CN111228213A - Preparation method and application of biocompatible nano composite hydrogel - Google Patents
Preparation method and application of biocompatible nano composite hydrogel Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
Abstract
The invention discloses a preparation method and application of a biocompatible nano composite hydrogel. According to the method, firstly, a eutectic solvent is combined with a wet ball milling process to extract nanofibrillated cellulose from cotton fiber powder, and then sodium alginate and chitosan are used as raw materials, nanofibrillated cellulose is used as a reinforcing phase, and the nano composite hydrogel is prepared based on an electrostatic effect, a hydrogen bond effect and a biomass nano effect. And the sodium alginate/chitosan/nano fibrillated cellulose composite hydrogel is used for loading the indometacin drug, so that the slow release effect of the indometacin drug is realized. The preparation method disclosed by the invention is simple in preparation process and rich in material source, and the prepared composite hydrogel is in a porous three-dimensional network structure, the porosity is maintained above 90%, the swelling rate reaches 1321%, and the composite hydrogel shows good mechanical properties; meanwhile, the hydrogel has pH sensitivity to the release of indometacin model drugs, and shows slow release property.
Description
Technical Field
The invention relates to the field of composite materials, in particular to a preparation method and application of a biocompatible nano composite hydrogel.
Background
The hydrogel is a functional polymer material which is formed by properly crosslinking natural polymers or synthetic polymers and has a three-dimensional network structure. It is insoluble in water, but can swell in water obviously, absorb a large amount of water and has strong water-retaining capacity. The smart hydrogel can sense small changes of external environment, such as pH value, temperature, ionic strength, magnetic field, electric field and the like, and rapidly respond to the stimuli through volume swelling or contraction.
Sodium alginate has low cost due to its biocompatibility, biodegradability and addition of divalent cation (such as Ca)2+) And the material with good gelling property is often used as a material for preparing hydrogel. Sodium alginate crosslinks with calcium ions mildly and quickly, but is generally weaker in strength. Because calcium ions belong to small molecules, when the calcium ions are crosslinked with sodium alginate, one calcium ion is generally reacted with two carboxyl groups on a molecular chain of the sodium alginate, and the crosslinking density is low, so that the application of the hydrogel is limited.
Cellulose is currently the most abundant and renewable resource on earth, nanofibrillated cellulose, one of nanocelluloses, consists of orderly separated bundles of elementary fibers with a high probability of forming entangled networks. According to different plant raw material types, the diameter of the nanofibrillated cellulose is 10-100 nm, and the length is micron-sized.
The nanofibrillated cellulose is mainly obtained by mechanically strong shearing force processing cellulose raw material, the amorphous area of the cellulose is not usually removed in the processing process, and the final nanofibrillated cellulose is still composed of crystalline area and amorphous area; compared with the nano microcrystalline cellulose, the nano microcrystalline cellulose has larger length-diameter ratio and better flexibility. The nanofibrillated cellulose has the characteristics of wide source, reproducibility, degradability, no toxicity and the like of common cellulose, and also has the advantages of obvious barrier property, mechanical property, colloid property, large specific surface area, low density, transparency and the like, and the properties enable the nanofibrillated cellulose to have wide application prospects in the fields of papermaking, composite materials, packaging, coatings, biomedicine, automobiles and the like.
With the development of production and science and technology, a novel composite hydrogel material with high performance, high biocompatibility and green color is the development direction of a high-molecular hydrogel material. Therefore, the invention aims to research a preparation method of the biocompatible nano composite hydrogel, the nano fibrillated cellulose with wide source, large specific surface area and excellent biocompatibility is used as a reinforcing phase, the nano composite hydrogel is prepared based on electrostatic action, hydrogen bond action and nano filler, the nano composite hydrogel is applied to loading of indometacin medicaments, the aim of medicament slow release is achieved, a new thought is developed for the preparation and application of the biocompatible nano composite hydrogel, and the preparation method has certain theoretical significance and application value.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a preparation method and application of a biocompatible nano composite hydrogel.
