Preparation, characterization, and release behavior of β-cyclodextrin inclusion complexes of trans-cinnamaldehyde

Preparation, characterization, and release behavior of β-cyclodextrin inclusion complexes of trans-cinnamaldehyde | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Preparation, characterization, and release behavior of β-cyclodextrin inclusion complexes of trans-cinnamaldehyde Jiazheng Li, Zhao Cui, Xi Xiong, Ruotong Zhang, Weiwen Lu, Zhipeng Cai, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4376749/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Although β-cyclodextrin (β-CD) inclusion is known to improves the stability and solubility of trans-cinnamaldehyde (CA), but data on the in vitro release, pharmacokinetics, and pharmacodynamics of such inclusion complexes are lacking. In this study, an inclusion complex of CA and β-CD (CA-β-CD) inclusion complex was prepared using a saturated solution method.Its in vitro release was determined using the dialysis bag method with a molecular cut-off of 1000 D, while its in vivo pharmacokinetics were studied in a rat model. A carrageenan-induced acute inflammation mouse model of foot swelling was used to evaluate the effects of the inclusion complex on drug efficacy. The CA-β-CD inclusion complex had a lower release rate within 2 h and a higher release rate than CA after 2 h in both release media. In vivo pharmacokinetic studies of the CA-β-CD inclusion showed a decrease in peak concentration, a significant increase in half-life ( p <0.05), and an increase in bioavailability. A pharmacodynamic study on the effects of the inclusion complex on toe swelling in mice showed that it had slightly slower effects than the CA, but a relatively long-lasting swelling inhibition effect. The above findings suggest that CA has a certain slow-release behavior in vitro and in vivo after being encapsulated by β-CD, which has an effect on the drug’s efficacy. Release behavior trans-cinnamaldehyde cyclodextrin release kinetics solubility bioavailability Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Introduction Trans-cinnamaldehyde (CA) is the main component of essential oils, such as cinnamon oil, and it can be obtained by steam distillation and supercritical CO 2 extraction [ 1 – 4 ]. This component has considerable broad-spectrum antibacterial activity and an inhibitory effect on various tumor cells [ 5 – 9 ]. At the same time, CA has inhibitory effects on several chronic inflammation and oxidative stress conditions and thus has certain prospects in the treatment of ulcerative colitis, rheumatoid arthritis, and other inflammatory diseases [ 10 – 12 ]. As shown in Fig. 1 (generated using ChemDraw 20.0), the aldehyde group and conjugate bond in CA make it extremely unstable and easily oxidizable in air, and cause poor water solubility [ 13 ]. Pure CA has poor thermal stability starting at a temperature of 60℃. With an increase in temperature, pure CA undergoes temperature-dependent conversion to benzaldehyde [ 14 ], whereas after encapsulation, CA can effectively avoid the influence of various environmental factors, such as humidity, light, and high temperature [ 15 , 16 ]. β-cyclodextrin (β-CD) is a commonly used matrix that effectively encapsulates some molecules in whole or in part as a guest molecule and is used in many applications in pharmaceuticals and food products [ 17 , 18 ]. Studies have shown that inclusion compounds prepared from CA and β-CD (CA-β-CD) have better thermal stability and water solubility than CA alone [ 19 , 20 ]. Cinnamaldehyde-chemotype leaf oil microencapsulated with β-CD had good thermal stability and xanthine oxidase inhibitory activity [ 21 ], while β-CD complexation was found to increase the solubility of CA and affect its antioxidant activity [ 22 ]. However, the in vitro release, pharmacokinetics, and pharmacodynamics of CA-β-CD have not been systematically studied. The authors hypothesized that the inclusion complex formed by CA and β-CD would improves the stability and solubility of CA, thereby inducing slow-release behavior that affects its pharmacokinetic parameters and efficacy. In this study, we prepared CA-β-CD inclusion complexes and characterized their structure using scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), thermogravimetry (TG), and nuclear magnetic resonance (NMR). We investigated the in vitro and in vivo slow-release characteristics of CA-β-CD through in vitro release and in vivo pharmacokinetic studies. Additionally, we evaluated the impact of CA and the inclusion complex on carrageenan-induced toe swelling in mice. Materials and methods Materials The following materials were obtained: Trans-cinnamaldehyde (MFY240F0219, Nantong Feiyu Biotechnology Co. Ltd., Nantong, China), β-cyclodextrin (20200503, Shandong Binzhou Zhiyuan Technology Co. Ltd., Shandong, China). Trans-cinnamaldehyde standard substance (710200011, National Institutes for Food and Drug Control, Beijing, China), cinnamic acid standard substance (110786–201604, National Institutes for Food and Drug Control). Carboxymethyl sodium cellulose (150701, Anhui Shanhe Pharmaceutical Excipients Co. Ltd., Anhui, China), Bayer Aspirin enteric tablets (BJ69523, Bayer HealthCare Manufacturing S.r.l., Milan, Italy). Carrageenan (C1013-25G, Sigma-Aldrich Co., St Louis, MO, USA). Acetonitrile (chromatographic grade, TeleChem Corp., Atlanta, GA, USA) Methanol (chromatographic grade, Shandong Yuwang Industrial Co., Ltd., Shandong, China). Ultrapure water (prepared in the laboratory using a pure water machine); acetone (analytical grade, Nanjing Chemical Reagent Co. Ltd., Nanjing, China); Ethanol (analytical grade, Nanjing Chemical Reagent Co., Ltd.). Molecular docking studies To further elucidate and verify the intermolecular interactions between the β-CD and CA, molecular-level simulations were performed to model molecular docking through theoretical studies to elaborate on the encapsulated binding behavior and obtain reliable structures and properties of the inclusion complexes. The three-dimensional structures of CA and β-CD were obtained from the PubChem database and processed for structure optimization using PyMOL 4.3.0 software. Molecular docking was performed using Autodock 1.5.7 software to simulate and predict the most favorable structures of the guest molecule CA and the main molecule β-CD in the inclusion complex (Fig. 2 ). The PyMOL software was used to map the conformations of the two bound small molecules [ 23 , 24 ]. Content determination Chromatographic conditions: A high performance liquid chromatography system (HPLC) (Waters, Milford, MA, USA) with a photodiode array detector was used to determine the content of CA on an Agilent C18 column (250 mm×4.6 mm, 5 µm) with acetonitrile-water solution (45:55) as the mobile phase, a flow rate of 1.0 mL/min, a detection wavelength of 290 nm, a column temperature of 35℃, and an injection volume of 10 µL. The sample was prepared by precisely weighing 4 mg of CA-β-CD inclusion, which was then dissolved with methanol in a 10 mL brown volumetric flask, CA was extracted from CA-β-CD by ultrasonic method, and the time was 15 min, finally diluted to 10 mL, fully mixed, and centrifuged at 130000 rpm for 10 min. The resulting supernatant was used to determine the CA concentration using HPLC. Inclusion complex preparation and physical examination Preparation CA and β-CD were accurately weighed according to a molar ratio of 1:1. Cyclodextrin was added to deionized water at a constant temperature of 60°C to prepare the cyclodextrin solution. The CA was dissolved with an appropriate amount of ethanol and the anhydrous ethanol CA solution was slowly injected into the cyclodextrin solution at a constant 60°C with constant stirring by syringe, saturated for 2 h, refrigerated at 4℃ for 12 h, and fully precipitated and filtered. Then the filter residue was washed three times with acetone and dried at 40℃, resulting in a CA inclusion compound (CA-β-CD) [ 20 , 25 – 27 ]. Dissolution studies To evaluate the dissolution profiles of CA and CA-β-CD, a dissolution study (paddle method) was performed. Samples of 100 mg of CA and a weight of CA-β-CD equivalent to 100 mg of CA were placed in a dissolution apparatus. The media used were hydrochloric acid (0.9 L, 0.1 M) at pH 1.2 or potassium dihydrogen phosphate (0.9 L, 0.18 M) at pH 4.5 and 37°C, and they were stirred at a speed of 50 rpm. Samples (2 mL) were removed at predetermined times of 5, 10, 20, 30, 45, 60, 90, and 120 min and immediately supplemented with an equal volume of dissolution medium. Samples were then passed through the membrane, and the CA content was determined using high pressure liquid chromatography (HPLC) (n = 6). The cumulative dissolution rate M i (%) was calculated using the following equation [ 28 , 29 ], where C i is the released concentration of CA at the i-th sample, V s is the volume before the first sampling (0.9 L), C i−1 is the concentration of CA at the previous sampling point at time sampling point i (mg/mL), V is the sample volume (2 mL), and W is the total amount of drug delivery (mg). $${M}_{i}\left(\text{%}\right)=\left[\left({V}_{s}{C}_{i}+V\sum _{n=1}^{i-1}{C}_{i}\right)/W\right]\times 100\text{%}$$ 1 In vitro release studies The shaking-bed method was used in this experiment. Hydrochloric acid (pH 1.2) and potassium dihydrogen phosphate (pH 4.5) solutions were used as the release media, and a dialysis bag with a molecular retention capacity of 1000 D was selected. Samples of CA (10 mg) or CA-β-CD (equivalent to 10 mg of CA) were added to the treated dialysis bag. A small amount of dissolution medium was added, and the ends were tightened using sealing clamps until no leakage was observed. Release medium (200 mL) was measured into a 200-mL wide-mouth flask. The temperature was controlled at 37 ± 0.5℃ and the rotation speed at 140 r/min. Samples (2 mL) were taken at 10, 20, and 40 min, and subsequently at 1, 2, 4, 6, 8, 10, and 12 h. After each sampling time point, the medium was promptly replaced with an equal amount of fresh release medium at the same temperature. The samples were passed through a membrane and analyzed using HPLC to determine the CA concentration. The experiment was performed in triplicate. The cumulative release rate, Q t (%), was calculated for all samples using the equation below. Cumulative release rate-time curves were plotted using GraphPad Prism 9.5 software (La Jolla, CA, USA). The curves were fitted using Origin 2021 software [ 30 – 32 ]. $${Q}_{t}\left(\text{%}\right)=\left[\left({V}_{0}{C}_{t}+V\sum _{n=1}^{t-1}{C}_{t}\right)/W\right]\times 100\text{%}$$ 2 C t is the released concentration of CA at time t (mg/mL), V 0 is the volume before the first sampling (200 mL), C t−1 is the concentration of CA at the previous sampling point at time sampling point t (mg/mL), V is the sample volume (2 mL), and W is the total amount of drug delivery (mg). Stability inspection To investigate the stability of CA-β-CD at room temperature, six batches of CA-β-CD were prepared simultaneously and stored in airtight glass vials, three of which were stored at room temperature (23 ± 5°C) under normal daylight conditions, and the remaining batches were stored at room temperature in the dark. The batches were sampled at 0, 7, 14, and 30 days for HPLC analysis and the cinnamic aldehyde content was used as the index. The retention time curve was plotted using GraphPad Prism 9.5 to investigate the stability of the inclusion complexes. Characterization of inclusion complexes Preparation of samples CA-β-CD was prepared in the same manner as described previously. A physical mixture of CA and β-CD (PM-CA-β-CD) was prepared by accurately weighing CA and β-CD in a mortar at a molar ratio of 1:1 and grinding them thoroughly to mix. SEM Small amounts of β-CD and CA-β-CD powders were scattered and dispersed on small pieces of double-sided tape that were fixed to the surface of a short aluminum rod. The particle shapes and surface characteristics of the samples were measured and photographed using SEM at 20 kV (Apreo 2, Thermo Fisher Scientific, USA). XRD Samples of 100 mg each of β-CD, PM-CA-β-CD, and CA-β-CD were analyzed using XRD (Smartlab9, Rigaku, Japan). The samples were mounted in an X-ray holder from the top in a flat quartz bath and scanned at a speed of 2°/min in a scanning range of 5°–90°. FTIR Various samples were examined by FTIR spectroscopy (Nicolet-iS10, Thermo Scientific, USA) using the KBr compression method. Approximately 2 mg of each of CA, β-CD, and CA-β-CD were weighed and mixed with approximately 200 mg of dried KBr powder in a mortar and pestle and then an appropriate amount was added into a press die and pressed into transparent flakes at a pressure of 108 Pa. The infrared absorption spectra were scanned in the wave number range of 400–4000 cm − 1 , and each sample was scanned three times in parallel. DSC Ten mg each of β-CD, PM-CA-β-CD, and CA-β-CD inclusions were taken under N2 airflow, and the samples were accurately