CN112048079A - Carboxymethyl chitosan-alginate injectable double-network temperature-sensitive hydrogel and preparation method and application thereof - Google Patents
Carboxymethyl chitosan-alginate injectable double-network temperature-sensitive hydrogel and preparation method and application thereof Download PDFInfo
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- CN112048079A CN112048079A CN202010939542.0A CN202010939542A CN112048079A CN 112048079 A CN112048079 A CN 112048079A CN 202010939542 A CN202010939542 A CN 202010939542A CN 112048079 A CN112048079 A CN 112048079A
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- alginate
- carboxymethyl chitosan
- solution
- sodium glycerophosphate
- sensitive hydrogel
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- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 title claims abstract description 53
- 229920000615 alginic acid Polymers 0.000 title claims abstract description 46
- 229940072056 alginate Drugs 0.000 title claims abstract description 41
- 239000000017 hydrogel Substances 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 229960002901 sodium glycerophosphate Drugs 0.000 claims abstract description 42
- 229910001626 barium chloride Inorganic materials 0.000 claims abstract description 38
- WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 claims abstract description 32
- 229940045511 barium chloride Drugs 0.000 claims abstract description 32
- 229940005550 sodium alginate Drugs 0.000 claims abstract description 32
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims abstract description 31
- 235000010443 alginic acid Nutrition 0.000 claims abstract description 31
- 229920001661 Chitosan Polymers 0.000 claims abstract description 29
- REULQIKBNNDNDX-UHFFFAOYSA-M sodium;2,3-dihydroxypropyl hydrogen phosphate Chemical compound [Na+].OCC(O)COP(O)([O-])=O REULQIKBNNDNDX-UHFFFAOYSA-M 0.000 claims abstract description 25
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- 238000011282 treatment Methods 0.000 claims abstract description 11
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- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical group CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 29
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- OKHHGHGGPDJQHR-YMOPUZKJSA-L calcium;(2s,3s,4s,5s,6r)-6-[(2r,3s,4r,5s,6r)-2-carboxy-6-[(2r,3s,4r,5s,6r)-2-carboxylato-4,5,6-trihydroxyoxan-3-yl]oxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylate Chemical compound [Ca+2].O[C@@H]1[C@H](O)[C@H](O)O[C@@H](C([O-])=O)[C@H]1O[C@H]1[C@@H](O)[C@@H](O)[C@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@H](O2)C([O-])=O)O)[C@H](C(O)=O)O1 OKHHGHGGPDJQHR-YMOPUZKJSA-L 0.000 claims description 5
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
- C08J3/075—Macromolecular gels
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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- A61L31/028—Other inorganic materials not covered by A61L31/022 - A61L31/026
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/145—Hydrogels or hydrocolloids
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- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/148—Materials at least partially resorbable by the body
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Abstract
The invention discloses an injectable double-network temperature-sensitive hydrogel of carboxymethyl chitosan-barium alginate and a preparation method and application thereof, wherein the preparation raw materials comprise carboxymethyl chitosan, sodium glycerophosphate, alginate and barium chloride, and the mass ratio of the carboxymethyl chitosan to the sodium glycerophosphate to the alginate to the barium chloride is (60-100): 350-450): 25-40): 10-60. The gel material of the invention effectively improves the problems of poor mechanical strength and uncontrollable temperature-sensitive phase change of the prepared injectable temperature-sensitive gel, and can effectively solve some practical problems clinically encountered at present when the gel material is applied to the treatment of dry eye diseases.
Description
Technical Field
The invention relates to an injectable temperature-sensitive gel preparation for eyes, in particular to an injectable double-network temperature-sensitive hydrogel of carboxymethyl chitosan-alginate, a preparation method and application thereof.
