CN101862454A - Physical cross-linking hydrogel composition and preparation method and application thereof - Google Patents
Physical cross-linking hydrogel composition and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of macromolecular materials and medicaments, and relates to a physical cross-linking hydrogel composition and a preparation method and application thereof. The composition is a mixture of two or more polymers, and the aqueous system of the composition has the temperature-sensitive reversible gelling property; when the temperature is lower than a sol-gel conversion temperature, the mixture can be dissolved in water; and when the temperature is higher than the sol-gel conversion temperature, the aqueous solution of the mixture forms gel, and the process is reversible, wherein the polymers comprise a block copolymer consisting of polyethylene glycol serving as a hydrophilic block and degradable polyester serving as a hydrophobic block. The aqueous solution of the composition can be applied to warm-blooded animals through non-stomach intestinal tract, eye, subcutaneous, muscle, vagina, urethra, nasal cavity or lung, forms gel at physiological related temperature, and also can be applied in a gel form. The release speed can be regulated by changing the mixing proportion, polymer composition, molecular weight and polydispersity.
Description
Technical field
The invention belongs to macromolecular material and medical technical field, relate to hydrogel composition of a kind of physical crosslinking and preparation method thereof, be specifically related to physical cross-linking hydrogel that has the heat-convertible gel performance and preparation method thereof, and this hydrogel is in the application of aspects such as parenteral route, eyes, subcutaneous, muscle administration.
Background technology
In recent years, along with biotechnology and engineered development, many polypeptides medicine commercializations with pharmacologically active.Yet easily by the degraded of the digestive enzyme in the gastrointestinal tract, biological half-life is short, makes that their route of administration is relatively limited, generally can only carry out administration by vein, muscle, hypodermic approach for polypeptide or pharmaceutical grade protein.Studies show that in the solvent of routine, the dissolubility of polypeptide or pharmaceutical grade protein or stability are limited, are difficult to preparation and administration.In order to overcome the deficiency that the conventional medicament dosage form exists, new delivery system (Drug Delivery System is called for short DDS) is developed in order to satisfy patient's demand.Usually, the DDS system can be at a fixed time in, discharge medicine according to predetermined direction continuously at whole body or certain organs, and control blood drug level increases bioavailability of medicament between minimal effective concentration and poisoning concentration, reduce the toxic and side effects of medicine, improve the compliance of patient's medication, wherein, degradable, high performance drug carrier material promotes and guaranteeing role for the slow/controlled release of realizing medicine plays.
At present, be to study the most transplantable and degradable slow releasing carrier of medication with polylactic acid (PLA), polyglycolic acid (PGA), their copolymer (PLGA) and polycaprolactone (PCL) solid polymer that is representative thereof.Because these polymer itself are hydrophobic, use in the process of these materials and use such as deleterious organic solvents such as dichloromethane, chloroforms inevitably.And the use of organic solvent causes fully removing thereafter and becomes very difficult, and remaining organic solvent can produce deleterious side effect, as carcinogenecity, neurotoxicity, teratogenecity etc.Various countries' pharmacopeia has all clearly been stipulated the maximum of the organic solvent that allows in medicine.Stipulate as American Pharmacopeia (USP): residual dichloromethane＜500ppm, chloroform＜50ppm.Simultaneously, for the polymer solids device of these transplanting, its migration process will inevitably bring because the caused wound of operation.Injectable polyesters microsphere (as the PLGA microsphere) can't be avoided the use of organic solvent equally though need not operation transplantation.
Bibliographical information is arranged, used the transplantable delivery system of injectable of low toxicity organic solvent, be equal to the organic solvent that medicine is dissolved in low toxicity together as PLA, PLGA, PCL, such as methyl pyrrolidone (NMP), dimethyl sulfoxine (DMSO), ethyl acetate etc., obtain concentration 30-70% polymer solution; After being subcutaneously injected in the body, because solvent exchanges with body fluid on every side, the polymer precipitation that has wrapped up medicine gets off to obtain the transplantation device (Dunn et al, U.S. Patent No. 4938763) of original position.This system is proper to dewatering medicament, but still makes its inactivation concerning pharmaceutical grade protein easily.The device that above-mentioned system obtains has random form and itself solid rigidity causes fierce tissue reaction easily.The difference of precipitation process Chinese medicine distribution simultaneously can cause different release modes, and the untimely of infall process also can cause tangible burst effect.
