CN102068719A - Adhesion prevention material formed by physical crosslinking hydrogel composition and preparation method and application thereof - Google Patents
Adhesion prevention material formed by physical crosslinking hydrogel composition and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of high polymer material and medical technology, and particularly relates to adhesion prevention material formed by physical crosslinking hydrogel composition and a preparation method and application thereof. The hydrogel composition material is formed by mixture of two polymers or more than two polymers, the water system of the hydrogel composition material can be thermo-sensitively gelated along with the rise of temperature, i.e. when the temperature is lower than gel transformation temperature, the composition is liquid, when the temperature raises to sol-gel transformation temperature or above the sol-gel transformation temperature, the composition spontaneously forms gel; the polymer generally is segmented copolymer formed by polyethylene glycol (PEG) being hydrophilic block and degradable polyester being lyophobic block, and polymer for mixing singly possibly has not the property of thermosensitive gelation. The hydrogel composition material has the effect of wound surface adhesion prevention after the hydrogel composition material is coated on the postoperative wound surface.
Description
Technical field
The invention belongs to macromolecular material and field of medical technology, be specifically related to a kind of physical cross-linking hydrogel composition material, heat-sensitive gelization can take place along with temperature raises in its aqueous systems, be that temperature is when being lower than gel transition temperature, compositions is a liquid, when temperature is increased to the sol-gel transition temperature or when above, the spontaneous formation gel of compositions.Postoperative wound surface can be injected and be coated in to this material, uses as medical post-operation adhesion preventing barrier material.
Background technology
Tissue adhesion is a major issue that perplexs surgical field for a long time.The adhesion meeting that after abdominal cavity operation produces causes pelvic pain, a series of complication such as intestinal obstruction and sterility and infertility, and in the tendon repair operation, the adhesion meeting causes the handicapped problem of patient moving.The method of prevention of postoperative adhesion at present is a lot, comprises the improvement of operation method, the application of postoperative topical remedy, the application of the local barrier material of postoperative, and the early stage suitable activity of postoperative and the exercise in later stage or the like.Wherein the barrier material that absorbs of degradable is because its good isolation effect of organizing, and need not the facility that second operation takes out material, and the Film with Preventing Adhesion field has received increasing concern after surgery.
Degradable barrier material commonly used at present is divided into two big classes:
One class is degradable solid film, comprises polylactic acid membrane, poly cellulose membrane etc., wherein part material industrialization.But this class material is because its solid forms has caused its application in Minimally Invasive Surgery to have certain difficulty.The more important thing is that thin film is bonded at the surface of carrying liqs easily, caused in the process of deployment instrument, being bonded at easily operator's glove and other non-wound site, so practical operation and inconvenient.
And another kind of material belongs to aqueous solution and gel, because it has certain fluid ability, can inject and be coated in surgical wound surface, improved the coverage rate of complex geometry form wound surface in the body, also increased the convenience that material is used, so its application as medical embedded material is paid close attention to more and more.Such as: the people such as Kohane of masschusetts, u.s.a Polytechnics once reported the glucosan of chemical crosslinking, sodium alginate and cellulose derivative hydrogel and were applied to post-operation adhesion preventing, this type of chemical gel need use the chemical crosslinking initiator with certain bio-toxicity, and its bio-safety hidden danger is a big problem of their practical applications of restriction.Some has the physical gel of temperature-responsive, because they possess spontaneous gelatigenous characteristics under body temperature, is considered to be hopeful to obtain clinical practice.Poloxamer (Poloxamer) is one of them, but this block polymer of being made up of PEG and PPG can not be by biodegradation, and gel can only keep a couple of days in vivo and promptly diluted by body fluid, and therefore the effect as the barrier material of Film with Preventing Adhesion is not very good.Application number 200910304210.9 and 201010138739.0 Chinese patent, the triblock copolymer that has proposed to be made up of PEG and PCL is used for post-operation adhesion preventing as temperature sensitive gel rubber material; The Chinese patent of application number 201010133541.3 has reported that the bi-block copolymer thermosensitive hydrogel of being made up of MPEG and PLA is used for post-operation adhesion preventing.The used material of above-mentioned patent is this based block copolymer of one-component.This base polymer has single composition and molecular weight distribution, has the performance of heat-sensitive gelization under the finite concentration.