Background
In recent years, the incidence of dry eye disease has been on the rise year by year and has become one of the most common ophthalmic diseases. The symptoms of dry eye are mainly dry eye, foreign body, burning, sticky eye secretion, poor sleep quality, aggravation by over-use of eyes, and even serious people can affect vision and normal life. The disease belongs to a multiple disease in the present society, and is generally closely related to factors such as age, sex, living environment, overuse of electronic equipment, various inflammations, ophthalmic surgery, and the like. The clinical treatment methods of xerophthalmia are mainly divided into non-drug treatment, drug treatment and surgical treatment. Non-drug treatments mainly include: the eye mask has the advantages of improving the environment of the ocular surface, wearing a front silica gel eyeshade, a therapeutic corneal contact lens or a wet chamber lens, and massaging, cleaning and hot compressing the eyelid. The drug therapy can be divided into artificial tear therapy, anti-inflammatory therapy, sex hormone therapy and the like, and the artificial tear therapy is still the most main treatment mode for treating moderate water-deficiency type dry eye at present. The main problems of the artificial tears in clinical application are: the physiological amount of tears required for the ocular surface cannot be stably maintained, the antimicrobial agent and preservative contained in the preparation aggravate ocular surface damage, and frequent use can reduce the treatment compliance of patients, etc. Surgical transplantation has irreversible property and high risk, and the current technology is relatively immature and has low success rate. The lacrimal passage embolism has the advantages of simple operation, small wound, reversibility, few complications, good curative effect and the like, and is widely applied. After the micro-size lacrimal passage suppository is adopted to embolize the lacrimal point, natural tears can be increased to provide longer moistening for the ocular surface; meanwhile, the increased natural tears can stimulate tear secretion and promote goblet cells to survive, thereby increasing the stability of the tear film; the medicine loss can be reduced and the medicine taking times can be reduced by embolizing the lacrimal passage. Currently, lacrimal suppository products used clinically are classified into two types, degradable and non-degradable. When the lacrimal duct suppository is implanted into lacrimal canaliculus, the degradable lacrimal duct suppository can only temporarily block lacrimal duct to prevent tear loss, so as to prolong the action time of tear. Common preparation materials include collagen, gelatin, hydroxymethyl cellulose, catgut and some synthetic materials. Degradable lacrimal embolization products include VisiPlugTM (USA), Soft Plug Collagen Plug (USA), UltraPlugTM (USA), etc. Non-degradable lacrimal embolization products major products include Herrik plug (USA), OdysseyTM (USA), Smart plug (USA), and Form FitTM (USA). The product is mainly prepared from polymers such as silicone, hydroxyethyl methacrylate, polyethylene, hydrophilic acrylic acid and the like. At present, lacrimal passage suppository products used for clinically treating dry eye diseases in China almost all depend on imports, are high in price, and greatly increase the economic burden of patients. In addition, based on different populations, the designed imported lacrimal passage suppository product cannot be completely adapted to Asian populations, and the problem that the operation fails due to the displacement or falling of the embolus in clinical application often exists. Therefore, the lacrimal passage suppository product which has the independent intellectual property rights of China, is suitable for the physiological characteristics of eyes of patients in China, has good lacrimal passage embolism effect and moderate cost has important significance and development value. In order to solve the problem, the injectable temperature-sensitive response hydrogel is injected into a human body to fill the lacrimal passage, and the sol is converted into gel at the body temperature, so that the lacrimal passage is blocked. And the temperature-sensitive gel material has excellent biocompatibility and biodegradability, is cheap and easy to obtain, and is favored by researchers. However, the traditional temperature-sensitive gel mainly has the problems of poor mechanical property, uncontrollable temperature-sensitive phase change and the like, and the lacrimal passage embolism has poor treatment effect, so that treatment failure is caused.
Disclosure of Invention
The invention mainly aims to provide an injectable double-network temperature-sensitive carboxymethyl chitosan-alginate hydrogel and a preparation method and application thereof, which aim to overcome the problems in the prior art.
In order to achieve the purpose, the invention adopts the following technical scheme:
the preparation raw materials of the carboxymethyl chitosan-alginate injectable double-network temperature-sensitive hydrogel comprise carboxymethyl chitosan, sodium glycerophosphate, alginate and barium chloride, wherein the mass ratio of the carboxymethyl chitosan to the sodium glycerophosphate to the alginate to the barium chloride is (60-100): (350-450): (25-40): (10-60).
Furthermore, the molecular weight of the carboxymethyl chitosan is 150000-300000, and the substitution degree is 70% -90%.
Further, the sodium glycerophosphate is selected from alpha-sodium glycerophosphate, beta-sodium glycerophosphate or alpha, beta-sodium glycerophosphate.
Further, the alginate is sodium alginate or calcium alginate.
