CN104861178A - Pullulan-hyaluronic acid hydrogel and preparation method thereof - Google Patents
Pullulan-hyaluronic acid hydrogel and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a preparation method of pullulan-hyaluronic acid hydrogel. The preparation method comprises steps as follows: hyaluronic acid is taken and dissolved in double distilled water, and then pullulan powder with different molecular weights is added to a hyaluronic acid solution for stirring reaction; a cross-linking agent solution is added for the stirring reaction; a reaction liquid is subjected to water bath heating to prepare the hydrogel; the prepared hydrogel is immersed and washed by pyrogen-free water and a phosphate buffered solution sequentially, and injectable particles with different particle sizes are prepared by a granulator. With the adoption of a chemical crosslinking method, 1, 4-butanediol diglycidyl ether and the hyaluronic acid are in butt joint with molecular chains of pullulan to form a polymer, the particles with the difference particle sizes can be prepared by the granulator and can be placed in an injector for injection use, and the pullulan-hyaluronic acid hydrogel has the advantages of high stability, high biological value and long degradation time, so that skin filling advantage is really realized.
Description
Technical field
The present invention relates to a kind of hydrogel, be specifically related to a kind of pulullan polysaccharide-hyaluronic acid gel and preparation method thereof.
Background technology
The design of hydrogel and develop into there is the focus of multi-functional high molecular polymer for tissue repair research.Recent years, a lot of hydrogel is by chemosynthesis (forming new covalent linkage) or the method synthesis of natural polymkeric substance of physical crosslinking (interaction between hydrogen bond, hydrophilic-hydrophobic and electrostatic interaction) or synthetic polymer.Material prepared by these methods can be easy to the environment adapting to human body, has been widely used in medical science, drug release, field of tissue engineering technology.With the growth of human age, the loss that skin follows the string gradually, moisture is a large amount of.Therefore, increasing people restores face or reinvents operation.Soft tissue filling material carries out correcting being paid close attention to by people gradually for skin and face.Generally prepare in soft tissue filling material, have chitosan, fat, chrondroitin, collagen, fibroin, hyaluronic acid, polysaccharide Fibronectin, hydroxyapatite, gelatin, poly(lactic acid), animal collagen or polymethylmethacrylate.Hyaluronic acid, has the propagation of promotion cell, the transmission expression of albumen, the biological activity of embodiment itself.Pulullan polysaccharide has good toxicological harmless effect, water-soluble, dispersed, water absorbability, can be used for makeup with viscosity additive.
Summary of the invention
The object of this invention is to provide a kind of pulullan polysaccharide-hyaluronic acid gel and preparation method thereof, adopt Chemical Crosslinking Methods preparation to have more the higher skin packing material of biocompatibility, security and implant frame material.
Implementation procedure of the present invention is as follows:
A preparation method for pulullan polysaccharide-hyaluronic acid gel, comprises the following steps:
(1) hyaluronic acid is dissolved in distilled water and obtains the hyaluronic acid solution that quality volume fraction is 30 ~ 200mg/mL, then in hyaluronic acid solution, pulullan polysaccharide is added, the mass ratio of hyaluronic acid and pulullan polysaccharide is 1 ~ 3:1 ~ 10, and it is 0 ~ 27 DEG C that temperature controls;
(2) add the linking agent Isosorbide-5-Nitrae butanediol diglycidyl ether solution that massfraction is 5 ~ 20%, stir, it is 20 ~ 30 DEG C that temperature controls; Wherein the mass ratio of hyaluronic acid and linking agent is 50 ~ 500:1 ~ 15;
(3) reaction solution is obtained hydrogels 45 ~ 55 DEG C of reactions;
(4) obtained hydrogel embathes 2 ~ 3 days with apirogen water and phosphate buffer soln in succession, makes injectable particle with nodulizer.
Above-mentioned pulullan polysaccharide is the outer neutral polysaccharide of water-soluble born of the same parents of Aureobasidium pullulans secretion, and molecular weight is 100000 ~ 530000g/mol; Hyaluronan molecule amount is 2000000 g/mol; The pH of phosphate buffer soln is 7.4.