weighed in a closed aluminum crimped cuvette (DSC 250, TA Instruments, New Castle, DE, USA) and heated at a rate of 10°C/min in the temperature range of 50 to 300°C. NMR A small amount of sample was dissolved in DMSO- d 6 for H-NMR and C-NMR detection at 400 MHz power (AVANCE NEO 400, Bruker, Switzerland). Thermogravimetric analysis Appropriate samples ranging from 2–10 mg of β-CD, PM-CA-β-CD, and CA-β-CD were placed in an aluminum crucible at a heating rate of 10°C/min. For TG analysis, the reference material used was α-Al 2 O 3 under an N 2 atmosphere with a flow rate of 100 mL/min, and a temperature range of 20–800 (NETZSCH STA 449F3, Netzsch, Selb, Germany). To minimize the experimental errors, the test was repeated for each sample [ 31 ]. Pharmacokinetic studies Twelve SD rats (weight, 200 ± 20 g) were randomly divided into two groups, namely, the CA and CA-β-CD groups, and fasted without water before the experiment. After weighing and numbering, the drug was administered via oral gavage at a dose of 50 mg/kg. Approximately 300–400 µL of blood was collected from the orbits at 5, 10, 30, and 45 min and at 1, 2, 4, 6, 8, 10, and 12 h after drug administration. The blood samples were transferred into centrifuge tubes containing sodium heparin, and plasma was isolated by centrifugation at 4000 r/min for 10 min at 4°C. The centrifuged plasma was stored in a freezer at − 80°C for subsequent analysis [ 33 , 34 ]. The plasma samples were thawed at room temperature (23 ± 5°C), then 100 µL of plasma was precisely aspirated and added to a 1.5 mL centrifuge tube with 35 µL of internal standard salicylic acid solution. Next, 365 µL of methanol was added, and the mixture was vortexed for 30 s, then centrifuged at 13000 r/min for 10 min at 4°C, and the supernatant was extracted. The plasma CA content was then determined using HPLC. The obtained data were calculated according to the internal standard method to obtain the content of cinnamic acid in rat plasma at different time points for each group. The blood concentration-time curves were plotted by GraphPad Prism 8.0 software and the blood concentration-time data were analyzed by non-atrial fitting using DAS 2.0 analysis software (China Mathematical Pharmacology Professional Committee, Shanghai, China) to calculate each pharmacokinetic parameter. One-way analysis of variance (ANOVA) and least significant difference (LSD) two-by-two comparison tests were performed to calculate the pharmacokinetic parameters based on the concentration-time profiles for each group using SPSS 22.0. Carrageenan-induced swelling of toes of mice Twenty-four Kunming mice were randomly divided into four groups: model group (0.5% sodium carboxymethyl cellulose solution), positive drug group (aspirin), CA group, and CA-β-CD group, with six mice in each group. The mice were fasted without water before the experiment. The dose for the positive drug group was 200 mg/kg, while the dose for the CA and CA-β-CD groups was 100 mg/kg CA, administered for 15 min. After administration, 50 µL of 1% carrageenan was injected subcutaneously into the toe of the right hind limb of each mouse to establish an acute inflammation model, and the toe circumference was measured before and 15, 30, 60, 120, 180, and 240 min after injection, and the degree of toe swelling was calculated. All data were expressed as means ± standard deviations (SDs), and statistical analysis was performed using SPSS software (version 22.0; IBM Corp., Armonk, NY, USA). One-way ANOVA and LSD tests were used to analyze and compare data from all experimental groups [ 35 – 37 ]. Toe swelling was calculated as (post-inflammatory toe circumference/pre-inflammatory toe circumference)/pre-inflammatory toe circumference × 100 and was expressed as a percentage. The inhibition rate of foot plantar swelling was calculated as ([average foot swelling in the model group - average foot swelling in the drug administration group]/average foot swelling in the model group) × 100%. Results Molecular docking studies As shown in Fig. 2 (generated by Chem 3D 20.0 and Pymol 4.3.0), the molecular docking results with β-CD as the acceptor (b) and CA as the ligand (a) show that the two diastereomeric binding fraction is − 3.86 Kcal/mol and the inclusion complex has good stability and spontaneous binding. In the 3D structure diagram shown in (c), the green bar indicates CA, the purple bar indicates β-CD, and the yellow dashed line indicates hydrogen bonds. CA is located in the middle of the β-CD and is completely encapsulated in the cavity; there is intermolecular hydrogen bonding between CA and cyclodextrin. Due to the higher binding fraction and the fully encapsulated structure, the CA-β-CD complexes have better stability and show a possible slow-release effect from the side. Dissolution studies Relevant studies have shown that CA has a significant effect on reducing the gastric emptying rate; therefore, the degree of dissolution of CA under acidic conditions has mainly been investigated. Figure 3a shows that the cumulative dissolution rate of CA-β-CD in both dissolution media reached approximately 90% after 30 min, while that of CA was only approximately 60%. The average cumulative dissolution rate of CA in the dissolution medium was 60.49% and 70.26% at pH 1.2 and pH 4.5, respectively, within 120 min; while that of CA-β-CD in both media reached 94.71% and 91.63%, which were 1.56 and 1.30 times higher than that of the CA, respectively. The solubility of the inclusion complex calculated using this method contained both forms of CA-β-CD and CA, which does not fully reflect the solubilization behavior of CA in the inclusion complex. In vitro release studies As shown in Fig. 3b, the cumulative release rate of CA raw material showed an increasing trend from 0 to 2 h and reached the highest value at 2 h with 51.69% (pH 1.2) and 45.33% (pH 4.5). The cumulative release rates from 2 to 12 h showed a decreasing trend, presumably due to the longer time and the degradation of CA occurring inside and outside the dialysis bag during the release process at 37°C. The cumulative release rate of CA-β-CD in both dissolution media reached over 80% within 12 h, with 82.59% (pH 1.2) and 83.08% (pH 4.5) within 2 h. The release rate of CA-β-CD was lower than that of CA raw material, owing to the inability of the cyclodextrin to pass through the dialysis bag. Free CA was the first to pass through the dialysis bag, while the encapsulated CA could only pass through the dialysis bag into the release medium after release from the complex. The free CA content was significantly lower than that of CA; therefore, the release degree was lower than that of the CA group, indicating that CA was encapsulated and had a certain slow release effect. After 2 h, the cumulative release rate of CA-β-CD was higher than that of CA, owing to the degradation of CA. Tables 1 and 2 show the first-level kinetic equation R 2 of CA-β-CD in two pH release media, which is greater than the zero-level kinetic equation R 2 . This suggests that the drug release process of CA-β-CD inclusion depends on the concentration. The results were treated with Higuchi and Ritger–Peppas models, where the Ritger–Peppas model fit results with n = 0.445 (pH 1.2) and n = 0.334 (pH 4.5). Both values were < 0.45, which indicated the release mechanism of the inclusion complex was controlled by Fickian diffusion. This demonstrates that the CA-β-CD inclusion complex operates through a slow release mechanism, while the release mechanism of CA is skeletal dissolution [ 38 , 39 ]. Table 1 , Results of release curve fitting for pH 1.2 release media Method Equation CA CA-β-CD Equation R 2 Equation R 2 Zero-order M t /M ∞ =Kt M t /M ∞ =0.84 t + 34.03 0.0204 M t /M ∞ =7.15 t + 16.03 0.7729 One-order ln(1- M t /M ∞ )=- Kt ln(1- M t /M ∞ ) = 44.95 − 4.19 t 0.8067 ln(1- M t /M ∞ ) = 83.69 − 0.41 t 0.9656 Higuchi M t /M ∞ =Kt 1/2 M t /M ∞ =5.73 t 1/2 +27.97 0.1531 M t /M ∞ =28.00 t 1/ −0.14 0.9061 Ritger–Peppas M t /M ∞ =Kt n M t /M ∞ =0.0097 t 5.59 0.9375 M t /M ∞ =31.36t 0.445 0.9975 CA, trans-cinnamaldehyde; CD, β-cyclodextrin; CA-β-CD, compounds prepared from CA and β-CD Table 2. Results of release curve fitting for pH 4.5 release media Method Equation CA CA-β-CD Equation R 2 Equation R 2 Zero-order M t /M ∞ =Kt M t /M ∞ =0.98 t +28.48 0.0494 M t /M ∞ =7.00 t +16.49 0.8253 One-order ln(1- M t /M ∞ )=- Kt ln(1- M t /M ∞ )=39.49−3.66 t 0.7260 ln(1- M t /M ∞ )=83.04−0.39 t 0.9785 Higuchi M t /M ∞ =Kt 1/2 M t /M ∞ =5.84 t 1/2 +22.80 0.1877 M t /M ∞ =27.15 t 1/2 −0.12 0.9442 Ritger–Peppas M t /M ∞ =Kt n M t /M ∞ =0.7134 t 2.607 0.9305 M t /M ∞ =38.49 t 0.334 0.9989 CA, trans-cinnamaldehyde; CD, β-cyclodextrin; CA-β-CD, compounds prepared from CA and β-CD Stability inspection As shown in Fig. 3c, the stability of the inclusions stored at room temperature and protected from light surpassed that of the inclusions exposed to light. By day 30, the CA content of the inclusions protected from light was significantly higher, reaching 73.12%, compared to 57.83% for those exposed to light. Characterization SEM Figure 4 shows the morphological characteristics of the β-CD and CA-β-CD inclusion complexes. The β-CD surface is flatter and appears as plate-like amorphous crystals under SEM, in consistency with related reports [ 40 ]. The CA-β-CD surface is smoother and has an irregular plate shape, presumably due to a change in the surface morphology of β-CD after encapsulation of CA. XRD Figure 5 a shows that a large number of crystalline peaks of β-CD occurred at 4°–40°, and the presence of crystalline diffraction peaks of β-CD in the physical mixture indicates that β-CD exists mainly in crystalline form in the physical mixture. The crystalline diffraction peak of β-CD at 9.16° in CA-β-CD disappears and the absorption peak at 12.7° shifts forward to 11.80° [ 4 ], indicating that the cyclodextrin inclusion complex is prepared successfully and cyclodextrin exists in amorphous form. FTIR As shown in Fig. 5 b, the CA spectrum has characteristic peaks at 3061.73 cm-1 (= C-H), 1625.38 cm-1, 1491.78 cm-1, and 1450.14 cm-1 (related to aromatic ring skeleton), and 1669.08 cm-1 (indicative of C = O stretching). Additionally, peaks are observed at 2814.40 cm − 1 , and 2742.98 cm − 1 (corresponding to -CHO), in consistency with a previous study [ 4 ]. β-CD patterns have characteristic peaks at 3383.16 cm − 1 (O-H), 2925.93 cm − 1 (C-H), 1157.16 cm − 1 (C-O), and 1028.59 cm − 1 (C-O-C). The main characteristic peaks of CA in the inclusion complex are almost completely absent, indicating that CA was successfully encapsulated by β-CD. DSC Figure 5 c shows that β-CD has an obvious heat absorption peak at 133.4°C, while the obvious heat absorption peak of CA at 118.83°C indicates that CA still exists mainly in liquid form in the physical mixture. In the heat absorption peak of CA-β-CD inclusion complex, the heat absorption peak of cinnamon volatile oil at 102.4°C disappears, indicating that cinnamon volatile oil is dispersed in β-CD in a non-aggregated form. TG The TG analysis curves of β-CD showed three stages of mass loss. There is approximately 10% mass loss in the first stage at 100°C representing the evaporation of surface and internal water. In addition, at this point, the mass loss of the physical mixture was relatively high, while the mass loss of the inclusion complex was low, approximately 5% as seen in Fig. 6 a. This indicates that when CA was encapsulated by β-CD, it replaced the water molecules in the β-CD cavity and formed the inclusion complex. A temperature of 100°C eliminates the water in the β-CD particles and the free CA in the physical mixture but does not eliminate the CA encapsulated in the inclusion complex. Thus, the thermal stability of CA is significantly improved due to the interaction between CA molecules and the inner cavity of β-CD. The differential thermal analysis curve of the physical mixture of β-CD and CA (Fig. 6 b) shows a weak heat absorption peak near this point, confirming the volatilization of water or free CA. This dehydration heat absorption peak disappears from the curve of CA-β-CD inclusion complex. This indicated the formation of inclusion complexes [ 41 ]. Up to approximately 330°C, the weight of the three samples decreased abruptly by 70%, indicating the decomposition of β-CD and the loss of protection of the inclusion complex [ 42 ]. NMR The 1H-NMR spectrum of CA-β-CD showed peaks of β-CD exchanging with those of CA as follows (Fig. 7 c). The chemical shift signals of β-CD mainly ranged from 2.75 ppm to 5.75 ppm (Fig. 7 b), although some peaks belonging to β-CD in CA-β-CD showed a shift to higher fields. The carbonyl H chemical signal shift in CA was 9.68 ppm, and the shift signals of the benzene ring were 7.41–7.71 ppm (Fig. 7 a) [ 43 ]. The chemical shift of the benzene ring (7.47–7.77 ppm) in CA-β-CD was shifted to a lower field compared to CA, which indicates the formation of new phases. CA is encapsulated in the cavity of the β-CD. The CA part of the