A preparation method of carboxymethyl chitosan-alginate injectable double-network temperature-sensitive hydrogel comprises the following steps:
1) dissolving carboxymethyl chitosan in deionized water, and then adjusting the pH value of the solution to 6.5-7.4 to prepare a carboxymethyl chitosan solution; dissolving sodium glycerophosphate in deionized water to prepare a sodium glycerophosphate aqueous solution; adding alginate into deionized water to prepare alginate aqueous solution; dissolving barium chloride in deionized water to prepare a barium chloride aqueous solution;
2) fully and uniformly mixing a carboxymethyl chitosan aqueous solution and a sodium glycerophosphate aqueous solution, then adding an alginate solution into the obtained mixed solution, and stirring to fully and uniformly mix the solution to obtain a mixed solution A;
3) dropwise adding the barium chloride solution into the mixed solution A, and uniformly stirring to obtain a mixed solution B;
4) and (3) moving the mixed solution B into a mold, and carrying out gelation treatment at the temperature of 35-39 ℃ to obtain the carboxymethyl chitosan-barium alginate injectable double-network temperature-sensitive hydrogel.
Further, the molecular weight of the carboxymethyl chitosan is 150000-300000, and the substitution degree is 70% -95%; the sodium glycerophosphate is selected from alpha-sodium glycerophosphate, beta-sodium glycerophosphate or alpha, beta-sodium glycerophosphate; the alginate is sodium alginate or calcium alginate.
Further, the concentration of the carboxymethyl chitosan solution is 60-100 mg/mL; the concentration of the sodium glycerophosphate aqueous solution is 300-450 mg/mL; the concentration of the alginate aqueous solution is 20-40 mg/mL; the concentration of the barium chloride aqueous solution is 10-60 mg/mL.
Further, in the step 1), a 0.1-1 mol/L NaOH solution is adopted to adjust the pH value of the carboxymethyl chitosan solution.
An application of carboxymethyl chitosan-barium alginate injectable double-network temperature-sensitive hydrogel in preparing lacrimal passage suppository for treating xerophthalmia.
Compared with the prior art, the invention has the following beneficial technical effects:
the carboxymethyl chitosan-barium alginate injectable double-network temperature-sensitive hydrogel adopts a double-network gel structure, takes a most common temperature-sensitive gel system, namely a chitosan derivative-sodium glycerophosphate system, as a first network, and is an amphoteric polyelectrolyte, wherein a molecular chain of the carboxymethyl chitosan contains cations (-NH3+), and anions (-COO-). The molecular chain of the gel contains more-COO-, and the gel has good water solubility, viscosity and gel property. The protonated amino groups on the molecular chain can be combined with phosphate ions due to electrostatic interaction and also can be combined with the carboxyl groups of the molecular chain. The double-network gel has the advantages that the sodium alginate and barium ion crosslinking are used as the second network, the mechanical strength of the gel is enhanced, the obtained gel keeps the temperature-sensitive characteristic of the gel, the gel can be gelled in a short time, meanwhile, the double-network gel has high mechanical strength, can be better applied to the treatment of dry eye diseases, is low in toxicity, tasteless and degradable, is simple in preparation method, mild in implementation condition, has good biocompatibility and mechanical performance, and is endowed with wider application.
The invention adopts a method for preparing the double-network gel, but does not use a complex method such as free radical polymerization and the like, only adopts a blending mode, has simple preparation method and mild preparation conditions, and the prepared double-network temperature-sensitive gel has better mechanical property compared with single-network temperature-sensitive gel, can realize controllable operation on the aperture, the mechanical strength and the like of the gel by changing the concentration of barium chloride, can prepare hydrogel with any required shape by adjusting a prepared hydrogel mould, namely controllable appearance size of the hydrogel, can inject the injectable double-network temperature-sensitive gel into a lacrimal canaliculus, utilizes the gelling property of the carboxymethyl chitosan-alginic acid barium injectable temperature-sensitive hydrogel at the body temperature, thereby blocking the lacrimal passage, reducing the excretion of tears, keeping the amount of lacrimal fluid on the ocular surface and achieving the purpose of treating xerophthalmia, and simultaneously utilizes the degradable property of the carboxymethyl chitosan-alginic acid barium injectable temperature-sensitive hydrogel, the product can be used as a semipermanent lacrimal passage plug for treating mild and moderate xerophthalmia, and has the advantages of simple operation, small wound, wide application range, low cost and the like compared with similar products.