The invention is realized by the following technical scheme:
a method for preparing a biocompatible nanocomposite hydrogel comprises the following steps:
(1) firstly, choline chloride and oxalic acid are weighed according to the molar ratio of 1:2 and placed in a three-neck flask, and the three-neck flask is heated and stirred in oil bath at 90 ℃ for half an hour to obtain a clear and transparent eutectic solvent. Secondly, adding the cotton fiber powder into the eutectic solvent with the solid-to-liquid ratio of 1:20, and carrying out purification pretreatment for 1-5 hours at 100-120 ℃. And then, washing with deionized water and absolute ethyl alcohol to remove the residual eutectic solvent to obtain the purified cellulose. And then, directly adding the purified cellulose into a ball milling tank for wet ball milling for 12-20 h, and then carrying out centrifugal separation for 8min at 8000r/min for 5 times. Finally, the nanofibrillated cellulose colloid with the mass concentration of 2 percent is prepared through rotary evaporation.
(2) Firstly, a certain volume of nano fibrillated cellulose colloid is taken to be dispersed in deionized water, and ultrasonic dispersion is carried out for a certain time by ultrasonic waves. Secondly, weighing a certain amount of sodium alginate powder, adding the sodium alginate powder into the aqueous dispersion of the nanofibrillated cellulose, and dispersing for a certain time by using a high-speed dispersion machine. Thirdly, weighing a certain amount of chitosan powder, adding the chitosan powder into the mixed solution, continuously dispersing for a certain time by using a high-speed dispersion machine, placing the mixture in a vacuum drying oven, vacuumizing and defoaming for a certain time to prepare the mixed solution of sodium alginate/chitosan/nanofibrillated cellulose. Subsequently, a certain amount of the sodium alginate/chitosan/nanofibrillated cellulose mixed solution was extracted by a disposable syringe with a cut head and left to stand in 2mol/l dilute hydrochloric acid for 24 hours. And finally, extruding the hydrogel in the disposable syringe, soaking the hydrogel in deionized water for 3 days, and cleaning residual hydrochloric acid on the surface to prepare the sodium alginate/chitosan/nanofibrillated cellulose nano composite hydrogel.
Further, the adding proportion of the sodium alginate/chitosan/nanofibrillated cellulose in the step (2) is that the mass ratio of the sodium alginate to the chitosan is 1: 1; the total mass of the added sodium alginate and chitosan is taken as a reference M, and the addition amount of the nanofibrillated cellulose is 0.5-2% M.
Further, the ultrasonic dispersion ultrasonic intensity in the step (2) is 300W, and the ultrasonic time is 30 min; the primary high-speed dispersion speed is 650r/min, and the time is 1 h; the secondary high-speed dispersion speed is 650r/min, and the time is 2 h; vacuum defoaming time is 3 h.
Further, the sodium alginate/chitosan/nanofibrillated cellulose composite hydrogel prepared in the step (2) is in a porous three-dimensional network structure, the porosity is maintained above 90%, and the swelling rate reaches 1321%.
Further, the application of the biocompatible nano composite hydrogel comprises the following steps: the sodium alginate/chitosan/nanofibrillated cellulose composite hydrogel is used for loading the indometacin medicine. Weighing a certain mass of indomethacin, dissolving the indomethacin in 20ml of ammonia water, and performing ultrasonic treatment to obtain indomethacin solutions (1, 3, 5 and 7mg/ml) with different concentrations. And (2) soaking the sodium alginate/chitosan/nanofibrillated cellulose composite hydrogel in 20ml of indomethacin solution for 24 hours, taking out the indomethacin solution, and drying the indomethacin solution in a 50-DEG C drying oven to obtain the indomethacin-loaded sodium alginate/chitosan/nanofibrillated cellulose composite hydrogel.
Furthermore, the sodium alginate/chitosan/nanofibrillated cellulose hydrogel prepared in the drug sustained release application of the biocompatible nano composite hydrogel has pH sensitivity to the release of indometacin model drugs, shows the slow release property and has the release time of 12-24 hours; in addition, the release amount and release rate of the indomethacin are obviously changed by changing the adding amount of the nanofibrillated cellulose. When the amount of nanofibrillated cellulose added was 1%, the release in simulated gastric fluid was reduced by 50.8%. Through the research of a drug release mechanism, the release of the sodium alginate/chitosan/nano fibrillated cellulose composite hydrogel in simulated human gastrointestinal fluid accords with a zero-order drug release model and an R-P model in the simulated intestinal fluid.
