CN118126357A - Sodium hyaluronate gel and preparation method thereof - Google Patents

Sodium hyaluronate gel and preparation method thereof Download PDF

Info

Publication number
CN118126357A
CN118126357A CN202410572939.9A CN202410572939A CN118126357A CN 118126357 A CN118126357 A CN 118126357A CN 202410572939 A CN202410572939 A CN 202410572939A CN 118126357 A CN118126357 A CN 118126357A
Authority
CN
China
Prior art keywords
sodium hyaluronate
hyaluronate gel
cross
linking agent
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202410572939.9A
Other languages
Chinese (zh)
Inventor
汪文继
王俊晨
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beijing Kainuo Ruihe Medical Devices Co ltd
Original Assignee
Beijing Kainuo Ruihe Medical Devices Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beijing Kainuo Ruihe Medical Devices Co ltd filed Critical Beijing Kainuo Ruihe Medical Devices Co ltd
Priority to CN202410572939.9A priority Critical patent/CN118126357A/en
Publication of CN118126357A publication Critical patent/CN118126357A/en
Pending legal-status Critical Current

Links

Landscapes

  • Polysaccharides And Polysaccharide Derivatives (AREA)

Abstract

The invention provides sodium hyaluronate gel and a preparation method thereof, and belongs to the technical field of medical materials. The invention combines other steps with controlling the mixing temperature of the cross-linking agent and the alkali liquor to obtain the sodium hyaluronate gel preparation method, and solves the problems of high degradation speed and short retention time after injection of sodium hyaluronate gel products in the prior art. The preparation method can effectively improve the reaction probability of the cross-linking agent and sodium hyaluronate, improve the yield, reduce the content of free sodium hyaluronate in the sodium hyaluronate gel, further avoid the rapid degradation speed of sodium hyaluronate gel products, ensure the retention time after injection, and ensure the product quality and the injection effect. The method provided by the invention can enable the free HA in the product to be reduced to 0.13mg/mL from the minimum of 2.28mg/mL in the prior art, and HAs remarkable effect.