Drawings
FIG. 1 is a diagram of the gelation mechanism of carboxymethyl chitosan-sodium glycerophosphate/barium alginate (CMCS-GP/Ba-Alg) hydrogel;
FIG. 2 is a photograph of a polymer morphology in a sol state;
FIG. 3 is a photograph of the morphology of a polymer in a coagulated state;
FIG. 4 is a Fourier infrared spectrum of a carboxymethyl chitosan (CMCS), sodium Glycerophosphate (GP), Sodium Alginate (SA), CMCS-GP/Ba-Alg gel according to the present invention;
FIG. 5 is a graph showing the results of the effect of barium chloride concentration on gelation time;
FIG. 6 is a graph showing the results of the effect of barium chloride concentration on the compressive modulus of elasticity of a gel;
FIG. 7 is a graph of degradation curves for gel samples of different barium chloride concentrations;
FIG. 8 is a graph of the swelling curves of gel samples at different barium chloride concentrations.
Detailed Description
Embodiments of the invention are described in further detail below:
an injectable double-network temperature-sensitive hydrogel of carboxymethyl chitosan-barium alginate is prepared from raw materials including carboxymethyl chitosan, sodium glycerophosphate, sodium alginate and barium chloride, wherein the mass ratio of the carboxymethyl chitosan to the sodium glycerophosphate to the sodium alginate to the barium chloride is (60-100): 350-450: (25-40): 10-60); the molecular weight of the carboxymethyl chitosan is 150000-300000, and the substitution degree is 70% -95%; the sodium glycerophosphate is selected from alpha-sodium glycerophosphate, beta-sodium glycerophosphate or alpha, beta-sodium glycerophosphate; the alginate is calcium alginate or sodium alginate.
A preparation method of carboxymethyl chitosan-barium alginate injectable double-network temperature-sensitive hydrogel comprises the following steps of: preparing a CMCS (carboxymethyl chitosan) solution, dissolving a certain amount of CMCS powder in deionized water, uniformly stirring, and adjusting the pH value with 0.1-1 mol/L NaOH solution to 6.5-7.4 for later use. Preparing a sodium glycerophosphate solution, and dissolving a certain amount of GP (sodium glycerophosphate) powder in deionized water for later use. Preparing alginate solution, weighing alginate powder, adding into deionized water, and stirring with magnetic stirrer at room temperature for 3 hr. Preparing barium chloride solution, adding BaCl2Dissolving in deionized water for later use, wherein the concentration of the carboxymethyl chitosan solution is 60-100 mg/mL; the concentration of the sodium glycerophosphate aqueous solution is 300-450 mg/mL; the concentration of the sodium alginate aqueous solution is 25-40 mg/mL; the concentration of the barium chloride aqueous solution is 10-60 mg/mL.
The gel was prepared by mixing CMMixing the CS solution and the GP solution uniformly, adding the SA solution, stirring by using a mechanical stirrer, and finally adding BaCl in a stirring state2Uniformly mixing the solution, transferring a part of the uniformly mixed solution into a test tube, placing the test tube into a constant-temperature water bath at 35-39 ℃ to enable the test tube to be gelatinized, and measuring the gelation time of a gel sample by adopting a test tube inversion method, wherein the specific method comprises the following steps: vertically placing the test tube filled with the sol sample into a constant-temperature water bath, inclining the test tube every 10s, observing whether the liquid level of the sol sample in the test tube changes along with the inclination of the test tube, and if not, recording the time at the moment, namely the gelation time of the gel sample; and transferring the other part of the sol into a mold, putting the mold into a drying oven at 35-39 ℃ to gelatinize the sol, wherein the length and the width of the mold are both 1cm, and the casting height is about 1 cm.
Example 1
Accurately weighing 1g of CMCS powder, dissolving in 10mL of deionized water, uniformly stirring, measuring the pH value of the solution, and if the pH value is high<6.5, the pH was adjusted to 6.5 with 1mol/L NaOH solution. After the pH value is adjusted, if the adding amount of the solvent is less than 10mL, adding distilled water to make up 10mL, and stirring uniformly for later use. Preparing 400mg/mL beta-GP solution, accurately weighing 2g of beta-GP powder and dissolving in 5mL of deionized water for later use. Preparing 30mg/mL SA solution, weighing 0.6g SA powder, adding into 20mL deionized water, and stirring thoroughly for 3h at normal temperature by using a magnetic stirrer for later use. Prepare 20mg/mL BaCl20.2g of the solution is weighed and dissolved in 10mL of deionized water for later use.
