CN108774330A - The preparation method and products obtained therefrom of a kind of cross-linked hyaluronic acid gel and application - Google Patents
The preparation method and products obtained therefrom of a kind of cross-linked hyaluronic acid gel and application Download PDFInfo
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Abstract
The invention discloses a kind of preparation method of cross-linked hyaluronic acid gel and products obtained therefrom and application, step is：HA and crosslinking agent are stood into 8-16h in alkaline solution, at 1-4 DEG C, reaction 5min-30min is stood at 50-80 DEG C, is subsequently placed at 1-4 DEG C and stands reaction 0.5-5 h；The step of repetition " stand reaction 5min-30min at 50 ~ 80 DEG C, be subsequently placed in stand at 1-4 DEG C and react 0.5-5 h " 3-5 times, obtains product.The present invention repeats " high temperature-low temperature " condition and prepares highly cross-linked hyaluronic acid derivatives particle; products obtained therefrom quality is neither too hard, nor too soft; there is special three-dimensional netted molecular structure inside particle; with adsorptivity and elasticity; it is environmentally friendly; the frosted particle or granule for massage that may be used as washing product play stimulation and promote blood circulation, promote the effects that new cytothesis, mild exfoliating, make skin smooth, softness and health.
Description
Technical field
The present invention relates to a kind of preparation method of cross-linked hyaluronic acid gel, further relate to the product obtained in the method and
The product belongs to cross-linked-hyaluronic acid preparing technical field as the washing product application of frosted particle or granule for massage.
Background technology
Mankind's skin metabolism period is 28 days.But this process will be slack-off if skin water shortage is dried, it is old useless
Cell can be accumulated in skin surface, and skin is enabled to be difficult to eupnea.Skin will become dim mute, coarse in this way.Periodically using mill
Sand product can change this situation.In traditional frosted product common frosted particle have miniature soft pearl, almond, walnut, bone meal,
Nacreous layer powder, calcium carbonate etc..With the increasingly rise of frosted product, new frosted granular materials also comes into being, such as west kind
Lotus fruit seed, cellulose, chemical synthesis wax pearl etc..
Its essence is miniature plastic grains for the most common miniature soft pearl of tradition, these substances are not soluble in water, cause environment
Serious pollution.After people are using cosmetics and nursing product, " miniature soft pearl " can be directly discharged into sewerage, sewage treatment plant
Water processing establishment be difficult this tiny plastic grain of filtering.These subsequent sewage are discharged into ocean, meeting after fish feed
Toxic plastic grain is sucked, and after being eaten up by other fish or the mankind, the toxin in the soft pearl of plastics will enter food chain.It grinds
Study carefully personnel to indicate that after " miniature soft pearl " enters in the mankind's body symptoms such as " meronecrosis, inflammation and tissue lacerated wounds " can be caused.According to
The U.S. House of Representatives by bill, the small bead harmful to environment was forbidden to use from 1 day July in 2017.Australia etc.
Country lists the product list containing " miniature soft pearl " also by participation " BeattheMircrobead " activity.Calcium carbonate etc.
Mineral powders quality is hard, is not suitable for commonly using, is not also suitable for sensitive skin.Almond, walnut, passionflower fruit seed etc. are naturally planted
Object production prepares the problems such as minitype particle has been easy dust pollution, energy consumption is big, and granular texture is also harder.
Patent CN 104194982A provide a kind of preparation method of sea sand soap, wherein addition sea sand is as frosted
Grain has particle hard, the big defect of skin friction irritation.It is mentioned in patent CN106726754A, CN106675890A
Frosted bath salt and bath soap use polyethylene frosted particle and rock salt for frosted particle, and there is polyethylene frosted particle to easily cause ring
The defect of border pollution.It is proposed in patent CN107280990A, CN107280991A and uses sugared (brown sugar etc.) as frosted particle, tool
There is frictional force big, is unsuitable for the defect being commonly used.
Hyaluronic acid (HA) is by (1 → 3) -2- acetylaminohydroxyphenylarsonic acid 2- deoxidations-β-D-Glucose-(1 → 4)-O- β-D- glucose
The straight-chained polysaccharide that aldehydic acid disaccharide recurring unit is formed, is widely present in skin, vitreum, cartilage and knuckle synovia etc.
In many connective tissues, the physiological actions such as moisturizing, nutrition and reparation are played.Being crosslinked HA has good physicochemical property and biofacies
Capacitive is commonly applied to beauty and shaping, isolating and protecting, ophthalmologic operation, joint cavity injection, operation protection, pharmaceutical carrier, cosmetics original
The fields such as material.Currently, the research about hyaluronic acid is primarily upon in resistance to enzymolysis, ageing resistance, biocompatibility, wetting
Property, there is no using hyaluronic acid or cross-linked-hyaluronic acid as the relevant report of frosted particle.
For example, the patent of 101107270 A of Publication No. CN discloses a kind of method being crosslinked HA with divinylsulfone,
This method refer to by DVS and HA 5-50 DEG C (preferably 20-30 DEG C), 20-100 DEG C (preferably 30-60 DEG C), 0-40 DEG C (preferably
10-30 DEG C) it is crosslinked at a temperature of three kinds, but hydrogel made from this method is mainly used for pharmaceutical carrier, excipient or dilution
Agent, its advantage is that there is good homogenieity, flexibility and syringeability, but its hardness is not appropriate for cleaning skin.Publication number
For the method that three steps under a kind of temperate condition of patent disclosure of CN 107936272A are crosslinked HA, this method is by HA and crosslinking agent
It is crosslinked at a temperature of 0-10 DEG C, 30-60 DEG C, 10-40 DEG C three kinds, gained, which is crosslinked HA gels, to be had good resistance to enzymolysis and resist
Radiance, but its hardness is also not suitable for cleaning skin.