Semisolid oligomerization ester (M
wLess than 5500) be another kind of injectable carrier system (Loskos et al, Biomaterials, 1995,16,313-317).When high temperature,, be expelled in the body, along with decrease of temperature forms gel preparation hydrophobic medicine and oligomerization ester mix homogeneously.This is actually a kind of gel injection system.Owing to face the inefficacy that high temperature in the medicine encapsulation process may cause drug molecule, operate this system and must control carefully.
Hydrogel be a kind of can be in water swelling, and undissolved polymer network; Its inside is filling a large amount of aqueous solutions, and is very similar with the body tissue of exuberant a large amount of body fluid, so hydrogel has excellent biological compatibility, also becomes a kind of original slow releasing carrier of medication material.In recent years, the hydrogel material of injectable heat-sensitive gelization has caused people's special concern, it has sol-gel transition temperature (sol-gel transition temperature), when this transition temperature is suitable, it exists with solution state in room temperature or when being lower than room temperature, can embedding such as bioactive substances such as medicine, cell under this state; When be injected in subcutaneous or muscular tissue after because temperature raises, make the solution that is embedded with medicine change gel rapidly into; Promote down by diffusion and/or gel self Degradation, medicine can discharge stably from gel inside, thereby reaches the purpose of slow release.The transition process that this type of material is finished sol-gel is the reversible process of a physical change, does not relate to organic solvent, also need not chemical reaction, so toxicity is low, blandness.Such polymeric material is generally amphipathic block, can self assembly in water forms micelle or nanoparticle, and the therefore effective hydrophobic drug molecule of solubilising is for the administration of insoluble drug provides solution.Copolymer with polyethylene glycol oxide (PEO)-polypropylene oxide (PPO)-polyethylene glycol oxide (PEO) of suitable molecular weight and composition (is also referred to as poloxamer, Poloxamer) be the material that a class has the heat-convertible gel performance, but this material can not biodegradation, and can only exist a couple of days promptly by body fluid dilution dissolving in vivo, the medicine that can provide continues the limited time of release.
Research is arranged by introducing degradable group or component in the polymeric material of temperature sensitive property, obtain degradable and temperature sensitive physical hydrogel material, and use this type of material in fields such as medicament slow release and organizational projects.At present, the research for degradable and temperature sensitive polymer comprises that mainly (R.C. draws think of etc. to triblock polyester-ethylene glycol copolymer: Chinese patent patent No. ZL99812495.8) etc.This base polymer has single composition and molecular weight distribution, has the performance of heat-convertible gelization under the finite concentration.
But still there are the following problems for this based block copolymer of one-component:
(1) exceeds the size of definite composition and/or molecular weight, just be merely able to water-soluble fully or partially or completely become precipitation, thereby lost sol-gel transition, no longer have a performance of relevant heat-sensitive gelization;
(2) in addition, even sensitive characteristic can appear in partial polymer, the also improper human body of its gelling temperature is used;
(3) range of accommodation of its degradation rate and dynamic process have certain limitation, have limited its medical usage.
Summary of the invention
The objective of the invention is to overcome the defective of prior art, hydrogel composition of a kind of physical crosslinking and preparation method thereof is provided, be specifically related to hydrogel material of a kind of degradable heat-convertible gelization with extensive controllability and preparation method thereof, such material has good biocompatibility, can be extensively as injectable slow releasing carrier material.
Further purpose of the present invention is to provide a kind of temperature sensitive injectable slow/controlled release drug-supplying system, is used for hydrophilic and hydrophobic drug, protein and polypeptide, nucleic acid/gene, hormone and antitumor drug gastrointestinal tract external administration.
Particularly, the invention provides the hot reversible hydrogel that a class is made up of mixture of polymers.The hydrogel composition of heat-convertible gelization of the present invention, it is two or more mixture of polymers, its aqueous systems has the character of temperature-sensitive and reversible gelation, when temperature is lower than the sol-gel transition temperature, polymeric blends is dissolvable in water water, when temperature was higher than the sol-gel transition temperature, the aqueous solution of polymeric blends formed gel, and this process is reversible; Comprise in the polymer wherein that be the block copolymer that hydrophobic block constituted by Polyethylene Glycol (PEG) for hydrophilic block, degradable polyester.
Have the aqueous systems of one or more block copolymers not have the character of heat-convertible gelization separately in the polymeric blends of the present invention, this all can only be dissolved in the water these one or more block copolymers in 1-50 ℃ of scope thereby heat-convertible gelization can not occur separately; Perhaps, one or more block copolymers can not be water-soluble in 1-50 ℃ of scope or can not be dissolved in the water fully thereby heat-convertible gelization can not occur separately.
