CN107459590A - A kind of preparation method of hyaluronic acid quaternary ammonium salt - Google Patents
A kind of preparation method of hyaluronic acid quaternary ammonium salt Download PDFInfo
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- CN107459590A CN107459590A CN201710880823.1A CN201710880823A CN107459590A CN 107459590 A CN107459590 A CN 107459590A CN 201710880823 A CN201710880823 A CN 201710880823A CN 107459590 A CN107459590 A CN 107459590A
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- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
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Abstract
The invention provides a kind of preparation method of hyaluronic acid quaternary ammonium salt, step are as follows：Hyaluronic acid metal salt is acidified in alcoholic solution, filter cake washes to obtain acid hyaluronic acid by alcohol after filtering；Acid hyaluronic acid is dissolved in the water, then pH is adjusted to weakly acidic pH with quaternary ammonium alkali solution, obtains hyaluronic acid quaternary ammonium salt solution；Hyaluronic acid quaternary ammonium salt dry powder is obtained by above-mentioned solution is lyophilized, and its metal ion content is 0.1% 1.0%.The preparation method of the present invention carries out ion exchange to carry out ion exchange in the state of viscous solution instead of hyaluronic acid by solid transparent matter acid；By medium of alcoholic solution instead of ion exchange resin be medium carry out ion exchange；Separated with simple separation of solid and liquid instead of centrifuge.The technique of the present invention is simple, and occupancy equipment is few, and production cost is low, ion exchange efficiency high, high income, is adapted to industrialized production.
Description
Technical field
The invention belongs to biological technical field, is related to a kind of preparation method of hyaluronic acid quaternary ammonium salt.
Background technology
Hyaluronic acid is existed by the straight chain polymer polysaccharide that glucuronic acid and Glucosamine are that dissacharide units form
In many connective tissues such as skin, vitreum, cartilage, knuckle synovia, and moisturizing, nutrition, reparation and pre- are played wherein
The physiological actions such as antisitic defect, hyaluronic acid are generally its sodium salt, i.e. Sodium Hyaluronate, are dissolved in water, but do not dissolve in organic solvent, grind
The person of studying carefully typically may require that to obtain modified hyaluronic acid and dissolve in organic solvent（Such as Er Jia base Ya Feng ﹑ dimethylformamides）
Hyaluronic acid, usually hyaluronic acid quaternary ammonium salt, such as the 4-butyl ammonium of hyaluronic acid（HA-TBA）.Chinese patent（It is public
The A of the number of opening CN 104725529）And Korean Patent（The A of patent No. KR 20100133688）Wherein report HA-TBA preparation side
Method.At present it has been reported that HA-TBA preparation method be that sodium ion is replaced as tetrabutyl ammonium root using ion exchange resin
Ion, but the technology has the characteristics that：Ion exchange resin is used in the technique, because hyaluronic acid is macromolecular complex
Matter, solution can be more sticky after being dissolved in water, is directly exchanged in ion exchange column, and hyaluronic acid solution is difficult outflow, actual
Operability is poor, and the time of consumption is also longer；If in addition by will be loaded with the ion exchange resin of tetrabutylammonium radical ion with
Sodium hyaluronate solution, which mixes, carries out ion exchange, then separates again, it is also desirable to mixes, separates and repeat the operation several times,
The sodium ion of Sodium Hyaluronate can be almost completely converted into ammonium ion, further, since hyaluronic acid solution is more sticky,
Hyaluronic acid solution separated with ion exchange resin by simple stratification decanting procedure it is just impossible, so necessary
Separation of solid and liquid could be carried out by the mode such as centrifuging or filtering.So the complex process, relatively time-consuming, laborious, the equipment used
Also it is more, be not suitable for industrialized production.
The content of the invention
Hyaluronic acid quaternary ammonium salt complex process is prepared for current ion exchange, is not suitable for the problems such as industrialized production, this
Invention provides the hyaluronic acid that a kind of technique is relatively easy, device therefor is relatively fewer, production cost is low, is adapted to industrialized production
The preparation method of quaternary ammonium salt.
To achieve the above object, the present invention adopts the following technical scheme that.
A kind of preparation method of hyaluronic acid quaternary ammonium salt, using following steps：
（1）Hyaluronic acid metal salt is acidified in alcoholic solution, filter cake washes to obtain acid hyaluronic acid by alcohol after filtering；
（2）By step（1）Middle acid hyaluronic acid is dissolved in the water, and then adjusts pH to weakly acidic pH with quaternary ammonium alkali solution, obtains
Bright matter acid quaternary ammonium salt solution；
（3）By step（2）In solution lyophilized to obtain hyaluronic acid quaternary ammonium salt dry powder.
