CN105949477B - A kind of undenatured collagen of water solubility and preparation method thereof - Google Patents
A kind of undenatured collagen of water solubility and preparation method thereof Download PDFInfo
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- CN105949477B CN105949477B CN201610348502.2A CN201610348502A CN105949477B CN 105949477 B CN105949477 B CN 105949477B CN 201610348502 A CN201610348502 A CN 201610348502A CN 105949477 B CN105949477 B CN 105949477B
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- C08H—DERIVATIVES OF NATURAL MACROMOLECULAR COMPOUNDS
- C08H1/00—Macromolecular products derived from proteins
Abstract
The present invention provides a kind of undenatured collagens of water solubility and preparation method thereof, including：Polycarboxylic acids NHS esters are made with polycarboxylic acids than the succimide for 1,/20 1/2 by absolute dry mass first；Again water-soluble undenatured collagen is prepared than being reacted with natural collagen for 1,/20 1/2 polycarboxylic acids NHS esters by absolute dry mass.The present invention can obtain while have the undenatured collagen of the water solubility of good fluidity and high thermal stability.
Description
Technical field
The present invention relates to a kind of undenatured collagens of water solubility, and water-soluble undenatured collagen preparations.
Background technology
Collagen is the protein that animal in-vivo content is most, distribution is most wide, accounts for about the 30% of vivo protein total amount.It is driven
Extracted, isolation and purification can prepare natural collagen in object tissue.Natural collagen remains complete triple helix structure, because
And assign collagen many excellent performances, such as good mechanical property, lower antigenicity and excellent biocompatibility, it can
Promote coagulating platelets, also excellent performance of keeping humidity and the excellent properties etc. for promoting epidermal growth breeding.As one kind
The natural macromolecular material of function admirable, collagen have obtained extensively in burn trauma treatment, beauty, orthopedic, tissue repair etc.
General application.
The main method for preparing undenatured collagen at present is acid-enzyme binding-method, and the collagen which obtains has close to neutral pH
Isoelectric point, therefore only could dissolve in acid condition and keep solution state.It, will if collagen is placed in neutral aqueous solution
Isoelectric precipitation occurs.Therefore although the collagen that acid-enzyme binding-method extracts is hydrophilic, but not soluble in water.However, in glue
Under many occasions of original application, the problem of being used in neutral environment can not be avoided.Require solution state collagen in neutral conditions
It is stabilized with solution state, while the natural triple helix structure of tropocollagen molecule being required not to be changed or destroy, it is good to retain
Bioactivity.
To solve these problems, Chinese patent application " preparation method of water soluble undenatured natural collagen " (CN
1597742A) proposing improves the water-soluble method of collagen, that is, utilizes acylating agent pimelic acid acid anhydride, maleic anhydride, adjacent first two
The part amino closing of collagen is increased the carboxyl-content of side chain, its isoelectric point is promoted to be moved to lower direction by benzoic anhydride, from
And enhance its solubility property in neutral conditions.It is said in principle, this belongs to implements acyl using small molecule acid anhydrides to collagen side chain
Change and is modified.
Chinese patent application " collagen gel " (CN 1264390A) is carried out polyanion and collagen using carbodiimides
Reaction forms gel.It is said in principle, this, which belongs to, is crosslinked two kinds of ingredients using a large amount of carbodiimides, and system is made to lose
Mobility is to obtain gel.The patent uses carbodiimides in aqueous solution, and hydrolysis easily occurs and forms urea
Derivative keeps its reactivity extremely low, needs just make system gel, cost very high using a large amount of carbodiimides；Secondly,
Gel belongs to stable three-dimensional net structure, and the impurity such as internal remaining reactant of institute are difficult to clean off；Furthermore made from the method
Collagen can only exist with gel state, have no the mobility of solution state, be not used to the occasion for needing collagen to have good fluidity.
Invention content
One of the technical problem to be solved in the present invention is to provide a kind of undenatured collagen of water solubility.
