CN110951091A - Preparation method of double-sensitive slow-release β -cyclodextrin hydrogel - Google Patents
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Abstract
The invention discloses a preparation method of double-sensitive slow-release β -cyclodextrin hydrogel, which comprises the steps of firstly carrying out esterification reaction on β -cyclodextrin and maleic anhydride to obtain maleic anhydride esterified β -cyclodextrin derivative, carrying out amidation reaction on the derivative and diethanolamine to obtain functionalized β -cyclodextrin derivative, carrying out reaction on the functionalized β -cyclodextrin derivative, cholic acid and epoxy chloropropane in a sodium hydroxide aqueous solution to obtain β -cyclodextrin polymer, carrying out redox free radical polymerization on β -cyclodextrin polymer, N-isopropyl acrylamide and acrylic acid monomer to obtain β -cyclodextrin hydrogel by using ammonium persulfate as an oxidizing agent, sodium sulfite as a reducing agent, N, N-methylene bisacrylamide as a cross-linking agent and distilled water as a solvent.
Description
Technical Field
The invention belongs to the field of high molecular functional materials, and particularly relates to a preparation method of a dual-sensitive slow-release β -cyclodextrin hydrogel.
Background
The hydrogel is a three-dimensional reticular polymer, can not be dissolved in water, and can also be subjected to water absorption swelling in water by utilizing a physical and chemical crosslinking structure of the hydrogel, so that the hydrogel has the advantages of high water content, soft property, high permeability, good biocompatibility and the like. These excellent properties make hydrogels have a wide range of applications in industry, agriculture, biomedicine and even life. In recent years, researchers at home and abroad are dedicated to developing novel hydrogels, and a large number of multifunctional and high-strength novel hydrogels, such as temperature, pH, light and electromagnetic stimulation responsive hydrogels, double-network and interpenetrating network hydrogels, nano-composite hydrogels and self-healing hydrogels, are developed.
Cyclodextrin (CD) is formed by acting Cyclodextrin glucose residual transferase on glucose polymers such as starch, glycogen, maltooligosaccharide and the like, most commonly comprises three cyclodextrins α, β and gamma, among the three cyclodextrins, β -Cyclodextrin (β -Cyclodex, abbreviated as β -CD) is water-soluble non-reducing white crystalline or amorphous powder, the main body configuration is a conical cylinder with a hollow in the middle and two unclosed ends, in the hollow structure, the inner cavity is hydrophobic, and can contain a plurality of guest molecules such as organic molecules, inorganic molecules, complexes, inert gas molecules and the like, so that the guest molecules can form various inclusion compounds through weak interaction of non-covalent bonds, and the physicochemical property and the biological property of the guest molecules are changed.
Although the hydrogel has a porous structure and can load and release drug molecules, the traditional hydrogel has poor mechanical properties and single function, so that the application of the hydrogel is limited to a certain extent. To modify the hydrogel set of problems, cyclodextrin derivatives with unique structures were incorporated into the hydrogel materials. The cyclodextrin derivative hydrogel has diversified functions, and can change the molecular acting force between drug molecules and polymers, so that the drug slow-release performance of the hydrogel is improved. The cyclodextrin derivatives are diverse, and the structure and the performance of the cyclodextrin derivatives are also diverse, so that the structure and the performance of the hydrogel are different.
Disclosure of Invention
In order to overcome the problems in the prior art, the invention provides a preparation method of a double-sensitive slow-release β -cyclodextrin hydrogel.
In order to achieve the aim, the technical scheme adopted by the invention is that the preparation method of the double-sensitive slow-release β -cyclodextrin hydrogel comprises the following steps:
(1) and (2) esterification reaction, namely fully grinding β -cyclodextrin and maleic anhydride until the system is uniformly mixed, reacting at the esterification temperature, and purifying after the reaction is finished to obtain the maleic anhydride esterified β -cyclodextrin derivative.
(2) And (2) performing amide reaction, namely reacting the maleic anhydride esterified β -cyclodextrin derivative prepared in the step (1) with diethanol amine in a tetrahydrofuran solvent, and purifying after the reaction is finished to prepare the amidated β -cyclodextrin derivative.
(3) β -preparation of cyclodextrin polymer, which is to react the amidated β -cyclodextrin derivative prepared in the step (2), cholic acid and epichlorohydrin in sodium hydroxide water solution, and purify the product after the reaction to prepare β -cyclodextrin polymer.
