Hydrogel of sulfydryl-modified high-molecular compound as well as preparation method and application of hydrogel

A technology of polymer compounds and hydrogels, which can be used in medical preparations, pharmaceutical formulations, drug delivery and other directions of non-active ingredients, and can solve the problems of slow speed, high price and affecting hydrogels.

Active Publication Date: 2021-05-18
블라파르바이오테크놀로지항저우리미티드
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Secondly, natural hyaluronic acid or its sodium salt has the disadvantages of poor stability and easy degradation
Third, natural hyaluronic acid or its sodium salt has the disadvantage of being too hydrophilic
Taking hyaluronic acid as an example, in the prior art, hydrogels made of hyaluronic acid as the main raw material have obvious shortcomings or technical biases including the following points: 1. Linkage is used in the cross-linking reaction of hyaluronic acid, and the toxic epoxy small molecule cross-linking agent remains in the cross-linked hyaluronic acid. After this cross-linked hyaluronic acid is made into a hydrogel, it will inevitably Adverse reactions or toxic effects have restricted the application of hyaluronic acid hydrogels
2. For chemically modified hyaluronic acid, cross-linked hyaluronic acid is obtained through cross-linking reaction, and the hydrogel prepared from this is expensive, and compared with transparent gels without structural modification and transformation The hydrogel prepared by cross-linking uric acid has improved in terms of viscosity, water retention, and shaping effect, but the improvement is limited
3. In the prior art, the reaction of generating cross-linked hyaluronic acid from hyaluronic acid through cross-linking reaction requires certain reaction conditions or relatively harsh reaction conditions, and it is impossible to achieve in-situ cross-linking under physiological conditions. The product is realized in the form of pre-crosslinking and pre-filling, which greatly affects the application range of the product and the compliance of the corresponding treatment group or cosmetic group
Still taking hyaluronic acid as an example, in the prior art, mercaptolated hyaluronic acid obtained by introducing free sulfhydryl groups into hyaluronic acid through a chemical reaction, summed up its characteristics, although compared with natural hyaluronic acid, it has better physical and chemical properties or biophase Capacitance and other aspects have been improved or improved, but it is still not enough to overcome the following shortcomings: 1. The speed of self-crosslinking or crosslinking reaction with other substances is slow, and it is usually necessary to add small molecular oxidants to accelerate the crosslinking reaction
2. The new hyaluronic acid compound modified by mercapto group, after cross-linking to form a hydrogel, has no substantial advantages compared with existing commercially available products or products in key indicators such as physical and chemical properties and biocompatibility Or do not have sufficient distinguishing technical characteristics, mainly reflected in viscosity, metabolic persistence and shaping effect
3. Thiolated hyaluronic acid, the synthesis and preparation methods in the prior art, all have the disadvantages of high toxicity or high cost
In addition, in the prior art, the hydrogel prepared by the cross-linking reaction of mercaptolated hyaluronic acid has disadvantages or technical prejudices, including: 1. In the prior art, the hyaluronic acid after chemical modification The cross-linking reaction results in cross-linked hyaluronic acid, and the resulting hydrogels are more expensive than hydrogels made by cross-linking natural hyaluronic acid
2. In the prior art, the chemically modified hyaluronic acid is cross-linked to obtain cross-linked hyaluronic acid, and the hydrogel prepared from this is compared with natural hyaluronic acid cross-linked. The prepared hydrogel has improved in terms of viscosity, water retention, and shaping effect, but the improvement is limited
3. The chemical modification of hyaluronic acid in the prior art has a certain degree of uncontrollability, which will affect the quality of its cross-linked hyaluronic acid, which in turn will cause the quality of the corresponding hydrogel to vary greatly. Fluctuating within the range, it is impossible to achieve the consistency of the therapeutic effect or cosmetic plastic effect of hydrogel products between different batches, which also affects the hydrogel to play a greater role in the application field

Method used

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  • Hydrogel of sulfydryl-modified high-molecular compound as well as preparation method and application of hydrogel
  • Hydrogel of sulfydryl-modified high-molecular compound as well as preparation method and application of hydrogel
  • Hydrogel of sulfydryl-modified high-molecular compound as well as preparation method and application of hydrogel

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preparation example Construction

[0202] [Preparation method of mercapto-modified polymer compound]

[0203] As mentioned above, the present invention provides a method for preparing the above-mentioned mercapto-modified polymer compound, which comprises the following steps:

[0204] 1) The structure contains -COOH, -NH 2 The acrylation step of at least one polymer compound in -OH, that is, the -COOH, -NH contained in the structure of the polymer compound 2 , at least one of -OH is directly or indirectly linked to the following groups:

[0205]

[0206] R 1 , R 2 and R 3 The definition of is the same as before; * represents the connection point;

[0207] Alternatively, a polymer compound structurally containing at least one of the acrylate group shown in the above formula a, the acrylamide group shown in the above formula b, and the acryloyl group shown in the above formula c is directly used as the reaction raw material;

[0208] 2) At least one of the polymer compounds obtained in step 1) and the po...

