KR101455359B1 - Polyester block copolymer having various functional groups in side chain or chain-end position of which mechanical strength and biodegradation period is adjustable - Google Patents

Abstract

The present invention relates to a polyester block copolymer whose mechanical property and biodegradation period are adjustable, the polyester block copolymer which has various functional groups in side chain or a chain end. The polyester block copolymer of the present invention is suitable for the human body and has mechanical properties and half life of biodegradation which are adjustable, thereby resolving adsorption of the protein in the body when applied to the human body and side effect from accumulated products of hydrolysis.

Description

[0001] The present invention relates to a polyester block copolymer having various mechanical functionalities and biodegradation period is adjustable in which various functional groups are introduced into a side chain or a terminal,

The present invention relates to a polyester block copolymer in which various functional groups are introduced into a side chain or a terminal and can control the mechanical properties and biodegradation period. More specifically, the present invention relates to a lactide, a caprolactone, a lactide having various functional groups, ≪ RTI ID = 0.0 > caprolactone. ≪ / RTI >

Recently, studies have been actively underway to replace the role of disease, disrupted function, and organs. The bio-implantable structures, which are mainly made of biomaterials, are designed to replace or disappear biological structures that have been lost, and much attention has been focused on them. In the past, silicon or metal was used, And it was necessary to perform surgery to remove it again because there was a problem that causes inflammation or other diseases. In order to solve these problems, biodegradable natural polymers or synthetic polymers have been used. Generally, synthetic polymers which are more excellent in mechanical properties than natural polymers and can control the rate of biodegradation have been used. Natural biodegradable polymers include polypeptides such as collagen and gelatin, polyamino acids such as poly-L-glutamic acid, poly-L-lysine, and alginic acid , Polysaccharides including chitin, and the like. However, such natural biodegradable polymeric materials have limited physical properties, as well as various limitations in terms of processability and mass productivity.

Therefore, in recent years, studies on synthetic polymers have been actively conducted, and many studies have been conducted on aliphatic polyesters having excellent physical properties and hydrolysis characteristics. However, since these synthetic polymer materials are used for living bodies, they must satisfy various conditions such as biostability, biocompatibility, low toxicity, and immunity. Therefore, studies are underway, limited to substances approved by agencies such as the US FDA and relatively well-known biocompatibility. Typically, there are polycaprolactone (PCL), polylactide (PLA), polyglycolide (PGA), and the like, and polyesters obtained by copolymerizing these at various ratios are often used. However, when they are used in the form of a single polymer, polycaprolactone (PCL) has a very slow biodegradation period of about 2 to 3 years and has poor mechanical properties. On the other hand, polylactide (PLA) and polyglycolide (PGA) have a relatively high biodegradation rate and excellent mechanical properties, but they have a disadvantage in that they cause damage to surrounding cells due to high crystallinity and degradation products have. In the case of the copolymer, the conventional widely used poly (lactide-co-glycolide) (PLGA) is decomposed in 1 to 2 months because of its rapid decomposition rate, but it is easy to manufacture a biologically applicable graft structure requiring excellent mechanical strength And it is difficult to apply for long-term use requiring decomposition several months later, and it is difficult to apply drugs having poor stability such as protein due to rapid degradation and a severe pH drop in the substrate. Therefore, the polyester has limitations in mechanical properties and biodegradation control, and has difficulties in the inflammatory reaction, immune response upon insertion into the body, or organization of the polyester.

In order to control the physical properties of the graft structure prepared using the above-mentioned polyesters, functional groups are introduced into the polyester itself or the prepared graft structure through processes such as electric discharge, plasma treatment and chemical treatment. However, such a functional group introduction process is disadvantageous in that the basic structure of a bio-implantable structure made of polyester or polyester is cut off, and therefore, a substantial change occurs in the inherent properties of the bio-implantable structure, have.

The present inventors have made efforts to overcome the problems of the prior art as described above, and as a result, they have found that it is possible to control the mechanical properties and the biodegradation period by introducing various functional groups at the side chain or terminal of the polyester block copolymer, .