CA-β-CD 13 C-NMR carbon spectrum shows chemical shifts toward the low field (Fig. 7 f), such as the chemical shift of the carbonyl H peak in CA (194.19 ppm) was shifted to 194.5 ppm. 1 H-NMR and 13 C-NMR of CA-β-CD together illustrate that CA is encapsulated by β-CD and causes changes in the chemical signal shifts of its H and C atoms [ 44 ]. Pharmacokinetic studies As shown in Fig. 8 and Table 3 , the half-life of the inclusion complex significantly increased compared to that of the active pharmaceutical ingredient (CA)( p < 0.05), indicating that elimination of the inclusion complex was slower after the distribution reached equilibrium in rats. There was no significant difference observed between the peak time (T max ) of the CA and the CA-β-CD. However, the C max in the CA-β-CD inclusion group was lower compared to that of the CA group. Nevertheless, the area under the curve from time zero to the last measurable time point (AUC 0 − t ) and the AUC from time zero to infinity (AUC 0−∞ ) increased in the CA-β-CD group compared to the CA group, attributable to a significant increase in half-life, which was 1.16 times higher than that of CA ( p > 0.05). The above data indicate that the inclusion compound prolonged the retention time of cinnamic acid in blood and tissues, suggesting that CA-β-CD has a slow-release effect in rats. The relevant studies have demonstrated that after oral administration, CA undergoes partial metabolism to cinnamic acid in the stomach and small intestine [ 45 ], the metabolism is rapid, and cinnamic acid can be readily absorbed. Moreover, the oxidative metabolism of cinnamaldehyde closely follows that of cinnamic acid through β-oxidation, resembling the metabolic pathway observed in fatty acids [ 46 – 48 ]. All this is closely related to the physicochemical properties of cinnamaldehyde. CA is rapidly and quantitatively released by β-CD and, therefore, there is little variability in T max [ 49 ]. The structural modifications have additionally resulted in enhanced stability of CA, leading to an increase in AUC 0−∞ and prolonging the time required to achieve dynamic equilibrium due to covalent bonding between CA and β-CD. Furthermore, there has been a noticeable elevation in t 1/2 [ 50 ]. The hydrophobic cavity of β-CD forms a host-guest structure upon the incorporation of CA into the cavity. This process results in the replacement of the space within the lipophilic central region of β-CD, thus, reducing the utilization rate of β-CD and leading to a decrease in C max [ 51 ]. Table 3 Main pharmacokinetic parameters of cinnamic acid in rat plasma (mean ± SD) Parameters Unit CA CA-β-CD t 1/2 h 0.244 ± 0.141 0.586 ± 0.191* T max h 0.111 ± 0.068 0.117 ± 0.075 C max µg/mL 10.839 ± 3.109 7.55 ± 2.845 AUC 0 − t µg/mL*h 4.304 ± 0.461 4.922 ± 0.587 AUC 0−∞ µg/mL*h 4.668 ± 0.528 5.437 ± 0.969 Significance* p < 0.05, indicating a significant difference to the CA group AUC, area under the curve; CA, trans-cinnamaldehyde; CD, β-cyclodextrin; CA-β-CD, compounds prepared from CA and β-CD; SD, standard deviation Table 4 Comparison of toe swelling inhibition ratio in each group (mean ± SD) Group 0.25 h 0.5 h 1 h 2 h 3 h 4 h Positive drug −50.20 3.73 24.86 18.59 39.30 73.42 CA 15.10 24.60 10.01 46.68 18.95 38.39 CA-β-CD −11.69 −1.34 57.58 70.25 41.51 54.23 CA, trans-cinnamaldehyde; CD, β-cyclodextrin; CA-β-CD, compounds prepared from CA and β-CD; SD, standard deviation Effects of CA and CA-βCD on the carrageenan-induced swelling of toes in mice Swelling of mouse feet is a common acute inflammation model that is now known to involve a variety of inflammatory factors, including injection trauma, serotonin, histamine, bradykinin, and prostaglandin 2 [ 52 – 54 ]. The experimental results showed that swelling of the mouse foot can be divided into two phases: the swelling phase (0–2 h) and the swelling reduction phase (2–4 h), in consistency with previous works [ 54 , 55 ]. At 0.25–0.5 h (i.e., 0.5–0.75 h of gavage) after the injection of carrageenan gum, the CA group showed inhibited toe swelling in mice ( p > 0.05), while the CA-β-CD group did not show significant inhibition of toe swelling. At 1 h, toe swelling was significantly reduced in the inclusion group compared with the model ( p < 0.01) and CA groups ( p < 0.05), and the inhibition rate of swelling was 57.58% [ 56 ]. At 2 h, swelling was significantly reduced in the inclusion group compared with the model group ( p < 0.05). The swelling inhibition rate was 70.25%, and the rate over 1–4 h was higher in the CA-β-CD group than in the CA group. After oral administration, CA demonstrated a rapid onset of action, while the slow-release nature of CA-β-CD resulted in a slightly delayed effect compared to CA. Notably, 1–2 h after the injection of carrageenan gum (i.e., 1.25–2.25 h of gavage), the sustained release of cinnamic aldehyde from the inclusion compound led to a gradual but intensified inhibition of toe swelling. The CA showed a weaker inhibition effect relative to the inclusion compound after 1 h, and the inclusion compound showed a long-lasting swelling inhibition effect due to its slow-release effect. CA has demonstrated significant anti-edema activity, effectively inhibiting carrageenan-induced swelling in a dose-dependent manner following oral administration, and the potential impact of this phenomenon could potentially be attributed to its interference with inflammatory mediators [ 56 ]. The results of related cell experiments also demonstrated that CA-β-CD significantly enhanced the efficacy of reactive oxygen species(ROS) reduction in RAW 264.7 cells treated with lipopolysaccharide(LPS) [ 57 ]. Three studies have shown that β-CD can increase the duration of action. Compared to the original drug, β-CD enhances and prolongs the analgesic and anti-inflammatory effects [ 58 – 61 ]. The improved stability half-life and bioavailability of β-CD may be the reason for the prolonged anti-inflammatory effect (Fig. 9 ). Conclusion Characterization and validation of CA-β-CD through SEM, XRD, FTIR, DSC, TG, NMR analyses demonstrated that CA was successfully encapsulated by β-cyclodextrin, resulting in enhanced CA stability. Molecular simulation studies have shown that CA is fully encapsulated by β-CD cavities, suggesting a controlled release mechanism. The results of in vitro release studies have shown that the accumulative release rate of CA-β-CD inclusion complex was higher than that of the bulk drug after 2 h in the two release media, with a slow and stable release profile. In rats, the peak concentration of CA-β-CD decreased, the half-life significantly increased ( p < 0.05), the AUC 0 − t and AUC 0−∞ both increased, and the sustained release effect was evident. In an efficacy experiment using a carrageenan-induced toe swelling mouse model, the inclusion complex exhibited its effect after approximately 1 h. Furthermore, the swelling inhibition effect observed after 1 h, was greater and more sustained than that of the CA bulk drug. In conclusion, molecular simulation and dialysis bag release studies suggest a controlled and delayed release of CA from the inclusion compound. Therefore, compared to the cinnamaldehyde raw material, the inclusion compound exhibited a decreased absorption peak concentration, prolonged half-life, delayed oral effect, and extended duration of action. Declarations Funding This work was supported by the Jiangsu Provincial TCM Science and Technology Development Plan Project under Grant number MS2021028 and Natural Science Foundation of Nanjing University of Chinese Medicine under Grant number XZR2020021. Competing interests No potential conflict of interest was reported by the authors. Author contributions Jiazheng Li was responsible for organizing and writing the article, and design of the “In-vitro release studies.” Zhao Cui analyzed the section “Characterization of inclusion complexes.” Xi Xiong was in charge of the “Dissolution studies.” Ruotong Zhang analyzed the section “Pharmacokinetic studies.” Weiwen Lu was in charge of the “Molecular docking study.” Zhipeng Cai analyzed the section “Effects of CA and CA-β-CD on the carrageenan-induced swelling of toes in mice.” Xuedan Fu was responsible for the experiments in “Pharmacokinetic studies” and “Effects of CA and CA-β-CD on the carrageenan-induced swelling of toes in mice.” sections. Zhenhai Zhang and Jianming Ju were responsible for the designing the experiment and revision of the article. Data availability All data generated or analyzed during this study are included in this submitted article. The data that support the findings of this study are available from the corresponding author, J. Ju, upon reasonable request. Ethics Approval The aim of this study was to study data on the in vitro release, pharmacokinetics, and pharmacodynamics of CA-β-CD. The pharmacokinetic characteristics of CA-β-CD in vivo were studied quantitatively and objectively in rats, and the pharmacokinetic parameters of its metabolites were predicted over time to confirm whether CA-β-CD has a sustained release effect in vivo . The mouse foot swelling experiment induced by carrageenan was to study the pharmacodynamic effect of the slow-release properties on its anti-inflammatory effect. The in vivo pharmacodynamic and pharmacokinetic studies involved in this study cannot be replaced by other experiments at present, and the use of animal models is effective and necessary. Animals in this study were supplied by the Experimental Animal Center of Jiangsu Academy of Traditional Chinese Medicine (Jiangsu, China) and were carefully housed in the animal center under constant temperature and humidity. Rats were anesthetized with 2% Isoflurane (0.4 ml/min at 4 L/min fresh gas flow) before the experiment and all animals were sacrificed by cervical dislocation at the end of the experiment. All animal procedures were performed in accordance with the Guidelines for Care and Use of Laboratory Animals of Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, and approved by the Animal Ethics Committee of Jiangsu Province Hospital on Integration of Chinese and Western Medicine (Jiangsu, China). Animal license: AEWC-20220622-225. All animal experiments were performed following the ARRIVE guidelines. References Gilani S, Najafpour G. Evaluation of the extraction process parameters on bioactive compounds of cinnamon bark: A comparative study. Process Biochem. 2022;114:93–101.http://doi.org/10.1016/j.procbio.2022.01.022. Masghati S, Ghoreishi SM. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4376749","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":305117146,"identity":"f75897a6-c993-41c2-b455-218b238966bf","order_by":0,"name":"Jiazheng Li","email":"","orcid":"","institution":"Nanjing University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jiazheng","middleName":"","lastName":"Li","suffix":""},{"id":305117147,"identity":"78d6a314-9366-4574-a77b-050997093b6d","order_by":1,"name":"Zhao Cui","email":"","orcid":"","institution":"Nanjing University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Zhao","middleName":"","lastName":"Cui","suffix":""},{"id":305117148,"identity":"c6f8a7d0-0980-4b4c-b133-c78f2ceb0d72","order_by":2,"name":"Xi Xiong","email":"","orcid":"","institution":"Nanjing University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Xi","middleName":"","lastName":"Xiong","suffix":""},{"id":305117149,"identity":"ed851e36-b0ef-4750-82ad-a4f2bb6d1c57","order_by":3,"name":"Ruotong Zhang","email":"","orcid":"","institution":"Nanjing University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ruotong","middleName":"","lastName":"Zhang","suffix":""},{"id":305117150,"identity":"e1413b51-285d-4b75-baaa-893c776868c7","order_by":4,"name":"Weiwen Lu","email":"","orcid":"","institution":"Nanjing University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Weiwen","middleName":"","lastName":"Lu","suffix":""},{"id":305117151,"identity":"ab4b32b5-55ee-42a3-b474-cfaeaf48073e","order_by":5,"name":"Zhipeng Cai","email":"","orcid":"","institution":"Nanjing University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Zhipeng","middleName":"","lastName":"Cai","suffix":""},{"id":305117152,"identity":"3ea2762d-b2ff-4d7d-bec5-60df70479f04","order_by":6,"name":"Xuedan Fu","email":"","orcid":"","institution":"Nanjing University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Xuedan","middleName":"","lastName":"Fu","suffix":""},{"id":305117153,"identity":"6e16a4cb-def6-4e2d-aa3d-1614ddc376d2","order_by":7,"name":"Zhenhai Zhang","email":"","orcid":"","institution":"Jiangsu Province Academy of Traditional Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Zhenhai","middleName":"","lastName":"Zhang","suffix":""},{"id":305117154,"identity":"a839c1a8-c053-4426-acc2-d662dac7e58f","order_by":8,"name":"Jianming Ju","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAr0lEQVRIiWNgGAWjYBACxoYDDAaJf2wY2EjSUvCxIY0ELSDwcWbDYRKUMzeeTtzMu+O8PZ908wOGHxXbiHHY2c3GvGduJ7bJHDNg7Dlzmygt24x52G4nsEkkGDAzthGnZftvHrZz9mwS6R+I1rLBcGbbAcY2iRzibdlg8OFMciJQS8FBovxiOAOoJaHCzl5+RvrGBz8qiNJyAME5gEsVCpDnbyBK3SgYBaNgFIxkAADuwkF/uvAy6AAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-8101-162X","institution":"Jiangsu Province Academy of Traditional Chinese Medicine","correspondingAuthor":true,"prefix":"","firstName":"Jianming","middleName":"","lastName":"Ju","suffix":""}],"badges":[],"createdAt":"2024-05-06 12:23:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4376749/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4376749/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57637798,"identity":"53221bae-4e0b-42ef-a03d-93e5d5ec10cf","added_by":"auto","created_at":"2024-06-03 16:23:24","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":5926,"visible":true,"origin":"","legend":"\u003cp\u003eStructure of CA (generated by ChemDraw20.0)\u003c/p\u003e\n\u003cp\u003eCA, trans-cinnamaldehyde\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4376749/v1/c4fca8a2f128e1d234ec4333.png"},{"id":57637176,"identity":"c57871c0-76b6-4b24-bd4d-fc438078bc23","added_by":"auto","created_at":"2024-06-03 16:15:24","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":115889,"visible":true,"origin":"","legend":"\u003cp\u003eMolecular docking diagram\u003c/p\u003e\n\u003cp\u003e(a) 3D structure of CA (generated by Chem 3D 20.0). (b) 3D structure of β-CD (generated by Pymol 4.3.0). (c) 3D structure of CA-β-CD (generated by Pymol 4.3.0).