One or more block copolymers originally all can only be dissolved in the water in 1-50 ℃ of scope in the polymeric blends of the present invention, simultaneously, another or more than one block copolymers can not be water-soluble in 1-50 ℃ of scope or can not be dissolved in the water fully.
The aqueous systems of each block copolymer in the polymeric blends of the present invention can all not have the character of heat-convertible gelization yet.
The weight percent content of every kind of block copolymer is between 5-95% in the polymeric blends of the present invention.
Block copolymer of the present invention comprises that containing of 10-90wt% has the hydrophilic A polymer blocks of Polyethylene Glycol of 400 to 8000 mean molecule quantity and the hydrophobicity B polymer blocks of 90-10wt%.
Hydrophobicity B polymer blocks of the present invention is the polyester with mean molecule quantity of 500-40000.
Polyester of the present invention is selected from any type of copolymer of any and above-mentioned each kind polyester in various poly DL-lactides, poly-D-lactide, poly-L-lactide, poly-Acetic acid, hydroxy-, bimol. cyclic ester, poe, poly-epsilon-caprolactone, poly-ε-alkyl replacement caprolactone, poly-δ-Wu Neizhi, polyesteramide, Merlon, polyacrylate, the polyether ester.
Block copolymer of the present invention is the triblock copolymer of ABA, BAB block configuration, the diblock copolymer and the A (BA) of BA block configuration
nOr B (AB)
nThe segmented copolymer of block configuration, wherein n is 2 to 10 integer.
In the system of polymeric blends of the present invention and solvent, except block copolymer and solvent, the polymer that can comprise other type is or/and the non-polymer composition.
The weight percent content of polymeric blends of the present invention in aqueous solution is between 3-50%.
Solvent in the polymeric blends solution of the present invention can be body fluid, tissue culture medium or the cell culture fluid of pure water, normal saline, buffer solution, animals and plants or human body, and other aqueous solution and not based on the medium of organic solvent.
Hydrogel composition of the present invention prepares by following method:
At first mix two or more polymer, then at the dissolution in low temperature polymeric blends in water; Perhaps at first dissolve two or more polymer respectively, mix aqueous solution separately then at low temperature; Perhaps at first have water miscible polymer, and then add and not have or not exclusively to have water miscible polymer and carry out solubilising, the preparation hydrogel composition at dissolution in low temperature.The above low temperature refers to be lower than the sol-gel transition temperature of compositions.The aqueous solution of prepared polymeric blends can hot reversible formation hydrogel when temperature is higher than the sol-gel transition temperature.
In the said method, low temperature refers to 0 ℃ to room temperature.
In the said method, low temperature refers in particular to refrigerator cold-storage temperature (4 ℃).
In the said method, polymer is for being that hydrophilic block, degradable polyester are the block copolymer that hydrophobic block constituted by Polyethylene Glycol (PEG).
In the said method, block copolymer obtains by thermal condensation or ring-opening polymerisation.
In the said method, the catalyst that ring-opening polymerisation is adopted is stannous iso caprylate, calcium hydride or zinc powder.
In the said method, have the aqueous systems of one or more block copolymers not have the character of heat-convertible gelization separately in the mixture, this all can only be dissolved in the water these one or more block copolymers in 1-50 ℃ of scope thereby heat-convertible gelization can not occur separately; Perhaps, one or more block copolymers can not be water-soluble in 1-50 ℃ of scope or can not be dissolved in the water fully thereby heat-convertible gelization can not occur separately.
In the said method, this can only be dissolved in the water one or more block copolymers in the mixture in 1-50 ℃ of scope, and simultaneously, another or more than one block copolymers can not be water-soluble in 1-50 ℃ of scope or can not be dissolved in the water fully.
In the said method, the aqueous systems of each block copolymer in the mixture does not have the character of heat-convertible gelization separately.
In the said method, the weight percent content of every kind of block copolymer in the mixture is between 5-95%.
In the said method, block copolymer comprises:
A) the hydrophilic A polymer blocks that contains Polyethylene Glycol of 10-90wt% with mean molecule quantity of 400 to 8000;
B) the hydrophobicity B polymer blocks of 90-10wt%.
In the said method, hydrophobicity B polymer blocks is the polyester with mean molecule quantity of 500-40000.