(4) And (3) preparing hydrogel, namely performing redox free radical polymerization on the β -cyclodextrin polymer prepared in the step (3), N-isopropylacrylamide, acrylic acid, ammonium persulfate, sodium sulfite and N, N-methylene bisacrylamide in distilled water to prepare the β -cyclodextrin hydrogel.
Further, the esterification reaction in the step (1) comprises the following specific preparation steps:
the β -cyclodextrin and maleic anhydride powder which are ground and mixed evenly are placed in a conical flask to react for 8 hours at the temperature of 80 ℃, and a glass rod is used for stirring continuously in the initial reaction stage until the system becomes viscous.
Further, the amidation reaction in the step (2) comprises the following specific preparation steps:
dissolving the maleic anhydride esterified β -cyclodextrin derivative prepared in the step (1) and diethanol amine in tetrahydrofuran, fully mixing, and reacting for 5 hours at the temperature of 60 ℃ and at the speed of 300 r/min.
Further, the specific preparation steps of the β -cyclodextrin polymer in the step (3) are as follows:
stirring and mixing the amidated β -cyclodextrin derivative prepared in the step (2) with cholic acid and sodium hydroxide aqueous solution for 24h, adding epichlorohydrin, stirring for 45min, soaking with acetone for 30min, removing acetone, and standing for 8 h.
Further, the hydrogel prepared in the step (4) comprises the following specific preparation steps:
and (3) uniformly stirring the β -cyclodextrin polymer prepared in the step (3) with N-isopropylacrylamide, acrylic acid, ammonium persulfate, sodium sulfite and N, N-methylene bisacrylamide in distilled water, introducing nitrogen for 10min, and reacting for 8h at the temperature of 50 ℃.
Further, the purification operation in the step (1) is: and after the reaction is finished, taking out the solid, grinding the solid into powder, then fully washing, filtering and drying the powder by using acetone and absolute ethyl alcohol in sequence.
Further, the purification operation in the step (2) is: precipitating the product with acetone as precipitant, separating, and drying.
Further, the purification operation in the step (3) is: neutralizing with 6mol/L hydrochloric acid to neutrality, precipitating with anhydrous ethanol as precipitant, separating, and drying.
Further, step 4 also comprises soaking the prepared β -cyclodextrin hydrogel in water for 24h, and drying.
Further, in the step (1), the molar ratio of β -cyclodextrin to maleic anhydride is 1:20, the molar ratio of the esterified maleic anhydride β -cyclodextrin derivative prepared in the step (1) to diethanolamine prepared in the step (2) is 1:99, the molar ratio of the amidated β -cyclodextrin derivative prepared in the step (2) in the step (3) to epichlorohydrin is 1:17, and the mass ratio of the β -cyclodextrin polymer prepared in the step (3) in the step (4) to N-isopropylacrylamide is 1: 1.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention utilizes esterification reaction to prepare the maleic anhydride esterified β -cyclodextrin derivative, and the method prepares the functionalized β -cyclodextrin derivative, does not damage the self cavity structure of β -cyclodextrin, and introduces carboxyl functional groups into the β -cyclodextrin structure, thereby being capable of carrying out more surface modification.
(2) According to the invention, the amidated β -cyclodextrin derivative is obtained through an amide reaction, so that the system becomes more stable under the condition of not damaging the body structure, and a large number of hydroxyl groups can enable the system to be subjected to surface modification through different methods.
(3) The β -cyclodextrin polymer is synthesized by the invention, so that the molecular weight of the system is increased, cholic acid with a polyfunctional group is introduced, and β -cyclodextrin derivatives and the cholic acid are connected together by epoxy chloropropane.
The β -cyclodextrin hydrogel prepared by redox free radical polymerization has sensitivity to pH and temperature, can swell and include aspirin in water, and is applied to drug slow release, so that the β -cyclodextrin hydrogel not only has good double sensitivity, but also has good slow release performance.
