CN104771331B - A kind of hyaluronic acid elastomer and its application - Google Patents
A kind of hyaluronic acid elastomer and its application Download PDFInfo
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Abstract
The present invention relates to hyaluronic acid sodium gel technical field, more particularly to a kind of hyaluronic acid elastomer：Hyaluronic acid and crosslinking agent are reacted, obtain cross-linking sodium hyaluronate gel A；Cross-linking sodium hyaluronate gel A is pelletized, obtains the different gel B of particle size and gel C；Gel B and gel C are mixed, carry out cross-linking reaction again, through overregulating pH value to neutral and dialysis, obtains hyaluronic acid elastomer.Hyaluronic acid elastomer of the invention, has excellent rheologic behavio(u)r, can be used as cosmetic material, for physics smooth out wrinkles, keeps moisture of skin, sustained release functional component, improvement to use sensation etc..Present invention simultaneously relates to its application.
Description
Technical field
The present invention relates to a kind of hyaluronic acid elastomer.The present invention has excellent viscoelasticity, can be used as cosmetic material,
For physics smooth out wrinkles, moisture of skin, sustained release functional component, improvement is kept to use sensation etc..Meanwhile the invention further relates to it
Using.
Background technology
Hyaluronic acid（Hyalouronic acid, HA）It is by glucuronic acid and the repetition of n acetylglucosamine n dissacharide units
A kind of straight chain polymer of composition sticks polysaccharide.Hyaluronic acid is the endogenous material having in itself in human body, has good life
Thing compatibility；With high viscoelasticity and non-Newtonian rheological characteristic；It is nontoxic, without immunogenicity, nonirritant, there is very high peace
Quan Xing.
The extensive use in cosmetics of noncrosslinking hyaluronic acid derivatives, but it is mainly used in moisture-keeping function, the amount of addition
Seldom, otherwise solution is relatively glutinous, easy wire drawing, a mud after painting.The hyaluronic acid of crosslinking or modification has different rheologic behavio(u)rs, can
Protection skin, physics smooth/filled wrinkle etc..Application of the hyaluronic acid for being crosslinked or modifying at present in cosmetics is less.
The B patents of Publication No. CN 101056891, which provide, can easily prepare that content of crosslinking agent is few and viscoelasticity is good
Crosslinking HA gels method.Characterized in that, hyaluronic acid 10% will be contained under acid or alkaline conditions（W/V）Above, hand over
The mixture of connection agent and water is stirred.This patent mainly by increase hyaluronic acid concentration mode, reduce dosage of crosslinking agent,
The method is single step reaction and does not consider the influence of other reactive materials.
The method that the cross-linked-hyaluronic acid in a kind of emulsion is disclosed in the B of Publication No. CN 101878230 patent, its
Step is：(a) alkaline aqueous solution comprising hyaluronic acid or its salt is provided；(b) in organic phase or oil phase, from step (a)
The droplet with desired size is formed in mixed solution, to form the emulsion of organic matter bag water or Water-In-Oil (W/O)；(c) to
The solution for including crosslinking agent is added in emulsion, thus hyaluronic acid is reacted with the crosslinking agent to provide the hyalomitome of crosslinking
Sour microballon；And (d) optionally in procedure of processing (c) the hyaluronic acid microballon of the crosslinking of gained dispersion.The method is reacted
Need to add organic reagent in system, organic reagent may be brought to remain equivalent risk.
Multiple cross-linked hyaluronic acid technology is mentioned in Publication No. CN1200951C patent of invention, utilizes two kinds or more
Kind is selected from hydroxyl, the functional group of carboxyl and amino and cross-linking hyaluronic acid, is contracted using glutaraldehyde, carbodiimides, butanediol two
Water glyceryl ether etc. is crosslinking agent.The cross-linked hyaluronic acid gel obtained in patent, the gel of different-grain diameter is not mixed again
Crosslinking, and washed with organic reagents such as acetone, pollution is larger.
A kind of biodegradable cohesive hydrogel, preparation side are proposed in Publication No. CN101925348 A patent
Method is that the polymer homogeneous that X kinds are had into the identical or different degree of cross linking mixes.The method is only to mix X kinds polymer progress physics
Close, there is no cross-bond between polymer, it is impossible to form cross-linked network structure.