The invention has the beneficial effects that:
the invention takes nanofibrillated cellulose as a reinforcing phase and prepares nano composite hydrogel based on electrostatic action, hydrogen bond action and nano filler. On one hand, chitosan powder is swelled but not dissolved in the sodium alginate/chitosan nano fibrillated cellulose mixed solution, when the chitosan/sodium alginate nano fibrillated cellulose mixed solution is soaked in hydrochloric acid, the hydrochloric acid is equivalent to a small molecule 'initiator', the hydrochloric acid is rapidly diffused, the chitosan is dissolved, amino molecules on a molecular chain are protonated to generate ammonium ions, and the ammonium ions and carboxylate ions on the molecular chain of the sodium alginate are subjected to electrostatic interaction to form a three-dimensional network structure; meanwhile, the nanofibrillated cellulose is added as a filler due to the nanometer size and high mechanical property, so that a three-dimensional network is more compact; and the surface of the nanofibrillated cellulose is negatively charged, so that hydrogen bonds are easily formed with sodium alginate in an acid environment, and the overall mechanical property of the composite hydrogel is more excellent under the action of static electricity and hydrogen bonds. On the other hand, the composite hydrogel has certain pH response capability and has the potential of drug loading and slow release. The addition of the nanofibrillated cellulose is beneficial to reducing the release of the indomethacin medicament in gastric juice and weakening the side effect of the indomethacin medicament on the stomach. The invention has the advantages of easily obtained raw materials, simple preparation process and low production cost, and is beneficial to industrial production.
Drawings
FIG. 1 is a schematic diagram of the mechanism of formation of a biocompatible nanocomposite hydrogel;
figure 2 micro-topography of biocompatible nanocomposite hydrogels at different nanofibrillated cellulose (NFC) addition levels;
figure 3 effect of different nanofibrillated cellulose (NFC) addition amounts on biocompatible nanocomposite hydrogel porosity;
FIG. 4 effect of different nanofibrillated cellulose (NFC) addition amounts on swelling performance of biocompatible nanocomposite hydrogels;
figure 5 effect of different nanofibrillated cellulose (NFC) addition amounts on pH response performance of biocompatible nanocomposite hydrogel;
figure 6 effect of different nanofibrillated cellulose (NFC) addition amounts on biocompatible nanocomposite hydrogel drug sustained release effect.
Detailed Description
The present invention is further illustrated by the following examples.
Example 1
(1) Firstly, weighing choline chloride and oxalic acid with a molar ratio of 1:2, placing the choline chloride and the oxalic acid in a three-neck flask, heating in an oil bath at 90 ℃ and stirring for half an hour to obtain a clear and transparent eutectic solvent; secondly, adding the cotton fiber powder into the eutectic solvent with the solid-liquid ratio of 1:20, and carrying out purification pretreatment for 3 hours at 110 ℃; and then, washing with deionized water and absolute ethyl alcohol to remove the residual eutectic solvent to obtain the purified cellulose. And then, directly adding the purified cellulose into a ball milling tank for wet ball milling for 16h, then carrying out centrifugal separation for 8min at 8000r/min, centrifuging for 5 times, and finally carrying out rotary evaporation to obtain the nanofibrillated cellulose colloid with the concentration of 2%.
(2) Firstly, dispersing a certain volume (the content of the nano fibrillated cellulose is 0.5 percent of sodium alginate/chitosan) of nano fibrillated cellulose colloid in deionized water, and ultrasonically dispersing for 30min by using 300W ultrasonic waves; secondly, weighing a certain amount of sodium alginate powder, dissolving the sodium alginate powder in the aqueous dispersion of the nanofibrillated cellulose, and dispersing the sodium alginate powder for 1 hour by a high-speed dispersion machine at the rotating speed of 650 r/min; thirdly, weighing a certain amount of chitosan polyelectrolyte powder, adding the chitosan polyelectrolyte powder into the mixed solution, continuously dispersing for 2 hours at the rotating speed of 650r/min by using a high-speed dispersion machine, placing the mixture in a vacuum drying oven, vacuumizing and defoaming for 5 hours, and obtaining the sodium alginate/chitosan nano fibrillated cellulose mixed solution. Then, a certain amount of sodium alginate/chitosan nanofibrillated cellulose mixed solution is extracted by a 5mL disposable syringe with the head cut off, and the mixed solution is kept stand for 24 hours in 2mol/L dilute hydrochloric acid; and finally, extruding the hydrogel in the disposable syringe, soaking the hydrogel in deionized water for 3 days, and cleaning residual hydrochloric acid on the surface to prepare the sodium alginate/chitosan/nanofibrillated cellulose composite hydrogel.
The application comprises the following steps: the prepared sodium alginate/chitosan/nanofibrillated cellulose nano composite hydrogel is used for loading indometacin medicaments. A certain mass of indomethacin was weighed, dissolved in 20ml of ammonia water and sonicated to give a 1mg/ml indomethacin solution. And soaking the sodium alginate/chitosan/nanofibrillated cellulose nano-composite hydrogel in 20ml of indomethacin solution for 24h, taking out and drying in an oven at 50 ℃ to obtain the indomethacin-loaded sodium alginate/chitosan/nanofibrillated cellulose nano-composite hydrogel.
Example 2
(1) Firstly, weighing choline chloride and oxalic acid with a molar ratio of 1:2, placing the choline chloride and the oxalic acid in a three-neck flask, heating in an oil bath at 90 ℃ and stirring for half an hour to obtain a clear and transparent eutectic solvent; secondly, adding the cotton fiber powder into the eutectic solvent with the solid-liquid ratio of 1:20, and carrying out purification pretreatment for 1 hour at 120 ℃; and then, washing with deionized water and absolute ethyl alcohol to remove the residual eutectic solvent to obtain the purified cellulose. And then, directly adding the purified cellulose into a ball milling tank for wet ball milling for 20h, then carrying out centrifugal separation for 8min at 8000r/min, centrifuging for 5 times, and finally carrying out rotary evaporation to obtain the nanofibrillated cellulose colloid with the concentration of 2%.
(2) Firstly, dispersing a certain volume (the content of the nano fibrillated cellulose is 1 percent of sodium alginate/chitosan) of nano fibrillated cellulose colloid in deionized water, and ultrasonically dispersing for 30min by using 300W ultrasonic waves; secondly, weighing a certain amount of sodium alginate powder, dissolving the sodium alginate powder in the aqueous dispersion of the nanofibrillated cellulose, and dispersing the sodium alginate powder for 1 hour by a high-speed dispersion machine at the rotating speed of 650 r/min; thirdly, weighing a certain amount of chitosan polyelectrolyte powder, adding the chitosan polyelectrolyte powder into the mixed solution, continuously dispersing for 2 hours at the rotating speed of 650r/min by using a high-speed dispersion machine, placing the mixture in a vacuum drying oven, vacuumizing and defoaming for 5 hours, and obtaining the sodium alginate/chitosan nano fibrillated cellulose mixed solution. Then, a certain amount of sodium alginate/chitosan nanofibrillated cellulose mixed solution is extracted by a 5mL disposable syringe with the head cut off, and the mixed solution is kept stand for 24 hours in 2mol/L dilute hydrochloric acid; and finally, extruding the hydrogel in the disposable syringe, soaking the hydrogel in deionized water for 3 days, and cleaning residual hydrochloric acid on the surface to prepare the sodium alginate/chitosan/nanofibrillated cellulose composite hydrogel.
The application comprises the following steps: the prepared sodium alginate/chitosan/nanofibrillated cellulose nano composite hydrogel is used for loading indometacin medicaments. A certain mass of indomethacin was weighed, dissolved in 20ml of ammonia water and sonicated to give a 3mg/ml indomethacin solution. And soaking the sodium alginate/chitosan/nanofibrillated cellulose nano-composite hydrogel in 20ml of indomethacin solution for 24h, taking out and drying in an oven at 50 ℃ to obtain the indomethacin-loaded sodium alginate/chitosan/nanofibrillated cellulose nano-composite hydrogel.
Example 3
(1) Firstly, weighing choline chloride and oxalic acid with a molar ratio of 1:2, placing the choline chloride and the oxalic acid in a three-neck flask, heating in an oil bath at 90 ℃ and stirring for half an hour to obtain a clear and transparent eutectic solvent; secondly, adding the cotton fiber powder into the eutectic solvent with the solid-liquid ratio of 1:20, and carrying out purification pretreatment for 5 hours at 100 ℃; and then, washing with deionized water and absolute ethyl alcohol to remove the residual eutectic solvent to obtain the purified cellulose. And then, directly adding the purified cellulose into a ball milling tank for wet ball milling for 12h, then carrying out centrifugal separation for 8min at 8000r/min, centrifuging for 5 times, and finally carrying out rotary evaporation to obtain the nanofibrillated cellulose colloid with the concentration of 2%.
