CN101862454B - 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
- Publication number
- CN101862454B CN101862454B CN2009100496646A CN200910049664A CN101862454B CN 101862454 B CN101862454 B CN 101862454B CN 2009100496646 A CN2009100496646 A CN 2009100496646A CN 200910049664 A CN200910049664 A CN 200910049664A CN 101862454 B CN101862454 B CN 101862454B
- Authority
- CN
- China
- Prior art keywords
- block
- gel
- water
- temperature
- copolymer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Landscapes
- Medicinal Preparation (AREA)
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 the aspects such as parenteral route, eyes, subcutaneous, muscle administration.
Background technology
In recent years, along with biotechnology and engineered development, many commercializations of polypeptides/proteins medicine with pharmacologically active.Yet easily by the degraded of the digestive enzyme in the gastrointestinal tract, biological half-life is short, so 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.The deficiency that exists in order to overcome the conventional medicament dosage form, new delivery system (Drug Delivery System is called for short DDS) is developed to satisfy patient's demand.Usually, the DDS system can be at a fixed time in, according to predetermined direction at whole body or certain organs continuous release medicine, and control blood drug level increases the bioavailability of medicine 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, take polylactic acid (PLA), polyglycolic acid (PGA), they copolymer (PLGA) and polycaprolactone (PCL) as the solid polymer of representative be to study the most transplantable and degradable slow releasing carrier of medication.Because these polymer itself are hydrophobic, use in the process of these materials and use inevitably poisonous organic solvents such as dichloromethane, chloroform.And the use of organic solvent causes fully removing thereafter and becomes very difficult, and remaining organic solvent can produce harmful side effect, such as carcinogenecity, neurotoxicity, teratogenecity etc.Pharmacopoeia of each country all clear the maximum of the organic solvent that in medicine, allows.Stipulate such 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 (such as the PLGA microsphere) can't be avoided the use of organic solvent equally although 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 such as PLA, PLGA, PCL, such as methyl pyrrolidone (NMP), dimethyl sulfoxine (DMSO), ethyl acetate etc. obtains 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 easily makes its inactivation concerning pharmaceutical grade protein.The rigidity that the device that above-mentioned system obtains has random form and itself solid easily causes fierce tissue reaction.The difference of simultaneously precipitation process Chinese medicine distribution can cause different release modes, and the untimely of infall process also can cause obvious 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, hydrophobic medicine and oligomerization ester mix homogeneously, be expelled in the body, along with the decline formation gel preparation of temperature.This is actually a kind of gel injection system.Because face the inefficacy that high temperature in the medicine encapsulation process may cause drug molecule, operating this system 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, therefore hydrogel has good biocompatibility, also becomes a kind of original slow releasing carrier of medication material.In recent years, the hydrogel material of injectable heat-sensitive gel 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 the bioactive substances such as medicine, cell under this state; When be injected in subcutaneous or muscular tissue after because temperature raises, change rapidly gel into so that be embedded with the solution of medicine; Lower by diffusion and/or the promotion of gel self Degradation, medicine can discharge stably from gel inside, thereby reaches the purpose of slow release.The transition process that materials is finished sol-gel is the reversible process of a physical change, does not relate to organic solvent, also need not chemical reaction, therefore toxicity is low, blandness.Such polymeric material is generally amphipathic block copolymer, can self assembly in water forms micelle or nanoparticle, therefore can the hydrophobic drug molecule of effective solubilization, and for the administration of insoluble drug provides solution.Copolymer with the polyethylene glycol oxide (PEO) of suitable molecular weight and composition-polypropylene oxide (PPO)-polyethylene glycol oxide (PEO) (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 in vivo a couple of days namely by body fluid dilution dissolving, the limited time that the sustained drug that can provide discharges.
Research is arranged by introducing degradable group or component in the Thermosensitive polymeric material, obtain degradable and temperature sensitive physical hydrogel material, and use materials 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 gel 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 fully water-soluble or partially or completely become precipitation, thereby lost sol-gel transition, no longer have a performance of relevant heat-sensitive gel;
(2) in addition, even sensitive characteristic can appear in partial polymer, its gelling temperature also improper human body 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 object 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 gel 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, proteins and peptides, nucleic acid/gene, hormone and antitumor drug gastrointestinal tract external administration.
Particularly, the invention provides a class by the hot reversible hydrogel of the compositions of mixtures of polymer.The hydrogel composition of heat-convertible gel of the present invention, it is the mixture of two or more polymer, 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 consists of by Polyethylene Glycol (PEG) for hydrophilic block, degradable polyester.