The gel preparation process comprises the steps of taking 1mL of 100mg/mL CMCS solution, uniformly mixing the CMCS solution and the beta-GP solution in a volume ratio of 1:1, adding 2.5mL of 30mg/mL SA solution, stirring by using a mechanical stirrer, and finally adding 0.5mL of 20mg/mL BaCl in a stirring state2And (3) uniformly mixing the solution, transferring a part of the uniformly mixed solution into a mold, placing the mold in a 37 ℃ oven to gelatinize the mold so as to carry out subsequent gel performance measurement, transferring a part of the uniformly mixed solution into a test tube, and measuring the gelation time by adopting a test tube inversion method.
Example 2
Accurately weighing 0.8g of CMCS powder, dissolving in 8mL of deionized water, stirring uniformly, measuring the pH value of the solution, and if the pH value is not high<7.2, adjusted with 0.1mol/L NaOH solutionThe pH value is adjusted to 7.2 for standby. Preparing 400mg/mL beta-GP solution, accurately weighing 2g of beta-GP powder and dissolving in 5mL of deionized water for later use. Preparing 30mg/mL Na-Alg (sodium alginate) solution, weighing 0.6g Na-Alg powder, adding into 20mL deionized water, and stirring with a magnetic stirrer at normal temperature for 3 h. Prepare 30mg/mL BaCl20.15g of the solution is weighed and dissolved in 5mL of deionized water for later use.
The gel preparation process comprises the steps of taking 1mL of 100mg/mL CMCS solution, uniformly mixing the CMCS solution and the alpha-GP solution in a volume ratio of 1:1.2, adding 3mL of 30mg/mL Ca-Alg solution, stirring by using a mechanical stirrer, and finally adding 0.8mL of 30mg/mL BaCl in a stirring state2And uniformly mixing the solution, transferring the mixed solution into a mold, placing the mold in a 35 ℃ oven to gelatinize the mold so as to measure the subsequent gel property, transferring one part of the gelled solution into a test tube, and measuring the gelation time by adopting a test tube inversion method.
Example 3
Accurately weighing 0.6g of CMCS powder, dissolving in 10mL of deionized water, stirring uniformly, measuring the pH value of the solution, and if the pH value is not high<And 7.4, adjusting the pH value to 7.4 by using 0.5mol/L NaOH solution for later use. Preparing 450mg/mL alpha, beta-GP solution, accurately weighing 2.25g of alpha, beta-GP powder and dissolving in 5mL of deionized water for later use. Preparing 35mg/mL SA solution, weighing 0.7g SA powder, adding into 20mL deionized water, and stirring thoroughly for 3h at normal temperature by using a magnetic stirrer for later use. 10mg/mL BaCl is prepared20.05g of the solution is weighed and dissolved in 5mL of deionized water for later use.
The gel preparation process comprises the steps of taking 1mL of 60mg/mL CMCS solution, uniformly mixing the CMCS solution and the alpha, beta-GP solution in a volume ratio of 1:0.8, adding 2mL of 35mg/mL SA solution, stirring by using a mechanical stirrer, and finally adding 0.3mL of 10mg/mL BaCl in a stirring state2And (3) uniformly mixing the solution, transferring the mixed solution into a mold, placing the mold in a 39 ℃ oven to gelatinize the mold so as to carry out subsequent gel performance measurement, transferring one part of the gelled solution into a test tube, and measuring the gelation time by adopting a test tube inversion method.
Example 4
Accurately weighing 1g of CMCS powder, dissolving in 10mL of deionized water, uniformly stirring, measuring the pH value of the solution,if the pH is<6.5, adjusting the pH value to 6.5 by using 1mol/L NaOH solution for later use. Preparing 450mg/mL beta-GP solution, accurately weighing 1.8g of beta-GP powder and dissolving in 4mL of deionized water for later use. Preparing 30mg/mL SA solution, weighing 0.6g SA powder, adding into 20mL deionized water, and stirring thoroughly for 3h at normal temperature by using a magnetic stirrer for later use. Prepare 40mg/mL BaCl20.2g of the solution is weighed and dissolved in 5mL of deionized water for later use.