In the said method, polyester is selected from any type of copolymer of any and above-mentioned each kind polyester in various poly DL-lactides, poly-D-lactide, poly-L-lactide, poly-Acetic acid, hydroxy-, bimol. cyclic ester, poe, poly-epsilon-caprolactone, poly-ε-alkyl replacement caprolactone, poly-δ-Wu Neizhi, polyesteramide, Merlon, polyacrylate or the polyether ester.
In the said method, block copolymer is the triblock copolymer of ABA, BAB block configuration, the diblock copolymer or the A (BA) of BA block configuration
nOr B (AB)
nThe segmented copolymer of block configuration, wherein n is 2 to 10 integer.
In the said method, the weight percentage of polymeric blends in aqueous solution is between 3-50%.
In the said method, the solvent in the polymeric blends solution can be body fluid, tissue culture medium or the cell culture fluid of pure water, normal saline, buffer solution, animals and plants or human body, and other aqueous solution and not based on the medium of organic solvent.
In the said method, the ratio of block copolymer can be regulated, thereby obtains needed sol-gel transition temperature and degradation rate etc.
In the said method, can in containing the mixture of block copolymer, further mix the polymer even the non-polymer composition of other types, with the appearance that promotes physical gel or be adjusted in the sol-gel transition temperature in the solution, the parameters such as degradation rate of material.
In a kind of temperature sensitive injectable slow/controlled release drug-supplying system that constitutes by polymeric blends solution and the medicine that evenly is contained in effective dose wherein of the present invention, polymeric blends is that two or more polymer mixed forms, wherein contain by Polyethylene Glycol (PEG) and be hydrophilic block, degradable polyester is the block copolymer that hydrophobic block constituted, its aqueous systems has the character of temperature-sensitive and reversible gelation, when temperature is lower than the sol-gel transition temperature, polymeric blends is dissolvable in water water, when temperature was higher than the sol-gel transition temperature, the aqueous solution of polymeric blends formed gel.
In a kind of injectable slow/controlled release drug-supplying system that constitutes by polymeric blends solution and medicine of the present invention, medicine is hydrophilic medicament or hydrophobic drug, can be in protein, polypeptide, nucleic acid, gene, hormone and the antitumor drug one or more.
In a kind of injectable slow/controlled release drug-supplying system that is made of polymeric blends solution and medicine of the present invention, medicine can be a hydrophilic medicament, also can be hydrophobic drug or their mixture.
The weight percent content of polymeric blends in aqueous solution is between 3-50% in the temperature sensitive injectable slow/controlled release drug-supplying system of the present invention.
Solvent in the temperature sensitive injectable slow/controlled release drug-supplying system of the present invention in the polymeric blends solution can be body fluid, tissue culture medium, the cell culture fluid of pure water, normal saline, buffer solution, animals and plants or human body, and other aqueous solution and not based on the medium of organic solvent.
In the temperature sensitive injectable slow/controlled release drug-supplying system of the present invention, medicine can partially or completely dissolve at polymeric blends solution.When drug moiety dissolving or when not dissolving substantially, can be to mix or emulsion form exists with outstanding.
Temperature sensitive injectable slow/controlled release drug-supplying system of the present invention can pass through parenteral route, eyes, subcutaneous, muscle, vagina, urethra, nasal cavity or lung drug administration by injection, produce part or whole body therapeutic effect, wherein the drug loading of drug-supplying system is unrestricted, unless the behavior of the physical gelization of impact polymer mixture makes it can not form gel.
The invention has the advantages that:
The hydrogel material that the present invention proposes has reversible temperature sensitive property, when can or being lower than room temperature at room temperature, its polymeric blends shows water solublity, and under the warm-blooded animal physiological condition (promptly pH value be about 7 and 37 ℃ under) can carry out reversible gelization, thereby make that the preparation process of drug-supplying system is simple, make things convenient for administration.
What the present invention proposed has obviously expanded the scope of application of corresponding block copolymer based on the thermo-sensitive material of mixture, make many be dissolved in fully in the water and do not present the polymer of heat-sensitive gelization and in water precipitation and the polymer that do not present heat-sensitive gelization the gel phenomenon that does not originally possess occurred by blended mode, be convenient to medical application.
Even for the material that can present heat-sensitive gelization originally in water, the blended method that the present invention proposes also provides the method for an easy adjusting gelation transition temperature; And as syringeability reversible heat-sensible medical material, its sol-gel transition temperature wishes to be between 0-37 ℃, and is significant on medical applications like this.
The hydrogel material that the present invention proposes has the compliance of excellent biological compatibility, degradability and gel, and this material can be degraded to nontoxic α-alkyd and other corresponding monomer fully in preset time.