Alternatively, the molecular weight of hyaluronic acid metal salt is 5 × 104-3×106 Da。
Alternatively, hyaluronic acid metal salt is alkali metal salt, alkali salt or the zinc salt of hyaluronic acid；Preferably sodium
Salt, sylvite or calcium salt.
Alternatively, step（1）The concentration of middle alcoholic solution is 50%-100%（v/v）.
Alternatively, step（1）Middle alcohol is methanol, ethanol, propyl alcohol or isopropanol, most preferably ethanol.
Alternatively, the mass volume ratio of hyaluronic acid metal salt and alcoholic solution is 1.0%-15%；Preferably 3.0%-10%.
Alternatively, step（1）In acid be hydrochloric acid, sulfuric acid, nitric acid or acetic acid, most preferably hydrochloric acid；The hydrochloric acid it is dense
Spend for 12 mol/L.
Alternatively, step（1）The acid solution of middle acidization and the volume ratio of alcoholic solution are 1:10-1:100, preferably 1:
50-80。
Preferably, step（1）Middle gained acidity hyaluronic acid, the pH of its 1wt% solution is 2.0-3.0.
Preferably, step（1）The middle alcohol that repeats washes step 2-4 times.
Alternatively, step（2）The concentration of middle acid hyaluronic acid is 0.5 wt %-5wt%.
Step（2）Described in quaternary ammonium base structural formula it is as follows：
Wherein, R1-R4Independently represent alkyl.
Alternatively, step（2）Middle pH is 6.0-8.0.
A kind of hyaluronic acid quaternary ammonium salt obtained by above-mentioned preparation method, its metal ion content are 0.1%-1.0%, nitrogen content
For 4.0%-5.5%.
The present invention has advantages below：
Ion exchange is carried out under hyaluronic acid solid state to replace hyaluronic acid to carry out ion in the state of viscous solution
Exchange；By medium of alcoholic solution instead of ion exchange resin be medium carry out ion exchange；Separation of solid and liquid is to be simply decanted generation
Separated for centrifuge.So the technical scheme that the present invention takes has the advantage that：Technique is simple, and occupancy equipment is few, production
Cost is low, ion exchange efficiency high, high income, is adapted to industrialized production.
Embodiment
With reference to embodiment, the present invention will be further described, but the present invention is not limited by following embodiments.
It is prepared by the tetraethyl ammonium salt of the hyaluronic acid of embodiment 1.
（1）In 1 L beakers, potassium hyaluronate is added（Molecular weight is 5 × 104Da）15.0 g, 100% methanol solution
100 mL, the mL of concentrated hydrochloric acid 10, stir 1 h with mechanical agitator at room temperature.Then stand, after solid-liquid layering, pass through decantation
Remove supernatant liquid.Then the methanol solution and hydrochloric acid of same amount are added, is stood, decantation removes supernatant liquid, repeats
State operation 4 times；Above-mentioned white solid is washed with the methanol solutions of 100 mL 100% again, is washed 4 times altogether, and then removes unnecessary salt
Acid.Suction filtration mode carries out separation of solid and liquid, obtains the i.e. acid hyaluronic acid of white wet product.
（2）In 3 L beakers, 300 mL purified waters are added, under mechanical stirring, wet product obtained in the previous step is added to
In beaker, stirring is to being completely dissolved.Then, toward 20% tetraethyl ammonium hydroxide solution is added dropwise in beaker, the pH for adjusting solution is
6.0。
（3）Solution is poured into the plate of circular stainless steel, thickness is not more than 1 cm, is put into freezing 24 in -40 DEG C of refrigerators
H, then plate is put into freeze drier, dries 48 h.Obtain the tetraethyl ammonium salt 18.0 of the i.e. hyaluronic acid of white dry powder
G, loss on drying 10%, potassium content 0.5%, nitrogen content 5.0%, yield 95%.
It is prepared by the tetrapropyl ammonium salt of the hyaluronic acid of embodiment 2.