Publication No. CN101909597A patent discloses a kind of fractal net work and macroscopic particles comprising nano particle
Gel rubber system.The gel rubber system can be formed " optical gel ", and the gel is due to big between fractal particle and macroscopic particles
Small domain is poor and effectively obscures wrinkle line and wrinkle.This patent proposes the concept that wrinkle is obscured with the gel rubber system for having particle, coagulates
Gel of the glue suitable for cosmetics but patent is the materials such as silica, aluminum oxide, silicone elastomer, does not use biofacies
The good hyaluronic acid gellike of capacitive.
The content of the invention
In order to solve the above technical problems, the invention provides a kind of hyaluronic acid elastomer.It can be used as cosmetics former
Expect, for physics smooth out wrinkles, keep moisture of skin, sustained release functional component, improvement to use sensation etc..
The present invention is achieved by the following measures：
A kind of hyaluronic acid elastomer, is obtained through the following steps：
（1）Hyaluronic acid and crosslinking agent are reacted, obtain cross-linking sodium hyaluronate gel A；
（2）Screen cloth of the selection with suitable aperture, cross-linking sodium hyaluronate gel A is pelletized, it is different to obtain particle size
Gel B and gel C；
（3）Gel B and gel C are mixed, cross-linking reaction is carried out again, regulation pH value to neutrality, dialysis, obtains hyaluronic acid
Elastomer.
Described hyaluronic acid elastomer, preferably crosslinking agent are carbodiimide, divinylsulfone, ethylene glycol diglycidyl
One kind in ether, 1,4- butanediol diglycidyl ethers, the more glycidyl ethers of polyglycereol.
Step（3）Middle cross-linking reaction can be acid condition, pH value 2~6, more preferably 2~4 or alkalescence condition,
PH value 9~14, more preferably 11~14.
Described hyaluronic acid elastomer, preferred steps（1）The quality accounting of middle crosslinking agent and hyaluronic acid be 0.02 ~
3.0%。
Described hyaluronic acid elastomer, preferred steps（3）Middle gel B and gel C mixed proportion are 1-9:9-1.
Described hyaluronic acid elastomer, preferred steps（1）（3）Middle cross-linking reaction temperature be 10 DEG C~60 DEG C, preferably 15
DEG C~50 DEG C；The h of reaction time 1~50, preferably 2~24 h.
So gel B particle diameter（X50）100 ~ 800 μm of selection.
So particle diameter of gel C（X50）70 ~ 100 μm of selection.
The different gel of particle size is made in hyaluronic acid sodium gel after crosslinking by the present invention, then carries out two step crosslinkings,
Make different hyaluronic acid network structures interspersed together, gel has excellent rheologic behavio(u)r.
The present invention, which stops crosslinking, to be completed by dialysis removing crosslinking agent and unreacted small-molecule substance.
The purpose of the present invention additionally provides the purposes of the gel, in cosmetics, physics smooth out wrinkles, keeping skin water
Point, it is sustained functional component.
The gel can be used for filling fine, moderate or deep wrinkles, and tissue filling.
The gel can be used for recovering skin water balance by mesotherapy, improve skin texture and elasticity.
The gel can be used for supplementing or substituting synovia.
Noncrosslinking hyaluronic acid, sun-screening agent, light protective agent, antioxidant, nutritional agents, dimension life can be added in the gel
It is element, skin conditioning agent, allergy inhibitor, disinfectant, preservative, antimicrobial, antiparasitic, plant extracts, special
One kind or wherein several combinations in the additive of effect.
According to embodiment of the present invention, the gel can sterilize or add preservative, sterilizing selection moist heat sterilization mode.
Beneficial effects of the present invention：
The hyaluronic acid elastomer of the present invention, is crosslinked again with the cross-linking sodium hyaluronate gel of two kinds of different-grain diameters, is handed over
It is few to join agent dosage, pollution is few, it is easy to accomplish industrialization；The gel of the present invention has excellent rheologic behavio(u)r and bio-compatible
Property, can physics smooth out wrinkles, keep moisture of skin, be sustained functional component, improve using feel.
Embodiment
In order to better illustrate the present invention, further illustrated with reference to specific embodiment.
