-release agents for matrix tablets, owing to their gel-forming ability, non-toxicity, and biodegradability [1]. The effects of two different SE on paracetamol release were investigated by Szűts et al. [10]. They concluded that S970 has a stronger gel structure than P1670, which is beneficial in maintaining sustained drug release. In a follow-up study by the same group, the gel properties of different SE (S970, S1170,

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S1570 and S1670) were evaluated [11]. The results revealed that SE with lower HLB

ro

values have greater gel strengths and greater potential to control drug release rates.

-p

Chansanroj et al. [1] concluded that the hydrophilic-lipophilic properties of SE as

re

controlled-release agents significantly affect drug release behavior in directly

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compacted matrix tablets. SE with high HLB values result in increased porosity and elastic recovery of the tablets, and also promote a swelling behavior that retards drug

na

release. However, we have not found any reports on the effects of the combination of

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OKGM-CS and SE on drug release behavior in matrix tablets. The objective of the present study was to evaluate the suitability of OKGM-CS and SE as excipients for sustained-release tablets. Bovine serum albumin (BSA) was selected as the model drug. BSA is not a therapeutic protein, but, as in many studies on controlled-release, BSA was used as the model protein because of its reasonable cost [12]. The effects of OKGM-CS and SE with various HLB values on tableting properties, internal structures, swelling behaviors and drug release of OKGM-CS/SE matrix tablets were studied.

2. Materials and methods 4

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2.1. Materials Konjac glucomannan and cassava starch were purchased from Shanghai Yuanye Bio-Technology Co., Ltd (Shanghai, China). Hydrogen peroxide (H2O2, 30%) and bovine serum albumin were bought from Sinopharm Chemical Reagent Co., Ltd (Shanghai, China). Sucrose stearates were provided by Mitsubishi-Kagaku Foods

of

Corporation (Tokyo, Japan), and their details are shown in Table 1. All other

ro

chemicals used were of analytical grade.

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2.2. Synthesis of the OKGM

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OKGM was prepared according to a previous report with slight modifications

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[13]. KGM (8 g) was dissolved in 800 mL of distilled water, and stirred at 500 rpm and 45ºC for 30 min. The pH was adjusted to 8.0 with 1%(w/v) NaOH, and then 28

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mL of H2O2 was added to the solution three times over the course of 30 min at 10 min

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intervals. After 4 h, Na2SO3 (1 mol/L) was added to terminate the reaction and the pH was adjusted to 6.5. The solution was precipitated with absolute ethanol and filtered through a vacuum filter. The OKGM was washed three times with 50%, 70% and 90% ethanol. The product was vacuum-dried at 50ºC and ground to pass through a 100-mesh sieve. 2.3. Determination of carboxyl group content The carboxyl content was determined according to the method described by Sukhija et al. [14] with some modifications. OKGM (0.5 g) was stirred in 25 mL of HCl (0.1 mol/L) for 30 min. The slurry was precipitated with absolute ethanol and 5

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washed with 75% ethanol until it was free of chloride ions. The filtered cake was dissolved in 300 mL of distilled water and stirred in a boiling water bath for 15 min to gelatinize. With phenolphthalein used as an indicator, the sample was immediately titrated with 0.1 mol/L NaOH. A blank test was performed with KGM. The carboxyl group content of OKGM was 0.648%, as calculated by Eq. (1).

(1)

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(Sample  Blank) mL  Molarity of NaOH  0.045 100 Sample weight

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Carboxyl content (%)=

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2.4. Synthesis of the OKGM-CS polymer

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The OKGM-CS polymer was prepared using OKGM and CS by dry heat treatment [15]. OKGM (4 g) was added slowly in distilled water (95 mL) with

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vigorous stirring. CS (1 g) was added to the gum solution and stirred at room

na

temperature for 1 h. The dispersion was transferred to a glass dish, then dried at 45ºC

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to a moisture content of less than 10%. The dried mixture was ground into powder and passed through a 100-mesh sieve. The powdered mixture was then heated at 130ºC for 4 h.