The invention is realized in this way：A kind of undenatured collagen preparations of water solubility, including the following contents：
(1) polycarboxylic acids-N- hydroxysuccinimide esters are prepared：In 10-50mL dimethyl sulfoxide (DMSO)s (DMSO), poly- carboxylic is added
Acid, stirring and dissolving；Succimide (NHS) is added, after stirring and dissolving, adds carbodiimides (EDC), stirs, reacts 9-
18h；Then absolute ethyl alcohol is added or precipitation is precipitated in acetone, precipitation is washed with absolute ethyl alcohol, n-hexane respectively, then vacuum is dry
It is dry to get polycarboxylic acids-N- hydroxysuccinimide esters；Wherein, the weight ratio of succimide and polycarboxylic acids is 1/20~1/2；
The weight ratio of carbodiimides and succimide is 1/3~1/1；
(2) water-soluble undenatured collagen is prepared：Natural collagen is dissolved in the hydrochloric acid solution of pH 2.5-4.5, is obtained dense
Degree is the collagen solution of 1-10mg/mL；Polycarboxylic acids-N- hydroxysuccinimide esters are dissolved in dimethyl sulfoxide (DMSO), are obtained dense
Degree is the polycarboxylic acids-N- hydroxysuccinimide ester solutions of 10-100mg/mL；Then it maintains temperature at 4-10 DEG C always, will gather
Collagen solution is added in carboxylic acid-N- hydroxysuccinimide ester solutions, and is stirred to react 12-24h, then with deionized water dialysis 1-
3d；Freeze-drying is to get water-soluble undenatured collagen；Wherein, the weight of polycarboxylic acids-N- hydroxysuccinimides ester and natural collagen
Amount is than being 1/20~1/2.
Further, in the step (2), temperature is 4-8 DEG C.
The second technical problem to be solved by the present invention is to provide a kind of undenatured collagen preparations of water solubility.
The invention is realized in this way：A kind of undenatured collagen of water solubility, including following raw material：Weight ratio is 1/20~1/
2 polycarboxylic acids-N- hydroxysuccinimides ester and natural collagen；
Polycarboxylic acids-N- hydroxysuccinimide the esters are esterified to obtain by following component：The fourth that weight ratio is 1/20~1/2
Imidodicarbonic diamide and polycarboxylic acids；
The polycarboxylic acids is polyglutamic acid or polymalic acid.
Further, the polyglutamic acid molecular weight is 20000~1000000.
Further, the polymalic acid molecular weight 2000~4000.
The advantage of the invention is that：The undenatured collagen of water solubility obtained is provided simultaneously with good fluidity and high heat stability
Property, and collagen isoelectric point is made to be remarkably decreased to assign the water solubility under collagen neutrallty condition.
Description of the drawings
The present invention is further illustrated in conjunction with the embodiments with reference to the accompanying drawings.
Fig. 1 is the differential scanning calorimetric curve figure of water-soluble undenatured collagen in invention.
Fig. 2 is the PAGE gel electrophoresis pattern of water-soluble undenatured collagen in invention.
Fig. 3 is the isoelectric point determination curve graph of water-soluble undenatured collagen in invention.
Specific implementation mode
A kind of undenatured collagen of water solubility, including following raw material：Polycarboxylic acids-N- hydroxyl the fourths that weight ratio is 1/20~1/2
Imidodicarbonic diamide ester and natural collagen；
Polycarboxylic acids-N- hydroxysuccinimide the esters are esterified to obtain by following component：The fourth that weight ratio is 1/20~1/2
Imidodicarbonic diamide and polycarboxylic acids；The polycarboxylic acids is polyglutamic acid or polymalic acid.The polyglutamic acid molecular weight be 20000~
1000000.The polymalic acid molecular weight 2000~4000.Esterification degree≤20% of the polyglutamic acid.The natural collagen
Amino group substitution degree≤18%.