Embodiment 1
Influence of the gel B particle sizes difference that the present embodiment is investigated to inventive gel property, preparation method are as follows：
（1）10 g hyaluronic acids are dissolved in 100 ml NaOH solution（PH value is 11~13）, after mixing, add and hand over
The quality accounting of connection agent BDDE, crosslinking agent and hyaluronic acid is 1%, is stirred and evenly mixed, in 35 DEG C of water-baths
6 h of middle reaction, obtain cross-linking sodium hyaluronate gel A；
（2）Cross-linking sodium hyaluronate gel A is pelletized, gel B particle diameter is as shown in table 1, and the particle diameter of gel C is 72 μm
（X50）；
（3）Gel B and gel C are pressed 1: 1（w : w）Mixing, regulation pH value to 2 ~ 4, add BDO two and contract
The quality accounting of water glycerin ether, crosslinking agent and hyaluronic acid is 0.8%, reacts 8 h in 30 DEG C of water-baths.PH value is adjusted to neutrality, thoroughly
Analysis removes unreacted small-molecule substance.
Compare the viscoelasticity and resistance to enzymatic for the gel that the gel B of different-grain diameter is prepared, assay method is as follows：
Viscoplasticity method of testing：With Haake RS6000（Sai Mo flies generation, and you are scientific and technological（China）Company）Instrument measuring viscoelastic
Property, condition is：Rotor：P20 Ti L；Gap values：1.00 mm；Temperature：25 ℃；Mode determination；Oscillation frequency sweep CD；Should
Power；1% ；Frequency range：0.01~1 Hz.Record the modulus of elasticity and viscous modulus during 0.1 Hz.
Resistance to enzymatic：Precision weighs the gel obtained in embodiment（Hyaluronic acid contents are 0.5 g）, add 0.1 mol/L
Phosphate buffer（pH 7.0）9 mL and hyaluronic acid enzyme liquid（100 U/mL）1 mL, it is well mixed, is placed in 37 DEG C of water-baths
8 h are digested, 10 min inactivations are then boiled at 100 DEG C.0.45 μm of filtering with microporous membrane, the ml of filtrate 1.0 is taken, adds water to be settled to
10 ml.Using improvement carbazole development process（Bibliography：Bitter .T, Muir H.M, (1962) A modified
uronic acid carbarbazole reation .Anal.Biochem.4, 330-333.）Glucuronic acid content is determined, is multiplied
With conversion after 2.07 to add the content a of cross-linking hyaluronic acid sodium in the sample of enzyme liquid；Cross-linked transparent in not enzyme-added liquid sample
Matter acid sodium content is b, calculates enzyme degradation rate=a/b × 100%.Enzyme degradation rate is lower, show sustained release effect of gel into
The ability divided is stronger, the maintainable time length of functional component.
The gel B of the different-grain diameter of table 1 influence
Gel B selections viscoplasticity is suitable, and degradation rate is moderate.When gel B particle is more than 800 μm, final gained is solidifying
Glue resistance to enzymatic is poor, effect hold time it is short, so gel B particle diameter select 100 ~ 800 μm.
Embodiment 2
Influence of the gel C particle size difference that the present embodiment is investigated to inventive gel property, preparation method are as follows：
（1）10 g hyaluronic acids are dissolved in 100 ml NaOH solution（PH value is 11~13）, after mixing, add
The quality accounting of crosslinking agent BDDE, crosslinking agent and hyaluronic acid is 1.0%, is stirred and evenly mixed, at 35 DEG C
6 h are reacted in water-bath, obtain cross-linking sodium hyaluronate gel A；
（2）Cross-linking sodium hyaluronate gel A is pelletized, gel B particle diameter is 198 μm（X50）, the particle diameter of gel C is such as
Shown in table 2；
（3）Gel B and gel C are pressed 1: 1（w : w）Mixing, regulation pH value to 2 ~ 4, add BDO two and contract
The quality accounting of water glycerin ether, crosslinking agent and hyaluronic acid is 0.8%, reacts 8 h in 30 DEG C of water-baths.PH value is adjusted to neutrality, thoroughly
Analysis removes unreacted small-molecule substance.
The method of reference example 1 determines gel viscoelastisity and resistance to enzymatic, data are shown in Table 2.