Specifically, the preparation method of above-mentioned pulullan polysaccharide-hyaluronic acid gel comprises the following steps:
(1) taking molecular weight is that the hyaluronic acid of 2000000 g/mol is dissolved in distilled water, obtain the hyaluronic acid solution 10mL that quality volume fraction is 30 ~ 200mg/mL, then in hyaluronic acid solution, the pulullan polysaccharide that molecular weight is 100000 ~ 530000g/mol is added, the mass ratio of hyaluronic acid and pulullan polysaccharide is 1 ~ 3:1 ~ 10, it is 0 ~ 27 DEG C that temperature of reaction controls, and reacts 0.5 ~ 1h under agitation;
(2) add 0.1 ~ 0.35mL, massfraction be 5 ~ 20% linking agent Isosorbide-5-Nitrae butanediol diglycidyl ether solution, temperature of reaction control be 20 ~ 30 DEG C, react 0.2 ~ 0.5h under agitation;
(3) reaction solution is put in 5 ~ 7h in 50 DEG C of thermostat water baths, obtained hydrogel;
(4) obtained hydrogel embathes 2 ~ 3 days with the phosphate buffer soln that apirogen water and pH are 7.4 in succession, makes injectable particle with nodulizer.
The present invention has the following advantages: the hydrogel of a kind of pulullan polysaccharide involved in the present invention and hyaluronic acid synthesis, the pulullan polysaccharide of different molecular weight and hyaluronic acid are combined the skin packing material made, with hyaluronic acid and the outer neutral polysaccharide of the water-soluble born of the same parents of different molecular weight secreted by Aureobasidium pullulans (Aureobasidium pullulans) for raw material, Chemical Crosslinking Methods is adopted to make.1; the molecular chain of 4-butanediol diglycidyl ether and hyaluronic acid and pulullan polysaccharide docks and is connected to form polymkeric substance; the particle of different-grain diameter is made by nodulizer; injection in syringe can be loaded use; have have good stability, biological value is high, degradation time is longer, thus really realize skin fill advantage.
Accompanying drawing explanation
Fig. 1 is the photo figure of hydrogel;
Fig. 2 is the scanning electron microscope (SEM) photograph of hydrogel; In figure, No. 1 is the scanning electron microscope (SEM) photograph (amplifying 100 times) of hydrogel, and No. 2 is the scanning electron microscope (SEM) photograph (amplifying 250 times) of hydrogel, and No. 3 is the scanning electron microscope (SEM) photograph (amplifying 100 times) of hydrogel, and No. 4 is the scanning electron microscope (SEM) photograph (amplifying 250 times) of hydrogel;
Fig. 3 is the crush test figure of hydrogel; 1 and No. 2 is the relation between the compression displacement of hydrogel and compressive load;
Fig. 4 is that hydrogel is injected in the subcutaneous figure of mouse; In figure, 1 is injected in the figure of mouse after subcutaneous two weeks for hydrogel, and 2 for being injected in the figure of the hydrogel that mouse is taken out after subcutaneous two weeks, and 3 hydrogels are be injected in the figure of mouse after subcutaneous two weeks, and 4 for being injected in the figure of the hydrogel that mouse is taken out after subcutaneous two weeks.
Embodiment
Below in conjunction with embodiment, the present invention will be described in detail.
The hydrogel of a kind of pulullan polysaccharide involved in the present invention and hyaluronic acid synthesis, the outer neutral polysaccharide of water-soluble born of the same parents of the different molecular weight secreted with Aureobasidium pullulans (Aureobasidium pullulans) and hyaluronic acid are for raw material, linking agent is adopted to carry out chemically crosslinked, be cross-linked under stirring at 27 DEG C again, after reaction terminates, at reaction solution being put into 50 DEG C, static placement 3 ~ 6h, prepares hydrogel.
The pulullan polysaccharide of what pulullan polysaccharide in raw material adopted is different molecular weight, pulullan polysaccharide and hyaluronic acid itself have good biocompatibility and degradability, can be applicable to field of tissue engineering technology.The higher polysaccharides class that hyaluronic basic structure is made up of dissacharide units D-Glucose aldehydic acid and N-acetyl-glucosamine, has special water retention, is the best material of the occurring in nature moisture retention that finds at present.Skin-nourishing metabolism can be improved, make skin tender, smooth, go wrinkle, increase elasticity, prevent aging, be again good Percutaneous absorption enhancer while moisturizing.
