CN107987323B - Slow-release aerogel and indometacin-loaded slow-release aerogel - Google Patents
Slow-release aerogel and indometacin-loaded slow-release aerogel Download PDFInfo
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Abstract
The invention belongs to the technical field of drug sustained release and high polymer materials, and discloses a sustained release aerogel and a sustained release aerogel loaded with indometacin. Performing oxidation reaction on the nanocellulose and sodium periodate to obtain aldehyde nanocellulose, then dispersing the aldehyde nanocellulose in a solvent, and adding lysine for reaction to obtain lysine modified nanocellulose; dispersing the obtained product in an aqueous solution of cationic guar gum and polyvinyl alcohol, then sequentially adding an alkaline catalyst and a macromolecular cross-linking agent, standing at 25-70 ℃ for cross-linking polymerization reaction for 6-24 hours to obtain hydrogel, and neutralizing, soaking, washing, freezing and drying the obtained hydrogel to obtain the slow-release aerogel. And soaking the slow-release aerogel in an ammonia water solution of the indomethacin for swelling adsorption, taking out the slow-release aerogel after adsorption balance, and drying to obtain the indomethacin-loaded slow-release aerogel. According to the invention, through adding the lysine modified nano-cellulose, the prepared aerogel has adjustable load rate and slow release rate on indometacin.
Description
Technical Field
The invention belongs to the technical field of drug sustained release and high polymer materials, and particularly relates to a sustained-release aerogel and a sustained-release aerogel loaded with indometacin.
Background
The indomethacin is a lipophilic non-steroidal anti-inflammatory drug (the molecular structure of the indomethacin is shown in figure 1), has obvious effects of relieving heat and relieving inflammatory pain, is commonly used for treating acute and chronic rheumatoid arthritis, gouty arthritis and cancer pain (western medicine carcinoid pain drugs), causes obvious adverse reactions such as nausea, vomiting, abdominal pain, diarrhea and ulcer and sometimes gastric bleeding and perforation due to the indomethacin, therefore, the problems that the taking frequency of the drug is reduced, the acting time of the drug is prolonged, the slow release of the drug is realized, the tolerance of a patient is increased are solved, the solubility of the indomethacin in water is less than 1ug/m L due to poor solubility of the indomethacin, the bioavailability in a human body is low, the elimination speed in the body is high, the peak valley is easy to appear in blood concentration due to the fact that the indomethacin is dissolved in water is poor, the research is mainly focused on changing the crystal structure of the indomethacin in water by micronization and solid dispersion technology, the dissolution rate of the indomethacin in the blood is improved, the technologies generally adopt solvents such as acetone or ethanol, various dispersants such as PVP K30, polyethylene glycol, the degradability of polyethylene glycol 50/13 (stearic acid), the surfactant is rapidly synthesized by the polyethylene glycol, the surface of polysufagin, the polyethylene glycol, the nano-loaded nano-sodium indomethacin is not capable of being prepared by the nano-loaded nano-sodium alginate, the nano-based on the nano-loaded nano-particle, the nano-loaded nano-.
According to the record of the pharmacopoeia of the people's republic of China, the indomethacin mainly comprises the following components: indometacin enteric-coated tablet, cream, patch, capsule, etc. They have the characteristics that the dissolution rate and the dissolution rate are improved, the clinical dosage of the medicine is reduced, the irritation to the digestive tract is reduced, and the curative effect is improved. However, no patent reports the slow release of indomethacin and the application of a loading material. The technology that indometacin is loaded by utilizing the porous hydrogel with biodegradability can improve the loading rate and realize the controllable slow release of the indometacin is not reported.
Disclosure of Invention
Aiming at the defects and shortcomings of the prior art, the invention mainly aims to provide a preparation method of the slow-release aerogel.
The invention also aims to provide the slow-release aerogel prepared by the method.
The invention further aims to provide the indometacin-loaded sustained-release aerogel.
The invention further aims to provide a preparation method of the indometacin-loaded sustained-release aerogel.