But 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 purpose of this invention is to provide a kind of medical macromolecular materials, as postoperative prevention tissue adhesion's barrier material with heat-sensitive gel voltinism energy.This material basic composition is the degradation material with good biocompatibility, degradation rate can be formed adjusting by changing copolymer within the specific limits, be complementary with the application demand of different occasions, material has excellent biological compatibility, does not have significant cytotoxicity and haemolysis behavior.
The adherence preventing material that the hydrogel composition of heat-sensitive gelization of the present invention constitutes, it is two or more mixture of polymers, heat-sensitive gelization can take place along with temperature raises in its aqueous systems, when temperature is lower than the sol-gel transition temperature, polymeric blends is dissolvable in water water, when temperature is higher than the sol-gel transition temperature, the spontaneous formation gel of the aqueous solution of polymeric blends, 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.
Contain regulator in the polymeric blends solution of the present invention, its weight percentage in aqueous systems is between 0-15%, preferred 0.5-15%, and more preferably 1-10% is because of concrete needs be decided; Regulator can be selected from a kind of or its combination in sugar, salt, sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, mountain plough alcohol, surfactant, polysorbas20, polysorbate40, Tween 80, xylitol, oligosaccharide, chrondroitin, chitin, chitosan, collagen protein, gelatin, albumin glue, hyaluronic acid, the Polyethylene Glycol.Regulator can be other medical dressing, as but be not limited to filler, solubilizing agent, absorption enhancer, film former, gel, porogen, excipient or blocker etc.
In the polymeric blends of the present invention, there is the aqueous systems of one or more block copolymers not have the character of heat-sensitive gelization separately, this all can only be dissolved in the water these one or more block copolymers in 1-50 ° of C scope, thereby heat-sensitive gelization can not occur separately; Perhaps, one or more block copolymers can not be water-soluble in 1-50 ° of C scope or can not be dissolved in the water fully, thereby heat-sensitive gelization can not occur separately.
In the polymeric blends of the present invention, one or more block copolymers are arranged, and this all can only be dissolved in the water in 1-50 ° of C scope, simultaneously, another or more than one block copolymers can not be water-soluble in 1-50 ° of C scope or can not be dissolved in the water fully.
In the polymeric blends of the present invention, the aqueous systems of each block copolymer can all not have the character of heat-sensitive 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 10-90 wt % has the hydrophilic A polymer blocks of Polyethylene Glycol of 400 to 8000 mean molecule quantity and the hydrophobicity B polymer blocks of 90-10 wt %.
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 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, poly-1,4, any in 8 – trioxa spiral shell [4.6] –, 9 – hendecanones, poly-P-Dioxane ketone, polyesteramide, Merlon, polyacrylate, the polyether ester, the perhaps any type of copolymer of above-mentioned each kind polyester.
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
n Or B (AB)
n The segmented copolymer of block configuration, wherein
nIt is 2 to 10 integer.
The weight percent content of polymeric blends of the present invention in aqueous solution be between 3-50%, but be preferred with 10-30%, and 15-28% is for most preferably.
Solvent in the polymeric blends solution of the present invention can be body fluid, tissue culture medium, the cell culture fluid of pure water, water for injection, normal saline, buffer solution, animals and plants or human body, perhaps for other aqueous solution with not based on the medium of organic solvent.
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 adherence preventing material that hydrogel composition of the present invention constitutes, its application scenario comprise intestinal adhesion, abdominal adhesions, adhesion of tendon, fallopian tube adhesion and the ureter adhesion etc. that cause after the prevention operation.