The hydrogel material that the present invention proposes can increase the dissolubility of part insoluble drug, improves stability of drug.
In the temperature sensitive injectable slow/controlled release drug-supplying system that the present invention proposes the rate of release of the degradation rate of material and medicine can by change be used for composition itself, the polymer of mixed proportion, the polymer of blended polymer concentration, molecular weight and polydispersity, add other type polymer or the non-polymer composition is regulated.
For the ease of understanding, below will describe in detail of the present invention by concrete drawings and Examples.It needs to be noted, instantiation and accompanying drawing only are in order to illustrate, obviously those of ordinary skill in the art can illustrate according to this paper, within the scope of the invention the present invention is made various corrections and change, and these corrections and change are also included in the scope of the present invention.
Description of drawings
The phasor of its aqueous solution of block copolymer mixture that Fig. 1 obtains according to the Different Weight mixed for explanation during along with variations in temperature measured with the tubule anastrophe.
Fig. 2 is the release profiles of explanation lysozyme from the triblock copolymer mixture hydrogel that different part by weight mixing obtain.
The specific embodiment
Embodiment 1
In the 250ml there-necked flask, add PEG (1500), oil bath is heated to 150 ℃, vacuum filtration is three hours under stirring, to remove residual moisture among the PEG, add mol ratio then and be 4: 1 DL-lactide and Acetic acid, hydroxy-, bimol. cyclic ester, heating makes after its complete fusion under the vacuum, adds 120 μ l stannous octoates, oil bath is warmed up to 160 ℃, continues reaction 24 hours under argon gas atmosphere.Reaction finishes, and vacuum filtration two hours is to remove responseless monomer and lower boiling product.Head product is dissolved in the dichloromethane solution, ether sedimentation, productive rate is about 80%.Measure described BAB block copolymer (PLGA-PEG-PLGA, number average Copolymer-1) and weight average molecular weight (M by chromatograph of gel permeation (GPC) (adopting polystyrene) as standard specimen
n, M
w) be respectively 5510 and 6390, molecular weight distribution coefficient (M
w/ M
n) be 1.16.This does not have the performance of heat-convertible gelization this copolymer in water.
Embodiment 2
In the 250ml there-necked flask, add single-ended methoxy poly (ethylene glycol) MPEG (550), oil bath is heated to 150 ℃, vacuum filtration is three hours under stirring, to remove residual moisture among the MPEG, add mol ratio then and be 3: 1 DL-lactide and Acetic acid, hydroxy-, bimol. cyclic ester, heating makes after its complete fusion under the vacuum, adds 120 μ l stannous octoates, oil bath is warmed up to 160 ℃, continues reaction 24 hours under argon gas atmosphere.Reaction finishes, and vacuum filtration two hours is to remove responseless monomer and lower boiling product.Head product is dissolved in the dichloromethane solution, ether sedimentation, productive rate is about 85%.Measure described BA block copolymer (MPEG-PLGA, number average Copolymer-14) and weight average molecular weight (M by chromatograph of gel permeation (GPC) (adopting polystyrene) as standard specimen
n, M
w) be respectively 3550 and 4620, molecular weight distribution coefficient (M
w/ M
n) be 1.30.This does not have the performance of heat-convertible gelization this copolymer in water.
Embodiment 3
In the 250ml there-necked flask, add Polyethylene Glycol (1000) and PLGA (M
n4750, M
w6020, mixture LA/GA=1/1), heating makes after its complete fusion under the vacuum, and oil bath is warmed up to 160 ℃ of condensation reactions 18 hours.Reaction finishes, and head product is dissolved in the dichloromethane solution, uses a large amount of ether sedimentations, and productive rate is about 85%.Measure the number average and the weight average molecular weight (M of described BAB block copolymer by chromatograph of gel permeation (GPC) (adopting polystyrene) as standard specimen
n, M
w) be respectively 6520 and 8340 (PLGA-PEG-PLGA, Copolymer-15), molecular weight distribution coefficient (M
w/ M
n) be 1.28.This does not have the performance of heat-convertible gelization this copolymer in water.
Embodiment 4
According to the basic step that embodiment 1 provides, synthesize other block copolymer with the PEG of different molecular weight and different monomers.