Invention content
Insufficient existing for existing washing product frosted particle in order to solve, the present invention provides a kind of cross-linked-hyaluronic acids
The preparation method and products obtained therefrom of gel, this method carry out repeating crosslinking, gained cross-linked transparent matter under different temperature conditions
Acid gel quality is neither too hard, nor too soft and skin-friendliness is good, has adsorptivity and elasticity, has frosted cleaning and massage functions.
Frosted particle or granule for massage the present invention also provides above-mentioned cross-linked-hyaluronic acid particle as washing product
Using the cross-linked-hyaluronic acid particle has special three-dimensional netted molecular structure, and quality hardness is moderate, and granular size can be free
Adjust, aged cells, cleaning skin can be effectively removed, also have adsorptivity and elasticity, can massage skin and hair follicle, promote blood
Liquid recycles, and can meet the requirement of various washing products, and from natural materials, environmental-friendly, energy consumption is small, skin is pierced
Swash small, suitable large-scale use.
Specific technical solution of the present invention is as follows：
A kind of preparation method of cross-linked hyaluronic acid gel, this approach includes the following steps：
(1) hyaluronic acid is uniformly mixed with crosslinking agent in alkaline solution, 8-16h is stood at 1-4 DEG C；
(2) reaction solution of step (1) is stood to reaction 5min-30min at 50-80 DEG C, is subsequently placed at 1-4 DEG C and stands
React 0.5-5h；
(3) after step (2), reaction solution obtained by step (2) is repeated " stood at 50~80 DEG C reaction 5min-30min,
It is subsequently placed in step 3-5 times for standing reaction 0.5-5h " at 1-4 DEG C, obtains gel C, gel C is cross-linked hyaluronic acid gel.
Further, in step (3), after step 3-5 times for repeating step (2), end reaction object all becomes gel C, nothing
It needs to filter.Can also include the steps that gel C dialysis, granulation are obtained into cross-linked hyaluronic acid gel after granulation after step (3)
Particle.What dialysis removed is unreacted crosslinking agent.Granulation may be used existing disclosed method of granulating and carry out, such as sieve system
Grain, for the ease of being used as frosted particle and granule for massage, the size of particle obtained within 30 μm of -2000 μ m,
Particle it is preferably spherical.
Further, in step (1), the hyaluronic acid refers to hyaluronic acid and its salt, preferably hyaluronate.
The hyaluronate is that arbitrarily can be used for cosmetics and washing product, hyaluronic acid soluble-salt, including but not limited to
Sodium Hyaluronate, calcium hyauronate, hyaluronic acid magnesium, potassium hyaluronate, zinc hyaluronate etc., the performance class of each hyaluronate
Seemingly, most common is Sodium Hyaluronate.The molecular weight of the hyaluronic acid and its salt is 50~3,500,000 Da, and molecular weight is to crosslinking
The expansion character (i.e. the degree of cross linking) of hyaluronic acid derivatives particle has an impact, and molecular weight is bigger, the expansion of cross-linked hyaluronic acid gel
Coefficient is smaller, i.e., the degree of cross linking is higher, and preferred molecular weight ranges are 150~2,500,000 Da.
Further, in step (1), the crosslinking agent is epoxides crosslinking agent, divinylsulfone, polyethylene glycols
Any one in crosslinking agent or carbodiimide, the epoxides crosslinking agent includes 1,4-butanediol diglycidyl ether
(BDDE), ethylene glycol diglycidylether etc., the polyethylene glycols crosslinking agent include polyethyleneglycol diglycidylether, four arms
Star polyethylene glycol epoxide etc..Crosslinking agent has an impact the viscoplasticity of final cross-linked hyaluronic acid gel, preferred to hand over
Connection agent is BDDE.The dosage of crosslinking agent is generally the 2%~10% of hyaluronic acid and its salt quality, preferably 4%~6%.
Further, in step (1), crosslinking agent is reacted with HA under alkaline environment, and alkali concentration is too small to be unfavorable for HA
Dissolving, the too big HA of concentration can degrade in strong basicity.The alkaline solution is in sodium carbonate, sodium bicarbonate or sodium hydroxide solution
Any one.The mass concentration of alkaline solution is preferably 0.5%~5wt%.The concentration of hyaluronic acid and its salt in lye
It is unsuitable excessively high, it also should not too low, generally 10-30% (w/v), preferably 20% (w/v).
Further, in step (3), reaction solution obtained by step (2) is repeated to the meaning of the operation 3~5 times of step (2)
It is：Step (2) gained reaction solution is repeated " to stand reaction 5min~30min at 50-80 DEG C, then be placed at 1~4 DEG C and stand instead
Answer step 3~5 time of 0.5~5h ".For example, repeating the step of the operation 3 times of step (2) is：After step (2), by step (2)
Gained reaction solution stands reaction 5min~30min at 50~80 DEG C, then is placed at 1~4 DEG C and stands reaction 0.5~5h (repetitions
Once)；Then reaction 5min~30min is stood at 50~80 DEG C again, then is placed at 1~4 DEG C and stands reaction 0.5~5h (weights
Again twice)；Then reaction 5min~30min is stood at 50~80 DEG C again, then is placed at 1~4 DEG C and stands 0.5~5h of reaction,
Finally obtain gel C (in triplicate).
Preferably, in step (1), the time for standing reaction is 10~12h.In step (2), reaction solution is at 50~80 DEG C
The time for standing reaction is preferably 15~20min, and the time that reaction is stood at 1~4 DEG C is preferably 2~3h.
Have inside present invention cross-linked hyaluronic acid gel obtained by the above method or gel particle special three-dimensional netted
Molecular structure, it is not soluble in water, quality is neither too hard, nor too soft, have adsorptivity and elasticity, have well removal aged cells, cleaning skin
The effect of skin, moreover it is possible to which massage skin and hair follicle promote blood circulation.Therefore, cross-linked-hyaluronic acid obtained according to the method described above
Gel or gel particle and its application as washing product frosted particle or granule for massage are also within the scope of the present invention.
