CN109010912A - A kind of sodium hyaluronate injectable packing material of modification and preparation method thereof - Google Patents

A kind of sodium hyaluronate injectable packing material of modification and preparation method thereof Download PDF

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CN109010912A
CN109010912A CN201811133176.9A CN201811133176A CN109010912A CN 109010912 A CN109010912 A CN 109010912A CN 201811133176 A CN201811133176 A CN 201811133176A CN 109010912 A CN109010912 A CN 109010912A
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sodium hyaluronate
gel
modification
packing material
crosslinking
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CN109010912B (en
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翁松青
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Fujian Tuo New Mstar Technology Ltd
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Fujian Tuo New Mstar Technology Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L31/04—Macromolecular materials
    • A61L31/042—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/10—Materials for lubricating medical devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction

Abstract

The invention discloses sodium hyaluronate injectable packing materials of a kind of modification and preparation method thereof, including freely transparent sodium hyaluronate gel, crosslinking sodium hyaluronate gel, water soluble vitamin, buffer solution, wherein the poly ethyldiol modified material of sodium hyaluronate-has the following structure:

Description

A kind of sodium hyaluronate injectable packing material of modification and preparation method thereof
Technical field
The present invention relates to beauty treatment fields, fill more particularly to a kind of modification sodium hyaluronate injectable by polyethylene glycol crosslinked Material Field.
Background technique
Sodium hyaluronate (hyaluronic acid) is that one kind is widely present in humans and animals body, by dissacharide units (glucuronic acid-N- The straight chain polymer polysaccharide of second sulphur aminoglucose composition), structural formula are as follows:
It widely exists in connective tissue, mucous tissue and the bacterium folder film of vertebrate, in epidermis, corium, navel Content in band, synovia and cartilaginous tissue is also higher.Since 1934, U.S. Meyer etc. was first from bovine vitreous body Since isolating sodium hyaluronate, good biocompatibility, height viscoplasticity, plasticity and permeability gradually have been found to have by the people Equal important performances.To be widely used in fields such as medical treatment, beauty and bioengineering.In shaping and beauty field, glass Uric acid is mainly used for filling Facial Depression, smoothing wrinkle, augmentation rhinoplasty etc..
In the past 10 years, sodium hyaluronate is widely used in medical cosmetology field as dermal filler, and injecting under corium can make The direct volume of subcutaneous tissue increases, and plays the role of " padding ", while can also absorb the moisture of surrounding tissue, to reach expansion body Long-pending effect keeps relaxation, the skin of recess again full, and this injection treatment has been widely used for reparation and aging Recess caused by relevant skinfold and some congenital or posteriori disease.
However, causing the hyaluronic acid of foreign aid to maintain in vivo due to human body hyaluronidase, free radical cracking etc. The existing time is shorter, limit sodium hyaluronate subcutaneous tissue filling or in terms of application.Therefore, how by changing Property processing technology improves the technical issues of degradation cycle of hyaluronic acid in vivo is urgent need to resolve.
Patent document CN105131348B disclose it is a kind of by cross-linked hyaluronic acid gel and free hyaluronic acid solution, Middle crosslinking agent is the sterile injection packing material that 1,4-butanediol glycidol ether is formed, although degradation cycle can be improved, Stability makes moderate progress, but the needs being still unable to satisfy in industry.
Patent document CN104870479B discloses one kind by hyaluronic acid compound and glucomannans via at least one The polymer that group bonding of a ester linkage derived from crosslinking agent is formed is formed by ball and polymer water capture with higher Ability bulges more preferably, faster, can be used for improving skin or mucosal hydration.However, since glucomannans price is higher, from And increase the cost of application.
Polyethylene glycol is a kind of non-ionic water-soluble polymer, since polyethylene glycol has many excellent properties concurrently: Water solubility, fixedness, physiological inertia, mildness, are widely used in Surface Modification of Medical Polymer Materials.
It does not disclose and is applied to by the way that sodium hyaluronate and polyethylene glycol are bonded together to form gel by ester bond in the prior art The document of subcutaneous packing material.
Summary of the invention
The present invention provides a kind of containing being coagulated by sodium hyaluronate and polyethylene glycol by the sodium hyaluronate that is crosslinked that ester bond bonds together to form The injectable packing material of glue.
