CN1255451C - Preparation method of bioactive polylactic acid its product and application - Google Patents
Preparation method of bioactive polylactic acid its product and application Download PDFInfo
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- CN1255451C CN1255451C CNB2003101210367A CN200310121036A CN1255451C CN 1255451 C CN1255451 C CN 1255451C CN B2003101210367 A CNB2003101210367 A CN B2003101210367A CN 200310121036 A CN200310121036 A CN 200310121036A CN 1255451 C CN1255451 C CN 1255451C
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Abstract
The present invention provides a method for preparing bioactivity polylactic acid material by using maleic anhydride modified polylactic acid and bioactive substance, products and the application thereof. The method comprises the following steps: 1, organic diamine or glycol or hydroxylamine or water is directly added to react; 2, polyethyleneglycol (which is also called polyethylene oxide) or derivatives thereof are added after products are separated and purified under the action of an organic crosslinking agent; 3, then the bioactive substance is added to react after the products are separated and purified under the action of an organic crosslinking agent, or the bioactive substance is directly added to react under the action of the organic crosslinking agent in step 2 to obtain a bioactive polylactic acid product. Polylactic acid material with different bioactivity can be prepared by using the method and changing the type of the bioactive substance. Some drugs are selected as reaction raw material to prepare a polymer drug by using the method of the present invention. The bioactive polylactic acid can serve as tissue engineering brackets, medicine targeting slow-release carriers, etc.
Description
Technical field
The present invention relates to a kind of preparation method of biological activity poly(lactic acid), or rather, the present invention relates to a kind of employing biologically active substance is raw material, on the basis of maleic anhydride modified poly(lactic acid), further the preparation method of polydactyl acid, with and products thereof and use.
Background technology
(1) poly(lactic acid) and chemical modification research thereof
The outstanding advantage of poly-lactic acid material is to have excellent biological compatibility, degradability and more moderate mechanical property, it in vivo or the product of extracorporeal hydrolysis be biological metabolizable lactic acid, and finally resolve into carbonic acid gas and water, be that a kind of U.S. FDA is with being intended to the synthesizing polymeric material that body uses.Because the advantageous property of poly(lactic acid), it is a kind of fine environment friendly materials, is subjected to environmentalist's favor; More outstanding is that it also receives publicity at present reparation medical science and pharmaceutical field, is subjected to organizational project and medicament slow release investigators' favor especially.But because the chemical structure of poly-lactic acid material itself is simple, contained chemical active radical is few, more do not have pair cell adhesion required in the Tissue Engineering Study, the cell signal of the regulating effect of having grown, also do not have required target signal in the target medicament slow release research, thereby it can only be used as a kind of inert material of universality in every field.
For this reason, the preparation of the poly(lactic acid) compound of a lot of scholar's research biologically actives.Comprise physical method and chemical process, be described below respectively:
Physical method mainly contains following dual mode: 1. simply mix with biological activity protein, polypeptide; 2. adsorb biological activity protein or polypeptide on the poly-lactic acid material surface by physisorption.Physical method can make performances such as the surface bioactive, hydrophilic/hydrophobic of material obtain to a certain degree improvement, but the problem that often may have following several respects: 1. blend is inhomogeneous, make the character on material and cells contacting surface inhomogeneous, thereby cause on the material growth conditions of cell inequality; 2. physical adsorption method is normally kept effect between adsorbed molecules and poly-lactic acid material by Van der Waals force, and a little less than the bonding force, the molecule that is adsorbed is easy to come off, thereby influences the biological activity of material.