The gel or gel particle do frosted particle or granule for massage used time, being capable of mild exfoliating, promotion skin blood circulation and skin
Skin compatibility is good, small to skin irritatin, is suitble to sensitive to use, can reach deep layer cleaning and massage effect.
Further, when cross-linked hyaluronic acid gel or gel particle as frosted particle or granule for massage in use, mill
The dosage of sand particle or granule for massage is the 0.01~10% of washing product gross mass.
Further, the washing product includes facial cleanser, facial cleanser breast, facial cleanser soap, washing cream, face cleaning dew, face cleaning
Honey, face cleaning powder, face cleaning gel, scrub cream, massage cream, exfoliating cream, exfoliating powder, toothpaste, tooth powder, perfumed soap, bath foam, bath salt,
Shampoo, hair conditioner etc..It can be added and wash one's face, face cleaning, exfoliating, used as frosted particle in bath product, it is mild to remove
Cutin can also be added in massage, hair washing, hair products and be used as granule for massage, and massage skin and hair follicle promote blood to follow
Ring.
The present invention has the following advantages：
The present invention uses special crosslinking means, and " high temperature-low temperature " condition of repetition prepares highly cross-linked hyaluronic acid derivatives
Particle, preparation process is easily manipulated, is environmental-friendly, energy consumption is small, and gained cross-linked hyaluronic acid gel particle is not soluble in water, matter
Ground is neither too hard, nor too soft, has special three-dimensional netted molecular structure inside particle, has adsorptivity and elasticity, environmentally friendly, and one
Aspect, the gel particle may be used as the frosted particle of washing product, leniently be removed from skin surface using physical friction dead
Cell achievees the purpose that deep layer cleaning；On the other hand, which may be used as the granule for massage of washing product, by suitable
The extruding massage of degree can stimulate and promote blood circulation, and promote new cytothesis；In another aspect, tool inside the gel particle
There is three-dimensional netted molecular structure, pore rubbish can be adsorbed, makes skin smooth, soft and health.
Specific implementation mode
With reference to specific embodiment, the present invention will be further described, and following the description is merely exemplary, not to this
Invention protection domain is limited.
In following embodiments, unless otherwise instructed, the concentration is mass concentration.
1 temperature of embodiment is examined or check
By Sodium Hyaluronate (2,000,000 Da of molecular weight) 2g and crosslinking agent B DDE (1,4- butanediol diglycidyl ethers)
0.05g is uniformly mixed in the sodium hydroxide solution of 10ml a concentration of 1%, parallel 6 parts, stands 8h in 1~4 DEG C of refrigerator, then
It is respectively placed at 1. 40 DEG C, 2. 50 DEG C, 3. 60 DEG C, 4. 70 DEG C, 5. 80 DEG C, 6. 90 DEG C and stands reaction 5min, then be placed in 1~4 DEG C
0.5h is reacted in ice water；It repeats " to be placed at 1. 40 DEG C, 2. 50 DEG C, 3. 60 DEG C, 4. 70 DEG C, 5. 80 DEG C, 6. 90 DEG C and stand reaction
5min, then the step 3 time for reacting 0.5h " is placed in 1~4 DEG C of ice water, HA gel pieces must be crosslinked.Crosslinking HA gel pieces are dialysed,
The crosslinking agent for having neither part nor lot in reaction is washed off, then pelletizes through 40 mesh screens, obtains the crosslinking HA gel particles of 100 μm of grain size.
Elasticity examination：It is crosslinked HA particle bullets with Haake RS6000 (silent winged scientific and technological (China) company of generation that of match) Instrument measuring
Property, condition is：Rotor：P20Ti L；Gap values：1.00mm；Temperature：25℃；Mode determination：Oscillation frequency sweep CD；Stress：
1%；Frequency range：0.01~1Hz.Record the elasticity modulus (G ') when 0.1Hz.It the results are shown in Table 1.
Table 1
| Sample number into spectrum | G’(Pa) |
| ① | 1201 |
| ② | 2015 |
| ③ | 2519 |
| ④ | 2805 |
| ⑤ | 2989 |
| ⑥ | 1890 |
Elasticity modulus (G ') can reflect the consistency and elasticity of cross-linked-hyaluronic acid (HA) particle, and G ' is too low, cross-linked transparent
Matter granulates hardness is insufficient, is not suitable for doing frosted particle, and when G ' is more than 2000, crosslinking HA pellet hardnesses and elasticity just conform to
It asks.By table 1 as it can be seen that second step crosslinking temperature meets the requirements when between 50~80 DEG C, at 40 DEG C, temperature is too low, and elasticity is not
Foot；Because temperature is too high at 90 DEG C, HA Partial digestions.
1~4 DEG C of the first step is stood and 1~4 DEG C of reaction of third step is refrigerator cold-storage placement or ice-water bath, without temperature
Degree examination.
2 crosslinking time of embodiment and number of repetition examination
(1) first step time of repose is examined or check
By Sodium Hyaluronate (2,000,000 Da of molecular weight) 2g and crosslinking agent B DDE (1,4- butanediol diglycidyl ethers)
0.05g is uniformly mixed in the sodium hydroxide solution of 10ml a concentration of 1%, parallel 7 parts, is respectively placed in 1~4 DEG C of refrigerator and is stood
1. then 6h, 2. 8h, 3. 10h, 4. 12h, 5. 14h, 6. 16h, 7. 18h react 5min for 50 DEG C, then be placed in 1~4 DEG C of ice water anti-
Answer 0.5h；Repeat " 50 DEG C of reaction 5min, then the step 3 time for reacting 0.5h " is placed in 1~4 DEG C of ice water, HA gel pieces must be crosslinked.
