CN102827446A - Temperature response type injectable hydrogel and preparation method and usage thereof - Google Patents

Abstract

The present invention relates to a temperature-responsive injectable hydrogel and its preparation method and application. The hydrogel is composed of component A, component B and water; wherein component A is cholesterol-polyethylene glycol-cholesterol ; Component B is aminated β-cyclodextrin grafted formaldehyde dextran. The preparation process of the present invention is simple and convenient, the prepared gel has certain strength and toughness, has self-healing property, improves the controllability of the gel performance and further improves the biocompatibility of the gel compared with the prior art; The gel prepared by the invention has biodegradability and can be metabolized by the human body; it has temperature responsiveness and injectability, and can be used as a drug carrier, embolism material and tissue engineering material.

Description

A temperature-responsive injectable hydrogel and its preparation method and use

technical field

The invention relates to polymer materials, in particular to a temperature-responsive injectable hydrogel and its preparation method and application.

Background technique

Hydrogels are aggregates with a three-dimensional network structure formed by cross-linking hydrophilic polymers. Although it is insoluble in water, the hydrophilic part of this aggregate can bind a large amount of water, so that the entire gel swells. Such high water retention properties and flexible characteristics make the structure of the hydrogel very similar to that of human tissue. Hydrogel materials are easy to modify, synthesize, and adjust properties. Ordinary hydrogels can be loaded with a large amount of water-soluble drugs, and after modification, they can also have good retention properties for oil-soluble drugs, and are more capable of loading Living cells or tissues that serve as scaffolding for growth.

In situ hydrogel means that the gel is administered in a solution state, and after being injected into the receiving site, a relatively stable three-dimensional gel network structure is formed to fix and function in the tissue. The classic gel is not very convenient to use in medicine because of its large volume. When it is used as a drug-loaded gel or tissue engineering material for embedding or transplantation in the body, it must cause a large wound on the surface of the organism to remove the gel. Glue is implanted into the body, which is not only expensive, but also causes additional damage to the human body, and is not suitable for use in relatively delicate and fragile tissues such as blood vessels and nerves. The emergence of in situ gels, especially injectable gels, meets the requirements of controlled drug release and tissue engineering, and has always been a research and development hotspot in pharmacy.

The formation of in situ hydrogel belongs to the solution-gel transition, requiring its solution to undergo a phase transition immediately after injection, from flowable to semi-fluid or immobile. From the perspective of molecular structure, the polymer chains are quickly cross-linked, forming enough cross-linking points to restrict the movement of the chains and thus the flow of fluids. This requires shorter cross-linking time and strong cross-linking force, and cross-linking methods that meet this feature include in-situ chemical cross-linking and physical cross-linking.

In-situ chemical crosslinking is to use crosslinking agents or reactive groups to form chemical bonds between molecular chains. The classic in-situ chemical cross-linking methods include small molecule cross-linking agent cross-linking, photochemical cross-linking, complexation cross-linking and special reaction cross-linking, etc. When using cross-linking agents to prepare in-situ chemical gels, the most commonly used cross-linking agents are epichlorohydrin, formaldehyde and silicone cross-linking agents, etc., but because these cross-linking agents are too toxic and residual toxic, only It can be used in engineering materials, etc., but cannot be applied to the human body in medicine.

Physically cross-linked gel means that the cross-linking of molecular chains in the gel is caused by the interaction of non-covalent bonds when the gel is formed. Some of the non-covalent interactions most commonly used in hydrogel formation are charge interactions, hydrogen bonds, hydrophilic-hydrophobic interactions, and host-guest interactions, among others. Since no toxic cross-linking agent is introduced, it has good application potential in biomedicine.