The research of chemical process started from after the nineties in 20th century, it mainly contains following dual mode: other segment of 1. introducing side chain band active reactive group with copolymerization mode on the poly(lactic acid) main chain, and be media with this active reactive group, the grafting bioactive molecules.Langer R laboratory delivered in 1993 the compound of lactic acid-Methionin copolymerization, it has introduced the polylysine segment on the poly(lactic acid) main chain, they utilize the amino on the polylysine side chain to be reactive active group, pass through cross-linking reaction, introduced other bioactive molecules again, as RGD peptide section
[1,2,3]By on the poly(lactic acid) main chain, introducing the method for other segment and active group, can on poly-lactic acid material, introduce bioactive material, studies show that the bioactive molecules biologically active of introducing simultaneously, promoted and cell between message exchange, help the adhesion and the growth of cell
[1,2]But when introducing bioactive molecules by this way, in the backbone structure of product, introduced other segment, the polymerization degree of polymkeric substance is reduced, molecular weight and molecular weight, degradation property changes, and influences the use propertieies such as mechanical strength of material.2. introduce bioactive molecules by the end of the chain of poly(lactic acid).A kind of novel biological activity poly-lactic acid material has been reported in Langer R laboratory in 1998, it is by (α-vitamin H, the poly(lactic acid) of the end of the chain band biotin molecule that polyoxyethylene glycol of ω-OH) and L-rac-Lactide aggregate into, by biotin molecule is media, with the antibiotin is coupling agent, can introduce other the biologically active substance that links to each other with vitamin H again
[4](the antibiotin molecule is the part of vitamin H, and the affinity between them is very high, antibiotin molecule can in conjunction with four biotin molecules).Other modification has the research of Japanese Kataoka K laboratory in report in 2000, they adopt the end of the chain is that the ethylene glycol-newborn multipolymer of acetal group is a raw material, change the acetal group into aldehyde radical through peracid treatment again, generate Schiff alkali by the reaction of the amino on aldehyde radical and amino acid or the polypeptide, through reduction, bioactive molecules is incorporated into the end of the chain of polylactic acid molecule
[5]By active group at the poly(lactic acid) end of the chain, bioactive material can be incorporated on the poly-lactic acid material, but it can only be in the end of the chain introducing of poly(lactic acid), the amount of introducing and position can not be regulated arbitrarily.Have not yet to see domestic about adopting chemical process poly(lactic acid) to be carried out the research of bioactivation modification.
(2) effect of polyoxyethylene glycol (PEG or PEO) and the absorption of prevention nonspecific proteins thereof
Studies show that, only there are at present several materials few in number to have the effect that stops nonspecific proteins absorption, comprise highly hydrophilic uncharged hydrogel, as polyacrylamide and agar osamine, polyoxyethylene glycol (PEG) etc., and has the effect that stops cell adhesion on polyoxyethylene glycol, derivatived cellulose and fluorochemical surface.PEG is that a kind of normal employing forms the material that can stop albumen non-specific adsorption surface.When the specific biological effect of albumen or polypeptide research, often utilize this character of PEG, albumen or polypeptide and PEG is covalently bound.In addition, aspect medicament slow release research, find that medicament slow-release microsphere surface-coated PEG can increase the time that microballoon stops in blood circulation, the slowly-releasing that helps medicine, this microballoon comprises poly(lactic acid) and immunoliposome, and this may also can stop the performance of proteic non-specific adsorption relevant with it.
People have also done a lot of research to adopting the PEG polydactyl acid, mainly by with the poly(lactic acid) copolymerization, at the commissure of the polymkeric substance end of the chain, be connected the research of bioactive molecules as what mention again with the poly(lactic acid) copolymerization on top, and PEG and poly(lactic acid) connect into new monomer with unsaturated double-bond respectively, again the research by free radical polymerization.
Summary of the invention
The deficiency that purpose of the present invention exists at prior art, a kind of preparation method who adopts chemical process poly(lactic acid) to be carried out the bioactivation modification is provided, the inventive method is introduced biologically active substance in poly(lactic acid) body chemical structure, reach the purpose of following several respects:, on the side chain of polylactic acid polymer, biologically active substance is incorporated in the structure of polymkeric substance 1. at the backbone structure that changes poly(lactic acid) hardly with do not reduce under the prerequisite of molecular weight of polymkeric substance; The amount of introducing can be regulated as required; 3. make the distribution uniform of biologically active substance on whole polylactic acid molecule chain of introducing; 4. make the reaction conditions gentleness of introducing biologically active substance, can guarantee bioactive molecules active keeping after reaction; 5. make the material of preparation can eliminate or reduce physical adsorption (being non-specific adsorption) to a certain extent, thereby help bringing into play the specific biological effect of grafting bioactive molecules other not grafted bioactive molecules; 6. make the more approaching neutrality of hydrolysis pH value of the designed compound of the present invention, overcome the phenomenon that the poly-lactic acid material degraded reduces environment PH.