Crosslinking HA gel pieces are dialysed, the crosslinking agent for having neither part nor lot in reaction is washed off, then pelletizes through 40 mesh screens, obtain the friendship of 100 μm of grain size
Join HA gel particles.
Elastic examination method is the same as embodiment 1.It the results are shown in Table 2.
Table 2
| Sample number into spectrum | G’(Pa) |
| ① | 1889 |
| ② | 2199 |
| ③ | 2310 |
| ④ | 2385 |
| ⑤ | 2200 |
| ⑥ | 2000 |
| ⑦ | 1982 |
As can be seen from Table 2, the crosslinking HA particles G ' that between 8~16h, obtains of first step time of repose is in 2000Pa or more,
It meets the requirements.It is optimal wherein between 10~12h.
(2) second step cross-linking reaction time is examined or check
By Sodium Hyaluronate (2,000,000 Da of molecular weight) 2g and crosslinking agent B DDE (1,4- butanediol diglycidyl ethers)
0.05g is uniformly mixed in the sodium hydroxide solution of 10ml a concentration of 1%, parallel 7 parts, is placed in 1~4 DEG C of refrigerator and is stood 8h,
Then it reacts 1. 5min, 2. 10min, 3. 15min, 4. 20min, 5. 25min, 6. 30min, 7. 35min for 50 DEG C, then is placed in 1~4
0.5h is reacted in DEG C ice water；Repeat " 50 DEG C reaction 1. 5min, 2. 10min, 3. 15min, 4. 20min, 5. 25min, 6. 30min,
7. 35min, then the step 3 time for reacting 0.5h " is placed in 1~4 DEG C of ice water, HA gel pieces must be crosslinked.It is saturating HA gel pieces will to be crosslinked
Analysis, washes off the crosslinking agent for having neither part nor lot in reaction, then pelletizes through 40 mesh screens, obtains the crosslinking HA gel particles of 100 μm of grain size.
Elastic examination method is the same as embodiment 1.It the results are shown in Table 3.
Table 3
| Sample number into spectrum | G’(Pa) |
| ① | 2199 |
| ② | 2323 |
| ③ | 2589 |
| ④ | 2617 |
| ⑤ | 2100 |
| ⑥ | 2001 |
| ⑦ | 1882 |
By table 3 as it can be seen that second step cross-linking reaction time is in 5~30min, gained crosslinking HA particles meet G ' and are more than
The requirement of 2000Pa, wherein 15~20min is optimal.
(3) third step cross-linking reaction time examination
By Sodium Hyaluronate (2,000,000 Da of molecular weight) 2g and crosslinking agent B DDE (1,4- butanediol diglycidyl ethers)
0.05g is uniformly mixed in the sodium hydroxide solution of 10ml a concentration of 1%, parallel 7 parts, is placed in 1~4 DEG C of refrigerator and is stood 8h,
Then 50 DEG C of reaction 5min, then be placed in 1~4 DEG C of ice water and react 1. 0.5h, 2. 1h, 3. 2h, 4. 3h, 5. 4h, 6. 5h, 7. 6h；
Repeat " 50 DEG C of reaction 5min, then be placed in 1~4 DEG C of ice water and react 1. 0.5h, 2. 1h, 3. 2h, 4. 3h, 5. 4h, 6. 5h, 7. 6h "
Step 3 time, HA gel pieces must be crosslinked.Crosslinking HA gel pieces are dialysed, the crosslinking agent for having neither part nor lot in reaction are washed off, then through 40 mesh
Sieve is pelletized, and the crosslinking HA gel particles of 100 μm of grain size are obtained.
Elastic examination method is the same as embodiment 1.It the results are shown in Table 4.
Table 4
| Sample number into spectrum | G’(Pa) |
| ① | 2199 |
| ② | 2323 |
| ③ | 2489 |
| ④ | 2517 |
| ⑤ | 2201 |
| ⑥ | 2010 |
| ⑦ | 1901 |
By table 4 as it can be seen that crosslinking HA particles obtained by when third step cross-linking reaction time is 0.5~5h meet G ' and are more than
The requirement of 2000Pa, wherein 2~3h is optimal.
(4) reaction times examination is repeated
By Sodium Hyaluronate (2,000,000 Da of molecular weight) 2g and crosslinking agent B DDE (1,4- butanediol diglycidyl ethers)
0.05g is uniformly mixed in the sodium hydroxide solution of 10ml a concentration of 1%, parallel 5 parts, is placed in 1~4 DEG C of refrigerator and is stood 8h,
Then 50 DEG C of reaction 5min, then be placed in 1~4 DEG C of ice water and react 0.5h, repeat " 50 DEG C of reaction 5min, then it is placed in 1~4 DEG C of ice
The step of 0.5h " is reacted in water 1. 2 times, 2. 3 times, 3. 4 times, 4. 5 times, 5. 6 times, must be crosslinked HA gel pieces.HA gels will be crosslinked
Block is dialysed, and the crosslinking agent for having neither part nor lot in reaction is washed off, and is then pelletized through 40 mesh screens, is obtained the crosslinking HA gel particles of 100 μm of grain size.
Elastic examination method is the same as embodiment 1.It the results are shown in Table 5.
Table 5
| Sample number into spectrum | G’(Pa) |
| ① | 1503 |
| ② | 2199 |
| ③ | 2389 |
| ④ | 2555 |
| ⑤ | 1986 |
By table 5 as it can be seen that repeating gained crosslinking HA particles when second step and third step reaction times are 3~5 times meets G '
Requirement more than 2000Pa.
