CN102070773A - Injectable temperature-sensitive polycarbonate-polyethylene glycol segmented copolymer hydrogel - Google Patents

Abstract

The invention relates to an injectable temperature-sensitive polycarbonate-polyethylene glycol segmented copolymer hydrogel. The hydrogel is an ABA triblock copolymer or a BAB triblock copolymer consisting of polycarbonate and other lactone and lactide copolymer, which serve as lyophobic chain segments (A), and polyethylene glycol (PEG) which serves as a hydrophilic chain segment (B). The aqueous solution of the hydrogel with a certain concentration exists in the form of liquid at the room temperature or at the temperature below the room temperature and becomes a gel state at a human body temperature. Because the polycarbonate does not generate small acidic molecules in a degradation process, the degradation period of the hydrogel can be adjusted and the pH of the hydrogel in a microenvironment is relatively stable and then the hydrogel contributes to the maintenance of the activity of biological macromolecule medicaments.

Description

Injectable temperature sensitive polycarbonate-polyethyleneglycol block copolymer hydrogel

Technical field

The present invention relates to Injectable temperature sensitive polycarbonate-polyethyleneglycol block copolymer hydrogel.It is with polycarbonate and with other lactones, lactide multipolymer be that hydrophobic segment (A) and polyoxyethylene glycol (PEG) they are the ABA or the BAB triblock copolymer of hydrophilic segment (B) composition, 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.Because polycarbonate do not produce acid small molecules in degradation process, this hydrogel degradation cycle is adjustable and also microenvironment in pH comparatively stable, help the active maintenance of biopharmaceutical macromolecular drug.

Background technology

Research controlled release preparation purpose is to seek a kind of activity that can keep medicine, keeps effective Plasma Concentration in the administration process in the affected part for a long time, and makes the Plasma Concentration 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 side effect 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 side effect 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 pharmaceutical activity.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 polymers soln 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 small molecules 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-(rac-Lactide-glycollide) [P (LA-GA)] be that hydrophobic chain segment A and polyoxyethylene glycol are the ABA type and the BAB type segmented copolymer of hydrophilic segment B composition, its certain density aqueous solution is flowable liquid state 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, Regular Insulin and taxol 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 substance in degradation process, be unfavorable for the active maintenance of active medicine, limited it in active ingredient 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 polyoxyethylene glycol are ABA type and the BAB type segmented 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.

People such as Cho, Biomaterials 25 (2004) 3733-3742 have reported poly-(6-caprolactone-D, L-rac-Lactide)-polyethylene glycol-(6-caprolactone-D, L-rac-Lactide) stomach externally applied medicine sustained release carrier.D, the demoted fusing point of polycaprolactone of L-rac-Lactide and caprolactone random copolymerization, the fusing point that makes multipolymer is about 40 ℃, a little more than body temperature.Medicine can mix at polymkeric substance melting state like this, injects in the body then.Because the temperature of mixing medicine, is unfavorable for the activity of medicines such as albumen, gene than higher and keeps.

In sum, material degradation speed and biocompatibility have certain associated part.PLA, PGA etc. are during as internal fixation material, because degradation rate is too fast, can make that a part is individual to produce the nonspecific inflammation reaction, show as the sterility tumour.Therefore, need novel in drug release process, not the producing a large amount of acidic substance, 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 main ingredient is not easy to produce extreme acidic micro-environment in drug release process, helps the active maintenance of active medicine.The PCL degraded is too slow, has influenced human body it is absorbed fully.PTMC has the Biodegradable material of suitable degradation rate, does not produce acidic substance in the degradation process.PCL and PTMC copolymerization can be regulated degradation speed.The polyester compound all contains hydrolyzable chemical bond, but in vivo except that the hydrolysis effect, the effect of enzyme is also depended in the degraded of multipolymer.In blood plasma and bile, because the content of lipase is fewer, the degradation speed of material depends on the TMC components contents that is easy to hydrolysis.The degraded of PCL depends primarily on the kind and the quality of enzyme in the environment.The pig pancreatin is very responsive to the PCL degraded, and much higher effect to material degradation is just more outstanding in the concentration ratio blood plasma of enzyme and the bile in the pancreatic tissue suspension, makes the degradation speed of PCL accelerate.Therefore, PCL and PTMC monomeric unit are incorporated in the hydrophobic segment of gel copolymer and go, help overcoming the slow defective of pure PCL degradation rate, the speed that hydrogel is absorbed by the body can satisfy actual service requirements.