Technical problem of the invention is solved to be achieved through the following technical solutions:
A kind of sodium hyaluronate injectable packing material of modification, it is characterised in that: including freely transparent sodium hyaluronate gel, crosslinking Sodium hyaluronate gel, water soluble vitamin, buffer solution, wherein the transparent sodium hyaluronate gel of the freedom and crosslinking sodium hyaluronate are solidifying The mass ratio of glue is 2:10-40:1；Wherein the molecular weight of the transparent sodium hyaluronate gel of freedom is 5K-200KDa, preferably 10K-100KDa, more preferably 50K-80KDa；Wherein the crosslinking sodium hyaluronate gel has the following structure I:
Wherein n is selected from 10-5000, and m is selected from 100-5000；Wherein the water soluble vitamin is selected from vitamin B, dimension life One of plain C, vitamin E or its respective derivative or any combination thereof.
In the preferred technical solution of the present invention, wherein the buffer solution maintain the pH of composition 5 and 8.5 it Between, between more preferably 6.8 and 8, between most preferably 7.0 and 8, wherein suitable buffer solution can be selected from phosphoric acid Salt buffer solution, for example, NaH2PO4-NaHPO4, acetate buffer solution, benzoate buffer solution, Citrate buffer are molten Liquid, maleate buffer solution, Tartrate buffer solution；
In the preferred technical solution of the present invention, wherein the molecular weight of the transparent sodium hyaluronate gel of freedom is 50K- 80KDa；
In the inventive solutions, the weight based on freely transparent sodium hyaluronate gel, wherein the water soluble vitamin The weight percent of raw element is 1.0%-5%, preferably 2.5%；
It in the inventive solutions, further include D-sorbite, wherein the weight based on freely transparent sodium hyaluronate gel, The mass fraction of D-sorbite can less than 3%, preferably 1%；
In the inventive solutions, wherein the sodium hyaluronate injectable packing material is needed before use through sterile place Reason.
In the inventive solutions, wherein aseptic process can sterilize for high-temperature sterilization, ultraviolet irradiation.
In the inventive solutions, wherein the modification sodium hyaluronate injectable packing material can be applied to soft tissue Filling, reparation and surgical operation, such as can be used for wrinkle, augmentation rhinoplasty, enlarge the bosom, it can be used for the anti-sticking of medical surgery operation Connect the lubrication with orthopaedics joint.
The present invention also provides a kind of preparation methods of modified sodium hyaluronate injectable packing material comprising following steps:
The preparation of step (1) crosslinking sodium hyaluronate gel: will be one on the hydroxyl and sodium hyaluronate skeleton in polyethylene glycol structures Or multiple carboxyls the step of being bonded, reaction process is as follows:
In a preferred embodiment, sodium hyaluronate solution, polyglycol solution, crosslinking agent are mixed including following steps a. It closes, and is stirred continuously；B. the pH=4-6 of reaction system is maintained；
C. control reaction temperature is 60-80 DEG C, and 12h is sufficiently stirred；D. by reaction product through dialysis treatment, through being dried After obtain sodium hyaluronate-polyethylene glycol graft crosslinking polymer；
In the optimal technical scheme of step (1), wherein the weight percent of sodium hyaluronate and polyethylene glycol is 10:1-1: 40；Preferably 5:1；
In the optimal technical scheme of step (1), wherein the solvent of the sodium hyaluronate solution and polyglycol solution is Water, the pH value of step b are preferably 5；
In the optimal technical scheme of step (1), wherein the crosslinking agent is selected from EDC or HOBt, or a combination thereof；
Step (2): proportionally weighing freely transparent sodium hyaluronate gel solution, is added to step (1) is prepared and obtains Crosslinking sodium hyaluronate gel preparation, and be sufficiently mixed stirring at room temperature；
Step (3): proportionally weighing water soluble vitamin and D-sorbite, be dissolved in the water after being sufficiently stirred be added to In the transparent sodium hyaluronate gel of step (2) resulting freedom and crosslinking sodium hyaluronate gel mixed liquor；And buffer solution is added, keeping body The pH of system is 6-6.8；
Step (4): by said mixture through dialysis treatment, the sodium hyaluronate that modification of the invention is obtained after being dried can Injection fillers material.
The sodium hyaluronate injectable packing material of modification provided by the present invention has the advantage that
1, syringeability can be good: the modified sodium hyaluronate injectable packing material of the present invention has preferable mobility；
2, good biocompatibility: the sodium hyaluronate injectable packing material of modification provided by the present invention has good Biocompatibility not will lead to subject after implanting and generate inflammatory response or immune response；
3, stability is good: it is provided by the present invention formed by sodium hyaluronate and polyethylene glycol by covalent bonding it is stable It is crosslinked sodium hyaluronate material, metabolic stability, is not easy to be degraded in vivo.