Adopt following measure to prepare bioactive poly(lactic acid) compound for achieving the above object: adopt maleic anhydride modified poly(lactic acid) (as the patent 01129046.X of applicant) to be raw material, 1. directly adding organic diamine or glycol or azanol or water reacts; 2. product under the effect of organic crosslinking agent, adds the bio-active substance qualitative response after separation and purification, thereby obtains the biological activity poly(lactic acid).
Preparation process 2. in, product also can be under the effect of organic crosslinking agent after separation and purification, adds the reaction of polyoxyethylene glycol (also claiming polyethylene oxide) or derivatives thereof earlier; Then, 3. with product after separation and purification, under the effect of organic crosslinking agent, add the bio-active substance qualitative response again, obtain biological activity poly(lactic acid) product equally.
Related biologically active substance comprises protein, oligosaccharide, dna fragmentation and the medicine etc. of all biologically actives such as various cells and tissue growth factor, regulatory factor, the target factor in the method.The amount of the biologically active substance that adds be in the polydactyl acid maleic anhydride mole dosage 1～50%, temperature of reaction is-20～60 ℃, time is 10 minutes～48 hours, pH value scope is 5～9, reaction process is according to the linking agent kind of using, select the catalyzer of its feature, as organic amine or organometallic compound.
Organic crosslinking agent can be binary or polybasic carbon imines such as dicyclohexylcarbodiimide, 1-ethyl-3 (3-dimethylamino-propyl) carbodiimide, binary or multicomponent isocyanate are as 1, the 6-hexamethylene diisocyanate, tolylene diisocyanate, 4,4 '-diphenylmethanediisocyanate etc., binary or polynary epoxy compounds are as 1,2,5,6-diepoxy hexane, 1,2,7,8-diepoxy octane etc., organometallic compound such as titanium, aluminium, zirconium, the alkoxide of tin, alkali formula inorganic acid salt etc., and the derivative of these materials, other some coupling agents are as 3 (2-pyridine ethyl) propionic acid-N-succinimide ester, between (N-dimaleoyl imino) benzoic ether, S-acetyl mercapto succinyl oxide, N-hydroxy-succinamide, 1,1 '-carbonyl dimidazoles etc.
Polyethyleneglycol derivative comprises derivatives such as the amino, carboxyl, aldehyde radical of its end group;
The add-on of organic diamine or glycol or azanol or water or polyoxyethylene glycol be in the polydactyl acid maleic anhydride mole dosage 1～50%, temperature of reaction is 0～100 ℃, the time is 10 minutes～24 hours.
Adopt the structural formula of the resulting biological activity poly-lactic acid products of this preparation method to be:
R is
Or
R wherein
1Be organic diamine or glycol or azanol or water, R
2Be organic crosslinking agent, R
3Be polyoxyethylene glycol, L is a biologically active substance;
Adopt designed method of the present invention, by the different biologically active substance of grafting, can prepare and have better cellular affinity, or has a modulability of cell growth, or the biological activity poly-lactic acid material with properties such as histocyte specific recognition, its product can be used as the timbering material of organizational project, the targeted carrier material of medicament slow release or the medicine of making high molecular.Comparing with poly(lactic acid), is the material of the novel biologically active of a class, biodegradability and good biocompatibility.