Drawings
FIG. 1 is an infrared spectrum of a maleated β -cyclodextrin derivative prepared in step (1) of example 1 of the present invention;
FIG. 2 is an infrared spectrum of amidated β -cyclodextrin derivative prepared in step (2) of example 1 of the present invention;
FIG. 3 is an infrared spectrum of β -cyclodextrin polymer prepared in step (3) of example 1 of the present invention;
FIG. 4 is an infrared spectrum of β -cyclodextrin hydrogel prepared in step (4) of example 1 of the present invention;
FIG. 5 is a swelling curve of a pH sensitivity experiment of β -cyclodextrin hydrogel prepared in example 1 of the present invention;
FIG. 6 is a swelling curve of a temperature sensitivity experiment for β -cyclodextrin hydrogel prepared in example 1 of the present invention;
FIG. 7 is a swelling curve of a pH sensitivity experiment of β -cyclodextrin hydrogel prepared in example 2 of the present invention;
FIG. 8 is a swelling curve of a temperature sensitivity experiment for β -cyclodextrin hydrogel prepared in example 2 of the present invention;
FIG. 9 is a release profile of a sustained release experiment of β -cyclodextrin hydrogel made according to example 1 of the present invention.
Detailed Description
The invention is described in more detail below with reference to the following examples:
example 1:
a preparation method of a double-sensitive slow-release β -cyclodextrin hydrogel comprises the following steps:
(1) preparation of maleic anhydride esterified β -cyclodextrin derivative by esterification reaction
Weighing β -cyclodextrin 5g and maleic anhydride 8.8g, fully grinding in a mortar until the system is uniformly mixed, transferring the mixed and ground powder into a conical flask by using a medicine spoon, heating and preserving heat for 8h in an oil bath kettle at 80 ℃, stirring in the early stage of heating to ensure that the powder is fully contacted and reacted, continuously stirring when the reaction system begins to become viscous until the system is stirred, sealing the conical flask (the maleic anhydride absorbs heat and sublimates in the reaction process, and sealing is required for fully reacting), taking out the solid in the conical flask after reacting for 8h, grinding into powder, sequentially and fully washing and filtering by using acetone and absolute ethyl alcohol, respectively washing for 3 times, filtering, and drying to obtain the maleinated β -cyclodextrin derivative.
FIG. 1 shows that the infrared spectrum of the maleic anhydride esterified β -cyclodextrin derivative is at 1728cm-1The infrared characteristic vibration absorption peak caused by the symmetric stretching vibration of the unsaturated carboxylic ester appears, and the infrared characteristic vibration absorption peak is combined with β -cyclodextrin at 580cm-1Ring vibration of (d) and 940cm-1The α -1, 4 glycosidic bond-containing skeletons vibrate basically in the same way, the data show that maleic anhydride with carboxyl is introduced into the system by adopting esterification reaction, thus proving that the maleic anhydride esterified β -cyclodextrin derivative is successfully prepared;
(2) amidated β -cyclodextrin derivatives by amide reaction
Adding 1g of the maleic anhydride esterified β -cyclodextrin derivative obtained in the step (1), 6.21mL of diethanolamine and 15mL of tetrahydrofuran into a three-neck flask, putting the three-neck flask into a rotor, carrying out full reaction in an oil bath kettle at 60 ℃ and 300r/min under the action of a magnetic stirrer, and carrying out condensation reflux, removing a product from the three-neck flask by using a suction pipe after 5h, putting the product into an acetone solution, precipitating by using acetone, and then sequentially carrying out separation and drying to obtain an amidated β -cyclodextrin derivative;
FIG. 2 shows that the infrared spectrum curve of the amidation β -cyclodextrin derivative is 3050-3700 cm-1The stretching vibration peak of-OH appears. since-C ═ O is a tertiary amide, 1630cm-1An absorption peak of-C ═ O, 647cm was observed-1The absorption peak of-CN, and the absorption peak of-CN, which is at 580cm with β -cyclodextrin-1Ring vibration of (d) and 940cm-1The α -1, 4 glycosidic linkages contained backbone vibrations were essentially identical, indicating that the introduction of hydroxyl-containing diethanolamine by the amide reaction demonstrated the successful preparation of the amidated β -cyclodextrin derivative;