The adherence preventing material that hydrogel composition of the present invention constitutes, but medicines such as also load antiinflammatory, analgesia or somatomedin with further promotion wound healing, prevent the generation of adhesion between the wound surface.
The preparation method of the adherence preventing material that hydrogel composition of the present invention constitutes is: 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 at dissolution in low temperature, thus 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 temperature-sensitive form hydrogel when temperature is higher than the sol-gel transition temperature.Usually, the aqueous solution of prepared polymeric blends is standby-10 ℃ or following storage, heats up before using to redissolve the back and use.
In the said method, also contain regulator in the polymeric blends solution, its weight percentage in aqueous systems is between 0-15%, preferred 0.5-15%, and more preferably 1-10% is because of concrete needs be decided; Regulator can be selected from a kind of or its combination in sugar, salt, sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, mountain plough alcohol, surfactant, polysorbas20, polysorbate40, Tween 80, xylitol, oligosaccharide, chrondroitin, chitin, chitosan, collagen protein, gelatin, albumin glue, hyaluronic acid, the Polyethylene Glycol.Regulator can be other medical dressing, as but be not limited to filler, solubilizing agent, absorption enhancer, film former, gel, porogen, excipient or blocker etc.
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, there is the aqueous systems of one or more block copolymers not have the character of heat-sensitive gelization separately in the mixture, this all can only be dissolved in the water these one or more block copolymers in 1-50 ° of C scope, thereby heat-sensitive gelization can not occur separately; Perhaps, one or more block copolymers can not be water-soluble in 1-50 ° of C scope or can not be dissolved in the water fully, thereby heat-sensitive 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 C scope, simultaneously, another or more than one block copolymers can not be water-soluble in 1-50 ° of C 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-sensitive 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 10-90 wt % with mean molecule quantity of 400 to 8000;
B) the hydrophobicity B polymer blocks of 90-10 wt %.
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 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, poly-1, the any type of copolymer of any and above-mentioned each kind polyester in 4,8 – trioxa spiral shell [4.6] –, 9 – hendecanones, poly-P-Dioxane ketone, polyesteramide, Merlon, polyacrylate, 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
n Or B (AB)
n The segmented copolymer of block configuration, wherein
nIt is 2 to 10 integer.
In the said method, the weight percentage of polymeric blends in aqueous solution be between 3-50%, but be preferred with 10-30%, and 15-28% is for most preferably.
In the said method, solvent in the polymeric blends solution can be body fluid, tissue culture medium, the cell culture fluid of pure water, water for injection, normal saline, buffer solution, animals and plants or human body, perhaps for other aqueous solution with not based on the medium of organic solvent.
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 the said method, medicines such as the also antiinflammatory of load simultaneously, analgesia, somatomedin with further promotion wound healing, prevent the generation of adhesion between the wound surface in the polymeric blends solution.
In the said method, the ratio of block copolymer can be regulated, thereby obtains needed sol-gel transition temperature and degradation rate etc.
The invention has the advantages that:
The adherence preventing 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 heat-convertible gelization, thereby make that the preparation process of material is simple, practical operation and application are very convenient.
The adherence preventing 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 adherence preventing material that the present invention proposes has comprised the PEG block, and owing to PEG has natural impedance cell and the adherent performance of albumen, therefore on the effect that stops adhesion to generate and develop, the polyester-polyether block copolymer that comprises PEG has better effect.
Description of drawings
Fig. 1. the phasor for its PBS solution of block copolymer mixture of obtaining according to the Different Weight mixed during along with variations in temperature.Measure with the tubule anastrophe.
Fig. 2. mean molecule quantity is with the change curve of degradation time (every 4 days exchange buffering liquid, keep pH stable) in the external degradation experiment for the block copolymer mixture hydrogel that obtains according to the Different Weight mixed, and illustrative material has degradability.
Fig. 3. for mtt assay characterizes the influence of the culture fluid of the block copolymer mixture material added variable concentrations and to have been obtained by the Different Weight mixed to the MC-3T3 cell viability, confirm that material has excellent biological compatibility.