（1）In 1L beakers, Sodium Hyaluronate is added（Molecular weight is 1.0 × 105Da）15.0 g, 80% hydrous ethanol
500 mL, the mL of concentrated hydrochloric acid 5, stir 1 h with mechanical agitator at room temperature.Then stand, after solid-liquid layering, pass through decantation
Remove supernatant liquid.Then the hydrous ethanol and hydrochloric acid of same amount are added, is stood, decantation removes supernatant liquid, repeats
State operation 6 times；Above-mentioned white solid is washed with the ethanol of 400 mL 80% again, is washed 3 times altogether, and then removes unnecessary hydrochloric acid.It is logical
Vacuum filtration mode is crossed by separation of solid and liquid, obtains the i.e. acid hyaluronic acid of white wet product.
（2）In 3 L beakers, 800 mL purified waters are added, under mechanical stirring, wet product obtained in the previous step is added to
In beaker, stirring is to being completely dissolved.Then, toward 25% TPAOH solution is added dropwise in beaker, the pH for adjusting solution is
8.0。
（3）Dried with freeze-drying method in embodiment 1, obtain white dry powder i.e. hyaluronic acid tetrapropyl ammonium salt 20.0
G, loss on drying 8%, sodium content 0.4%, nitrogen content 5.0%, yield 92%.
It is prepared by the 4-butyl ammonium of the hyaluronic acid of embodiment 3.
（1）In 1 L beakers, Sodium Hyaluronate is added（Molecular weight is 2.8 × 105Da）22.0 g, 75% hydrous ethanol
800 mL, the mL of concentrated hydrochloric acid 80, are stirred at room temperature 1 h.Then stand, after solid-liquid layering, upper liquid is removed by decantation
Body.Then the hydrous ethanol and hydrochloric acid of same amount are added, is stood, decantation removes supernatant liquid, repeats aforesaid operations 2
It is secondary；Above-mentioned white solid is washed with the hydrous ethanols of 600 mL 75% again, is washed 4 times altogether, and then removes unnecessary hydrochloric acid.Filter,
Obtain the i.e. acid hyaluronic acid of white wet product.
（2）In 3 L beakers, 1000 mL purified waters are added, under agitation, above-mentioned wet product is added in beaker, stirred
To being completely dissolved.Then, toward 25% TBAH solution is added dropwise in beaker, the pH for adjusting solution is 6.95.
（3）Dried with freeze-drying method in embodiment 1, obtain the g of hyaluronic acid 4-butyl ammonium 32.0, loss on drying
For 10%, sodium content 0.1%, nitrogen content 4.3%, yield 90%.
It is prepared by the 4-butyl ammonium of the hyaluronic acid of embodiment 4.
（1）In 1 L beakers, Sodium Hyaluronate is added（Molecular weight is 1.0 × 106Da）20 g, 50% hydrous ethanol 1000
ML, the mL of concentrated hydrochloric acid 15, are stirred at room temperature 1 h.Then stand, after solid-liquid layering, supernatant liquid is removed by being decanted.So
The hydrous ethanol and hydrochloric acid of same amount are added afterwards, is stood, and decantation removes supernatant liquid, repeats aforesaid operations 2 times；Use again
The hydrous ethanols of 500 mL 50% wash above-mentioned white solid, wash 2 times altogether, and then remove unnecessary hydrochloric acid.Filter, obtain white
Wet product is acid hyaluronic acid.
（2）In 3 L beakers, 2000 mL purified waters are added, under agitation, acid hyaluronic acid is added in beaker,
Stirring and dissolving.Then toward 25% TBAH solution is added dropwise in beaker, regulation pH value of solution is 7.15.
（3）It is freeze-dried with method in embodiment 1, obtains the g of hyaluronic acid 4-butyl ammonium 28.4, loss on drying is
10%, sodium content 0.3%, nitrogen content 4.5%, yield 92%.
Claims (10)
1. a kind of preparation method of hyaluronic acid quaternary ammonium salt, it is characterised in that using following steps：
（1）Hyaluronic acid metal salt is acidified in alcoholic solution, filter cake washes to obtain acid hyaluronic acid by alcohol after filtering；
（2）By step（1）Middle acid hyaluronic acid is dissolved in the water, and then adjusts pH to weakly acidic pH with quaternary ammonium alkali solution, obtains
Bright matter acid quaternary ammonium salt solution；
（3）By step（2）In solution lyophilized to obtain hyaluronic acid quaternary ammonium salt dry powder.