Description

Sodium hyaluronate gel and preparation method thereof
Technical Field
The invention relates to the technical field of medical materials, in particular to sodium hyaluronate gel and a preparation method thereof.
Background
Sodium Hyaluronate (HA), an inherent component in the human body, is a glucuronic acid, which HAs no species specificity and is widely found in tissues and organs such as placenta, amniotic fluid, lens, articular cartilage, dermis of skin, etc. It is distributed in cytoplasm and cell interstitium, and has lubricating and nourishing effects on cells and organelles contained in the cytoplasm and the cell interstitium. The sodium hyaluronate has extremely strong moisturizing capability, can adsorb and lock a large amount of moisture, and can provide lasting moisturizing for skin. Therefore, the composition is widely applied to skin care products and cosmetics to improve the problems of skin dryness, water shortage and the like; sodium hyaluronate can inhibit inflammatory reaction and relieve inflammation symptoms. In medicine, it is often used to treat inflammatory diseases such as arthritis, stomatitis, etc., to reduce pain and discomfort in patients; sodium hyaluronate can promote cell proliferation and migration, and promote wound healing. In the treatment process of surgery, burn, wound and the like, the sodium hyaluronate can be used as an auxiliary treatment drug to improve the healing speed; sodium hyaluronate is the main component in joint cavity, has lubricating and buffering effects, and can protect joint from abrasion. When treating joint diseases, sodium hyaluronate can be supplemented into joint cavities by injection and the like to relieve joint pain and stiffness; sodium hyaluronate is also widely used in the ophthalmic field, for example, in the treatment of ocular diseases such as dry eye, keratitis, or in ophthalmic surgery to protect the cornea and other ocular structures. In summary, sodium hyaluronate is a biopolymer with multiple functions and is widely used in the medical and cosmetic fields.
The natural sodium hyaluronate is easy to disperse and is degraded by enzymes and free radicals existing in body tissues, and the chain sodium hyaluronate is crosslinked to form a net structure by introducing a crosslinking agent to obtain the material, so that the defect of the natural sodium hyaluronate material can be overcome to a certain extent, the crosslinking degree is increased, the degradation time of sodium hyaluronate gel can be prolonged, and the retention time of sodium hyaluronate gel after injection is prolonged.
Chinese patent CN114805633a discloses a gradient cross-linked sodium hyaluronate gel and a preparation process thereof, relating to the technical field of medical cosmetology; the method comprises the following steps: s1, adding a crosslinking agent into a sodium hydroxide solution, and uniformly stirring to obtain a crosslinking solution; s2, adding sodium hyaluronate into the crosslinking solution, heating and carrying out ultrasonic crosslinking reaction after fully swelling, and then placing the solution under the conditions of low temperature and ultrasonic to carry out crosslinking reaction, and gradually heating according to a temperature gradient to obtain a first reaction material; s3, heating and standing the first reaction material for crosslinking reaction, standing at a low temperature, and carrying out crosslinking reaction, and gradually heating according to a temperature gradient to obtain a second reaction material; and S4, dialyzing the second reaction material in phosphate buffer, crushing, and sieving to obtain sodium hyaluronate gel.
However, the above process and other sodium hyaluronate gel preparation processes in the prior art have the following disadvantages: 1. the crosslinking efficiency of sodium hyaluronate is low, the yield is low, the reaction rate of sodium hyaluronate raw materials is low, and the waste of sodium hyaluronate raw materials is serious. 2. In the sodium hyaluronate gel prepared by the prior art, the content of free sodium hyaluronate is higher, and the technical requirement of the product is not met.
The sodium hyaluronate gel product has high degradation speed, reduces the retention time after injection and seriously influences the product quality and the injection effect due to the existence of the problems.
Disclosure of Invention
The invention aims to provide sodium hyaluronate gel and a preparation method thereof, which can effectively improve the reaction probability of a cross-linking agent and sodium hyaluronate, improve the yield and reduce the content of free sodium hyaluronate in the sodium hyaluronate gel.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of sodium hyaluronate gel, which comprises the following steps:
S1, mixing a cross-linking agent with alkali liquor at the temperature of-20-10 ℃ to obtain a mixed liquor 1;
s2, mixing the mixed solution 1 with sodium hyaluronate to obtain a mixed solution 2;
and S3, heating the mixed solution 2, and adjusting the pH to 6-8 to obtain the sodium hyaluronate gel.
Preferably, the cross-linking agent is selected from one or more of 1, 4-butanediol diglycidyl ether, 1,2,7, 8-diepoxyoctane and divinyl sulfone.
Preferably, the alkali liquor is sodium hydroxide aqueous solution.
Preferably, the volume percentage concentration of the alkali liquor is 1-2%.
Preferably, the volume ratio of the cross-linking agent to the alkali liquor is 1:80-120.
Preferably, the volume ratio of the sodium hyaluronate to the cross-linking agent is 0.8-1.2 g/0.1 mL.
Preferably, the molecular weight of the sodium hyaluronate is 160-250 ten thousand.
Preferably, in S3, the heating time is 1 to 4 hours;
and/or the heating temperature is 40-60 ℃.
Preferably, in S1, the step of mixing the crosslinking agent and the alkali liquor at the temperature of-20-10 ℃ specifically comprises the following steps:
s1.1, adjusting the temperature of a cross-linking agent to-20-10 ℃;
S1.2, adjusting the temperature of the alkali liquor to-20-10 ℃;
s1.3, mixing the crosslinking agent with alkali liquor.