2.5. Characterization

The morphologies of samples were investigated using a scanning electron microscope (SEM) (S-3400N, Hitachi, Tokyo, Japan) at an accelerating voltage of 15 kV and magnification of 3000×. Fourier transform infrared (FTIR) spectra of the samples were recorded with a spectrometer (TENSOR II, Bruker, Karlsruhe, Germany) in the range of 4000–400 cm-1 at a resolution of 4 cm-1. All samples were prepared 6

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with the KBr disk method. Solid-state

C CP/MAS NMR experiments were

conducted with a spectrometer (AV300, Bruker, Karlsruhe, Germany) at a

13

C

frequency of 75.48 MHz. The sample was packed into a 4-mm diameter zirconia rotor and spun at the magic angle (54.7°) with a rate of 12 kHz. The cross polarization contact time was 3 ms with a recycle delay of 5 s for an acquisition time of 50 ms. At

of

least 2400 scans were performed for each spectrum.

ro

2.6. Solubility and swelling power

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The swelling power and solubility were determined using the method described by

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Sukhija et al. [14] with slight modifications. The sample (0.5 g) was dissolved in 50

lP

mL of phosphate buffer (pH 7.4) and stirred at 100 rpm for 12 h (37ºC). After the mixture was centrifuged at 4500 rpm for 20 min, the supernatant was dried to constant

(2)

Weight of soluble sample 100 Weight of sample

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Solubility (%)=

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weight at 105ºC. Subsequently, the sediment was weighed.

Swelling power (%) =

Weight of sediment 100 Weight of sample on dry basis (100  %solubility)

(3) 2.7. Preparation of matrix tablets Matrix tablets were prepared by wet granulation. The OKGM-CS/SE (mass ratio 7:3) (45% w/w), methylcellulose (45% w/w) and model drug (10% w/w) were mixed to uniform, and the mixture was wetted with hydroxypropyl methylcellulose ethanol solution (4% w/v). The prepared wet mass was then passed through an 18-mesh sieve 7

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to prepare granules and dried at 45ºC to a constant moisture content. The dried granules were passed through a 80-mesh sieve. Before compaction, magnesium stearate (1% w/w) was added to the powder blend. Cylindrical tablets (500 mg weight, 13 mm diameter) were prepared by compression of the blends at a pressure of 8 kN. A formulation without SE was prepared for comparison, in which the proportion of SE

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was replaced by OKGM-CS to maintain the same tablet mass. Similarly, SE tablets

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were prepared according to the above formulation, in which the proportion of

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2.8. Physical characteristics of tablets

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OKGM-CS was replaced by SE.

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The thickness (T1) of the tablets after compaction and the thickness (T2) after storage for 24 h were measured with a vernier caliper. Elastic recovery of the tablets

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was calculated by Eq. (4) [1]. Relative porosity (ε) was calculated by Eq. (5)

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according to the apparent density (ρA) and true density (ρT) of the tablets analyzed using a gas displacement pycnometer (AccuPyc 1330, Micromeritics, Atlanta, USA) by the helium displacement procedure [1]. Elastic recovery (%)=

 =1 

T2  T1  100 T1

(4)

A T

(5)

2.9. Internal structures of tablets The tablets were cut vertically in half with a sharp knife. The cut surfaces of the tablets were investigated through SEM (F16502, Phenom, Eindhoven, Netherlands) at an acceleration voltage of 5 kV and magnification of 300×. 8

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2.10. Swelling characteristics of tablets Swelling studies of tablets were performed with an intelligent dissolution tester (ZRS-8LD, Tianda Tianfa, Tianjin, China) equipped with baskets at a rotation rate of 50 rpm [16]. Weighed tablets (W0) were immersed in 900 mL phosphate buffer (pH 7.4) at 37±0.5°C. After 1 h, the tablets were removed and blotted to remove excess

2.11. In vitro drug release studies

(6)

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W1 - W0 100 W0

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Swelling (%) =

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water and then weighed (W1).

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In vitro dissolution tests for each formulation (three tablets) were performed with

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an intelligent dissolution tester in 900 mL phosphate buffer (pH 7.4) with a paddle

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rotating rate of 50 rpm at 37±0.5°C. Five milliliters of dissolution samples were withdrawn at predetermined time intervals within 16 h and replenished with fresh

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medium of the same volume and temperature. The BSA release concentration was measured using a UV-vis spectrophotometer (UV-2802S, Unico, Shanghai, China) at 279 nm [17].

