CN102304193A - Preparation method and application of oligomeric hyaluronic acid - Google Patents
Preparation method and application of oligomeric hyaluronic acid Download PDFInfo
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Abstract
The invention relates to a method for one-step degradation of large-molecular-weight hyaluronic acid to obtain oligomeric hyaluronic acid. The method comprises the step of hydrolyzing large-molecular-weight hyaluronic acid or a salt thereof used as a raw material under the conditions of solution pH value not more than 3 and temperature of 80-110 DEG C for at least 2 hours to obtain the oligomeric hyaluronic acid. The oligomeric hyaluronic acid prepared by the method provided by the invention has the advantages that the molecular weight is mainly distributed at 700-3000 Daltons, the gaussian distribution peak area ratio is over 82%, the oligomeric hyaluronic acid mainly exists in the forms of hyaluronic acid unimer, dimer, trimer and tetramer, the preparation process is simple, the cost is lower, and the preparation method is suitable for large-scale industrial production.
Description
Technical field
The present invention relates to the hyaluronic preparation method and its usage of a kind of oligomerization, concrete, the present invention relates to a kind of macromolecule mucinase one is gone on foot and degrade, obtain the hyaluronic method of oligomerization, and relate to the hyaluronic purposes of oligomerization of preparation.
Background technology
(Hyaluronic Acid HA), has another name called Hyaluronic Acid to mucinase, is a kind of acid mucopolysaccharides macromolecular compound, extensively is present in reticular tissue, vitreous body of eye, intercellular substance, synovium of joint liquid, cornea and the bacteria wall of humans and animals.
Mucinase is by D-glucuronic acid and N-acetyl-glucosamine disaccharide monomer repeated arrangement and the linear polymer that forms.The effect of hydrogen bond between the monose on the mucinase straight chain chain rivet, molecule is inflexible spiral column type in the space; Its radius is 200nm, and post is inboard because of there being great amount of hydroxy group to produce strongly hydrophilic, and the affine moisture content of HA is about 1000 times of itself weight in the solution, is one of internationally recognized best wetting Agent for Printing Inks.
Mucinase mainly is divided into: pharmaceutical grade mucinase, food grade mucinase and cosmetics-stage mucinase etc.Mucinase is widely used as the added ingredients of makeup at present.Mucinase as the makeup added ingredients mainly contains following effect:
(1) absorbs water
Mucinase can help skin to draw a large amount of moisture, and skin has had moisture, just can keep elasticity and softness naturally.Before soon; We can only be that skin replenishes mucinase through the medical injection means; Present class medical science skin care item then can act on skin with 1,000,000 molecular weight hyaluronic acids compression packing with a spot of mucinase as wetting Agent for Printing Inks, just can absorb the water that is equivalent to 1000 times of own wts approximately; Make epidermic cell full once again, smooth wrinkle.Though responding time less than direct injection, can constantly replenish every day, lets cell fill naturally.
(2) reparation and water conservation
But mucinase moment deep moisturizing, increase skin elasticity and tension force help and recover the normal oil-water balance of skin, improve dry and the skin that relaxes.Mucinase also is a kind of important composition in the skin, has the function that face tissue repairs.When skin histology is exposed to UVB ray following time, skin can be tanned severely, inflammation, and dermal tissue can stop to produce mucinase, accelerates hyaluronic fading rate simultaneously.Mucinase is present in the reticular tissue and skin corium of human body in a large number; Have powerful water-retaining capacity and moisture-keeping functions; Can also strengthen the long water retention capacity of skin, can help spandex and collagen protein to be in the environment that is full of moisture, let more flexible that skin shows.
The mucinase preparation method mainly contains two kinds of animal extraction method (as from umbilical cord, live chickens hat, extracting) and microbial fermentation processes.These two kinds of mucinases that method obtains, molecular-weight average majority are tens to millions of, the polymerization degree several thousand to several ten thousand.Though the macromole mucinase has good water absorption character, soltion viscosity is high behind the absorption moisture.If as makeup, be applied on the skin and can form a skim, hindered the permeability of skin.If as food or foodstuff additive, because viscosity is high, hinder addition, mouthfeel is poor, digests and assimilates poor performance, and cosmetology function is difficult to realize.The oligomerization mucinase preferably resolves above problem.
