CN106589424A - Crosslinked hyaluronic acid gel for injection and preparation method thereof - Google Patents
Crosslinked hyaluronic acid gel for injection and preparation method thereof Download PDFInfo
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Abstract
The invention relates to the technical field of crosslinked hyaluronic acid, in particular to a crosslinked hyaluronic acid gel for injection and a preparation method thereof. The preparation method comprises the following steps: dissolving a first part of hyaluronic acid in a NaOH solution containing a crosslinking agent, and mixing the materials uniformly to obtain a gel 1; dissolving a second part of hyaluronic acid in the NaOH solution containing the crosslinking agent, mixing the materials uniformly, and then mixing the obtained mixture with the gel 1 uniformly for crosslinking; and after completion of the crosslinking, adjusting the pH value to be neutral, and performing dialysis. Compared with single crosslinking, the gradient crosslinking provided by the invention has high cohesion, high viscoelasticity and strong filling power, and can be maintained for a long time in subcutaneous tissues, thereby reducing generation of gel migration. The prepared gel has more compact intermolecular networks, and the crosslinking efficiency is improved, so that the gel is more stable in structure, stable in network structure, and is obviously strengthened in enzymolysis resistance, and can be maintained in a body for a longer time.
Description
Technical field
The present invention relates to cross-linked-hyaluronic acid technical field, more particularly to a kind of injection cross-linked hyaluronic acid gel and its
Preparation method.
Background technology
Hyaluronic acid (Hyaluronic acid, HA) is a kind of straight chain polymer mucopolysaccharide, by N-Acetyl-D-glucosamine and
Maltonic acid is constituted, in being widely present in animal body and microbial body, without species difference, non-immunogenicity, with very high
Security, therefore be the well received new bio medical material of current medical circle, with very high medical value.
In Minimally Invasive Surgery, Soft-tissue operation operation be becoming increasingly popular, mainly fill wrinkle, fill and lead up depressed area,
Amendment face contour (rich lip, filling apple flesh and augmentation rhinoplasty).In soft tissue filler used, hyaluronic acid is because of its security
Height, good biocompatibility, postoperative bad reaction are few, filling effect such as manifests immediately at the advantage after injection becomes the most frequently used both at home and abroad
Soft tissue filler.
Noncrosslinking HA can degrade quickly in vivo absorption, it is difficult to maintain preferable filling effect, therefore be crosslinked HA to meet the tendency of
And give birth to.The crosslinked rear resistance to enzymolysis abilities of HA are obviously improved, it is possible to obtain more longlasting filling effect.It is used for soft group in the market
The hyaluronic acid derivatives of filling are knitted, crosslinking HA is.At present conventional crosslinking agent has：1,4- butanediol diglycidyl ethers (1,
4-Butanediol diglycidyl ether, BDDE), divinylsulfone (Divinyl sulfone, DVS) etc..
The patent of the A of Publication No. CN 102863631 prepares surgical plastic cross-linked hyaluronic acid gel there is provided one kind
Method.Characterized in that, HA is dissolved in into the mixed liquor of the NaOH aqueous solution and dimethyl sulfoxide (DMSO), crosslinking agent (Isosorbide-5-Nitrae-fourth two is added
Alcohol diglycidyl ether or the polyethyleneglycol diglycidylether that molecular weight is 500-6000), acetone precipitation is used after the completion of crosslinking,
It is dried vacuum to obtain being crosslinked HA powder.HA powder is swelling afterwards with injection water and brine, obtain being crosslinked HA gels.This
Process is complex, and adds dimethyl sulfoxide (DMSO), and to subsequent wash purifying pressure is brought.
A kind of injection hyaluronic acid-collagen compound water congealing of the patented invention of the A of Publication No. CN 103333349
The preparation method of glue, it is characterised in that first dissolve hyaluronic acid in alkaline solution, stirs in addition collagen, plus
Enter crosslinking agent (polyethyleneglycol diglycidylether, ethylene glycol diglycidylether, 1,4- butanediol diglycidyl ethers, poly- third
One kind in Hexanediol diglycidyl ether etc.) crosslinking, granulation is crushed after gel is purified.The addition of collagen causes hyalomitome
The cross-linking efficiency of acid declines, and this will make, and gel viscoelastisity is not good, and filling capacity is not strong.