The influence of the gel C of the different-grain diameter of table 2
Gel C selection viscoplasticity is suitable, and degradation rate is moderate.When the particle of gel C is less than 60 μm, final gained is solidifying
Glue elasticity is larger, it is difficult to smears, so the particle diameter of gel C（X50）70 ~ 100 μm of selection.
Embodiment 3
By the gel B in embodiment 2（198 µm）And gel C（72 µm）After being well mixed with different quality ratio, by pH value
2~4 are transferred to, and adds BDDE, the quality accounting of crosslinking agent and hyaluronic acid is 0.8%（w/w）,
6 h are reacted in 30 DEG C of water-baths, pH value to neutrality, dialysis is then adjusted and removes unreacted small-molecule substance.
The method of reference example 1 determines gel viscoelastisity and resistance to enzymatic, viscoplasticity test data are shown in Table 3.
The gel X of table 3 and gel Y ratio
It can see from above-mentioned data, gel B ratio is bigger, and enzyme degradation rate is higher, and functional component discharges faster, bullet
Property and viscosity it is lower, tend to smear out；The ratio of gel C is bigger, and enzyme degradation rate is lower, and resistance to enzymatic is better, and functional component discharges
It is slower.According to functional component release time and viscoelastic it can need to select suitable ratio.
Embodiment 4
The present embodiment investigates the influence of the crosslinker ratio of step crosslinking, and method is as follows：
（1）10 g hyaluronic acids are dissolved in 100 ml NaOH solution（PH value is 13~14）, after mixing, add
Crosslinking agent divinylsulfone（DVS）, the mass ratio of crosslinking agent and hyaluronic acid is as shown in table 4, stirs and evenly mixs, in 25 DEG C of water-baths
8 h are reacted, obtain cross-linking sodium hyaluronate gel A；
（2）Cross-linking sodium hyaluronate gel A is pelletized, gel B particle diameter is 198 μm（X50）, the particle diameter of gel C is
81 µm（X50）；
（3）Gel B and gel C are pressed 1: 1（w : w）Mixing, regulation pH value to 11 ~ 12, add divinylsulfone
（DVS）, crosslinking agent is 1.0% with hyaluronic acid mass ratio, reacts 30 h in 25 DEG C of water-baths.PH value to neutrality, dialysis is adjusted to remove
Unreacted small-molecule substance.
The step of table 4 one is crosslinked the influence of crosslinker ratio
When the crosslinking agent and hyaluronic acid mass ratio of the crosslinking of one step are 0.02 ~ 3.0%, the viscoplasticity of gel is moderate, enzyme degraded
Rate is adjustable；When crosslinking agent is less than 0.02% with hyaluronic acid mass ratio, the viscoelasticity of gel is very poor, and enzyme is degraded quickly, so one
The crosslinking agent and hyaluronic acid mass ratio for walking crosslinking are set to 0.02 ~ 3.0%.
Embodiment 5
The present embodiment investigates the influence of the crosslinker ratio of two steps crosslinking, and method is as follows：
（1）10 g hyaluronic acids are dissolved in 100 ml NaOH solution（PH value is 13~14）, after mixing, add and hand over
Join agent divinylsulfone（DVS）, crosslinking agent is 1.0% with hyaluronic acid mass ratio, stirs and evenly mixs, reacts 8 in 25 DEG C of water-baths
H, obtain cross-linking sodium hyaluronate gel A；
（2）Cross-linking sodium hyaluronate gel A is pelletized, gel B particle diameter is 198 μm（X50）, the particle diameter of gel C is
81 µm（X50）；
（3）Gel B and gel C are pressed 1: 1（w : w）Mixing, regulation pH value to 11 ~ 12, add divinylsulfone
（DVS）, the mass ratio of crosslinking agent and hyaluronic acid is as shown in table 5, reacts 30 h in 25 DEG C of water-baths.PH value is adjusted to neutrality, thoroughly
Analysis removes unreacted small-molecule substance.
The step of table 5 two is crosslinked the influence of crosslinker ratio
When the crosslinking agent and hyaluronic acid mass ratio of the crosslinking of two steps are 0.1 ~ 3.0%, the viscoplasticity of gel is moderate, enzyme degraded
Rate is adjustable；When crosslinking agent is less than 0.1% with hyaluronic acid mass ratio, the viscoelasticity of gel is very poor, and enzyme is degraded quickly, so two
The crosslinking agent and hyaluronic acid mass ratio for walking crosslinking are set to 0.1 ~ 3.0%.
