CN105085708A - Preparation method for original nature hyaluronic acid graft modified polymer and derivative thereof - Google Patents
Preparation method for original nature hyaluronic acid graft modified polymer and derivative thereof Download PDFInfo
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- CN105085708A CN105085708A CN201510432391.9A CN201510432391A CN105085708A CN 105085708 A CN105085708 A CN 105085708A CN 201510432391 A CN201510432391 A CN 201510432391A CN 105085708 A CN105085708 A CN 105085708A
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Abstract
The invention discloses a preparation method for an original nature hyaluronic acid graft modified polymer and a derivative thereof. The preparation method comprises the following steps: (1) by being mediated by a cross-linking agent, carrying out cross-linking graft modification reaction on hyaluronic acid to obtain graft modified hyaluronic acid; and (2) carrying out pre-cut mild dialysis on the graft modified hyaluronic acid to obtain the original nature hyaluronic acid graft modified polymer and the derivative thereof. The characteristic of the graft modified hyaluronic acid polymer or the derivative thereof is swelling but not dissolved as a covalent cross-linking network is formed. As a lot of hydrophilic groups exist in the hyaluronic acid, for example, -OH, -CONH2 and the like, a lot of water can be absorbed and maintained, so that the weight and volume are obviously increased. The molecular structure of the hyaluronic acid is changed by carrying out pre-cut mild dialysis, so that the swelling degree of the hyaluronic acid can be regulated. As a result of the properties, original nature hyaluronic acid graft modified derivative can be widely applied to the field of biomedicine and pharmacy.
Description
Technical field
The present invention relates to the preparation method of a kind of hyaluronic acid polymer and derivative thereof, be specifically related to the preparation method of a kind of originality hyaluronic acid grafting and modifying polymkeric substance and derivative thereof.
Background technology
Hyaluronic acid be extensively distribute in whole reticular tissue, epithelium and nervous tissue naturally-occurring, negatively charged ion, non sulphate glycosaminoglycan.The people of body weight 70kg roughly has 15 grams of hyaluronic acids in vivo, and hyaluronic acid is natural to be present in many tissues of health.Therefore, it is acknowledged as the very good biomedical material of physiologically acceptable, but because inside of human body is containing hyaluronic acid degradation enzyme, it is degraded usually in body fast, thus have impact on its use effect as biomaterial.Such as, hyaluronate sodium obtains good application clinically as function of joint activator, but can degrade in being injected into one week, therefore must inject weekly once.How to keep hyaluronic originality, overcome again it in vivo by the defect of fast degradation, this carries out grafting and modifying with regard to needing the basis retaining hyaluronic acid originality.
Summary of the invention
Because the defect of prior art, technical problem to be solved by this invention is: the preparation method providing a kind of originality hyaluronic acid grafting and modifying polymkeric substance and derivative thereof, originality hyaluronic acid grafting and modifying polymkeric substance prepared by this method and derivative thereof, hyaluronic originality can be kept, overcome again it in vivo by the defect of fast degradation.
The present invention adopts epoxy crosslinked dose (as 1,4-butanediol diglycidyl ether (BDDE)) mediation under, cross-linked graft modification is carried out to Natural hyaluronic acid structure, and adopt the gentle dialysis of precut formula, obtain and there is more excellent physics-chem characteristic, retain the original good biocompatibility of hyaluronic acid simultaneously, obtain originality hyaluronic acid grafting and modifying polymkeric substance and derivative thereof.Resulting polymers or derivative can be used as the biomedical adhesive and the encapsulant that supply local delivery biologically active agent, such as, promote Wound-healing agent, cell growth inhibiting agent, immunostimulant, immunosuppressor, or other form biomass product, such as, gel diaphragm, gel particle, biological sponge material, plastotype embedded material etc.