Accordingly, it is an object of the present invention to provide a polyester block copolymer capable of regulating mechanical properties and controlling the biodegradation period, in which various functional groups are introduced into side chains or terminals, and a method for producing the same.

The present invention also provides a drug carrier, gene carrier, or tissue engineering support comprising the polyester block copolymer.

The present invention provides a polyester block copolymer capable of regulating mechanical properties and controlling the biodegradation period, in which various functional groups are introduced into side chains or terminals, and a method for producing the same.

The present invention also provides a drug carrier, gene carrier, or tissue engineering support comprising the polyester block copolymer.

The polyester block copolymer of the present invention is not only suitable for a living body but also can control mechanical properties and has a biodegradable half-life controlled by introducing various functional groups to the side chain or terminal. Therefore, Adsorption and side effects due to local accumulation of hydrolysis products in the body. In addition, it can contain drugs, and it is possible to release pharmacological drugs by controlling the duration of biodegradation, and it is not necessary to undergo biodegradation after a certain period of time after the procedure, Biologically active therapeutic substances, including inhibitory drugs, can be slowly released from the body for long-term delivery. Accordingly, the polyester block copolymer according to the present invention can be effectively used as a biodegradable biodegradable material for a medical material such as a medical matrix, a wound covering material, and a tissue engineering material.

1 is a view showing a method of introducing a functional group into a side chain of a copolymer through a conventional method.
2 is a view showing a method of introducing a functional group into a side chain of a copolymer through polymerization of a monomer having a functional group.
FIGS. 3 to 6 show ¹ H-NMR spectra of Examples 1 to 4 prepared by the present invention.
7 and 8 are graphs showing tensile strength measurement results of the specimens prepared in Example 1-1 and Comparative Examples 1 to 3 prepared by the present invention.
FIG. 9 is a diagram showing the contact angle measurement results of Examples 1 to 3 produced by the present invention. FIG.
10 is a GPC graph (in vitro) of the biodegradation behavior of (a) Example 1-1 produced by the present invention (b) a GPC graph (in vitro) and (c) of the biodegradation behavior of Example 1-2 Fig. 2 is a graph showing the half-life half-lives of Examples 1-1 and 1-2.
FIG. 11 is a photograph showing the H & E staining of the graft structure prepared according to the present invention after being inserted into the rat subcutaneously.
FIG. 12 is a photograph showing the ED1 immunofluorescent staining of the graft structure prepared according to the present invention after being inserted into the rat subcutaneously.
13 is a graph showing in vitro drug release behavior according to the functional groups of Example 3 and Comparative Example 2 produced by the present invention.

The present invention relates to a polyester (F-PCLA) block comprising lactide (LA), caprolactone (CL), lactide (fLA) having a functional group and caprolactone (fCL) Copolymer.

[Chemical Formula 1]

In Formula 1, R is a methyl group, a benzyl ether group, a hydroxyl group, a carboxyl group, an amine group or a peptide; a, b, c and d are molar ratios of monomers, and a + b + c + d = 1.

Hereinafter, the present invention will be described in more detail.

The biodegradable block copolymer of the present invention can appropriately control the decomposition period by controlling the molecular weight and the component ratio and can control the composition of the lactide and caprolactone by appropriately controlling the composition so that the excellent mechanical properties of the polylactide and the polycaprolactone The biodegradability and mechanical strength of the polymer can be improved.

The polyester block copolymer of the present invention comprises lactide (LA), caprolactone (CL), lactide (fLA) having a functional group, and caprolactone (fCL) segment having a functional group and having a molecular weight of 1,000 to 3,000,000 g / mole It is preferable to have a molecular weight. If the molecular weight of the polyester is less than 1,000 g / mole, there is a problem that the graft structure is easily broken or difficult to be applied to the living body. When the molecular weight is more than 3,000,000 g / mole, the fluidity of the polymer is very large, It is preferable to maintain the above range.