Research shows that the oligomerization mucinase has following outstanding role:
(1) can stimulate the hyperplasia and the migration of vascular endothelial cell, thereby promote the generation of new vessel, the hyaluronic acid oligomer body can promote synthetic I type of endotheliocyte and VIII Collagen Type VI simultaneously, and these two kinds of collagens play an important role in the vascularization process;
(2) can be penetrated into skin corium, the protection granulation tissue is avoided the destruction of oxyradical, and can promote wound healing;
(3) antitumor action;
(4) immunoregulation effect;
(5) promote the bone forming effect.
The method of hyaluronic acid degradation has at present:
Physical method: factors such as heating, mechanical shear stress, ultraviolet ray, UW, 60Co irradiation, gamma-radiation radiation all can make HA degrade.
The chemical degradation method of chemical process: HA has hydrolysis method and oxidation degradation method, and hydrolysis method is divided acid hydrolysis and basic hydrolysis, and oxidative degradation oxygenant commonly used is Youxiaolin and hydrogen peroxide.Use the relative molecular mass of chemical degradation method degraded product to control through the add-on and the reaction times that change soda acid or oxygenant, the degraded cost is lower, be easy to scale operation, but oxidative degradation may have oxygenant residual.
Enzyme solution: Unidasa, cellulase etc.The enzymolysis process cost is higher, is inappropriate for large-scale industrial production.
CN 101146830A discloses a kind of in the aqueous acidic medium of acetone and other organic solvent, the degraded and has obtained the hyaluronic acid oligomer body, and technology is loaded down with trivial details, and organic solvent is residual easily.
CN 101020724A discloses a kind of preparation method of low molecular weight sodium hyaluronate, particularly a kind of method that from hyaluronic acid fermentation liquid, prepares low molecular weight sodium hyaluronate.Its method is that hyaluronic acid fermentation liquid is removed thalline, ethanol sedimentation, and dissolution precipitation, the mucinase enzyme liberating uses membrane module to make low molecular weight sodium hyaluronate solution, ethanol sedimentation once more, washing precipitation, vacuum-drying obtains finished product.Its method can also be that hyaluronic acid fermentation liquid is used ethanol sedimentation, dissolution precipitation, and the elimination solid substance, filtrating use the mucinase enzyme liberating, and the use membrane module makes low molecular weight sodium hyaluronate solution, ethanol sedimentation once more, washing precipitation, vacuum-drying obtains finished product.Its molecular-weight average of hyaluronate sodium of this law preparation can be controlled in 8,000～20, between 000, minimum can be to about 5,000, and MWD is narrower, protein contnt is not higher than 0.1%.This method preparation cost is high, is inappropriate for large-scale commercial prodn.
CN 101293934A discloses a kind of with hydrogen peroxide and the hyaluronic method of Ascorbic Acid Oxidation edman degradation Edman production small molecular weight, belongs to the applied technical field of redox reaction in the preparation small molecular weight polymer.It adopts hydrogen peroxide (0.1～1.0mmol/g mucinase) and xitix (0.05～0.5mmol/g mucinase) oxidative degradation high molecular weight hyaluronic acid to produce the small molecular weight mucinase; Temperature is 30～50 ℃; PH is 4～6; Reaction times is 30～90min, and the hyaluronic molecular weight of the small molecular weight of being produced is between 20～100kDa.This method is simple, efficient is high, but is easy to generate residual peroxide, is unfavorable for environmental protection.
CN 101429255A has announced the preparation method of a kind of low-numerator sodium hyaluronate (LMHA); Be that hyaluronate sodium (HA) pressed powder is in the organic solvent that contains acid (like sulfuric acid, hydrochloric acid etc.) (organic solvent concentration 70%～100%); Carry out the acid catalysis degraded, preparation molecular weight 5 * 10
3～9 * 10
5The LMHA of Da.But this method need remove organic solvent, and technology is loaded down with trivial details.