The specific embodiment
Further describe the present invention below by example, but be not limited to these embodiment.
In 250 ml there-necked flasks, add PEG(1500), oil bath is heated to 150 ℃, vacuum filtration is three hours under stirring, to remove residual moisture among the PEG, adding mol ratio then is DL-lactide and the Acetic acid, hydroxy-, bimol. cyclic ester of 4:1, and 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%.By chromatograph of gel permeation (GPC) (adopt polystyrene as standard specimen) measure described BAB block copolymer (PLGA-PEG-PLGA, number average Copolymer-1) and weight average molecular weight (
M n ,
M w ) be respectively 5510 and 6390, the molecular weight distribution coefficient (
M w /
M n ) be 1.16.This does not have the performance of heat-sensitive gelization this copolymer in water.
In 250 ml there-necked flasks, 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, adding mol ratio then is DL-lactide and the Acetic acid, hydroxy-, bimol. cyclic ester of 3:1, and 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%.By chromatograph of gel permeation (GPC) (adopt polystyrene as standard specimen) measure described AB block copolymer (MPEG-PLGA, number average Copolymer-14) and weight average molecular weight (
M n ,
M w ) be respectively 3550 and 4620, the molecular weight distribution coefficient (
M w /
M n ) be 1.30.This does not have the performance of heat-sensitive gelization this copolymer in water.
Embodiment 3
In 250 ml there-necked flasks, add Polyethylene Glycol (1000) and PLGA(
M n 4750,
M w 6020, 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%.By chromatograph of gel permeation (GPC) (adopt polystyrene as standard specimen) measure the number average of described BAB block copolymer and weight average molecular weight (
M n ,
M w ) be respectively 6520 and 8340(PLGA-PEG-PLGA, Copolymer-15), the molecular weight distribution coefficient (
M w /
M n ) be 1.28.This does not have the performance of heat-sensitive 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 performance of these copolymers is listed in the table below 1:
| The sample title | The GPC weight average molecular weight | A-block mean molecule quantity | Wt % A-block | B-block mol ratio | Heat-sensitive gel |
| PLGA-PEG-PLGA Copolymer-1 | 6390 | 1500 | 37 | LA/GA=4/1 | Not |
| PLGA-PEG-PLGA Copolymer-2 | 6020 | 2000 | 47 | LA/GA=4/1 | Not |
| PLGA-PEG-PLGA Copolymer-3 | 6410 | 2000 | 48 | LA/GA=4/1 | Not |
| PLGA-PEG-PLGA Copolymer-4 | 3080 | 800 | 51 | LA/GA=10/1 | Not |
| PEG-PLGA-PEG Copolymer-5 | 10350 | 4000 | 89 | LA/GA=1/2 | Not |
| PEG-PCL-PEG Copolymer-6 | 4050 | 750 | 64 | / | Not |
| PCL-PEG-PCL Copolymer-7 | 1450 | 400 | 69 | / | Not |
| PCLA-PEG-PCLA Copolymer-8 | 7350 | 4000 | 81 | CL/LA=1/5 | Not |
Table 2:
| The sample title | The GPC weight average molecular weight | A-block mean molecule quantity | Wt % A-block | B-block mol ratio | Heat-sensitive gel |
| PLGA-PEG-PLGA Copolymer-9 | 7430 | 1000 | 24 | LA/GA=4/1 | Not |
| PLGA-PEG-PLGA Copolymer-10 | 8150 | 800 | 20 | LA/GA=4/1 | Not |
| PCLA-PEG-PCLA Copolymer-11 | 9510 | 600 | 12 | CL/LA=3/1 | Not |
| PEG-PLGA-PEG Copolymer-12 | 9750 | 750 | 17 | LA/GA=1/4 | Not |
| PCL-PEG-PCL Copolymer-13 | 4686 | 1000 | 30 | / | Not |
| MPEG-PLGA Copolymer-14 | 4620 | 550 | 22 | LA/GA=3/1 | Not |
| PLGA-PEG-PLGA Copolymer-15 | 8340 | 1000 | 21 | LA/GA=1/1 | Not |
Table 3:
| The sample title | The GPC weight average molecular weight | A-block mean molecule quantity | Wt % A-block | B-block mol ratio | Heat-sensitive 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 |
| PCLA-PEG-PCLA Copolymer-20 | 6250 | 1500 | 31 | CL/LA=4/1 | Be |
| MPEG-PCLA Copolymer-21 | 4700 | 750 | 23 | CL/LA=19/1 | Be |
| PLA-PEG-PLA Copolymer-22 | 6400 | 1500 | 32 | / | Be |
The block copolymer of table 1 and table 2 does not all have the performance of heat-sensitive 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-sensitive 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-sensitive gelization with certain proportion with from table 2, choosing one or more block copolymers.
