CN106730029A - A kind of injection fillers crosslinking polyglutamic acid gel particle and its preparation method and application - Google Patents
A kind of injection fillers crosslinking polyglutamic acid gel particle and its preparation method and application Download PDFInfo
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Abstract
The invention provides a kind of injection fillers preparation method for being crosslinked polyglutamic acid particle：(1) by Isosorbide-5-Nitrae butanediol diglycidyl ether addition deionized water, after stirring, polyglutamate is added, is stirred, be incubated, obtain pre-composition；(2) add aqueous solution to be homogenized in the pre-composition described in step (1), obtain homogenate；(3) pH adjusting agent and osmotic pressure regulator are added in the homogenate described in step (2), instrumentality is obtained；(4) the separated collection gel particle thing of instrumentality described in step (3), sterilization treatment is obtained final product.The method gained crosslinking polyglutamic acid gel particle tolerance high pressure steam sterilization is without liquefaction；Crosslinking polyglutamic acid gel particle prepared by the present invention can be used to prepare the beauty injection fillers agent for increasing volume of tissue, length of holding time is filled, it is safe.
Description
Technical field
The invention belongs to natural polymerses application field, and in particular to a kind of injection fillers crosslinking polyglutamic acid
Gel particle and its preparation method and application.
Background technology
Polyglutamic acid is the chain anionic polypeptides type polymer being polymerized by γ-amido link by D-/L- glutamic acid.Poly- paddy
Propylhomoserin is initially found from the mucus of the fermented food natto of japanese traditional.Polyglutamic acid non-immunogenicity, in nature or
Can be completely degraded in human body, equal safety non-toxic edible, medical or used for cosmetic.Current polyglutamic acid can be sent out by microorganism
Ferment prepare with scale.Polyglutamic acid main chain contains a large amount of hydrophilic radicals, with the water imbibition more stronger than hyaluronic acid.
The B1 of United States Patent (USP) US 8 486 467 disclose a kind of polyglutamic acid with molecular weight up to more than 1,000,000 as raw material
Injection of skin filler.The patent is pointed out, compared with hyaluronic acid filler, polyglutamic acid is not human body itself contents
Matter, the speed that it is eliminated by body degraded is slower, reaches and retains more long tissue filling effect in vivo.In addition, polyglutamic acid
Fermentation strain for safety non-toxic high yield bacillus subtilis, and the fermentation strain of hyaluronic acid be pathogenic strain epizootic disease hammer
Bacterium, therefore the safety in utilization of polyglutamic acid is higher, fermentation costs are lower.The polyglutamic acid filling formulation patent composition be
1%~3% polyglutamic acid and 0.1%~1% contains calcium salt soln, carries out 48h filling experiments to family's rabbit skin with it, is filled out after 48h
Fill thing residual 76%~77%.Filling situation more than 48h is not reported further, if being counted according to 48h fillers loss 23.5%
Calculate, to filler residual 1% when the 32nd day (about January), the filling extrapolated is held time about 1 month.With the friendship of current application
Connection hyaluronic acid filler held time 6~12 months and compares, and the filling polyglutamic acid preparation is held time short, it is necessary to change
Enter preparation method extension filling to hold time, improve application value.
The content of the invention
To overcome the deficiencies in the prior art, the invention provides a kind of injection fillers crosslinking polyglutamic acid gel particle
Preparation method, obtains can be used for the safe and effective polyglutamic acid ejection preparation of skin histology injection fillers.
In addition polyglutamic acid gel particle is crosslinked for increasing group present invention also offers a kind of above-mentioned injection fillers
Knit the application in the beauty injection fillers preparation of capacity.
To achieve the above object, the present invention uses following technical scheme.
A kind of injection fillers preparation method of crosslinking polyglutamic acid gel particle, comprises the following steps：
(1) by BDDE addition deionized water, after stirring, polyglutamic acid is added
Salt, stirs, insulation, obtains pre-composition；
(2) add aqueous solution to be homogenized in the pre-composition described in step (1), obtain homogenate；
(3) pH adjusting agent and osmotic pressure regulator are added in the homogenate described in step (2), instrumentality is obtained；
(4) the separated collection gel particle thing of instrumentality described in step (3), sterilization treatment is obtained final product.