The purpose of the invention is realized by the following technical scheme:
a preparation method of the sustained-release aerogel comprises the following preparation steps:
(1) carrying out oxidation reaction on the nano-cellulose and sodium periodate to obtain aldehyde nano-cellulose;
(2) dispersing the aldehyde nanocellulose obtained in the step (1) in a mixed solvent of dimethyl sulfoxide and water, adding lysine for reaction, adding sodium borohydride for reduction after the reaction is finished, and dialyzing with deionized water to obtain lysine modified nanocellulose;
(3) dispersing the lysine modified nanocellulose obtained in the step (2) in an aqueous solution of cationic guar gum and polyvinyl alcohol, uniformly stirring, then sequentially adding an alkaline catalyst and a macromolecular cross-linking agent, uniformly stirring and mixing, keeping the temperature at 25-70 ℃, standing for cross-linking polymerization reaction for 6-24 hours to obtain hydrogel, soaking and washing the hydrogel, and freeze-drying to obtain the slow-release aerogel.
The oxidation process of the oxidation reaction between the nano-cellulose and the sodium periodate in the step (1) is similar to that reported in the general literature. Preferably, the temperature of the oxidation reaction is between room temperature and 50 ℃, the reaction time is 2 to 13 hours, and higher temperature can bring about excessive oxidation of the nanocellulose, so that the molecular weight is greatly reduced. The reaction adopts weak acid buffer solution, and the pH value is between 4 and 5.
Preferably, the temperature of the lysine adding reaction in the step (2) is 30-60 ℃, and the time is 0.5-8 h; more preferably, the reaction temperature is 50 ℃ and the reaction time is 4 hours.
Preferably, the mass ratio of the lysine to the aldehyde nanocellulose in the step (2) is (0.5-2) to 1; more preferably at a mass ratio of 1: 1.
Preferably, the mass ratio of the lysine modified nanocellulose to the cationic guar gum in the step (3) is (0.1-0.4): 1; the mass ratio of the polyvinyl alcohol to the cationic guar gum is (0.1-0.5): 1.
Preferably, the basic catalyst in step (3) is selected from sodium hydroxide, potassium hydroxide, tetramethylammonium hydroxide, hydrazine hydrate, and the like.
Preferably, the macromolecular crosslinking agent in step (3) is selected from polyethylene glycol diglycidyl ether or polypropylene glycol diglycidyl ether; the addition amount of the macromolecular cross-linking agent is 0.1-0.5 times of the mass of the cationic guar gum.
A sustained-release aerogel is prepared by the above method.
An indometacin-loaded sustained-release aerogel is obtained by loading indometacin on the sustained-release aerogel.
The preparation method of the indometacin-loaded sustained-release aerogel comprises the following steps:
and soaking the slow-release aerogel in an ammonia water solution of the indomethacin for swelling adsorption, taking out the slow-release aerogel after adsorption balance, and drying to obtain the indomethacin-loaded slow-release aerogel.
Preferably, the concentration of the ammonia water solution is 0.02-1.0M; the soaking time is 2-24 h.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) the prior art mainly relates to the improvement of the dissolution rate and the bioavailability of the indometacin, and does not relate to the slow release behavior of the indometacin. The invention obtains the lysine modified nano-cellulose based on the derivatization reaction of the nano-cellulose, and the nitrogen content of the nano-cellulose is measured to be up to 2 percent through element analysis. As the amino acid group is linked to the nanocellulose, the nanocellulose is endowed with amphiphilicity; and compounding the derivatized nano-cellulose, cationic guar gum and polyvinyl alcohol, preparing interpenetrating network hydrogel with excellent performance through various chemical crosslinking, and freeze-drying to obtain the aerogel material with excellent strength. The preparation process of the aerogel material is green and environment-friendly, the conditions are mild, the used materials are all easily biodegradable, and the aerogel material is safe and non-toxic and has no harm to human bodies.
(2) The aerogel is soaked in a low-concentration ammonia water solution, the hydrogel swells, and indometacin dissolved in the ammonia water diffuses in pore channels of the hydrogel and is adsorbed to active sites of the hydrogel by various chemical or physical actions. Therefore, the indometacin is loaded by the ammonia water medium, the loading efficiency is high, the ammonia water is easy to volatilize, and the post-treatment is not needed.
(3) The aerogel material loaded with indometacin has different slow release behaviors under different pH values and shows certain pH sensitivity. By adjusting the content of the nano-cellulose-lysine derivative, the prepared aerogel has adjustable indometacin loading rate and slow release rate.
Drawings
FIG. 1 is a molecular structural formula of indomethacin.
Fig. 2 is an infrared spectrum of Nanocellulose (NFC), aldehyde nanocellulose (NFC-CHO-H), and lysine-modified nanocellulose (NFC-c-lysine-H) in example 1 of the present invention.
Fig. 3 is a product morphology diagram of indomethacin-loaded tawny slow-release aerogel (d) finally obtained from the tawny hydrogel (c) obtained by cross-linking polymerization of white nanocellulose (a), tawny lysine-modified nanocellulose (b) in example 1 of the present invention.
Fig. 4 is a slow release kinetic curve diagram of the indomethacin-loaded aerogel products obtained in examples 1 to 2 and comparative examples 1 to 2 of the present invention.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the present invention is not limited thereto.
Example 1
(1) Dispersing 1g of nano-cellulose raw material in 0.1M acetic acid buffer solution (pH 4.5) to obtain 1% viscous solution, adding 0.8g of sodium periodate, stirring uniformly, reacting at 40 ℃ for 10h, adding 2ml of ethylene glycol to terminate the reaction, and dialyzing for 2 days by using a large amount of water to obtain the purified aldehyde nano-cellulose. And (3) performing freeze drying treatment to obtain the white aldehyde nanocellulose. The whole reaction was carried out in a three-necked flask, which was wrapped with black paper to protect from light.
(2) Adding the aldehyde nanocellulose (with absolute dry mass of 0.5g) obtained in the step (1) into a mixed solvent consisting of 9m L DMSO and 1m L water, soaking to fully swell the material, then adding 0.5g of lysine solid, reacting at 50 ℃ for 4 hours to change the color of the material from colorless to brown, cooling the reaction material to room temperature, adding 0.5g of sodium borohydride alcohol solution to reduce the generated imine group (C ═ N) into amino, and finally dialyzing the product solution with a large amount of deionized water to obtain the lysine modified nanocellulose.
The infrared spectra of the Nanocellulose (NFC), the aldehyde nanocellulose (NFC-CHO-H), and the lysine-modified nanocellulose (NFC-c-lysine-H) in this example are shown in fig. 2. As can be seen from FIG. 2, 1725cm appears on the spectrum of the aldehyde nano-cellulose-1The peak of aldehyde group of lysine modified nano-cellulose appears to be 1580cm-1Indicating that lysine is attached to the nanocellulose.
(3) Dispersing the lysine modified nanocellulose (with an absolute dry mass of 0.25g) obtained in the step (2) into an aqueous solution containing 2g of cationic guar gum and 0.2g of polyvinyl alcohol, stirring at a high speed to obtain a viscous white solution, adding an aqueous solution of sodium hydroxide (containing 0.2g of sodium hydroxide and 0.2g of water), continuing to stir for 5min, adding an anhydrous alcohol solution of polyethylene glycol diglycidyl ether (1.0g of polyethylene glycol diglycidyl ether and 10M L of anhydrous alcohol), continuing to stir for 0.5h, stopping stirring, allowing the reactant to stand at 60 ℃ for crosslinking polymerization for 12h to obtain a hydrogel with good elasticity, soaking the hydrogel in deionized water, adding a few drops of 0.5M acetic acid solution, neutralizing the residual sodium hydroxide, and finally freeze-drying the hydrogel sample to obtain the aerogel slow release.
(4) Loading of indomethacin: and (3) soaking the slow-release aerogel obtained in the step (3) in a weak ammonia water solution of the indomethacin, wherein the concentration of ammonia water is 1.0M, taking out the expanded hydrogel after soaking and adsorption for 12 hours, and naturally drying to obtain the indomethacin-loaded slow-release aerogel product. The loading rate of the indometacin is 65%.
The product morphology of the nanocellulose (a), the lysine modified nanocellulose (b), the hydrogel (c) obtained by crosslinking polymerization reaction and the indometacin-loaded sustained-release aerogel (d) in this example is shown in fig. 3. As seen from figure 3, the nanocellulose is pure white loose, the lysine modified nanocellulose is light yellow loose solid, the hydrogel obtained by the crosslinking polymerization reaction is yellow brown and has certain elasticity, the indometacin-loaded slow-release aerogel is darker in color, is more loose and porous, and has reduced strength.
The slow release performance of the indometacin-loaded slow release aerogel obtained in the example is tested as follows:
the prepared indometacin-loaded slow-release aerogel material is soaked in a simulated aqueous solution with the pH value of 7.4, and the release rate of the material is tested. The sustained release kinetics graph is shown in fig. 4.
Example 2
Step (1) was the same as in example 1.
(2) Adding the aldehyde nanocellulose (with absolute dry mass of 0.5g) obtained in the step (1) into a mixed solvent consisting of 9m L DMSO and 1m L water, soaking to fully swell the material, adding 1.0g of lysine solid, reacting at 60 ℃ for 8 hours to change the color of the material from colorless to brown, cooling the reaction material to room temperature, adding 0.5g of sodium borohydride alcohol solution to reduce generated imine groups (C ═ N) into amino groups, and dialyzing the product solution with a large amount of deionized water to obtain the lysine modified nanocellulose.
(3) Dispersing the lysine modified nanocellulose (with an absolute dry mass of 0.4g) obtained in the step (2) in an aqueous solution containing 1.6g of cationic guar gum and 0.2g of polyvinyl alcohol, stirring at a high speed to obtain a viscous white solution, adding an aqueous solution of sodium hydroxide (containing 0.2g of sodium hydroxide and 0.2g of water), continuing to stir for 5min, adding an ethanol solution of polyethylene glycol diglycidyl ether (0.4g of polyethylene glycol diglycidyl ether and 10M L of anhydrous ethanol), continuing to stir for 0.5h, stopping stirring, allowing the reactant to stand at 70 ℃ for crosslinking polymerization for 8h to obtain hydrogel with good elasticity, soaking the hydrogel in deionized water, adding a few drops of 0.5M acetic acid solution, neutralizing the residual sodium hydroxide, and finally freeze-drying the hydrogel sample to obtain the aerogel slow release.
(4) Loading of indomethacin: and (3) soaking the slow-release aerogel obtained in the step (3) in a weak ammonia water solution of the indomethacin, wherein the concentration of ammonia water is 1.0M, taking out the expanded hydrogel after soaking and adsorption for 12 hours, and naturally drying to obtain the indomethacin-loaded slow-release aerogel product. The data show that the loading rate of the indometacin loaded on the indometacin is 70%.
The slow release performance of the indometacin-loaded slow release aerogel obtained in the example is tested as follows:
the prepared indometacin-loaded slow-release aerogel material is soaked in a simulated aqueous solution with the pH value of 7.4, and the release rate of the material is tested. The sustained release kinetics graph is shown in fig. 4.
Example 3
Step (1) was the same as in example 1.
(2) Adding the aldehyde nanocellulose (with absolute dry mass of 0.5g) obtained in the step (1) into a mixed solvent consisting of 9m L DMSO and 1m L water, soaking to fully swell the material, adding 0.25g of lysine white solid, reacting at 30 ℃ for 4 hours to change the color of the material from colorless to brown, cooling the reaction material to room temperature, adding 0.5g of sodium borohydride alcohol solution to reduce the generated imine group (C ═ N) into amino, and finally dialyzing the product solution with a large amount of deionized water to obtain the lysine modified nanocellulose.
(3) Dispersing the lysine modified nanocellulose (with the absolute dry mass of 0.2g) obtained in the step (2) into an aqueous solution containing 2g of cationic guar gum and 0.2g of polyvinyl alcohol, stirring at a high speed to obtain a viscous white solution, adding an aqueous solution of sodium hydroxide (containing 0.2g of sodium hydroxide and 0.2g of water), continuing stirring for 5min, adding 0.5g of polypropylene glycol diglycidyl ether, continuing stirring for 0.5h, stopping stirring, and allowing the reactant to stand at 30 ℃ for crosslinking polymerization reaction for 12h to obtain the hydrogel with good elasticity. The hydrogel was soaked in deionized water and a few drops of 0.5M acetic acid solution were added to neutralize the remaining sodium hydroxide. And finally, freeze-drying the hydrogel sample to obtain the slow-release aerogel. The lysine modified nanocellulose was 10% of the mass of the cationic guar gum in this example.