The patent of the A of Publication No. CN 102573941 provides a kind of method of modified hyaluronic acid polymer composition,
It is characterized in that the hydroxyl of hyaluronic acid reacts with divinylsulfone, hydroxyl is converted into 2- (vinylsulfonyl) ethyoxyl.
Under specific conversion ratio, the hyaluronic acid of derivatization and the Thiolation polyethylene glycol reaction containing two or more mercapto, hand over
Hyaluronic acid after connection can be used for joint injection and treat acute or chronic inflammation.But this method needs to control derivatization hyaluronic acid
Conversion ratio, technological requirement is high, is unfavorable for large-scale production.
The content of the invention
The unclean safety and environmental protection of preparation process that injection hyaluronic acid derivatives are present in order to solve above prior art,
Gel cohesion, viscoplasticity is not good, and resistance to enzymolysis ability is weak, the problem that filling capacity is not strong, this application discloses it is a kind of have compared with
High cohesion, viscoplasticity, and stronger filling capacity, while implantation is subcutaneous to be not susceptible to displacement, and resistance to enzymolysis ability is higher,
The injection cross-linked hyaluronic acid gel of longer time filling effect can be maintained.
Present invention also offers the preparation method of the injection cross-linked hyaluronic acid gel.
What the present invention was obtained through the following steps：
A kind of crosslinking hyaluronic acid sodium gel for injection, is obtained by following steps：
(1) Part I hyaluronic acid is dissolved in the NaOH solution containing crosslinking agent, is mixed, and is crosslinked to obtain gel 1；
(2) Part II hyaluronic acid is dissolved in the NaOH solution containing crosslinking agent, it is after mixing then mixed with gel 1
Even crosslinking；PH is adjusted after the completion of crosslinking to neutral, dialysis, injection cross-linked hyaluronic acid gel is obtained.
Described crosslinking hyaluronic acid sodium gel for injection, the quality of two parts hyaluronic acid in preferred steps (1), (2)
Than for 15:1-1:15, preferably 9:1-1:9, preferably 5:1-1:5, preferably 1:1-5.
Described injection cross-linked hyaluronic acid gel, the preferably crosslinking agent are modified poly (ethylene glycol).
Dosage of crosslinking agent in described injection cross-linked hyaluronic acid gel, the preferably step (1) (2) is respectively saturating
The 2%-15% of bright matter acid quality, the dosage of crosslinking agent in preferred steps (1) for hyaluronic acid quality 2-15%, step (2)
In dosage of crosslinking agent for hyaluronic acid quality 2-8%.
The quality of hyaluronic acid and NaOH in described injection cross-linked hyaluronic acid gel, the preferably step (1)
Than for 1:4-12, the hyaluronic acid in step (2) is 1 with the mass ratio of NaOH:4-12, the hyaluronic acid in preferred steps (1)
It is 1 with the mass ratio of NaOH:5-10, the hyaluronic acid in step (2) is 1 with the mass ratio of NaOH:5-8.
Described injection cross-linked hyaluronic acid gel, preferred crosslinking temperature is 20-60 DEG C, crosslinking time in step (1)
For 30-90min, crosslinking time is 2-12h in step (2), and preferred crosslinking temperature is 20 DEG C, and crosslinking time is 60- in step (1)
90min, crosslinking time is 4-10h in step (2), and preferred crosslinking temperature is 40 DEG C, and crosslinking time is 60min in step (1), is walked
Suddenly crosslinking time is 3h in (2), and preferred crosslinking temperature is 60 DEG C, and crosslinking time is 30-60min in step (1), in step (2)
Crosslinking time is 2-4h.
Described injection cross-linked hyaluronic acid gel, preferred crosslinking agent is polyethyleneglycol diglycidylether or four arm stars
Shape polyethylene glycol epoxide.