Above-mentioned preparation method, preferred operating method is：
(1) by 1.0~3.6 parts of BDDEs 90~110 parts of deionized waters of addition, stir
Afterwards, 20~35 parts of polyglutamates are added, is stirred, be incubated, obtain pre-composition, wherein described part is mass fraction；Its
The weight average molecular weight of middle polyglutamate is 1,500,000~2,500,000 dalton；Wherein polyglutamate is polyglutamic acid sodium, poly- paddy
One or more in propylhomoserin potassium, polyglutamic acid magnesium, polyglutamic acid calcium, polyglutamic acid zinc；Wherein holding temperature is 20~100
℃；Preferably, the polyglutamate is polyglutamic acid sodium, and holding temperature is 40~80 DEG C；
(2) aqueous solution is added to be homogenized in the pre-composition described in step (1), the gel particle grain of homogenate to 95%
Footpath is less than 1.1mm, obtains homogenate；Wherein aqueous solution is containing 0~0.9% salts solution；Wherein salt is sodium chloride
(NaCl), sodium dihydrogen phosphate (NaH2PO4), disodium hydrogen phosphate (Na2HPO4), potassium dihydrogen phosphate (KH2PO4), dipotassium hydrogen phosphate
(K2HPO4) in one or more, including the hydrated form containing the crystallization water；Preferably, 80% gel particle diameter 0.1~
Between 0.9mm；
(3) pH adjusting agent is added in the homogenate described in step (2) makes pH be 6.0~8.0, adds osmotic pressure regulator
Osmotic pressure is set to be 250~340mOsm/kgH2O, obtains instrumentality；Wherein pH adjusting agent is NaH2PO4、KH2PO4、Na2HPO4、
K2HPO4In one or more, including the hydrated form containing the crystallization water；Wherein osmotic pressure regulator is NaCl, glucose, sweet
Dew alcohol, potassium chloride (KCl), calcium chloride (CaCl2), sorbierite, including the hydrated form containing the crystallization water；Preferably, it is described
PH adjusting agent is NaH2PO4Or Na2HPO4, pH is 7.35~7.45, and osmotic pressure regulator is NaCl, osmotic pressure is 280~
310mOsm/kg·H2O；
(4) instrumentality described in step (3) separates and collects gel particle thing through filtering or centrifugal process, and sterilization treatment is obtained final product；
Wherein sterilising conditions are 110~160 DEG C of sterilizings of high steam, and the time is 2s~40min；Preferably, the sterilising conditions are 120
~155 DEG C, the time is 4s~30min.
The crosslinking polyglutamic acid gel particle that a kind of preparation method as described above is prepared.
The crosslinking polyglutamic acid gel particle that a kind of preparation method as described above is prepared, tissue is increased for preparing
Application in the beauty filling injection of capacity.
The crosslinking polyglutamic acid gel particle that a kind of preparation method as described above is prepared, prepares beauty filling injection
Agent.Gained injection is main component to be crosslinked polyglutamic acid particle, with the pH and osmotic pressure that are adapted with human body, by height
Pressure steam sterilizing, can be through needle injection in skin position to be filled.Filling injection use tunnel injection, needle slope upward,
Oblique inserting needle, moves back while injecting, crosslinking polyglutamic acid particle is played into skin position to be filled increases tissue appearance
The effect of amount；Also can be according to that need to be injected using tiling, netted, the tunnel combined method such as link work at selected spots with that in entire areas, more preferably to reach stereotactic injection
Effect.