3 dosage of crosslinking agent of embodiment is examined or check
1. by Sodium Hyaluronate (2,000,000 Da of molecular weight) 2g and crosslinking agent B DDE (1,4- butanediol diglycidyl ethers)
2. 3. 4. 5. 6. 0.20g (10%) is 7. by 0.16g (8%) by 0.12g (6%) by 0.08g (4%) by 0.04g (2%) by 0.02g (1%)
0.24g (12%) is uniformly mixed in the sodium hydroxide solution of 10ml a concentration of 1%, is placed in 1~4 DEG C of refrigerator and is stood 8h, so
50 DEG C of reaction 5min afterwards, then be placed in 1~4 DEG C of ice water and react 0.5h, repeat " 50 DEG C of reaction 5min, then it is placed in 1~4 DEG C of ice water
The step 3 time of middle reaction 0.5h ", must be crosslinked HA gel pieces.Crosslinking HA gel pieces are dialysed, the crosslinking for having neither part nor lot in reaction is washed off
Then agent pelletizes through 40 mesh screens, obtains the crosslinking HA gel particles of 100 μm of grain size.
Residual cross-linker assay method：Take sample appropriate, acetone solution dilution.It is with 1,4-butanediol diglycidyl ether
Reference substance, according to《Pharmacopoeia of People's Republic of China》Method is tested as defined in 2015 editions the 4th 0521 external standard methods of general rule,
Using DB-17 capillary columns as chromatographic column, column temperature：150 DEG C of initial temperature rises to 260 DEG C with 30 DEG C/min, keeps 10min；Detector is
Flame ionization ditector (FID), detector temperature are 300 DEG C；Injector temperature is 260 DEG C；Carrier gas is nitrogen, and flow velocity is
5mL/min.It is accurate respectively to measure test solution and 1 μ L of reference substance solution, gas chromatograph is injected, chromatogram is recorded, by outer
Mark method is with calculated by peak area.It the results are shown in Table 6.
Elastic examination method is the same as embodiment 1.It the results are shown in Table 6.
Table 6
| Sample number into spectrum | G’(Pa) | Crosslinking agent remains (μ g/g) |
| ① | 1866 | 0.05 |
| ② | 2056 | 0.1 |
| ③ | 2337 | 0.5 |
| ④ | 2479 | 1.0 |
| ⑤ | 2580 | 1.8 |
| ⑥ | 2613 | 1.9 |
| ⑦ | 2787 | 3.5 |
By table 6 as it can be seen that when dosage of crosslinking agent is 2%~12%, G ' meets the requirement more than 2000Pa, but works as dosage
It is 12%, crosslinking agent residual quantity is more than 2 μ g/g.Because BDDE has certain toxicity, crosslinking agent residual is generally required to be not more than 2 μ
The fewer g/g, residual the better.Consider G ' and crosslinking agent residual quantity, final choice dosage of crosslinking agent is 2~10%, preferably 4%
~6%.
4 hyaluronan molecule amount of embodiment is examined or check
By Sodium Hyaluronate molecular weight 1. 100,000,2. 500,000,3. 1,000,000,4. 1,500,000,5. 2,000,000,6. 2,500,000,7. 300
Ten thousand, 8. 3,500,000 Da) 2g and crosslinking agent B DDE (1,4- butanediol diglycidyl ethers) 0.05g 10ml a concentration of 1% hydrogen-oxygen
Change in sodium solution and be uniformly mixed, 10h is stood in 1~4 DEG C of refrigerator, is subsequently placed at 50 DEG C and stands reaction 15min, then be placed in 1~4
2h is reacted in DEG C ice-water bath；It repeats " to stand reaction 15min at 50 DEG C, then be placed in 1~4 DEG C of ice-water bath the step 4 for reacting 2h "
It is secondary, HA gel pieces must be crosslinked.Crosslinking HA gel pieces are dialysed, the crosslinking agent for having neither part nor lot in reaction are washed off, then through 40 mesh screen systems
Grain, obtains the crosslinking HA gel particles of 100 μm of grain size.
Flexibility Test Method the results are shown in Table 7 with embodiment 1.
The coefficient of expansion measures：Crosslinking HA gel particle about 5g are taken, adds the physiological saline 50mL of 9g/L, 20min is stirred at room temperature,
No. six are sieved through filter, and standing is dripped to no liquid in 2min, sets in the culture dish of constant weight and gel is weighed m1, 105 DEG C of dryings are extremely
Constant weight, the cross-linking sodium hyaluronate gel after drying are weighed m2.According to the formula coefficient of expansion=m1/m2It calculates.It the results are shown in Table 7.
Table 7
| Sample number into spectrum | The coefficient of expansion | G’(Pa) |
| ① | 75.3 | 768 |
| ② | 20.0 | 2010 |
| ③ | 18.5 | 2150 |
| ④ | 15.3 | 2233 |
| ⑤ | 15.1 | 2360 |
| ⑥ | 14.8 | 2487 |
| ⑦ | 13.5 | 2591 |
| ⑧ | 11.2 | 2699 |
HA molecular weight is different, and the coefficient of expansion for preparing sample is different, that is, the degree of cross linking is different, and has with HA molecular weight
Increase, the coefficient of expansion has the tendency that decline (degree of cross linking rising).The coefficient of expansion is too big, i.e., the degree of cross linking is too low, influences crosslinking HA
The frosted finish effect of grain, it is believed that the crosslinking HA particles of the coefficient of expansion (especially 15 or so) between 10 and 20 are most suitable to be ground
Sand particle.In this experiment, crosslinking HA particle expansions coefficient and G ' prepared by the HA between molecular weight 50~3,500,000 conform to
It asks, it is optimal with regard to from the point of view of the coefficient of expansion wherein 150~2,500,000 HA.