Have the aqueous systems of one or more block copolymers not have separately the character of heat-convertible gel in the polymeric blends of the present invention, these one or more block copolymers originally all can only be dissolved in the water in 1-50 ℃ of scope thereby heat-convertible gel 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 gel 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 gel 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, PLLA, PGA, poe, poly-epsilon-caprolactone, poly-ε-alkyl replacement caprolactone, poly-δ-valerolactone, polyesteramide, Merlon, polyacrylate, the polyether ester.
Block copolymer of the present invention is the triblock copolymer of ABA, BAB block configuration, 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, can comprise that the polymer of 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 the medium take organic solvent as main body not.
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 respectively two or more polymer at low temperature, then mix aqueous solution separately; Perhaps at first have water miscible polymer at dissolution in low temperature, and then add and not have or not exclusively to have water miscible polymer and carry out solubilising, the preparation hydrogel composition.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 consists of 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 separately the character of heat-convertible gel in the mixture, these one or more block copolymers originally all can only be dissolved in the water in 1-50 ℃ of scope thereby heat-convertible gel 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 gel 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 separately the character of heat-convertible gel.
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 the Polyethylene Glycol with mean molecule quantity of 400 to 8000 of 10-90wt%;
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, PLLA, PGA, poe, poly-epsilon-caprolactone, poly-ε-alkyl replacement caprolactone, poly-δ-valerolactone, polyesteramide, Merlon, polyacrylate or the polyether ester.
In the said method, block copolymer is the triblock copolymer of ABA, BAB block configuration, 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 the medium take organic solvent as main body not.
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 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 is consisted of 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 consists of, 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 is consisted of 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 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 the medium take organic solvent as main body not.
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 substantially not dissolving, can be to exist with outstanding mixed or emulsion form.
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 affect the behavior of the physical gel of polymeric blends, make it can not form gel.
The invention has the advantages that:
The hydrogel material that the present invention proposes has reversible Thermo-sensitive, 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 (namely pH value be about 7 and 37 ℃ under) can carry out reversible gel, thereby so 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, so that many be dissolved in fully in the water and do not present the polymer of heat-sensitive gel and in water precipitation and the polymer that do not present heat-sensitive gel the gel phenomenon that does not originally possess occurred by the mode of mixing, be convenient to medical application.
Even for the material that can present heat-sensitive gel originally in water, the method for the mixing 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 good biocompatibility, degradability and gel, and this material can be degradable within preset time be nontoxic α-alkyd and other corresponding monomer.
The hydrogel material that the present invention proposes can increase the dissolubility of part insoluble drug, improves the stability of medicine.
The own composition that the rate of release of the degradation rate of material and medicine can be by changing the mixed proportion that is used for the polymer that mixes, polymer in the temperature sensitive injectable slow/controlled release drug-supplying system that the present invention proposes, concentration, molecular weight and the polydispersity of polymer, 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 is mixed to get according to the Different Weight ratio 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 are mixed to get.
The specific embodiment
Embodiment 1
In the 250ml there-necked flask, add PEG (1500), oil bath is heated to 150 ℃, stirred lower vacuum filtration three hours, to remove residual moisture among the PEG, then add mol ratio and be 4: 1 DL-lactide and Acetic acid, hydroxy-, bimol. cyclic ester, heating makes after its complete melting under the vacuum, adds 120 μ l stannous octoates, oil bath is warmed up to 160 ℃, continues reaction 24 hours under argon gas atmosphere.React complete, 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 number average and the weight average molecular weight (M of described BAB block copolymer (PLGA-PEG-PLGA, Copolymer-1) 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 gel 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 ℃, stirred lower vacuum filtration three hours, to remove residual moisture among the MPEG, then add mol ratio and be 3: 1 DL-lactide and Acetic acid, hydroxy-, bimol. cyclic ester, heating makes after its complete melting under the vacuum, adds 120 μ l stannous octoates, oil bath is warmed up to 160 ℃, continues reaction 24 hours under argon gas atmosphere.React complete, 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 number average and the weight average molecular weight (M of described BA block copolymer (MPEG-PLGA, Copolymer-14) 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 gel 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 melting under the vacuum, and oil bath is warmed up to 160 ℃ of condensation reactions 18 hours.React complete, head product is dissolved in the dichloromethane solution, use a large amount of ether sedimentations, productive rate is about 85%.Measure 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 gel 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 gel, and wherein the block copolymer of table 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 gel.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 from table 1 and/or table 2, choosing one or more block copolymers with the mixture that certain proportion is mixed to get, 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 also have the performance of heat-convertible gel with from table 2, choosing one or more block copolymers with the mixture that certain proportion is mixed to get.