First aspect present invention, provides the preparation method of a kind of originality hyaluronic acid grafting and modifying polymkeric substance and derivative thereof, comprises the steps:
(1), under adopting linking agent mediation, cross-linked graft modification reaction is carried out to hyaluronic acid, obtains grafting and modifying hyaluronic acid;
(2) grafting and modifying hyaluronic acid is carried out to the gentle dialysis of precut formula, obtain originality hyaluronic acid grafting and modifying polymkeric substance and derivative thereof.
Further, linking agent and hyaluronic usage ratio scope are 1: 50 ~ 1: 5000.
Further, linking agent is selected from the one among epoxy compounds, ester compound, ether compound.
Further, linking agent adopts BDDE.
Further, the temperature range of cross-linked graft modification reaction is at 20 DEG C ~ 60 DEG C; Wherein, at the cross-linked graft modification reaction initial stage, under DEG C condition of temperature of reaction >=30, keep constant speed to stir or vibrate 2 hours.
Further, the dialyzate used in dialysis by inorganic salt and water formulated, inorganic salt are phosphoric acid salt, vitriol or sodium-chlor, and water is purified water or water for injection.
Further, the ratio of dialyzate consumption and grafting and modifying hyaluronic acid consumption is 500: 1 ~ 5000: 1.
Second aspect present invention, provide the inclusion method of above-mentioned hyaluronic acid polymer and derivative and drug molecule, by a kind of art breading mode among static reaction, stirring reaction, mechanical oscillation, ultra-sonic oscillation, hyaluronic acid polymer and derivative thereof and drug molecule are carried out inclusion process.
Further, ultra-sonic oscillation are adopted to carry out inclusion process, ultrasonic frequency range 30kHz ~ 80kHz, ultrasonic treatment time 20 ~ 120 seconds, ultrasonication number of times 1 ~ 3 time.
A third aspect of the present invention, provides the application method of above-mentioned hyaluronic acid polymer and derivative thereof, and hyaluronic acid polymer and derivative thereof are used as the biomedical adhesive and the encapsulant that supply local delivery biologically active agent.
The invention has the beneficial effects as follows:
(1) by the gentle dialysis to cross-linked graft modification and precut formula, final generation originality hyaluronic acid polymer and derivative are while the original hyaluronic acid good biocompatibility of maintenance, produce uniform tridimensional network, thus overcome the defect that hyaluronic acid is easily degraded and absorbed in vivo.
(2) after cross-linked graft modification reaction completes, in crosslinking reaction system not with an organic solvent, very large facility is brought to the aftertreatment of originality hyaluronic acid polymer and derivative, also considerably increase the security that it uses.
(3) employing of the gentle dialysis of precut formula, can remove unreacted linking agent more up hill and dale, add security.
(4) carried out the inclusion reaction of drug molecule by the method for ultra-sonic oscillation, effectively ensure that the inclusion efficiency of originality hyaluronic acid polymer and derivative, shorten inclusion process.
Embodiment
Elaborate to embodiments of the invention below, the present embodiment is implemented under premised on technical solution of the present invention, give detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
Hyaluronic acid and BDDE form the reaction of derivatize hyaluronic acid (HA-VS)
Hyaluronic acid polymer after grafting and modifying or derivative, owing to defining covalent cross-linking network, its characteristic shows as swelling and does not dissolve.Owing to there is a large amount of hydrophilic radicals in hyaluronic acid, as-OH ,-CONH
2deng, therefore, it is possible to absorb and keep large quantity of moisture, weight and volume is all significantly increased.Use the gentle dialysis of precut formula to change hyaluronan molecule structure, can regulate and control hyaluronic swelling capacity, these character make originality hyaluronic acid grafting and modifying derivative can be widely used in biomedicine and art of pharmacy.
The modification of HA-OH group
Wherein, the speed that the rate of release of originality hyaluronic acid grafting and modifying polymkeric substance or derivative inclusion medicine enters primarily of its degree of crosslinking, skeleton relaxation rate and water diffusion determines.In polymkeric substance or derivative skeleton some chemical bond in specific environment by enzymolysis or hydrolysis, cause polymkeric substance or derivative skeleton from surface or overall corrosion, medicine outwards discharges along with the disintegration of skeleton, to arrive the object of slowly-releasing and controlled release.