Embodiment 5
By Sodium Hyaluronate (500,000 Da of molecular weight) 2g and crosslinking agent carbodiimide 0.04g 10ml's a concentration of 0.5%
It is uniformly mixed in sodium carbonate liquor, 8h is stood at 1~4 DEG C, be subsequently placed at 50 DEG C and stand reaction 30min, then be placed in 1~4 DEG C
Lower reaction 0.5h；It repeats " to be placed at 50 DEG C and stand reaction 30min, then be placed at 1 DEG C the step 5 time for reacting 0.5h ", must be crosslinked
HA gel pieces.Crosslinking HA gel pieces are dialysed, the crosslinking agent for having neither part nor lot in reaction is washed off, then pelletizes through 20 mesh screens, obtain grain size
2000 μm of crosslinking HA gel particles.
Embodiment 6
Sodium Hyaluronate (3,500,000 Da of molecular weight) 2g and crosslinking agent DVS (divinylsulfone) 0.2g is a concentration of in 10ml
It is uniformly mixed in 5% sodium bicarbonate solution, 16h is stood at 1~4 DEG C, be subsequently placed at 80 DEG C and stand reaction 5min, then be placed in
5h is reacted at 1~4 DEG C；It repeats " to be placed at 80 DEG C and stand reaction 5min, then be placed at 4 DEG C the step 3 time for reacting 5h ", must be crosslinked
HA gel pieces.Crosslinking HA gel pieces are dialysed, the crosslinking agent for having neither part nor lot in reaction is washed off, then pelletizes through 200 mesh screens, obtain grain size
30 μm of crosslinking HA gel particles.
Embodiment 7
By Sodium Hyaluronate (2,000,000 Da of molecular weight) 2g and crosslinking agent B DDE (1,4- butanediol diglycidyl ethers) 0.1g
It is uniformly mixed in the sodium hydroxide solution of 10ml a concentration of 1%, 10h is stood at 1~4 DEG C, be subsequently placed at 65 DEG C and stand instead
15min is answered, then is placed at 1~4 DEG C and reacts 3h；It repeats " to be placed at 65 DEG C and stand reaction 15min, then be placed at 1~4 DEG C and react
The step 4 time of 3h " must be crosslinked HA gel pieces.Crosslinking HA gel pieces are dialysed, the crosslinking agent for having neither part nor lot in reaction is washed off, then passes through
40 mesh screens are pelletized, and the crosslinking HA gel particles of 100 μm of grain size are obtained.
A kind of facial cleanser of addition crosslinking HA frosted particles of embodiment 8
It is added the crosslinking HA gel particles of embodiment 7 as frosted particle in facial cleanser, addition frosted particle is made
Facial cleanser.Formula is (wt%)：Stearic acid 10%, palmitic acid 10%, lanolin 2%, coconut oil 2%, glyceryl monostearate
2%, N- acyl-N-methyl sodium taurocholate 2%, potassium hydroxide 4%, EDETATE SODIUM 0.1%, glycerine 10%, preservative 0.3%,
Frosted particle 0.01%, deionized water surplus.
Preparation method is：Stearic acid, palmitic acid, lanolin, coconut oil, glycerine and preservative are added in oil phase pot, adds
Thermal agitation is added in emulsification pot to 70 DEG C, after filtering and keeps its temperature 70 C；Potassium hydroxide is added in water phase pot, spend from
Sub- water fully dissolves, and is added after filtering in emulsification pot, and keeps 70 DEG C of reaction 1h, and 45 DEG C are cooled to after reaction, is added and removes frosted
Other raw materials other than particle, stir and evenly mix, and frosted particle is added when temperature is down to 30 DEG C, and mixing must add frosted particle
Facial cleanser.
Embodiment 9
The facial cleanser of addition frosted particle is prepared according to the method for embodiment 8, unlike：The content of frosted particle is
10wt%.
Embodiment 10
The facial cleanser of addition frosted particle is prepared according to the method for embodiment 8, unlike：The content of frosted particle is
0.5wt%.
Comparative example 1
(1) temperate condition is crosslinked：It feeds intake according to the ingredient proportion of embodiment 7, except reaction temperature and time difference, Qi Tacao
Make all same.Step is：By Sodium Hyaluronate (2,000,000 Da of molecular weight), (1,4- butanediols two shrink sweet 2g and crosslinking agent B DDE
Oily ether) 0.1g in the sodium hydroxide solution of 10ml a concentration of 1% be uniformly mixed, stand 10h at 1~4 DEG C, be then allowed to stand in 40
DEG C reaction 13h.By gained crosslinking HA gel pieces dialysis, the crosslinking agent for having neither part nor lot in reaction is washed off, then pelletizes, obtains through 40 mesh screens
The crosslinking HA gel particles of 100 μm of grain size.
(2) " hypo-hyperthermia-low temperature " three steps are crosslinked：By Sodium Hyaluronate (2,000,000 Da of molecular weight) 2g and crosslinking agent B DDE
(1,4-butanediol diglycidyl ether) 0.1g is uniformly mixed in the sodium hydroxide solution of 10ml a concentration of 1%, at 1~4 DEG C
10h is stood, is subsequently placed at 65 DEG C and stands reaction 15min, then be placed at 1~4 DEG C and react 3h.Gained crosslinking HA gel pieces is saturating
Analysis, washes off the crosslinking agent for having neither part nor lot in reaction, then pelletizes through 40 mesh screens, obtains the crosslinking HA gel particles of 100 μm of grain size.
(3) " hypo-hyperthermia-low temperature " three steps are crosslinked：By Sodium Hyaluronate (2,000,000 Da of molecular weight) 2g and crosslinking agent B DDE
(1,4-butanediol diglycidyl ether) 0.1g is uniformly mixed in the sodium hydroxide solution of 10ml a concentration of 1%, 25 DEG C of standings
10h is reacted, 50 DEG C is subsequently placed in and stands reaction 15min, then is placed in 20 DEG C of reaction 3h.By gained crosslinking HA gel pieces dialysis, wash
Fall to have neither part nor lot in the crosslinking agent of reaction, then pelletizes through 40 mesh screens, obtain the crosslinking HA gel particles of 100 μm of grain size.