Table 1
| The sample title | The GPC weight average molecular weight | A-block mean molecule quantity | The wt%A-block | B-block mol ratio | Heat-convertible gel |
| PLGA-PEG-PLGA Copolymer-1 | 6390 | 1500 | 37 | LA/GA＝4/1 | No |
| PLGA-PEG-PLGA Copolymer-2 | 6020 | 2000 | 47 | LA/GA＝4/1 | No |
| PLGA-PEG-PLGA Copolymer-3 | 6410 | 2000 | 48 | LA/GA＝4/1 | No |
| PLGA-PEG-PLGA Copolymer-4 | 3080 | 800 | 51 | LA/GA＝10/1 | No |
| PLGA-PEG-PLGA Copolymer-5 | 10860 | 8000 | 90 | LA/GA＝1/1 | No |
| PCL-PEG-PCL Copolymer-6 | 4140 | 1500 | 62 | / | No |
| PCL-PEG-PCL Copolymer-7 | 1450 | 400 | 69 | / | No |
| PCL-PEG-PCL Copolymer-8 | 7440 | 4000 | 80 | / | No |
Table 2:
| The sample title | The GPC weight average molecular weight | A-block mean molecule quantity | The wt%A-block | B-block mol ratio | Heat-convertible gel |
| PLGA-PEG-PLGA Copolymer-9 | 7430 | 1000 | 24 | LA/GA＝4/1 | No |
| PLGA-PEG-PLGA Copolymer-10 | 8150 | 800 | 20 | LA/GA＝4/1 | No |
| PLGA-PEG-PLGA Copolymer-11 | 9375 | 600 | 10 | LA/GA＝1/1 | No |
| PLGA-PEG-PLGA Copolymer-12 | 9850 | 1500 | 18 | LA/GA＝1/3 | No |
| PCL-PEG-PCL Copolymer-13 | 4686 | 1000 | 30 | / | No |
| MPEG-PLGA Copolymer-14 | 4620 | 550 | 22 | LA/GA＝3/1 | No |
| PLGA-PEG-PLGA Copolymer-15 | 8340 | 1000 | 21 | LA/GA＝1/1 | No |
Table 3:
| The sample title | The GPC weight average molecular weight | A-block mean molecule quantity | The wt%A-block | B-block mol ratio | Heat-convertible gel |
| PLGA-PEG-PLGA Copolymer-16 | 5400 | 1000 | 26 | LA/GA＝3/1 | Be |
| PLGA-PEG-PLGA Copolymer-17 | 3850 | 1000 | 32 | LA/GA＝2/1 | Be |
| PLGA-PEG-PLGA Copolymer-18 | 6320 | 1500 | 30 | LA/GA＝10/1 | Be |
| PLGA-PEG-PLGA Copolymer-19 | 5820 | 1500 | 32 | LA/GA＝4/1 | Be |
Embodiment 5
At first obtain corresponding mixture with the block copolymer C opolymer-1 in 1/1 the ratio mixture table 1 and the block copolymer C opolymer-9 in the table 2, then add a certain amount of water, be mixed with weight percent concentration and be 25% sample, pass through magnetic agitation in refrigerator cold-storage temperature (4 ℃) at last, so that polymeric blends dissolves the corresponding aqueous solution of preparation in water.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, so that block copolymer C opolymer-9 solubilising enters 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
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 in refrigerator cold-storage temperature (4 ℃) preparation weight percent concentration at first, then evenly mix the aqueous solution that mentioned solution prepares corresponding polymeric blends with 1/1 ratio.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 are mixed to get according to the Different Weight ratio.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.Observe and in 20 seconds, not flow to define whether gelation when test tube is inverted.Fig. 1 has shown the phasor when Copolymer-1 and Copolymer-9 Different Weight ratio are mixed to get its variable concentrations aqueous solution of sample along with variations in temperature.
Embodiment 9
When Copolymer-1 and Copolymer-9 were mixed to get concentration and add PEG (2000) polymer of percentage by weight as 2% in 25% aqueous solution take 1/1 part by weight, its sol-gel transition temperature was reduced to 32 ℃ from 34 ℃.