BDDE (BDDE) is a kind of double-functional group linking agent, can the hydroxyl of open loop and pulullan polysaccharide is crosslinked generates ehter bond, and also can be oxidized hydroxyl is aldehyde radical, also can realize pulullan polysaccharide and to be hyaluronicly cross-linked.And BDDE has been the certification of FDA/EMEA regulation.Therefore select BDDE linking agent, novel hydrogel prepared by the pulullan polysaccharide of different molecular weight and hyaluronic acid.
The preparation method of the pulullan polysaccharide-hyaluronic acid gel that the present invention relates to, is realized by following steps:
Step one: take hyaluronic acid and be dissolved in distilled water, obtain the hyaluronic acid solution 10mL that quality volume fraction is 30 ~ 200mg/mL, then in hyaluronic acid solution, add the pulullan polysaccharide powder of different molecular weight, make the mass ratio of hyaluronic acid and pulullan polysaccharide for (1 ~ 3): (1 ~ 10), it is 0 ~ 27 DEG C that temperature of reaction controls, and reacts 0.5 ~ 1h under agitation;
Step 2: add 0.1 ~ 0.35mL, massfraction is the cross-linking agent solution of 5 ~ 20%, it is 20 ~ 30 DEG C that temperature of reaction controls, and reacts 0.2 ~ 0.5h under agitation;
Step 3: reaction solution is put in 5h ~ 7h in 50 DEG C of thermostat water baths, obtained hydrogel;
Step 4: obtained hydrogel embathes 2 ~ 3 days with apirogen water and phosphate buffer soln in succession, makes the injectable particle of different-grain diameter with nodulizer.
In step one, pulullan polysaccharide is the outer neutral polysaccharide of water-soluble born of the same parents of the different molecular weight of Aureobasidium pullulans secretion, and molecular weight is 100000g/mol ~ 530000g/mol.
In step one, hyaluronan molecule amount is 2000000 g/mol.
In step 2, linking agent is Isosorbide-5-Nitrae butanediol diglycidyl ether.
In step 4, the pH of phosphate buffer soln is 7.4.
Wherein, linking agent BDDE can dock with the pulullan polysaccharide molecular chain of different molecular weight and form polymkeric substance, also can realize the pulullan polysaccharide of different molecular weight and hyaluronic crosslinked.
Graft (co) polymers is formed at 50 DEG C of temperature to the hydrogel being similar to g., jelly-like, impurity residual in apirogen water and phosphate buffer soln wash water gel and some unreacted BDDEs.Scavenging period is 2 ~ 6 days.The grade particle of different-grain diameter made by hydrogel granulation machine after purifying, then can load in syringe for injection.
Embodiment 1:
Step one: take hyaluronic acid and be dissolved in distilled water, obtain the hyaluronic acid solution 10mL that quality volume fraction is 30mg/mL, then in hyaluronic acid solution, add the pulullan polysaccharide powder of different molecular weight, the mass ratio of hyaluronic acid and pulullan polysaccharide is made to be 3:1, it is 27 DEG C that temperature of reaction controls, and reacts 0.5h under agitation;
Step 2: add 0.35mL, massfraction is the cross-linking agent solution of 5%, it is 30 DEG C that temperature of reaction controls, and reacts 0.2h under agitation;
Step 3: reaction solution is put in 7h in 50 DEG C of thermostat water baths, obtained hydrogel;
Step 4: obtained hydrogel embathes 2 days with apirogen water and phosphate buffer soln in succession, makes the injectable particle of different-grain diameter with nodulizer.
In step one, pulullan polysaccharide is the outer neutral polysaccharide of water-soluble born of the same parents of the different molecular weight of Aureobasidium pullulans secretion, and molecular weight is 380000g/mol ~ 530000g/mol.
In step one, hyaluronan molecule amount is 2000000 g/mol.
In step 2, linking agent is Isosorbide-5-Nitrae butanediol diglycidyl ether.
In step 4, the pH of phosphate buffer soln is 7.4.