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 PBS solution 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 PBS, dissolve the corresponding aqueous solution of preparation.The PBS solution of the polymeric blends of preparation can spontaneous formation gel when temperature is higher than the sol-gel transition temperature.During concrete the use solution is sterilized by 0.22 mm microporous filter membrane, slowly drip on the wound surface with syringe then, because the body temperature effect can form layer of gel at once on wound surface.
Embodiment 6
At first be the PBS 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% PBS 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 PBS solution of the block copolymer C opolymer-16 of the PBS solution of 25% block copolymer C opolymer-1 and same weight percent concentration, then with the PBS 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.
Embodiment 8
Studied the gelation behavior of triblock copolymer mixture in PBS solution that block copolymer C opolymer-1 and Copolymer-9 obtain according to the Different Weight mixed.The mixture PBS solution that has prepared from 5% to 25% Different Weight percent concentration has been measured its viscosity between 0 ℃ to 60 ℃ and has been changed.Observing did not flow in 20 seconds when test tube is inverted defines whether gelation.Phasor when Fig. 1 is PBS solution that Copolymer-1 and Copolymer-9 Different Weight mixed obtain its variable concentrations 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 to add percentage by weight in the 25%PBS solution be 2% PEG(2000) during polymer, significant change does not take place in its gel strength, and its sol-gel transition temperature is reduced to 30 ℃ from 32 ℃.
Mix with 1/1 part by weight at Copolymer-1 and Copolymer-9 that to obtain concentration be when to add percentage by weight in the 25%PBS solution be 0.5% hyaluronic acid, its sol-gel transition temperature is reduced to 31 ℃ from 32 ℃, and its maximum gel strength has descended about 25%.
Embodiment 11
The concentration of block copolymer C opolymer-16 in the table 3 is that sol-gel transition takes place in the time of 9 ℃ 25%PBS solution, forms hydrogel; The 25%PBS 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 9～37 ℃.
Embodiment 12
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%PBS solution or gel (0.5 ml) external degradation situation during at 37 ℃.Fig. 2 be block copolymer mixture hydrogel that Copolymer-1 and Copolymer-9 Different Weight mixed obtain in the external degradation experiment mean molecule quantity with the change curve of degradation time.
Embodiment 13
Adopt the MC-3T3 cell of In vitro culture, under aseptic condition with cell inoculation in 96 porocyte culture plates, density 10
4Individual/well, at cell during to exponential phase, mix Copolymer-1 and Copolymer-9 in the sample adding Tissue Culture Plate that obtains variable concentrations with 1/1 or 1/2 part by weight, one group of blank that is that does not add sample, one group of F-127 that adds same concentration as negative control, other one group of SDS that adds same concentration as positive control, every group of 4 parallel sample.Put into incubator (37 ℃) and leave standstill cultivation, cell and material are cultivated tetramethyl azo azoles salt trace enzyme reaction colorimetry (mtt assay) detection cell viability after 24 hours altogether.Fig. 3 is mtt assay and characterizes the influence of the culture fluid of the block copolymer mixture material added variable concentrations and to have been obtained by the Different Weight mixed to the MC-3T3 cell viability, confirms that material has excellent biological compatibility.
