CN1958074B - Injectable block copolymer hydrogel of temperature sensibility(epsi - caprolactone - glycolide)- polyethyleneglycol - Google Patents
Injectable block copolymer hydrogel of temperature sensibility(epsi - caprolactone - glycolide)- polyethyleneglycol Download PDFInfo
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- CN1958074B CN1958074B CN2006100216251A CN200610021625A CN1958074B CN 1958074 B CN1958074 B CN 1958074B CN 2006100216251 A CN2006100216251 A CN 2006100216251A CN 200610021625 A CN200610021625 A CN 200610021625A CN 1958074 B CN1958074 B CN 1958074B
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Abstract
An injectable temp-sensitive hydrogel with high affinity to both hydrophobic and hydrophilic medicines is a poly (epsilon-caprolactone-glycolide)-polyethylene glycol block copolymer or poly (epsilon-caprolactone-paradioxy hexacyclone)- polyethylene glycol block copolymer, which is composed of poly (epsilon- caprolactone-glycolide) [P(epsilon-CL-GA)] or poly (epsilon-caprolactone- paradioxyhexacyclone) [P(epsilon-CL-PDO)] as hydrophobic chain and the polyethylene glycol as hydrophilic chain. It appears as liquid at room temp or gel at the temp of human body.
Description
Technical field
The present invention relates to poly-(6-caprolactone-P-Dioxane the ketone)-Polyethylene Glycol of Injectable temperature sensitive, poly-(6-caprolactone-P-Dioxane ketone)-polyethyleneglycol block copolymer hydrogel and controlled drug delivery system thereof.It is be that hydrophobic segment (A) and Polyethylene Glycol (PEG) are the ABA or the BAB triblock copolymer of hydrophilic segment (B) composition with poly-(6-caprolactone-Acetic acid, hydroxy-, bimol. cyclic ester) [P (ε-CL-GA)] or poly-(6-caprolactone-P-Dioxane ketone) [P (ε-CL-PDO)], its certain density aqueous solution exists with liquid form in room temperature or below the room temperature, and at the next gel state that becomes of human body temperature.The invention belongs to Biodegradable material and medicine sustained release field.
Background technology
Research controlled release preparation purpose is to seek a kind of activity that can keep medicine, keeps effective blood drug level in the administration process in the affected part for a long time, and makes the blood drug level at other position of human body drop to minimum method.Traditional administering mode has a lot of limitation, and is low as bioavailability of medicament, and toxic and side effects is bigger etc.The gel sustained release system that grew up in recent years is for reducing drug dose, control drug effect zone, and improving bioavailability of medicament and reducing its toxic and side effects etc. all is a kind of extraordinary administering modes.
Biodegradable temperature-sensitive hydrogel, have following advantage or characteristics as the carrier of sustained release medicine: at first, it is liquid that aqueous solutions of polymers at room temperature is, and viscosity is little, has flowability, can filtration sterilization.Secondly, various medicines can load with simple blended method, the drug loading height, and not with an organic solvent, help the maintenance of pharmaceutically active.Once more, adopt the mode administration of injecting to reduce patient's misery, administering mode is convenient, and patient is strong along being subjected to property; The mixture of medicine and polymer solution can adapt to different cavity shape in the body after injecting in the body with liquid form, is not easy migration, and the fixed point that helps medicine discharges.At last, biodegradable hydrogel can slowly be degraded into the micromolecule product and be absorbed in human body, does not need to take out by operation behind the injection human body.
Except that using as injectable medicine carrying hydrogel, biodegradable temperature-sensitive hydrogel also can be advantageously used in the medicine sustained release of skin surface, promotes the growth or the healing of skin.People such as Lee, Pharmaceutical Research, 20 (12), 1995-2000 (2003), the PEG-PLGA-PEG aqueous solution that will contain plasmid TGF-_1 spreads upon on the experimental mouse wound, contrast and experiment shows that the PEG-PLGA-PEG aquagel membrane of carrying genes medicine has been accelerated the growth of skin cell proliferation and collagen, has promoted the epidermal growth of wound.