The inventive method is introduced biologically active substance in poly(lactic acid) body chemical structure, the advantage that is had has: 1. at the backbone structure that changes poly(lactic acid) hardly with do not reduce under the prerequisite of molecular weight of polymkeric substance, biologically active substance is incorporated in the structure of polymkeric substance on the side chain of polylactic acid polymer; 2. the amount of Yin Ruing can be regulated as required; 3. the distribution uniform of the biologically active substance of Yin Ruing on whole polylactic acid molecule chain; 4. introduce the reaction conditions gentleness of biologically active substance, can guarantee bioactive molecules active keeping after reaction; 5. the physical adsorption (being non-specific adsorption) to other not grafted bioactive molecules can be eliminated or reduce to the designed material of the present invention to a certain extent, thereby help the specific effect of grafting bioactive molecules; 6. the more approaching neutrality of hydrolysis pH value of the designed compound of the present invention can overcome the phenomenon that the poly-lactic acid material degraded reduces environment PH.
A kind of preparation method of biological activity poly(lactic acid) ties up on the basis of maleic anhydride modified poly(lactic acid), adopts the following steps preparation: 1. directly add organic diamine or glycol or azanol or water and react; 2. product under the effect of organic crosslinking agent, adds the bio-active substance qualitative response after separation and purification, obtains biological activity poly(lactic acid) product.
In above-mentioned preparation method, the 2. middle product of step also can add the reaction of polyoxyethylene glycol or derivatives thereof earlier under the effect of organic crosslinking agent after separation and purification; Then, 3. product under the effect of organic crosslinking agent, adds the bio-active substance qualitative response again after separation and purification, obtains biological activity poly(lactic acid) product.
In above-mentioned preparation method, described biologically active substance is selected from biologically active polypeptides, oligosaccharide, dna fragmentation or medicine.
In above-mentioned preparation method, the separation purification method of product adds and precipitates in the aqueous solution for after adopting the tetrahydrofuran solvent dissolving, and the collecting precipitation thing carries out vacuum-drying.
In above-mentioned preparation method, the add-on of organic diamine or glycol or azanol or water or polyoxyethylene glycol be in the polydactyl acid maleic anhydride mole dosage 1～50%, temperature of reaction is 0～100 ℃, the time is 10 minutes～24 hours.
In above-mentioned preparation method, organic crosslinking agent is binary or polybasic carbon imines, isocyanic ester, epoxy compounds, organometallic compound, imide or ester.
In above-mentioned preparation method, the amount of the biologically active substance that adds be in the polydactyl acid maleic anhydride mole dosage 1～50%, temperature of reaction is-20～60 ℃, time is 10 minutes～48 hours, pH value scope is 5～9, reaction process is selected the catalyzer of its feature according to the linking agent kind of using.
The biological activity poly(lactic acid) that adopts method for preparing mainly is the timbering material as organizational project, the targeted carrier material of medicament slow release or the medicine of making high molecular.
Description of drawings
Fig. 1 is the LS-50B spectrophotofluorometer test of adopting U.S. Perkin-Elmer company, with the fluorescein-labeled antibiotin of FITC (also being avidin) mark and use H
2The vitamin H polydactyl acid (1) after the separation and purification of O/THF mixed solvent and the fluorescence emission spectrogram of organic diamine polydactyl acid (2).
Embodiment
Embodiment 1: get the maleic anhydride modified poly(lactic acid) (MPLA) that raw material 100 grams adopt 10% weight ratio, be dissolved among the 400ml THF, again this solution is added in the 12 gram hydroxyl methylamines, reaction is 10 minutes under room temperature, product is after the separation and purification drying, be dissolved in again in THF (tetrahydrofuran (THF))/DMF (dimethyl formamide) (3: 1) mixed solvent of 400ml, with 25 gram molecular weights is 1 of 1000 polyoxyethylene glycol and 8 grams, 6-hexamethylene diisocyanate (HDI) is dissolved in the mixed solvent, three kinds of compositions are mixed the back to react 2 hours down at 60 ℃, product is after separation and purification, dissolve with mixed solvent, add with mixed solvent dissolved 50 gram semi-lactosis (a kind of glucide that can be discerned by hepatic tissue), reacted 2 hours in 60 ℃, product is the poly(lactic acid) of grafting semi-lactosi.