The invention also provides sodium hyaluronate gel obtained by the preparation method.
The invention has the beneficial effects that:
The preparation method of the sodium hyaluronate gel is obtained by controlling the mixing temperature of the cross-linking agent and the alkali liquor and combining other steps, the reaction probability of the cross-linking agent and the sodium hyaluronate can be effectively improved, the yield of a final product is improved, the content of free sodium hyaluronate in the sodium hyaluronate gel is reduced, the degradation speed of the sodium hyaluronate gel product is further avoided, the retention time after injection is short, and the product quality and the injection effect are ensured. The method provided by the invention can enable the free HA in the product to be reduced to 0.13mg/mL from the minimum of 2.28mg/mL in the prior art, and HAs remarkable effect.
Drawings
FIG. 1 is a schematic illustration of the reaction process of the present invention.
Detailed Description
The invention provides a preparation method of sodium hyaluronate gel, which comprises the following steps:
S1, mixing a cross-linking agent with alkali liquor at the temperature of-20-10 ℃ to obtain a mixed liquor 1;
s2, mixing the mixed solution 1 with sodium hyaluronate to obtain a mixed solution 2;
and S3, heating the mixed solution 2, and adjusting the pH to 6-8 to obtain the sodium hyaluronate gel.
In the invention, in S1, the mixing of the crosslinking agent and the alkali liquor at the temperature of-20-10 ℃ is preferably realized by controlling the temperature of the reagent, and the method specifically comprises the following steps: s1.1, adjusting the temperature of a cross-linking agent to-20-10 ℃; s1.2, adjusting the temperature of the alkali liquor to-20-10 ℃; s1.3, mixing the crosslinking agent with alkali liquor.
In the present invention, the crosslinking agent is preferably one or more selected from 1, 4-butanediol diglycidyl ether, 1,2,7, 8-diepoxyoctane and divinyl sulfone; the alkali liquor is preferably sodium hydroxide aqueous solution; the volume percentage concentration of the alkali liquor is preferably 1-2%; the volume ratio of the cross-linking agent to the alkali liquor is preferably 1:80-120; the volume ratio of the sodium hyaluronate to the cross-linking agent is preferably 0.8-1.2 g:0.1mL, and the cross-linked sodium hyaluronate gel with different cross-linking degrees can be obtained by adjusting the volume ratio of the sodium hyaluronate to the cross-linking agent; the molecular weight of the sodium hyaluronate is preferably 160-250 ten thousand; in the step S3, the heating time is preferably 1-4 hours; and/or, the heating temperature is preferably 40-60 ℃.
The invention also provides sodium hyaluronate gel obtained by the preparation method.
In the invention, taking 1, 4-butanediol diglycidyl ether as a cross-linking agent as an example, under alkaline conditions, a 6-hydroxyl in a molecular structure of sodium Hyaluronate (HA) attacks a1, 4-butanediol diglycidyl ether (BDDE) epoxy structure, so that the epoxy structure is ring-opened to form a stable ether bond; the epoxy structure of BDDE molecules can also be opened by attack from free water hydroxyl groups, so BDDE HAs two binding events with HA: one end of BDDE is connected with HA molecule, called hanging modification (pendent modification); HA molecules are simultaneously linked at both ends, known as cross-linking modification (cross-link modification), and the reaction is shown in FIG. 1.
In the process, the effective reaction of BDDE is improved, the crosslinking modification reaction is increased, the suspension modification reaction is furthest inhibited, namely the reaction with HA is a key for solving the problem of low yield.
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
40ML of 1% NaOH was cooled to-10 ℃, 0.36mL of 1% 1, 4-butanediol diglycidyl ether cooled to-20 ℃ was added, 4.2g of sodium hyaluronate with a molecular weight of 200 ten thousand was added, and the mixture was stirred rapidly and thoroughly mixed, heated at 50 ℃ for 2.5 hours, and then neutralized to pH=7, to obtain a crosslinked sodium hyaluronate gel.
The free HA in the product was tested according to YYT0962 2021 appendix C, which showed free HA content: 0.13mg/mL.
Example 2
The only difference from example 1 is that NaOH was cooled to 4 ℃ and 1, 4-butanediol diglycidyl ether was cooled to 4 ℃.
The free HA in the product was tested according to YYT0962 2021 appendix C, which showed free HA content: 2.10mg/mL.
Example 3
The only difference from example 1 is that NaOH was cooled to 0 ℃ and 1, 4-butanediol diglycidyl ether was cooled to 0 ℃.
The free HA in the product was tested according to YYT0962 2021 appendix C, which showed free HA content: 1.52mg/mL.
Example 4
The only difference from example 1 is that NaOH was cooled to-10℃and 1, 4-butanediol diglycidyl ether was cooled to-10 ℃.
The free HA in the product was tested according to YYT0962 2021 appendix C, which showed free HA content: 0.52mg/mL.
Comparative example 1
35ML of 1% NaOH, 0.33mL of 1% 1, 4-butanediol diglycidyl ether, and 4g of sodium hyaluronate having a molecular weight of 200 ten thousand were stirred and thoroughly mixed at room temperature, heated at 50℃for 2.5 hours, and then neutralized to pH=7, to obtain a crosslinked sodium hyaluronate gel.
The free HA in the product was tested according to YYT0962 2021 appendix C, which showed free HA content: 2.28mg/mL.
Comparative example 2
Referring to the prior art method for preparing crosslinked sodium hyaluronate gel: 43mL of 1% NaOH was added to 0.40mL of 1% 1, 4-butanediol diglycidyl ether, 4.5g of sodium hyaluronate having a molecular weight of 180 ten thousand was added, and the mixture was stirred rapidly and thoroughly, heated at 52℃for 3 hours, and then neutralized to pH=7, to obtain a crosslinked sodium hyaluronate gel.
The free HA in the product was tested according to YYT0962 2021 appendix C, which showed free HA content: 2.53mg/mL.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.