Embodiment 10
In pH is 7.4 PBS, measure Copolymer-1 and Copolymer-9 and be mixed to get concentration as 25% aqueous solution or gel (1ml) external degradation situation during at 37 ℃ take 1/1 or 1/2 part by weight.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
Copolymer-1 is observed in research and Copolymer-9 is mixed to get concentration as 25% aqueous solution take 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 are mixed to get.
Hydroxy camptothecin and paclitaxel all are hydrophobic drugs, almost insoluble in water, the hydroxy-camptothecin alkali solubility is up to 5mg/ml in 25% aqueous solution yet the present invention is mixed to get concentration at Copolymer-1 and Copolymer-9 take 1/2 part by weight, and taxol solubility is up to 7mg/ml.And after storing 90 days, all have the former medicine more than 85% to be maintained, the stability of medicine is significantly increased.
Embodiment 13
The concentration of block copolymer C opolymer-16 in the table 3 is that sol-gel transition occurs in the time of 11 ℃ 25% aqueous solution, forms hydrogel; 25% aqueous solution of Copolymer-1 does not have the performance of heat-sensitive gel; 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 (18)
1. the hydrogel composition of a physical crosslinking, it is characterized by: formed by two or more polymer mixed, 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; Wherein,
Comprise by Polyethylene Glycol being that hydrophilic A block, degradable polyester are the block copolymer that hydrophobic B block consists of in the described polymer, the mean molecule quantity of hydrophilic block Polyethylene Glycol is 400-8000, weight content is 10-90%, the mean molecule quantity of hydrophobic block polyester is 500-40000, and weight content is 90-10%;
Described block copolymer is the triblock copolymer of ABA, BAB block configuration, 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;
Described polyester is selected from various poly DL-lactides, poly-D-lactide, PLLA, PGA, poe, poly-epsilon-caprolactone, gathers any type of copolymer that ε-alkyl replaces any and above-mentioned each kind polyester in caprolactone, poly-δ-valerolactone, polyesteramide, Merlon, polyacrylate, the polyether ester;
The weight percent content of every kind of block copolymer in the described polymeric blends is between 5-95%;
The weight percentage of described polymeric blends in aqueous solution is between 3-50%, solvent in its solution is selected from 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 the medium take organic solvent as main body not.
2. polymeric blends according to claim 1 is characterized in that, has the aqueous systems of one or more block copolymers not have separately the character of heat-convertible gel in the described mixture.
3. polymeric blends 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 thereby heat-convertible gel can not occur separately, perhaps can not be water-soluble or can not be dissolved in the water fully thereby heat-convertible gel can not occur separately.
4. polymeric blends according to claim 1, 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. polymeric blends according to claim 1 is characterized in that, the aqueous systems of each block copolymer in the described mixture does not have separately the character of heat-convertible gel.
6. the preparation method of the hydrogel composition of a physical crosslinking is characterized by: at first mix two or more polymer, then at the dissolution in low temperature polymeric blends in water; Perhaps at first dissolve respectively two or more polymer at low temperature, then mix aqueous solution separately; Perhaps at first have water miscible polymer at dissolution in low temperature, and then add and not have or not exclusively to have water miscible polymer and carry out solubilising, thus the preparation hydrogel composition; Described low temperature is the sol-gel transition temperature that is lower than compositions; The aqueous solution of prepared polymeric blends can hot reversible formation hydrogel when temperature is higher than the sol-gel transition temperature.
7. the preparation method of hydrogel composition according to claim 6 is characterized in that, described low temperature refers to 0 ℃ to room temperature, refers in particular to 4 ℃ of refrigerator cold-storage temperature.
8. the preparation method of hydrogel composition according to claim 6 is characterized in that, described low temperature is 4 ℃ of refrigerator cold-storage temperature.
9. the preparation method of hydrogel composition according to claim 6, it is characterized in that, described polymer is for being that hydrophilic A block, degradable polyester are the block copolymer that hydrophobic B block consists of by Polyethylene Glycol, the mean molecule quantity of hydrophilic block Polyethylene Glycol is 400-8000, weight content is 10-90wt%, the mean molecule quantity of hydrophobic block polyester is 500-40000, and weight content is 90-10wt%;
Described block copolymer is the triblock copolymer of ABA, BAB block configuration, 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;
Described polyester is selected from various poly DL-lactides, poly-D-lactide, PLLA, PGA, poe, poly-epsilon-caprolactone, gathers any type of copolymer that ε-alkyl replaces any and above-mentioned each kind polyester in caprolactone, poly-δ-valerolactone, polyesteramide, Merlon, polyacrylate, the polyether ester;
The weight percent content of every kind of block copolymer in the described polymeric blends is between 5-95%.
