CN110193007B - Preparation method and application of pH response type hydrogel - Google Patents
Preparation method and application of pH response type hydrogel Download PDFInfo
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Abstract
The invention discloses a preparation method and application of pH response type hydrogel, wherein the preparation method of the pH response type hydrogel comprises the following steps: dissolving gamma-polyglutamic acid in alkali liquor, adding chitosan, and uniformly mixing to obtain a mixed solution A; adding a sodium alginate solution with the same volume as the mixed solution into the mixed solution, and uniformly stirring to obtain a mixed solution B; dropwise adding a glacial acetic acid solution into the mixed solution B, and stirring to react to obtain a reaction solution C; and (3) dropwise adding the reaction solution C into a calcium chloride solution, carrying out curing reaction, and then cleaning to obtain the pH response type hydrogel. The hydrogel prepared by the invention has good pH responsiveness, and the used base material has good biocompatibility, no toxic or side effect and no irritation. The preparation process is simple and easy to implement, does not use organic solvents, catalysts or initiators with toxic and side effects, does not need emulsifiers, is high in safety, is green and pollution-free, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of biological materials, and particularly relates to a preparation method and application of a pH response type hydrogel.
Background
Some bioactive agents, such as proteins, nucleic acids, enzymes, etc., affect availability by causing premature degradation of the material upon oral administration. The main reason is that most of the biological activity of these biological agents or biological products is destroyed when they are taken orally through the extremely acidic environment of the stomach, the active ingredients reaching the small intestine, where they are mainly absorbed, are greatly reduced, and the direct release of high concentrations of the drugs or biological products may cause damage to the gastrointestinal mucosa. Therefore, an environment-responsive drug release system is designed, an intelligent carrier is constructed, and targeted release of the drug is realized, so that the method becomes a research hotspot of pharmaceutics, polymer material science and nano science.
In recent years, the intelligent hydrogel has attractive application prospects in the fields of controlled release of medicines, gene delivery, tissue engineering and the like. The pH response carrier realizes pH response by adjusting the charging property of the carrier matrix based on the obvious difference of the pH of the stomach and the intestine. The drug delivery system can not only protect the drug from stably passing through the strong acid environment of the stomach, but also reduce the side effect of the drug on the stomach, can be transported to the colon part in a targeted manner, improves the drug effect and action time of the drug through slow release, and has obvious advantages in the field of drug delivery.
Disclosure of Invention
The invention provides a preparation method and application of pH response type hydrogel, the prepared hydrogel has good pH response, and the used base material has good biocompatibility, no toxic or side effect and no irritation. The preparation process is simple and easy to implement, does not use organic solvents, catalysts or initiators with toxic and side effects, does not need emulsifiers, is high in safety, is green and pollution-free, and is suitable for industrial production.
The technical scheme adopted by the invention is as follows:
a method of making a pH-responsive hydrogel, the method comprising the steps of:
(1) Dissolving gamma-polyglutamic acid in alkali liquor, adding chitosan, and uniformly mixing to obtain a mixed solution A;
(2) Adding a sodium alginate solution with the same volume as the mixed solution into the mixed solution, and uniformly stirring to obtain a mixed solution B;
(3) Dropwise adding glacial acetic acid solution into the mixed solution B, and stirring to react to obtain reaction liquid C;
(4) And (3) dropwise adding the reaction solution C into a calcium chloride solution, carrying out curing reaction, and then cleaning to obtain the pH response type hydrogel.
In the step (1), the pH value of the alkali liquor is 8.5-9.5, and is preferably 9.0.
The mass volume ratio of the gamma-polyglutamic acid to the alkali liquor is 1g.
In the step (1), the alkali liquor is sodium hydroxide solution.
In the step (1), the mass ratio of the gamma-polyglutamic acid to the chitosan is 1.
In the step (2), the mass fraction of the sodium alginate solution is 1.0-6.0%, preferably 3%.
In the step (3), the volume ratio of the glacial acetic acid solution to the mixed solution B is 1; the volume concentration of the glacial acetic acid solution is 2-8%, and the preferred volume concentration is 4%.
In the step (3), the dropping speed of the glacial acetic acid solution is 50 mu L/min; the stirring reaction time is 1h.