The block copolymer of table 1 and table 2 does not all have the performance of heat-convertible gelization, and the block copolymer of its invading the exterior 1 just can dissolve in water, and the block copolymer of table 2 can not be dissolved in water or can not be dissolved in water fully; And the block copolymer of table 3 itself just has the performance of heat-convertible gelization.One or more block copolymers can be from table 3, chosen and water can be when temperature is lower than gel transition temperature, be dissolved in the mixture that the certain proportion mixing obtains with from table 1 and/or table 2, choosing one or more block copolymers, when temperature is higher than gel transition temperature, the aqueous solution of polymeric blends forms gel, and this process is reversible; Also can from table 1, choose one or more block copolymers and mix the performance that the mixture that obtains also has heat-convertible gelization with certain proportion with from table 2, choosing one or more block copolymers.
Table 1
Table 2:
Table 3:
Embodiment 5
At first obtain corresponding mixture with block copolymer C opolymer-1 in 1/1 the mixed table 1 and the block copolymer C opolymer-9 in the table 2, add a certain amount of water then, be mixed with weight percent concentration and be 25% sample, pass through magnetic agitation in refrigerator cold-storage temperature (4 ℃) at last, make polymeric blends in water, dissolve the corresponding aqueous solution of preparation.The aqueous solution of the polymeric blends of preparation can spontaneous formation gel when temperature is higher than the sol-gel transition temperature.
Embodiment 6
It at first is the aqueous solution of 12.5% block copolymer C opolymer-1 in room temperature preparation weight percent concentration, and then in above-mentioned aqueous solution, add the block copolymer C opolymer-9 of same percentage by weight, pass through magnetic agitation in room temperature at last, make block copolymer C opolymer-9 solubilising enter solution, prepare corresponding weight percent concentration and be 25% aqueous solution.The aqueous solution of polymeric blends of preparation can spontaneous formation gel when temperature is higher than the sol-gel transition temperature; And gelling performance is identical with the sample of preparation among the embodiment 5.
Embodiment 7
At first be the aqueous solution of the block copolymer C opolymer-16 of the aqueous solution of 25% block copolymer C opolymer-1 and same weight percent concentration, then with the aqueous solution of 1/1 the above-mentioned formulations prepared from solutions corresponding polymer of ratio uniform mixing mixture in refrigerator cold-storage temperature (4 ℃) preparation weight percent concentration.When temperature was higher than the sol-gel transition temperature, the aqueous solution of the polymeric blends of preparation can spontaneous formation gel.
Research and analyse the gelation behavior of triblock copolymer mixture in aqueous solution that block copolymer C opolymer-1 and Copolymer-9 obtain according to the Different Weight mixed.The mixture aqueous solution of the Different Weight percent concentration of preparation from 5% to 25% is measured its viscosity between 0 ℃ to 60 ℃ and is changed.Observing did not flow in 20 seconds when test tube is inverted defines whether gelation.Fig. 1 has shown the phasor when Copolymer-1 and Copolymer-9 Different Weight mixed obtain its variable concentrations aqueous solution of sample along with variations in temperature.
Embodiment 9
Mix with 1/1 part by weight at Copolymer-1 and Copolymer-9 that to obtain concentration be that its sol-gel transition temperature was reduced to 32 ℃ from 34 ℃ when to add percentage by weight in 25% aqueous solution be 2% PEG (2000) polymer.
Embodiment 10
In pH is 7.4 PBS, measured Copolymer-1 and Copolymer-9 and mixed with 1/1 or 1/2 part by weight that to obtain concentration be 25% aqueous solution or gel (1ml) external degradation situation during at 37 ℃.Its hydrolysis by ester bond is degraded, and its degradation cycle is all above 5 weeks, and last product is lactic acid, hydroxyacetic acid and Polyethylene Glycol.
Embodiment 11
It is 25% aqueous solution that research observation Copolymer-1 and Copolymer-9 obtain concentration with the mixing of 1/1 or 1/2 part by weight, and the 20mg lysozyme is dissolved in the above-mentioned aqueous solutions of polymers of 1ml.Behind 37 ℃ of formation gels, adding 8ml pH is 7.4 PBS buffer solution.At set intervals, from test tube, take out 4ml PBS buffer, and add fresh 4mlPBS buffer to keep constancy of volume.The external sustainable release of lysozyme is more than 50 days.Fig. 2 has shown the release profiles of lysozyme from the triblock copolymer mixture hydrogel that different part by weight mixing obtain.