Embodiment 2: get the maleic anhydride modified poly(lactic acid) (MPLA) that raw material 100 grams adopt 5% weight ratio, be dissolved among the 400ml THF, this solution is added in the distilled water again, collecting precipitation in 8 hours is after drying again with 400ml THF dissolving.Adding 14 gram N-hydroxy-succinamides and 5 gram DCC at room temperature placed 20 hours 0 ℃ of reaction in 2 hours again, product is removed post precipitation after filtration and is added with anti-knurl amino acid (a kind of cancer therapy drug of 50ml THF dissolved 60 grams, act on chronic myelocytic leukemia), at room temperature react 20 hours product, be the anti-knurl amino acid of high molecular after this product separation and purification.
Embodiment 3: get the maleic anhydride modified poly(lactic acid) (MPLA) that raw material 100 grams adopt 15% weight ratio, be dissolved among the 400ml THF, add butanediamine 35 grams, reaction is 60 minutes under room temperature, product is after the separation and purification drying, mixed solvent dissolving with 400ml THF/DMF (3: 1), again respectively with 50ml and 100ml this mixed solvent dissolving 30 gram DCC and 300 gram Collagen Hydrolysates, three kinds of compositions are mixed the back in-20 ℃ of reactions 24 hours, room temperature reaction got reaction product in 24 hours, was the poly(lactic acid) of Collagen Hydrolysate modification after this product separation and purification.
Embodiment 4: get the maleic anhydride modified poly(lactic acid) (MPLA) that raw material 100 grams adopt 5% weight ratio, be dissolved among the 400ml THF, this solution is added in the sodium hydroxide solution of 0.01N again, collecting precipitation in 2 hours is after drying again with 400ml THF dissolving.Add again with 100ml THF dissolved 30 gram DCC and interferon gene 0.02 and restrain in 0 ℃ of reaction 24 hours, and be 8-9 with the pH value of N-first class morpholine regulator solution, room temperature reaction 12 hours, after the separation and purification product, the poly(lactic acid) of gene fragment that this product has been grafting.
Embodiment 5: get the maleic anhydride modified poly(lactic acid) (MPLA) that raw material 100 grams adopt 5% weight ratio, be dissolved among the 200ml THF, add quadrol 8 grams, reaction is 30 minutes under room temperature, product is after the separation and purification drying, with 200ml THF dissolving, the F of the 10ml DMSO (methyl-sulphoxide) of adding usefulness again dissolved IgG antibody (ab ')
2Fragment and 15 grams 1,2,5,6-diepoxy hexane is 9 with the pH value of N-first class morpholine regulator solution, and reacts 4 hours in 50 ℃, must product after the separation and purification, the poly(lactic acid) of antibody that this product has been grafting.
Embodiment 6: get the maleic anhydride modified poly(lactic acid) (MPLA) that raw material 100 grams adopt 10% weight ratio, be dissolved among the 400ml THF, this solution is added in the distilled water again, collecting precipitation in 5 hours dissolves with 400mlTHF after drying again.The aqueous solution and the 1ml that add the 5ml weight ratio respectively and be 1% basic aluminium sulphate contain the endothelial cell growth factor (ECGF) aqueous solution that concentration is 5PPM, 40 ℃ of reactions 2 hours, after the separation and purification product, the poly(lactic acid) of endothelial cell growth factor (ECGF) that this product has been grafting.
Embodiment 7: get the maleic anhydride modified poly(lactic acid) (MPLA) that raw material 100 grams adopt 10% weight ratio, be dissolved among the 400ml THF, again this solution is added 90 gram molecular weights and is 300 α, the amino polyoxyethylene glycol that replaces of ω was in 60 ℃ of reactions 4 hours, product is after the separation and purification drying, mixed solvent dissolving with 400ml THF/DMF (3: 1), again respectively with 50ml and 100ml this mixed solvent dissolving 10 gram DCC and 3 gram anti-CD 33 monoclonal antibodies, three kinds of compositions are mixed the back in 0 ℃ of reaction 24 hours, room temperature reaction 24 hours, get product, the poly(lactic acid) of anti-CD 33 monoclonal antibody that this product has been grafting after the separation and purification.