(3) preparation of β -Cyclodextrin polymers by Ring opening reaction
Weighing 3mL of amidated β -cyclodextrin derivative obtained in the step (2), 0.1g of cholic acid, 10g of sodium hydroxide and 10mL of water in a three-neck flask, reacting in a water bath kettle at 25 ℃ for 24 hours under the action of an electronic stirrer to fully activate the amidated β -cyclodextrin derivative and the hydroxyl group of the cholic acid, then dripping 2.5mL of epoxy chloropropane for crosslinking reaction under the condition of stirring at 30 ℃ for 45 minutes, then adding 15mL of acetone, soaking for 30 minutes to stop the crosslinking reaction, and then removing the acetone (the acetone is specifically removed by directly pouring the acetone into a beaker, and in the process, the product cannot be poured out (the acetone is separated directly when soaked), standing for 8 hours at 50 ℃ and neutralizing the product to be neutral by 6mol/L of hydrochloric acid, precipitating with absolute ethyl alcohol, separating and drying to obtain a β -cyclodextrin polymer;
as can be seen from the IR spectrum curve of the cyclodextrin polymer of FIG. 3 β, the absorption peak of-C ═ O is shifted to 1640cm-1，1040cm-1The characteristic absorption peak of epichlorohydrin is shown, 737cm-1The C-Cl disappears, and the C-Cl is mixed with β -cyclodextrin at 580cm-1Ring vibration of (d) and 940cm-1The vibration of the skeletons containing α -1, 4 glycosidic bonds is basically consistent, which shows that the ring-opening reaction successfully prepares β -cyclodextrin polymer;
(4) preparation of β -Cyclodextrin hydrogels by Redox free radical polymerization
Weighing 1.5g of β -cyclodextrin polymer obtained in the step (3), 1.5g of N-isopropylacrylamide, 0.05g of ammonium persulfate, 0.023g of sodium sulfite, 0.008g of N, N-methylenebisacrylamide, 0.45mL of acrylic acid and 10mL of distilled water, putting the mixture into a three-neck flask, uniformly stirring, introducing nitrogen for 10min, reacting in a water bath environment at 50 ℃ for 8h, soaking the product in distilled water for 24h to remove raw materials which do not participate in the reaction and a product with insufficient crosslinking degree, and drying (specifically, taking out the hydrogel in a 50 ℃ environment by using a forceps, putting the hydrogel into a beaker, and drying at 80 ℃ under vacuum) to obtain the β -cyclodextrin hydrogel.
FIG. 4 β -cyclodextrin hydrogel IR spectrum curve shows that 3130-3760 cm-1at-NH and-OH absorption peaks at 1730cm-1Is the absorption peak of-C ═ O in carboxylic ester, 1640cm-1Absorption peak of-C ═ O in the amide group, 1540cm-1Is the second band of-NH and is at 580cm with β -cyclodextrin-1Ring vibration of (d) and 940cm-1The vibration of the skeletons containing α -1, 4 glycosidic bonds is basically consistent, and the result shows that β -cyclodextrin hydrogel is prepared by free radical synthesis work.
Example 2
(1) The method for preparing the maleic anhydride esterified β -cyclodextrin derivative by esterification reaction is the same as that of example 1;
(2) the amidation β -cyclodextrin derivative was prepared by the same method as in example 1;
(3) the ring-opening and ring-closing process for preparing β -cyclodextrin polymer is the same as in example 1;
(4) preparing β -cyclodextrin hydrogel by redox free radical polymerization;
weighing 1.5g of β -cyclodextrin polymer obtained in the step (3), 1.5g of N-isopropylacrylamide, 0.05g of ammonium persulfate, 0.023g of sodium sulfite, 0.008g of N, N-methylenebisacrylamide, 0.15mL of acrylic acid and 10mL of distilled water in a three-neck flask, uniformly stirring, introducing nitrogen for 10min, reacting in a water bath environment at 50 ℃ for 8h, soaking the product in distilled water for 24h, and drying to obtain β -cyclodextrin hydrogel.
Effects of the embodiment
1.β -Cyclodextrin hydrogel pH sensitivity test method as follows;
β -cyclodextrin hydrogel is respectively placed in buffer solution with pH of 2.2, 5.0, 7.4, 8.0 and 8.6 to swell at 25 ℃, the time is set to 0h, 0.5h, 1.0h, 1.5h, 2.0h, 2.5h, 3h, 5h, 7h, 9h, 13h, 17h, 21h, 25h, 33h and 41h, the gel is taken out at each time point, the buffer solution on the surface of the gel is sucked by filter paper, the mass of the gel is weighed, and the swelling ratio is calculated.