As the molecular weight of the polyester (F-PCLA) block copolymer increases, the biodegradation period increases. Therefore, the biodegradation period can be appropriately controlled according to the purpose of use. The biodegradation half-life period of the produced block copolymer is usually 1 to 2 years It is possible to control within. Further, since the biodegradation period and the mechanical properties can be controlled depending on the ratio of each segment used, a more detailed decomposition period and mechanical characteristics can be controlled through the combination thereof.

The present invention

(a) drying the alcohol initiator through azeotropic distillation; And

(b) a step of adding lactide, caprolactone, lactide having a functional group and caprolactone having a functional group to the dried initiator and conducting polymerization, and a process for producing a polyester block copolymer .

[Reaction Scheme 1]

In the above Reaction Scheme 1, R is a methyl group, a benzyl ether group, a hydroxyl group, a carboxyl group, an amine group or a peptide; n is an integer from 1 to 300; a, b, c and d are molar ratios of the monomers constituting the polyester, respectively, and a + b + c + d = 1.

The process for producing the polyester block copolymer according to the present invention will be described in detail as follows.

In step (a), water, methanol, ethanol, ethylene glycol, propylene glycol, carbitol, polyethylene glycol and the like may be used as the step of drying the alcohol initiator. In the present invention, polyethylene glycol is preferable. Polyethylene glycol (PEG) is not toxic and has no immunological rejection reaction and is suitable for use in living bodies. In addition, it has an effect of inhibiting restenosis when it is used as a material of a biotransplantation structure because it has a protein adsorption inhibiting effect. In addition, since the mechanical properties of polyethylene glycol vary depending on the degree of polymerization, the mechanical properties can be controlled by using the same.

When polyethylene glycol is used as the alcohol initiator, the molecular weight of the polyethylene glycol is not limited, but it is preferably 32 to 20,000 g / mole in terms of mechanical properties such as flexibility and elasticity, more preferably 134 to 5,000 g / mole, most preferably 750 to 2,000 g / mole.

The step (b) is a step of ring-opening polymerization of an initiator, lactide, caprolactone, lactide having a functional group and caprolactone having a functional group together to prepare a copolymer. The ester monomer and toluene, which is a reaction solvent, Polymerization is carried out using Sn (Oct) ₂ as an activating agent. At this time, the polymerization reaction is carried out at 50 to 160 ° C, preferably 130 to 160 ° C for about 12 to 48 hours, preferably about 20 to 28 hours.

Although the conventional method of introducing a functional group into a copolymer uses an electric discharge, a plasma treatment, a chemical treatment, or the like as shown in FIG. 1, the present invention is different from the conventional method in that monomers having functional groups are polymerized, A method for introducing a functional group, and a schematic process thereof is shown in Fig.

The present invention also provides a tissue engineering support comprising said polyester block copolymer, an adhesion inhibitor, a drug delivery vehicle or a biodegradable stent.

The polyester block copolymer according to the present invention is capable of producing a copolymer which is not only suitable for living body but also can control the mechanical properties and has excellent tensile strength and elongation by introducing various functional groups at side chains or terminals, It is possible to solve problems such as adsorption of proteins in the body to the surface of the block copolymer and side effects due to local accumulation of hydrolysis products in the body. In addition, when a drug is contained, the release rate can be controlled and the degree of drug release can be controlled stepwise. Thus, the polyester block copolymers according to the invention can be used as effective tissue engineering supports, adhesion inhibitors, drug delivery vehicles and biodegradable stents.

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit or scope of the invention as defined by the appended claims. It will be obvious to you.

Example 1. Preparation of methoxypolyethylene glycol- (polycaprolactone-co-poly F caprolactone-co-polylactide-co-poly F lactide) block copolymer

1-1. Preparation of block copolymer of methoxypolyethylene glycol- (polycaprolactone-co-poly F caprolactone-co-polylactide-co-poly F lactide) having a molecular weight of 500,000 g / mole [MPEG- (PCL- PfCL-co-PLLA-co-PLfLA) (caprolactone: F caprolactone: lactide: F lactide = 45: 45: 5: 5)