Embodiment 14
At first obtained Copolymer-1 and Copolymer-9 and mixed with 1/2 part by weight that to obtain concentration be 25%PBS solution according to the method for embodiment 5, then toward wherein adding the antibiotic medicine ibuprofen, concentration is that 0.1-5 %(preferred concentration is 1-2 %), solution at room temperature stirs and more than 2 hours medicine is fully dissolved and mix, and adopts the sterilization of 0.22 mm microporous filter membrane then.Directly solution is dripped to during use and form gel on the wound surface.
The check of embodiment 15, medical anti-adhesive effect (1)
Used Copolymer-1 and Copolymer-9 to obtain concentration in the present embodiment and be 25%PBS solution,, prepared sterilized hydrogel material at first according to the method for embodiment 5 with the mixing of 1/2 part by weight.Experimental animal model adopts the stomach wall-caecum damage model of new zealand rabbit, after the new zealand rabbit anesthesia, cut the abdominal cavity along centrage, in right side intraperitoneal span outside 1 centimetre of position of otch, cut one 3 * 4 centimeter square abdominal wall muscle, about 1 millimeter of the wound surface degree of depth, the caecum with correspondence position rubs with the operation brush then, and mucosa destroys to oozing of blood.For the gel rubber material group, we slowly drop in hydrogel on the wound surface of abdominal wall and caecum, and the wound surface of control animals does not add processing, sew up abdominal wall muscle and skin after operation is finished.The normal raising after one month of animal put to death, and opens the abdominal cavity and checks the adhesion situation, and experimental result shows, animals of control group, and there are serious adhesion in stomach wall and caecum; And the animal of using hydrogel material does not stick together between stomach wall and caecum, and wound healing is good.Illustrate that this degradable temperature-sensitive hydrogel can effectively suppress the generation of tissue adhesion, and biocompatibility is good, does not influence the healing of wound surface.
The check of embodiment 16, medical anti-adhesive effect (2)
Used among the embodiment 10 sample of preparation in the present embodiment, promptly Copolymer-1 and Copolymer-9 mix with 1/1 part by weight that to obtain concentration be 25%PBS solution, and have added 0.5% hyaluronic acid in the sample.According to the method for embodiment 5, hydrogel material is sterilized equally.Experimental animal model adopts the stomach wall-caecum damage model of new zealand rabbit, after the new zealand rabbit anesthesia, cut the abdominal cavity along centrage, in right side intraperitoneal span outside 1 centimetre of position of otch, cut one 3 * 4 centimeter square abdominal wall muscle, about 1 millimeter of the wound surface degree of depth, the caecum with correspondence position rubs with the operation brush then, and mucosa destroys to oozing of blood.For the gel rubber material group, we slowly drop in hydrogel on the wound surface of abdominal wall and caecum, and the wound surface of control animals does not add processing, sew up abdominal wall muscle and skin after operation is finished.The normal raising after one month of animal put to death, and opens the abdominal cavity and checks the adhesion situation, and experimental result shows, animals of control group, and there are serious adhesion in stomach wall and caecum; And the animal of using hydrogel material does not stick together between stomach wall and caecum, and wound healing is good.Illustrate that this degradable temperature-sensitive hydrogel can effectively suppress the generation of tissue adhesion, and biocompatibility is good, does not influence the healing of wound surface.
Claims (16)
1. adherence preventing material that is made of the physical cross-linking hydrogel compositions is characterized by:
Form by two or more polymer mixed, its aqueous systems can be along with the temperature spontaneous generation physical gelization that raises: 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; Comprise by Polyethylene Glycol being that hydrophilic block, degradable polyester are the block copolymer that hydrophobic block constituted in the polymer wherein;
This aquogel system contains regulator, and its weight percentage in aqueous systems is between 0.5-15%; Regulator is selected from a kind of in sugar, salt, sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, mountain plough alcohol, surfactant, polysorbas20, polysorbate40, Tween 80, xylitol, oligosaccharide, chrondroitin, chitin, chitosan, collagen protein, gelatin, albumin glue, hyaluronic acid, the Polyethylene Glycol or wherein several combinations.