People such as Rathi are in U.S. Pat 6,117,949, US 6,201,072, US 6,004,573 with and corresponding Chinese patent CN 1161396C in to disclose with poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester) [P (LA-GA)] be that hydrophobic chain segment A and Polyethylene Glycol are the ABA type and the BAB type block copolymer of hydrophilic segment B composition, its certain density aqueous solution is flowable liquid condition when low temperature, begin to form hydrogel in the time of between 30-35 ℃, and hydrogel subsides when temperature is elevated between 40-70 ℃.Vitro drug release experiment shows, under human body temperature, insulin and paclitaxel respectively in 200 hours and 50 days in the described hydrogel at the uniform velocity release finish.Yet because the acid catalysis characteristic that described hydrogel degradation speed is very fast and degraded is had, hydrogel inside can produce a large amount of acidic materials in degradation process, be unfavorable for the active maintenance of active medicine, limited it in active component sustained release Application for Field.In addition, the drug release cycle of the hydrogel described in these patents is about 1 month, can't satisfy the demand of longer medicine some needs deenergized period.
People such as Martini, J Chem Soc, 90 (13), 1961-1966 (1994), people such as Hwang, Biomacromolecules, 6,885-890 (2005), and people such as Bae, Macromolecules, 38 (12), 5260-5265 (2005) has reported that with poly-(6-caprolactone) be that hydrophobic chain segment A and Polyethylene Glycol are ABA type and the BAB type block copolymer that hydrophilic segment B forms (PCL), and its certain density aqueous solution has suitable sol-gel transition temperature.Yet because the degradation rate of poly-(6-caprolactone) is extremely slow, the hydrogel of being reported is not absorbed in human body for a long time, is easy to generate bad tissue reaction and side effect, has limited it in injectable medicine carrying hydrogel Application for Field.
In sum, need novel in drug release process, not the producing a large amount of acidic materials, be adapted to the injection aquagel that active medicine discharges of development.Poly-(6-caprolactone) is a kind of Biodegradable material with good biocompatibility, drug permeability is good, because it has the advantages that hydrophobicity is strong, degradation speed is slow, with it is that the hydrogel of hydrophobic segment key component is not easy to produce extreme acidic micro-environment in drug release process, helps the active maintenance of active medicine.Polyglycolic acid (PGA) and poly-P-Dioxane ketone (PPDO) all are used for human body by drugs approved by FDA and have the Biodegradable material of quick degradation rate, the monomer whose unit is incorporated in the hydrophobic segment of gel copolymer and goes, help overcoming the slow defective of pure PCL degradation rate, the speed that hydrogel is absorbed by the body can satisfy actual instructions for use.
Summary of the invention
The object of the present invention is to provide the novel Injectable temperature sensitive hydrogel and the controlled drug delivery system thereof that in drug release process, can not produce a large amount of acid degradation products.The material of described hydrogel is the triblock copolymer that biodegradable hydrophobic chain segment and Polyethylene Glycol hydrophilic segment are formed, the mixture that its certain density aqueous solution or medicine are dispersed in its aqueous solution exists with flowable liquid form in room temperature or below the room temperature, and exists with stabilizing gel attitude form in that human body temperature is next.
Above-mentioned purpose of the present invention can be by be that hydrophobic segment (A) and Polyethylene Glycol (PEG) are ABA or the realization of BAB triblock copolymer that hydrophilic segment (B) is formed with poly-(6-caprolactone-Acetic acid, hydroxy-, bimol. cyclic ester) [P (ε-CL-GA)] or poly-(6-caprolactone-P-Dioxane ketone) [P (ε-CL-PDO)].Wherein the content of hydrophobic segment A is 50-90wt%, and the content of hydrophilic segment B is 10-50wt%.
The number-average molecular weight of the hydrophilic segment PEG of triblock copolymer is 500-10000, and more suitable molecular weight is 500-5000.
Among the hydrophobic segment A of triblock copolymer, the content of 6-caprolactone is 10-100mol%, Acetic acid, hydroxy-, bimol. cyclic ester or be 0-90mol% to the content of dioxy Ketohexamethylene; More suitable composition is, the content of 6-caprolactone is 20-95mol%, Acetic acid, hydroxy-, bimol. cyclic ester or be 5-80mol% to the content of dioxy Ketohexamethylene.