CN 101507733A relates to a kind of preparation method of nano micromolecule hyaluronic acid; This method comprise with molecular weight be several ten thousand to millions of mucinase through method for hydrolysis such as enzymes; Obtain the ultra-low molecular amount mucinase below molecular-weight average 1000 dalton, i.e. nano level oligomerization mucinase.The nano micromolecule hyaluronic acid that obtains with present method; Have the promotion capillary vessel significantly different and form, promote functional characteristicss such as wound healing, significant skin affinity and perviousness, can be used as high-grade beauty treatment, protective foods, medical material with the acid of normal transparent matter.But the hydrolyzed solution that this method obtains is opaque, follow-up will the filtration, and complex process, and high with the enzyme preparation cost, be not suitable for large-scale industrial production.
Mucinase is mainly used in fields such as medicine, makeup, food at present, and is therefore higher to its purity requirement.In the prior art, exist product to have other raw material or dissolvent residual, perhaps preparation cost is high, is not suitable for problems such as large-scale industrial production.
Summary of the invention
To the deficiency of prior art, one of the object of the invention is to provide a kind of preparation oligomerization hyaluronic method.The oligomerization mucinase of said method preparation, molecular weight mainly is distributed between the 700-3000 dalton, and the Gaussian distribution peak area ratio surpasses 82%, is mainly mucinase one aggressiveness, dimer to the tetramer.
The hyaluronic method of said preparation oligomerization, it is a raw material with polymer hyaluronic acid or its salt, adds solvent, in pH value of solution≤3, temperature is that hydrolysis at least 2 hours obtains the oligomerization mucinase under 80 ℃～110 ℃ conditions.
The preferred water-soluble salt of said hyaluronate is preferably hyaluronate sodium especially.
Said hyaluronan molecule amount is preferably 1,000,000-2,000,000 dalton.
Said mucinase or its salt concn (mass concentration) further are preferably 0.01%～10% preferably less than 10%, preferred especially 0.1%-6%.
Said solvent preferably is merely water, is preferably deionized water especially.
Said solution is preferably through adding pH value regulator to regulate the pH value; Preferred said pH regulator agent is a mineral acid; Said mineral acid preferably sulfuric acid, hydrochloric acid, acetic acid, nitric acid, Hydrocerol A or its mixture; Further be preferably sulfuric acid, hydrochloric acid, acetic acid, nitric acid or its mixture, be preferably hydrochloric acid especially.
In the said hydrolytic process, preferred solution pH is 0.5～3, and further preferred pH is 0.8～2.
In the said hydrolytic process, temperature is preferably 85 ℃～105 ℃, further is preferably 90 ℃～100 ℃.
Said hydrolysis time is preferably 2～18 hours, further is preferably 4～10 hours.
Said polymer hyaluronic acid or its salt are meant D-glucuronic acid and N-acetyl-glucosamine disaccharide monomer repeated arrangement and the polysaccharide that forms; Can also can commercially availablely obtain through obtaining from prior art/new technologies such as biological tissue extracted such as cockscomb, umbilical cord or microbial fermentation processes.
One of the object of the invention also is to provide and adopts the prepared hyaluronic purposes of oligomerization of preparation method that the present invention relates to.
Said oligomerization mucinase is preferred for makeup, food and field of medicaments.
The inventive method has the following advantages:
1, the inventive method prepares oligomerization hyaluronan molecule amount and mainly is distributed between the 700-3000 dalton, and the Gaussian distribution peak area ratio surpasses 82%, be mainly mucinase one aggressiveness, dimer to the tetramer, and unharmful substance is residual;
2, compare with the hyaluronic method of prior art for preparing oligomerization, the inventive method technology is simple, and cost is lower, is fit to large-scale industrial production;
3, the oligomerization mucinase of the present invention's preparation has good skin affinity, perviousness and subsensitivety, can promote capillary vessel to generate, and promotes wound healing, promotes the synthetic of endotheliocyte I type and VIII collagen type.
Embodiment
For ease of understanding the present invention, it is following that the present invention enumerates embodiment.Those skilled in the art should understand, and said embodiment helps to understand the present invention, should not be regarded as concrete restriction of the present invention.
Embodiment one
Remove ionized water 1000 grams, regulate pH to 1.2, slowly add molecular weight 1,500,000 daltonian hyaluronate sodiums (glucuronic acid content 47.3%) 10 grams with 10% hydrochloric acid; Fully stir swelling under the room temperature; Slowly be warming up to 95 ℃, constant temperature hydrolysis 6 hours can obtain colourless, tasteless, transparent oligomerization hyaluronic acid degradation liquid; Said product is through 60 ℃ of vacuum concentration, and spraying drying obtains white mucinase powder.