Specific embodiment
Embodiment 1
The preparation of step (1) crosslinking sodium hyaluronate gel:
A. sodium hyaluronate/polyethylene glycol/HOBc/EDC (sodium hyaluronate/polyethylene glycol/HOBt/EDC=is weighed according to a certain percentage 1g/0.5g/0.1/0.1, w/w), it is dissolved separately in the deionized water of 50mL to be sufficiently stirred and is allowed to uniformly mixed；
B. NaH is added into reaction system2PO4-NaHPO4, pH value=5 of reaction system are controlled,；
C. control reaction temperature is 60-80 DEG C, and 12h is sufficiently stirred；
D. reaction product is obtained into crosslinking sodium hyaluronate gel through dialysis treatment.
Step (2): it is (freely transparent proportionally to weigh freely transparent sodium hyaluronate gel solution (molecular weight 50KDa) Sodium hyaluronate gel: crosslinking sodium hyaluronate gel=0.8g/1g, w/w), it is added solidifying to the preparation-obtained crosslinking sodium hyaluronate of step (1) The preparation of glue, and it is sufficiently mixed stirring at room temperature；
Step (3): proportionally weigh watermiscible vitamin E (watermiscible vitamin E: freely transparent sodium hyaluronate gel= 0.02g:1g, w/w) and D-sorbite (D-sorbite: freely transparent sodium hyaluronate gel=0.02g:1g, w/w), it is dissolved in the water It is added after being sufficiently stirred into the transparent sodium hyaluronate gel of step (2) resulting freedom and crosslinking sodium hyaluronate gel mixed liquor；And add Enter buffer solution, keeping the pH of system is 6.8；
Step (4): by said mixture through dialysis treatment, the sodium hyaluronate that modification of the invention is obtained after being dried can Injection fillers material.
Embodiment 2
The preparation of step (1) crosslinking sodium hyaluronate gel:
A. sodium hyaluronate/polyethylene glycol/HOBc/EDC (sodium hyaluronate/polyethylene glycol/HOBt/EDC=is weighed according to a certain percentage 1g/1g/0.1/0.1, w/w), it is dissolved separately in the deionized water of 50mL to be sufficiently stirred and is allowed to uniformly mixed；
B. NaH is added into reaction system2PO4-NaHPO4, pH value=5 of reaction system are controlled,；
C. control reaction temperature is 60-80 DEG C, and 12h is sufficiently stirred；
D. reaction product is obtained into crosslinking sodium hyaluronate gel through dialysis treatment.
Step (2): it is (freely transparent proportionally to weigh freely transparent sodium hyaluronate gel solution (molecular weight 50KDa) Sodium hyaluronate gel: crosslinking sodium hyaluronate gel=0.5g/1g, w/w), it is added solidifying to the preparation-obtained crosslinking sodium hyaluronate of step (1) The preparation of glue, and it is sufficiently mixed stirring at room temperature；
Step (3): proportionally weigh watermiscible vitamin E (watermiscible vitamin E: freely transparent sodium hyaluronate gel= 0.02g:1g, w/w) and D-sorbite (D-sorbite: freely transparent sodium hyaluronate gel=0.02g:1g, w/w), it is dissolved in the water It is added after being sufficiently stirred into the transparent sodium hyaluronate gel of step (2) resulting freedom and crosslinking sodium hyaluronate gel mixed liquor；And add Enter buffer solution, keeping the pH of system is 6.8；
Step (4): by said mixture through dialysis treatment, the sodium hyaluronate that modification of the invention is obtained after being dried can Injection fillers material.
Embodiment 3
The preparation of step (1) crosslinking sodium hyaluronate gel:
A. sodium hyaluronate/polyethylene glycol/HOBc/EDC (sodium hyaluronate/polyethylene glycol/HOBt/EDC=is weighed according to a certain percentage 0.5g/1/0.1/0.1, w/w), it is dissolved separately in the deionized water of 50mL to be sufficiently stirred and is allowed to uniformly mixed；B. to reactant NaH is added in system2PO4-NaHPO4, control pH value=5 of reaction system；
C. control reaction temperature is 60-80 DEG C, and 12h is sufficiently stirred；
D. reaction product is obtained into crosslinking sodium hyaluronate gel through dialysis treatment.
Step (2): it is (freely transparent proportionally to weigh freely transparent sodium hyaluronate gel solution (molecular weight 50KDa) Sodium hyaluronate gel: crosslinking sodium hyaluronate gel=0.5g/1g, w/w), it is added solidifying to the preparation-obtained crosslinking sodium hyaluronate of step (1) The preparation of glue, and it is sufficiently mixed stirring at room temperature；
Step (3): proportionally weigh watermiscible vitamin E (watermiscible vitamin E: freely transparent sodium hyaluronate gel= 0.02g:1g, w/w) and D-sorbite (D-sorbite: freely transparent sodium hyaluronate gel=0.02g:1g, w/w), it is dissolved in the water It is added after being sufficiently stirred into the transparent sodium hyaluronate gel of step (2) resulting freedom and crosslinking sodium hyaluronate gel mixed liquor；And add Enter buffer solution, keeping the pH of system is 6.8；
Step (4): by said mixture through dialysis treatment, the sodium hyaluronate that modification of the invention is obtained after being dried can Injection fillers material.