(4) Loading of indomethacin: and (3) soaking the slow-release aerogel obtained in the step (3) in a weak ammonia water solution of the indomethacin, wherein the concentration of ammonia water is 0.02M, taking out the expanded hydrogel after sealed soaking and adsorption for 24 hours, and naturally drying to obtain the indomethacin-loaded slow-release aerogel product. The data show that the loading rate of the indometacin loaded on the indometacin is 70%.
The slow release performance of the indometacin-loaded slow release aerogel obtained in the example is tested as follows:
the prepared indometacin-loaded slow-release aerogel material is soaked in a simulated aqueous solution with the pH value of 7.4, and the release rate of the material is tested. The data show a cumulative release rate of 17% over 20 h.
Example 4
Step (1) was the same as in example 1.
(2) Adding the aldehyde nanocellulose (with absolute dry mass of 0.5g) obtained in the step (1) into a mixed solvent consisting of 8m L DMSO and 2m L water, soaking to fully swell the material, adding 0.8g of lysine solid, reacting at 60 ℃ for 4 hours to change the color of the material from colorless to brown, cooling the reaction material to room temperature, adding 0.8g of sodium borohydride alcohol solution to reduce generated imine groups (C ═ N) into amino groups, and finally dialyzing the product solution with a large amount of deionized water to obtain the lysine modified nanocellulose, wherein the nitrogen content of the product solution is higher than that of the nanocellulose obtained in the example 2.
(3) Dispersing the lysine modified nanocellulose (with the absolute dry mass of 0.2g) obtained in the step (2) into an aqueous solution containing 2g of cationic guar gum and 0.2g of polyvinyl alcohol, stirring at a high speed to obtain a viscous white solution, adding an aqueous solution of sodium hydroxide (containing 0.2g of sodium hydroxide and 0.2g of water), continuing stirring for 5min, adding 1.2g of polypropylene glycol diglycidyl ether, continuing stirring for 1.0h, stopping stirring, and allowing the reactant to stand at 60 ℃ for crosslinking polymerization reaction for 12h to obtain the hydrogel with good elasticity. The hydrogel was soaked in deionized water and a few drops of 0.5M acetic acid solution were added to neutralize the remaining sodium hydroxide. And finally, freeze-drying the hydrogel sample to obtain the slow-release aerogel. The lysine modified nanocellulose was 10% of the mass of the cationic guar gum in this example.
(4) Loading of indomethacin: and (3) soaking the slow-release aerogel obtained in the step (3) in a weak ammonia water solution of the indomethacin, wherein the concentration of ammonia water is 0.05M, taking out the expanded hydrogel after soaking and adsorption for 16h, and naturally drying to obtain the indomethacin-loaded slow-release aerogel product. The data show that the loading rate of the indometacin is 62%.
The slow release performance of the indometacin-loaded slow release aerogel obtained in the example is tested as follows:
the prepared indometacin-loaded slow-release aerogel material is soaked in a simulated aqueous solution with the pH value of 7.4, and the release rate of the material is tested. The data show a 10h cumulative release of 10%.
Example 5
Step (1) was the same as in example 1.
(2) Adding the aldehyde nanocellulose (with absolute dry mass of 0.5g) obtained in the step (1) into a mixed solvent consisting of 9m L DMSO and 1m L water, soaking to fully swell the material, adding 0.25g of lysine solid, reacting at 50 ℃ for 4 hours to change the color of the material from colorless to brown, cooling the reaction material to room temperature, adding 0.5g of sodium borohydride alcohol solution to reduce generated imine groups (C ═ N) into amino groups, and dialyzing the product solution with a large amount of deionized water to obtain the lysine modified nanocellulose.
(3) Dispersing the lysine modified nanocellulose (with the absolute dry mass of 0.2g) obtained in the step (2) into an aqueous solution containing 2g of cationic guar gum and 0.2g of polyvinyl alcohol, stirring at a high speed to obtain a viscous white solution, adding an aqueous solution of sodium hydroxide (containing 0.2g of sodium hydroxide and 0.2g of water), continuing stirring for 5min, adding 1.0g of polyethylene glycol diglycidyl ether, continuing stirring for 0.5h, stopping stirring, and allowing the reactant to stand at 50 ℃ for crosslinking polymerization reaction for 16h to obtain the hydrogel with good elasticity. The hydrogel was soaked in deionized water and a few drops of 0.5M acetic acid solution were added to neutralize the remaining sodium hydroxide. And finally, freeze-drying the hydrogel sample to obtain the slow-release aerogel. The lysine modified nanocellulose was 10% of the mass of the cationic guar gum in this example.