Described injection cross-linked hyaluronic acid gel, NaOH concentration preferably used is 0.5-1.5%, preferably 0.6-
1.2%.
Dialysis in described injection cross-linked hyaluronic acid gel, preferred steps (2) is in pH neutral phosphoric acid by gel
Dialyse 12-48h in salt buffer.
Described injection cross-linked hyaluronic acid gel, the injection cross-linked hyaluronic acid gel obtained by preferred steps (2)
Middle addition ester type or acid amide type local anesthetic, the preferably one kind in lidocaine, totokaine, Bupivacaine and procaine
And more than.
Using BDDE as crosslinking agent more than presently commercially available hyaluronic acid filler.It is guarantee due to the toxicity of BDDE itself
Product Safety will control the usage amount of BDDE in cross-linking process.And the gel that prepared as crosslinking agent with BDDE of majority is in it
Poly- property is poor, easily dispersion and displacement after implantation hypodermis, it is impossible to reach preferable moulding effect.Simultaneously with a traditional step
Its viscoplasticity of gel and cohesion prepared by method cannot get both, i.e., cannot have high viscoplasticity while high cohesion is obtained,
The filling capacity of gel is poor；Obtaining high viscoelastic while the cohesion of gel is poor, be implanted into it is subcutaneous after easily dispersion send out
Raw displacement.And the preparation method of the present invention is by changing crosslinking method, crosslinking time, crosslinking temperature, dosage of crosslinking agent, hyalomitome
The mass ratio of acid and crosslinking agent realizes the gradient crosslinked of hyaluronic acid derivatives.With single cross-linked phase ratio, possess high cohesion, height
Viscoplasticity, filling capacity is strong, and subcutaneous dispersion is difficult, and reduces the generation of Gel migration.
Modified poly (ethylene glycol) crosslinking agent itself is non-toxic, can be used as excipient substance, and no antigen, with good water
Dissolubility, has very high security using the cross-linked hyaluronic acid gel that modified poly (ethylene glycol) is prepared as crosslinking agent；Its molecular weight
Size can adjust, different molecular weight and different activated forms so that the hyaluronic acid derivatives tool of modified poly (ethylene glycol) crosslinking
There is huge property regulation space, the gel of high viscoplasticity and high cohesion can be had concurrently in acquisition.
The invention has the advantages that：
1st, the present invention is by changing crosslinking method, crosslinking time, crosslinking temperature, dosage of crosslinking agent, hyaluronic acid and crosslinking
The mass ratio of agent realizes the gradient crosslinked of hyaluronic acid derivatives.With single cross-linked phase ratio, possess high cohesion, high viscoplasticity,
Filling capacity is strong, and subcutaneous dispersion is difficult, and reduces the generation of Gel migration.
2nd, gel prepared by the present invention has high viscoplasticity and cohesion, and network structure is stable, and its resistance to enzymolysis performance is obvious
Strengthen, can in vivo maintain the longer time.
Description of the drawings
Fig. 1 is followed successively by from left to right, from top to bottom shapes of gel 1-1 to the 3-7 prepared in embodiment in 95s
State；
Fig. 2 is followed successively by from left to right, from top to bottom the gel 3-8 prepared in embodiment to comparative example 3 in 95s
When state.
Specific embodiment
The present invention is further described with reference to specific embodiment：
Embodiment 1
The present embodiment mainly investigates the impact with comparison inventive gel property of two parts of hyaluronic acids, and preparation method is as follows：
By 6g hyaluronic acids in proportion 5:1 is divided into two parts, and takes the NaOH that 5g hyaluronic acids are dissolved in the 1% of 50g, adds crosslinking
Agent polyethyleneglycol diglycidylether (molecular weight is 500), crosslinking agent is the 5% of hyaluronic acid quality, is put into after being well mixed
60min is crosslinked in 40 DEG C of water-baths, gel 1 is obtained；
(2) NaOH that 1g hyaluronic acids are dissolved in the 1% of 10g is taken, crosslinking agent polyethyleneglycol diglycidylether, crosslinking is added
Agent is the 5% of hyaluronic acid quality, mixes with gel 1 again after mixing, continues to be crosslinked 4h in 40 DEG C of water-baths.Adjust after the completion of crosslinking
To neutrality, dialyse pH 24h in the phosphate buffer that pH is neutral, obtains injection cross-linked hyaluronic acid gel 1-1.