Embodiment 6
The present embodiment investigates the moisture retention of hyaluronic acid elastomer, and method is as follows：
By the gel B in embodiment 2（198 µm）And gel C（72 µm）By 1: 1（w : w）After well mixed, by pH
Value is transferred to 2~4, and adds BDDE, and crosslinking agent is 0.8% with hyaluronic acid mass ratio（w/w）,
30 h are reacted in 15 DEG C of water-baths, pH value to neutrality, dialysis is then adjusted and removes unreacted small-molecule substance and obtain hyaluronic acid bullet
Property body sample.
With the Essence containing the polyalcohols such as glycerine, thickener and gel prepare respectively 5% sample and 0.1% HA it is molten
Liquid.5 4cm × 4cm of side mark pilot region is bent in 10 left and right forearms of subject, smears the elite containing 5% sample respectively
Liquid（w/w）, 0.1%HA Essences（w/w）And control（Essence）, applying amount is 3.0 ± 0.1 mg/cm2, gently it is massaged into sample
Product absorb.Using moisture of skin analyzer and skin water loss analyzer measure smear before and apply after 30min, 1h, 3h, 6h,
Skin moisture content and skin water loss amount during 8h and 24h in each region.
Data processing（Average）：
Skin moisture content increment rate（%）=×100
Skin water loss increment rate（%）=×100
Influence of the Sodium Hyaluronate elastomer sample to skin moisture content is shown in Table 6, table 7.
Table 6 smears front and rear skin moisture content increment rate（%）
As a result show, 5% sample makes the sustainable 24h of the increased effect of skin water content, and moistening effect compares always
0.1%HA and blank are good.
Table 7 smears front and rear moisture of skin windage increment rate（%）
As a result show, within 3 h, 5% sample solution can effectively suppress moisture loss, and effect is better than 0.1%HA and blank.
Embodiment 7
The present embodiment investigates hyaluronic acid elastomer（The sample of embodiment 6）Wrinkle filling efficacy assessments, method is as follows：
Subject smears sample and control in left and right canthus respectively（Elite containing the polyalcohols such as glycerine, thickener and gel
Liquid）, applying amount is 3.0 ± 0.1 mg/cm2, is gently massaged into sample absorption.3D skin fast imaging systems on probation（PRIMOS,
Germany）Evaluation smear before and smear after 30min, 1h, 3h and 6h crow's foot mean depth change.
Wrinkle mean depth Sa increment rates（%）=×100
The crow's foot mean depth increment rate of table 8
| Sa relative values（%） | 30min | 1h | 3h | 6h |
| 5% sample | -2.67 | -2.24 | -1.96 | -1.85 |
| Control | 1.28 | 2.40 | 2.36 | 2.72 |
Hyaluronic acid elastomer, the aobvious reduction of illumination is compared using rear crow's foot mean depth increment rate, so of the invention
Hyaluronic acid elastomer there is good wrinkle filling effect.
Embodiment 8
The present embodiment investigates the cytotoxicity of hyaluronic acid elastomer, according to EN ISO 10993-5：2009《Medical treatment device
The biological assessment of tool -- the 5th part：Vitro cytotoxicity test》Standard, detects cell proliferation rate, and specific method is as follows：
（1）Method according to embodiment 4 prepares hyaluronic acid elastomer sample, and sample is added into RPMI1640 nutrient solutions
（0.2 g / ml）, 72 h are extracted after mixing under 37 DEG C, 5% carbon dioxide conditions, 0.22 μm of membrane filtration is degerming, is soaked
Extract.
（2）By 1 × 105Individual/mL L929 cell suspending liquids are inoculated in 96 porocyte culture plates, are placed in 37 DEG C of dioxies
Change and cultivated 24 hours in carbon incubator, after cell attachment growth, remove supernatant, be divided into two groups of control group and experimental group.
（3）Control group adds RPMI1640 nutrient solutions；Experimental group adds the RPMI1640 containing 50% above-mentioned leaching liquor and trained
Nutrient solution；Control group and experimental group are respectively placed in 37 DEG C of CO2gas incubators and continue to cultivate, was taken out after 2 days, culture plate
MTT solution is added per hole（5mg/ml）20 μ L, continue to cultivate 4 h in 37 DEG C, terminate culture.