Linking agent selected by crosslinking reaction of the present invention comprises epoxy compounds, ester class, ether compound.
In the present invention, the usage ratio scope of linking agent and reactant is 1: 50 ~ 1: 5000.
Apply the combination of different linking agents and reactant, and different usage ratio, the originality hyaluronic acid grafting and modifying polymkeric substance of generation and derivative thereof, can be used as the biomedical adhesive for local delivery biologically active agent and encapsulant, such as, promote Wound-healing agent, cell growth inhibiting agent, immunostimulant, immunosuppressor, or other form biomass product, such as, gel diaphragm, gel particle, biological sponge material, plastotype embedded material etc.
By the selection of reaction system and the gentle dialysis technique of precut formula, ensure fast degradation in its original biocompatibility, security and non-body, resulting polymers or derivative can be used as the biomedical adhesive and the encapsulant that supply local delivery biologically active agent, such as, promote Wound-healing agent, cell growth inhibiting agent, immunostimulant, immunosuppressor, or other form biomass product, such as, gel diaphragm, gel particle, biological sponge material, plastotype embedded material etc.
The crosslinking reaction system that the present invention relates to, its process temperature should control at 20 DEG C ~ 60 DEG C.
Heating unit guarantee system temperature should be able to arrive rapidly design temperature and keeps stable.Along with the carrying out of reaction, need to change system temperature.In the early stage of system reaction, require that temperature is not less than 30 DEG C.
The early stage of crosslinking reaction needs by stirring, reactant fully to be contacted with linking agent.The rotating speed of agitator can have an impact to crosslinked degree and reticulated structure in some cases, and thus suitable rotating speed factor should be taken into full account.And the shape of stirrer or stirring arm can affect the efficiency that reactant fully contacts with linking agent, thus the homogeneity generation effect to final cross-linking products.System reaction should keep constant speed to stir or concussion maintenance more than 2 hours early stage.
In some reaction system, by the method for mechanical oscillation, reactant and linking agent are fully contacted and also can obtain desirable effect.
In the present invention, crosslinking reaction can be carried out in the scope of system pH 3.0 ~ 10.0.After the completion of reaction, system pH should be adjusted in the scope of 6.5 ~ 8.5.The determination of final ph and the environment for use of originality hyaluronic acid polymer or derivative, and the drug molecule of pre-inclusion is correlated with.
The reagent of adjust ph is mineral acid and mineral alkali.Commonly use in mineral acid as hydrochloric acid.Commonly use in mineral alkali as sodium hydroxide and potassium hydroxide.Mineral acid and mineral alkali before use, should be mixed with 0.1mol/L ~ 1mol/L in advance.
Final obtained originality hyaluronic acid polymer or derivative need through dialysis treatment process.
Dialyzate by inorganic salt and water formulated.Wherein, inorganic salt comprise phosphoric acid salt, vitriol and sodium-chlor; Water is purified water through strictly processing or water for injection.
Dialysis procedure can be static or dynamic; Also can in whole process in different ways.
The consumption of dialyzate and the ratio of originality hyaluronic acid amount are 500: 1 ~ 5000: 1.
The degree of uniformity of dialysis is most important in the preparation technology of whole originality hyaluronic acid polymer and derivative thereof.Therefore the gentle dialysis of originality hyaluronic acid being carried out to precut formula is necessary, to ensure that gel contacts fully with dialyzate.Due to the difference of cross linking conditions, in its dialysis procedure, corresponding conditions also needs adjustment, and the gel of enough hemodialysis can reach the requirement of the security of use and the inclusion power to drug molecule.
The originality hyaluronic acid derivatives that the present invention prepares can obtain different polymkeric substance and derivative by mechanical force hierarchical approaches of sieving.The specified sieve pore structure device used in classification process, its material comprises metal or macromolecular material, or the mixture of two kinds of materials.