\u003c/p\u003e\n\u003cp\u003e3D, three-dimensional; CA, trans-cinnamaldehyde; CD, β-cyclodextrin; CA-β-CD, compounds prepared from CA and β-CD\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4376749/v1/e2cb71481dac7a3ff208a294.png"},{"id":57637178,"identity":"60a66961-1f6b-4777-b058-adb858d5a21d","added_by":"auto","created_at":"2024-06-03 16:15:24","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":86115,"visible":true,"origin":"","legend":"\u003cp\u003e(a) Cumulative dissolution rates diagram of CA and CA-β-CD in two media (n=6). (b) Accumulated release diagram of CA and CA-β-CD in two media (n=3). (c) Stability diagram of CA-β-CD\u003c/p\u003e\n\u003cp\u003eCA, trans-cinnamaldehyde; CD, β-cyclodextrin; CA-β-CD, compounds prepared from CA and β-CD\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4376749/v1/9c5129ffad361a1c49c01288.png"},{"id":57637181,"identity":"51e9b91d-93d7-46b1-a429-b8eea3a45867","added_by":"auto","created_at":"2024-06-03 16:15:24","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":315598,"visible":true,"origin":"","legend":"\u003cp\u003eSEM diagram of the CA-β-CD inclusion complex\u003c/p\u003e\n\u003cp\u003e(a), (b) β-CD. (c), (d) CA-β-CD\u003c/p\u003e\n\u003cp\u003eCA, trans-cinnamaldehyde; CD, β-cyclodextrin; CA-β-CD, compounds prepared from CA and β-CD\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4376749/v1/a05a1429aab8f3dc55463cf6.png"},{"id":57638405,"identity":"a548839f-e548-43d1-a3fa-62c099d89152","added_by":"auto","created_at":"2024-06-03 16:31:24","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":79216,"visible":true,"origin":"","legend":"\u003cp\u003e(a) XRD diagram of CA-β-CD inclusion complex. (b) FT-IR diagram of CA-β-CD inclusion complex. (c) DSC diagram of CA-β-CD inclusion complex.\u003c/p\u003e\n\u003cp\u003eCA, trans-cinnamaldehyde; CD, β-cyclodextrin; CA-β-CD, compounds prepared from CA and β-CD; DSC, differential scanning calorimetry; FTIR, Fourier-transform infrared spectroscopy;\u003c/p\u003e\n\u003cp\u003eXRD, X-ray diffraction;\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-4376749/v1/de4d5b80c7804bc1ba257bc3.png"},{"id":57637183,"identity":"6f7e9dc9-7121-4ad0-8d1f-c4a55497f12e","added_by":"auto","created_at":"2024-06-03 16:15:25","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":53481,"visible":true,"origin":"","legend":"\u003cp\u003eTG diagram of the CA-β-CD inclusion complex\u003c/p\u003e\n\u003cp\u003eCA-β-CD, compounds prepared from CA and β-CD; TG, thermogravimetry\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-4376749/v1/00bf58684c6ed1edc47ae1ad.png"},{"id":57637800,"identity":"e08eed57-c121-4358-906f-5b865e229d56","added_by":"auto","created_at":"2024-06-03 16:23:24","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":134720,"visible":true,"origin":"","legend":"\u003cp\u003e(a) \u003csup\u003e1\u003c/sup\u003eH-NMR diagram of CA; (b) \u003csup\u003e1\u003c/sup\u003eH-NMR diagram of β-CD; (c) \u003csup\u003e1\u003c/sup\u003eH-NMR diagram of CA-β-CD; (d) \u003csup\u003e13\u003c/sup\u003eC-NMR diagram of CA; (e)The \u003csup\u003e13\u003c/sup\u003eC-NMR diagram of β-CD; (f) \u003csup\u003e13\u003c/sup\u003eC-NMR diagram of CA-β-CD. (All generated by MestReNova 14.2)\u003c/p\u003e\n\u003cp\u003eCA, trans-cinnamaldehyde; CD, β-cyclodextrin; CA-β-CD, compounds prepared from CA and β-CD; NMR, nuclear magnetic resonance\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-4376749/v1/72af9a71ff2e8a7727026474.png"},{"id":57637179,"identity":"cb474ca9-d192-4d9a-81c0-4c5808ea319a","added_by":"auto","created_at":"2024-06-03 16:15:24","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":21937,"visible":true,"origin":"","legend":"\u003cp\u003eCurve of the mean plasma drug concentration versus time in rats after intragastric administration of CA or CA-β-CD\u003c/p\u003e\n\u003cp\u003eCA, trans-cinnamaldehyde; CD, β-cyclodextrin; CA-β-CD, compounds prepared from CA and β-CD\u003c/p\u003e","description":"","filename":"8.png","url":"https://assets-eu.researchsquare.com/files/rs-4376749/v1/49ee0f1919a8fcc4a4d06aeb.png"},{"id":57637182,"identity":"54077fbf-4b53-4392-a0c3-1e56d28ab2cb","added_by":"auto","created_at":"2024-06-03 16:15:24","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":48467,"visible":true,"origin":"","legend":"\u003cp\u003eCurve of pedal swelling of mice in each group with time after injection\u003c/p\u003e\n\u003cp\u003eNote: ⋇\u003cem\u003ep\u003c/em\u003e\u0026lt;0.05, significant ratio compared to the model group at the same time point; ⋇⋇\u003cem\u003ep\u003c/em\u003e\u0026lt;0.01, highly significant ratio compared to the model group at the same time point; #\u003cem\u003ep\u003c/em\u003e\u0026lt;0.05, extremely a highly significant ratio compared to that of the CA group at the same time point.\u003c/p\u003e\n\u003cp\u003eCA, trans-cinnamaldehyde\u003c/p\u003e","description":"","filename":"9.png","url":"https://assets-eu.researchsquare.com/files/rs-4376749/v1/686bda9a09473e326fd5cb06.png"},{"id":58440989,"identity":"b3a2207a-dae7-4745-932a-f47723087643","added_by":"auto","created_at":"2024-06-16 11:07:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1595468,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4376749/v1/8d5c65f6-883a-4c8c-8c92-bbcb4a480701.pdf"},{"id":57637174,"identity":"29870602-c00c-44d8-bf36-dddf8443723b","added_by":"auto","created_at":"2024-06-03 16:15:24","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":132268,"visible":true,"origin":"","legend":"\u003cp\u003eGraphical abstract\u003c/p\u003e","description":"","filename":"Graphicalabstract.png","url":"https://assets-eu.researchsquare.com/files/rs-4376749/v1/e858b2a340caadcdbae7c6be.png"}],"financialInterests":"","formattedTitle":"Preparation, characterization, and release behavior of β-cyclodextrin inclusion complexes of trans-cinnamaldehyde","fulltext":[{"header":"Introduction","content":"\u003cp\u003eTrans-cinnamaldehyde (CA) is the main component of essential oils, such as cinnamon oil, and it can be obtained by steam distillation and supercritical CO\u003csub\u003e2\u003c/sub\u003e extraction [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This component has considerable broad-spectrum antibacterial activity and an inhibitory effect on various tumor cells [\u003cspan additionalcitationids=\"CR6 CR7 CR8\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. At the same time, CA has inhibitory effects on several chronic inflammation and oxidative stress conditions and thus has certain prospects in the treatment of ulcerative colitis, rheumatoid arthritis, and other inflammatory diseases [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e(generated using ChemDraw 20.0), the aldehyde group and conjugate bond in CA make it extremely unstable and easily oxidizable in air, and cause poor water solubility [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Pure CA has poor thermal stability starting at a temperature of 60℃. With an increase in temperature, pure CA undergoes temperature-dependent conversion to benzaldehyde [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], whereas after encapsulation, CA can effectively avoid the influence of various environmental factors, such as humidity, light, and high temperature [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\u003cp\u003eβ-cyclodextrin (β-CD) is a commonly used matrix that effectively encapsulates some molecules in whole or in part as a guest molecule and is used in many applications in pharmaceuticals and food products [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Studies have shown that inclusion compounds prepared from CA and β-CD (CA-β-CD) have better thermal stability and water solubility than CA alone [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Cinnamaldehyde-chemotype leaf oil microencapsulated with β-CD had good thermal stability and xanthine oxidase inhibitory activity [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], while β-CD complexation was found to increase the solubility of CA and affect its antioxidant activity [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. However, the \u003cem\u003ein vitro\u003c/em\u003e release, pharmacokinetics, and pharmacodynamics of CA-β-CD have not been systematically studied.\u003c/p\u003e \u003cp\u003eThe authors hypothesized that the inclusion complex formed by CA and β-CD would improves the stability and solubility of CA, thereby inducing slow-release behavior that affects its pharmacokinetic parameters and efficacy. In this study, we prepared CA-β-CD inclusion complexes and characterized their structure using scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), thermogravimetry (TG), and nuclear magnetic resonance (NMR). We investigated the \u003cem\u003ein vitro\u003c/em\u003e and \u003cem\u003ein vivo\u003c/em\u003e slow-release characteristics of CA-β-CD through \u003cem\u003ein vitro\u003c/em\u003e release and \u003cem\u003ein vivo\u003c/em\u003e pharmacokinetic studies. Additionally, we evaluated the impact of CA and the inclusion complex on carrageenan-induced toe swelling in mice.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eMaterials\u003c/p\u003e \u003cp\u003eThe following materials were obtained: Trans-cinnamaldehyde (MFY240F0219, Nantong Feiyu Biotechnology Co. Ltd., Nantong, China), β-cyclodextrin (20200503, Shandong Binzhou Zhiyuan Technology Co. Ltd., Shandong, China). Trans-cinnamaldehyde standard substance (710200011, National Institutes for Food and Drug Control, Beijing, China), cinnamic acid standard substance (110786\u0026ndash;201604, National Institutes for Food and Drug Control). Carboxymethyl sodium cellulose (150701, Anhui Shanhe Pharmaceutical Excipients Co. Ltd., Anhui, China), Bayer Aspirin enteric tablets (BJ69523, Bayer HealthCare Manufacturing S.r.l., Milan, Italy). Carrageenan (C1013-25G, Sigma-Aldrich Co., St Louis, MO, USA). Acetonitrile (chromatographic grade, TeleChem Corp., Atlanta, GA, USA) Methanol (chromatographic grade, Shandong Yuwang Industrial Co., Ltd., Shandong, China). Ultrapure water (prepared in the laboratory using a pure water machine); acetone (analytical grade, Nanjing Chemical Reagent Co. Ltd., Nanjing, China); Ethanol (analytical grade, Nanjing Chemical Reagent Co., Ltd.).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eMolecular docking studies\u003c/h2\u003e \u003cp\u003eTo further elucidate and verify the intermolecular interactions between the β-CD and CA, molecular-level simulations were performed to model molecular docking through theoretical studies to elaborate on the encapsulated binding behavior and obtain reliable structures and properties of the inclusion complexes. The three-dimensional structures of CA and β-CD were obtained from the PubChem database and processed for structure optimization using PyMOL 4.3.0 software. Molecular docking was performed using Autodock 1.5.7 software to simulate and predict the most favorable structures of the guest molecule CA and the main molecule β-CD in the inclusion complex (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The PyMOL software was used to map the conformations of the two bound small molecules [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eContent determination\u003c/h2\u003e \u003cp\u003eChromatographic conditions: A high performance liquid chromatography system (HPLC) (Waters, Milford, MA, USA) with a photodiode array detector was used to determine the content of CA on an Agilent C18 column (250 mm\u0026times;4.6 mm, 5 \u0026micro;m) with acetonitrile-water solution (45:55) as the mobile phase, a flow rate of 1.0 mL/min, a detection wavelength of 290 nm, a column temperature of 35℃, and an injection volume of 10 \u0026micro;L.