In the step (4), the volume ratio of the reaction solution C to the calcium chloride solution is 1.5-2.0.
In the step (4), the mass concentration of the calcium chloride solution is 1.5-2.5%, preferably 2.0%, the dropping speed is 3mL/min, and the curing reaction time is 0.5-2h.
In the raw materials used in the preparation method provided by the invention, gamma-polyglutamic acid (gamma-PGA) and Sodium Alginate (SA) contain a large amount of carboxyl groups, and are natural polyanionic compounds; the chitosan (chitosan, CS) contains a large amount of primary amino acid, is a natural polycation compound, forms a polyelectrolyte membrane through electrostatic attraction to form the gamma-PGA-SA/CS hydrogel, has better pH responsiveness, can stably exist in simulated gastric juice 6h in vitro, is sensitive in simulated intestinal juice in vitro, is easy to dissolve and break, has obvious pH responsiveness, and is very suitable for a carrier for targeted transportation of bioactive products. The targeted transportation efficiency of the embedded Nattokinase (NK) reaches 87%, so that the loss of the NK in a strong acid environment of gastric juice is greatly reduced, and the actual utilization rate of the NK is effectively improved.
The pH response type hydrogel disclosed by the invention has more compact pore diameter with the increase of the concentration of calcium chloride used for curing. The slow release of the embedding substance can be realized by regulating and controlling the concentration of calcium chloride, and the damage of the high-concentration substance to the intestinal tract can be effectively relieved. Therefore, the pH response type hydrogel prepared by the invention can be used for embedding probiotics and adjusting intestinal flora balance.
According to the invention, through the action of glacial acetic acid by applying CS and gamma-PGA, linear molecular chains are mutually crosslinked to form a crosslinked network-shaped macromolecular structure with a three-dimensional structure. Among them, CS has a large number of amino groups, and γ -PGA has a large number of carboxyl groups, and the two are combined with each other by electrostatic interaction, so that the pH value response is sensitive; on the basis, SA contains a large amount of hydroxyl and carboxyl, can not only have electrostatic action with CS, but also can be combined with calcium chloride to form calcium alginate, and has the functions of pH response and slow release regulation. Therefore, the invention can regulate and control the balance of pH responsiveness and slow release of the SA balance hydrogel, thereby realizing the double functions of targeted delivery and slow release of the embedding substance.
The pH response type hydrogel provided by the invention can be used as a targeted transport carrier of a drug, and the drug can be directionally transported to the environment of intestinal juice for action, so that the loss of the drug in the strong acid environment of gastric juice is avoided, and the actual utilization rate of the drug is effectively improved.
The CS, SA and gamma-PGA used in the invention are all high in biocompatibility and degradability, and have no toxic or side effect on human bodies, and the prepared hydrogel not only has the advantages of pH responsiveness and controllable slow release, but also is green and has no side effect. The method has the advantages of mild reaction, low energy consumption, simple equipment and simple and easy preparation process, and is an efficient and convenient production mode. The method has the advantages of low cost, low equipment requirement, greenness, no pollution and huge development potential. Therefore, the invention has important social significance and application and popularization value.
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FIG. 1 is an optical microscope image of the surface of the CS/SA/γ -PGApH responsive hydrogel prepared in example 1;
FIG. 2 is a surface cross-sectional optical microscope photograph of the CS/SA/γ -PGApH-responsive hydrogel prepared in example 1;
FIG. 3 is a scanning electron micrograph of the CS/SA/γ -PGApH responsive hydrogel (a) prepared in example 1, treated with gastric fluid 3h (b), intestinal fluid 2h (c), gastric fluid 3h and intestinal fluid 1h (d); e-f are sectional scanning electron micrographs of a-d, respectively;
FIG. 4 is a cross-sectional scanning electron micrograph of the gel microspheres prepared in comparative example 1 (a), example 1 (b) and comparative example 2 when the concentration of the calcium chloride solution is 10%;
FIG. 5 shows the effect of different concentrations of calcium chloride on the pH responsiveness of microspheres in gastric (upper) and intestinal (lower) fluids, wherein a and b refer to gastric fluid at pH3.0 and intestinal fluid at pH7.2 respectively, and a and b refer to microspheres prepared in calcium chloride solutions at concentrations of 2%, 4%, 6%, 8% and 10% respectively;
FIG. 6 is an optical microscope photograph of gel microspheres prepared in comparative examples 3, 4 and 5.