(2) Firstly, dispersing a certain volume of nano fibrillated cellulose colloid (the content of nano fibrillated cellulose is 1.5 percent of sodium alginate/chitosan) in deionized water, and ultrasonically dispersing for 30min by using 300W ultrasonic waves; secondly, weighing a certain amount of sodium alginate powder, dissolving the sodium alginate powder in the aqueous dispersion of the nanofibrillated cellulose, and dispersing the sodium alginate powder for 1 hour by a high-speed dispersion machine at the rotating speed of 650 r/min; thirdly, weighing a certain amount of chitosan polyelectrolyte powder, adding the chitosan polyelectrolyte powder into the mixed solution, continuously dispersing for 2 hours at the rotating speed of 650r/min by using a high-speed dispersion machine, placing the mixture in a vacuum drying oven, vacuumizing and defoaming for 5 hours, and obtaining the sodium alginate/chitosan nano fibrillated cellulose mixed solution. Then, a certain amount of sodium alginate/chitosan nanofibrillated cellulose mixed solution is extracted by a 5mL disposable syringe with the head cut off, and the mixed solution is kept stand for 24 hours in 2mol/L dilute hydrochloric acid; and finally, extruding the hydrogel in the disposable syringe, soaking the hydrogel in deionized water for 3 days, and cleaning residual hydrochloric acid on the surface to prepare the sodium alginate/chitosan/nanofibrillated cellulose composite hydrogel.
The application comprises the following steps: the prepared sodium alginate/chitosan/nanofibrillated cellulose nano composite hydrogel is used for loading indometacin medicaments. A certain mass of indomethacin was weighed, dissolved in 20ml of ammonia water and sonicated to give a 5mg/ml indomethacin solution. And soaking the sodium alginate/chitosan/nanofibrillated cellulose nano-composite hydrogel in 20ml of indomethacin solution for 24h, taking out and drying in an oven at 50 ℃ to obtain the indomethacin-loaded sodium alginate/chitosan/nanofibrillated cellulose nano-composite hydrogel.
The drawings are further described below:
FIG. 1 is a diagram of the mechanism of formation of a biocompatible nanocomposite hydrogel. And (3) mechanism analysis: the chitosan powder swells but does not dissolve in the sodium alginate/chitosan nano fibrillated cellulose mixed solution, when the chitosan/chitosan nano fibrillated cellulose mixed solution is soaked in hydrochloric acid, the hydrochloric acid is equivalent to a small molecule initiator, the hydrochloric acid is rapidly diffused, the chitosan is dissolved, amino molecules on a molecular chain are protonated to generate ammonium ions, and the ammonium ions and carboxylate ions on the molecular chain of the sodium alginate are subjected to electrostatic interaction to form a three-dimensional network structure. Meanwhile, the NFC is added as a filler due to the nanometer size and high mechanical property, so that a three-dimensional network is more compact; and the surface of the NFC is negatively charged, so that hydrogen bonds are easily formed with sodium alginate in an acid environment, and the sodium alginate/chitosan/nanofibrillated cellulose composite hydrogel is formed under the electrostatic action and the hydrogen bonds.
Fig. 2 is a microscopic morphology of biocompatible nanocomposite hydrogels with different NFC addition amounts. The figure shows the micro-morphology of the hydrogel with different amounts of added NFC, 0% (a, b), 1% (c, d), 2% (e, f), respectively. In a whole view, the three-dimensional network structure of the hydrogel is not changed by adding the NFC, and all hydrogel samples show a better three-dimensional network structure. Specifically, when the amount of NFC added was 1% or 2%, NFC with a length in the order of micrometers and a diameter in the order of nanometers was observed. It can be found that the influence of NFC on the aperture is small, because the NFC particle size is small, and the influence is small compared with that of holes with the diameters of 30-50 μm.
Figure 3 is a graph of the effect of different NFC addition levels on the porosity of biocompatible nanocomposite hydrogels. As can be seen from the figure, the influence of the addition amount of NFC on the porosity of the hydrogel is small, and the porosities of the hydrogels with several addition amounts are maintained between 90% and 95%. As can be seen from the SEM image of FIG. 3, the pore size of the hydrogel is 30-50 μm, which is very large compared to the particle size of NFC. Therefore, the influence of the addition of NFC on the hydrogel porosity is small, and the hydrogel with high porosity is beneficial to application of the hydrogel in tissue engineering and drug sustained release.