The ABA type triblock copolymer that the present invention proposes can be according to " coordination insertion " mechanism, under the condition of suitable catalyst, is initiator with the Polyethylene Glycol of terminal hydroxyl, causes corresponding monomer generation ring-opening polymerisation and prepare.Synthetic method is as follows: the catalyst of a certain proportion of 6-caprolactone, Acetic acid, hydroxy-, bimol. cyclic ester (or to dioxy Ketohexamethylene) and Polyethylene Glycol and appropriate amount is added in the reaction vessel of band stirring, at room temperature the system decompression is evacuated, feed nitrogen subsequently, so repeated multiple times; Under vacuum condition, place the oil bath of suitable temperature to react the some time reaction vessel; Product is filtered after dissolution/precipitation is handled, and is dried to constant weight in vacuum drying oven.
In the above-mentioned synthetic method, the condition of ring-opening polymerisation is: reaction system vacuum is below 1mmHg; Catalyst content is 0.005-0.5wt%, and more suitable content is 0.01-0.2wt%; Polymeric reaction temperature is 60-240 ℃, and more suitable temperature is 80-180 ℃, and optimal reaction temperature is 110-160 ℃; Polymerization reaction time is between 1-48 hour, and the more suitable time is 4-36 hour, and Best Times is 8-24 hour; Catalyst generally uses stannous octoate, stannous chloride or triethyl aluminum.
In the above-mentioned synthetic method, resulting polymers dissolves with dichloromethane, precipitates in a large amount of freezing ether then, to remove unreacted monomer and catalyst, filters, and is dry in vacuum drying oven.
The triblock copolymer that the present invention proposes, its solution only just can demonstrate tangible solution-gel conversion under suitable concentration.When concentration was too low, its solution raise with temperature colloidal sol-precipitation transformation only takes place, and gel state can not occur under human body temperature; When concentration is too high, its solution room temperature or below the room temperature promptly the form with gel state exist, be unfavorable for the loading of medicine.Therefore, when using as injectable medicine carrying hydrogel, the concentration of copolymer should be 5-50wt%, and more suitable concentration is 10-40wt%.
The medicament contg of the hydrogel that the present invention proposes does not have bound theoretically.Yet, consider the dispersibility of medicine in hydrogel, and medicine is to hydrogel heat deflection Effect on Performance, the suitable concn of medicine in hydrogel is 0.001-50wt%, more suitable concentration is 0.01-25wt%.
The hydrogel that the present invention proposes is applicable to the purpose of multiple medicine sustained release, the medicine of degeneration or inactivation particularly takes place in sour environment easily, these medicines comprise the medicine of polypeptide, protein, nucleic acid, gene, vaccine, hormone, cancer therapy drug and other natural extract or synthetic, more more concrete, these medicines comprise Hepatitis B virus vaccine, interferon, insulin, Rayleigh medicine series, paclitaxel, rifampicin, adopted cigarette hydrazine, risperidone, naltrexone, nerve growth factor, skeletal growth factor etc.
Description of drawings
Fig. 1 is the (ε-CL-GA)-PEG-P (phasor of triblock copolymer sol-gel transition of ε-CL-GA) of P under different temperatures and the concentration.
((cumulative percentage that discharges the triblock copolymer hydrogel of ε-CL-GA) contains discharge curve to ε-CL-GA)-PEG-P to Fig. 2 from P for rifampicin.
The specific embodiment
Embodiment 1
P (ε-CL-GA)-(ε-CL-GA) triblock copolymer is synthetic for PEG-P
Be equipped with in 100 milliliters of reaction vessels of magnetic stirring apparatus one, the adding molecular weight is 1540 Polyethylene Glycol 20 grams, 6-caprolactone 40 gram g, and Acetic acid, hydroxy-, bimol. cyclic ester 4 restrains, and then injects 0.5 milliliter of stannous octoate solution (concentration is 0.1g/ml) with microsyringe.At room temperature the reaction system decompression is evacuated, replaces system with high pure nitrogen, so repeated multiple times every half an hour.Polyreaction was carried out 12 hours under 120 ℃ oil bath and stirring condition.After reaction finished, resulting polymers dissolved with dichloromethane, and then with a large amount of freezing ether sedimentations, behind the polymer after the purification in 70 ℃ of vacuum drying ovens drying 24 hours.