The proportioning of three parts of hyaluronic acids used by preparation injection cross-linked hyaluronic acid gel 1-2 to 1-5 is according to following table institute
Show operation：
| Gel is numbered | Two parts of hyaluronic acid proportionings |
| 1-2 | 3:1 |
| 1-3 | 1:1 |
| 1-4 | 1:3 |
| 1-5 | 1:5 |
Embodiment 2
The present embodiment mainly investigates the impact of crosslinking temperature and crosslinking time to inventive gel property, and preparation method is as follows：
By 6g hyaluronic acids in proportion 1:1 is divided into three parts, takes the NaOH that 3g hyaluronic acids are dissolved in the 1% of 30g, adds crosslinking
Agent polyethyleneglycol diglycidylether (molecular weight is 500), crosslinking agent is 5% with the mass ratio of hyaluronic acid.After being well mixed
It is put in 20 DEG C of water-baths and is crosslinked 60min, obtains gel 1.
(2) NaOH that 3g hyaluronic acids are dissolved in the 1% of 30g is taken, crosslinking agent polyethyleneglycol diglycidylether, crosslinking is added
The mass ratio of agent and hyaluronic acid is 5%, is mixed with gel 1 again after mixing, continues to be crosslinked 6h in 20 DEG C of water-baths.After the completion of crosslinking
PH is adjusted to neutrality, dialyse 24h in the phosphate buffer that pH is neutral, obtains injection cross-linked hyaluronic acid gel 2-1.
Injection cross-linked hyaluronic acid gel 2-2 to 2-12 is prepared, crosslinking temperature and crosslinking time used is operated according to shown in following table：
| Gel is numbered | Crosslinking temperature | The crosslinking time of gel 1 | Crosslinking time after two parts of gels merging |
| 2-2 | 20℃ | 90min | 6h |
| 2-3 | 20℃ | 60min | 12h |
| 2-4 | 20℃ | 90min | 12h |
| 2-5 | 40℃ | 60min | 3h |
| 2-6 | 40℃ | 60min | 3h |
| 2-7 | 40℃ | 30min | 6h |
| 2-8 | 40℃ | 60min | 6h |
| 2-9 | 60℃ | 30min | 2h |
| 2-10 | 60℃ | 60min | 2h |
| 2-11 | 60℃ | 30min | 4h |
| 2-12 | 60℃ | 60min | 4h |
Embodiment 3
The present embodiment mainly investigates impact of the dosage of crosslinking agent to inventive gel property, and preparation method is as follows：
With embodiment 2, difference is the mass ratio of crosslinking agent and hyaluronic acid to the preparation method of gel, according to following table
It is shown to be operated：
| Gel is numbered | Dosage of crosslinking agent in gel 1 | Dosage of crosslinking agent in second part of gel |
| 3-1 | 2% | 2% |
| 3-2 | 2% | 8% |
| 3-3 | 2% | 15% |
| 3-4 | 8% | 2% |
| 3-5 | 8% | 8% |
| 3-6 | 8% | 15% |
| 3-7 | 15% | 2% |
| 3-8 | 15% | 8% |
| 3-9 | 15% | 15% |
Embodiment 4
The present embodiment mainly investigates impact of the hyaluronic acid with the mass ratio of NaOH to inventive gel property, and preparation method is such as
Under：
With embodiment 2, difference is the mass ratio of hyaluronic acid and NaOH to the preparation method of gel, according to following table institute
Show and operated：
Comparative example 1
With embodiment 2, it is BDDE that difference is crosslinking agent to the preparation method of gel
(BDDE), the consumption of crosslinking agent is for calculation in the molar ratio.