The aforesaid liquid product is through chemical analysis, and the affinity tag glucuronic acid content reaches 46.8%, and degraded back retention value reaches 98.9%; According to the JY/T 024-1996 of high efficient liquid phase analysis method detection molecules amount commonly used in the industry, QB/T 2879-2007 standard is done mensuration to the MWD of extract, and it is following to obtain its Gaussian distribution result:
Table 1 oligomerization hyaluronan molecule amount distributes
Molecular weight mainly is distributed between the 700-3000 dalton, and the Gaussian distribution peak area ratio surpasses 82%, is mainly mucinase one aggressiveness, dimer to the tetramer.
Embodiment two
Remove ionized water 1000 grams, regulate pH to 1.1, slowly add molecular weight 1,500,000 daltonian hyaluronate sodiums (glucuronic acid content 47.3%) 30 grams with 10% hydrochloric acid; Fully stir swelling under the room temperature; Slowly be warming up to 97 ℃, constant temperature hydrolysis 7 hours can obtain colourless, tasteless, transparent oligomerization hyaluronic acid degradation liquid; Said product is through 60 ℃ of vacuum concentration, and spraying drying obtains white mucinase powder.
The aforesaid liquid product is through chemical analysis, and the affinity tag glucuronic acid content reaches 46.9%, and degraded back retention value reaches 99.1%; According to the JY/T 024-1996 of high efficient liquid phase analysis method detection molecules amount commonly used in the industry, QB/T 2879-2007 standard is done mensuration to the MWD of extract, and it is following to obtain its Gaussian distribution result:
Table 1 oligomerization hyaluronan molecule amount distributes
Molecular weight mainly is distributed between the 700-3000 dalton, and the Gaussian distribution peak area ratio surpasses 82%, is mainly mucinase one aggressiveness, dimer to the tetramer.
Embodiment three
Remove ionized water 1000 grams, regulate pH to 3, slowly add molecular weight 1,000,000 daltonian hyaluronate sodiums (glucuronic acid content 47.3%) 0.1 gram with 10% sulfuric acid; Fully stir swelling under the room temperature; Slowly be warming up to 90 ℃, constant temperature hydrolysis 18 hours can obtain colourless, tasteless, transparent oligomerization hyaluronic acid degradation liquid; Said product is through 60 ℃ of vacuum concentration, and spraying drying obtains white mucinase powder.
The aforesaid liquid product is through chemical analysis, and the affinity tag glucuronic acid content reaches 47%, and degraded back retention value reaches 99.3%; JY/T024-1996 according to high efficient liquid phase analysis method detection molecules amount commonly used in the industry; QB/T 2879-2007 standard is done mensuration to the MWD of extract; Molecular weight mainly is distributed between the 700-3000 dalton; The Gaussian distribution peak area ratio surpasses 82%, is mainly mucinase one aggressiveness, dimer to the tetramer.
Embodiment four
Remove ionized water 1000 grams, regulate pH to 1.4, slowly add molecular weight 2,000,000 daltonian hyaluronate sodiums (glucuronic acid content 47.3%) 111 grams with 10% acetic acid; Fully stir swelling under the room temperature; Slowly be warming up to 100 ℃, constant temperature hydrolysis 8 hours can obtain colourless, tasteless, transparent oligomerization hyaluronic acid degradation liquid; Said product is through 60 ℃ of vacuum concentration, and spraying drying obtains white mucinase powder.
The aforesaid liquid product is through chemical analysis, and the affinity tag glucuronic acid content reaches 46.6%, and degraded back retention value reaches 98.6%; JY/T 024-1996 according to high efficient liquid phase analysis method detection molecules amount commonly used in the industry; QB/T 2879-2007 standard is done mensuration to the MWD of extract; Molecular weight mainly is distributed between the 700-3000 dalton; The Gaussian distribution peak area ratio surpasses 82%, is mainly mucinase one aggressiveness, dimer to the tetramer.