\u003c/p\u003e \u003cp\u003eThe sample was prepared by precisely weighing 4 mg of CA-β-CD inclusion, which was then dissolved with methanol in a 10 mL brown volumetric flask, CA was extracted from CA-β-CD by ultrasonic method, and the time was 15 min, finally diluted to 10 mL, fully mixed, and centrifuged at 130000 rpm for 10 min. The resulting supernatant was used to determine the CA concentration using HPLC.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eInclusion complex preparation and physical examination\u003c/h2\u003e \u003cp\u003ePreparation\u003c/p\u003e \u003cp\u003eCA and β-CD were accurately weighed according to a molar ratio of 1:1. Cyclodextrin was added to deionized water at a constant temperature of 60\u0026deg;C to prepare the cyclodextrin solution. The CA was dissolved with an appropriate amount of ethanol and the anhydrous ethanol CA solution was slowly injected into the cyclodextrin solution at a constant 60\u0026deg;C with constant stirring by syringe, saturated for 2 h, refrigerated at 4℃ for 12 h, and fully precipitated and filtered. Then the filter residue was washed three times with acetone and dried at 40℃, resulting in a CA inclusion compound (CA-β-CD) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDissolution studies\u003c/p\u003e \u003cp\u003eTo evaluate the dissolution profiles of CA and CA-β-CD, a dissolution study (paddle method) was performed. Samples of 100 mg of CA and a weight of CA-β-CD equivalent to 100 mg of CA were placed in a dissolution apparatus. The media used were hydrochloric acid (0.9 L, 0.1 M) at pH 1.2 or potassium dihydrogen phosphate (0.9 L, 0.18 M) at pH 4.5 and 37\u0026deg;C, and they were stirred at a speed of 50 rpm. Samples (2 mL) were removed at predetermined times of 5, 10, 20, 30, 45, 60, 90, and 120 min and immediately supplemented with an equal volume of dissolution medium. Samples were then passed through the membrane, and the CA content was determined using high pressure liquid chromatography (HPLC) (n\u0026thinsp;=\u0026thinsp;6). The cumulative dissolution rate \u003cem\u003eM\u003c/em\u003e\u003csub\u003ei\u003c/sub\u003e (%) was calculated using the following equation [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], where \u003cem\u003eC\u003c/em\u003e\u003csub\u003e\u003cem\u003ei\u003c/em\u003e\u003c/sub\u003e is the released concentration of CA at the i-th sample, \u003cem\u003eV\u003c/em\u003e\u003csub\u003e\u003cem\u003es\u003c/em\u003e\u003c/sub\u003e is the volume before the first sampling (0.9 L), \u003cem\u003eC\u003c/em\u003e\u003csub\u003e\u003cem\u003ei\u0026minus;1\u003c/em\u003e\u003c/sub\u003e is the concentration of CA at the previous sampling point at time sampling point \u003cem\u003ei\u003c/em\u003e (mg/mL), \u003cem\u003eV\u003c/em\u003e is the sample volume (2 mL), and \u003cem\u003eW\u003c/em\u003e is the total amount of drug delivery (mg).\u003cdiv id=\"Equ1\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equ1\" name=\"EquationSource\"\u003e\n$${M}_{i}\\left(\\text{%}\\right)=\\left[\\left({V}_{s}{C}_{i}+V\\sum _{n=1}^{i-1}{C}_{i}\\right)/W\\right]\\times 100\\text{%}$$\u003c/div\u003e\u003cdiv class=\"EquationNumber\"\u003e1\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003e \u003cem\u003eIn vitro\u003c/em\u003e release studies\u003c/p\u003e \u003cp\u003eThe shaking-bed method was used in this experiment. Hydrochloric acid (pH 1.2) and potassium dihydrogen phosphate (pH 4.5) solutions were used as the release media, and a dialysis bag with a molecular retention capacity of 1000 D was selected. Samples of CA (10 mg) or CA-β-CD (equivalent to 10 mg of CA) were added to the treated dialysis bag. A small amount of dissolution medium was added, and the ends were tightened using sealing clamps until no leakage was observed. Release medium (200 mL) was measured into a 200-mL wide-mouth flask. The temperature was controlled at 37\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5℃ and the rotation speed at 140 r/min. Samples (2 mL) were taken at 10, 20, and 40 min, and subsequently at 1, 2, 4, 6, 8, 10, and 12 h. After each sampling time point, the medium was promptly replaced with an equal amount of fresh release medium at the same temperature. The samples were passed through a membrane and analyzed using HPLC to determine the CA concentration. The experiment was performed in triplicate. The cumulative release rate, \u003cem\u003eQ\u003c/em\u003e\u003csub\u003et\u003c/sub\u003e (%), was calculated for all samples using the equation below. Cumulative release rate-time curves were plotted using GraphPad Prism 9.5 software (La Jolla, CA, USA). The curves were fitted using Origin 2021 software [\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003cdiv id=\"Equ2\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equ2\" name=\"EquationSource\"\u003e\n$${Q}_{t}\\left(\\text{%}\\right)=\\left[\\left({V}_{0}{C}_{t}+V\\sum _{n=1}^{t-1}{C}_{t}\\right)/W\\right]\\times 100\\text{%}$$\u003c/div\u003e\u003cdiv class=\"EquationNumber\"\u003e2\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003e \u003cem\u003eC\u003c/em\u003e \u003csub\u003e \u003cem\u003et\u003c/em\u003e \u003c/sub\u003e is the released concentration of CA at time \u003cem\u003et\u003c/em\u003e (mg/mL), \u003cem\u003eV\u003c/em\u003e\u003csub\u003e\u003cem\u003e0\u003c/em\u003e\u003c/sub\u003e is the volume before the first sampling (200 mL), \u003cem\u003eC\u003c/em\u003e\u003csub\u003e\u003cem\u003et\u0026minus;1\u003c/em\u003e\u003c/sub\u003e is the concentration of CA at the previous sampling point at time sampling point \u003cem\u003et\u003c/em\u003e (mg/mL), \u003cem\u003eV\u003c/em\u003e is the sample volume (2 mL), and \u003cem\u003eW\u003c/em\u003e is the total amount of drug delivery (mg).\u003c/p\u003e \u003cp\u003eStability inspection\u003c/p\u003e \u003cp\u003eTo investigate the stability of CA-β-CD at room temperature, six batches of CA-β-CD were prepared simultaneously and stored in airtight glass vials, three of which were stored at room temperature (23\u0026thinsp;\u0026plusmn;\u0026thinsp;5\u0026deg;C) under normal daylight conditions, and the remaining batches were stored at room temperature in the dark. The batches were sampled at 0, 7, 14, and 30 days for HPLC analysis and the cinnamic aldehyde content was used as the index. The retention time curve was plotted using GraphPad Prism 9.5 to investigate the stability of the inclusion complexes.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eCharacterization of inclusion complexes\u003c/h2\u003e \u003cp\u003ePreparation of samples\u003c/p\u003e \u003cp\u003eCA-β-CD was prepared in the same manner as described previously. A physical mixture of CA and β-CD (PM-CA-β-CD) was prepared by accurately weighing CA and β-CD in a mortar at a molar ratio of 1:1 and grinding them thoroughly to mix.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSEM\u003c/h3\u003e\n\u003cp\u003eSmall amounts of β-CD and CA-β-CD powders were scattered and dispersed on small pieces of double-sided tape that were fixed to the surface of a short aluminum rod. The particle shapes and surface characteristics of the samples were measured and photographed using SEM at 20 kV (Apreo 2, Thermo Fisher Scientific, USA).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eXRD\u003c/h2\u003e \u003cp\u003eSamples of 100 mg each of β-CD, PM-CA-β-CD, and CA-β-CD were analyzed using XRD (Smartlab9, Rigaku, Japan). The samples were mounted in an X-ray holder from the top in a flat quartz bath and scanned at a speed of 2\u0026deg;/min in a scanning range of 5\u0026deg;\u0026ndash;90\u0026deg;.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eFTIR\u003c/h2\u003e \u003cp\u003eVarious samples were examined by FTIR spectroscopy (Nicolet-iS10, Thermo Scientific, USA) using the KBr compression method. Approximately 2 mg of each of CA, β-CD, and CA-β-CD were weighed and mixed with approximately 200 mg of dried KBr powder in a mortar and pestle and then an appropriate amount was added into a press die and pressed into transparent flakes at a pressure of 108 Pa. The infrared absorption spectra were scanned in the wave number range of 400\u0026ndash;4000 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, and each sample was scanned three times in parallel.\u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003eDSC\u003c/h2\u003e \u003cp\u003eTen mg each of β-CD, PM-CA-β-CD, and CA-β-CD inclusions were taken under N2 airflow, and the samples were accurately weighed in a closed aluminum crimped cuvette (DSC 250, TA Instruments, New Castle, DE, USA) and heated at a rate of 10\u0026deg;C/min in the temperature range of 50 to 300\u0026deg;C.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eNMR\u003c/h2\u003e \u003cp\u003eA small amount of sample was dissolved in DMSO-\u003cem\u003ed\u003c/em\u003e\u003csub\u003e\u003cem\u003e6\u003c/em\u003e\u003c/sub\u003e for H-NMR and C-NMR detection at 400 MHz power (AVANCE NEO 400, Bruker, Switzerland).\u003c/p\u003e \u003cp\u003eThermogravimetric analysis\u003c/p\u003e \u003cp\u003eAppropriate samples ranging from 2\u0026ndash;10 mg of β-CD, PM-CA-β-CD, and CA-β-CD were placed in an aluminum crucible at a heating rate of 10\u0026deg;C/min. For TG analysis, the reference material used was α-Al\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003e under an N\u003csub\u003e2\u003c/sub\u003e atmosphere with a flow rate of 100 mL/min, and a temperature range of 20\u0026ndash;800 (NETZSCH STA 449F3, Netzsch, Selb, Germany). To minimize the experimental errors, the test was repeated for each sample [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePharmacokinetic studies\u003c/h2\u003e \u003cp\u003eTwelve SD rats (weight, 200\u0026thinsp;\u0026plusmn;\u0026thinsp;20 g) were randomly divided into two groups, namely, the CA and CA-β-CD groups, and fasted without water before the experiment. After weighing and numbering, the drug was administered via oral gavage at a dose of 50 mg/kg. Approximately 300\u0026ndash;400 \u0026micro;L of blood was collected from the orbits at 5, 10, 30, and 45 min and at 1, 2, 4, 6, 8, 10, and 12 h after drug administration. The blood samples were transferred into centrifuge tubes containing sodium heparin, and plasma was isolated by centrifugation at 4000 r/min for 10 min at 4\u0026deg;C. The centrifuged plasma was stored in a freezer at \u0026minus;\u0026thinsp;80\u0026deg;C for subsequent analysis [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe plasma samples were thawed at room temperature (23\u0026thinsp;\u0026plusmn;\u0026thinsp;5\u0026deg;C), then 100 \u0026micro;L of plasma was precisely aspirated and added to a 1.5 mL centrifuge tube with 35 \u0026micro;L of internal standard salicylic acid solution. Next, 365 \u0026micro;L of methanol was added, and the mixture was vortexed for 30 s, then centrifuged at 13000 r/min for 10 min at 4\u0026deg;C, and the supernatant was extracted. The plasma CA content was then determined using HPLC.\u003c/p\u003e \u003cp\u003eThe obtained data were calculated according to the internal standard method to obtain the content of cinnamic acid in rat plasma at different time points for each group. The blood concentration-time curves were plotted by GraphPad Prism 8.0 software and the blood concentration-time data were analyzed by non-atrial fitting using DAS 2.0 analysis software (China Mathematical Pharmacology Professional Committee, Shanghai, China) to calculate each pharmacokinetic parameter. One-way analysis of variance (ANOVA) and least significant difference (LSD) two-by-two comparison tests were performed to calculate the pharmacokinetic parameters based on the concentration-time profiles for each group using SPSS 22.0.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eCarrageenan-induced swelling of toes of mice\u003c/h2\u003e \u003cp\u003eTwenty-four Kunming mice were randomly divided into four groups: model group (0.5% sodium carboxymethyl cellulose solution), positive drug group (aspirin), CA group, and CA-β-CD group, with six mice in each group. The mice were fasted without water before the experiment. The dose for the positive drug group was 200 mg/kg, while the dose for the CA and CA-β-CD groups was 100 mg/kg CA, administered for 15 min. After administration, 50 \u0026micro;L of 1% carrageenan was injected subcutaneously into the toe of the right hind limb of each mouse to establish an acute inflammation model, and the toe circumference was measured before and 15, 30, 60, 120, 180, and 240 min after injection, and the degree of toe swelling was calculated. All data were expressed as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations (SDs), and statistical analysis was performed using SPSS software (version 22.0; IBM Corp., Armonk, NY, USA). One-way ANOVA and LSD tests were used to analyze and compare data from all experimental groups [\u003cspan additionalcitationids=\"CR36\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eToe swelling was calculated as (post-inflammatory toe circumference/pre-inflammatory toe circumference)/pre-inflammatory toe circumference \u0026times; 100 and was expressed as a percentage.