Embodiment 2
P (ε-CL-GA)-PEG-P (the heat deflection performance of triblock copolymer of ε-CL-GA)
Under different concentration, measure the sol-gel heat deflection behavior of triblock copolymer aqueous solution among the embodiment 1.The aqueous solution for preparing the triblock copolymer of variable concentrations is at low temperatures observed its viscosity between 20-50 ℃ and is changed.The definition of gel is that when the aqueous solution that triblock copolymer will be housed was inverted, mobile state did not take place solution.Figure 1 shows that the phasor of the sol-gel transition of the triblock copolymer aqueous solution among the embodiment 1.By this phasor as can be seen, be 25wt% when above in concentration, the aqueous solution of triblock copolymer is flowable liquid in room temperature or below the room temperature, and exists with the stabilizing gel attitude in that human body temperature is next.
Embodiment 3
The different ABA type P that form (ε-CL-GA)-PEG-P (the temperature sensitive property of triblock copolymer of ε-CL-GA)
Adopting the synthetic method among the embodiment 1, is that 1540 Polyethylene Glycol is a hydrophilic segment with molecular weight, syntheticly forms different a series of triblock copolymer compounds.Have reversible heat deflection behavior P (ε-CL-GA)-PEG-P (ε-CL-GA) the raw material ratio of components of triblock copolymer is as shown in the table:
| The sample sequence number | Polyethylene Glycol (g) | 6-caprolactone (g) | Acetic acid, hydroxy-, bimol. cyclic ester (g) | Whether reversible |
| 2 3 4 5 | 20 20 20 20 | 38 36 32 28 | 4.2 3.6 3.2 2.8 | Be |
Embodiment 4
The different BAB type PEG-P that form (the temperature sensitive property of ε-CL-GA)-PEG triblock copolymer
Adopt the synthetic method among the embodiment 1, with molecular weight is that 550 poly glycol monomethyl ether is a hydrophilic segment, synthetic different a series of PEG-P (two block copolymers of ε-CL-GA) of forming, and then be coupling agent with the hexamethyl vulcabond, obtain BAB type PEG-P (ε-CL-GA)-PEG triblock copolymer.Have reversible heat deflection behavior PEG-P (ε-CL-GA)-PEG triblock copolymer the raw material ratio of components as shown in the table:
| The sample sequence number | Polyethylene Glycol (g) | 6-caprolactone (g) | Acetic acid, hydroxy-, bimol. cyclic ester (g) | Whether reversible |
| 6 7 | 20 40 | 40 36 | 4 3.6 | Be |
Embodiment 5
P (ε-CL-PDO)-(ε-CL-PDO) triblock copolymer is synthetic for PEG-P
Be equipped with in 100 milliliters of reaction vessels of magnetic stirring apparatus one, the adding molecular weight is 1540 Polyethylene Glycol 20 grams, and 6-caprolactone 40 gram g restrain dioxy Ketohexamethylene 4, and then inject 0.5 milliliter of stannous octoate solution (concentration is 0.1g/ml) with microsyringe.At room temperature the reaction system decompression is evacuated, replaces system with high pure nitrogen, so repeated multiple times every half an hour.Polyreaction was carried out 12 hours under 120 ℃ oil bath and stirring condition.After reaction finished, resulting polymers dissolved with dichloromethane, and then with a large amount of freezing ether sedimentations, behind the polymer after the purification in 70 ℃ of vacuum drying ovens drying 24 hours.
The aqueous solution of the 25wt% of gained triblock polymer at room temperature is flowable liquid, begin to form gel in the time of 30 ℃, and gel caves in the time of 39 ℃.
Embodiment 6
Rifampicin is from the P (ε-CL-GA)-PEG-P (release behavior the triblock copolymer hydrogel of ε-CL-GA)
Get (ε-CL-GA)-PEG-P (the triblock copolymer of ε-CL-GA) of synthetic P among the 0.25 gram embodiment 1, add an amount of redistilled water and be configured to the aqueous solution that concentration is 25wt%, add 10 milligrams of rifampicin then, oscillation treatment 5 minutes, become uniform solution to system till.The solution system of gained after two minutes, becomes gel 37 ℃ of placements.In the test tube that the medicine carrying gel is housed, add 10ml buffer solution, take out buffer at regular intervals, measure the wherein content of rifampicin, promptly obtain rifampicin cumulative release curve (Fig. 2) with ultraviolet spectrophotometer.