(4) Loading of indomethacin: and (3) soaking the slow-release aerogel obtained in the step (3) in a weak ammonia water solution of the indomethacin, wherein the concentration of ammonia water is 0.8M, taking out the expanded hydrogel after soaking and adsorption for 12 hours, and naturally drying to obtain the indomethacin-loaded slow-release aerogel product. The data show that the loading rate of the indometacin is 68%.
The slow release performance of the indometacin-loaded slow release aerogel obtained in the example is tested as follows:
the prepared indometacin-loaded slow-release aerogel material is soaked in a simulated aqueous solution with the pH value of 7.4, and the release rate of the material is tested. The data show a cumulative release rate of 15% over 20 h.
Comparative example 1
(1) Dispersing nanocellulose (absolute dry mass 0.4g) in an aqueous solution containing 1.6g of cationic guar gum and 0.8g of polyvinyl alcohol, stirring at high speed to obtain a viscous white solution, adding an aqueous solution of sodium hydroxide (containing 0.2g of sodium hydroxide and 0.2g of water), continuing to stir for 5min, adding an ethanol solution of polyethylene glycol diglycidyl ether (0.4g of polyethylene glycol diglycidyl ether and 10M L of absolute ethanol), continuing to stir for 0.5h, stopping stirring, allowing the reaction to stand at 70 ℃ for crosslinking polymerization for 8h to obtain hydrogel, soaking the hydrogel in deionized water, adding a few drops of 0.5M acetic acid solution, neutralizing the remaining sodium hydroxide, and finally freeze-drying the hydrogel sample to obtain aerogel, wherein the nanocellulose is 25% by mass of the cationic guar gum in this example.
(2) Loading of indomethacin: and (2) soaking the aerogel obtained in the step (1) in a weak ammonia water solution of indomethacin, wherein the concentration of ammonia water is 1.0M, taking out the expanded hydrogel after soaking and adsorption for 12h, and naturally drying to obtain an indomethacin-loaded aerogel product.
The slow release performance test of the aerogel loaded with the indometacin obtained in the comparative example comprises the following steps:
the prepared indomethacin-loaded aerogel material was soaked in a simulated aqueous solution of ph7.4 and tested for release rate. The sustained release kinetics graph is shown in fig. 4.
Comparative example 2
(1) Stirring and mixing an aqueous solution containing 1.6g of cationic guar gum and 0.8g of polyvinyl alcohol uniformly, adding an aqueous solution of sodium hydroxide (containing 0.2g of sodium hydroxide and 0.2g of water), continuing stirring for 5min, adding an ethanol solution of polyethylene glycol diglycidyl ether (0.4g of polyethylene glycol diglycidyl ether and 10M L of absolute ethanol), continuing stirring for 0.5h, stopping stirring, allowing the reaction product to stand at 70 ℃ for crosslinking polymerization for 8h to obtain hydrogel, soaking the hydrogel in deionized water, adding a few drops of 0.5M acetic acid solution, neutralizing the residual sodium hydroxide, and finally freeze-drying a hydrogel sample to obtain the aerogel.
(2) Loading of indomethacin: and (2) soaking the aerogel obtained in the step (1) in a weak ammonia water solution of indomethacin, wherein the concentration of ammonia water is 1.0M, taking out the expanded hydrogel after soaking and adsorption for 12h, and naturally drying to obtain an indomethacin-loaded aerogel product.
The slow release performance test of the aerogel loaded with the indometacin obtained in the comparative example comprises the following steps:
the prepared indomethacin-loaded aerogel material was soaked in a simulated aqueous solution of ph7.4 and tested for release rate. The sustained release kinetics graph is shown in fig. 4.