2.12. Kinetics of drug release In order to study the drug release mechanism from tablets, in vitro release data were fitted to zero-order (Eq. (7) [18], Higuchi (Eq. (8) [19], Ritger-Peppas (Eq. (9)) [20] and Peppas-Sahlin kinetic models (Eq. (10)) [21]. The first 60% of the drug release data were analyzed according to the Ritger-Peppas and Peppas-Sahlin models. The model with the highest correlation coefficient (R2) was considered to be the best 9

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fit.

M t  M 0 +k0t

(7)

1 2

M t  k1t

(8)

Mt  k2t n M

(9)

Mt  k3t m +k4t 2 m M

of

(10)

ro

Where Mt is the amount of drug released at time t, M0 is the initial amount of

-p

drug in the solution, M∞ is the total amount of drug released. k0, k1, k2, k3, and k4 are

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the release-rate constants for the zero-order, Higuchi, Ritger-Peppas and

mechanism of drug release.

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Peppas-Sahlin models, respectively, and n is the release exponent indicative of the

na

The mean dissolution time (MDT) was used to characterize the drug release rate,

 MDT  

n

i 1 n

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which was calculated by Eq. (11) [1]. t *i M i

(11)

M i i 1

Where i is the sample number, ti* is the midpoint of the time period between ti and ti−1, and ΔMi is the amount of drug released between ti and ti−1. 2.13. Statistical analysis Experiments were conducted in triplicate and the data are expressed as mean values ± standard deviation (SD). Analysis of variance (ANOVA) was performed using IBM SPSS Statistics 24.0 software (IBM, Armonk, New York, USA) and significant differences were detected by Tukey's test (p < 0.05). 10

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3. Results and discussion 3.1. Morphological properties Fig. 1 shows SEM micrographs of KGM, OKGM, CS and OKGM-CS. KGM exhibited a rough surface (Fig. 1a), which was consistent with previous reports [22]. Compared with KGM, OKGM granules were smoother (Fig. 1b), which might have

of

been caused by degradation of amorphous regions of KGM during the oxidation

ro

reaction [22]. The CS granules were round with a truncated end on one side and had a

-p

smooth surface (Fig. 1c). As shown in Fig. 1d, CS granules had a rough surface and

re

formed large lumps after dry heating, which was attributed to CS being wrapped by

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OKGM. 3.2. FTIR and NMR spectra analysis

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The FTIR spectra of KGM, OKGM, CS and OKGM-CS are shown in Fig. 2A.

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For KGM, the broad peak at 3346 cm-1 and the peak at 2927 cm-1 were assigned to the stretching vibration of O-H and C-H of methyl groups, respectively [23]. The small peak at 1734 cm-1 was attributed to the C=O stretching vibration of acetyl groups [24]. Compared with KGM, the peak of OKGM at 1727 cm-1 weakened, indicating the presence of mild alkali in the KGM solution cleaved the acetyl groups [24]. In addition, we observed a new absorption peak of carboxyl groups at 1610 cm-1 [25], which was consistent with the carboxyl content presented in Section 2.3. In the CS spectrum, the bands at 3383 cm-1 and 2929 cm-1 were also attributed to hydroxyl groups and C-H bond stretching, respectively [14]. After dry heating, the spectrum of 11

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OKGM-CS was similar to OKGM, and no new functional groups were found, which indicated that the interaction between OKGM and CS was physical. This was consistent with previous findings which investigated the effect of microwave-assisted dry heating with xanthan on normal and waxy corn starches [26]. Fig. 2B demonstrates the FTIR spectra of SE with various HLB values. As the

of

HLB value decreased, the enhanced absorption peak observed at 1739 cm-1 was

ro

attributed to an increase in the ester group content [27], thus providing evidence of an

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increase in the hydrophobic moieties. In contrast, the broad hydroxyl peak intensity at

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3342 cm-1 increased when the HLB value increased, thus indicating the increased

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hydrophilicity and hydrogen bonding capacity of SE with higher HLB values [28]. To further confirm the structural changes among KGM, OKGM and OKGM-CS, 13

C NMR spectra (Fig. 2C). As shown in Fig. 2C(b), for KGM, the

na

we analyzed the

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carbon signal caused by acetyl groups was observed at 174.0 ppm [29]. Meanwhile, a new signal appeared at 178.6 ppm, which was attributed to the carboxyl groups of OKGM [30]. The

13

C NMR spectrum of OKGM-CS was similar to OKGM, and no

new signals were found. These results were consistent with those from FTIR analysis. 3.3. Solubility and swelling power Table 2 shows the differences between solubility and swelling power of KGM, OKGM, and OKGM-CS. Compared with KGM, the increased solubility of OKGM might be attributed to structural weakening and depolymerization of the granules [14]. In addition, the introduction of carboxyl groups into OKGM granules made it easier to 12

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incorporate into water, which also increased its solubility [25]. The decreased swelling power of OKGM might be the result of structural disruption within its granules during modification [25]. OKGM-CS demonstrated a significant decrease in solubility and swelling power (p < 0.05). The heating of OKGM and CS at high temperature led to structural damage, which limited their swelling [31]. The decrease

of

in solubility might be attributed to the interaction between OKGM and CS under dry

ro

heating. Vashisht et al. [6] confirmed that the decreased drug release in tablets could

-p

be attributed to restricted swelling and solubility of starches modified by dry heating

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sustained-release drug formulations.

re

with ionic gums. Therefore, OKGM-CS may have potential as an adjuvant for

3.4. Tableting properties of tablets

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The elastic recovery and relative porosity of OKGM-CS/SE tablets compared

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with SE tablets are shown in Fig. 3A and B. Problems in tablet production, such as capping and lamination, are attributed to the elasticity of the compacted material under unloading and ejection. Elastic recovery is caused by the release of stored elastic energy in the compacted material after removal of the compaction load [32]. After the addition of SE, there was no significant increase in the elastic recovery of OKGM-CS/SE tablets (Fig. 3A), indicating that the material had good compressibility. Therefore, the suitability of powder mixtures as a compression excipient was demonstrated. However, the incorporation of SE significantly decreased relative porosity from 0.121 to 0.058 (Fig. 3B), which indicated that SE improved the 13

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compactability of powder mixtures regardless of their hydrophilic-lipophilic properties [1]. Onofre et al. [33] indicated that the porosity of tablets was mainly associated with their stress relaxation. Stress relaxation was a result of the release of stored energy in the matrix during compression, which resulted in structural expansion and porosity.

The

compactability

of

tablets

was

affected

by

the

of

increased

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hydrophilic-lipophilic properties of SE. Tablets containing SE with an HLB value of 5

-p

had the lowest porosity, which was attributed to the fact that matrices with lower

re

storage modulus may have less stress relaxation [33]. With increasing HLB values,

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more hydroxyl groups in SE form hydrogen bonds (Fig. 2B), thus resulting in enhanced intergranular bonding ability [1]. When HLB values increase from 5 to 11,

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the bond formation may be insufficient to withstand stress relaxation, resulting in

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increased porosity of tablets. Nevertheless, when HLB values increased from 11 to 16, more bonding formed and porosity decreased slightly. This result was consistent with those from a report by Chansanroj et al. [1]. Lower porosity results in slower drug release, because more closed structures hinder the free movement of the drug [33]. 3.5. Internal structures and swelling behaviors of tablets Fig. 4 exhibits SEM images of the cut surfaces of the tablets. Tablets without SE clearly had loose structures with many void spaces (Fig. 4a). Tablets containing SE exhibited more compact structures (Fig. 4b-f), particularly those with an HLB value of 5 (Fig. 4b). This finding was consistent with the results of relative porosity of 14

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tablets. This decrease in void space may play an important role in resisting penetration by water and delaying drug release [33]. The swelling behaviors of polymers in oral matrix tablets play an important role in controlling drug release. Fig. 3C illustrates the swelling behaviors of OKGM-CS/SE tablets containing SE with various HLB values. After being placed in

of

the test medium, all tablets rapidly swelled, owing to water penetration. Tablets

ro

containing SE showed lower swelling rates, a finding attributable to the significantly