preparation example 1

[0305] Preparation Example 1 Synthesis of acrylate-modified hyaluronic acid (HA-A1 for short)

[0306] Add 1 gram of hyaluronic acid (purchased from Huaxi Freda Company, its weight average molecular weight is about 300kDa), 50 milliliters of deionized water, 50 milliliters of dimethylformamide, 12 milliliters of triethylamine in a 200 milliliter beaker, 14 ml glycidyl acrylate. After stirring at room temperature until homogeneous and transparent, the stirring was continued for 48 hours. 300 ml of acetone was added, resulting in a large amount of white precipitate. The precipitate obtained by centrifugation was dissolved in 100 ml of deionized water to obtain a colorless transparent solution. The above solution was put into a dialysis bag (molecular weight cut-off 8kDa), dialyzed with 5 liters of deionized water for 5 days, and changed the water twice a day. Finally, the solution in the dialysis bag was collected and freeze-dried to obtain 921 mg of white flocculent solid, n...

preparation example 2

[0309] Preparation Example 2 Synthesis of acrylate-modified hyaluronic acid (HA-A2 for short)

[0310] Add 1 gram of hyaluronic acid (purchased from Huaxi Freda Company, its weight average molecular weight is about 400kDa), 50 milliliters of deionized water, 50 milliliters of dimethylformamide, 6.3 grams of acrylic anhydride in a 200 milliliter beaker, stir dissolve. The pH of the solution was maintained at 8±0.5 with 1 mole per liter of NaOH, and stirring was continued for 24 hours. 300 ml of acetone was added, resulting in a large amount of white precipitate. The precipitate obtained by centrifugation was dissolved in 100 ml of deionized water to obtain a colorless transparent solution. The above solution was packed into a dialysis bag (molecular weight cut-off 8kDa, Spectrum), dialyzed with 5 liters of deionized water for 5 days, and changed the water twice a day. Finally, the solution in the dialysis bag was collected and freeze-dried to obtain 789 mg of white flocculen...

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Abstract

The invention relates to a hydrogel of a sulfydryl-modified high-molecular compound and a preparation method and application thereof. The sulfydryl-modified high-molecular compound with a novel structure is adopted, and the hydrogel is formed by matching the sulfydryl-modified high-molecular compound with an acryloylated high-molecular compound and / or an acryloyl micromolecular cross-linking agent. The sulfydryl modified high-molecular compound can be cross-linked with the acryloylated high-molecular compound and / or the acryloyl small-molecular cross-linking agent under physiological conditions to form the hydrogel; besides, the physical properties and chemical properties related to the molding effect, metabolism resistance and degradation resistance of the formed hydrogel are obviously superior to those of hydrogel in the prior art, and specifically, the metabolism resistance and degradation resistance of the hydrogel are obviously superior to those of the hydrogel in the prior art; and in addition, due to the characteristic of the rapidness of a sulfydryl-vinyl cross-linking reaction, the hydrogel system formed by the two compounds can be rapidly gelled in situ after being injected into a body. The hydrogel disclosed by the invention is more favorable for being used in the fields of biological medicine, medical aesthetic plastic surgery, cosmetics and the like.

Description

technical field [0001] The invention belongs to the field of biological materials, and in particular relates to a hydrogel of a mercapto-modified polymer compound, a preparation method and application thereof. Background technique [0002] Biomedical materials, also referred to as biomaterials (Biomaterials in English), are new high-tech materials used to diagnose, treat, repair or replace diseased tissues and organs or enhance their functions. One of the key technologies of tissue engineering is to use biomaterials to prepare cell scaffolds that have good biocompatibility and can be degraded and absorbed by the body. The gel state is an intermediate state between solid and liquid. Hydrogel refers to a hydrophilic cross-linked three-dimensional polymer network that can swell in water and retain a large amount of water without dissolving. Its water content can reach more than 90%. Hydrogels are an ideal class of biomaterials, which can have satisfactory physical and chemical...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08J3/24C08J3/075C08F251/00C08F289/00C08F265/06C08F261/04C08F283/06C08F222/14A61L27/16A61L27/52A61L27/50C08L51/02C08L51/00C08L51/08C08L5/08C08L89/00C08L71/02C08L29/04C08L33/14
CPCC08J3/246C08J3/075C08F251/00C08F289/00C08F265/06C08F261/04C08F283/065A61L27/16A61L27/52A61L27/50C08J2351/02C08J2351/00C08J2351/08C08J2305/08C08J2389/00C08J2371/02C08J2329/04C08J2333/14A61L2400/06C08L51/02C08L51/00C08L51/08C08L5/08C08L89/00C08L71/02C08L29/04C08L33/14C08G65/3344A61L31/145C08L89/06C08B37/0072C08B37/0069C08H1/06C08B37/003C08F8/14C08F8/34C08J2389/06C08J2489/06C08J2405/08C08F120/20C08F216/06C08J3/24C08F283/06A61K47/36A61K8/042A61K8/735A61K8/8152A61K8/86A61K9/06A61K47/10A61K47/32A61L27/20A61L27/222C08J2351/06
Inventor 王文新
Owner 블라파르바이오테크놀로지항저우리미티드
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