Hydroxy camptothecin and paclitaxel all are hydrophobic drugs, almost insoluble in water, yet the present invention mixes with 1/2 part by weight at Copolymer-1 and Copolymer-9 that to obtain concentration be that the hydroxy-camptothecin alkali solubility is up to 5mg/ml in 25% aqueous solution, and taxol solubility is up to 7mg/ml.And after storing 90 days, all have the former medicine more than 85% to be maintained, stability of drug is significantly increased.
Embodiment 13
The concentration of block copolymer C opolymer-16 in the table 3 is that sol-gel transition takes place in the time of 11 ℃ 25% aqueous solution, forms hydrogel; 25% aqueous solution of Copolymer-1 does not have the performance of heat-sensitive gelization; Mix above-mentioned two kinds of samples that solution obtains with different part by weight, its sol-gel transition temperature can be regulated between 11～37 ℃.
Claims (32)
1. the hydrogel composition of a physical crosslinking, it is characterized in that, by two or more polymer mixed composition mixture, its aqueous systems has the character of temperature-sensitive and reversible gelation, when temperature is lower than the sol-gel transition temperature, this mixture is dissolvable in water water, and when temperature was higher than the sol-gel transition temperature, the aqueous solution of this mixture formed gel; Comprise by Polyethylene Glycol being that hydrophilic block, degradable polyester are the block copolymer that hydrophobic block constituted in the polymer wherein.
2. the hydrogel composition of physical crosslinking according to claim 1 is characterized in that, has the aqueous systems of one or more block copolymers not have the character of heat-convertible gelization separately in the described mixture.
3. the hydrogel composition of physical crosslinking according to claim 2, it is characterized in that, in the described mixture, this can only be dissolved in the water one or more block copolymers in 1-50 ℃ of scope, heat-convertible gelization can not occur separately, perhaps can not be water-soluble or can not be dissolved in the water fully, heat-convertible gelization can not occur separately.
4. the hydrogel composition of physical crosslinking according to claim 2, it is characterized in that, in the described mixture, this can only be dissolved in the water one or more block copolymers in 1-50 ℃ of scope, simultaneously, another or more than one block copolymers can not be water-soluble in 1-50 ℃ of scope or can not be dissolved in the water fully.
5. the hydrogel composition of physical crosslinking according to claim 1 is characterized in that, the aqueous systems of each block copolymer in the described mixture does not have the character of heat-convertible gelization separately.
6. the hydrogel composition of physical crosslinking according to claim 1 is characterized in that, the weight percent content of every kind of block copolymer in the described mixture is between 5-95%.
7. the hydrogel composition of physical crosslinking according to claim 1 is characterized in that, described block copolymer comprises:
A) the hydrophilic A polymer blocks that contains Polyethylene Glycol of 10-90wt% with mean molecule quantity of 400 to 8000;
B) the hydrophobicity B polymer blocks of 90-10wt%.
8. the hydrogel composition of physical crosslinking according to claim 7 is characterized in that, described hydrophobicity B polymer blocks is the polyester with mean molecule quantity of 500-40000.
9. the hydrogel composition of physical crosslinking according to claim 8, it is characterized in that described polyester is selected from any type of copolymer of any and above-mentioned each kind polyester in various poly DL-lactides, poly-D-lactide, poly-L-lactide, poly-Acetic acid, hydroxy-, bimol. cyclic ester, poe, poly-epsilon-caprolactone, poly-ε-alkyl replacement caprolactone, poly-δ-Wu Neizhi, polyesteramide, Merlon, polyacrylate or the polyether ester.
10. the hydrogel composition of physical crosslinking according to claim 1 is characterized in that, described block copolymer is the triblock copolymer of ABA, BAB block configuration, the diblock copolymer or the A (BA) of BA block configuration
nOr B (AB)
nThe segmented copolymer of block configuration, wherein n is 2 to 10 integer.
11. the hydrogel composition of physical crosslinking according to claim 1 is characterized in that, the weight percentage of described mixture in aqueous solution is between 3-50%.
12. the hydrogel composition of physical crosslinking according to claim 1, it is characterized in that, solvent in the described mixture solution is selected from body fluid, tissue culture medium or the cell culture fluid of pure water, normal saline, buffer solution, animals and plants or human body, and other aqueous solution and not based on the medium of organic solvent.
13. the preparation method of the hydrogel composition of a physical crosslinking is characterized by and comprises the steps:
At first mix two or more polymer, then at the dissolution in low temperature mixture in water; Perhaps at first dissolve two or more polymer respectively, mix aqueous solution separately then at low temperature; Perhaps at first have water miscible polymer, and then add and not have or not exclusively to have water miscible polymer and carry out solubilising, the preparation hydrogel composition at dissolution in low temperature; Described low temperature is the sol-gel transition temperature that is lower than compositions; The aqueous solution of prepared mixture can hot reversible formation hydrogel when temperature is higher than the sol-gel transition temperature.