Polyglutamic acid adjusts substrate polyglutamic acid and crosslinking agent BDO 2-glycidyl when crosslinking Treatment is carried out
The ratio of ether, can obtain the product of different crosslinking degrees.Generally, crosslinking substrate and crosslinker concentration are higher, are crosslinked journey
Degree is bigger.Find in an experiment, the crosslinking degree for being crosslinked polyglutamic acid is unsuitable too low, otherwise occur crosslinking polyglutamic acid because not
Tolerance sterilizing high temperature and rapid liquefied situation, the filling that liquefaction products easily dispersion will weaken its as tissue filling agent maintain effect
Really；The crosslinking degree for being crosslinked polyglutamic acid is also unsuitable too high, otherwise occurs that a large amount of polyglutamic acids are difficult few in preparatory phase
Stirred and evenly mixed in amount aqueous solution, or even the phenomenon that can not be completely dissolved, can not finally obtain the crosslinking polyglutamic of uniformity
Acid.
Preparation method of the invention is first by preparing the crosslinking polyglutamic acid of specific crosslinking degree, then is made with suitable
The gel particle of pH, osmotic pressure and particle diameter, the gel particle is resistant to high pressure steam sterilization without liquefaction, finally causes that injection is filled out
On the one hand fill can enter skin histology with crosslinking polyglutamic acid gel particle by safely injection, on the other hand also because it can be with solidifying
The form of glue particle resides at skin histology and reaches and extend the effect that its filling is held time.
Advantages of the present invention：(1) crosslinking modification after polyglutamic acid, overcome polyglutamic acid easily disperse it is degradable not
Foot, with the effect that extension tissue filling is held time.Injection fillers prepared by present invention crosslinking polyglutamic acid gel
Grain is in the beauty injection fillers art for increasing volume of tissue, clinical efficacy to be significantly, safe.(2) polyglutamic acid is micro- life
Thing source, the natural degradable polymer of safety non-toxic, and with superpower water suction performance of keeping humidity.Injection prepared by the present invention is filled out
Fill with polyglutamic acid gel particle is crosslinked, be the new filler that a class can be used for injection beauty, enrich existing few in number
Injectable beauty filler category, for it is vast to injection fillers beauty have need patient more more options are provided, especially to show
Have injection beauty filler category allergy needs patient.
Specific embodiment
The present invention is further illustrated with comparative example in conjunction with the embodiments, it should explanation, the description below be only for
The present invention is explained, its content is not defined.
Embodiment 1
By in BDDE 1.4g addition deionized waters 110g, after stirring, weight is added equal
The polyglutamic acid sodium 25g of the dalton of molecular weight 1,700,000, stirs, 100 DEG C of insulation 0.5h；Add the 0.9%NaCl aqueous solution
1.0L is homogenized, and 35000r/min homogenate about 10s, the gel particle particle diameter to 95% is less than 0.2mm, and median is
0.08mm；To adding about 0.074g NaH in homogenate2PO4With 0.040g Na2HPO4, adjust pH 6.5；Add NaCl about
0.65g, regulation osmotic pressure 288mOsm/kgH2O；5000r/min is centrifuged 10min, collects beds of precipitation gel particle thing；Packing,
157 DEG C of high pressure steam sterilization 3s are obtained final product.
Embodiment 2
By in BDDE 3.2g addition deionized waters 105g, after stirring, weight is added equal
The polyglutamic acid magnesium 33g of the dalton of molecular weight 2,100,000, stirs, 90 DEG C of insulation 2h；Add 0.9%NaCl aqueous solution 0.9L
It is homogenized, 19000r/min homogenate about 60s, the gel particle particle diameter to 95% is less than 0.5mm；To being added about in homogenate
0.043g NaH2PO4With 0.217g Na2HPO4, adjust pH 7.40；NaCl about 0.815g are added, osmotic pressure is adjusted
300mOsm/kg·H2O；Gel particle thing is collected by filtration；Packing, 115 DEG C of high pressure steam sterilization 38min are obtained final product.
Embodiment 3
By in BDDE 1.6g addition deionized waters 95g, after stirring, add and divide equally again
The polyglutamic acid zinc 27g of son 1,800,000 dalton of amount, stirs, 80 DEG C of insulation 4h；Deionized water 1.5L is added to be homogenized,
25000r/min is homogenized about 20s, and the gel particle particle diameter to 80% is between 0.01~0.6mm；To being added about in homogenate
The KH of 0.091g2PO4With the K of 0.145g2HPO4, adjust pH 6.9；Mannitol 71.77g is added, osmotic pressure is adjusted
260mOsm/kg·H2O；15000r/min is centrifuged 5min, collects beds of precipitation gel particle thing；Packing, 120 DEG C of high steams go out
Bacterium 20min is obtained final product.