From the results of fig. 4, it can be seen that the aerogels prepared in example 1 and example 2 respectively contain 12.5% and 25% of lysine modified nanocellulose, and the slow release rate thereof is significantly lower than that of the aerogels prepared in comparative example 1 (containing nanocellulose, cationic guar gum and polyvinyl alcohol) and comparative example 2 (only cationic guar gum and polyvinyl alcohol), which indicates that the release of indomethacin is effectively controlled, and the reason for analyzing is that lysine is grafted into the molecular chain of nanocellulose, and the adhesion of lysine to the drug is improved.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (6)
1. A preparation method of indometacin-loaded sustained-release aerogel is characterized by comprising the following steps:
(1) carrying out oxidation reaction on the nano-cellulose and sodium periodate to obtain aldehyde nano-cellulose;
(2) dispersing the aldehyde nanocellulose obtained in the step (1) in a mixed solvent of dimethyl sulfoxide and water, adding lysine for reaction, adding sodium borohydride for reduction after the reaction is finished, and dialyzing with deionized water to obtain lysine modified nanocellulose;
(3) dispersing the lysine modified nanocellulose obtained in the step (2) in an aqueous solution of cationic guar gum and polyvinyl alcohol, uniformly stirring, then sequentially adding an alkaline catalyst and a macromolecular cross-linking agent, uniformly stirring and mixing, keeping the temperature at 25-70 ℃, standing for cross-linking polymerization reaction for 6-24 hours to obtain hydrogel, soaking and washing the hydrogel, and freeze-drying to obtain the slow-release aerogel;
(4) soaking the slow-release aerogel in an ammonia water solution of indomethacin for swelling adsorption, taking out after adsorption is balanced, and drying to obtain the indomethacin-loaded slow-release aerogel;
the mass ratio of the lysine modified nanocellulose to the cationic guar gum in the step (3) is (0.1-0.4): 1; the mass ratio of the polyvinyl alcohol to the cationic guar gum is (0.1-0.5): 1;
the alkaline catalyst in the step (3) is selected from sodium hydroxide, potassium hydroxide, tetramethyl ammonium hydroxide or hydrazine hydrate; the macromolecular crosslinking agent is selected from polyethylene glycol diglycidyl ether or polypropylene glycol diglycidyl ether; the addition amount of the macromolecular cross-linking agent is 0.1-0.5 times of the mass of the cationic guar gum.
2. The preparation method of the indomethacin-loaded slow-release aerogel as claimed in claim 1, is characterized in that: the temperature of the oxidation reaction in the step (1) is room temperature to 50 ℃, the reaction time is 2 to 13 hours, and the reaction pH is carried out in a weak acid buffer solution with the pH value of 4 to 5.
3. The preparation method of the indomethacin-loaded slow-release aerogel as claimed in claim 1, is characterized in that: and (3) adding lysine to react at the temperature of 30-60 ℃ for 0.5-8 h in the step (2).
4. The preparation method of the indomethacin-loaded slow-release aerogel as claimed in claim 1, is characterized in that: in the step (2), the mass ratio of lysine to aldehyde nanocellulose is (0.5-2) to 1.
5. The preparation method of the indomethacin-loaded slow-release aerogel as claimed in claim 1, is characterized in that: the concentration of the ammonia water solution is 0.02-1.0M; the soaking time is 2-24 h.
6. The slow-release aerogel loaded with indometacin is characterized in that: prepared by the method of any one of claims 1 to 5.