Embodiment five
Remove ionized water 1000 grams,, slowly add molecular weight 1,200,000 daltonian hyaluronate sodiums (glucuronic acid content 47.3%) 64 grams with 10% lemon acid for adjusting pH to 2; Fully stir swelling under the room temperature; Slowly be warming up to 98 ℃, constant temperature hydrolysis 11 hours can obtain colourless, tasteless, transparent oligomerization hyaluronic acid degradation liquid; Said product is through 60 ℃ of vacuum concentration, and spraying drying obtains white mucinase powder.
The aforesaid liquid product is through chemical analysis, and the affinity tag glucuronic acid content reaches 46.7%, and degraded back retention value reaches 98.7%; JY/T 024-1996 according to high efficient liquid phase analysis method detection molecules amount commonly used in the industry; QB/T 2879-2007 standard is done mensuration to the MWD of extract; Molecular weight mainly is distributed between the 700-3000 dalton; The Gaussian distribution peak area ratio surpasses 82%, is mainly mucinase one aggressiveness, dimer to the tetramer.
Embodiment six
Remove ionized water 1000 grams, regulate pH to 0.8, slowly add molecular weight 1,800,000 daltonian hyaluronate sodiums (glucuronic acid content 47.3%) 100 grams with 10% nitric acid; Fully stir swelling under the room temperature; Slowly be warming up to 105 ℃, constant temperature hydrolysis 3 hours can obtain colourless, tasteless, transparent oligomerization hyaluronic acid degradation liquid; Said product is through 60 ℃ of vacuum concentration, and spraying drying obtains white mucinase powder.
The aforesaid liquid product is through chemical analysis, and the affinity tag glucuronic acid content reaches 46.9%, and degraded back retention value reaches 99.1%; JY/T 024-1996 according to high efficient liquid phase analysis method detection molecules amount commonly used in the industry; QB/T 2879-2007 standard is done mensuration to the MWD of extract; Molecular weight mainly is distributed between the 700-3000 dalton; The Gaussian distribution peak area ratio surpasses 82%, is mainly mucinase one aggressiveness, dimer to the tetramer.
Embodiment seven
Remove ionized water 1000 grams, regulate pH to 1, slowly add molecular weight 1,900,000 daltonian mucinases (glucuronic acid content 47.3%) 80 grams with 10% nitric acid; Fully stir swelling under the room temperature; Slowly be warming up to 110 ℃, constant temperature hydrolysis 2 hours can obtain colourless, tasteless, transparent oligomerization hyaluronic acid degradation liquid; Said product is through 60 ℃ of vacuum concentration, and spraying drying obtains white mucinase powder.
The aforesaid liquid product is through chemical analysis, and the affinity tag glucuronic acid content reaches 46.6%, and degraded back retention value reaches 98.5%; JY/T 024-1996 according to high efficient liquid phase analysis method detection molecules amount commonly used in the industry; QB/T 2879-2007 standard is done mensuration to the MWD of extract; Molecular weight mainly is distributed between the 700-3000 dalton; The Gaussian distribution peak area ratio surpasses 82%, is mainly mucinase one aggressiveness, dimer to the tetramer.
Comparative Examples one
Following method is the hyaluronic representative method of preparation small molecular weight in the prior art:
The hyaluronate sodium of molecular weight 1,500,000 (glucuronic acid content 47.3%) 50g adds water 950g, stirring and dissolving.Hydrolysis under the acidic conditions: the pH value is 2,70 ℃ of constant temperature hydrolysis 4 hours; Enzyme liberating: cool to 40 ℃, add Unidasa (enzyme dosage 800,000 U/L), the pH value is 6,40 ℃ of constant temperature hydrolysis 3 hours, is heated to go out enzyme 10 minutes of 90 ℃ of constant temperature then.Use filter paper filtering, obtain clear, colorless, tasteless, transparent micromolecule hyaluronic acid degraded solutions.Said product through spraying drying, obtains the white powder micromolecule hyaluronic acid through 60 ℃ of vacuum concentration.