（4）Careful inhale abandons culture supernatant in hole, and 200 μ L DMSO are added per hole, vibrates 10 minutes after mixing, uses enzyme
Connection immune detector determines its absorbance respectively under 630 nm.
（5）Cell is calculated according to the following equation with respect to appreciation rate（RCR）：
RCR（%）=（Experimental group mean absorbance values/control group mean absorbance values）×100% .
Cell is as follows with respect to appreciation rate RCR and cytotoxicity classification relationship：
RCR is not less than 100%, and cytotoxicity is classified as 0 grade；
RCR is 75~99%, and cytotoxicity is classified as 1 grade；
RCR is 50~74%, and cytotoxicity is classified as 2 grades；
RCR is 25~49%, and cytotoxicity is classified as 3 grades；
RCR is 1~24%, and cytotoxicity is classified as 4 grades；
RCR is 0%, and cytotoxicity is classified as 5 grades；
The cell measured in aforementioned manners judges the biocompatibility of Sodium Hyaluronate elastomer with respect to appreciation rate.RCR is got over
Height, show that the biocompatibility of cross-linked-hyaluronic acid elastomer to be measured is better.
Hyaluronic acid elasticity Cytotoxicity testing result：Cell is 93.49% with respect to proliferation rate（The cell of negative control
Proliferation rate is 100%）, cytotoxicity is I levels.The biocompatibility of gained hyaluronic acid elastomer of the invention is very good.
To sum up, present invention gained gel has excellent viscoelasticity, moisture-retaining capacity, physics filling wrinkle ability, can be sustained work(
Imitate composition, improve using sensation, and there is good biocompatibility.
Above-described embodiment is the preferable embodiment of the present invention, but embodiments of the present invention are not limited by embodiment
System, it is other it is any without departing from the present invention Spirit Essences with made under principle change, modification, combine, replacement, simplification should be
Equivalence replacement mode, is included within protection scope of the present invention.
Claims (8)
1. a kind of hyaluronic acid elastomer, it is characterised in that be obtained through the following steps：
(1) hyaluronic acid and crosslinking agent are reacted, obtains cross-linking sodium hyaluronate gel A；
(2) cross-linking sodium hyaluronate gel A is taken, selects the screen cloth of different pore size to pelletize respectively, the different gel B of particle diameter is obtained and coagulates
Glue C；
(3) gel B and gel C are mixed, carries out cross-linking reaction again, regulation pH value to neutrality, dialysis, obtain hyaluronic acid elasticity
Body；
The quality accounting of crosslinking agent and hyaluronic acid is 0.02%~3.0% in step (1), in step (3) crosslinking agent with it is transparent
The quality accounting of matter acid is 0.1%~3.0%；
Gel B particle size range is 100~800 μm；The particle size range of gel C is 70~100 μm.
2. hyaluronic acid elastomer according to claim 1, it is characterised in that crosslinking agent is carbodiimide, divinyl
One kind in sulfone, ethylene glycol diglycidylether, 1,4- butanediol diglycidyl ethers, the more glycidyl ethers of polyglycereol.
3. hyaluronic acid elastomer according to claim 1, it is characterised in that the pH value of step (3) cross-linking reaction be 2~
4。
4. hyaluronic acid elastomer according to claim 1, it is characterised in that the pH value of cross-linking reaction is in step (3)
11~14.
5. hyaluronic acid elastomer according to claim 1, it is characterised in that gel B and gel C is mixed in step (3)
Composition and division in a proportion example is (1-9):(9-1).
6. hyaluronic acid elastomer according to claim 1, it is characterised in that cross-linking reaction temperature in step (1), (3)
For 15 DEG C~50 DEG C；Reaction time is 2~24h.
7. the composition that the hyaluronic acid elastomer any one of a kind of claim 1-6 is prepared into, it is characterised in that also
Including one kind in light protective agent, antioxidant, nutritional agents, skin conditioning agent, allergy inhibitor, preservative or antiparasitic
Or more than one.
8. the hyaluronic acid elastomer any one of a kind of claim 1-6 is preparing cosmetics, beauty filling, orthopaedics note
Penetrate or ophthalmology viscoelastic agent in application.
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