Detailed Description
The present invention will be described in detail with reference to examples.
Example 1
A preparation method of CS/SA/gamma-PGApH response type hydrogel comprises the following steps:
(1) Dissolving 0.04g of gamma-polyglutamic acid in 15mL of sodium hydroxide solution with the pH value of 9.0, then adding 0.36g of chitosan for mixing, and uniformly stirring at 45 ℃ and 800rpm to obtain a mixed solution A;
(2) Adding a 3% mass concentration sodium alginate solution with the same volume as the mixed solution A, and uniformly stirring to obtain a mixed solution B;
(3) Dripping 2mL of glacial acetic acid solution with the volume concentration of 4% into the mixed solution B at the speed of 50 mu L/min, and stirring for reacting for 1h to obtain reaction solution C;
(4) And dripping the reaction liquid C into 50mL calcium chloride solution with the mass concentration of 2% at the speed of 3mL/min, curing and reacting for 0.5h, and washing with distilled water to obtain the CS/SA/gamma-PGApH response type hydrogel. The optical microscopic images are shown in fig. 1 and 2, and it can be seen that the CS/SA/γ -PGApH responsive hydrogel prepared in this example is dense and uniform microspheres.
Scanning electron micrographs of the surface and the cross section of the CS/SA/gamma-PGApH responsive hydrogel microspheres obtained in the embodiment are respectively shown in FIGS. 3a and 3e, and it can be seen from FIGS. 3a and 3e that the hydrogel has a smooth and dense surface and a porous structure inside.
The CS/SA/γ -PGApH responsive hydrogel obtained in this example was divided into three groups, which were placed in an in vitro simulated gastric fluid of pH3.0 for 3 hours, an in vitro simulated intestinal fluid of pH7.2 for 2 hours, and first in gastric fluid for 3 hours and then in intestinal fluid for 1 hour, and then the undissolved hydrogel microspheres in each group were rinsed with distilled water, and after drying, the scanning electron microscopy images of the surfaces and sections of the microspheres were respectively tested, and the results are shown as b-d and f-h in fig. 3, respectively. It can be seen from FIG. 3 that gastric juice has little effect on the structure of the hydrogel; intestinal juice can obviously corrode the surface of the hydrogel, so that the hydrogel becomes rough, and the pores of the internal structure are increased to form a net structure; gastrointestinal fluid processing exhibits additive effects.
Example 2
A method for preparing a pH-responsive hydrogel is otherwise the same as that in example 1, except that in step (3), the volume of the glacial acetic acid solution is 1mL, and the obtained hydrogel microspheres have good pH responsiveness after being tested as in example 1.
Example 3
The other steps are the same as example 1 except that in the step (2), the mass concentration of the sodium alginate solution is 5%, and the obtained hydrogel microspheres have good pH responsiveness after being tested like example 1.
Comparative example 1
The rest is the same as example 1, except that in the step (2), the mass concentration of the sodium alginate solution is 1%, and the section scanning electron microscope image of the obtained microsphere is shown in FIG. 4 a.
Comparative example 2
Otherwise, the same as example 1 except that in the step (4), the concentrations of the calcium chloride solution were 4%, 6%, 8% and 10%, respectively, and the scanning electron micrograph of the cross section of the microsphere obtained when the concentration of the calcium chloride solution was 10% is shown in FIG. 4 c.
As can be seen from fig. 4, the sodium alginate concentration and the calcium ion concentration have a significant effect on the internal pore size structure of the hydrogel, and the internal structure of the hydrogel is denser as the sodium alginate and calcium ion concentrations increase.