At present, physical gels commonly used in drug gel dosage forms and tissue engineering materials include poloxamer407 (polyethylene glycol-polypropylene glycol-polyethylene glycol block copolymer) and the like. When this type of physical gel is formulated into a hydrosol, it is in a solution state at low temperature and can be used for injection. After injection, a sol-gel transformation occurs, the viscosity increases, the fluidity decreases, and it becomes a gel state. Mixed with drugs or cells before injection, it can be used as drug-loaded gel, embolic material or tissue engineering carrier. However, the preparation and purification process of this kind of physical gel is not only complicated, but also cannot be degraded by the human body, and it is difficult to remove from the human body's circulatory system after use, which will cause adverse effects on the human body in the long run. Another class of degradable injectable gels are PCL-PEG-PCL (polycaprolactone-polyethylene glycol-polycaprolactone block copolymer), PCLA-PEG-PCLA (lactide/caprolactone Copolymer - block copolymer of polyethylene glycol-lactide/caprolactone copolymer) and PEO-PLGA-PEO [polyethylene glycol-(polylactic acid-polyglycolic acid copolymer)-polyethylene glycol Alcohol block copolymer] and so on. This type of gel can also undergo sol-gel transformation after injection, but the production process is complicated, purification is difficult, and the controllability of the gel performance is not good.

Contents of the invention

Aiming at the deficiencies of the prior art, the present invention provides a temperature-responsive injectable hydrogel and its preparation method and application.

The concrete technical scheme that the present invention takes is as follows:

1. A temperature-responsive injectable hydrogel is characterized in that: it is made of component A, component B and water; the mass of the component A and component B and the mass percentage in the hydrogel are 5%-50%, of which component A is cholesterol-polyethylene glycol-cholesterol; component B is aminolated β-cyclodextrin grafted aldodextran.

As a preference:

The mass of the component A and the component B and the mass percentage in the hydrogel are 5%-30%.

The mass ratio of component A and component B is component A/component B=(0.5-25)/1, and the content of β-cyclodextrin in component B is (0.5-0.6) g/g.

The pH of the hydrogel is ≥5.

2. A method for preparing a temperature-responsive injectable hydrogel, comprising the following steps:

Step 1, prepare cholesterol-polyethylene glycol-cholesterol, obtain component A, set aside;

Step 2. Prepare aminoated β-cyclodextrin grafted with aldoglucan to obtain component B for later use;

Step 3: Mix and swell component A and component B prepared in the previous step with water to obtain the product.

As a preference:

The mass of the component A and the component B and the mass percentage in the hydrogel are 5%-30%;

The mass ratio of component A to component B is component A/component B=(0.5-25)/1;

The content of β-cyclodextrin in component B is (0.5-0.6) g/g.

The pH of the hydrogel is ≥5.

the

In the above scheme, the cholesterol-polyethylene glycol-cholesterol triblock compound is prepared by the following method: after the carboxylic acid chlorination of cholesteryl succinate with thionyl chloride, it is mixed with dioxane in dioxane Hydroxypolyethylene glycol or bisaminopolyethylene glycol reaction, adding enough pyridine or triethylamine or sodium carbonate or potassium carbonate as a catalyst and acid-binding agent to neutralize the acid produced by the reaction, the reactant obtained after the reaction is complete It was obtained by precipitation in ether, centrifugation and drying.

the

In the above scheme, the aminoated β-cyclodextrin grafted aldodextran was prepared by the following method: after the dextran was oxidized with periodic acid in water, it was dialyzed with water as the medium, and dialyzed to the final conductivity of the dialysis medium. When it is lower than 1 μS/cm, the product obtained by freeze-drying and aminated β-cyclodextrin react completely in aqueous solution at 30-50 ^o C, then dialyze with water as the medium, and dialyze to the final conductivity of the dialysis medium Freeze-dried at a rate below 1 μS/cm.

the

The hydrogel that the present invention makes has following characteristics:

1) When the mass ratio of component A and component B is component A/component B=(0.5-25)/1, the mass sum of component A and component B is 5%-30% of the total mass Forms a stable gel.

2) At room temperature, when the total concentration is 5-20%, it can be injected through a syringe; when the concentration is above 20%, the gel can be demoulded and exists stably.