-p

decreased porosity (Fig. 3B). With increasing HLB value, the swelling rate of the

re

tablet increased, thus indicating that its hydrophilicity was enhanced, possibly as a

3.6. In vitro drug release

lP

result of the increased hydroxyl content of SE (Fig. 2B) and porosity (Fig. 3B).

na

The cumulative drug release in tablets over time is plotted in Fig. 5. From the

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release profile, tablets without SE showed the highest drug release rate. SE incorporation retarded the drug release, which was consistent with the report by Chansanroj et al. [1]. In particular, tablets containing SE with an HLB value of 5 displayed better controlled-release performance, the cumulative release decreased from 94.36% to 83.29% and the MDT increased from 4.50 h to 5.79 h (Table 3). The hydrophilic-lipophilic properties of SE played a very important role in the drug release. Tablets containing SE with higher HLB values showed lower MDT values (Table 3). The increased drug release rates might be attributed to increased hydrophilicity of the tablets (Fig. 3C). In addition, increased porosity of the tablets 15

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(Fig. 3B) facilitated the infiltration of moisture, which also accelerated drug release. 3.7. Mechanisms of drug release In vitro release data were fitted to zero-order, Higuchi and Ritger-Peppas kinetic models for the purpose of studying the drug release mechanism of OKGM-CS/SE tablets. The results indicated that the drug release followed Ritger-Peppas kinetic

of

model based on higher R2 value (Table 3). In the Ritger-Peppas model, the value of n

ro

was used to characterize different release mechanisms [20]. For cylindrical tablets, the

-p

drug release mechanism is Fickian diffusion when n < 0.45. At 0.45 < n < 0.89, it is

re

non-Fickian diffusion, including the dual mechanism of diffusion and polymer

relaxation/dissolution.

lP

relaxation. When n > 0.89, drug release is primarily dominated by polymer

na

The fitted values of n in Ritger-Peppas model (Eq. (9)) varied from 0.67 to 0.80

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(Table 3), thus indicating that the release characteristics of the tablets followed the non-Fickian diffusion mechanism, in which the diffusion and relaxation rates were comparable [34]. To further investigate the contributions of diffusion and polymer relaxation to drug release, the Peppas-Sahlin model (Eq. (10)) was used to analyze the release mechanism [21]. In this study, the first term on the right side of Eq. (10) represents the Fickian diffusion (F) contribution, while the second term represents the relaxation (R) contribution, where k3 and k4 are diffusional and erosional exponents respectively, and m is a constant of 0.45 for cylindrical tablets. According to the report by Jian et al. [35], the release mechanism is dominated by diffusion when k3 > k4, the 16

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release is primarily attributable to matrix swelling when k3 < k4, and the release mechanism is a combination of diffusion and polymer relaxation when k3 ≈ k4. From Table 3, the drug release mechanisms of all tablets were dominated by Fickian diffusion except the tablets containing SE with an HLB value of 5 in which the release process was mainly dominated by polymer relaxation.

of

The fraction of drug release caused by the Fickian diffusion mechanism was

1 1  k 4 k3 t m

-p

F

ro

calculated by Eq. (12) [21].

(12)

re

The ratio of relaxation (R) over Fickian diffusion (F) contributions was

na

R k4 m  t F k3

lP

calculated by Eq. (13) [21].

(13)

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Fig. 6 visually illustrates the contribution of Fickian diffusion and polymer relaxation to drug release from tablets. For tablets without SE and containing SE with HLB values of 15 and 16, the entire drug release process was primarily dominated by Fickian diffusion due to the high hydrophilicity of tablets (Fig. 3C). For tablets containing SE with HLB values of 5–11, the initial drug release mechanisms were dominated by Fickian diffusion, and then the release was primarily dominated by polymer relaxation. In particular, the relaxation contribution was the highest for the drug release process of tablets containing SE with an HLB value of 5, in agreement with the results in Table 3. 17