The gel microspheres obtained in example 1 and comparative example 2 were placed in simulated gastric fluid at pH3.0 and simulated intestinal fluid at pH7.2 for 6 hours, and the dissolution of each gel microsphere was observed, and the results are shown in fig. 5. As can be seen from fig. 5, each of the gel microspheres prepared in example 1 and comparative example 2 was not dissolved after being left in gastric juice for 6 hours; in the in vitro simulated intestinal fluid with the pH value of 7.2, the gel microspheres prepared in example 1 are substantially completely dissolved and actually are substantially completely dissolved after being placed in the intestinal fluid for 3 hours, and the dissolution degree of the gel microspheres in the intestinal fluid is smaller as the mass concentration of the calcium chloride solution used in the solidification process in the preparation process of the gel microspheres is increased, which shows that the CS/SA/gamma-PGApH response type hydrogel prepared by the technical scheme disclosed by the invention can be directionally dissolved in the intestinal fluid.
Comparative example 3
A gelatin/sodium alginate (GN/SA) hydrogel is prepared by the following steps:
(1) Dissolving 0.3g GN in 15mL deionized water, stirring at 1500rpm for 30min at 55 ℃;
(2) Adding 3% of SA solution to (1) in a volume ratio of 1;
(3) The reaction mixture of (2) was dropped into 50mL of 2% calcium chloride solution at a rate of 3mL/min, solidified for half an hour, and washed with distilled water, and the optical micrograph of the resulting microspheres is shown in FIG. 6 a.
Comparative example 4
A chitosan/sodium alginate (CS/SA) hydrogel is prepared by the following steps:
(1) 15mL of a pH 9.0NaOH solution was dissolved in 0.3g of CS, and the solution was stirred at 45 ℃ and 900rpm for 30min;
(2) Dripping 15mL of 4% glacial acetic acid solution into the solution (1) at the speed of 50 mu L/min, and stirring for 1h;
(3) To (2), 3% of SA solution was added in a volume ratio of 1.
(4) The reaction mixture of (3) was dropped into 50mL of 2% calcium chloride solution at a rate of 3mL/min, solidified for half an hour, and washed with distilled water, and the optical micrograph of the resulting microspheres is shown in FIG. 6 b.
Comparative example 5
A carboxymethyl cellulose/sodium alginate (CMC/SA) hydrogel is prepared by the following steps:
(1) Dissolving 0.75g CMC in 15mL deionized water, stirring at 65 deg.C and 1500rpm for 30min;
(2) To (1), 3% of SA solution was added in a volume ratio of 1.
(3) The reaction solution in (2) was dropped into 50mL of 2% calcium chloride solution at a rate of 3mL/min, solidified for half an hour, and then washed with distilled water, and the optical micrograph of the resulting microspheres is shown in FIG. 6 c.
From FIG. 6, it can be seen that the CS/SA hydrogel is denser than the GN/SA and CMC/SA hydrogels. In order to maintain the structural stability of the hydrogel in the strongly acidic gastric juice and prevent the leakage of the internal contents, the invention adds a proper amount of gamma-PGA on the basis of selecting CS/SA as a main component, and CS which competes with SA, and maintains the balance relationship between pH response and slow release through the reaction of SA with CS and calcium ions. The CS/SA/gamma-PGA hydrogel prepared by the method is shown in figures 1 and 2, the composition structure is relatively compact and firm, and the internal structure is hollow and porous.
Example 4
Application of CS/SA/gamma-PGApH responsive hydrogel as drug targeting transport carrier
Embedding the CS/SA/gamma-PGA pH response type hydrogel into NK by the following method:
(1) Dissolving 0.04g of gamma-polyglutamic acid in 15mL of sodium hydroxide solution with the pH value of 9.0, then adding 0.36g of chitosan for mixing, and uniformly stirring at 45 ℃ and 800rpm to obtain a mixed solution A;
(2) Mixing 15mL of sodium alginate solution with the mass concentration of 3% with 2mL of 52.94mg/mL NK solution to obtain a mixed solution B;
(3) Uniformly mixing the solution A and the solution B, dropwise adding 2mL of 6.6% glacial acetic acid solution at the speed of 50 mu L/min, and stirring for reacting for 1h to obtain a reaction solution C;
(4) And dropwise adding the reaction solution C into 50mL calcium chloride solution with the mass concentration of 2% at the speed of 3mL/min, curing and reacting for 0.5h, and then washing with distilled water to obtain the hydrogel microspheres embedded with NK.