2. adherence preventing material according to claim 1 is characterized in that, has the aqueous systems of one or more block copolymers not have the character of heat-sensitive gelization separately in the described polymeric blends; This can only be dissolved in the water these one or more block copolymers in 1-50 ° of C scope, thereby separately heat-sensitive gelization can not appear, perhaps these one or more block copolymers itself can not be water-soluble or can not be dissolved in the water fully, thereby heat-sensitive gelization can not occur separately.
3. adherence preventing material according to claim 1, it is characterized in that, in the described polymeric blends, this can only be dissolved in the water one or more block copolymers in 1-50 ° of C scope, simultaneously, another or more than one block copolymers can not be water-soluble in 1-50 ° of C scope or can not be dissolved in the water fully.
4. adherence preventing material according to claim 1 is characterized in that, the aqueous systems of each block copolymer in the described polymeric blends does not have the character of heat-sensitive gelization separately.
5. adherence preventing material according to claim 1 is characterized in that, the weight percent content of every kind of block copolymer in the described polymeric blends is 5-95%.
6. adherence preventing material according to claim 1 is characterized in that, described block copolymer comprises:
A) the hydrophilic A polymer blocks that contains Polyethylene Glycol of 10-90 wt % with mean molecule quantity of 400 to 8000;
B) the hydrophobicity B polymer blocks of 90-10 wt %.
7. adherence preventing material according to claim 6 is characterized in that, described hydrophobicity B polymer blocks is the polyester with mean molecule quantity of 500-40000.
8. adherence preventing material according to claim 7, it is characterized in that, described polyester is selected from poly DL-lactide, 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, poly-1,4, any in 8 – trioxa spiral shell [4.6] –, 9 – hendecanones, poly-P-Dioxane ketone, polyesteramide, Merlon, polyacrylate, the polyether ester, the perhaps any type of copolymer of above-mentioned each kind polyester.
9. adherence preventing material 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
n Or B (AB)
n The segmented copolymer of block configuration, wherein
nIt is 2 to 10 integer.
10. adherence preventing material according to claim 1 is characterized in that, the weight percent content of described polymeric blends in aqueous solution is 3-50%.
11. adherence preventing material according to claim 1, it is characterized in that, solvent in the described polymeric blends solution is body fluid, tissue culture medium, the cell culture fluid of pure water, water for injection, normal saline, buffer solution, animals and plants or human body, perhaps for other aqueous solution with not based on the medium of organic solvent.
12. adherence preventing material according to claim 1 is characterized in that this aqueous systems has temperature-responsive, i.e. spontaneous formation hydrogel under body temperature.
13. adherence preventing material according to claim 1 is characterized in that this aqueous systems load simultaneously antiinflammatory, analgesia or somatomedin class medicine.
14. the preparation method as one of claim 1-13 described adherence preventing material is characterized in that concrete steps are: 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 at dissolution in low temperature, thus the preparation hydrogel composition;
Add regulator in above-mentioned polymeric blends solution, its weight percentage in system is between 0.5-15%; Regulator is selected from a kind of in sugar, salt, sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, mountain plough alcohol, surfactant, polysorbas20, polysorbate40, Tween 80, xylitol, oligosaccharide, chrondroitin, chitin, chitosan, collagen protein, gelatin, albumin glue, hyaluronic acid, the Polyethylene Glycol or wherein several combinations;
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.
15. as the application of anti aspect after surgery of the described adherence preventing material of one of claim 1-13.
16. application according to claim 15 is characterized in that, described post-operation adhesion preventing comprises intestinal adhesion, abdominal adhesions, adhesion of tendon, fallopian tube adhesion or the ureter adhesion that causes after the operation.
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