3) When the mass ratio of component A and component B is component A/component B=(0.5-2.5)/1, and the concentration is 5-15%, it is in a fluid state above 50 ^o C, and it is In gel state, it can be injected at high temperature and gels at around body temperature.

the

The preparation process of the present invention is simple and convenient, the prepared gel has certain strength and toughness, has self-healing property, improves the controllability of the gel performance and further improves the biocompatibility of the gel compared with the prior art; The gel prepared by the invention has biodegradability and can be metabolized by the human body; it has temperature responsiveness and injectability, and can be used as a drug gel carrier, embolism material and tissue engineering material.

Description of drawings:

Figure 1: Gel prepared in Example 2 .

Detailed ways

The present invention will be further described below in conjunction with specific embodiments. This specific embodiment does not limit its protection scope.

Example 1

Step 1: Select polyethylene glycol 2000 as the hydrophilic segment, use succinic anhydride as a cross-linking agent, carboxylate the monoester of cholesterol, acyl chloride and secondary esterify to obtain cholesterol-polyethylene glycol-2000-cholesterol, That is component A.

Step 2: Dextran with a molecular weight of 40 kDa was oxidized in a periodic acid aqueous solution with a periodic acid/sugar ring molar ratio of 20%, and dialyzed with deionized water until the final conductivity of the dialysis medium was lower than 1 μS/cm Finally, the product obtained after lyophilization and aminated β-cyclodextrin reacted completely in aqueous solution at 30-50 ^o C, and then dialyzed again until the final conductivity of the dialysis medium was lower than 1 μS/cm, and then lyophilized to obtain . The content of β-cyclodextrin measured by the phenolphthalein probe method is 0.5-0.6 g/g, which is component B.

Step 3: According to the mass ratio of component A and component B, component A/component B=7/3, the mass sum of component A and component B is 30% of the total mass and weigh component A, component B Divide B and water, mix components A and B with water to swell, and obtain a stable release gel with certain strength and self-healing properties.

Example 2.

Cholesterol-polyethylene glycol-2000-cholesterol is obtained according to the method in step 1 and step 2 of Example 1, that is, component A, β-cyclodextrin whose content of β-cyclodextrin is 0.5-0.6g/g Refined grafted dextran, component B.

According to the mass ratio of component A and component B, component A/component B=7/3, the mass sum of component A and component B is 20% of the total mass and weigh component A, component B, Water, mix and swell components A and B with water to obtain a stable gel with certain strength and self-healing properties, and has a sustained release effect on hydrophilic and protein drugs.

Example 3.

Cholesterol-polyethylene glycol-2000-cholesterol is obtained according to the method in step 1 and step 2 of Example 1, that is, component A, β-cyclodextrin whose content of β-cyclodextrin is 0.5-0.6g/g Refined grafted dextran, component B.

According to the mass ratio of component A and component B, it is component A/component B=1/1, and the mass sum of component A and component B is 20% of total mass and takes component A, component B, Water, mix and swell components A and B with water to obtain a stable gel with certain strength, injectability and self-healing properties, and has a sustained release effect on hydrophilic and protein drugs.

Example 4.

Cholesterol-polyethylene glycol-4000-cholesterol is obtained according to the method in step 1 and step 2 of Example 1, that is, component A, β-cyclodextrin whose content of β-cyclodextrin is 0.5-0.6g/g Refined grafted dextran, component B.

According to the mass ratio of component A and component B, it is component A/component B=4/5, and the mass sum of component A and component B is 20% of total mass and takes component A, component B, Water, mix and swell component A and component B with water to obtain a stable gel with high viscosity, self-healing and injectability, which can be used as a drug carrier and tissue engineering material.

Example 5.

Cholesterol-polyethylene glycol-10000-cholesterol is obtained according to the method in step 1 and step 2 of Example 1, that is, component A, β-cyclodextrin whose content of β-cyclodextrin is 0.5-0.6g/g Refined grafted dextran, component B.

According to the mass ratio of component A and component B, component A/component B=25/1, the mass sum of component A and component B is 5% of the total mass and weigh component A, component B, Water, mix component A and component B with water to swell to obtain a stable gel, which has certain strength and brittleness.

the

Example 6

Cholesterol-polyethylene glycol 2000-cholesterol was prepared according to the method in step 1 and step 2 of Example 1, that is, component A, β-cyclodextrin with a content of 0.5-0.6 g/g of β-cyclodextrin Graft aldoglucan, ie component B.