Embodiment 4
By in BDDE 2.0g addition deionized waters 100g, after stirring, weight is added equal
The polyglutamic acid sodium 28g of the dalton of molecular weight 2,200,000, stirs, 60 DEG C of insulation 5h；Add 0.021%K2HPO4·3H2O water
Solution 1.6L is homogenized, 10000r/min homogenate about 3min, the gel particle particle diameter to 80% between 0.05~0.8mm,
Median is 0.1mm；To adding NaH in homogenate2PO4·2H2O about 0.065g, adjust pH 7.35；Add CaCl2
26.88g, regulation osmotic pressure 280mOsm/kgH2O；3000r/min is centrifuged 3min, collects beds of precipitation gel particle thing；Packing,
121 DEG C of high pressure steam sterilization 15min are obtained final product.
Embodiment 5
By in BDDE 2.5g addition deionized waters 100g, after stirring, weight is added equal
The polyglutamic acid sodium 30g of the dalton of molecular weight 2,400,000, stirs, 50 DEG C of insulation 6h；Add 0.053%Na2HPO4·12H2O
Aqueous solution 0.5L is homogenized, 30000r/min homogenate about 15s, the gel particle particle diameter to 80% between 0.05~1mm, in
Digit is 0.2mm；To adding KH in homogenate2PO4About 0.022g, adjusts pH 7.45；Sorbierite 28.35g is added, regulation is oozed
310mOsm/kgH is pressed thoroughly2O；Gel particle thing is collected by filtration；Packing, 140 DEG C of high pressure steam sterilization 10s are obtained final product.
Embodiment 6
By in BDDE 2.8g addition deionized waters 100g, after stirring, weight is added equal
The polyglutamic acid sodium 31g of the dalton of molecular weight 2,000,000, stirs, 40 DEG C of insulation 8h；Add 0.025%K2HPO4·3H2O water
Solution 2.0L is homogenized, 15000r/min homogenate about 2min, the gel particle particle diameter to 80% between 0.1~0.9mm, in
Digit is 0.4mm；To the KH that about 0.242g is added in homogenate2PO4, adjust pH7.7；Add KCl 23.66g, regulation infiltration
Pressure 320mOsm/kgH2O；Gel particle thing is collected by filtration；Packing, 155 DEG C of high pressure steam sterilization 4s are obtained final product.
Embodiment 7
By in BDDE 3.6g addition deionized waters 100g, after stirring, weight is added equal
The polyglutamic acid calcium 35g of the dalton of molecular weight 2,500,000, stirs, 30 DEG C of insulation 9h；Add 0.037%Na2HPO4·2H2O
Aqueous solution 1.3L is homogenized, 18000r/min homogenate about 60s, and the gel particle particle diameter to 80% is between 0.1~1mm；To
About 0.021g NaH are added in homogenate2PO4·H2O, adjusts pH 8.0；Glucose about 64.07g is added, osmotic pressure is adjusted
250mOsm/kg·H2O；Gel particle thing is collected by filtration；Packing, 160 DEG C of high pressure steam sterilization 2s are obtained final product.
Embodiment 8
By in BDDE 1.0g addition deionized waters 90g, after stirring, add and divide equally again
The polyglutamic acid potassium and each 10g of polyglutamic acid calcium of son 1,500,000 dalton of amount, stir, 20 DEG C of insulation 10h；Add 0.9%
NaCl aqueous solution 1.2L is homogenized, and 21000r/min homogenate about 30s, the gel particle particle diameter to 95% is less than 1.1mm；Xiang Yun
About 0.101g NaH are added in slurry thing2PO4With 0.017g Na2HPO4, adjust pH 6.0；NaCl about 2.76g are added, regulation is oozed
340mOsm/kgH is pressed thoroughly2O；9000r/min is centrifuged 1min, collects beds of precipitation gel particle thing；Packing, 110 DEG C of high steams
Sterilizing 40min is obtained final product.