Embodiment 2:
Step one: take hyaluronic acid and be dissolved in distilled water, obtain the hyaluronic acid solution 10mL that quality volume fraction is 100mg/mL, then in hyaluronic acid solution, add the pulullan polysaccharide powder of different molecular weight, the mass ratio of hyaluronic acid and pulullan polysaccharide is made to be 2:5, it is 14 DEG C that temperature of reaction controls, and reacts 0.7h under agitation;
Step 2: add 0.14mL, massfraction is the cross-linking agent solution of 10%, it is 25 DEG C that temperature of reaction controls, and reacts 0.3h under agitation;
Step 3: reaction solution is put in 6h in 50 DEG C of thermostat water baths, obtained hydrogel;
Step 4: obtained hydrogel embathes 2.5 days with apirogen water and phosphate buffer soln in succession, makes the injectable particle of different-grain diameter with nodulizer.
In step one, pulullan polysaccharide is the outer neutral polysaccharide of water-soluble born of the same parents of the different molecular weight of Aureobasidium pullulans secretion, and molecular weight is 240000g/mol ~ 380000g/mol.
In step one, hyaluronan molecule amount is 2000000 g/mol.
In step 2, linking agent is Isosorbide-5-Nitrae butanediol diglycidyl ether.
In step 4, the pH of phosphate buffer soln is 7.4.
Embodiment 3:
Step one: take hyaluronic acid and be dissolved in distilled water, obtain the hyaluronic acid solution 10mL that quality volume fraction is 200mg/mL, then in hyaluronic acid solution, add the pulullan polysaccharide powder of different molecular weight, the mass ratio of hyaluronic acid and pulullan polysaccharide is made to be 1:10, it is 0 DEG C that temperature of reaction controls, and reacts 1h under agitation;
Step 2: add 0.1mL, massfraction is the cross-linking agent solution of 20%, it is 20 DEG C that temperature of reaction controls, and reacts 0.5h under agitation;
Step 3: reaction solution is put in 5h in 50 DEG C of thermostat water baths, obtained hydrogel;
Step 4: obtained hydrogel embathes 3 days with apirogen water and phosphate buffer soln in succession, makes the injectable particle of different-grain diameter with nodulizer.
In step one, pulullan polysaccharide is the outer neutral polysaccharide of water-soluble born of the same parents of the different molecular weight of Aureobasidium pullulans secretion, and molecular weight is 100000g/mol ~ 240000g/mol.
In step one, hyaluronan molecule amount is 2000000 g/mol.
In step 2, linking agent is Isosorbide-5-Nitrae butanediol diglycidyl ether.
In step 4, the pH of phosphate buffer soln is 7.4.
Carry out scanning electron microscope analysis, sample observation and H & E staining analysis to the product of above embodiment, result is as follows:
1, the sample of hydrogel packing material as shown in Figure 1, and Hydrogels is similar to the gel of g., jelly-like.No. 1 for molecular weight be hydrogel prepared by 100,000g/moL pulullan polysaccharide and hyaluronic acid, transparent, No. 2 for molecular weight be hydrogel prepared by 530,000g/moL pulullan polysaccharide and hyaluronic acid, be creamy white.
2, the scanning electron microscope analysis of hydrogel packing material is as shown in Figure 2,1, No. 2 for molecular weight be 100, hydrogel prepared by 000g/moL pulullan polysaccharide and hyaluronic acid, 3, No. 4 for molecular weight be hydrogel prepared by 530,000g/moL pulullan polysaccharide and hyaluronic acid.Hydrogel is the vesicular structure of three-dimensional network shape, arranges more regular.
3, the crush test of hydrogel is as shown in Figure 3, and hydrogel is 6mm in compression displacement, No. 1 for molecular weight be hydrogel prepared by 100,000g/moL pulullan polysaccharide and hyaluronic acid, compressive load is 0.05; No. 2 for molecular weight be hydrogel prepared by 530,000g/moL pulullan polysaccharide and hyaluronic acid, compressive load is 0.15MPa.