Claims (10)

1. The preparation method of the sodium hyaluronate gel is characterized by comprising the following steps of:
S1, mixing a cross-linking agent with alkali liquor at the temperature of-20-10 ℃ to obtain a mixed liquor 1;
s2, mixing the mixed solution 1 with sodium hyaluronate to obtain a mixed solution 2;
and S3, heating the mixed solution 2, and adjusting the pH to 6-8 to obtain the sodium hyaluronate gel.
2. The method for preparing sodium hyaluronate gel according to claim 1, wherein the cross-linking agent is one or more selected from the group consisting of 1, 4-butanediol diglycidyl ether, 1,2,7, 8-diepoxyoctane and divinyl sulfone.
3. The method for preparing sodium hyaluronate gel according to claim 1, wherein the alkali solution is sodium hydroxide aqueous solution.
4. The method for preparing sodium hyaluronate gel according to claim 3, wherein the volume percentage concentration of the alkali solution is 1-2%.
5. The method for preparing sodium hyaluronate gel according to claim 3, wherein the volume ratio of the cross-linking agent to the alkali solution is 1:80-120.
6. The method for preparing sodium hyaluronate gel according to claim 1, wherein the volume ratio of the mass of sodium hyaluronate to the cross-linking agent is 0.8-1.2 g/0.1 ml.
7. The method for preparing sodium hyaluronate gel according to claim 1, wherein the molecular weight of sodium hyaluronate is 160-250 ten thousand.
8. The method for preparing sodium hyaluronate gel according to claim 1, wherein in S3, the heating time is 1-4 hours;
and/or the heating temperature is 40-60 ℃.
9. The method for preparing the sodium hyaluronate gel according to claim 1, wherein in S1, the step of mixing the crosslinking agent with the alkali solution at-20 to 10 ℃ comprises the following steps:
s1.1, adjusting the temperature of a cross-linking agent to-20-10 ℃;
S1.2, adjusting the temperature of the alkali liquor to-20-10 ℃;
s1.3, mixing the crosslinking agent with alkali liquor.
10. Sodium hyaluronate gel obtained by the preparation method according to any one of claims 1 to 9.
CN202410572939.9A 2024-05-10 2024-05-10 Sodium hyaluronate gel and preparation method thereof Pending CN118126357A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202410572939.9A CN118126357A (en) 2024-05-10 2024-05-10 Sodium hyaluronate gel and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202410572939.9A CN118126357A (en) 2024-05-10 2024-05-10 Sodium hyaluronate gel and preparation method thereof

Publications (1)

Publication Number Publication Date
CN118126357A true CN118126357A (en) 2024-06-04