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 polyoxyethylene 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 stable 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 polyoxyethylene glycol (PEG) are the ABA or the realization of BAB triblock copolymer of hydrophilic segment (B) composition with poly-(6-caprolactone-trimethylene carbonate) [P (ε-CL-TMC)].Wherein the content of hydrophobic segment A is 40-90wt%, and the content of hydrophilic segment B is 10-60wt%.

The number-average molecular weight of the hydrophilic segment PEG of triblock copolymer is 500-10000, and more suitable molecular weight is 500-8000.

Among the hydrophobic segment A of triblock copolymer, the content of 6-caprolactone is 20-90mol%, and the content of trimethylene carbonate is 10-80mol%; More suitable composition is, the content of 6-caprolactone is 40-80mol%, and the content of trimethylene carbonate is 20-60mol%.

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 polyoxyethylene glycol of terminal hydroxyl, causes corresponding monomer generation ring-opening polymerization and prepare.Synthetic method is as follows: the catalyzer of a certain proportion of 6-caprolactone, trimethylene carbonate and polyoxyethylene 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 temp to react the some time reaction vessel; Reaction 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 polymerization is: reaction system vacuum tightness 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; Catalyzer generally uses stannous octoate, tin protochloride or triethyl aluminum.

In the above-mentioned synthetic method, resulting polymers dissolves with methylene dichloride, precipitates in a large amount of freezing ether then, to remove unreacted monomer and catalyzer, 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 multipolymer should be 5-50wt%, and more suitable concentration is 5-40wt%.

Description of drawings

Fig. 1 is the (ε-CL-TMC)-PEG-P (phasor of triblock copolymer sol-gel transition of ε-CL-TMC) of P under differing temps and the concentration.

Fig. 2 different time P (ε-CL-TMC)-PEG-P (ε-CL-TMC) variation of hydrogel buffer pH.

Embodiment

Embodiment 1

P (ε-CL-TMC)-(ε-CL-TMC) 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 polyoxyethylene glycol 20 grams, 6-caprolactone 40 gram g, trimethylene carbonate 8 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 agitation condition.After reaction finished, resulting polymers dissolved with methylene dichloride, and then with a large amount of freezing ether sedimentations, behind the polymkeric substance after the purification in 70 ℃ of vacuum drying ovens drying 24 hours.

Embodiment 2

P (ε-CL-TMC)-PEG-P (the heat deflection performance of triblock copolymer of ε-CL-TMC)

Under different concentration, measure the sol-gel heat deflection behavior of the triblock copolymer aqueous solution among the embodiment 1.The aqueous solution for preparing the triblock copolymer of different concns 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, the 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 stable gel attitude in that human body temperature is next.

Embodiment 3.

With the water-soluble solution that is made into about 25wt% of PI, inject the 50ml plastics tubing with syringe accurate weighing 2g liquid on electronic balance, place 10min at 37 ℃ and make it become gel.With the phosphate buffer soln of 7.4,37 ℃ of 50ml syringe extraction 20mlpH, along in the slow injecting tube of tube wall, through the pH value of sampling and measuring residual buffer solution after the different timed intervals.In the scope, the pH value stabilization of buffered soln is more than 7.2 at the trial.

Claims (8)

1. the biodegradable triblock copolymer that has temperature sensitive property is made up of by hydrophobic segment (A) and polyoxyethylene glycol (PEG) hydrophilic segment (B) polycarbonate and multipolymer thereof, it is characterized in that: the content of hydrophobic segment A is 40-90wt% in (1) multipolymer, and the content of hydrophilic segment B is 10-60wt%; (2) carbonate content is 20-90mol% among the hydrophobic segment A, and the content of other lactides, lactone is 10-80mol%.

2. the triblock copolymer in the claim 1, it is characterized in that: this triblock copolymer is the ABA type.

3. the triblock copolymer in the claim 1, it is characterized in that: this triblock copolymer is the BAB type.

4. the triblock copolymer in the claim 1 is characterized in that: its certain density aqueous solution is flowable liquid in room temperature or below the room temperature, and exists with the stable gel form in that human body temperature is next.

5. the triblock copolymer in the claim 1, it is characterized in that: the mean number average molecular weight of hydrophilic segment B is 500-8000.

6. the injectable drug delivery systme that has temperature sensitive property, it is characterized in that: medicine is dispersed in formed mixture in the aqueous solution of any segmented copolymer described in the aforesaid right requirement 1-5, in room temperature or below the room temperature is flowable liquid, and exists with the stable gel form in that human body temperature is next.

7. the drug delivery system in the claim 6, it is characterized in that: the content of triblock copolymer is 5-40wt% in the described mixture.

8. the drug delivery system in the claim 6, it is characterized in that: the content of described mixture Chinese traditional medicine is 0.01-30wt%.

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