\u003c/p\u003e \u003cp\u003eThe inhibition rate of foot plantar swelling was calculated as ([average foot swelling in the model group - average foot swelling in the drug administration group]/average foot swelling in the model group) \u0026times; 100%.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eMolecular docking studies\u003c/p\u003e \u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e (generated by Chem 3D 20.0 and Pymol 4.3.0), the molecular docking results with β-CD as the acceptor (b) and CA as the ligand (a) show that the two diastereomeric binding fraction is \u0026minus;\u0026thinsp;3.86 Kcal/mol and the inclusion complex has good stability and spontaneous binding. In the 3D structure diagram shown in (c), the green bar indicates CA, the purple bar indicates β-CD, and the yellow dashed line indicates hydrogen bonds. CA is located in the middle of the β-CD and is completely encapsulated in the cavity; there is intermolecular hydrogen bonding between CA and cyclodextrin. Due to the higher binding fraction and the fully encapsulated structure, the CA-β-CD complexes have better stability and show a possible slow-release effect from the side.\u003c/p\u003e \u003cp\u003eDissolution studies\u003c/p\u003e \u003cp\u003eRelevant studies have shown that CA has a significant effect on reducing the gastric emptying rate; therefore, the degree of dissolution of CA under acidic conditions has mainly been investigated. Figure\u0026nbsp;3a shows that the cumulative dissolution rate of CA-β-CD in both dissolution media reached approximately 90% after 30 min, while that of CA was only approximately 60%. The average cumulative dissolution rate of CA in the dissolution medium was 60.49% and 70.26% at pH 1.2 and pH 4.5, respectively, within 120 min; while that of CA-β-CD in both media reached 94.71% and 91.63%, which were 1.56 and 1.30 times higher than that of the CA, respectively. The solubility of the inclusion complex calculated using this method contained both forms of CA-β-CD and CA, which does not fully reflect the solubilization behavior of CA in the inclusion complex.\u003c/p\u003e \u003cp\u003eIn vitro release studies\u003c/p\u003e \u003cp\u003eAs shown in Fig.\u0026nbsp;3b, the cumulative release rate of CA raw material showed an increasing trend from 0 to 2 h and reached the highest value at 2 h with 51.69% (pH 1.2) and 45.33% (pH 4.5). The cumulative release rates from 2 to 12 h showed a decreasing trend, presumably due to the longer time and the degradation of CA occurring inside and outside the dialysis bag during the release process at 37\u0026deg;C. The cumulative release rate of CA-β-CD in both dissolution media reached over 80% within 12 h, with 82.59% (pH 1.2) and 83.08% (pH 4.5) within 2 h. The release rate of CA-β-CD was lower than that of CA raw material, owing to the inability of the cyclodextrin to pass through the dialysis bag. Free CA was the first to pass through the dialysis bag, while the encapsulated CA could only pass through the dialysis bag into the release medium after release from the complex. The free CA content was significantly lower than that of CA; therefore, the release degree was lower than that of the CA group, indicating that CA was encapsulated and had a certain slow release effect. After 2 h, the cumulative release rate of CA-β-CD was higher than that of CA, owing to the degradation of CA.\u003c/p\u003e \u003cp\u003eTables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e show the first-level kinetic equation R\u003csup\u003e2\u003c/sup\u003e of CA-β-CD in two pH release media, which is greater than the zero-level kinetic equation R\u003csup\u003e2\u003c/sup\u003e. This suggests that the drug release process of CA-β-CD inclusion depends on the concentration. The results were treated with Higuchi and Ritger\u0026ndash;Peppas models, where the Ritger\u0026ndash;Peppas model fit results with n\u0026thinsp;=\u0026thinsp;0.445 (pH 1.2) and n\u0026thinsp;=\u0026thinsp;0.334 (pH 4.5). Both values were \u0026lt;\u0026thinsp;0.45, which indicated the release mechanism of the inclusion complex was controlled by Fickian diffusion. This demonstrates that the CA-β-CD inclusion complex operates through a slow release mechanism, while the release mechanism of CA is skeletal dissolution [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e, Results of release curve fitting for pH 1.2 release media\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMethod\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eEquation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eCA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eCA-β-CD\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEquation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eR\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEquation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eR\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZero-order\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003csub\u003et\u003c/sub\u003e/M\u003csub\u003e\u0026infin;\u003c/sub\u003e=Kt\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eM\u003c/em\u003e\u003csub\u003e\u003cem\u003et\u003c/em\u003e\u003c/sub\u003e\u003cem\u003e/M\u003c/em\u003e\u003csub\u003e\u003cem\u003e\u0026infin;\u003c/em\u003e\u003c/sub\u003e=0.84\u003cem\u003et\u003c/em\u003e\u0026thinsp;+\u0026thinsp;34.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0204\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eM\u003c/em\u003e\u003csub\u003e\u003cem\u003et\u003c/em\u003e\u003c/sub\u003e\u003cem\u003e/M\u003c/em\u003e\u003csub\u003e\u003cem\u003e\u0026infin;\u003c/em\u003e\u003c/sub\u003e=7.15\u003cem\u003et\u003c/em\u003e\u0026thinsp;+\u0026thinsp;16.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.7729\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOne-order\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eln(1-\u003cem\u003eM\u003c/em\u003e\u003csub\u003e\u003cem\u003et\u003c/em\u003e\u003c/sub\u003e\u003cem\u003e/M\u003c/em\u003e\u003csub\u003e\u003cem\u003e\u0026infin;\u003c/em\u003e\u003c/sub\u003e)=-\u003cem\u003eKt\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eln(1-\u003cem\u003eM\u003c/em\u003e\u003csub\u003e\u003cem\u003et\u003c/em\u003e\u003c/sub\u003e\u003cem\u003e/M\u003c/em\u003e\u003csub\u003e\u003cem\u003e\u0026infin;\u003c/em\u003e\u003c/sub\u003e)\u0026thinsp;=\u0026thinsp;44.95\u0026thinsp;\u0026minus;\u0026thinsp;4.19\u003cem\u003et\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.8067\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eln(1- \u003cem\u003eM\u003c/em\u003e\u003csub\u003e\u003cem\u003et\u003c/em\u003e\u003c/sub\u003e\u003cem\u003e/M\u003c/em\u003e\u003csub\u003e\u003cem\u003e\u0026infin;\u003c/em\u003e\u003c/sub\u003e)\u0026thinsp;=\u0026thinsp;83.69\u0026thinsp;\u0026minus;\u0026thinsp;0.41\u003cem\u003et\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.9656\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHiguchi\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003csub\u003et\u003c/sub\u003e/M\u003csub\u003e\u0026infin;\u003c/sub\u003e=Kt\u003csup\u003e1/2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eM\u003c/em\u003e\u003csub\u003e\u003cem\u003et\u003c/em\u003e\u003c/sub\u003e\u003cem\u003e/M\u003c/em\u003e\u003csub\u003e\u003cem\u003e\u0026infin;\u003c/em\u003e\u003c/sub\u003e=5.73\u003cem\u003et\u003c/em\u003e\u003csup\u003e1/2\u003c/sup\u003e+27.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.1531\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eM\u003c/em\u003e\u003csub\u003e\u003cem\u003et\u003c/em\u003e\u003c/sub\u003e\u003cem\u003e/M\u003c/em\u003e\u003csub\u003e\u003cem\u003e\u0026infin;\u003c/em\u003e\u003c/sub\u003e=28.00\u003cem\u003et\u003c/em\u003e\u003csup\u003e1/\u003c/sup\u003e\u0026minus;0.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.9061\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRitger\u0026ndash;Peppas\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003csub\u003et\u003c/sub\u003e/M\u003csub\u003e\u0026infin;\u003c/sub\u003e=Kt\u003csup\u003en\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eM\u003c/em\u003e\u003csub\u003e\u003cem\u003et\u003c/em\u003e\u003c/sub\u003e\u003cem\u003e/M\u003c/em\u003e\u003csub\u003e\u003cem\u003e\u0026infin;\u003c/em\u003e\u003c/sub\u003e=0.0097\u003cem\u003et\u003c/em\u003e\u003csup\u003e5.59\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.9375\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eM\u003c/em\u003e\u003csub\u003e\u003cem\u003et\u003c/em\u003e\u003c/sub\u003e\u003cem\u003e/M\u003c/em\u003e\u003csub\u003e\u003cem\u003e\u0026infin;\u003c/em\u003e\u003c/sub\u003e=31.36t\u003csup\u003e0.445\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.9975\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eCA, trans-cinnamaldehyde; CD, β-cyclodextrin; CA-β-CD, compounds prepared from CA and β-CD\u003c/p\u003e \u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Results of release curve fitting for pH 4.5 release media\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"761\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.868421052631579%\" rowspan=\"2\"\u003e\n \u003cp\u003eMethod\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.842105263157894%\" rowspan=\"2\"\u003e\n \u003cp\u003eEquation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.26315789473684%\" colspan=\"2\" style=\"width: 35.4016%;\"\u003e\n \u003cp\u003eCA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.026315789473685%\" colspan=\"2\" style=\"width: 34.9006%;\"\u003e\n \u003cp\u003eCA-\u0026beta;-CD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.22350674373796%\" style=\"width: 26.5789%;\"\u003e\n \u003cp\u003eEquation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.414258188824663%\" style=\"width: 10.0402%;\"\u003e\n \u003cp\u003eR\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.26011560693642%\" style=\"width: 28.9874%;\"\u003e\n \u003cp\u003eEquation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.102119460500964%\"\u003e\n \u003cp\u003eR\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.868421052631579%\"\u003e\n \u003cp\u003eZero-order\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003csub\u003et\u003c/sub\u003e/M\u003csub\u003e\u0026infin;\u003c/sub\u003e=Kt\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.736842105263158%\" style=\"width: 26.5789%;\"\u003e\n \u003cp\u003e\u003cem\u003eM\u003csub\u003et\u003c/sub\u003e/M\u003csub\u003e\u0026infin;\u003c/sub\u003e\u003c/em\u003e=0.98\u003cem\u003et\u003c/em\u003e+28.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.526315789473685%\" style=\"width: 10.0402%;\"\u003e\n \u003cp\u003e0.0494\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.07894736842105%\" style=\"width: 28.9874%;\"\u003e\n \u003cp\u003e\u003cem\u003eM\u003csub\u003et\u003c/sub\u003e/M\u003csub\u003e\u0026infin;\u003c/sub\u003e\u003c/em\u003e=7.00\u003cem\u003et\u003c/em\u003e+16.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.947368421052632%\"\u003e\n \u003cp\u003e0.8253\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.868421052631579%\"\u003e\n \u003cp\u003eOne-order\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003eln(1-\u003cem\u003eM\u003csub\u003et\u003c/sub\u003e/M\u003csub\u003e\u0026infin;\u003c/sub\u003e\u003c/em\u003e)=-\u003cem\u003eKt\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.736842105263158%\" style=\"width: 26.5789%;\"\u003e\n \u003cp\u003eln(1-\u003cem\u003eM\u003csub\u003et\u003c/sub\u003e/M\u003csub\u003e\u0026infin;\u003c/sub\u003e\u003c/em\u003e)=39.49\u0026minus;3.66\u003cem\u003et\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.526315789473685%\" style=\"width: 10.0402%;\"\u003e\n \u003cp\u003e0.7260\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.07894736842105%\" style=\"width: 28.9874%;\"\u003e\n \u003cp\u003eln(1-\u003cem\u003eM\u003csub\u003et\u003c/sub\u003e/M\u003csub\u003e\u0026infin;\u003c/sub\u003e\u003c/em\u003e)=83.04\u0026minus;0.39\u003cem\u003et\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.947368421052632%\"\u003e\n \u003cp\u003e0.9785\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.868421052631579%\"\u003e\n \u003cp\u003eHiguchi\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003csub\u003et\u003c/sub\u003e/M\u003csub\u003e\u0026infin;\u003c/sub\u003e=Kt\u003csup\u003e1/2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.736842105263158%\" style=\"width: 26.5789%;\"\u003e\n \u003cp\u003e\u003cem\u003eM\u003csub\u003et\u003c/sub\u003e/M\u003csub\u003e\u0026infin;\u003c/sub\u003e\u003c/em\u003e=5.84\u003cem\u003et\u003c/em\u003e\u003csup\u003e1/2\u003c/sup\u003e+22.