Comparative example 2
(1) facial cleanser of minerals calcium carbonate frosted particle is added：Facial cleanser is prepared according to the method for embodiment 10, it is different
Be：The crosslinking HA gel particles of embodiment 7 are replaced with into calcium carbonate granule, the grain size of calcium carbonate granule is 100 μm.
(2) facial cleanser of guava seed frosted particle is added：Facial cleanser is prepared according to the method for embodiment 10, it is different
It is：The crosslinking HA gel particles of embodiment 7 are replaced with into guava seed particle, the grain size of guava seed particle is 100 μm.
(3) addition comparative example 1 (1) is crosslinked the facial cleanser of HA gel particles：Facial cleanser is prepared according to the method for embodiment 10,
Unlike：The crosslinking HA gel particles of embodiment 7 are replaced with to the crosslinking HA gel particles of comparative example 1 (1).
(4) addition comparative example 1 (2) is crosslinked the facial cleanser of HA gel particles：Facial cleanser is prepared according to the method for embodiment 10,
Unlike：The crosslinking HA gel particles of embodiment 7 are replaced with to the crosslinking HA gel particles of comparative example 1 (2).
(5) addition comparative example 1 (3) is crosslinked the facial cleanser of HA gel particles：Facial cleanser is prepared according to the method for embodiment 10,
Unlike：The crosslinking HA gel particles of embodiment 7 are replaced with to the crosslinking HA gel particles of comparative example 1 (3).
Application examples 1 is crosslinked HA particle flexibility tests
Flexibility test is carried out to the gel particle of embodiment 5~7 and comparative example 1, Flexibility Test Method is surveyed with embodiment 1
Test result is shown in Table 8.
Table 8
| Product | G’(Pa) |
| Embodiment 5 | 2209 |
| Embodiment 6 | 2689 |
| Embodiment 7 | 2963 |
| Comparative example 1 (1) | 330 |
| Comparative example 1 (2) | 295 |
| Comparative example 1 (3) | 497 |
It can be seen that from upper table data：Of the invention " high temperature-low temperature " repeat cross-linking method crosslinking agent select carbodiimide,
When the equal requirements that can meet more than 2000Pa of the G ' of the crosslinking HA particles obtained by when DVS, BDDE, wherein crosslinking agent selection BDDE most
It is high.And temperate condition crosslinking, the crosslinking of " hypo-hyperthermia-low temperature " three steps cannot obtain the crosslinking HA for meeting condition in comparative example 1
Particle.
2 cleaning effect of application examples is evaluated
Take 7 pieces of pig skin of back (8cm × 8cm), defeathering uniformly smears 0.01g activated carbons on every piece of skin, prepare by
Skin model is tried, A, B, C, D, E, F, G are denoted as.A models are using the facial cleanser commonly without frosted particle (i.e. by embodiment 10
Facial cleanser formula removes frosted particle), according to the step cleaning that washes one's face, the facial cleanser that B models are prepared using embodiment 10, according to washing
Face step is cleaned, and C model uses facial cleanser prepared by comparative example 2 (1), and according to the step cleaning that washes one's face, D models use comparative example 2
(2) facial cleanser prepared, according to the step cleaning that washes one's face, E models use facial cleanser prepared by comparative example 2 (3), according to the step that washes one's face
Cleaning, F models use facial cleanser prepared by comparative example 2 (4), and according to the step cleaning that washes one's face, G models are prepared using comparative example 2 (5)
Facial cleanser, according to wash one's face step cleaning.It is observed clearly by the way of naked eye and 2.5 times of amplification sem observations after cleaning
Clean effect and skin irritatin situation.Cleaning performance MAIN OUTCOME MEASURES is the activated carbon residual in dermatoglyph and pore, scurf
Residual etc., skin irritatin situation MAIN OUTCOME MEASURES are frosted damage etc..Cleaning performance is calculated as 10-0 points by excellent to bad, irritation
It is denoted as 10-0 points from high to low.Evaluation result is shown in Table 9.
The different facial cleanser cleaning performance evaluations of table 9
| Group | Cleaning performance | Irritation |
| A | 6 points | 0 point |
| B | 10 points | 2 points |
| C | 7 points | 8 points |
| D | 7 points | 6 points |
| E | 6 points | 1 point |
| F | 6 points | 1 point |
| G | 7 points | 1 point |
From the comparison of A-G as can be seen that adding the facial cleanser cleaning performance of crosslinking HA gel particles prepared by the present invention most
Good, irritation is minimum, this is because present invention gained crosslinking HA gel particles be natural materials, have it is elastic, neither too hard, nor too soft and
Skin-friendliness is good, so small to skin irritatin.In addition, having inside crosslinking HA gel particles prepared by the present invention three-dimensional netted
Molecular structure has adsorptivity, can adsorb pore rubbish, not only have the function of mild frosted, it is clear to may also reach up deep layer
Clean effect.Temperate condition crosslinking, " hypo-hyperthermia-low temperature " three steps crosslinking friendship obtained are can be seen that from the comparison of B, E, F, G
Join HA particles because elasticity and hardness are insufficient, does not have the effect of frosted particle, cleaning effect is poor.
3 exfoliation of application examples is evaluated
The exfoliation of facial cleanser is evaluated as index using skin water loss, skin water loss is bigger, goes
Cutin effect is stronger.