Comparative example 1
The polyglutamic acid sodium of 1g weight average molecular weight 1,500,000 is dissolved in the 80mL aqueous solution, 1g calcium chloride is added, is settled to water
100mL, 121 DEG C of high pressure steam sterilization 30min are obtained final product.
Comparative example 2
The polyglutamic acid sodium of 2g weight average molecular weight 2,100,000 is dissolved in the 80mL aqueous solution, 0.9g calcium chloride is added, water constant volume is used
To 100mL, 121 DEG C of high pressure steam sterilization 30min are obtained final product.
Comparative example 3
The polyglutamic acid sodium of 3g weight average molecular weight 2,800,000 is dissolved in the 80mL aqueous solution, 0.8g calcium chloride is added, water constant volume is used
To 100mL, 121 DEG C of high pressure steam sterilization 30min are obtained final product.
Efficacy test：Rabbit ear skin filling test
To protrude and being easy to the filling for detecting injection fillers thing to maintain effect, selection carries out skin in rabbit ear dorsal skin
Interior injection fillers, the filler of concentration of local increases local subcutaneous tissue amount and makes outer surface of the skin in the outer of substantially protuberance
See, observe holding time for cutaneous protuberance state.The healthy new zealand rabbit 2 of selection, makees blank for 1 and does not inject, another 1
Carry out injection fillers experiment.4 injection sites, each injection location 0.1mL lifes are selected in the rabbit left side ear for receiving injection
Injection fillers prepared by reason salt solution and embodiment 1, embodiment 4, embodiment 5, embodiment 6 crosslinking polyglutamic acid gel
Grain.Receiving corresponding 4 positions of rabbit right ear of injection, 0.1mL physiological saline and comparative example 1, contrast are being injected respectively
Injection fillers polyglutamic acid preparation prepared by example 2 and comparative example 3.Rabbit ear skin is observed 48 weeks after filler injection, record
Filling area skin maintains the time of protuberance state, and its result is referring to table 1.Filling area skin maintains the inspection of protuberance state,
It is to check filler existence with finger touch by visual observation, thumb and forefinger touch the upper and lower surface for filling position simultaneously,
By with flat surface around injection site, compare rabbit and confirm with the contrast of portion faces situation the presence of filler.
Holding time for different polyglutamic acid preparations is filled in the rabbit ear intracutaneous injection of table 1
After rabbit ear intracutaneous injection filling polyglutamic acid preparation, the polyglutamic acid preparation group and physiological saline group of crosslinking are in injection
Position occurs local slight redness phenomenon, can in 1~7 day self-healing recovery it is normal；Uncrosslinked polyglutamic acid preparation group is then
There is the local red and swollen, phenomenon of glowing skin, can in 3~7 days self-healing recovery it is normal.After experiment terminates, with blank
Rabbit is compared, and the rabbit blood routine for receiving injection is normal, and the main organs such as the heart, liver, spleen, lung, kidney show no obvious abnormalities through dissecting.
From table 1, it is 1 week that the comparative example filling of uncrosslinked polyglutamic acid preparation is held time, and compares physiological saline group
It is slightly longer, and the filling for being crosslinked the embodiment of polyglutamic acid gel particle is held time up to more than 22~48 weeks, when filling is maintained
Between be considerably longer than uncrosslinked polyglutamic acid preparation.Uncrosslinked polyglutamic acid preparation is in the state of solution fluid, in injection site
It is easily dispersed and is absorbed by Tissue approximation, therefore filler maintains DeGrain.