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.526315789473685%\" style=\"width: 10.0402%;\"\u003e\n \u003cp\u003e0.1877\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.07894736842105%\" style=\"width: 28.9874%;\"\u003e\n \u003cp\u003e\u003cem\u003eM\u003csub\u003et\u003c/sub\u003e/M\u003csub\u003e\u0026infin;\u003c/sub\u003e\u003c/em\u003e=27.15\u003cem\u003et\u003c/em\u003e\u003csup\u003e1/2\u003c/sup\u003e\u0026minus;0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.947368421052632%\"\u003e\n \u003cp\u003e0.9442\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.868421052631579%\"\u003e\n \u003cp\u003eRitger\u0026ndash;Peppas\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.842105263157894%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003csub\u003et\u003c/sub\u003e/M\u003csub\u003e\u0026infin;\u003c/sub\u003e=Kt\u003csup\u003en\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.736842105263158%\" style=\"width: 26.5789%;\"\u003e\n \u003cp\u003e\u003cem\u003eM\u003csub\u003et\u003c/sub\u003e/M\u003csub\u003e\u0026infin;\u003c/sub\u003e\u003c/em\u003e=0.7134\u003cem\u003et\u003c/em\u003e\u003csup\u003e2.607\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.526315789473685%\" style=\"width: 10.0402%;\"\u003e\n \u003cp\u003e0.9305\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.07894736842105%\" style=\"width: 28.9874%;\"\u003e\n \u003cp\u003e\u003cem\u003eM\u003csub\u003et\u003c/sub\u003e/M\u003csub\u003e\u0026infin;\u003c/sub\u003e\u003c/em\u003e=38.49\u003cem\u003et\u003c/em\u003e\u003csup\u003e0.334\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.947368421052632%\"\u003e\n \u003cp\u003e0.9989\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCA, trans-cinnamaldehyde; CD, \u0026beta;-cyclodextrin; CA-\u0026beta;-CD, compounds prepared from CA and \u0026beta;-CD\u003c/p\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eStability inspection\u003c/h2\u003e \u003cp\u003eAs shown in Fig.\u0026nbsp;3c, the stability of the inclusions stored at room temperature and protected from light surpassed that of the inclusions exposed to light. By day 30, the CA content of the inclusions protected from light was significantly higher, reaching 73.12%, compared to 57.83% for those exposed to light.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eCharacterization\u003c/h2\u003e \u003cdiv id=\"Sec17\" class=\"Section3\"\u003e \u003ch2\u003eSEM\u003c/h2\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e shows the morphological characteristics of the β-CD and CA-β-CD inclusion complexes. The β-CD surface is flatter and appears as plate-like amorphous crystals under SEM, in consistency with related reports [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. The CA-β-CD surface is smoother and has an irregular plate shape, presumably due to a change in the surface morphology of β-CD after encapsulation of CA.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eXRD\u003c/h2\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e5\u003c/span\u003ea shows that a large number of crystalline peaks of β-CD occurred at 4\u0026deg;\u0026ndash;40\u0026deg;, and the presence of crystalline diffraction peaks of β-CD in the physical mixture indicates that β-CD exists mainly in crystalline form in the physical mixture. The crystalline diffraction peak of β-CD at 9.16\u0026deg; in CA-β-CD disappears and the absorption peak at 12.7\u0026deg; shifts forward to 11.80\u0026deg; [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], indicating that the cyclodextrin inclusion complex is prepared successfully and cyclodextrin exists in amorphous form.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eFTIR\u003c/h2\u003e \u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e5\u003c/span\u003eb, the CA spectrum has characteristic peaks at 3061.73 cm-1 (=\u0026thinsp;C-H), 1625.38 cm-1, 1491.78 cm-1, and 1450.14 cm-1 (related to aromatic ring skeleton), and 1669.08 cm-1 (indicative of C\u0026thinsp;=\u0026thinsp;O stretching). Additionally, peaks are observed at 2814.40 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, and 2742.98 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (corresponding to -CHO), in consistency with a previous study [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. β-CD patterns have characteristic peaks at 3383.16 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (O-H), 2925.93 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (C-H), 1157.16 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (C-O), and 1028.59 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (C-O-C). The main characteristic peaks of CA in the inclusion complex are almost completely absent, indicating that CA was successfully encapsulated by β-CD.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eDSC\u003c/h2\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e5\u003c/span\u003ec shows that β-CD has an obvious heat absorption peak at 133.4\u0026deg;C, while the obvious heat absorption peak of CA at 118.83\u0026deg;C indicates that CA still exists mainly in liquid form in the physical mixture. In the heat absorption peak of CA-β-CD inclusion complex, the heat absorption peak of cinnamon volatile oil at 102.4\u0026deg;C disappears, indicating that cinnamon volatile oil is dispersed in β-CD in a non-aggregated form.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eTG\u003c/h2\u003e \u003cp\u003eThe TG analysis curves of β-CD showed three stages of mass loss. There is approximately 10% mass loss in the first stage at 100\u0026deg;C representing the evaporation of surface and internal water. In addition, at this point, the mass loss of the physical mixture was relatively high, while the mass loss of the inclusion complex was low, approximately 5% as seen in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e6\u003c/span\u003ea. This indicates that when CA was encapsulated by β-CD, it replaced the water molecules in the β-CD cavity and formed the inclusion complex. A temperature of 100\u0026deg;C eliminates the water in the β-CD particles and the free CA in the physical mixture but does not eliminate the CA encapsulated in the inclusion complex. Thus, the thermal stability of CA is significantly improved due to the interaction between CA molecules and the inner cavity of β-CD.\u003c/p\u003e \u003cp\u003eThe differential thermal analysis curve of the physical mixture of β-CD and CA (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e6\u003c/span\u003eb) shows a weak heat absorption peak near this point, confirming the volatilization of water or free CA. This dehydration heat absorption peak disappears from the curve of CA-β-CD inclusion complex. This indicated the formation of inclusion complexes [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Up to approximately 330\u0026deg;C, the weight of the three samples decreased abruptly by 70%, indicating the decomposition of β-CD and the loss of protection of the inclusion complex [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eNMR\u003c/h2\u003e \u003cp\u003eThe 1H-NMR spectrum of CA-β-CD showed peaks of β-CD exchanging with those of CA as follows (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e7\u003c/span\u003ec). The chemical shift signals of β-CD mainly ranged from 2.75 ppm to 5.75 ppm (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e7\u003c/span\u003eb), although some peaks belonging to β-CD in CA-β-CD showed a shift to higher fields. The carbonyl H chemical signal shift in CA was 9.68 ppm, and the shift signals of the benzene ring were 7.41\u0026ndash;7.71 ppm (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e7\u003c/span\u003ea) [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. The chemical shift of the benzene ring (7.47\u0026ndash;7.77 ppm) in CA-β-CD was shifted to a lower field compared to CA, which indicates the formation of new phases. CA is encapsulated in the cavity of the β-CD. The CA part of the CA-β-CD \u003csup\u003e13\u003c/sup\u003eC-NMR carbon spectrum shows chemical shifts toward the low field (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e7\u003c/span\u003ef), such as the chemical shift of the carbonyl H peak in CA (194.19 ppm) was shifted to 194.5 ppm.\u003csup\u003e1\u003c/sup\u003eH-NMR and \u003csup\u003e13\u003c/sup\u003eC-NMR of CA-β-CD together illustrate that CA is encapsulated by β-CD and causes changes in the chemical signal shifts of its H and C atoms [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003ePharmacokinetic studies\u003c/h2\u003e \u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e8\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, the half-life of the inclusion complex significantly increased compared to that of the active pharmaceutical ingredient (CA)(\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), indicating that elimination of the inclusion complex was slower after the distribution reached equilibrium in rats. There was no significant difference observed between the peak time (T\u003csub\u003emax\u003c/sub\u003e) of the CA and the CA-β-CD. However, the C\u003csub\u003emax\u003c/sub\u003e in the CA-β-CD inclusion group was lower compared to that of the CA group. Nevertheless, the area under the curve from time zero to the last measurable time point (AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e) and the AUC from time zero to infinity (AUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e) increased in the CA-β-CD group compared to the CA group, attributable to a significant increase in half-life, which was 1.16 times higher than that of CA (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). The above data indicate that the inclusion compound prolonged the retention time of cinnamic acid in blood and tissues, suggesting that CA-β-CD has a slow-release effect in rats. The relevant studies have demonstrated that after oral administration, CA undergoes partial metabolism to cinnamic acid in the stomach and small intestine [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e], the metabolism is rapid, and cinnamic acid can be readily absorbed. Moreover, the oxidative metabolism of cinnamaldehyde closely follows that of cinnamic acid through β-oxidation, resembling the metabolic pathway observed in fatty acids [\u003cspan additionalcitationids=\"CR47\" citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. All this is closely related to the physicochemical properties of cinnamaldehyde. CA is rapidly and quantitatively released by β-CD and, therefore, there is little variability in T\u003csub\u003emax\u003c/sub\u003e [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. The structural modifications have additionally resulted in enhanced stability of CA, leading to an increase in AUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e and prolonging the time required to achieve dynamic equilibrium due to covalent bonding between CA and β-CD. Furthermore, there has been a noticeable elevation in t\u003csub\u003e1/2\u003c/sub\u003e [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. The hydrophobic cavity of β-CD forms a host-guest structure upon the incorporation of CA into the cavity. This process results in the replacement of the space within the lipophilic central region of β-CD, thus, reducing the utilization rate of β-CD and leading to a decrease in C\u003csub\u003emax\u003c/sub\u003e [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMain pharmacokinetic parameters of cinnamic acid in rat plasma (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnit\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCA-β-CD\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003et\u003csub\u003e1/2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eh\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e0.244\u0026thinsp;\u0026plusmn;\u0026thinsp;0.141\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e0.586\u0026thinsp;\u0026plusmn;\u0026thinsp;0.191*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003emax\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eh\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e0.111\u0026thinsp;\u0026plusmn;\u0026thinsp;0.068\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e0.117\u0026thinsp;\u0026plusmn;\u0026thinsp;0.075\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026micro;g/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e10.839\u0026thinsp;\u0026plusmn;\u0026thinsp;3.109\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e7.55\u0026thinsp;\u0026plusmn;\u0026thinsp;2.845\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026micro;g/mL*h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e4.304\u0026thinsp;\u0026plusmn;\u0026thinsp;0.461\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e4.922\u0026thinsp;\u0026plusmn;\u0026thinsp;0.587\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026micro;g/mL*h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e4.668\u0026thinsp;\u0026plusmn;\u0026thinsp;0.528\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e5.437\u0026thinsp;\u0026plusmn;\u0026thinsp;0.969\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\u003cp\u003eSignificance*\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, indicating a significant difference to the CA group\u003c/p\u003e \u003cp\u003eAUC, area under the curve; CA, trans-cinnamaldehyde; CD, β-cyclodextrin; CA-β-CD, compounds prepared from CA and β-CD; SD, standard deviation\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of toe swelling inhibition ratio in each group (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.25 h\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.5 h\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 h\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 h\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3 h\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4 h\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive drug\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus;50.