10. the preparation method of hydrogel composition according to claim 6 is characterized in that, described polymer is block copolymer and obtains by thermal condensation or ring-opening polymerisation.
11. the preparation method of hydrogel composition according to claim 6 is characterized in that, has the aqueous systems of one or more block copolymers not have separately the character of heat-convertible gel in the described mixture.
12. the preparation method of hydrogel composition according to claim 6, it is characterized in that, in the described mixture, this is dissolved in the water, does not occur separately heat-convertible gel one or more block copolymers in 1-50 ℃ of scope, perhaps water insoluble or not exclusively be dissolved in the water, also do not occur separately heat-convertible gel.
13. the preparation method of hydrogel composition according to claim 6, it is characterized in that, in the described mixture, this is 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 in water in 1-50 ℃ of scope or not exclusively are dissolved in the water.
14. the preparation method of hydrogel composition according to claim 6 is characterized in that, the aqueous systems of each block copolymer in the described mixture does not have separately the character of heat-convertible gel.
15. the preparation method of hydrogel composition according to claim 6, it is characterized in that, the weight percentage of described polymeric blends in aqueous solution is between 3-50%, solvent in the described polymeric blends solution is 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 the medium take organic solvent as main body not.
16. temperature sensitive injectable slow/controlled release drug-supplying system that is consisted of by polymeric blends solution and medicine, it is characterized in that, described mixture is polymeric blends claimed in claim 1, wherein, described medicine is one or more in protein, polypeptide, nucleic acid, gene, hormone and the antitumor drug.
17. temperature sensitive injectable slow/controlled release drug-supplying system according to claim 16, it is characterized in that, the weight percentage of described polymeric blends in aqueous solution is between 3-50%, solvent in the described polymeric blends solution is 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 the medium take organic solvent as main body not.
18. temperature sensitive injectable slow/controlled release drug-supplying system according to claim 16, 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 affect the behavior of the physical gel of polymeric blends, make it can not form gel.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100496646A CN101862454B (en) | 2009-04-20 | 2009-04-20 | Physical cross-linking hydrogel composition and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100496646A CN101862454B (en) | 2009-04-20 | 2009-04-20 | Physical cross-linking hydrogel composition and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101862454A CN101862454A (en) | 2010-10-20 |
| CN101862454B true CN101862454B (en) | 2013-04-10 |
Family
ID=42954509
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009100496646A Active CN101862454B (en) | 2009-04-20 | 2009-04-20 | Physical cross-linking hydrogel composition and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101862454B (en) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102068719A (en) * | 2011-01-18 | 2011-05-25 | 复旦大学 | Adhesion prevention material formed by physical crosslinking hydrogel composition and preparation method and application thereof |
| AU2012237260A1 (en) | 2011-03-31 | 2013-11-14 | Ingell Technologies Holding B.V. | Biodegradable compositions suitable for controlled release |
| CA2831471C (en) | 2011-03-31 | 2020-02-25 | Ingell Technologies Holding B.V. | Biodegradable compositions suitable for controlled release |
| CN102204881A (en) * | 2011-06-08 | 2011-10-05 | 复旦大学 | Gel sustained-release injection containing camptothecin or derivatives thereof, and preparation method thereof |
| CN102731981B (en) * | 2012-06-01 | 2014-08-27 | 华中科技大学 | Temperature-sensitive injectable mixed hydrogel |
| CN102755282A (en) * | 2012-06-01 | 2012-10-31 | 华中科技大学 | Temperature sensitive injectable drug-loading controlled release system |
| CN103622902B (en) * | 2012-08-24 | 2016-12-21 | 上海现代药物制剂工程研究中心有限公司 | A kind of thermosensitive hydrogel pharmaceutical preparation and preparation method thereof |
| CN103251986B (en) * | 2013-05-17 | 2015-03-04 | 四川大学 | Use of PDLLLA (Poly Dl Lactic Acid)-PEG (Polyethylene Glycol)-PDLLA triblock copolymer in preparing medical anti-adhesion material |