2.β -Cyclodextrin hydrogel temperature sensitivity test method as follows:
β -cyclodextrin hydrogel is placed in buffer solution with pH of 2.2, 5.0, 7.4, 8.0, and 8.6, and is respectively placed in environment with temperature of 25 deg.C, 30 deg.C, 35 deg.C, 40 deg.C, 45 deg.C, 50 deg.C, 55 deg.C, and 60 deg.C for swelling for 41h, the swollen gel is taken out, the buffer solution on the surface is absorbed by filter paper, the mass is weighed, and the swelling ratio is calculated.
3.β -cyclodextrin hydrogel slow release performance test method comprises weighing 7.54g aspirin, dissolving in 100mL distilled water, soaking 0.5g β -cyclodextrin hydrogel in 10mL aspirin water solution, clathrating at 50 deg.C for 24h, drying, placing 0.1g of the clathrated hydrogel in 50mL distilled water, performing slow release experiment at 37 deg.C, setting time to 15min, 30min, 45min, 60min, 90min, 120min, 150min, 180min, 210min, 270min, 330min, 390min, 450min, 510min, 570min, 630min, taking 3mL of clear liquid at each time, simultaneously supplementing 3mL of continuous filtrate at the same temperature, titrating with 0.1mol/mL sodium hydroxide to pH 9-10, titrating with 0.1mol/mL hydrochloric acid to pH 3-4, adding slightly excessive ferric chloride hexahydrate, and measuring sample absorbance A under visible light wavelength of 526.5 nm.
Referring to fig. 5, for the pH sensitivity curve of the β -cyclodextrin hydrogel prepared in example 1, it can be seen that the swelling degree increases with time and finally reaches an equilibrium, meanwhile, the swelling degree of the hydrogel increases with the increase of the system pH, and after the pH reaches 8.0, the swelling degree of the hydrogel gradually becomes stable, and the maximum swelling multiple can reach 29.03.
Referring to fig. 6, for the temperature sensitivity curve of the β -cyclodextrin hydrogel prepared in example 1, it can be seen that the swelling degrees of the hydrogel are different at different temperatures, when the temperature is increased from 25 ℃ to 60 ℃, the equilibrium swelling is decreased no matter how much the PH is, the multiple of the equilibrium swelling is continuously decreased with the increase of the temperature, and is most obvious at 35 ℃ to 40 ℃, and after the temperature reaches 45 ℃, the equilibrium swelling of the system gradually becomes stable, so that the hydrogel is known to have temperature sensitivity.
Referring to FIG. 7, which is a pH sensitive curve of the β -cyclodextrin hydrogel prepared in example 2, it can be seen that the swelling degree of the hydrogel is increased with time and gradually reaches a stable state, and the swelling degree of the hydrogel is greatly changed in the process of adjusting the pH from 2.2 to 8.6 and gradually becomes stable after the pH reaches 8.0, and the highest swelling degree can reach 21.99.
Referring to FIG. 8, the temperature sensitivity curve of the β -cyclodextrin hydrogel prepared in example 2 shows that the equilibrium swelling of the hydrogel varies at different temperatures, and decreases with increasing temperature.
Referring to FIG. 9, the sustained release curve of the β -cyclodextrin hydrogel prepared in example 1 shows that the hydrogel has sustained release effect on ASA. with the time being prolonged, the hydrogel has a rapid sustained release rate at the beginning, and the sustained release rate decreases after 210min, and then gradually approaches an equilibrium state, which indicates that the sustained release amount reaches the maximum.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and their concepts should be equivalent or changed within the technical scope of the present invention.
Claims (10)
1. A preparation method of a double-sensitive slow-release β -cyclodextrin hydrogel is characterized by comprising the following steps:
(1) esterification reaction, namely fully grinding β -cyclodextrin and maleic anhydride until the system is uniformly mixed, reacting at esterification temperature, and purifying after the reaction is finished to obtain maleic anhydride esterified β -cyclodextrin derivatives;
(2) performing amide reaction, namely reacting the maleic anhydride esterified β -cyclodextrin derivative prepared in the step (1) with diethanol amine in a tetrahydrofuran solvent, and purifying after the reaction is finished to prepare an amidated β -cyclodextrin derivative;
(3) β -preparation of cyclodextrin polymer, which is to react the amidated β -cyclodextrin derivative prepared in the step (2), cholic acid and epichlorohydrin in sodium hydroxide water solution, and purify the product after the reaction to prepare β -cyclodextrin polymer;
(4) and (3) preparing hydrogel, namely performing redox free radical polymerization on the β -cyclodextrin polymer prepared in the step (3), N-isopropylacrylamide, acrylic acid, ammonium persulfate, sodium sulfite and N, N-methylene bisacrylamide in distilled water to prepare the β -cyclodextrin hydrogel.