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e24.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e18.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e39.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e73.42\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e24.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e46.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e18.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e38.39\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCA-β-CD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus;11.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;1.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e57.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e70.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e41.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e54.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eCA, trans-cinnamaldehyde; CD, β-cyclodextrin; CA-β-CD, compounds prepared from CA and β-CD; SD, standard deviation\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003eEffects of CA and CA-βCD on the carrageenan-induced swelling of toes in mice\u003c/h2\u003e \u003cp\u003eSwelling of mouse feet is a common acute inflammation model that is now known to involve a variety of inflammatory factors, including injection trauma, serotonin, histamine, bradykinin, and prostaglandin 2 [\u003cspan additionalcitationids=\"CR53\" citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. The experimental results showed that swelling of the mouse foot can be divided into two phases: the swelling phase (0\u0026ndash;2 h) and the swelling reduction phase (2\u0026ndash;4 h), in consistency with previous works [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]. At 0.25\u0026ndash;0.5 h (i.e., 0.5\u0026ndash;0.75 h of gavage) after the injection of carrageenan gum, the CA group showed inhibited toe swelling in mice (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05), while the CA-β-CD group did not show significant inhibition of toe swelling. At 1 h, toe swelling was significantly reduced in the inclusion group compared with the model (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and CA groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and the inhibition rate of swelling was 57.58% [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. At 2 h, swelling was significantly reduced in the inclusion group compared with the model group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The swelling inhibition rate was 70.25%, and the rate over 1\u0026ndash;4 h was higher in the CA-β-CD group than in the CA group. After oral administration, CA demonstrated a rapid onset of action, while the slow-release nature of CA-β-CD resulted in a slightly delayed effect compared to CA. Notably, 1\u0026ndash;2 h after the injection of carrageenan gum (i.e., 1.25\u0026ndash;2.25 h of gavage), the sustained release of cinnamic aldehyde from the inclusion compound led to a gradual but intensified inhibition of toe swelling. The CA showed a weaker inhibition effect relative to the inclusion compound after 1 h, and the inclusion compound showed a long-lasting swelling inhibition effect due to its slow-release effect.\u003c/p\u003e \u003cp\u003eCA has demonstrated significant anti-edema activity, effectively inhibiting carrageenan-induced swelling in a dose-dependent manner following oral administration, and the potential impact of this phenomenon could potentially be attributed to its interference with inflammatory mediators [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. The results of related cell experiments also demonstrated that CA-β-CD significantly enhanced the efficacy of reactive oxygen species(ROS) reduction in RAW 264.7 cells treated with lipopolysaccharide(LPS) [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. Three studies have shown that β-CD can increase the duration of action. Compared to the original drug, β-CD enhances and prolongs the analgesic and anti-inflammatory effects [\u003cspan additionalcitationids=\"CR59 CR60\" citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e]. The improved stability half-life and bioavailability of β-CD may be the reason for the prolonged anti-inflammatory effect (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eCharacterization and validation of CA-β-CD through SEM, XRD, FTIR, DSC, TG, NMR analyses demonstrated that CA was successfully encapsulated by β-cyclodextrin, resulting in enhanced CA stability. Molecular simulation studies have shown that CA is fully encapsulated by β-CD cavities, suggesting a controlled release mechanism. The results of \u003cem\u003ein vitro\u003c/em\u003e release studies have shown that the accumulative release rate of CA-β-CD inclusion complex was higher than that of the bulk drug after 2 h in the two release media, with a slow and stable release profile.\u003c/p\u003e \u003cp\u003eIn rats, the peak concentration of CA-β-CD decreased, the half-life significantly increased (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), the AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e and AUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e both increased, and the sustained release effect was evident. In an efficacy experiment using a carrageenan-induced toe swelling mouse model, the inclusion complex exhibited its effect after approximately 1 h. Furthermore, the swelling inhibition effect observed after 1 h, was greater and more sustained than that of the CA bulk drug.\u003c/p\u003e \u003cp\u003eIn conclusion, molecular simulation and dialysis bag release studies suggest a controlled and delayed release of CA from the inclusion compound. Therefore, compared to the cinnamaldehyde raw material, the inclusion compound exhibited a decreased absorption peak concentration, prolonged half-life, delayed oral effect, and extended duration of action.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Jiangsu Provincial TCM Science and Technology Development Plan Project under Grant number\u0026nbsp;MS2021028\u0026nbsp;and Natural Science Foundation of Nanjing University of Chinese Medicine under Grant number XZR2020021.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eNo potential conflict of interest was reported by the authors.\u003c/p\u003e\n\u003cp\u003eAuthor contributions\u003c/p\u003e\n\u003cp\u003eJiazheng Li was responsible for organizing and writing the article, and design of the “In-vitro release studies.”\u0026nbsp;Zhao Cui analyzed the section “Characterization of inclusion complexes.” Xi Xiong\u0026nbsp;was in charge of the “Dissolution studies.” Ruotong Zhang\u0026nbsp;analyzed the section “Pharmacokinetic studies.”\u0026nbsp;Weiwen Lu was in charge of the “Molecular docking study.” Zhipeng Cai\u0026nbsp;analyzed\u0026nbsp;the section\u0026nbsp;“Effects of CA and CA-β-CD on the carrageenan-induced swelling of toes in mice.” Xuedan Fu was responsible for the experiments in “Pharmacokinetic studies” and “Effects of CA and CA-β-CD on the carrageenan-induced swelling of toes in mice.” sections.\u0026nbsp;Zhenhai Zhang and Jianming Ju were responsible for the designing the experiment and revision of the article.\u003c/p\u003e\n\u003cp\u003eData availability\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this submitted article. The data that support the findings of this study are available from the corresponding author, J. Ju, upon reasonable request.\u003c/p\u003e\n\u003cp\u003eEthics Approval\u003c/p\u003e\n\u003cp\u003eThe aim of this study was to study data on the \u003cem\u003ein vitro\u003c/em\u003e release, pharmacokinetics, and pharmacodynamics of CA-β-CD. The pharmacokinetic characteristics of CA-β-CD \u003cem\u003ein vivo\u003c/em\u003e were studied quantitatively and objectively in rats, and the pharmacokinetic parameters of its metabolites were predicted over time to confirm whether CA-β-CD has a sustained release effect \u003cem\u003ein vivo\u003c/em\u003e. The mouse foot swelling experiment induced by carrageenan was to study the pharmacodynamic effect of the slow-release properties on its anti-inflammatory effect. The \u003cem\u003ein vivo\u003c/em\u003e pharmacodynamic and pharmacokinetic studies involved in this\u0026nbsp;study\u0026nbsp;cannot be replaced by other experiments at present, and the use of animal models is effective and necessary. Animals in this study were\u0026nbsp;supplied by\u0026nbsp;the Experimental Animal Center of Jiangsu Academy of Traditional Chinese Medicine (Jiangsu, China) and were carefully housed in the animal center under constant temperature and humidity. Rats were anesthetized with 2% Isoflurane (0.4 ml/min\u0026nbsp;at 4 L/min fresh gas flow) before the experiment and all animals\u0026nbsp;were sacrificed by cervical dislocation at the end of the experiment.\u003c/p\u003e\n\u003cp\u003eAll animal procedures were performed in accordance with the Guidelines for Care and Use of Laboratory Animals of Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, and approved by the Animal Ethics Committee of Jiangsu Province Hospital on Integration of Chinese and Western Medicine (Jiangsu, China). Animal license: AEWC-20220622-225. All animal experiments were performed following the ARRIVE guidelines.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGilani S, Najafpour G. Evaluation of the extraction process parameters on bioactive compounds of cinnamon bark: A comparative study. 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Int J Mol Sci. 2021;22:11524.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Release behavior, trans-cinnamaldehyde, cyclodextrin, release kinetics, solubility, bioavailability","lastPublishedDoi":"10.21203/rs.3.rs-4376749/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4376749/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAlthough β-cyclodextrin (β-CD) inclusion is known to improves the stability and solubility of trans-cinnamaldehyde (CA), but data on the \u003cem\u003ein vitro\u003c/em\u003erelease, pharmacokinetics, and pharmacodynamics of such inclusion complexes are lacking. In this study, an inclusion complex of CA and β-CD (CA-β-CD) inclusion complex was prepared using a saturated solution method.Its \u003cem\u003ein vitro\u003c/em\u003e release was determined using the dialysis bag method with a molecular cut-off of 1000 D, while its \u003cem\u003ein vivo \u003c/em\u003epharmacokinetics were studied in a rat model. A carrageenan-induced acute inflammation mouse model of foot swelling was used to evaluate the effects of the inclusion complex on drug efficacy. The CA-β-CD inclusion complex had a lower release rate within 2 h and a higher release rate than CA after 2 h in both release media. \u003cem\u003eIn vivo\u003c/em\u003epharmacokinetic studies of the CA-β-CD inclusion showed a decrease in peak concentration, a significant increase in half-life (\u003cem\u003ep\u003c/em\u003e\u0026lt;0.05), and an increase in bioavailability. A pharmacodynamic study on the effects of the inclusion complex on toe swelling in mice showed that it had slightly slower effects than the CA, but a relatively long-lasting swelling inhibition effect. The above findings suggest that CA has a certain slow-release behavior \u003cem\u003ein vitro\u003c/em\u003e and \u003cem\u003ein vivo \u003c/em\u003eafter being encapsulated by β-CD, which has an effect on the drug’s efficacy.\u003c/p\u003e","manuscriptTitle":"Preparation, characterization, and release behavior of β-cyclodextrin inclusion complexes of trans-cinnamaldehyde","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-03 16:15:20","doi":"10.21203/rs.3.rs-4376749/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8b5b81e4-48ef-4881-897d-b51ce3e5c032","owner":[],"postedDate":"June 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-16T10:59:14+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-03 16:15:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4376749","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4376749","identity":"rs-4376749","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}