The aforesaid liquid product is through chemical analysis, and mucinase disaccharide mark unit glucuronic acid content reaches 46.5% in its product molecule, and its effective retention rate of degraded back reaches 98.3%; The aforesaid liquid product is through liquid-phase chromatographic analysis, and the MWD that obtains product is following:
The MWD analytical results shows in the table, and degraded product 90% above MWD is at 300-1300, and the corresponding mucinase polymerization degree is 1～3, belongs to ultra-low molecular amount distribution range in the oligomerization mucinase.
Comparative example one to seven and Comparative Examples can be known, mucinase disaccharide mark unit glucuronic acid in the oligomerization hyaluronan molecule of method preparation of the present invention, and degraded its effective retention rate of back and Comparative Examples are approximate; The oligomerization hyaluronan molecule amount of the inventive method preparation is bigger slightly than Comparative Examples, but can satisfy application need fully.The more important thing is that the inventive method has only adopted that hydrolysis promptly obtains the oligomerization mucinase under the acidic conditions.Form contrast with it, Comparative Examples also increases enzyme liberating, the high temperature process steps such as enzyme, filtration that go out under adopting acidic conditions the hydrolysing step, and complicated operation increase cost, and the enzyme liberating cost is higher, and is unfavorable for large-scale industrial production.Therefore, the inventive method has obvious improvement with respect to prior art, has solved the unsolved always technical barrier of prior art.
Only if point out in addition, practice of the present invention will be used the routine techniques of biotechnology and organic chemistry, inorganic chemistry etc., obviously except that the special description of institute in above-mentioned explanation and embodiment, can also other mode realize the present invention.Other technical scheme within the scope of the present invention will be conspicuous to those skilled in the art in the invention with improving.According to instruction of the present invention, many changes and variation are feasible, therefore all within scope of the present invention.
Applicant's statement; The present invention explains detailed process equipment of the present invention and technical process through the foregoing description; But the present invention is not limited to above-mentioned detailed process equipment and technical process, does not mean that promptly the present invention must rely on above-mentioned detailed process equipment and technical process could be implemented.The person of ordinary skill in the field should understand, and to any improvement of the present invention, to the interpolation of the equivalence replacement of each raw material of product of the present invention and ancillary component, the selection of concrete mode etc., all drops within protection scope of the present invention and the open scope.
Claims (10)
1. the hyaluronic preparation method of oligomerization is characterized in that, it is a raw material with polymer hyaluronic acid or its salt, adds solvent, and in pH value of solution≤3, temperature is that hydrolysis at least 2 hours obtains the oligomerization mucinase under 80 ℃～110 ℃ conditions.
2. the method for claim 1 is characterized in that, said hyaluronate is water-soluble salt, is preferably hyaluronate sodium especially.
3. the method for claim 1 is characterized in that, said hyaluronan molecule amount is 1,000,000-2,000,000 dalton.
4. the method for claim 1 is characterized in that, said mucinase or its salt concn (mass concentration) further are preferably 0.01%～10% preferably less than 10%, preferred especially 0.1%-6%.
5. the method for claim 1 is characterized in that, said solvent preferably is merely water, is preferably deionized water especially.
6. the method for claim 1; It is characterized in that; Preferably through adding pH value regulator to regulate the pH value, preferred said pH regulator agent is a mineral acid to said solution, said mineral acid preferably sulfuric acid, hydrochloric acid, acetic acid, nitric acid, Hydrocerol A or its mixture; Further be preferably sulfuric acid, hydrochloric acid, acetic acid, nitric acid or its mixture, be preferably hydrochloric acid especially.
7. the method for claim 1 is characterized in that, in the said hydrolytic process, preferred solution pH is 0.5～3, and further preferred pH is 0.8～2.
8. the method for claim 1 is characterized in that, in the said hydrolytic process, temperature is preferably 85 ℃～105 ℃, further is preferably 90 ℃～100 ℃.
Said hydrolysis time is preferably 2～18 hours, further is preferably 4～10 hours.
9. oligomerization mucinase; It is characterized in that making according to each described method of claim 1-8; Oligomerization hyaluronan molecule amount mainly is distributed between the 700-3000 dalton, and the Gaussian distribution peak area ratio surpasses 82%, is mainly mucinase one aggressiveness, dimer to the tetramer.
10. like the hyaluronic purposes of the said oligomerization of claim 9, it is characterized in that said oligomerization mucinase is used for makeup, food and field of medicaments.
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