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4. Conclusions In summary, OKGM-CS treated by dry heat exhibited low solubility and swelling power, which was beneficial for the preparation of tablets. The results indicated that SE incorporation significantly decreased the porosity and swelling rates of tablets and retarded drug release. Tablets containing SE with an HLB value of 5

of

showed better sustained-release performance, the cumulative drug release decreased

ro

from 94.36% to 83.29%, and the MDT increased from 4.50 h to 5.79 h. Drug release

-p

from all tablets followed non-Fickian diffusion mechanisms (0.45 < n < 0.89), where

re

the diffusion and relaxation rates were comparable. Furthermore, the drug release

lP

mechanisms of all tablets were dominated by Fickian diffusion (k3 > k4) except the tablets containing SE with an HLB value of 5 in which the release process was mainly

na

dominated by polymer relaxation (k3 < k4). The results of this study provide data on

release.

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the potential of OKGM-CS and SE as novel materials to sustain and control drug

Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant numbers 20864001, 31160326) and the Opening Project of Guangxi Key Laboratory of Biorefinery.

18

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Journal Pre-proof Figure captions Fig. 1. SEM micrographs of KGM (a), OKGM (b), CS (c) and OKGM-CS (d). Fig. 2. (A) FTIR spectra of KGM, OKGM, CS and OKGM-CS, (B) FTIR spectra of SE samples, (C) 13C CP/MAS NMR spectra of KGM, OKGM and OKGM-CS.

Fig. 3. Elastic recovery (A), relative porosity (B) and swelling (%) (C) of tablets

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containing SE with various HLB values.

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H-7, (d) H-11, (e) H-15, (f) H-16.

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Fig. 4. SEM micrographs of the internal structures of tablets. (a) no SE, (b) H-5, (c)

values.

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Fig. 5. Release profiles of OKGM-CS/SE tablets containing SE with various HLB

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Fig. 6. The contributions of Fickian diffusion (solid lines) and relaxation/Fickian

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diffusion (dotted lines) mechanisms over the first 60% of drug release from tablets.

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Table 1 HLB values and composition of different types of sucrose stearate Type

HLB value

Monoester content (%)

H-5

S-570

5

30

H-7

S-770

7

40

H-11

S-1170

11

55

H-15

S-1570

15

70

H-16

S-1670

16

75

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Abbreviation

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Table 2 Solubility and swelling power of KGM, OKGM and OKGM-CS Parameters

KGM

OKGM

OKGM-CS

Solubility (%)

77.26±0.51b

87.53±0.95a

31.78±0.42c

Swelling Power (%)

71.89±0.37a

68.14±0.63b

7.02±0.13c

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a-c: The mean values with different lowercase letters in the same row are significantly different (p < 0.05).

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Table 3 Drug release kinetic parameters and MDT of OKGM-CS/SE tablets Formulations

Zero-order Higuchi Ritger-Peppas

Peppas-Sahlin

MDT

(R2)

(R2)

n

R2

no SE

0.8769

0.9650

0.67

0.9988

20.45 7.39 0.9986

4.50

H-5

0.9432

0.9883

0.80

0.9988

6.84

8.24 0.9984

5.79

H-7

0.9337

0.9865

0.76

0.9994

9.86

7.76 0.9992

5.45

H-11

0.9189

0.9819

0.75

0.9981

11.23 8.28 0.9979

5.20

H-15

0.9066

0.9786

0.70

0.9987

H-16

0.8958

0.9748

0.69

0.9984

k4

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k3

R2

(h)

4.99

18.13 7.58 0.9982

4.77

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16.06 7.59 0.9984

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Author Contributions

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Jianbin Li designed the reported study, evaluated the results, prepared and reviewed

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the manuscript. Cancan Liu is responsible for the entire experiment, analyzed the results, and prepared the manuscript. Kai Li contributed to planning the reported

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research, evaluate the results, review and approve the manuscript. Caifeng Xie and Jidong Liu helped to analyze the experimental data and revised the manuscript. All authors both read and approved the manuscript.

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Highlights



OKGM-CS treated by dry heat exhibited low solubility and swelling power.



Sucrose esters with an HLB value of 5 retarded drug release more effectively.



In vitro release of BSA from matrices showed non-Fickian diffusion

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mechanism.

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Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6