Experiment uses Self-control method, subject 20, male 5, women 15,30 years old to 45 years old age.Tested
The left and right arm forearm of person bends side mark test region, totally seven test zones, each test zone 3cm × 3cm, labeled as A,
B, seven test areas of C, D, E, F, G, each subject are all corresponded in identical position.The areas A of each subject use general
The logical facial cleanser (the facial cleanser formula of embodiment 10 is removed frosted particle) without frosted particle, the areas B use embodiment
10 facial cleansers prepared, the areas C use facial cleanser prepared by comparative example 2 (1), the areas D to use washing one's face for comparative example 2 (2) preparation
Milk, the areas E use facial cleanser prepared by comparative example 2 (3), the areas F to use facial cleanser prepared by comparative example 2 (4), and the areas G use
Facial cleanser prepared by comparative example 2 (5).According to the step cleaning that washes one's face：Test zone is soaked, is washed one's face respectively using same amount of correspondence
Milk softly massages 1min, is cleaned after rinsing well.It is measured and is cleaned using Corneometer CM825, Corneometer TM300
Before, each region inner skin water loss amount when 30min, 1h, 3h, 6h after cleaning, calculate skin water loss increment rate.Skin water
Skin water loss before increment rate=(skin water loss amount before skin water loss amount-cleaning after cleaning)/cleaning is lost in shunting
Amount * 100%.It the results are shown in Table 10.
Skin water loss increment rate (%) after the different facial cleanser cleanings of table 10
| Test zone | 30min | 1h | 3h | 6h |
| A | 17.56 | 16.23 | 17.19 | 14.33 |
| B | 28.08 | 25.34 | 26.47 | 24.29 |
| C | 51.55 | 50.37 | 48.69 | 46.01 |
| D | 41.03 | 40.17 | 39.32 | 38.04 |
| E | 16.85 | 15.73 | 15.79 | 13.74 |
| F | 17.11 | 16.07 | 15.55 | 13.89 |
| G | 17.88 | 16.93 | 15.67 | 13.97 |
As can be seen from Table 10, the facial cleanser exfoliation of minerals frosted particle and guava seed frosted particle is added
It is very strong, but water loss is too many, skin irritation is too big, is unsuitable for using daily.Crosslinking HA prepared by the addition present invention is solidifying
The facial cleanser of glue particle also has the function of exfoliating, but its exfoliation is mild, is suitable for using daily, deep layer cleaning.
Crosslinking HA gel particles prepared by the method for addition comparative example 1 do not have exfoliating effect, it could even be possible to meeting blocked pore, skin
Skin water loss increment rate is declined slightly compared with the facial cleanser for not adding frosted particle, but does not have significant difference.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied, such as selects other soluble transparent matter hydrochlorates, coagulates crosslinking HA
Glue particle is for other washing products as frosted particle or granule for massage.All within the spirits and principles of the present invention, made
Any modification, equivalent substitution and improvements, imitation etc., be all included in the scope of protection of the present invention.
Claims (10)
1. a kind of preparation method of cross-linked hyaluronic acid gel, it is characterized in that including the following steps：
（1）Hyaluronic acid is uniformly mixed with crosslinking agent in alkaline solution, 8-16h is stood at 1-4 DEG C；
（2）By step（1）Reaction solution stood at 50-80 DEG C reaction 5min-30min, be subsequently placed at 1-4 DEG C stand reaction
0.5-5 h；
（3）Step（2）Afterwards, by step（2）Gained reaction solution repeats " to stand reaction 5min-30min at 50 ~ 80 DEG C and then set
The step of standing reaction 0.5-5 h " 3-5 times, obtains gel C, gel C is cross-linked hyaluronic acid gel at 1-4 DEG C.
2. preparation method according to claim 1, it is characterized in that：Step（3）In, further include by gel C dialysis, granulation,
The step of obtaining cross-linked hyaluronic acid gel particle；Preferably, the size of gained cross-linked hyaluronic acid gel particle be 30 μm-
2000 μm。
3. preparation method according to claim 1 or 2, it is characterized in that：The hyaluronic acid refer to hyaluronic acid and its
Salt, preferably hyaluronate；The crosslinking agent is epoxides crosslinking agent, divinylsulfone, polyethylene glycols crosslinking agent
Or any one in carbodiimide, preferably epoxides crosslinking agent, most preferably 1,4-butanediol diglycidyl ether.
4. preparation method according to claim 1 or 3, it is characterized in that：The molecular weight of hyaluronic acid and its salt is 50-350
Ten thousand Da, preferably 150-250 ten thousand；Step（1）In, a concentration of 10-30% of hyaluronic acid and its salt in alkaline solution（w/
v）, preferably 20%（w/v）.
5. preparation method according to claim 1 or 3, it is characterized in that：The dosage of crosslinking agent is hyaluronic acid and its salt matter
The 2%-10% of amount, preferably 4%-6%.
6. preparation method according to claim 1 or 2, it is characterized in that：Step（1）In, the alkaline solution be sodium carbonate,
Any one in sodium bicarbonate or sodium hydroxide solution；The mass concentration of alkaline solution is preferably 0.5-5wt%.
7. preparation method according to claim 1 or 2, it is characterized in that：Step（1）In, the time for standing reaction is 10-
12h；Step（2）In, reaction solution stood at 50-80 DEG C reaction time be 15-20min, stood at 1-4 DEG C reaction when
Between preferably 2-3h.
8. cross-linked transparent matter made from the preparation method according to the cross-linked hyaluronic acid gel described in any one of claim 1-7
Acid gel.
9. application of the cross-linked hyaluronic acid gel according to any one of claims 8 as washing product frosted particle or granule for massage, excellent
Choosing, the washing product includes facial cleanser, facial cleanser breast, facial cleanser soap, washing cream, face cleaning dew, face cleaning honey, face cleaning powder, clean
Face gel, scrub cream, massage cream, exfoliating cream, exfoliating powder, toothpaste, tooth powder, perfumed soap, bath foam, bath salt, shampoo, hair care
Element.
10. application according to claim 9, it is characterized in that：The dosage of the cross-linked hyaluronic acid gel is washing product
The 0.01-10% of gross mass.
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