Reference examples 1
Step (1): freely transparent sodium hyaluronate gel solution (molecular weight 50KDa), water soluble vitamin are proportionally weighed Raw element E (watermiscible vitamin E: freely transparent sodium hyaluronate gel=0.02g:1g, w/w) and D-sorbite (D-sorbite: freely Transparent sodium hyaluronate gel=0.02g:1g, w/w), it is dissolved in the water and is sufficiently stirred；
Step (2): being added buffer solution, and keeping the pH of system is 6.8；
Step (3): by said mixture through dialysis treatment, the sodium hyaluronate that modification of the invention is obtained after being dried can Injection fillers material.
Embodiment 4: infrared spectrum analysis
Infrared spectrum characterization is carried out to the poly ethyldiol modified material of the obtained sodium hyaluronate-of embodiment 1- embodiment 3.Wherein The strong vibration that ester group ehter bond occur at 1092,1136,1186cm-1 wave number in polyethylene glycol and sodium hyaluronate-polyethylene glycol absorbs Peak, meanwhile, polyethylene glycol has the absorption of vibrations of free-OH near 3500cm-1, but after having an effect with sodium hyaluronate, it should Locate vibration absorption peak to disappear, illustrate in modification, the hydroxyl of polyethylene glycol has also assisted in chemical reaction.
The analysis of 5 rheological property of embodiment
It is specific to try with the rheological property of the rheometer analysis poly ethyldiol modified material of the obtained sodium hyaluronate-of embodiment 1-3 Proved recipe method is using the square position 30mm, Temperature Gradient, and temperature range is 10-50 DEG C, and heating rate is 2 DEG C/min.
It can be concluded that for material poly ethyldiol modified for sodium hyaluronate-, obtained material has rheology analysis result There is good response to temperature.For example, the modified material of embodiment 1 storage modulu (G ') at 25 DEG C is 452Pa, loss modulus (G ") For 218Pa；The modified material of embodiment 2 storage modulu (G ') at 25 DEG C is 446Pa, and loss modulus (G ") is 202Pa；Implement The modified material of example 3 storage modulu (G ') at 25 DEG C is 468Pa, and loss modulus (G ") is 176Pa.
6 injectable performance evaluation of embodiment
Method: the aqueous solution of embodiment 1-3 material prepared that weight percent is 10-20% is prepared, being sufficiently stirred makes Be completely dissolved, sample is transferred in syringe, is tested using No. 27 syringe needles.As can be seen from the test results, embodiment The modification sodium hyaluronate packing material of 1- embodiment 3 can easily pass through No. 27 syringe needles at room temperature, to show that the material has There is preferable syringeability.
7 external degradation performance of embodiment
The present embodiment compare the poly ethyldiol modified material (test group 1-3) of embodiment 1-3 sodium hyaluronate-obtained with not The external degradation performance of modified sodium hyaluronate (control group 1) and auspicious blue 2 (Restylance) (control groups 2) is specific to test Method is:
1g sample is fitted into 1mL centrifuge tube, then it is transparent that 50 μ L are added in the flat intraluminal fluid face of centrifugal drying into each testing tube Matter acid enzyme solutions, so that the activity of hyaluronidase reaches 100IU/mL.Constant temperature is kept for 12 hours at 37 DEG C, after reaction Each pipe is stood upside down, fluid sample is absorbed with paper, measurement remains in the example weight of bottom of the tube.The example weight of each test group with And the results are shown in Table 1 for theoretical residual sample percentage (%):
Group Sodium hyaluronate concentration (mg/mL) Percentage
Embodiment 1 34.2 84.2 ± 0.2%
Embodiment 2 32.6 82.4 ± 0.2%
Embodiment 3 31.4 80.6 ± 0.2%
Control group 1 24.2 64.1 ± 0.2%
Control group 2 18.6 50.4 ± 0.2%
From the results shown in Table 1, modified sodium hyaluronate injectable packing material of the invention and non-modified Sodium hyaluronate or auspicious blue No. 2 are compared, and degradation cycle is obviously improved.