The gel preparation process comprises the steps of taking 1mL of 100mg/mL CMCS solution, uniformly mixing the CMCS solution and the beta-GP solution in a volume ratio of 1:1, adding 2.5mL of 30mg/mL SA solution, stirring by using a mechanical stirrer, and finally adding 0.5mL of 40mg/mL BaCl in a stirring state2Mixing the solution, transferring into a mold, placing the mold in a 37 deg.C oven to allow gelation, transferring part of the solution into a test tube, and measuring gelation time by tube inversion method.
Example 5
Accurately weighing 0.8g of CMCS powder, dissolving in 10mL of deionized water, stirring uniformly, measuring the pH value of the solution, and if the pH value is not high<6.5, adjusting the pH value to 6.5 by using 1mol/L NaOH solution for later use. 350mg/mL alpha-GP solution is prepared, 1.4g of alpha-GP powder is accurately weighed and dissolved in 4mL of deionized water for later use. Preparing 40mg/mL SA solution, weighing 0.8g SA powder, adding into 20mL deionized water, and stirring thoroughly for 3h at normal temperature by using a magnetic stirrer for later use. 50mg/mL BaCl is prepared20.25g of the solution is weighed and dissolved in 5mL of deionized water for later use.
The gel preparation process comprises the steps of taking 1mL of 80mg/mL CMCS solution, uniformly mixing the CMCS solution and the beta-GP solution in a volume ratio of 1:1, adding 2.5mL of 40mg/mL SA solution, stirring by using a mechanical stirrer, and finally adding 0.5mL of 50mg/mL BaCl in a stirring state2Mixing the solution, transferring into a mold, placing the mold in a 37 deg.C oven to allow gelation, transferring part of the solution into a test tube, and measuring gelation time by tube inversion method.
Example 6
Accurately weighing 1g of CMCS powder, dissolving in 10mL of deionized water, stirring uniformly, and measuring the solutionpH value, if pH<6.8, adjusting the pH value to 6.8 by using 1mol/L NaOH solution for later use. Preparing 400mg/mL alpha-GP solution, accurately weighing 2g of alpha-GP powder and dissolving in 5mL of deionized water for later use. Preparing 25mg/mL SA solution, weighing 0.5g SA powder, adding into 20mL deionized water, and stirring thoroughly for 3h at normal temperature by using a magnetic stirrer for later use. Prepare 60mg/mL BaCl20.3g of the solution is weighed and dissolved in 10mL of deionized water for later use.
The gel preparation process comprises the steps of taking 1mL of 100mg/mL CMCS solution, uniformly mixing the CMCS solution and the alpha-GP solution in a volume ratio of 1:1, adding 2.5mL of 25mg/mL SA solution, stirring by using a mechanical stirrer, and finally adding 0.5mL of 60mg/mL BaCl in a stirring state2Mixing the solution, transferring into a mold, placing the mold in a 37 deg.C oven to allow gelation, transferring part of the solution into a test tube, and measuring gelation time by tube inversion method.
The gel mechanism diagram is shown in figure 1, a CMCS-GP temperature-sensitive gel system is a first network, water molecules can be adsorbed on a CMCS chain through hydrogen bond action at room temperature to form a hydration film, and a small amount of GP molecules are also adsorbed on the CMCS chain through hydrogen bond action. When the temperature is raised to 35-39 ℃, hydrogen bonds between water molecules and CMCS chains and between CMCS chains and GP molecules are unstable and are easy to break. The phosphate group with negative charge in GP molecule and the protonized amino group with positive charge on CMCS molecule have electrostatic interaction, so that more GP molecules are attached to CMCS long chain, and the un-protonized amino group can be combined with carboxyl group. And the other end of the GP molecule leads to a more stable hydrogen bond between the negatively charged O atom attached to the GP molecule and the positively charged H atom of the GP molecule due to the induction effect of electrons (the C atom adjacent to the phosphate group is positively charged, the O atom connected to the C atom is negatively charged, and the H atom connected to the O atom is positively charged). Ba-Alg is a second network, 1 Ba2+Forms a complex with 2 guluronic acid (G unit) G segments in the Na-Alg molecular chain segment through 4 coordination bonds, namely the egg lattice structure. The Ba-Alg structure is inserted in the first network, so that the rigidity of the gel is increased, and the gel structure is more compact.