Comparative example 2
5g hyaluronic acids are dissolved in the 1% of 50g NaOH, crosslinking agent polyethyleneglycol diglycidylether (molecular weight is added
For 500), crosslinking agent is the 5% of hyaluronic acid quality, is put into after being well mixed in 40 DEG C of water-baths and is crosslinked 4h.Adjust after the completion of crosslinking
To neutrality, dialyse section pH 24h in the phosphate buffer that pH is neutral, obtains injection cross-linked hyaluronic acid gel.
Comparative example 3
(1) by 6g hyaluronic acids in proportion 1:1:1 is divided into three parts, takes the NaOH that 2g hyaluronic acids are dissolved in the 1% of 20g, plus
Enter crosslinking agent polyethyleneglycol diglycidylether (molecular weight is 500), crosslinking agent is the 5% of hyaluronic acid quality, is well mixed
After be put in 40 DEG C of water-baths and be crosslinked 30min；
(2) NaOH that 2g hyaluronic acids are dissolved in the 1% of 20g is taken, crosslinking agent polyethyleneglycol diglycidylether, crosslinking is added
Agent is the 5% of hyaluronic acid quality, mixes with gel in (1) again after mixing, and crosslinking 30min is continued in 40 DEG C of water-baths.
(3) NaOH that 2g hyaluronic acids are dissolved in the 1% of 20g is taken, crosslinking agent polyethyleneglycol diglycidylether, crosslinking is added
Agent is the 5% of hyaluronic acid quality, mixes with gel in (2) again after mixing, crosslinking 3h is continued in 40 DEG C of water-baths, after the completion of crosslinking
PH is adjusted to neutrality, dialyse 24h in the phosphate buffer that pH is neutral, obtains injection cross-linked hyaluronic acid gel.
Ergonomy is tested
Test 1：Gel viscoelastisity is evaluated
Gel prepared by each embodiment and comparative example Haake RS6000 (silent winged generation that (China) company of match) instrument
The viscoplasticity of gel is determined, its condition is：Rotor：P20Ti；Temperature：25℃；Gap values：1.00mm；Mode determination：Frequency of oscillation
Scanning CD；Stress：1%；Frequency range：0.01-1Hz.Storage modulus (G') and loss modulus under record 0.1Hz frequencies
(G″)。
(G ") is as shown in the table for the storage modulus (G') under 0.1Hz and loss modulus of each embodiment and comparative example：
As a result show, with the increasing of dosage of crosslinking agent, the increase of crosslinking temperature, the growth of crosslinking time, hyaluronic acid
Gel storage modulus (G') prepared by reduction with NaOH mass ratioes gradually increases, and its filling capacity is strong, there is preferably moulding
Effect, by the crosslinking temperature, crosslinking time, dosage of crosslinking agent, hyaluronic acid and the NaOH that change two step cross-linked gels respectively
Ratio can preferably adjust the property of hyaluronic acid derivatives, so as to obtain more preferably gel.
Test 2：Gel resistance to enzymolysis performance evaluation
Gel precision prepared by embodiment and comparative example weighs 0.4g, adds the phosphate buffer (pH of 0.1mol/L
7.0) 2mL and hyaluronic acid enzyme liquid (600U/mL) 2mL, after being well mixed, in being placed in 42 DEG C of water-baths, takes 50 μ L's every 10min
Mixed liquor is mixed with the phosphate buffer (pH 7.0) of the 0.1mol/L of 3mL, is surveyed with Shimadzu UV-2550 ultraviolet specrophotometer
Determine the absorbance at 232nm, absorbance stops measurement after being not changed in, and the record time is the enzymolysis time of gel.
The enzymolysis time of each embodiment and comparative example is as shown in the table：
Test result indicate that, compared with gel (comparative example 1) prepared by conventional crosslinking agent B DDE, use polyethylene glycol diglycidyl
The enzymolysis time of gel prepared by glycerin ether is longer, illustrates its resistance to enzymolysis performance more preferably, and the filling time in vivo is longer.