Family

ID=91242157

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202410572939.9A Pending CN118126357A (en) 2024-05-10 2024-05-10 Sodium hyaluronate gel and preparation method thereof

Country Status (1)

Country Link
CN (1) CN118126357A (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103146003A (en) * 2013-03-06 2013-06-12 上海其胜生物制剂有限公司 Preparation method of low-temperature secondary cross-linked sodium hyaluronate gel
CN112940300A (en) * 2019-12-10 2021-06-11 爱博诺德(北京)医疗科技股份有限公司 Preparation method of crosslinked hyaluronic acid gel
CN114805633A (en) * 2022-03-30 2022-07-29 湖南精准医疗器械科技有限公司 Gradient cross-linked sodium hyaluronate gel and preparation process thereof
CN115572396A (en) * 2022-12-08 2023-01-06 四川兴泰普乐医疗科技有限公司 Sodium hyaluronate gel capable of being degraded in gradient manner and preparation method thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103146003A (en) * 2013-03-06 2013-06-12 上海其胜生物制剂有限公司 Preparation method of low-temperature secondary cross-linked sodium hyaluronate gel
CN112940300A (en) * 2019-12-10 2021-06-11 爱博诺德(北京)医疗科技股份有限公司 Preparation method of crosslinked hyaluronic acid gel
CN114805633A (en) * 2022-03-30 2022-07-29 湖南精准医疗器械科技有限公司 Gradient cross-linked sodium hyaluronate gel and preparation process thereof
CN115572396A (en) * 2022-12-08 2023-01-06 四川兴泰普乐医疗科技有限公司 Sodium hyaluronate gel capable of being degraded in gradient manner and preparation method thereof

Similar Documents

Publication Publication Date Title
EP2121026B1 (en) Novel injectable chitosan mixtures forming hydrogels
Fakhari et al. Applications and emerging trends of hyaluronic acid in tissue engineering, as a dermal filler and in osteoarthritis treatment
RU2683286C2 (en) Method for crosslift of hyaluronic acid, method for preparation of injection hydrogel, hydrogel and use thereof
US5827937A (en) Polysaccharide gel composition
US8551975B1 (en) Hyaluronic acid in soft gel form
Li et al. Click chemistry-based biopolymeric hydrogels for regenerative medicine
JPH01265970A (en) Collagen water solution or water dispersion solution including hyaluronic acid
CN107189119B (en) Preparation method and application of composite hyaluronic acid collagen hydrogel
JP2003516775A (en) Implantable prosthesis or tissue expansion device
CN111150881A (en) Medical recombinant collagen spray and preparation method thereof
CN107184961A (en) A kind of competent cell renovation agent and preparation method thereof
CN106421868A (en) Chitosan quaternary ammonium salt porcine acellular dermal matrix dressing material and preparation method thereof
KR101875115B1 (en) Manufacturing method for hydrogel foam using agarose form seaweed
CN108743921A (en) It is a kind of to prevent the reparation liquid and its preparation method and application that scar is formed
EP3574022B1 (en) Hyaluronic acid cross-linked with natural or semi-synthetic crosslinking agents
CN113350567A (en) Biocompatible polymer dressing based on collagen
CN118126357A (en) Sodium hyaluronate gel and preparation method thereof
CN115569104A (en) Hair loss prevention and hair growth composition containing plant extract and application thereof
CN113350568A (en) Biocompatible polymer dressing based on gelatin
KR100511011B1 (en) Moisturizing Chitosan-hydroxy acid Complex Compound and Composition of Their Aqueous Solution
CN1285193A (en) preparing and application of oral hyaluronic acid skin-beautifying health care preparation
ES2329879T3 (en) COLOID COSMETIC COMPOSITION COMPOSED BY HIALURONIC AND CHITOSAN ACIDS.
CN108635312A (en) A kind of plant essence scar rehabilitating solution and preparation method thereof
CN114716578B (en) Preparation method and application of soluble euglena polysaccharide
CN106975073A (en) Prevent and treat biomaterial preparation of mastitis for milk cows and preparation method thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination