Curcumin co-crystal solvent-loaded composite hydrogel beads, and preparation method and application thereof

Abstract

The application discloses a kind of curcumin eutectic solvent loaded composite hydrogel beads and preparation method and application thereof, it is related to drug carrier technical field.The composite hydrogel bead is prepared by sodium alginate-curcumin eutectic solvent blend and coagulation liquid;The sodium alginate-curcumin eutectic solvent blend includes curcumin eutectic solvent and sodium alginate aqueous solution;The curcumin eutectic solvent includes curcumin, amino acid and glycerol.The mass-volume concentration of sodium alginate in sodium alginate-curcumin eutectic solvent blend is limited to 6-8%, to achieve the technical effect of encapsulating curcumin in hydrogel bead;The mass-volume concentration of curcumin eutectic solvent in sodium alginate-curcumin eutectic solvent blend is limited to 30%, to improve the encapsulation efficiency of composite hydrogel bead;The mass-volume concentration of sodium alginate in sodium alginate-curcumin eutectic solvent blend is limited to 6%, to improve the encapsulation efficiency and drug loading of composite hydrogel bead.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of drug carriers, and relates to a composite hydrogel bead loaded with curcumin eutectic solvent and a preparation method and application thereof. BACKGROUND

[0002] A drug carrier refers to a system capable of changing the way a drug enters the human body and its distribution in the body, controlling the release speed of the drug and delivering the drug to a target organ. Drug carrier materials play a very important role in the research of controlled release preparations. A drug controlled release system can improve the utilization rate, safety and effectiveness of the drug, thereby reducing the frequency of drug administration.

[0003] Ulcerative colitis belongs to one of inflammatory bowel diseases, commonly known as "green cancer", which is a chronic nonspecific inflammatory disease of the colon and rectum with unclear etiology, and the lesion is limited to the mucosa and submucosa of the large intestine. The lesion is mostly located in the sigmoid colon and rectum, and can extend to the descending colon, even the entire colon. The disease course is long and often recurrent. The initial manifestations of ulcerative colitis are abdominal pain, diarrhea, weight loss, rectal bleeding, and later complications or malignant changes. So far, there is no standard treatment for UC, so people with this disease must take medication for life. However, taking drugs including antibiotics, mesalazine, immunosuppressants, corticosteroids and non-steroidal anti-inflammatory drugs can cause adverse reactions such as nausea, osteoporosis, neurotoxicity and nephrotoxicity.

[0004] Curcumin (CUR) is a natural polyphenolic compound, and studies have shown that curcumin has immunosuppressive, anti-inflammatory and antioxidant properties, and has very little toxic side effects. Experiments have shown that curcumin can slow down the increase of nuclear factor-kappa B (NF-kB), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) in B lymphocytes, thereby achieving effective anti-inflammatory effect. However, free curcumin shows poor solubility, limited stability and low bioavailability.

[0005] CN202311652479.2 discloses a curcumin-containing therapeutic eutectic solvent and a preparation method thereof. The curcumin-containing therapeutic eutectic solvent comprises components: curcumin, amino acid and solvent, the solvent is selected from at least one of water and glycerol; the amino acid is selected from at least one of L-arginine, L-histidine, L-threonine, L-proline, L-alanine, L-glutamine, L-lysine and L-cysteine. The preparation method is: when the solvent is water, the amino acid is mixed with the curcumin, then water is added dropwise, and stirring is performed to obtain the curcumin-containing therapeutic eutectic solvent; when the solvent is glycerol, the components are mixed, then heating and stirring are performed to obtain the curcumin-containing therapeutic eutectic solvent. The curcumin, the amino acid and the glycerol or water system can improve the solubility of curcumin, increase the solubility and DPPH free radical scavenging rate of curcumin without changing the original biological activity of curcumin, but cannot improve the stability and absorption rate of curcumin.

[0006] CN115844811B discloses a double-layer heterogeneous microgel delivery system based on PVA-GG and application thereof in preparation of a drug for treating colitis. The double-layer heterogeneous microgel delivery system: the inner layer is made of polyvinyl alcohol (PVA) and guar gum (GG), the outer layer is modified with a layer of SA hydrogel, the outermost layer is modified with a polyelectrolyte film of CS and SA, and curcumin is used as the experimental drug. The inner and outer layers of the double-layer microgel have different matrix materials, so that the delivery system can have multiple functions in one. The solubility and absorption performance of curcumin are improved. The hydrogel can effectively reduce the burst release and premature release behavior of the anti-inflammatory drug curcumin in the gastrointestinal tract through oral administration. However, the raw materials used in the hydrogel are various, and the preparation process is complex.

[0007] Therefore, in order to solve the problems in the prior art, the present application provides a curcumin eutectic solvent-loaded composite hydrogel bead, a preparation method and application thereof. The curcumin hydrogel bead prepared by the present application can be applied to the preparation of a drug for treating ulcerative colitis, and has good research and development prospects. SUMMARY

[0008] The purpose of the present application is to overcome the shortcomings in previous studies, provide a curcumin eutectic solvent-loaded composite hydrogel bead, a preparation method and application thereof, fully exert the pharmacological effect of curcumin, effectively solve the problem of treating ulcerative colitis, and have popularization and development value.

[0009] To achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows:

[0010] Firstly, the present application provides a composite hydrogel bead loaded with curcumin eutectic solvent, which is prepared from a sodium alginate-curcumin eutectic solvent blend and a coagulation solution; the sodium alginate-curcumin eutectic solvent blend comprises a curcumin eutectic solvent and a sodium alginate aqueous solution; the curcumin eutectic solvent comprises curcumin, an amino acid and glycerol; and the coagulation solution comprises polyvinyl alcohol, calcium chloride and water.

[0011] Preferably, the amino acid is selected from at least one of lysine and proline.

[0012] Further preferably, the amino acid is lysine.

[0013] Preferably, the mass-volume concentration of polyvinyl alcohol in the coagulation solution is 0.1-10%, and the concentration of calcium chloride is 0.05-0.5 mol / L.

[0014] Further preferably, the mass-volume concentration of polyvinyl alcohol in the coagulation solution is 0.5%, and the concentration of calcium chloride is 0.1 mol / L.

[0015] Preferably, the molar ratio of the amino acid, glycerol and curcumin in the curcumin eutectic solvent is 1-20:1-20:1-20.

[0016] Further preferably, the molar ratio of the amino acid, glycerol and curcumin in the curcumin eutectic solvent is 1:19:2.

[0017] Preferably, the mass-volume concentration of the curcumin eutectic solvent in the sodium alginate-curcumin eutectic solvent blend is 10-50%.

[0018] Further preferably, the mass-volume concentration of the curcumin eutectic solvent in the sodium alginate-curcumin eutectic solvent blend is 30%.

[0019] Preferably, the mass-volume concentration of sodium alginate in the sodium alginate-curcumin eutectic solvent blend is 6-8%.

[0020] Further preferably, the mass-volume concentration of sodium alginate in the sodium alginate-curcumin eutectic solvent blend is 6%.

[0021] Secondly, the present application provides a preparation method of the above-mentioned composite hydrogel bead loaded with curcumin eutectic solvent, comprising the following steps:

[0022] S1, uniformly mixing an amino acid and glycerol to obtain a clear solution, and uniformly mixing the clear solution and curcumin to obtain a uniform fluid, i.e. a curcumin eutectic solvent;

[0023] S2, uniformly mixing a sodium alginate aqueous solution and the curcumin eutectic solvent to obtain a sodium alginate-curcumin eutectic solvent blend;

[0024] S3, mixing the sodium alginate-curcumin co-crystal solvent blend and the coagulation liquid to obtain the composite hydrogel beads loaded with the curcumin co-crystal solvent.

[0025] Preferably, in step S1, the temperature for mixing the amino acid and glycerol is 40-80℃.

[0026] Further preferably, in step S1, the temperature for mixing the amino acid and glycerol is 70-80℃.

[0027] Preferably, in step S3, the volume ratio of the sodium alginate-curcumin co-crystal solvent blend to the coagulation liquid is 1-10:1-10.

[0028] Further preferably, in step S3, the volume ratio of the sodium alginate-curcumin co-crystal solvent blend to the coagulation liquid is 1:1.