14. preparation method according to claim 13 is characterized in that, described low temperature is 0 ℃ and arrives room temperature.
15. preparation method according to claim 13 is characterized in that, described low temperature is the refrigerator cold-storage temperature.
16. preparation method according to claim 13 is characterized in that, described polymer is for being that hydrophilic block, degradable polyester are the block copolymer that hydrophobic block constituted by Polyethylene Glycol.
17. preparation method according to claim 13 is characterized in that, described polymer makes by thermal condensation or ring-opening polymerisation.
18. preparation method according to claim 13 is characterized in that, has the aqueous systems of one or more block copolymers not have the character of heat-convertible gelization separately in the described mixture.
19. preparation method according to claim 13, it is characterized in that, in the described mixture, this can only be dissolved in the water one or more block copolymers in 1-50 ℃ of scope, heat-convertible gelization can not occur separately, perhaps can not be water-soluble or can not be dissolved in the water fully, heat-convertible gelization can not occur separately.
20. preparation method according to claim 13, it is characterized in that, in the described mixture, this can only be dissolved in the water one or more block copolymers in 1-50 ℃ of scope, simultaneously, another or more than one block copolymers can not be water-soluble in 1-50 ℃ of scope or can not be dissolved in the water fully.
21. preparation method according to claim 13 is characterized in that, the aqueous systems of each block copolymer in the described mixture does not have the character of heat-convertible gelization separately.
22. preparation method according to claim 13 is characterized in that, the weight percent content of every kind of block copolymer in the described mixture is between 5-95%.
23. preparation method according to claim 13 is characterized in that, described block copolymer comprises:
A) the hydrophilic A polymer blocks that contains Polyethylene Glycol of 10-90wt% with mean molecule quantity of 400 to 8000;
B) the hydrophobicity B polymer blocks of 90-10wt%.
24. the preparation method of hydrogel composition according to claim 23 is characterized in that, described hydrophobicity B polymer blocks is the polyester with mean molecule quantity of 500-40000.
25. preparation method according to claim 24, it is characterized in that described polyester is selected from any type of copolymer of any and above-mentioned each kind polyester in various poly DL-lactides, poly-D-lactide, poly-L-lactide, poly-Acetic acid, hydroxy-, bimol. cyclic ester, poe, poly-epsilon-caprolactone, poly-ε-alkyl replacement caprolactone, poly-δ-Wu Neizhi, polyesteramide, Merlon, polyacrylate or the polyether ester.
26. preparation method according to claim 13 is characterized in that, described block copolymer is the triblock copolymer of ABA, BAB block configuration, the diblock copolymer or the A (BA) of BA block configuration
nOr B (AB)
nThe segmented copolymer of block configuration, wherein n is 2 to 10 integer.
27. preparation method according to claim 13 is characterized in that, the weight percentage of described mixture in aqueous solution is between 3-50%.
28. preparation method according to claim 13, it is characterized in that, solvent in the described mixture solution can be body fluid, tissue culture medium or the cell culture fluid of pure water, normal saline, buffer solution, animals and plants or human body, and other aqueous solution and not based on the medium of organic solvent.
29. temperature sensitive injectable slow/controlled release drug-supplying system that constitutes by polymeric blends solution and medicine, it is characterized in that, described mixture is the described mixture of claim 1, and described medicine is one or more in protein, polypeptide, nucleic acid, gene, hormone and the antitumor drug.
30. temperature sensitive injectable slow/controlled release drug-supplying system according to claim 29 is characterized in that the weight percentage of described mixture in aqueous solution is between 3-50%.
31. temperature sensitive injectable slow/controlled release drug-supplying system according to claim 29, it is characterized in that, solvent in the described mixture solution is body fluid, tissue culture medium or the cell culture fluid of pure water, normal saline, buffer solution, animals and plants or human body, and other aqueous solution and not based on the medium of organic solvent.
32. temperature sensitive injectable slow/controlled release drug-supplying system according to claim 29, it is characterized in that, described drug-supplying system is by parenteral route, eyes, subcutaneous, muscle, vagina, urethra, nasal cavity or lung drug administration by injection, wherein the drug loading of drug-supplying system is unrestricted, unless influence the behavior of the physical gelization of mixture, make it can not form gel.
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