2. The preparation method of the double-sensitive slow-release β -cyclodextrin hydrogel according to claim 1, wherein the esterification reaction in step (1) comprises the following specific preparation steps:
the β -cyclodextrin and maleic anhydride powder which are ground and mixed evenly are placed in a conical flask to react for 8 hours at the temperature of 80 ℃, and a glass rod is used for stirring continuously in the initial reaction stage until the system becomes viscous.
3. The preparation method of the double sensitive slow release β -cyclodextrin hydrogel as claimed in claim 1, wherein the amidation reaction in step (2) comprises the following specific steps:
dissolving the maleic anhydride esterified β -cyclodextrin derivative prepared in the step (1) and diethanol amine in tetrahydrofuran, fully mixing, and reacting for 5 hours at the temperature of 60 ℃ and at the speed of 300 r/min.
4. The preparation method of the double sensitive slow release β -cyclodextrin hydrogel according to claim 1, wherein the β -cyclodextrin polymer of step (3) is prepared by the following steps:
stirring and mixing the amidated β -cyclodextrin derivative prepared in the step (2) with cholic acid and sodium hydroxide aqueous solution for 24h, adding epichlorohydrin, stirring for 45min, soaking with acetone for 30min, removing acetone, and standing for 8 h.
5. The preparation method of the double-sensitive slow-release β -cyclodextrin hydrogel according to claim 1, wherein the hydrogel prepared in step (4) is prepared by the following specific steps:
and (3) uniformly stirring the β -cyclodextrin polymer prepared in the step (3) with N-isopropylacrylamide, acrylic acid, ammonium persulfate, sodium sulfite and N, N-methylene bisacrylamide in distilled water, introducing nitrogen for 10min, and reacting for 8h at the temperature of 50 ℃.
6. The preparation method of the double-sensitive slow-release β -cyclodextrin hydrogel as claimed in claim 2, wherein the purification operation in step (1) is that after the reaction is finished, the solid is taken out, ground into powder, then washed with acetone and absolute ethyl alcohol fully, filtered and dried.
7. The method for preparing the double sensitive slow release β -cyclodextrin hydrogel as claimed in claim 3, wherein the purification operation in step (2) comprises precipitating the product with acetone as a precipitating agent, separating, and drying.
8. The preparation method of the double sensitive slow release β -cyclodextrin hydrogel as claimed in claim 4, wherein the purification operation in step (3) comprises neutralizing to neutrality with 6mol/L hydrochloric acid, precipitating with anhydrous ethanol as precipitant, separating, and drying.
9. The method for preparing the double sensitive slow release β -cyclodextrin hydrogel as claimed in claim 3, wherein the step 4 further comprises soaking the prepared β -cyclodextrin hydrogel in water for 24h, and drying.
10. The preparation method of the double sensitive slow release β -cyclodextrin hydrogel as claimed in claim 1, wherein the molar ratio of β -cyclodextrin to maleic anhydride in step (1) is 1:20, the molar ratio of the maleated β -cyclodextrin derivative to diethanolamine in step (1) in step (2) is 1:99, the molar ratio of the amidated β -cyclodextrin derivative to epichlorohydrin in step (2) in step (3) is 1:17, and the mass ratio of the β -cyclodextrin polymer to N-isopropylacrylamide in step (3) in step (4) is 1: 1.
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| CN115124729A (en) * | 2022-07-18 | 2022-09-30 | 华南理工大学 | Cross-linking agent based on beta-cyclodextrin and bile acid, and preparation method and application thereof |
| CN115336677A (en) * | 2022-09-22 | 2022-11-15 | 福州大昌盛饲料有限公司 | Preparation of cyclodextrin slow-release urea and application of cyclodextrin slow-release urea in aquaculture feed |
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