| CN104689381A (en) * | 2013-12-10 | 2015-06-10 | 复旦大学 | Hydrogel composition for gastrointestinal submucosal injection and application of hydrogel composition |
| CN103755970B (en) * | 2014-01-08 | 2016-05-25 | 上海大学 | Dynamically temperature sensitive star-like branch fluidized polymer of binding and preparation method thereof |
| CN110638745A (en) * | 2019-06-27 | 2020-01-03 | 复旦大学 | HER-2 humanized monoclonal antibody long-acting sustained-release preparation and preparation method thereof |
| CN111110626A (en) * | 2019-12-04 | 2020-05-08 | 复旦大学 | Gel drug sustained-release preparation based on hydrophobic modified gemcitabine derivative and preparation method and application thereof |
| CN111346047B (en) * | 2020-03-12 | 2022-04-01 | 复旦大学 | Thermotropic hydrogel metformin sustained-release preparation and preparation method and application thereof |
| CN111286204B (en) * | 2020-03-12 | 2021-08-20 | 复旦大学 | Polymer compound capable of being rapidly dissolved or dispersed in aqueous solvent and preparation method and application thereof |
| CN115364046B (en) * | 2022-08-16 | 2024-04-30 | 上海交通大学医学院附属第九人民医院 | Thermosensitive sol for treating vasospasm and preparation method and application thereof |
-
2009
- 2009-04-20 CN CN2009100496646A patent/CN101862454B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN101862454A (en) | 2010-10-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101862454B (en) | Physical cross-linking hydrogel composition and preparation method and application thereof | |
| CN100540055C (en) | Be used for the Biodegradable block copolymeric compositions that medicine is sent | |
| JP4903256B2 (en) | Biodegradable low molecular weight triblock poly (lactide-co-glycolide) -polyethylene glycol copolymer with inverse thermal gelation properties | |
| RU2232779C2 (en) | Biodegradable three-block polyester/polyethylene glycol copolymers possessing low molecular mass and reversible thermal gelling properties | |
| CN1429120B (en) | Stable polymeric micelle-type drug composition and method for preparation thereof | |
| CN1234416C (en) | Compositions for sustained delivery of hydrophobic drugs and process for preparation thereof | |
| DK1778191T3 (en) | Biodegradable DIBLOKCOPLYMERE having reverse thermal gelling properties, and methods of use thereof | |
| JP4187789B2 (en) | Thermosensitive biodegradable polymer based on poly (ether-ester) block polymer | |
| CN100427144C (en) | Degradable temperature sensitive physical aquagel and its preparation method | |
| CN102068719A (en) | Adhesion prevention material formed by physical crosslinking hydrogel composition and preparation method and application thereof | |
| ZA200102453B (en) | Biodegradable low molecular weight triblock polyester polythylene glycol copolymers having reverse thermal gelation properties. | |
| JP2003531927A (en) | Mixture of triblock polyester polyethylene glycol copolymer | |
| CN101366693A (en) | Drug delivery system | |
| CN1965802B (en) | Injectable hydrogel preparation of pegylated medicament and preparing method thereof | |
| JP5653441B2 (en) | Reconfigurable reverse heat gelling polymer | |
| CN1706879A (en) | Temperature-sensitive biodegradable block copolymer and its prepn process | |
| JP6176998B2 (en) | Temperature-responsive biodegradable polymer composition and method for producing the same | |
| JP6222984B2 (en) | Temperature-responsive biodegradable polymer composition and method for producing the same | |
| CN113143851A (en) | Solvent exchange-based injectable hydrogel and preparation method and application thereof | |
| Truc Huynh et al. | Injectable Temperature-and pH/Temperature-Sensitive Block Copolymer Hydrogels |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20190606 Address after: No. 1599 Military Industrial Road, Yangpu District, Shanghai, 200432, Building 5 (Centralized Registration Place) Patentee after: Shanghai Fu Ning Technology Co., Ltd. Address before: 200433 No. 220, Handan Road, Shanghai Patentee before: Fudan University |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20190710 Address after: No. 1599 Military Industrial Road, Yangpu District, Shanghai, 200432, Building 5 (Centralized Registration Place) Co-patentee after: Fudan University Patentee after: Shanghai Fu Ning Technology Co., Ltd. Address before: No. 1599 Military Industrial Road, Yangpu District, Shanghai, 200432, Building 5 (Centralized Registration Place) Patentee before: Shanghai Fu Ning Technology Co., Ltd. |