In classification process, additional mechanical force is provided by the device matched with sieve pore structure device, should keep in balance in mechanical force applying process, may on the impact of sieve pore structure device to avoid irregular, violent mechanical force to change.
The originality hyaluronic acid polymer prepared according to above technique and derivative thereof can inclusion therapeutic or preventative drug molecules, and in use control the rate of release of medicine and the distribution of medicine.
The feature of water-soluble or facultative molecule should be had by the drug molecule of inclusion.
Drug molecule is first fully dissolved in the aqueous solution, and carries out inclusion reaction with a certain amount of originality hyaluronic acid polymer added and derivative thereof.Drug molecule should be made in reaction process fully to contact with originality hyaluronic acid polymer or derivative, and the inside of cyberspace structure can be entered.
Static or mechanical oscillation or stirring mode has comparatively ideal effect to originality hyaluronic acid polymer or derivative inclusion reaction, but the time of tackling this reaction controls, and general control was at 0.5 ~ 3 hour.
The mode of ultra-sonic oscillation, can obtain desirable inclusion effect.
Reply ultrasonic treatment time and the frequency control.The general single treatment time is 20 ~ 120 seconds, and total number of processes should be no more than 3 times.
Enter the drug molecule of originality hyaluronic acid network structure inside, the effect intercepted, its rate of release receives control.The same drug molecule free list of different size gel to inclusion reveals different controllabilities.When the gel of different size inclusion drug molecule combinationally uses in certain proportion, it shows the more efficient control of drug molecule release.
Some originality hyaluronic acid polymer or derivative, after implanting, be subject to the effect of the factor such as electrochemical conditions, biological enzyme and degrade gradually, metabolism, its Application Areas is also more extensive.
Wherein, some hyaluronic acid itself has the feature of biological endogenous property, can supplement or alternative endogenous composition temporarily.Hyaluronic acid is a kind of representational polysaccharide polymer.This feature ensure that the security that its polymkeric substance or derivative and organism are removed or implanted, and contact or the position of implanting comprise epidermal area and skin corium.
Embodiment 1
The preparation one of originality hyaluronic acid polymer
It is in the ealkaline buffer of 8.0 that 20 grams of hyaluronic acids are dissolved in 100 milliliters of pH, keeps temperature of reaction system 35 DEG C, and stir and make evenly, add crosslinking agent B DDE, consumption is 0.05%.Continue stirring 4 hours, obtain originality hyaluronic acid polymer.
Embodiment 2
The preparation two of originality hyaluronic acid polymer
It is in the ealkaline buffer of 9.0 that 20 grams of hyaluronic acids are dissolved in 60 milliliters of pH, keeps temperature of reaction system 30 DEG C, and stir and make evenly, add linking agent DVS, consumption is 0.08%.Continue stirring 4 hours, obtain originality hyaluronic acid polymer.
Embodiment 3
The preparation three of originality hyaluronic acid polymer
Weigh 1.1 grams of hyaluronic acids (molecular-weight average 2,300,000), add 10 ml concn 0.25M sodium hydroxide dilutions, reaction 4 hours in stirred at ambient temperature device.1.0 milliliters of BDDE are added while stirring, 50 degree of waters bath with thermostatic control 4 hours in step 1 solution.Get 500 milliliters of phosphate solutions, add agitator, cleaning purifying, obtains hydrogel.Repeatedly rinse 6 times, leave standstill 2.5 days, the unnecessary phosphate buffered saline buffer of elimination, taking-up gelating soln is put into agitator paddle and is stirred 4 hours.Finally obtain gel weight 55 grams, after autoclaving, be fed into syringe, can be used for injection.
Embodiment 4
The preparation of originality Hyaluronan fibers element
Under alkaline condition, 20 grams of Mierocrystalline celluloses are added in 5 times of bulk solution, stir within 4 hours, make fully swelling.Add the epoxy chloropropane of 0.2% concentration, the stirring that remains a constant speed makes crosslinking reaction complete.Dialyse 24 hours to remove unreacted linking agent.The hydrogel intensity obtained is higher, has good water absorbing properties.