2. preparation method according to claim 1, it is characterised in that the molecular weight of hyaluronic acid metal salt is 5 × 104-3
×106 Da。
3. preparation method according to claim 1, it is characterised in that hyaluronic acid metal salt is the alkali metal of hyaluronic acid
Salt, alkali salt or zinc salt.
4. preparation method according to claim 1, it is characterised in that step（1）The concentration of middle alcoholic solution is 50%-100%
（v/v）.
5. preparation method according to claim 1, it is characterised in that step（1）Middle hyaluronic acid metal salt and alcoholic solution
Mass volume ratio be 1.0%-15%.
6. preparation method according to claim 1, it is characterised in that step（1）The acid solution and alcoholic solution of middle acidization
Volume ratio be 1:10-1:100.
7. preparation method according to claim 1, it is characterised in that step（1）The 1wt% of middle gained acidity hyaluronic acid
The pH of solution is 2.0-3.0.
8. preparation method according to claim 1, it is characterised in that step（2）The concentration of middle acid hyaluronic acid is
0.5 wt %-5 wt %。
9. preparation method according to claim 1, it is characterised in that step（2）Described in quaternary ammonium base structural formula it is as follows：
Wherein, R1-R4Independently represent alkyl.
A kind of 10. hyaluronic acid quaternary ammonium product salt made from preparation method as claimed in claim 1, it is characterised in that metal
Ion concentration is 0.1%-1.0%, nitrogen content 4.0%-5.5%.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110790960A (en) * | 2019-11-13 | 2020-02-14 | 华熙生物科技股份有限公司 | Hyaluronic acid quaternary ammonium salt crosslinked powder and preparation method and application thereof |
| CN114133465A (en) * | 2020-09-03 | 2022-03-04 | 山东华熙海御生物医药有限公司 | Preparation method of potassium hyaluronate, obtained product and application |
| CN114397399A (en) * | 2021-12-31 | 2022-04-26 | 华熙生物科技股份有限公司 | Method for determining content of quaternary ammonium salt in hyaluronic acid-quaternary ammonium salt polymer |
| CN116041565A (en) * | 2022-11-18 | 2023-05-02 | 山东焦点福瑞达生物股份有限公司 | Preparation and purification method of sodium hyaluronate cationic quaternary ammonium salt in homogeneous medium |
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| CN1624002A (en) * | 2003-12-04 | 2005-06-08 | 财团法人工业技术研究院 | Biodegradable hyaluronic acid derivative, biodegradable polymeric micelle composition and pharmaceutical composition |
| CN101418049A (en) * | 2008-12-22 | 2009-04-29 | 山东福瑞达生物化工有限公司 | A kind of hyaluronic preparation method |
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2017
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1624002A (en) * | 2003-12-04 | 2005-06-08 | 财团法人工业技术研究院 | Biodegradable hyaluronic acid derivative, biodegradable polymeric micelle composition and pharmaceutical composition |
| CN101418049A (en) * | 2008-12-22 | 2009-04-29 | 山东福瑞达生物化工有限公司 | A kind of hyaluronic preparation method |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110790960A (en) * | 2019-11-13 | 2020-02-14 | 华熙生物科技股份有限公司 | Hyaluronic acid quaternary ammonium salt crosslinked powder and preparation method and application thereof |
| CN110790960B (en) * | 2019-11-13 | 2023-01-24 | 华熙生物科技股份有限公司 | Hyaluronic acid quaternary ammonium salt crosslinked powder and preparation method and application thereof |
| CN114133465A (en) * | 2020-09-03 | 2022-03-04 | 山东华熙海御生物医药有限公司 | Preparation method of potassium hyaluronate, obtained product and application |
| CN114133465B (en) * | 2020-09-03 | 2023-03-21 | 山东华熙海御生物医药有限公司 | Preparation method of potassium hyaluronate, obtained product and application |
| CN114397399A (en) * | 2021-12-31 | 2022-04-26 | 华熙生物科技股份有限公司 | Method for determining content of quaternary ammonium salt in hyaluronic acid-quaternary ammonium salt polymer |
| CN116041565A (en) * | 2022-11-18 | 2023-05-02 | 山东焦点福瑞达生物股份有限公司 | Preparation and purification method of sodium hyaluronate cationic quaternary ammonium salt in homogeneous medium |
| CN116041565B (en) * | 2022-11-18 | 2024-02-09 | 山东焦点福瑞达生物股份有限公司 | Preparation and purification method of sodium hyaluronate cationic quaternary ammonium salt in homogeneous medium |
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