By table 1 furthermore, it can be seen that (1) obtains pre-composition the step of polyglutamic acid particle preparation is crosslinked, with polyglutamic
The gradually increase (embodiment 1, embodiment 4, embodiment 5, embodiment 6) of sour sodium and BDDE consumption,
And step (2) when obtaining homogenate crosslinking polyglutamic acid grain diameter incrementally increase (embodiment 1, implement within the specific limits
Example 4, embodiment 5, embodiment 6), the final crosslinking polyglutamic acid particle injection for obtaining is in rabbit ear intracutaneous injection filling test
Manifest longer filling to hold time.This is due to when one side is crosslinked the degree of cross linking of polyglutamic acid particle itself with crosslinking Treatment
The concentration of polyglutamic acid raw material and crosslinking agent increases and increases, and the compactness extent of the degree of cross linking then gelinite high is higher；On the other hand,
The increase of polyglutamic acid grain diameter is crosslinked, the surface area with bioresorbable, two aspect reason collective effects is substantially reduced
So that particle resistance autoclaving high temperature degradation and the ability of body fluid environment digestion degraded are higher, therefore in filling test
In show longer filling and hold time.
Experiment is injected in the injection for being crosslinked polyglutamic acid particle
, it is necessary to operator's precise control injection speed and strength in beauty injection fillers art, to reduce because being blocked up in injection
Fill in and make to inject risk out of control, experiment is injected in the injection for be crosslinked polyglutamic acid particle.30G injection needles are chosen, is installed
On the 1.0mL injection needle tubes of pre- filling different crosslinking polyglutamic acid particles, thrust is set by syringe thrust test instrument
Injection in 10N, simulated skin, observation injection ram propulsion rate profile.When injection ram propulsion rate profile is
Steady smoothed curve, it is believed that continuous uniform is injected in injection；Such as there is speed to be 0 or the fluctuating of trough crest occur, then it is assumed that note
Penetrate and inject discontinuously uniformly.The injection for being crosslinked polyglutamic acid Particles Example injects speed situation of change referring to table 2.
Test is injected in the injection of the filling different crosslinking polyglutamic acid gel particles of table 2
From table 2, what crosslinking polyglutamic acid gel particle prepared by embodiment manifested in test is injected in injection injects
Continuous uniform rate >=98%, injection safety is higher.Simultaneously it can be seen that with crosslinking polyglutamic acid gel particle particle size interval
Gradually expand, the probability occurred with the particle of large-size particles particularly 1.1mm or so gradually increases, and the company of process is injected in injection
Continuous evening ratio is somewhat reduced, that is, the risk for injecting blocking has risen, therefore preferably controls the gel particle grain of grain diameter 95%
Footpath is within 1.1mm.It is visible in conjunction with rabbit ear skin filling test 1 result of table, with crosslinking polyglutamic acid grain diameter median
Reduce, it is held time in the filling of rabbit ear intracutaneous and is gradually shortened.Consider raising crosslinking polyglutamic acid particle injects safety
Property and extension filling hold time, grain diameter is unsuitable excessive or too small.
The crosslinking heating condition selection of polyglutamic acid
During crosslinking polyglutamic acid particle-making step (1) obtains pre-composition, intensification is conducive to accelerating cross-linking reaction.
To reach effective crosslinking of polyglutamic acid and crosslinking agent, it was observed that heating-up temperature and time-consuming relation that substantially jelly condenses
It is shown in Table 3.
The polyglutamic acid of table 3 heating-up temperature required when being crosslinked and setting time
From table 3, during polyglutamic acid is changed into jelly condensation by fluid crosslinking, heating-up temperature is more up to arrived
The time that jelly condenses accordingly shortens.In view of the too high potential safety hazard that such as embodiment 1 operation may be brought to scald of temperature, and
Temperature is too low as the elapsed time of embodiment 8 is long, and comprehensively preferably moderate 40~80 DEG C, setting time is true naturally with temperature
It is fixed.
In addition, in crosslinking polyglutamic acid particle-making step (3) adjusted thing, choosing pH and adjusting to 6.0~8.0, ooze
Pressure is adjusted to 250~340mOsm/kgH thoroughly2O, is data area that human body fluid can be received.It is right to reduce to greatest extent
The influence of human injection position physiological environment, preferably tissue liquid optimal pH 7.35~7.45, and osmotic pressure 280~
310mOsm/kg·H2O。
In sum, injection fillers disclosed in this invention are crosslinked polyglutamic acid gel particle to increase skin histology
In injection fillers formulation application for the purpose of capacity, injection safety, adverse reaction situation incidence is low, without severe complication situation
Occur；Its tissue compatibilization effect is protruded, and volume of tissue filling effect is held time and is above considerably longer than uncrosslinked polyglutamic acid system
The injection fillers effect of agent.