Test 3：Gel cohesive performance is evaluated
Bibliography《Cohesivity of hyaluronic acid fillers:development and
clinical implications of a novel assay,pilot validation with a five-point
grading scale,and evaluation of six U.S.Food and Drug Administration–approved
fillers》In method, gel is fitted in the BD needle tubings of 1mL, will be gel-colored with toluidine blue.By the beaker of 1000mL
Middle loading 700mL water is put into the magnetic agitation rotor of 2.5cm length, and regulation rotating speed is 160r/min, by the liquid again of the gel after dyeing
Slow at the 2cm of face top to release, (gel can not in whole experiment process to record state of the gel in 15s, 70s and 95s in water
Encounter rotor, otherwise restart), then scored (scoring group is made up of 20 people) according to 5 grades of gel state.
Appraisal result such as following table：
Test result indicate that, cohesion and the not positively related relation of viscoplasticity of gel, though such as embodiment 2-12,3-9
So viscoelastic property is fine, but cohesion is poor, and this gellike easily disperses, and is more suitable for deep skin filling, is not suitable for shallow-layer skin
Filling.Compared with gel prepared by the present invention, its cohesion of the gel of the preparation of comparative example 2 is poor, and the technique of comparative example 3 is more
Complexity, and gel easily disperses.Under same identical process conditions, prepare by crosslinking agent of polyethyleneglycol diglycidylether
Gel its cohesion much stronger than the gel prepared as crosslinking agent with BDDE, so gel its cohesion prepared by the present invention is strong,
It is difficult to disperse and is shifted over after implantation is subcutaneous, is able to maintain that more preferable moulding effect.
Above-described embodiment is not limited for the present invention preferably embodiment, but embodiments of the present invention by embodiment
System, other any Spirit Essences and the changes, modification made under principle without departing from the present invention, combines, substitutes, simplifying and should be
Equivalence replacement mode, is included within protection scope of the present invention.
Claims (10)
1. a kind of crosslinking hyaluronic acid sodium gel for injection, it is characterised in that obtained by following steps：
（1）Part I hyaluronic acid is dissolved in the NaOH solution containing crosslinking agent, is mixed, and is crosslinked to obtain gel 1；
（2）Part II hyaluronic acid is dissolved in the NaOH solution containing crosslinking agent, after mixing, then friendship is mixed with gel 1
Connection, adjusts pH to neutral, dialysis after the completion of crosslinking, obtain injection cross-linked hyaluronic acid gel.
2. crosslinking hyaluronic acid sodium gel for injection according to claim 1, it is characterised in that step（1）、（2）In three
The mass ratio for dividing hyaluronic acid is 15:1-1:15.
3. the injection cross-linked hyaluronic acid gel according to claims 1, it is characterised in that the crosslinking agent is modified
Polyethylene glycol.
4. the injection cross-linked hyaluronic acid gel according to claims 1, it is characterised in that the step（1）（2）In
Dosage of crosslinking agent for hyaluronic acid quality 2%-15%.
5. the injection cross-linked hyaluronic acid gel according to claims 1, it is characterised in that the step（1）（2）In
The mass ratio of hyaluronic acid and NaOH solution be 1:4-12.
6. the injection cross-linked hyaluronic acid gel according to claims 1, it is characterised in that crosslinking temperature is 10-60°
C, crosslinking time is 0-40 h, and preferred crosslinking temperature is 20-60°C, step（1）Middle crosslinking time be 0.5-4 h, step（2）
Middle crosslinking time is 2-12 h.
7. the injection cross-linked hyaluronic acid gel according to claims 1, it is characterised in that crosslinking agent is polyethylene glycol
Diglycidyl ether or four arm star polyethylene glycol epoxides.
8. the injection cross-linked hyaluronic acid gel according to claims 1, it is characterised in that NaOH concentration used is
0.5-1.5% is preferably 0.6-1.2%.
9. the injection cross-linked hyaluronic acid gel according to claims 1, it is characterised in that step（2）It is middle dialysis be by
Gel dialysis 12-48 h in the neutral phosphate buffers of pH.
10. the injection cross-linked hyaluronic acid gel according to claims 1, it is characterised in that step（2）The note of gained
Penetrate with addition ester type or acid amide type local anesthetic in cross-linked hyaluronic acid gel.
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