4, hydrogel packing material is injected in the subcutaneous analysis of mouse as shown in Figure 4,1, No. 2 for molecular weight be 100, hydrogel prepared by 000g/moL pulullan polysaccharide and hyaluronic acid, 3, No. 4 for molecular weight be hydrogel prepared by 530,000g/moL pulullan polysaccharide and hyaluronic acid.Mouse is present in subcutaneous, slightly some degraded at second week hydrogel; After hydrogel packing material is injected in mouse taking-up in subcutaneous two weeks, hydrogel adapts to surrounding tissue gradually.
The hydrogel packing material that the present invention obtains shows for the experimentation on animals of Adult female ICR mouse: the hydrogel prepared with chemical crosslink technique, has good biocompatibility and histocompatibility, and degraded is slow, is suitable for tissue filling.
Content of the present invention is not limited to cited by embodiment, and the conversion of those of ordinary skill in the art by reading specification sheets of the present invention to any equivalence that technical solution of the present invention is taked, is claim of the present invention and contains.
Claims (6)
1. a preparation method for pulullan polysaccharide-hyaluronic acid gel, is characterized in that comprising the following steps:
(1) hyaluronic acid is dissolved in distilled water and obtains the hyaluronic acid solution that quality volume fraction is 30 ~ 200mg/mL, then in hyaluronic acid solution, pulullan polysaccharide is added, the mass ratio of hyaluronic acid and pulullan polysaccharide is 1 ~ 3:1 ~ 10, and it is 0 ~ 27 DEG C that temperature controls;
(2) add the linking agent Isosorbide-5-Nitrae butanediol diglycidyl ether solution that massfraction is 5 ~ 20%, stir, it is 20 ~ 30 DEG C that temperature controls; Wherein the mass ratio of hyaluronic acid and linking agent is 50 ~ 500:1 ~ 15;
(3) reaction solution is obtained hydrogels 45 ~ 55 DEG C of reactions;
(4) obtained hydrogel embathes 2 ~ 3 days with apirogen water and phosphate buffer soln in succession, makes injectable particle with nodulizer.
2. the preparation method of pulullan polysaccharide-hyaluronic acid gel according to claim 1, is characterized in that: pulullan polysaccharide is the outer neutral polysaccharide of water-soluble born of the same parents of Aureobasidium pullulans secretion, and molecular weight is 100000 ~ 530000g/mol.
3. the preparation method of pulullan polysaccharide-hyaluronic acid gel according to claim 1, is characterized in that: hyaluronan molecule amount is 2000000 g/mol.
4. the preparation method of pulullan polysaccharide-hyaluronic acid gel according to claim 1, is characterized in that: the pH of phosphate buffer soln is 7.4.
5. the preparation method of pulullan polysaccharide-hyaluronic acid gel according to claim 1, is characterized in that:
(1) taking molecular weight is that the hyaluronic acid of 2000000 g/mol is dissolved in distilled water, obtain the hyaluronic acid solution 10mL that quality volume fraction is 30 ~ 200mg/mL, then in hyaluronic acid solution, the pulullan polysaccharide that molecular weight is 100000 ~ 530000g/mol is added, the mass ratio of hyaluronic acid and pulullan polysaccharide is 1 ~ 3:1 ~ 10, it is 0 ~ 27 DEG C that temperature of reaction controls, and reacts 0.5 ~ 1h under agitation;
(2) add 0.1 ~ 0.35mL, massfraction be 5 ~ 20% linking agent Isosorbide-5-Nitrae butanediol diglycidyl ether solution, temperature of reaction control be 20 ~ 30 DEG C, react 0.2 ~ 0.5h under agitation;
(3) reaction solution is put in 5 ~ 7h in 50 DEG C of thermostat water baths, obtained hydrogel;
(4) obtained hydrogel embathes 2 ~ 3 days with the phosphate buffer soln that apirogen water and pH are 7.4 in succession, makes injectable particle with nodulizer.
6. pulullan polysaccharide-hyaluronic acid gel of obtaining of preparation method described in claim 1.
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CN108795550B (en) * | 2018-05-21 | 2021-08-03 | 九江职业技术学院 | Environment-friendly heat-conducting cutting fluid containing conjugated linoleic acid salt and preparation method thereof |
CN116173303A (en) * | 2023-04-27 | 2023-05-30 | 北赛泓升(北京)生物科技有限公司 | Biological tympanic membrane and preparation method and application thereof |
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