The hydrogel microspheres embedded with nattokinase NK are sequentially placed in an in-vitro simulated gastric fluid with pH of 3.0 for 6h and an in-vitro simulated intestinal fluid with pH of 7.2 for 6h, and the change of protein in the simulated gastric and intestinal fluids is respectively detected, and the result is shown in table 1. Calculating the target transport efficiency R of NK according to equation 1:
R＝100％*n 2 *(D 4 -D 3 )*v 2 /[n 1 *(D 2 -D 1 )*v 1 +n 2 *(D 4 -D 3 )*v 2 ] (1)
in the above formula, R represents the efficiency of targeted transport；D 1 、D 2 、D 3 And D 4 Respectively showing the OD of the original gastric juice, the gastric juice after soaking the nattokinase NK embedded hydrogel microspheres for 6 hours, the original intestinal juice and the nattokinase NK embedded hydrogel microspheres in the gastric juice for 6 hours, transferring the gastric juice to the intestinal juice and soaking the intestinal juice for 6 hours 280nm ；v 1 And v 2 The volumes of gastric juice and intestinal juice are respectively expressed in mL; n is a radical of an alkyl radical 1 And n 2 、n 3 The dilution factor of the gastric juice and the intestinal juice respectively.
The result shows that the targeted transportation efficiency of the NK embedded by the microspheres reaches 87%, the loss of the NK in a gastric acid strong acid environment is greatly reduced, the actual utilization rate of the NK is effectively improved, and the microsphere carrier prepared by the invention has good pH responsiveness and important application value in the aspect of targeted transportation of bioactive products.
TABLE 1 gastric and intestinal fluids A before and after immersion 280nm Variations of (2)
| Sample(s) | OD 280nm | volume/mL | Dilution factor |
| Raw gastric juice (D) 1 ) | 0.918 | 20 | 10 |
| Gastric juice after immersion (D) 2 ) | 0.999 | 20 | 10 |
| Original intestinal juice (D) 3 ) | 0.326 | 20 | 10 |
| Intestinal juice after immersion (D) 4 ) | 0.869 | 20 | 10 |
The above detailed description of the method for preparing a pH-responsive hydrogel and the use thereof with reference to the examples is illustrative and not restrictive, and several examples are set forth in order to limit the scope thereof, so that variations and modifications may be made without departing from the general inventive concept and therefore fall within the scope thereof.
Claims (3)
1. A preparation method of pH response type hydrogel is characterized by comprising the following steps:
(1) Dissolving gamma-polyglutamic acid in alkali liquor, adding chitosan, mixing and stirring uniformly to obtain a mixed solution A;
(2) Adding a sodium alginate solution with the same volume as the mixed solution A into the mixed solution A, and uniformly stirring to obtain a mixed solution B;
(3) Dropwise adding a glacial acetic acid solution into the mixed solution B, and stirring to react to obtain a reaction solution C;
(4) Dropwise adding the reaction solution C into a calcium chloride solution, carrying out curing reaction, and then cleaning to obtain the pH response type hydrogel;
in the step (1), the pH value of the alkali liquor is 8.5-9.5; the mass volume ratio of the gamma-polyglutamic acid to the alkali liquor is 1g and is within 0.3-0.4L;
in the step (1), the alkali liquor is sodium hydroxide solution;
in the step (2), the mass fraction of the sodium alginate solution is 1.0 to 6.0 percent;
in the step (3), the volume ratio of the glacial acetic acid solution to the mixed solution B is 1; the volume fraction of the glacial acetic acid solution is 2-8%;
in the step (3), the dropping speed of the glacial acetic acid solution is 50 mu L/min; the stirring reaction time is 1h;
in the step (1), the mass ratio of the gamma-polyglutamic acid to the chitosan is 1;
in the step (4), the volume ratio of the reaction liquid C to the calcium chloride solution is 1.5 to 2.0;
in the step (4), the mass concentration of the calcium chloride solution is 1.5-2.5%;
the pH response type hydrogel is a dense and uniform microsphere.
2. The method according to claim 1, wherein in the step (4), the dropping speed is 30 mL/min, and the curing reaction time is 0.5 to 2 hours.
3. Use of the pH-responsive hydrogel prepared by the preparation method according to claim 1 or 2 in the preparation of a drug targeting delivery carrier.
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