Methoxypolyethylene glycol (0.06 g, 0.08 mmol), initiator, and 70 ml of toluene were placed in a well-dried 100 ml round bottom flask and azeotropically distilled at 140 ° C for 3 hours using a Dean Stark trap. After distillation, 30 ml of toluene was removed and the prepolymerized caprolactone (CL) (1.47 g, 12.8 mmol), F caprolactone (fCL) (0.315 g, 1.43 mmol), methoxypolyethylene glycol (MPEG) (0.857 g, 1.43 mmol) of lactide (LA) (1.85 g, 12.8 mmol) and Flactide (fLA) were placed and 40 ml of preliminarily purified toluene was added as a reaction solvent. Then, Sn (Oct) ₂ And the mixture was stirred at 130 DEG C for 24 hours. All procedures were carried out under high purity nitrogen. After the reaction, the reactants were slowly added dropwise to 1,600 ml of hexane and 400 ml of ether to remove unreacted monomers and initiator. The precipitate was dissolved in methylene chloride (MC), filtered with filter paper, the solvent was removed through a rotary evaporator, and dried under reduced pressure to obtain the title copolymer. The molecular weight with respect to the molar ratio of the constituent components of the prepared copolymer was measured by ¹ H-NMR, and the measurement results are shown in FIG.

As shown in FIG. 3, the molecular weight of the prepared copolymer was 511,000 g / mole, which is similar to the theoretical predicted value. The polydispersity was measured by gel permeation chromatography (GPC) Respectively.

1-2. Preparation of block copolymer of methoxypolyethylene glycol- (polycaprolactone-co-poly F caprolactone-co-polylactide-co-poly F lactide) having a molecular weight of 50,000 g / mole [MPEG- (PCL- PfCL-co-PLLA-co-PLfLA) (caprolactone: F caprolactone: lactide: F lactide = 75: 15: 5: 5)

Methoxypolyethylene glycol (0.6 g, 0.8 mmol), initiator, and 70 ml of toluene were placed in a well-dried 100 ml round bottom flask and azeotropically distilled at 140 ° C for 3 hours using a Deanstock trap. After distillation, 30 ml of toluene was removed and the prepolymerized caprolactone (CL) (2.45 g, 21.45 mmol), F caprolactone (fCL) (0.315 g, 1.43 mmol), methoxypolyethylene glycol (MPEG) (0.357 g, 1.43 mmol), Lactide (LA) (1.03 g, 4.3 mmol) and Flactide (fLA) (40 ml) were added to the reaction mixture. Then, Sn (Oct) ₂ And the mixture was stirred at 130 DEG C for 24 hours. All procedures were carried out under high purity nitrogen. After the reaction, the reactants were slowly added dropwise to 1,600 ml of hexane and 400 ml of ether to remove unreacted monomers and initiator. The precipitate was dissolved in methylene chloride (MC), filtered with filter paper, the solvent was removed through a rotary evaporator, and dried under reduced pressure to obtain the title copolymer. The molecular weight with respect to the molar ratio of the constituent components of the prepared copolymer was measured by ¹ H-NMR, and the molecular weight of the copolymer prepared was 49,100 g / mole, which was similar to the theoretical predicted value. The gel permeation chromatography (GPC) showed a polydispersity of 1.5.

Example 2. Methoxypolyethylene glycol- (polycaprolactone-co-poly F caprolactone-co-polylactide-co-poly F lactide) [MPEG- (PCL-co-PfCL- PLfLA)] Introduction of hydroxyl group on the side chain of block copolymer

2 g of the block copolymer of Example 1-1 and 1000 mg of palladium carbon (Pd / C) were placed in anhydrous tetrahydrofuran (200 ml), hydrogen bubbling was performed using a syringe needle, stirring was carried out at room temperature for 16 hours Lt; / RTI > After the reaction, the reaction mixture was filtered using celite, the solvent was removed using a rotary evaporator, and the filtrate was dried under reduced pressure to obtain the title copolymer. ¹ H-NMR was used to determine whether hydroxyl groups of the prepared copolymer were introduced, and the results are shown in FIG.

As shown in Fig. 4, the produced copolymer showed no specific peak of the benzyl group at 7.3 ppm, and hydroxyl group was introduced into the side chain.