The undenatured collagen preparations of water solubility, including the following contents：
(1) polycarboxylic acids-N- hydroxysuccinimides ester (polycarboxylic acids-NHS esters) is prepared：In 10-50mL dimethyl sulfoxide (DMSO)s
(DMSO) in, polycarboxylic acids 500-2000mg is added, stirring, dissolving is completely；Succimide (NHS) is added, after stirring and dissolving, then
Carbodiimides (EDC) is added, 9-18h is reacted in stirring；Then absolute ethyl alcohol is added or precipitation polycarboxylic acids-N- hydroxyls are precipitated in acetone
Precipitation is used absolute ethyl alcohol, just by base succimide ester, and most carbodiimides is stayed and will not be precipitated in a solvent respectively
Hexane washs, and removes remaining a small amount of EDC in product, and then vacuum drying precipitation is to get polycarboxylic acids-N- hydroxysuccinimides
Ester；Wherein, the weight ratio of succimide and polycarboxylic acids is 1/20~1/2, excessive to avoid the esterification degree of polycarboxylic acids, causes to change
Property natural collagen when collagen gelation occurs, the weight ratio of carbodiimides and succimide is 1/3~1/1；
(2) water-soluble undenatured collagen is prepared：Natural collagen is dissolved in the hydrochloric acid solution of pH 2.5-4.5, is obtained dense
Degree is the collagen solution of 1-10mg/mL；Polycarboxylic acids-N- hydroxysuccinimide esters are dissolved in dimethyl sulfoxide (DMSO), are obtained dense
Degree is the polycarboxylic acids-N- hydroxysuccinimide ester solutions of 10-100mg/mL；Then maintain temperature at 4-10 DEG C always, preferably
Be 4-8 DEG C, collagen solution be added in polycarboxylic acids-N- hydroxysuccinimide ester solutions, and is stirred to react 12-24h, then spend from
Sub- water dialysis 1-3d；Freeze-drying is to get water-soluble undenatured collagen；Wherein, polycarboxylic acids-N- hydroxysuccinimides ester and day
The weight ratio of right collagen is 1/20~1/2.The ratio of polycarboxylic acids-N- hydroxysuccinimide ester dry weights and collagen dry weight is controlled
In 1/20-1/2, gel can be generated to avoid polycarboxylic acids-N- hydroxysuccinimides ester and collagen overreaction；By the temperature of reaction
Degree control is at 10 DEG C hereinafter, thermal denaturation can occur to avoid collagen.System after reaction has to pass through dialysis treatment, thoroughly removes
The NHS of generation makes to be free of any residual impurity in system, so as to get the undenatured collagen of water solubility be do not have completely it is virose.
Wherein, natural collagen is what three polypeptide chains were constituted, and the natural undenatured collagen with triple helix structure divides greatly
Son, molecular weight are about 300,000.The reaction equation of natural collagen and polycarboxylic acids-N- hydroxysuccinimides ester (polycarboxylic acids-NHS esters) is such as
Under, polycarboxylic acids is by taking polyglutamic acid macromolecular as an example：
By taking above-mentioned reaction equation as an example, esterification degree=a/ (a+b) * 100% of polyglutamic acid, to obtain water-soluble undenatured glue
The esterification degree of original, polyglutamic acid is not to be exceeded 20%, and (k is a collagen point to amino group substitution degree=m/k*100% of natural collagen
The amino sum having on son, to the different collagen value difference), to obtain water-soluble undenatured collagen, the ammonia of collagen
Base degree of substitution is not to be exceeded 18%；All carboxyl sums on each polyglutamic acid molecule, depend on poly- before a+b=m+n=esterifications
The molecular weight of glutamic acid.
When using polymalic acid, the esterification degree of polymalic acid is not to be exceeded 20%；To obtain water-soluble undenatured collagen, glue
Former amino group substitution degree is not to be exceeded 18%.
Embodiment 1
(1) polymalic acid of 1000mg is added in the DMSO solution of 20mL, stirring, until polymalic acid is completely dissolved.
The NHS of 50mg is added, stirring adds the EDC of 50mg, and 18h is reacted under room temperature, and absolute ethyl alcohol, which is added, makes product be precipitated.With nothing
Water-ethanol washs 2 times, and after n-hexane washs 1 time, vacuum drying obtains polymalic acid-NHS esters.After measured, polymalic acid-NHS esters
Esterification degree be 2.8%.