Embodiment 8: get the maleic anhydride modified poly(lactic acid) (MPLA) that raw material 100 grams adopt 15% weight ratio, be dissolved among the 400ml THF, add 5 gram type-IV collagenase-resisting monoclonal antibody 3G11, in 60 ℃ of reactions 4 hours, get product, the poly(lactic acid) of type-IV collagenase-resisting monoclonal antibody 3G11 that this product has been grafting after the separation and purification.
Above-mentioned maleic anhydride modified poly(lactic acid) (MPLA) adopts among the patent 01129046.X and relates to product.
The invention effect proves: referring to Fig. 1, the employing vitamin H is a reaction raw materials, through this inventive method, has prepared the poly(lactic acid) of vitamin H modification.Product with the separating for several times purifying after, dissolve with tetrahydrofuran (THF) (THF), adopt the fluorescein-labeled antibiotin of FITC (also to claim avidin, Sigma company product) mark (marking method is by the explanation of this test kit), after the separation and purification, the fluorescence emission spectrogram of the poly(lactic acid) of plain polydactyl acid of the LS-50B spectrophotofluorometer test organisms of employing U.S. Perkin-Elmer company and organic diamine modification.As can be seen from the figure vitamin H polydactyl acid (1) has tangible emission peak about 510nm, and it is the feature emission peak of FITC, and is then not obvious on the poly(lactic acid) (2) of organic diamine modification.Proof is through this inventive method, and vitamin H is grafted on the poly(lactic acid).
Claims (8)
1. the preparation method of a biological activity poly(lactic acid) ties up on the basis of maleic anhydride modified poly(lactic acid), adopts the following steps preparation: 1. directly add organic diamine or glycol or azanol or water and react; 2. product under the effect of organic crosslinking agent, adds the bio-active substance qualitative response after separation and purification, obtains biological activity poly(lactic acid) product.
2. the preparation method of biological activity poly(lactic acid) according to claim 1 is characterized in that: step 2. in, product also can be under the effect of organic crosslinking agent after separation and purification, adds the reaction of polyoxyethylene glycol or derivatives thereof earlier; Then, 3. product under the effect of organic crosslinking agent, adds the bio-active substance qualitative response again after separation and purification, obtains biological activity poly(lactic acid) product.
3. preparation method as claimed in claim 1 or 2 is characterized in that: described biologically active substance is selected from biologically active polypeptides, oligosaccharide, dna fragmentation or medicine.
4. preparation method as claimed in claim 1 or 2 is characterized in that: the separation purification method of product adds and precipitates in the aqueous solution for after adopting the tetrahydrofuran solvent dissolving, and the collecting precipitation thing carries out vacuum-drying.
5. preparation method as claimed in claim 1 or 2, it is characterized in that: the add-on of organic diamine or glycol or azanol or water or polyoxyethylene glycol be in the polydactyl acid maleic anhydride mole dosage 1～50%, temperature of reaction is 0～100 ℃, and the time is 10 minutes～24 hours.
6. preparation method as claimed in claim 1 or 2 is characterized in that: organic crosslinking agent is binary or polybasic carbon imines, isocyanic ester, epoxy compounds, organometallic compound, imide or ester.
7. preparation method as claimed in claim 1 or 2, it is characterized in that: the amount of the biologically active substance of adding be in the polydactyl acid maleic anhydride mole dosage 1～50%, temperature of reaction is-20～60 ℃, time is 10 minutes～48 hours, pH value scope is 5～9, reaction process is selected the catalyzer of its feature according to the linking agent kind of using.
8. press the application of the biological activity poly(lactic acid) of the described method preparation of claim 1, it is characterized in that: as the timbering material of organizational project, the targeted carrier material of medicament slow release or the medicine of making high molecular.
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