Example 3 Preparation of methoxypolyethylene glycol- (polycaprolactone-co-poly F caprolactone-co-polylactide-co-poly F lactide) [MPEG- (PCL-co-PfCL- PLfLA)] Introduction of carboxyl groups on the side chains of block copolymers

2 g of the block copolymer of Example 2 and 160 ml of toluene were placed in a well dried 200 ml round bottom flask and azeotropically distilled at 140 캜 for 3 hours using a Dean Stark trap. After distillation, 60 ml of toluene was left, and the mixture was cooled to room temperature. And 1.04 g of glutaric acid hydride (GA) were charged. Then, 1.2 ml of acetic acid was added as a polymerization catalyst, and the mixture was reacted at 110 ° C for 24 hours. All procedures were carried out under high purity nitrogen. After the reaction, the reaction product was slowly dropped into 800 ml of hexane and 200 ml of ether to remove unreacted monomers and initiator. The precipitate was dissolved in methylene chloride (MC), filtered with filter paper, the solvent was removed through a rotary evaporator, and dried under reduced pressure to obtain the title copolymer. The ¹ H-NMR was used to confirm whether or not the carboxyl group of the prepared copolymer was introduced, and the measurement result is shown in FIG.

As shown in Fig. 5, it was confirmed that a carboxyl group was introduced into the side chain of the produced copolymer.

Example 4. Methoxypolyethylene glycol- (polycaprolactone-co-poly F caprolactone-co-polylactide-co-poly F lactide) [MPEG- (PCL- PLfLA)] Introduction of amine groups in block copolymers

2 g of the block copolymer of Example 3 and 160 ml of toluene were placed in a well dried 200 ml round bottom flask and azeotropic distillation was carried out at 140 캜 for 3 hours using a Dean Stark trap. After distillation, 60 ml of toluene was left, and the mixture was cooled to room temperature. After adding 1.04 g of 2-methyl aziridine, 1.2 ml of acetic acid was added as a polymerization catalyst, and the mixture was reacted at 50 ° C for 24 hours. All procedures were carried out under high purity nitrogen. After the reaction, the reaction was slowly dropped to 700 ml of hexane and 300 ml of ether to remove unreacted monomers and initiator. The precipitate was dissolved in methylene chloride (MC), filtered with filter paper, the solvent was removed through a rotary evaporator, and dried under reduced pressure to obtain the title copolymer. The ¹ H-NMR measurement was conducted to confirm whether or not the emulsion of the prepared copolymer was introduced, and the measurement results are shown in FIG.

As shown in Fig. 6, it was confirmed that an amine device was introduced into the side chain of the produced copolymer.

Example 5 Preparation of methoxypolyethylene glycol- (polycaprolactone-co-poly F caprolactone-co-polylactide-co-poly F lactide) [MPEG- (PCL-co-PfCL- PLfLA)] Introduction of a peptide into the side chain of a block copolymer

1 g of NHS (N-Hydroxysuccinimide), 1.8 g of DCC (N, N'-Dicyclohexylcarbodiimide) and 0.007 g of DMAP (4-Dimethylaminopyridine) were dissolved in 3 ml of anhydrous dimethylsulfoxide (anhydrous DMSO) in 1 g of the block copolymer of Example 4 The reaction was allowed to proceed at room temperature for 24 hours. All procedures were carried out under high purity nitrogen. After completion of the reaction, the reaction mixture was precipitated in excess ether, washed with methanol using ultrasonic waves, and then the solvent was removed using a rotary evaporator and dried under reduced pressure to obtain the title copolymer. 0.1 g of the prepared polymer and 10 mg of RGD were dissolved in 5 ml of anhydrous dimethylsulfoxide (anhydrous DMSO), and 0.25 ml of triethylamine was added thereto, followed by reaction at room temperature for 4 days. After completion of the reaction, the polymer was precipitated in 100 ml of hexane and 200 ml of ether, dialyzed for 2 days using a cellulose membrane, and lyophilized.