(2) natural collagen is dissolved in hydrochloric acid solution (pH 2.5), obtains the collagen solution of a concentration of 5mg/ml；By poly- apple
Tartaric acid-NHS esters are dissolved in DMSO, a concentration of 100mg/mL；Collagen solution 20ml is taken, polymalic acid-NHS ester solutions are added
500 μ L (1/2) are stirred, and react 18h under room temperature；With deionized water dialysis 2d, water-soluble undenatured glue is obtained after freeze-drying
It is former.After measured, water-soluble undenatured collagen still remains with natural structure, amino group substitution degree 6.1%, isoelectric point 4.2, thermal change
Warm-natured degree is 46.3 DEG C.
Embodiment 2
(1) polyglutamic acid of 500mg is added in the DMSO solution of 10mL, stirring, until polyglutamic acid is completely dissolved；Add
Enter the NHS of 100mg, stir, add the EDC of 33mg, 9h is reacted under room temperature, absolute ethyl alcohol, which is added, makes product be precipitated；With anhydrous
Ethyl alcohol washs 2 times, and after n-hexane washs 2 times, vacuum drying obtains polyglutamic acid-NHS esters.After measured, polyglutamic acid-NHS esters
Esterification degree is 5.3%.
(2) natural collagen is dissolved in hydrochloric acid solution (pH 3.0), a concentration of 10mg/ml；Polyglutamic acid-NHS esters are molten
Solution is in DMSO, a concentration of 50mg/mL；Collagen solution 40ml is taken, 1200 μ L (1/5) of polyglutamic acid-NHS ester solutions are added, stir
It mixes, reacts 12h under room temperature；With deionized water dialysis 1d, water-soluble undenatured collagen is obtained after freeze-drying.After measured, water-soluble
The undenatured collagen of property still remains with natural structure, amino group substitution degree 9.4%, isoelectric point 3.6, thermal denaturation temperature 47.2
℃。
Embodiment 3
(1) polyglutamic acid of 1200mg is added in the DMSO solution of 30mL, stirring, until polyglutamic acid is completely dissolved；
The NHS of 300mg is added, stirring adds the EDC of 200mg, and 13.5h is reacted under room temperature, and acetone, which is added, makes product be precipitated；With nothing
Water-ethanol washs 3 times, and after n-hexane washs 1 time, vacuum drying obtains polyglutamic acid-NHS esters.After measured, polyglutamic acid-NHS esters
Esterification degree be 8.7%.
(2) natural collagen is dissolved in hydrochloric acid solution (pH 4.0), a concentration of 2.5mg/ml；Polyglutamic acid-NHS esters are molten
Solution is in DMSO, a concentration of 25mg/mL；Collagen solution 100ml is taken, 1000 μ L (1/10) of polyglutamic acid-NHS ester solutions are added,
It stirs, reacts 20h under room temperature；Deionized water dialysis 3d obtains water-soluble undenatured collagen after freeze-drying.After measured, water-soluble
The undenatured collagen of property still remains with natural structure, amino group substitution degree 11.6%, isoelectric point 3.7, thermal denaturation temperature 47.8
℃。
Embodiment 4
(1) polyglutamic acid of 2000mg is added in the DMSO solution of 50mL, stirring, until polyglutamic acid is completely dissolved；
The NHS of 1000mg is added, stirring adds the EDC of 800mg, and 15h is reacted under room temperature, and acetone, which is added, makes product be precipitated；With anhydrous
Ethyl alcohol washs 3 times, and after n-hexane washs 2 times, vacuum drying obtains polyglutamic acid-NHS esters.After measured, polyglutamic acid-NHS esters
Esterification degree is 15.3%.
(2) natural collagen is dissolved in hydrochloric acid solution (pH 4.5), a concentration of 1mg/ml；Polyglutamic acid-NHS esters dissolve
In DMSO, a concentration of 10mg/mL；Collagen solution 30ml is taken, 150 μ L (1/20) of polyglutamic acid-NHS ester solutions are added, stir,
It is reacted for 24 hours under room temperature.With deionized water dialysis 3d, water-soluble undenatured collagen is obtained after freeze-drying.After measured, it is water-soluble not
Denatured collagen still remains with natural structure, and amino group substitution degree 14.7%, isoelectric point 3.9, thermal denaturation temperature is 48.1 DEG C.
Water-soluble undenatured collagen made from embodiment 4 is subjected to differential scanning calorimetric curve, PAGE gel respectively
Electrophoresis and isoelectric point determination characterization, are compared, specifically such as with the natural undenatured ox-hide acid -soluble collagen of acid-enzyme binding-method extraction
Under：
Fig. 1 is the differential scanning calorimetric curve figure of collagen, and mark A curves are the undenatured collagen of water solubility of the present invention, mark
The natural undenatured ox-hide acid -soluble collagen that B curves are acid-enzyme binding-method extraction is known, it can be seen from figure 1 that natural undenatured ox-hide acid is molten
The denaturation temperature of collagen is 38.8 DEG C, and the denaturation temperature of the undenatured collagen of water solubility of the present invention is improved to 48.1 DEG C, and heat is steady
It is qualitative to significantly improve.
In Fig. 2,3 curves of mark are the undenatured collagen of water solubility of the present invention, and 2 curves of mark are acid-enzyme binding-method extraction
Natural undenatured ox-hide acid -soluble collagen, as it is clear from fig. 2 that as natural undenatured ox-hide acid -soluble collagen, water solubility of the invention
Undenatured collagen illustrates that water-soluble undenatured collagen still remains with natural structure by α 1, α 2 and β chains composition.In addition, the present invention
Water-soluble undenatured collagen high molecular weight moieties (>β chains) showed increased, there are cross-bonds between declaratives tropocollagen molecule.
In Fig. 3, mark A curves are the undenatured collagen of water solubility of the present invention, and mark B curves are acid-enzyme binding-method extraction
Natural undenatured ox-hide acid -soluble collagen, it is seen then that the isoelectric point of natural undenatured ox-hide acid -soluble collagen is about 6.95, and the present invention
The isoelectric point of water-soluble undenatured collagen falls to approximately 3.92.The decline of isoelectric point can be obviously improved collagen in neutrallty condition
Under water solubility.
The method comprises the steps of firstly, preparing polycarboxylic acids-NHS esters, then are reacted with natural collagen, make the amino of natural collagen side chain and gather
NHS ester groups on carboxylic acid reactive's ester carry out reaction and form covalent crosslink, keep multiple tropocollagen molecules crosslinked together.On the one hand,
Covalent cross-linking acts on the thermal stability that collagen can be improved；On the other hand, cross-linking reaction encloses the amino of collagen, and connect
Polycarboxylic acids can be that collagen increases a large amount of carboxyls again, to promote collagen isoelectric point to be remarkably decreased, assign under collagen neutrallty condition
It is water-soluble.
The present invention is by the absolute dry mass of succimide and polycarboxylic acids than control in 1/20-1/2；In water-soluble undenatured glue
In former preparation, the absolute dry mass of polycarboxylic acids-NHS esters and collagen than control for 1/20-1/2, so as to obtain while having
The undenatured collagen of water solubility of good fluidity and high thermal stability.
In conclusion the present invention has the following advantages：
1, the present invention can to natural collagen simultaneously realize acylation modification with it is cross-linking modified, avoiding traditional method of modifying makes water
The drawbacks of undenatured collagen thermal stability of dissolubility reduces, and it is apparent while improving water-soluble (collagen isoelectric point is made to decline)
Collagen thermal stability (collagen thermal denaturation temperature is made to improve) is improved, makes collagen in environment such as processing, storage, transport, sale
Under be not susceptible to be denaturalized；
2, the present invention provides a kind of undenatured collagen of water solubility with good fluidity, can meet collagen need to have it is good
The requirement of all kinds of cosmetics, beauty injection material and biomedical material of good mobility；
3, product final application form of the present invention is water-soluble solution state collagen, and non-solid or gel state collagen, thus
The impurity that reaction generates can thoroughly be removed with the method for dialysis, leaves behind the pure undenatured collagen of water solubility；
4, the polycarboxylic acids sheet on tropocollagen molecule is grafted on as a kind of macromolecular of good biocompatibility, being completely suitable for
Cosmetic and field of biomedical materials.