Fig. 4 is a graph of the effect of different NFC addition amounts on the swelling performance of biocompatible nanocomposite hydrogels. As can be seen, overall, the swelling ratios of all hydrogel samples increased with time, reaching a swelling equilibrium around 24 h; and the swelling ratio of the hydrogel shows a tendency to decrease as the NFC content increases. Specifically, when the swelling equilibrium was reached, the swelling ratio of the hydrogel with 0% NFC addition was 1455.5%, while the swelling ratios of the hydrogels with 1%, 1.5%, 2% NFC addition were 1321.4%, 1378.4%, 1204.8%, respectively, which were decreased by 9.2%, 5.3%, and 17.2%, respectively. This is probably because the swelling degree is mainly controlled by the hydrophilic functional group, whereas highly crystalline NFC is less hydrophilic; in addition, NFC as a nano filler can form hydrogen bond interaction with a hydrogel matrix, so that a three-dimensional network structure becomes denser, and the swelling degree of the hydrogel is further reduced.
Fig. 5 shows the effect of different NFC addition amounts on pH response performance of biocompatible nanocomposite hydrogels. As shown in the figure, the addition amount of NFC did not change the pH response performance of the hydrogel as a whole, and the NFC hydrogel added in different proportions still showed similar swelling ratios in different pH buffers, i.e., good swelling in phosphate buffer at pH 7.4 and poor swelling in hydrochloric acid buffer at pH 1.2. However, the addition of NFC impairs the swelling properties of the hydrogel as a whole, and the swelling properties in each buffer solution are reduced. Specifically, when the amount of NFC added was 1.5%, the swelling ratios in buffer solutions having a pH of 7.4, a pH of 6.5, and a pH of 1.2 were decreased by 5.3%, 4.1%, and 8.0%, respectively. The method means that the mechanical property of the hydrogel can be changed by adjusting the addition of NFC, and the swelling property of the hydrogel can be influenced, so that the drug loading and drug release of the hydrogel can be adjusted within a certain range
Fig. 6 shows the effect of different NFC addition amounts on the sustained release effect of biocompatible nanocomposite hydrogel drugs. In order to avoid the side effects of indomethacin drugs on the stomach, the hydrogel should release no or as little as possible in simulated gastric fluid (pH 1.2). As can be seen from the figure, the cumulative release in the simulated gastric fluid is small in all the samples, and the cumulative release rate is lower than 10%. The addition of NFC is beneficial to reducing the release amount of indometacin in simulated gastric juice, and when NFC is not added, the release amount of indometacin in 2h is 1177.9 mug; when the addition amount of NFC is 0.5%, 1, 1.5% and 2%, the release amount of 2h is 834.1, 579.6, 746.2 and 558.4 μ g respectively, and the release amount of indomethacin is reduced by 29.2%, 50.8%, 36.6% and 52.6% respectively. The main reason is that the hydrogel obtains a more compact three-dimensional network structure due to the excellent resistance of the porous sodium alginate matrix to gastric acid and the addition of NFC, the network structure can effectively delay the release of indomethacin in gastric acid, and the following table shows the research of a drug release mechanism and model analysis.
TABLE 1
As can be seen from table 1, the release process of indomethacin consists mainly of 2 stages: in simulated gastric juice with pH of 1.2, the model drug is linearly released and conforms to a zero-order model; in simulated intestinal fluid with pH of 6.5 and 7.4, the release rule of the model drug is closer to that of the R-P model. In the R-P model, when n is less than 0.45, the diffusion is performed; when n is more than 0.89, the skeleton is corroded, and the values of n measured by experiments are 0.49 and 0.51 respectively, and are within the range of 0.45-0.89, the drug release at the moment is shown to have diffusion and corrosion, and the synergistic effect of the two results is obtained.