Embodiment 5
The preparation of dialyzate
Dialyzate formula one: add Na by every 10L purified water or water for injection
2hPO
47.55g, NaH
2pO
41.50g, NaCl60.00g, use after 0.45um secondary filter.
Dialyzate formula two: add NaOH2.1g, NaH by every 10L purified water or water for injection
2pO
43.3g, NaCl50.0g, regulate pH to 7.5, use after 0.45um secondary filter.
Dialyzate formula three: add Na2HPO by every 10L purified water or water for injection
48.3g, NaH
2pO
422.5g, NaCl60.00g, regulate pH to 6.7, use after 0.45um secondary filter.
Embodiment 6
The gentle dialysis of the precut formula of cross-linked-hyaluronic acid polymkeric substance
By the hyaluronic acid solution completing crosslinking reaction in 1: 1000 ratio put into dialyzate one, dialyse 24 hours, change a dialyzate.With the crosslinking agent B DDE in vapor-phase chromatography or high performance liquid chromatography detection gel or DVS, meet control overflow.
Embodiment 7
Originality hyaluronic acid polymer or derivative mechanical force cross screen sizing
Select to have the sieve pore structure device in suitable aperture, by the ring groove of originality hyaluronic acid embedding device for preparing, be uniformly distributed.Start outer mechanical force device, according to aperture specification and the gel content that sieves, regulate outer mechanical force to be 0.05 ~ 0.3MPa, detect its particle diameter through powerful microscope, meet the requirement of default different polymkeric substance or derivative.
Embodiment 8
The preparation of the originality hyaluronic acid polymer of inclusion drug molecule
Drug molecule is quantitatively dissolved, adds the previously prepared originality hyaluronic acid polymer completed, adopt the mixing of ultra-sonic oscillation method.Selection ultrasonic frequency is 30 ~ 80kHz, and single action time is 30 seconds, acts on 2 times altogether, 5 minutes, interval.Filter the originality hyaluronic acid polymer obtaining inclusion drug molecule.
Embodiment 9
The preparation of originality hyaluronic acid urea derivative
Be linking agent with epoxy chloropropane, prepare originality hyaluronic acid, add in aqueous solution of urea, Keep agitation 4 hours, filter the originality hyaluronic acid urea derivative obtaining inclusion urea.
Embodiment 10
The release of originality hyaluronic acid polymer controls
Had by inclusion the originality hyaluronic acid polymer of hydrocortisone to carry out the test of external and in vivo release to show: this polymkeric substance all can be degraded by the distinctive dextranase of colon site, and find that the chemical constitution of telomerized polymer can control the expansion character of polymkeric substance in Digestive system and physical strength, ensure that medicine does not discharge or discharges on a small quantity in stomach and small intestine.
Embodiment 11
The preparation of the lower originality derivatives of hyaluronic acids of EDC mediation
(1) weigh hyaluronic acid 0.3 gram, dry powder (molecular-weight average 2,060,000), add 30ml distilled water and dissolve, left at room temperature one night, obtain homogeneous transparent concentration 1% solution.
(2) weigh glycol-chitosan 1.5 grams (molecular-weight average 500,000), add 100ml distilled water solution and leave standstill a night, obtain ph9.1, concentration 1.5% solution.Cleaner liquid.
(3) step 1 solution, adding appropriate concentration is 0.1 molar hydrochloric acid solution, stirs, and adjustment ph value is to 4.0 ~ 4.3 scopes.
(4) get 17ml step 2 solution, add step 3 solution.Obtain clear solution, ph value 7.2 ~ 7.5 scope.
(5) step 4 solution stirring 30 minutes.
(6) weigh 0.26 gram of 1-ethyl-3-(dimethylamine propyl) carbodiimide or 0.17 gram of 1-ethyl-3-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, add 2ml distilled water and dissolve.
(7) step 6 solution adds step 5 solution, and stirred at ambient temperature 4 hours, obtains hydrogel.