Claims (10)
1. biodegradable triblock copolymer with temperature sensitive property, formed by poly-(6-caprolactone-P-Dioxane ketone) [P (ε-CL-PDO)] hydrophobic segment (A) and Polyethylene Glycol (PEG) hydrophilic segment (B), it is characterized in that: the content of hydrophobic segment A is 50-90wt% in (1) copolymer, and the content of hydrophilic segment B is 10-50wt%; (2) content of 6-caprolactone is 20-95mol% among the hydrophobic segment A, is 5-80mol% to the content of dioxy Ketohexamethylene.
2. triblock copolymer according to claim 1 is characterized in that: this triblock copolymer is the ABA type.
3. triblock copolymer according to claim 1 is characterized in that: this triblock copolymer is the BAB type.
4. triblock copolymer according to claim 1 is characterized in that: the aqueous solution the when concentration of copolymer is 5-50wt% room temperature or below the room temperature for flowable liquid, and exist with the stabilizing gel form in that human body temperature is next.
5. triblock copolymer according to claim 1 is characterized in that: the average average molecular weight of hydrophilic segment B is 500-5000.
6. injectable drug delivery systme with temperature sensitive property, it is characterized in that: medicine is dispersed in formed mixture in the aqueous solution of any block copolymer described in the aforesaid right requirement 1-5, in room temperature or below the room temperature is flowable liquid, and exists with the stabilizing gel form in that human body temperature is next.
7. drug delivery system according to claim 6 is characterized in that: the content of triblock copolymer is 10-40wt% in the described mixture.
8. according to the drug delivery system described in the claim 6, it is characterized in that: the medicine in the described mixture comprises the medicine of polypeptide, nucleic acid, vaccine, hormone, cancer therapy drug and other natural extract or synthetic.
9. drug delivery system according to claim 8 is characterized in that: medicine comprises Hepatitis B virus vaccine, interferon, insulin, Rayleigh medicine series, paclitaxel, rifampicin, adopted cigarette hydrazine, risperidone, naltrexone, nerve growth factor or skeletal growth factor.
10. drug delivery system according to claim 6 is characterized in that: the content of described mixture Chinese medicine is 0.01-25wt%.
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| CN110423337A (en) * | 2019-07-08 | 2019-11-08 | 浙江大学衢州研究院 | A kind of Thermo-sensitive supermolecule polymer and preparation method thereof of multiple hydrogen bonding regulation |
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| US9155722B2 (en) | 2009-09-18 | 2015-10-13 | Protherics Salt Lake City, Inc. | Reconstitutable reverse thermal gelling polymers |
| KR101838304B1 (en) * | 2009-09-18 | 2018-03-13 | 비티지 인터내셔널 리미티드 | BAB triblock polymers having improved release characteristics |
| US8753621B2 (en) | 2009-09-18 | 2014-06-17 | Protherics Salt Lake City, Inc. | BAB triblock polymers having improved release characteristics |
| US20120045511A1 (en) * | 2010-08-17 | 2012-02-23 | Industrial Technology Research Institute | Thermosensitive hepatitis b vaccine |
| CN102731981B (en) * | 2012-06-01 | 2014-08-27 | 华中科技大学 | Temperature-sensitive injectable mixed hydrogel |
| JP6143286B2 (en) * | 2013-05-13 | 2017-06-07 | 学校法人 関西大学 | Anti-adhesion material and method for producing the same |
| CN105982845A (en) * | 2015-02-17 | 2016-10-05 | 复旦大学 | Thermotropic hydrogel hypoglycemic drug preparation and preparing method thereof |
| CN105801825B (en) * | 2016-05-26 | 2018-01-09 | 四川理工学院 | It is catalyzed method of the annular lactone copolymerization containing multiple bromo functional groups amphipathic nature polyalcohols and its cationisable's graft copolymer |
| JP6403297B2 (en) * | 2017-05-02 | 2018-10-10 | 川澄化学工業株式会社 | Method for producing anti-adhesion material |
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| CN110423337A (en) * | 2019-07-08 | 2019-11-08 | 浙江大学衢州研究院 | A kind of Thermo-sensitive supermolecule polymer and preparation method thereof of multiple hydrogen bonding regulation |
| CN110423337B (en) * | 2019-07-08 | 2022-06-07 | 浙江大学衢州研究院 | Temperature-sensitive supramolecular polymer regulated and controlled by multiple hydrogen bonds and preparation method thereof |
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