Claims (6)
1. A method for preparing a biocompatible nano composite hydrogel is characterized by comprising the following steps:
(1) firstly, weighing choline chloride and oxalic acid according to the molar ratio of 1:2, placing the choline chloride and the oxalic acid into a three-neck flask, heating and stirring the mixture in an oil bath at 90 ℃ for half an hour to obtain a clear and transparent eutectic solvent;
secondly, adding cotton fiber powder into the eutectic solvent with a solid-to-liquid ratio of 1:20, and carrying out purification pretreatment for 1-5 hours at 100-120 ℃;
then, washing with deionized water and absolute ethyl alcohol to remove residual eutectic solvent to obtain purified cellulose;
then, directly adding the purified cellulose into a ball milling tank for wet ball milling for 12-20 h, and then carrying out centrifugal separation for 8min at 8000r/min for 5 times;
finally, the nanofibrillated cellulose colloid with the mass concentration of 2 percent is prepared through rotary evaporation;
(2) firstly, dispersing a certain volume of nano fibrillated cellulose colloid in deionized water, and ultrasonically dispersing for a certain time by using ultrasonic waves;
secondly, weighing a certain amount of sodium alginate powder, adding the sodium alginate powder into the aqueous dispersion of the nanofibrillated cellulose, and dispersing for a certain time by using a high-speed dispersion machine;
thirdly, weighing a certain amount of chitosan powder, adding the chitosan powder into the mixed solution, continuously dispersing for a certain time by using a high-speed dispersion machine, placing the mixture in a vacuum drying oven, vacuumizing and defoaming for a certain time to prepare a sodium alginate/chitosan/nanofibrillated cellulose mixed solution;
then, extracting a certain amount of mixed solution of sodium alginate/chitosan/nanofibrillated cellulose by using a disposable syringe with the head cut off, and standing for 24 hours in 2mol/l dilute hydrochloric acid;
and finally, extruding the hydrogel in the disposable syringe, soaking the hydrogel in deionized water for 3 days, and cleaning residual hydrochloric acid on the surface to prepare the sodium alginate/chitosan/nanofibrillated cellulose nano composite hydrogel.
2. The method of claim 1, wherein the method comprises the steps of:
the adding proportion of the sodium alginate/the chitosan/the nano fibrillated cellulose in the step (2) is that the mass ratio of the sodium alginate to the chitosan is 1: 1; the total mass of the added sodium alginate and chitosan is taken as a reference M, and the addition amount of the nanofibrillated cellulose is 0.5-2% M.
3. The method of claim 1, wherein the method comprises the steps of:
the ultrasonic dispersion ultrasonic intensity in the step (2) is 300W, and the ultrasonic time is 30 min; the first high-speed dispersion speed is 650r/min, and the time is 1 h; the second high-speed dispersion speed is 650r/min, and the time is 2 h; vacuum defoaming time is 3 h.
4. The method of claim 1, wherein the method comprises the steps of:
the sodium alginate/chitosan/nanofibrillated cellulose nano composite hydrogel prepared in the step (2) is in a porous three-dimensional network structure, the porosity is maintained above 90%, and the swelling rate reaches 1321%.
5. Use of the biocompatible nanocomposite hydrogel prepared according to claim 1 for loading indomethacin drugs.
6. Use according to claim 5, characterized in that:
weighing indometacin with a certain mass, dissolving the indometacin in 20ml of ammonia water, and performing ultrasonic treatment to obtain indometacin solutions with different concentrations;
and (3) soaking the composite hydrogel in 20ml of indometacin solution for 24h, taking out and placing in a 50 ℃ drying oven for drying to obtain the indometacin-loaded sodium alginate/chitosan/nanofibrillated cellulose nano composite hydrogel.
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| CN111978793A (en) * | 2020-08-18 | 2020-11-24 | 江南大学 | Preparation method of biological composite coating and intelligent colorimetric film material |
| CN112316860A (en) * | 2020-10-13 | 2021-02-05 | 华南农业大学 | Biomass-based hydrogel and preparation method and application thereof |
| CN114699385A (en) * | 2022-03-28 | 2022-07-05 | 安徽理工大学 | Preparation method of cellulose sodium alginate composite hydrogel |
| CN116675901A (en) * | 2023-07-13 | 2023-09-01 | 昆明理工大学 | Method for preparing water-stable cellulose aerogel without cross-linking agent and application |
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| CN111978793A (en) * | 2020-08-18 | 2020-11-24 | 江南大学 | Preparation method of biological composite coating and intelligent colorimetric film material |
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| CN112316860A (en) * | 2020-10-13 | 2021-02-05 | 华南农业大学 | Biomass-based hydrogel and preparation method and application thereof |
| CN114699385A (en) * | 2022-03-28 | 2022-07-05 | 安徽理工大学 | Preparation method of cellulose sodium alginate composite hydrogel |
| CN116675901A (en) * | 2023-07-13 | 2023-09-01 | 昆明理工大学 | Method for preparing water-stable cellulose aerogel without cross-linking agent and application |
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