Claims (8)
1. a kind of injection fillers use is crosslinked the preparation method of polyglutamic acid gel particle, it is characterised in that comprise the following steps：
(1) by BDDE addition deionized water, after stirring, polyglutamate is added, is stirred
Mix uniform, insulation obtains pre-composition；
(2) add aqueous solution to be homogenized in the pre-composition described in step (1), obtain homogenate；
(3) pH adjusting agent and osmotic pressure regulator are added in the homogenate described in step (2), instrumentality is obtained；
(4) the separated collection gel particle thing of instrumentality described in step (3), sterilization treatment is obtained final product.
2. preparation method as claimed in claim 1, it is characterised in that comprise the following steps：
(1) in 1.0~3.6 parts of BDDEs being added into 90~110 parts of deionized waters, after stirring,
20~35 parts of polyglutamates are added, is stirred, be incubated, obtain pre-composition, wherein described part is mass fraction；Wherein gather
The weight average molecular weight of glutamate is 1,500,000~2,500,000 dalton；Wherein polyglutamate is polyglutamic acid sodium, polyglutamic acid
One or more in potassium, polyglutamic acid magnesium, polyglutamic acid calcium, polyglutamic acid zinc；Wherein holding temperature is 20~100 DEG C；
(2) aqueous solution is added to be homogenized in the pre-composition described in step (1), the gel particle particle diameter of homogenate to 95% is small
In 1.1mm, homogenate is obtained；Wherein described aqueous solution is that, containing 0~0.9% salts solution, the salt is sodium chloride
(NaCl), sodium dihydrogen phosphate (NaH2PO4), disodium hydrogen phosphate (Na2HPO4), potassium dihydrogen phosphate (KH2PO4), dipotassium hydrogen phosphate
(K2HPO4) in one or more, including the hydrated form containing the crystallization water；
(3) pH adjusting agent is added in the homogenate described in step (2) makes pH be 6.0~8.0, adds osmotic pressure regulator to make to ooze
Pressure is 250~340mOsm/kgH thoroughly2O, obtains instrumentality；Wherein described pH adjusting agent is NaH2PO4、KH2PO4、Na2HPO4、
K2HPO4In one or more, including the hydrated form containing the crystallization water；Wherein described osmotic pressure regulator is NaCl, grape
Sugar, mannitol, potassium chloride (KCl), calcium chloride (CaCl2), sorbierite, including the hydrated form containing the crystallization water；
(4) instrumentality described in step (3) separates and collects gel particle thing through filtering or centrifugal process, and sterilization treatment is obtained final product；Wherein
Sterilising conditions are 110~160 DEG C of sterilizings of high steam, and the time is 2s~40min；Preferably, the sterilising conditions be 120~
155 DEG C, the time is 4s~30min.
3. the preparation method as described in claim 1 and 2 is any, it is characterised in that the polyglutamate is polyglutamic acid sodium.
4. the preparation method as described in claim 1 and 2 is any, it is characterised in that in the step (1) holding temperature be 40~
80℃。
5. the preparation method as described in claim 1 and 2 is any, it is characterised in that the step (2) is described in step (1)
Aqueous solution is added to be homogenized in pre-composition, the gel particle diameter of homogenate to 80% obtains homogenate between 0.1~0.9mm.
6. the preparation method as described in claim 1 and 2 is any, it is characterised in that the pH adjusting agent is NaH2PO4Or
Na2HPO4, pH is 7.35~7.45, and the osmotic pressure regulator is NaCl, and osmotic pressure is 280~310mOsm/kgH2O。
7. the crosslinking polyglutamic acid gel particle that prepared by a kind of preparation method as described in claim 1 and 2 is any.
8. the crosslinking polyglutamic acid gel particle that prepared by a kind of preparation method as described in claim 1 and 2 is any, for preparing
Increase the application in the beauty filling injection of volume of tissue.
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