The above is the preferred embodiment of the present invention, is not intended to restrict the invention, although referring to aforementioned implementation Invention is explained in detail for example, for those skilled in the art, still can be to foregoing embodiments The technical solution of record is modified or equivalent replacement of some of the technical features.It is all in spirit of the invention and Within principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.

Claims (8)

1. a kind of sodium hyaluronate injectable packing material of modification, it is characterised in that: including freely transparent sodium hyaluronate gel, crosslinking glass Uric acid gel, water soluble vitamin, buffer solution, wherein the transparent sodium hyaluronate gel of the freedom and crosslinking sodium hyaluronate gel Mass ratio be 2:10-40:1；Wherein the molecular weight of the transparent sodium hyaluronate gel of freedom is 5K-200KDa；It is wherein described Crosslinking sodium hyaluronate gel have such as following formula (I) structure:
Wherein n is selected from 10-5000, and m is selected from 100-5000；Wherein the water soluble vitamin be selected from vitamin B, vitamin C, One of vitamin E and its respective derivative or any combination thereof.
2. a kind of sodium hyaluronate injectable packing material of modification as described in claim 1, which is characterized in that the buffering is molten Liquid maintains the pH of composition between 5 to 8.5, between more preferably 6.8 to 8, between most preferably 7.0 to 8, and wherein institute It states buffer solution and is selected from phosphate buffer solution (for example, NaH2PO4-NaHPO4), acetate buffer solution, benzoate buffering One or more of solution, citrate buffer solution, maleate buffer solution and Tartrate buffer solution.
3. a kind of sodium hyaluronate injectable packing material of modification as described in claim 1, which is characterized in that described is freely saturating The molecular weight of bright sodium hyaluronate gel is 50K-80KDa.
4. a kind of sodium hyaluronate injectable packing material of modification as described in claim 1, which is characterized in that the water solubility The weight percent for accounting for the transparent sodium hyaluronate gel of the freedom of vitamin be 1.0%-5%, preferably 2.5%.
5. a kind of sodium hyaluronate injectable packing material of modification according to any one of claims 1-4, which is characterized in that also wrap Including D-sorbite, D-sorbite accounts for the weight percent of the transparent sodium hyaluronate gel of the freedom less than 3%, and preferably 1%.
6. a kind of sodium hyaluronate injectable packing material of modification as described in any one in claim 1-5, which is characterized in that described Sodium hyaluronate injectable packing material need before use through aseptic process.
7. a kind of sodium hyaluronate injectable packing material of modification as claimed in claim 6, it is characterized in that, aseptic process is High-temperature sterilization or ultraviolet irradiation sterilizing.
8. a kind of preparation method of the sodium hyaluronate injectable packing material of modification as described in claim 1, which is characterized in that packet Include following steps:
The preparation of step (1) crosslinking sodium hyaluronate gel: will be one or more on the hydroxyl and sodium hyaluronate skeleton in polyethylene glycol structures The step of a carboxyl is bonded, reaction process is as follows:
,
Including following steps: sodium hyaluronate solution, polyglycol solution, crosslinking agent are mixed, and are stirred continuously by a.；B. it maintains The pH=4-6 of reaction system；C. control reaction temperature is 60-80 DEG C, and 12h is sufficiently stirred；D. by reaction product through dialysis treatment, Sodium hyaluronate-polyethylene glycol graft crosslinking polymer is obtained after being dried, wherein in step (1), wherein sodium hyaluronate and poly- The weight percent of ethylene glycol is 10:1-1:40；Preferably 5:1；Wherein, in step (1), the sodium hyaluronate solution and poly- The solvent of ethylene glycol solution is water, and the pH value of step b is preferably 5；Wherein the crosslinking agent be selected from EDC perhaps HOBt or A combination thereof；
Step (2): freely transparent sodium hyaluronate gel solution is proportionally weighed, is added to step (1) preparation-obtained friendship Join the preparation of sodium hyaluronate gel, and is sufficiently mixed stirring at room temperature；
Step (3): proportionally weighing water soluble vitamin and D-sorbite, is dissolved in the water after being sufficiently stirred and is added to step (2) in the transparent sodium hyaluronate gel of resulting freedom and crosslinking sodium hyaluronate gel mixed liquor；And buffer solution is added, keep system PH is 6-6.8；
Step (4): by said mixture through dialysis treatment, the sodium hyaluronate injectable of modification of the invention is obtained after being dried Packing material.
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