[0029] Preferably, in step S3, the mixing time of the sodium alginate-curcumin co-crystal solvent blend and the coagulation liquid is 30-90 minutes.

[0030] Further preferably, in step S3, the mixing time of the sodium alginate-curcumin co-crystal solvent blend and the coagulation liquid is 30-60 minutes.

[0031] Finally, the present application provides the use of the above-mentioned composite hydrogel beads loaded with the curcumin co-crystal solvent in the preparation of a drug for treating ulcerative colitis.

[0032] Compared with the prior art, the present application has the following beneficial effects:

[0033] (1) By limiting the mass-volume concentration of sodium alginate in the sodium alginate-curcumin co-crystal solvent blend to 6-8%, the technical effect of encapsulating curcumin in the hydrogel beads is achieved.

[0034] (2) By limiting the mass-volume concentration of curcumin co-crystal solvent in the sodium alginate-curcumin co-crystal solvent blend to 30%, the encapsulation efficiency of the composite hydrogel beads is improved.

[0035] (3) By limiting the mass-volume concentration of sodium alginate in the sodium alginate-curcumin co-crystal solvent blend to 6%, the encapsulation efficiency and drug loading of the composite hydrogel beads are improved. BRIEF DESCRIPTION OF DRAWINGS

[0036] Figure 1Particle size chart for the appearance of Examples 1-6, Comparative Examples 1-6. Among them, A is Comparative Example 1, B is Comparative Example 2, C is Comparative Example 3, D is Comparative Example 4, E is Comparative Example 5, F is Comparative Example 6, G is Example 1, H is Example 2, I is Example 3, J is Example 4, K is Example 5, and L is Example 6.

[0037] Figure 2 Scanning electron microscope chart for Examples 1-3, Comparative Examples 1-6. Among them, A is Comparative Example 1, B is Comparative Example 2, C is Comparative Example 3, D is Comparative Example 4, E is Comparative Example 5, F is Comparative Example 6, G is Example 1, H is Example 2, and I is Example 3.

[0038] Figure 3 Infrared spectrum chart for Examples 1-3. Among them, F1 is Example 1, F2 is Example 2, and F3 is Example 3.

[0039] Figure 4 Swelling rate of Examples 1-3 in simulated body fluid SGF. Among them, F1 is Example 1, F2 is Example 2, and F3 is Example 3.

[0040] Figure 5 Swelling rate of Examples 1-3 in simulated body fluid SIF. Among them, F1 is Example 1, F2 is Example 2, and F3 is Example 3.

[0041] Figure 6 Swelling rate of Examples 1-3 in simulated body fluid SCF. Among them, F1 is Example 1, F2 is Example 2, and F3 is Example 3.

[0042] Figure 7 In vitro drug release chart for Example 2, Example 7. Among them, A is Example 2, and B is Example 7.

[0043] Figure 8 Change of storage modulus (G') for Examples 1-3.

[0044] Figure 9 Change of loss modulus (G'') for Examples 1-3.

[0045] Figure 10 Column chart for antioxidant activity experiment results, from left to right, curcumin, curcumin eutectic solvent, and Example 2.

[0046] Figure 11 Line chart for antioxidant activity experiment results.

[0047] Figure 12 Hydrogel bead digestive tract distribution experiment results chart for Example 2. DETAILED DESCRIPTION

[0048] The following non-limiting examples can provide a more complete understanding of the application to one of ordinary skill in the art, but are not intended to limit the application in any way. The following examples are merely illustrative of the scope of the application as claimed and various modifications and changes can be made by others skilled in the art using the disclosure provided herein, which are also intended to be within the scope of the application claimed.

[0049] The application is further described in the following specific examples. The various chemicals used in the examples are obtained through routine commercial channels unless otherwise specified.

[0050] Example 1

[0051] The curcumin eutectic solvent was prepared by heating method. The corresponding counterpart was prepared with lysine and glycerol as eutectic solvent. Lysine and glycerol were mixed in a 1:19 molar ratio in a round bottom flask, and the lysine-glycerol system was prepared at a temperature of 70-80°C to obtain a clear solution. Curcumin was then added, and continuous stirring was performed until a homogeneous fluid, i.e., the curcumin eutectic solvent, was obtained. The molar ratio of lysine, glycerol, and curcumin was 1:19:2. Sodium alginate was added to deionized water to prepare a sodium alginate aqueous solution. The sodium alginate solution was mixed with the curcumin eutectic solvent to prepare a sodium alginate-curcumin eutectic solvent blend, and the volume of the blend was 40 mL. The concentration of the sodium alginate-curcumin eutectic solvent was 10% (w / v), and the concentration of sodium alginate was 6% (w / v). The obtained sodium alginate-curcumin eutectic solvent blend was dropped into a coagulation liquid using a disposable syringe. The coagulation liquid contained polyvinyl alcohol at a mass concentration of 0.5%, calcium chloride at a concentration of 0.1 mol / L, and water as a solvent, and the volume was 40 mL. After the sodium alginate-curcumin eutectic solvent blend and the coagulation liquid were mixed for 30-60 minutes, a curcumin eutectic solvent-containing hydrogel bead was obtained. The hydrogel bead was collected and dried at 60°C to constant weight for later use.

[0052] Example 2

[0053] The concentration of the sodium alginate-curcumin eutectic solvent in the sodium alginate-curcumin eutectic solvent blend was changed to 30% (w / v), and the remaining raw materials and preparation process were the same as in Example 1.

[0054] Example 3

[0055] The concentration of the sodium alginate-curcumin eutectic solvent in the sodium alginate-curcumin eutectic solvent blend was changed to 50% (w / v), and the remaining raw materials and preparation process were the same as in Example 1.

[0056] Example 4

[0057] The concentration of sodium alginate in the sodium alginate-curcumin co-solvent blend was changed to 8% (w / v), and the remaining raw materials and preparation process were the same as Example 1.

[0058] Example 5

[0059] The concentration of sodium alginate in the sodium alginate-curcumin co-solvent blend was changed to 8% (w / v), and the remaining raw materials and preparation process were the same as Example 2.

[0060] Example 6

[0061] The concentration of sodium alginate in the sodium alginate-curcumin co-solvent blend was changed to 8% (w / v), and the remaining raw materials and preparation process were the same as Example 3.

[0062] Example 7

[0063] A counterpart was prepared with proline and glycerol as co-solvents, and the remaining raw materials and preparation process were the same as Example 2.

[0064] Comparative Example 1

[0065] The concentration of sodium alginate in the sodium alginate-curcumin co-solvent blend was changed to 2% (w / v), and the remaining raw materials and preparation process were the same as Example 1.

[0066] Comparative Example 2

[0067] The concentration of sodium alginate in the sodium alginate-curcumin co-solvent blend was changed to 2% (w / v), and the remaining raw materials and preparation process were the same as Example 2.

[0068] Comparative Example 3

[0069] The concentration of sodium alginate in the sodium alginate-curcumin co-solvent blend was changed to 2% (w / v), and the remaining raw materials and preparation process were the same as Example 3.

[0070] Comparative Example 4

[0071] The concentration of sodium alginate in the sodium alginate-curcumin co-solvent blend was changed to 4% (w / v), and the remaining raw materials and preparation process were the same as Example 1.

[0072] Comparative Example 5

[0073] The concentration of sodium alginate in the sodium alginate-curcumin co-solvent blend was changed to 4% (w / v), and the remaining raw materials and preparation process were the same as Example 2.

[0074] Comparative Example 6

[0075] The concentration of sodium alginate in the sodium alginate-curcumin co-solvent blend was changed to 4% (w / v), and the remaining raw materials and preparation process were the same as Example 3.

[0076] Results and Discussion

[0077] 1. Morphological assessment

[0078] 1.1 Diameter of hydrogel beads

[0079] The diameter of the beads was measured using vernier calipers, and the average reading was calculated using at least 10 dried hydrogel beads. The results are as follows: Figure 1 As shown.

[0080] 1.2 Scanning Electron Microscope

[0081] The surface and morphology of the hydrogel beads were analyzed using scanning electron microscopy (SEM). The samples were fixed to an aluminum rod using double-sided tape, coated with gold by sputtering, and then scanned at 30 kV. The results are shown below. Figure 2 As shown.

[0082] like Figure 1 As shown, the wet beads exhibited regular spherical shapes, smooth surfaces, and uniform size. After drying, as water molecules diffused out of the beads, the diameter decreased significantly. At lower sodium alginate concentrations (2%), the stability, shape, and size of the hydrogel beads were severely affected by the DES content. Therefore, the hydrogel beads showed slight surface collapse after drying, attributed to the lower sodium alginate content, resulting in a rougher bead surface and faster water evaporation. With increasing sodium alginate content, the diameter of the hydrogel beads increased slightly, and the surface became denser and more compact. The degree of bead shrinkage during drying depended not only on the drying process but also on the mass ratio of sodium alginate to curcumin co-crystal solvent. The figure shows that different concentrations of curcumin co-crystal solvent all produced uniform hydrogel bead structures at a sodium alginate concentration of 6%. Therefore, hydrogel beads of this concentration were used for further experiments.

[0083] 2. Determination of drug loading and encapsulation efficiency

[0084] A certain amount of hydrogel beads was first crushed in a grinder and transferred to a 25 mL volumetric flask, then ethanol was added. The mixture was then sonicated for 20 min to obtain a homogeneous curcumin solution. Subsequently, the curcumin content was determined using a UV-Vis spectrophotometer at 425 nm. The formulas for calculating the drug loading and encapsulation efficiency are as follows:

[0085]

[0086]

[0087] The actual curcumin content in hydrogel beads = initial curcumin content - free curcumin content

[0088] After obtaining the hydrogel beads, the absorbance of the polyvinyl alcohol solution at 425 nm was determined by UV-visible spectrophotometer to determine the content of free curcumin in the polyvinyl alcohol solution.

[0089] The encapsulation efficiency (EE %), loading capacity (LC %) and diameter of Examples 1-7 and Comparative Examples 1-6 are shown in Table 1.

[0090] Table 1. EE %, LC %, diameter of Examples 1-7 and Comparative Examples 1-6

[0091]

[0092]

[0093] As shown in Table 1, the encapsulation efficiency (EE %) and loading capacity (LC %) of Examples 1-7 are higher than 93 % and 17.645 % respectively, indicating that most of the curcumin dissolved in the polymer solution is encapsulated in the process of ionized gel. In addition, with the increase of curcumin eutectic solvent, the loading capacity of the prepared microbeads slowly increases to 43.02 %, but the encapsulation efficiency slightly decreases, and the diameter of the prepared hydrogel beads also increases from 1.397 mm to 1.988 mm. The results show that the hydrogel beads prepared in Examples 1-7 all have high loading capacity and encapsulation efficiency, and are excellent potential carriers for curcumin.

[0094] As shown in Table 1, no curcumin content in Comparative Examples 1-6 can be detected by UV-spectrophotometer at 425 nm, so the encapsulation efficiency and loading capacity cannot be calculated.

[0095] In summary, the concentration of sodium alginate will affect whether the composite hydrogel beads load curcumin. When the mass concentration of sodium alginate is 6-8 %, the hydrogel beads have high loading capacity and encapsulation efficiency, and are excellent potential carriers for curcumin.

[0096] 3. FTIR spectrum analysis

[0097] The FTIR spectra of sodium alginate, polyvinyl alcohol, curcumin, curcumin eutectic solvent, Examples 1-3 were recorded using a real-time online in-situ infrared monitoring system (Model: Nicolet iS50) in the range of 400-4000 cm -1 FTIR spectra in solid state.

[0098] From the spectrum of sodium alginate, it can be observed that there are three characteristic peaks at 3257 cm -1 , 1590 cm -1 and 1410 cm -1 , which are respectively attributed to -OH stretching, asymmetric and symmetric stretching vibration of -COO-; from the spectrum of polyvinyl alcohol, it can be observed that there are three characteristic peaks at 3270 cm -1O-H stretching vibration of the left and right hydroxyl groups, 2940 -1 and 2910 cm -1 are related to the asymmetric and symmetric elongation vibration of -CH bonds, respectively; from the spectrum of curcumin, it can be observed that there is a sharp peak at 3512 cm -1 and a large weak band at 3340 cm -1 are attributed to the O-H stretching of the benzene ring and aliphatic O-H stretching, respectively, while the peaks at 2924-2853 cm -1 belong to aromatic C-H stretching vibration. The DES spectrum presents the characteristic peaks of the counterparts and indicates that intermolecular interactions are established between lysine and glycerol, curcumin is masked by the intensity peaks of other counterparts due to low concentration, and the characteristic peaks of curcumin are not detected due to the establishment of intermolecular interactions. Similar characteristic peaks of pure polymer are detected in the FTIR spectra of prepared examples 1-3, and the characteristic peaks of curcumin eutectic solvent appear at 2940-2884 cm -1 , confirming the incorporation of the drug into the sample.

[0099] 4. Swelling experiment

[0100] The swelling behavior of hydrogel beads was studied by the immersion method. The known weight of hydrogel beads (5 mg) of examples 1-3 were immersed in 15 mL of simulated gastric fluid (SGF, pH = 1.2), simulated intestinal fluid (SIF, pH = 6.8) and simulated colon fluid (SCF, pH = 7.4), and the swollen hydrogel beads were taken out at predetermined time points, and the water on the surface of the hydrogel beads was carefully wiped off with filter paper, and the weight of the hydrogel beads was weighed using a balance, and the swelling capacity was calculated as follows:

[0101]

[0102] where W W and W i are the weights of the swollen and dried hydrogel beads, respectively.

[0103] When evaluating the swelling performance of dried hydrogel beads, the hydrogel beads were immersed in different simulated gastrointestinal fluids, including SGF (pH 1.2), SIF (pH 6.8), and SCF (pH 7.4), and the results are shown in Figure 4 , 5The dried hydrogel beads undergo a swelling process when in contact with a fluid, mainly due to the hydration of the hydrophilic groups (such as hydroxyl, amine, carboxyl and alcohol groups). The swelling rate is low in acidic medium and increases gradually after pH > 6.8, mainly because at lower pH, the carboxyl groups of SA are protonated and form a layer of alginate insoluble in the liquid, thus creating an ionotopic protection of SA. In addition, the protonation of the carboxyl groups favors the strength of the hydrogen bond interactions, increasing the stability of the hydrogel beads, limiting their swelling. At higher pH, the free carboxyl groups are ionized into carboxylate, generating repulsive electrostatic interactions, leading to a higher swelling effect. In addition, as the carboxyl groups gradually ionize, the hydrogen bond interactions are also dissociated and the ionic crosslinks are no longer stable. Thus, the swelling rate of the hydrogel beads increases rapidly as the pH increases. The lower the DES content, the higher the swelling rate of the hydrogel beads and the swelling disintegration can occur. Based on the in vitro release results of the hydrogel beads, the hydrogel beads of Example 2 were selected for further experiments.

[0104] 5. In vitro drug release experiment

[0105] Pre-weighed hydrogel beads of Example 2, Example 7 (0.04 g) were placed in 10 mL of release medium, which was simulated gastric fluid (SGF, pH = 1.2), simulated intestinal fluid (SIF, pH = 6.8) and simulated colon fluid (SCF, pH = 7.4) at 37°C with constant rotation speed of 50 rpm. At predetermined time points, 3 mL of solution was removed from the release medium and immediately added with the same volume of fresh solution. The removed curcumin solution was added with anhydrous ethanol and ultrasonicated to ensure complete dissolution of curcumin, followed by analysis with UV-spectrophotometer at 425 nm.

[0106] As Figure 7As shown in FIG. 6, in SGF, the hydrogel beads are relatively stable, so the amount of curcumin released is small. Compared with SGF, the release amount in SIF solution is higher, and explosive release occurs after 2 h, mainly because the high swelling of the beads leads to partial disintegration. Therefore, a large amount of curcumin is released from the hydrogel beads earlier. In the SCF release medium, the hydrogel beads will swell to a high degree, so a large amount of curcumin will be released from the hydrogel beads earlier. The disintegration of the hydrogel beads occurs after 1 hour, resulting in the explosive release of natural compounds. Example 2 The cumulative release amount of curcumin in SGF is 0.28% within 8 hours, while for SIF, the cumulative release amount of curcumin is 51.76%, and for SCF, the cumulative release amount of curcumin is 90.44%. Example 7 The cumulative release amount of curcumin in SGF is 0.057% within 8 hours, while for SIF, the cumulative release amount of curcumin is 33.822%, and for SCF, the cumulative release amount of curcumin is 94.242%. The results obtained from the curcumin release curve are consistent with the results obtained from the swelling behavior study.

[0107] 6. Rheological experiment

[0108] The rheological properties of the hydrogel beads were measured using a modular intelligent advanced rotational rheometer (Anton Paar MCR 102) in oscillation mode. The hydrogel beads prepared in Examples 1-3 (10-15) were soaked in deionized water for 1 hour and carefully placed on the lower plate, and the upper cone was lowered to a gap distance of 1 mm. The rheological behavior of the hydrogel was tested by frequency scanning at a constant strain of 0.5% to 25%.

[0109] The storage modulus (G') and the loss modulus (G") describe the elastic behavior and energy loss of the material when subjected to stress. The changes of G' and G" of the curcumin hydrogel beads with frequency are shown in FIGS. 7 and 8, respectively. Figure 8 、 9 As shown in FIGS. 7 and 8, the G' of Examples 1-3 is greater than the G", and the elasticity of the hydrogel beads is stronger as the DES content increases.

[0110] 7. Antioxidant activity experiment

[0111] The antioxidant activity of the beads was determined by 1,1-Diphenyl-2-picryl-hydrazyl (DPPH) radical scavenging method. A certain amount of curcumin, curcumin DES, and Example 2 were dissolved in a certain amount of anhydrous ethanol and ultrasonically dispersed. Curcumin, curcumin DES, and Example 2 were prepared into a solution containing 0.05 mg / mL of curcumin, and the corresponding reagents were added according to Table 2. After shaking well, the solution was reacted for 30 minutes at room temperature in the dark. The absorbance A was measured at a wavelength of 517 nm. The absorbance of a mixture of 2 mL of anhydrous ethanol solution and 2 mL of DPPH solution was measured as A0. The detection was repeated three times, and the DPPH scavenging rate was calculated by the following formula.

[0112]

[0113] Table 2. Volume of corresponding reagent added

[0114] Group Sample volume / mL Anhydrous ethanol / mL DPPH / mL Final concentration / mg mL -1 ]] Total volume / mL [A0] 0.00 2.00 2.00 0.000 4.00 [A1] 0.20 1.80 2.00 0.0025 4.00 [A2] 0.40 1.60 2.00 0.005 4.00 [A3] 0.60 1.40 2.00 0.0075 4.00 [A4] 0.80 1.20 2.00 0.01 4.00 [A5] 1.00 1.00 2.00 0.0125 4.00

[0115] The DPPH radical scavenging ability of curcumin, curcumin eutectic solvent, and Example 2 is shown in Figure 10 、 11 As the concentration of the sample increased from 2.5 μg / mL to 12.5 μg / mL, the DPPH radical scavenging ability of each sample gradually increased. The scavenging rates of curcumin, curcumin DES, and Example 2 were 67.46%, 68.82%, and 72.26%, respectively. By linear fitting to calculate the half scavenging rate (IC50) of DPPH radicals, the IC50 of curcumin was 0.008186 mg / mL, the IC50 of curcumin eutectic solvent was 0.007924 mg / mL, and the IC50 of curcumin hydrogel beads was 0.007106 mg / mL. The DPPH radical scavenging effect of curcumin hydrogel beads was slightly higher than that of free curcumin.

[0116] 8. Digestive tract distribution experiment of hydrogel beads

[0117] C57BL / 6J male mice (7 weeks old) were selected as experimental mice, and the modeling method was to give the mice a 3% (w / v) dextran sulfate sodium (DSS) solution for 7 days to establish an ulcerative colitis mouse model. The mice were fasted for 12-14 h without water the day before the experiment. A certain amount of hydrogel beads of Example 2 was administered to each mouse, and then the mice were euthanized at predetermined time intervals (1, 3, 6, 9, 12, and 24 hours). The distribution of curcumin hydrogel beads in the digestive tract of the mice was observed.

[0118] From Figure 12It can be seen that 1h after the hydrogel beads were distributed in the stomach, the intestinal wall of the mouse jejunum and ileum was transparent; 3h after 5 hydrogel beads were distributed in the stomach and did not burst after swelling; 1 was distributed in the colon, the intestinal wall of the mouse jejunum and ileum was transparent; 6h after 4 hydrogel beads were distributed in the stomach and did not burst after swelling; 2 were distributed in the colon, the intestinal wall of the mouse jejunum and ileum was transparent; 9h after a small amount of hydrogel beads were distributed in the stomach, the mouse digestive tract was yellowish; 12h after the mouse digestive tract did not see hydrogel beads, the mouse overall digestive tract was yellowish, and the mouse feces did not see hydrogel beads; 24h after the mouse digestive tract did not see hydrogel beads, the colon was yellowish, and the mouse feces did not see hydrogel beads. It can be seen that before 6h, the hydrogel beads in the stomach swell and slightly disintegrate after meeting water, which is mainly due to the low pH in the stomach, the carboxyl group of SA is protonated and forms a layer of alginate insoluble in the liquid, thereby producing the ion permeation protection effect of SA. 12-24h later, the hydrogel beads are distributed in the colon, the pH in the colon is higher, the hydrogel beads swell and disintegrate rapidly after meeting water, and a large amount of curcumin is released, and the entire digestive tract is yellowish. This is consistent with the in vitro swelling results of the hydrogel beads.

[0119] Finally, it should be noted that the above content is only used to illustrate the technical solutions of the present application, and is not a limitation on the protection scope of the present application. Simple modifications or equivalent replacements of the technical solutions of the present application made by those skilled in the art do not deviate from the essence and scope of the technical solutions of the present application.

Claims

1. A composite hydrogel bead loaded with curcumin cocrystal solvent, characterized in that, The composite hydrogel beads are prepared from a sodium alginate-curcumin co-crystal solvent blend and a coagulation solution; the sodium alginate-curcumin co-crystal solvent blend includes a curcumin co-crystal solvent and an aqueous solution of sodium alginate; the curcumin co-crystal solvent includes curcumin, proline, and glycerol; the coagulation solution includes polyvinyl alcohol, calcium chloride, and water; the mass-volume concentration of the curcumin co-crystal solvent in the sodium alginate-curcumin co-crystal solvent blend is 30%; the mass-volume concentration of sodium alginate in the sodium alginate-curcumin co-crystal solvent blend is 6%.

2. The composite hydrogel beads according to claim 1, characterized in that, The polyvinyl alcohol concentration in the coagulation solution is 0.1-10% by mass and the calcium chloride concentration is 0.05-0.5 mol / L; the molar ratio of proline, glycerol and curcumin in the curcumin eutectic solvent is 1-20:1-20:1-20.

3. The method for preparing the composite hydrogel beads according to any one of claims 1-2, characterized in that, Includes the following steps: S1. Mix proline and glycerol evenly to obtain a clear solution. Mix the above clear solution with curcumin until a homogeneous fluid is obtained, which is the curcumin cocrystal solvent. S2. Mix the sodium alginate aqueous solution and curcumin co-crystal solvent evenly to obtain the sodium alginate-curcumin co-crystal solvent blend. S3. Mix the sodium alginate-curcumin co-crystal solvent blend with the coagulation liquid to obtain composite hydrogel beads loaded with curcumin co-crystal solvent.

4. The preparation method according to claim 3, characterized in that, In step S1, the temperature at which the amino acids and glycerol are mixed is 40-80°C.

5. The preparation method according to claim 3, characterized in that, In step S3, the volume ratio of the sodium alginate-curcumin eutectic solvent blend to the coagulated liquid is 1-10:1-10.

6. The use of the composite hydrogel beads prepared according to any one of claims 1-2, or according to any one of claims 3-5, in the preparation of a drug for treating ulcerative colitis.

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