Claims (5)
1. a kind of undenatured collagen preparations of water solubility, it is characterised in that：Including the following contents：
(1) polycarboxylic acids-N- hydroxysuccinimide esters are prepared：In 10-50mL dimethyl sulfoxide (DMSO)s, polycarboxylic acids is added, stirring is molten
Solution is complete；N- hydroxysuccinimides are added, after stirring and dissolving, add carbodiimides, stir, react 9-18h；Then plus
Enter absolute ethyl alcohol or precipitation is precipitated in acetone, precipitation is washed with absolute ethyl alcohol, n-hexane respectively, is then dried in vacuo to get poly-
Carboxylic acid-N- hydroxysuccinimide esters；Wherein, the weight ratio of N- hydroxysuccinimides and polycarboxylic acids is 1/20~1/2；Carbonization
The weight ratio of diimine and N- hydroxysuccinimides is 1/3~1/1；
(2) water-soluble undenatured collagen is prepared：Natural collagen is dissolved in the hydrochloric acid solution of pH 2.5-4.5, is obtained a concentration of
The collagen solution of 1-10mg/mL；Polycarboxylic acids-N- hydroxysuccinimide esters are dissolved in dimethyl sulfoxide (DMSO), are obtained a concentration of
Polycarboxylic acids-N- hydroxysuccinimide the ester solutions of 10-100mg/mL；Then maintain temperature at 4-10 DEG C always, by polycarboxylic acids-
Collagen solution is added in N- hydroxysuccinimide ester solutions, and is stirred to react 12-24h, then with deionized water dialysis 1-3d；Freezing
Drying is to get water-soluble undenatured collagen；Wherein, the weight ratio of polycarboxylic acids-N- hydroxysuccinimides ester and natural collagen is
1/20~1/2.
2. water-soluble undenatured collagen preparations as described in claim 1, it is characterised in that：In the step (2), temperature
It is 4-8 DEG C.
3. one kind water-soluble undenatured collagen made from preparation method described in claim 1, it is characterised in that：Including following
Raw material：Polycarboxylic acids-N- hydroxysuccinimides the ester and natural collagen that weight ratio is 1/20~1/2；
Polycarboxylic acids-N- hydroxysuccinimide the esters are esterified to obtain by following component：The N- hydroxyls that weight ratio is 1/20~1/2
Succimide and polycarboxylic acids；
The polycarboxylic acids is polyglutamic acid or polymalic acid.
4. water-soluble undenatured collagen as claimed in claim 3, it is characterised in that：The polyglutamic acid molecular weight is 20000
~1000000.
5. water-soluble undenatured collagen as claimed in claim 3, it is characterised in that：The polymalic acid molecular weight 2000~
4000。
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1264390A (en) * | 1997-05-28 | 2000-08-23 | 清水庆彦 | Collagen gel |
| CN1597742A (en) * | 2004-08-19 | 2005-03-23 | 四川大学 | Preparation method of water soluble undenatured natural collagen |
| CN101961508A (en) * | 2010-09-30 | 2011-02-02 | 浙江大学 | Method for preparing polyelectrolyte composite coating |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3959470B2 (en) * | 2003-12-26 | 2007-08-15 | 独立行政法人物質・材料研究機構 | Activated polymalic acid derivatives and crosslinked polymers |
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2016
- 2016-05-24 CN CN201610348502.2A patent/CN105949477B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1264390A (en) * | 1997-05-28 | 2000-08-23 | 清水庆彦 | Collagen gel |
| CN1597742A (en) * | 2004-08-19 | 2005-03-23 | 四川大学 | Preparation method of water soluble undenatured natural collagen |
| CN101961508A (en) * | 2010-09-30 | 2011-02-02 | 浙江大学 | Method for preparing polyelectrolyte composite coating |
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