According to the mass ratio of component A and component B, component A/component B=0.5/1, the mass sum of component A and component B is 50% of the total mass and weigh component A, component B, Water, mix and swell components A and B with water to obtain a stable gel with high strength and certain brittleness.

the

Example 7

Cholesterol-polyethylene glycol-4000-cholesterol is obtained according to the method in step 1 and step 2 of Example 1, that is, component A, β-cyclodextrin whose content of β-cyclodextrin is 0.5-0.6g/g Refined grafted dextran, component B.

According to the mass ratio of component A and component B, component A/component B=1/1, the mass sum of component A and component B is 15% of total mass and weighs component A, component B, Water, mix and swell components A and B with water to obtain a stable gel, which has certain strength, injectability and self-healing properties. It is in a fluid state above 50 ^o C, and it is in a gel state at room temperature. It can be used at high temperatures. When injected, it gels at body temperature. It can be used as drug carrier and tissue engineering material.

Claims (10)

1. a temperature response type injection aquagel is characterized in that: be made up of component A, B component and water; The quality of said component A and B component and the mass percent in hydrogel are 5%-50%, and wherein component A is CPEG-SUV; B component is an amination grafted by beta cyclodextrin hydroformylation VISOSE.

2. temperature response type injection aquagel as claimed in claim 1 is characterized in that: the quality of said component A and B component and the mass percent in hydrogel are 5%-30%.

3. temperature response type injection aquagel as claimed in claim 1 is characterized in that: the mass ratio of said component A and B component is that component A/ B component=(0.5-25)/1, the content of beta-cyclodextrin is (0.5-0.6) g/g in the B component.

4. temperature response type injection aquagel as claimed in claim 1 is characterized in that: said hydrogel pH >=5.

5. a temperature response type injection aquagel preparation method as claimed in claim 1 comprises the steps:

Step 1, preparation CPEG-SUV get component A, and be subsequent use;

Step 2, preparation amination grafted by beta cyclodextrin hydroformylation VISOSE get B component, and be subsequent use;

Step 3, will go up the component A that makes of step and B component and add water and mix swelling, promptly get.

6. preparation method as claimed in claim 5: it is characterized in that:

1) quality of said component A and B component and the mass percent in hydrogel are 5%-30%;

2) mass ratio of component A and B component is a component A/ B component=(0.5-25)/1;

3) content of beta-cyclodextrin is (0.5-0.6) g/g in the B component.

7. temperature response type injection aquagel as claimed in claim 5 is characterized in that: said hydrogel pH >=5.

8. the preparation method of the described novel physical hydrogel of claim 5; It is characterized in that: the CPEG in the said step 1--SUV three block compounds adopt following method preparation: after the carboxylic acyloxy chlorination of thionyl chloride with the monobutane diacid cholesteryl ester; In dioxane, react again with two hydroxyl polyoxyethylene glycol or two amino polyoxyethylene glycol; Pyridine or triethylamine or yellow soda ash or the salt of wormwood of amount that adds the acid that enough neutralization reactions produces is as catalyzer and acid binding agent, and the reactant that obtains after reacting completely precipitates in ether, centrifugal and dry obtaining.

9. preparation method as claimed in claim 5: it is characterized in that: the amination grafted by beta cyclodextrin hydroformylation VISOSE in the said step 2 adopts the preparation of following method: with VISOSE with Periodic acid 99 after water oxygenization; Dialyse with water as medium; After dialysis to the final specific conductivity of the medium of dialysing is lower than 1 μ S/cm, product that lyophilize makes and amidized beta-cyclodextrin in the aqueous solution, 30-50 ^oAfter reacting completely under the C, with the water as medium dialysis, the final specific conductivity of dialysis to the medium of dialysing is lower than 1 μ S/cm postlyophilization and obtains.

10. temperature response type injection aquagel as claimed in claim 1 is used for the purposes of pharmaceutical carrier, embolism materials and tissue engineering material.

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