(8) step 7 hydrogel is soaked into pH7.4 phosphate solution, the reagent that removing is residual, and a small amount of small molecules.Water swelling degree 5400%.
More than describe preferred embodiment of the present invention in detail.Should be appreciated that those of ordinary skill in the art just design according to the present invention can make many modifications and variations without the need to creative work.Therefore, all technician in the art, all should by the determined protection domain of claims under this invention's idea on the basis of existing technology by the available technical scheme of logical analysis, reasoning, or a limited experiment.
Claims (10)
1. a preparation method for originality hyaluronic acid grafting and modifying polymkeric substance and derivative thereof, is characterized in that, comprises the steps:
(1), under adopting linking agent mediation, cross-linked graft modification reaction is carried out to hyaluronic acid, obtains grafting and modifying hyaluronic acid;
(2) described grafting and modifying hyaluronic acid is carried out to the gentle dialysis of precut formula, obtain originality hyaluronic acid grafting and modifying polymkeric substance and derivative thereof.
2. the preparation method of a kind of originality hyaluronic acid grafting and modifying polymkeric substance according to claim 1 and derivative thereof, is characterized in that, described linking agent and described hyaluronic usage ratio scope are 1: 50 ~ 1: 5000.
3. the preparation method of a kind of originality hyaluronic acid grafting and modifying polymkeric substance according to claim 1 and derivative thereof, it is characterized in that, described linking agent is selected from the one among epoxy compounds, ester compound, ether compound.
4. the preparation method of a kind of originality hyaluronic acid grafting and modifying polymkeric substance according to claim 3 and derivative thereof, is characterized in that, described linking agent adopts BDDE.
5. the preparation method of a kind of originality hyaluronic acid grafting and modifying polymkeric substance according to claim 1 and derivative thereof, is characterized in that, the temperature range of described cross-linked graft modification reaction is at 20 DEG C ~ 60 DEG C; Wherein, at the described cross-linked graft modification reaction initial stage, under DEG C condition of temperature of reaction >=30, keep constant speed to stir or vibrate 2 hours.
6. the preparation method of a kind of originality hyaluronic acid grafting and modifying polymkeric substance according to claim 1 and derivative thereof, it is characterized in that, the dialyzate used in described dialysis by inorganic salt and water formulated, described inorganic salt are phosphoric acid salt, vitriol or sodium-chlor, and described water is purified water or water for injection.
7. the preparation method of a kind of originality hyaluronic acid grafting and modifying polymkeric substance according to claim 6 and derivative thereof, is characterized in that, the ratio of described dialyzate consumption and described grafting and modifying hyaluronic acid consumption is 500: 1 ~ 5000: 1.
8. the inclusion method of a hyaluronic acid polymer and derivative and drug molecule, it is characterized in that, described hyaluronic acid polymer and derivative thereof are the described originality hyaluronic acid grafting and modifying polymkeric substance that obtains of the preparation method according to any one of the claims 1-7 and derivative thereof; By a kind of art breading mode among static reaction, stirring reaction, mechanical oscillation, ultra-sonic oscillation, described hyaluronic acid polymer and derivative thereof and described drug molecule are carried out inclusion process.
9. the inclusion method of a kind of hyaluronic acid polymer according to claim 8 and derivative and drug molecule, it is characterized in that, ultra-sonic oscillation are adopted to carry out described inclusion process, ultrasonic frequency range 30kHz ~ 80kHz, ultrasonic treatment time 20 ~ 120 seconds, ultrasonication number of times 1 ~ 3 time.
10. the application method of a hyaluronic acid polymer and derivative thereof, it is characterized in that, described hyaluronic acid polymer and derivative thereof are the described originality hyaluronic acid grafting and modifying polymkeric substance that obtains of the preparation method according to any one of the claims 1-7 and derivative thereof; Described hyaluronic acid polymer and derivative thereof are used as the biomedical adhesive and the encapsulant that supply local delivery biologically active agent.
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Application publication date: 20151125 |