The CMCS-GP/Ba-Alg mixed aqueous solution of example 1 is transferred into a penicillin bottle, and as can be seen from the result shown in FIG. 2, the mixed solution is fluid at room temperature, and after gelation occurs at 37 ℃, the carboxymethyl chitosan-barium alginate double-network temperature-sensitive gel (FIG. 3) without fluidity is obtained.
The single component powder samples (CMCS, GP, SA) and the CMCS-GP/Ba-Alg gel sample from example 1 were dried under vacuum, ground to a fine powder in a clean agate mortar and dried for 3 days with phosphorus pentoxide for use. The infrared absorption spectrum was measured by a Fourier infrared spectrometer using KBr pellet method. As shown in FIG. 4, at 3296cm in SA-1The absorption peak is the stretching vibration peak of-OH, and the absorption peaks at 1581cm-1 and 1408cm-1 are respectively corresponding to the symmetrical and asymmetrical stretching vibration absorption peaks of-COOH. The expansion vibration peak of C-O is at 1010 cm-1. The beta-GP is a stretching vibration peak of-OH near 3219cm-1, and the peak shape is wider because the-OH forms intermolecular hydrogen bonds. 952cm-1 and 1055cm-1 correspond to the symmetric and asymmetric absorption peaks of the phosphate radical. The peak at 3300cm-1 in CMCS is an overlapping peak of-OH and-NH stretching vibrations, and is relatively narrow because the hydrogen at the primary amino group at position 2 and the hydroxyl group at position 6 are partially substituted. The O-H vibration peak at 2931cm-1 is on the carboxyl group. The characteristic peak at 1523cm-1 corresponds to the bending vibration peak of N-H, and the characteristic peak at 1053cm-1 corresponds to the characteristic stretching vibration absorption peak of carbohydrate C-O, which proves that carboxyl is introduced on the chitosan. The absorption peak of CMCS-GP/Ba-Alg gel corresponding to N-H at 1535cm-1 is weakened, and the characteristic absorption peaks of phosphate radicals at 948cm-1 and 1047cm-1 are weakened, which proves that electrostatic interaction occurs between protonated amino in carboxymethyl and phosphate radicals in GP. This demonstrates the formation of a CMCS-GP/Ba-Alg complex gel.
As can be seen from fig. 5, the larger the concentration of barium chloride solution, the shorter the gelation time, and when the concentration of barium chloride is 30 to 50mg/mL, the gelation time of the gel sample is suitable, which is advantageous for injection and enables rapid gel phase transition.
Placing the gel samples of examples 1-6 at a constant temperature of 37 ℃ for 24h, taking out the gel samples, and compressing the gel samples to 70% deformation at a certain speed by using a texture analyzer to obtain the gel samplesCompressive modulus of the gel sample. The effect of different barium chloride concentrations on the compressive modulus was investigated, and as shown in FIG. 6, the compressive modulus showed a tendency of increasing first and then decreasing with increasing barium chloride concentration, when C isBaCl2The elastic modulus of the gel reached a maximum at 40 mg/mL. And further, the mechanical property of the gel can be effectively regulated and controlled by changing the concentration of the barium chloride solution.
The initial weights of the CMCS-GP/Ba-Alg (20mg/mL) gel sample in example 1, the CMCS-GP/Ba-Alg (30mg/mL) gel sample in example 2, and the CMCS-GP/Ba-Alg (40mg/mL) gel sample in example 4 were recorded as W0. The gel was placed in a simulated tear fluid (10 mL) at 37 ℃ and the weight of the gel was measured at regular intervals and recorded as Wt. Before measuring the weight of the gel, the water on the surface of the gel was removed by blotting with a filter paper. At a rate of change of weight Wt/W0The degradation rate of the gel was characterized and three groups of samples were run in parallel for each formulation. The degradation profile is shown in fig. 7, and it is clearly observed that the gel degrades more slowly with higher barium chloride concentration. Because the interaction force among the CMCS-GP/Ba-Alg gel molecules is enhanced, the crosslinking degree is increased immediately, the gel structure is more compact, and the degradation rate of the gel is reduced, which shows that the barium chloride has a regulating effect on the degradation performance of the CMCS-GP/Ba-Alg gel.
The CMCS-GP/Ba-Alg (20mg/mL) gel samples in example 1, the CMCS-GP/Ba-Alg (30mg/mL) gel samples in example 2, and the CMCS-GP/Ba-Alg (40mg/mL) gel samples in example 4 were freeze-dried. Initial weight is recorded as W0Placing the gel in simulated tear fluid of 10mL at 37 deg.C, taking out every 10-20min, removing water on the surface of the gel with filter paper, and measuring the weight W of the gel after water absorptiontTo (W)t-W0)/W0The swelling ratio of the gel was characterized and three sets of samples were run in parallel for each formulation. As shown in FIG. 8, it is clearly observed that the gel swelling property is weaker and weaker with the higher concentration of barium chloride, because the interaction force between the CMCS-GP/Ba-Alg gel molecules is enhanced, the crosslinking degree is increased, the gel structure is denser, the pores of the gel are smaller and smaller, and the swelling property is reduced, which shows that the barium chloride can adjust the swelling property of the CMCS-GP/Ba-Alg gelAnd (4) acting.
Claims (9)
1. The injectable double-network temperature-sensitive hydrogel is characterized in that raw materials for preparing the injectable double-network temperature-sensitive hydrogel comprise carboxymethyl chitosan, sodium glycerophosphate, alginate and barium chloride, wherein the mass ratio of the carboxymethyl chitosan to the sodium glycerophosphate to the alginate to the barium chloride is (60-100): 350-450: (25-40): 10-60).
2. The carboxymethyl chitosan-alginate injectable dual-network temperature-sensitive hydrogel according to claim 1, wherein the molecular weight of the carboxymethyl chitosan is 150000-300000, and the degree of substitution is 70-90%.
3. The carboxymethyl chitosan-alginate injectable dual-network temperature-sensitive hydrogel according to claim 1, wherein the sodium glycerophosphate is selected from alpha-sodium glycerophosphate, beta-sodium glycerophosphate or alpha, beta-sodium glycerophosphate.
4. The carboxymethyl chitosan-alginate injectable double-network temperature-sensitive hydrogel as claimed in claim 1, wherein the alginate is sodium alginate or calcium alginate.
5. The preparation method of the carboxymethyl chitosan-alginate injectable double-network temperature-sensitive hydrogel according to claim 1, which is characterized by comprising the following steps:
1) dissolving carboxymethyl chitosan in deionized water, and then adjusting the pH value of the solution to 6.5-7.4 to prepare a carboxymethyl chitosan solution; dissolving sodium glycerophosphate in deionized water to prepare a sodium glycerophosphate aqueous solution; adding alginate into deionized water to prepare alginate aqueous solution; dissolving barium chloride in deionized water to prepare a barium chloride aqueous solution;
2) fully and uniformly mixing a carboxymethyl chitosan aqueous solution and a sodium glycerophosphate aqueous solution, then adding an alginate solution into the obtained mixed solution, and stirring to fully and uniformly mix the solution to obtain a mixed solution A;
3) dropwise adding the barium chloride solution into the mixed solution A, and uniformly stirring to obtain a mixed solution B;
4) and (3) moving the mixed solution B into a mold, and carrying out gelation treatment at the temperature of 35-39 ℃ to obtain the carboxymethyl chitosan-barium alginate injectable double-network temperature-sensitive hydrogel.
6. The preparation method of the carboxymethyl chitosan-alginate injectable dual-network temperature-sensitive hydrogel according to claim 5, wherein the molecular weight of the carboxymethyl chitosan is 150000-300000, and the substitution degree is 70% -95%; the sodium glycerophosphate is selected from alpha-sodium glycerophosphate, beta-sodium glycerophosphate or alpha, beta-sodium glycerophosphate; the alginate is sodium alginate or calcium alginate.
7. The preparation method of the carboxymethyl chitosan-alginate injectable dual-network temperature-sensitive hydrogel according to claim 5, wherein the concentration of the carboxymethyl chitosan solution is 60-100 mg/mL; the concentration of the sodium glycerophosphate aqueous solution is 300-450 mg/mL; the concentration of the alginate aqueous solution is 20-40 mg/mL; the concentration of the barium chloride aqueous solution is 10-60 mg/mL.
8. The preparation method of the carboxymethyl chitosan-alginate injectable dual-network temperature-sensitive hydrogel according to claim 5, wherein the pH value of the carboxymethyl chitosan solution is adjusted by using 0.1-1 mol/L NaOH solution in the step 1).
9. Use of the carboxymethyl chitosan-barium alginate injectable double-network temperature-sensitive hydrogel of claim 1 in the preparation of lacrimal passage suppository for treating dry eye.
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