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Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63222112A (en) * | 1987-03-10 | 1988-09-16 | Nippon Soda Co Ltd | Sustained release granule |
| CN1771939A (en) * | 2005-11-04 | 2006-05-17 | 陈茜 | Indomethacin dripping pill and its prepn |
| CN102786642A (en) * | 2012-08-10 | 2012-11-21 | 南京林业大学 | Nanometer cellulose/polyvinyl alcohol gel composite material |
| CN103099795A (en) * | 2012-12-07 | 2013-05-15 | 深圳市国源药业有限公司 | Indometacin sustained release tablet, preparation method thereof, as well as release controlling method and standard |
| CN103145914A (en) * | 2013-03-25 | 2013-06-12 | 湖南工业大学 | Preparation method of high-strength nano-composite hydrogel with rapid dual responses of pH and temperature |
| CN103520739A (en) * | 2013-10-22 | 2014-01-22 | 东北林业大学 | Self-assembly compound system of cellulose nanometer fibril and indometacin and preparation method of self-assembly compound system |
| CN103665439A (en) * | 2013-11-22 | 2014-03-26 | 东华大学 | Stimuli-responsive composite material made from bacterial nano cellulose as well as preparation method and application of stimuli-responsive composite material |
| CN104086785A (en) * | 2014-06-20 | 2014-10-08 | 华南理工大学 | Method for preparing composite hydrogel through modifying bamboo shoot leftovers and application of composite hydrogel |
| CN104984759A (en) * | 2015-07-17 | 2015-10-21 | 中国林业科学研究院林产化学工业研究所 | Nanometer cellulose supported nanometer palladium catalyst and preparation method thereof |
| CN105153438A (en) * | 2015-10-27 | 2015-12-16 | 南京林业大学 | Preparation method of high-strength high-swelling nanocellulose and polyving akohol composite hydrogel |
| CN106076283A (en) * | 2016-06-11 | 2016-11-09 | 华南理工大学 | A kind of nano-cellulose/poly-dopamine hydrogel adsorbent and preparation method and application |
| CN107028896A (en) * | 2017-04-26 | 2017-08-11 | 盐城工业职业技术学院 | A kind of carried medicine sustained-release system and medicine |
| CN107177049A (en) * | 2017-05-23 | 2017-09-19 | 佛山市因诺维生物科技有限公司 | A kind of HPG nano cellulose composite film and preparation method thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050037082A1 (en) * | 2003-08-13 | 2005-02-17 | Wan-Kei Wan | Poly(vinyl alcohol)-bacterial cellulose nanocomposite |
-
2017
- 2017-11-13 CN CN201711112948.6A patent/CN107987323B/en active Active
Patent Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63222112A (en) * | 1987-03-10 | 1988-09-16 | Nippon Soda Co Ltd | Sustained release granule |
| CN1771939A (en) * | 2005-11-04 | 2006-05-17 | 陈茜 | Indomethacin dripping pill and its prepn |
| CN102786642A (en) * | 2012-08-10 | 2012-11-21 | 南京林业大学 | Nanometer cellulose/polyvinyl alcohol gel composite material |
| CN103099795A (en) * | 2012-12-07 | 2013-05-15 | 深圳市国源药业有限公司 | Indometacin sustained release tablet, preparation method thereof, as well as release controlling method and standard |
| CN103145914A (en) * | 2013-03-25 | 2013-06-12 | 湖南工业大学 | Preparation method of high-strength nano-composite hydrogel with rapid dual responses of pH and temperature |
| CN103520739A (en) * | 2013-10-22 | 2014-01-22 | 东北林业大学 | Self-assembly compound system of cellulose nanometer fibril and indometacin and preparation method of self-assembly compound system |
| CN103665439A (en) * | 2013-11-22 | 2014-03-26 | 东华大学 | Stimuli-responsive composite material made from bacterial nano cellulose as well as preparation method and application of stimuli-responsive composite material |
| CN104086785A (en) * | 2014-06-20 | 2014-10-08 | 华南理工大学 | Method for preparing composite hydrogel through modifying bamboo shoot leftovers and application of composite hydrogel |
| CN104984759A (en) * | 2015-07-17 | 2015-10-21 | 中国林业科学研究院林产化学工业研究所 | Nanometer cellulose supported nanometer palladium catalyst and preparation method thereof |
| CN105153438A (en) * | 2015-10-27 | 2015-12-16 | 南京林业大学 | Preparation method of high-strength high-swelling nanocellulose and polyving akohol composite hydrogel |
| CN106076283A (en) * | 2016-06-11 | 2016-11-09 | 华南理工大学 | A kind of nano-cellulose/poly-dopamine hydrogel adsorbent and preparation method and application |
| CN107028896A (en) * | 2017-04-26 | 2017-08-11 | 盐城工业职业技术学院 | A kind of carried medicine sustained-release system and medicine |
| CN107177049A (en) * | 2017-05-23 | 2017-09-19 | 佛山市因诺维生物科技有限公司 | A kind of HPG nano cellulose composite film and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| 赖氨酸改性纳米纤维素基水凝胶的制备及对吲哚美辛的缓释行为研究;刘宝联;《中国知网》;20191113;第15-58页 * |
| 赖氨酸改性纳米纤维素的表征及其对亚甲基蓝的吸附行为研究;万小芳等;《中国造纸》;20170515;第36卷(第5期);第7-13页 * |
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