Comparative Example 1. Preparation of methoxypolyethylene glycol (MPEG) - (polylactide (PLLA) block copolymer having a molecular weight of 200,000 g / mole)

The initiator methoxypolyethylene glycol (MPEG) and 70 ml of toluene were placed in a well-dried 100 ml round bottom flask and azeotropically distilled at 140 ° C for 3 hours using a Deanstock trap. After distillation, 40 ml of toluene was removed, methoxypolyethylene glycol (MPEG) was cooled to 25 ° C, preliminarily purified lactide (LA) (4 g, 27.75 mmol) was added and 30 ml of preliminarily purified toluene was added as a reaction solvent. Sn (Oct) ₂ was added as a polymerization catalyst and stirred at 130 캜 for 24 hours. All procedures were carried out under high purity nitrogen. After completion of the reaction, the reaction was precipitated by slowly dropping the reaction into 1,600 ml of hexane and 400 ml of ether to remove unreacted monomers and initiator. The precipitate was dissolved in methylene chloride (MC) and filtered through filter paper. The solvent was removed through a rotary evaporator and dried under reduced pressure to obtain the title copolymer.

COMPARATIVE EXAMPLE 2 Preparation of methoxypolyethylene glycol (MPEG) - (polylactide (PLLA) -co-polycaprolactone (PCL)) block copolymer with a molecular weight of 300,000 g / mole [caprolactone and lactide )]

The initiator methoxypolyethylene glycol (MPEG) and 70 ml of toluene were placed in a well-dried 100 ml round bottom flask and azeotropically distilled at 140 ° C for 3 hours using a Deanstock trap. After distillation, 40 ml of toluene was removed and methoxypolyethylene glycol (MPEG) was cooled to 25 DEG C, and then preliminarily purified caprolactone (CL) (1.77 g, 15.5 mmol) and lactide (LA) (2.23 g, 15.5 mmol) 30 ml of preliminarily purified toluene was added as a reaction solvent, and Sn (Oct) ₂ was added as a polymerization catalyst, followed by stirring at 130 ° C for 24 hours. All procedures were carried out under high purity nitrogen. After completion of the reaction, the reaction was precipitated by slowly dropping the reaction into 1,600 ml of hexane and 400 ml of ether to remove unreacted monomers and initiator. The precipitate was dissolved in methylene chloride (MC) and filtered through filter paper. The solvent was removed through a rotary evaporator and dried under reduced pressure to obtain the title copolymer.

Comparative Example 3. Preparation of a copolymer of caprolactone and lactide (50:50) having a molecular weight of 500,000 g / mole

(MPEG) - (polylactide (PLLA) -co-polycaprolactone (PCL)) block copolymer having a molecular weight of 500,000 g / mole was prepared in the same manner as in Comparative Example 2.

The molar ratios of the monomers of Example 1-1 and Comparative Examples 1 to 3 are shown in Table 2 below.

polymer
Molecular weight (g / mole)
The molar ratio of monomers Caprolactone F caprolactone Lactide F Lactide Example 1-1 511,000 47 5 43 5 Examples 1-2 491,000 39 9 41 11 Comparative Example 1 180,000 100 Comparative Example 2 260,000 48 52 Comparative Example 3 470,000 51 49

As shown in Table 1, the theoretical molecular weight of the prepared copolymer was similar to the measured molecular weight, and it was confirmed that the ratio of the monomer was not significantly different from the theoretical ratio.

Experimental Example 1. Determination of mechanical properties of the graft material according to the molecular weight

The copolymer of Example 1-1 and Comparative Examples 1 to 3 was packed in a silicone mold having a size of 1 cm x 5 cm and a thickness of 1 mm and a constant pressure was applied thereto to prepare a tensile strength specimen. The tensile strength and elongation of the prepared sample were measured by pulling the UTM (H5KT) at a rate of 3 mm / min. The measurement results are shown in FIG. 7, FIG. 8, and Table 2.

Tensile strength measurement results of prepared specimens sample Strength (N / cm ² ) Elongation (%) Example 1-1 2.5 1000 Examples 1-2 0.15 400 Comparative Example 1 4.5 100 Comparative Example 2 0.5 600 Comparative Example 3 1.5 450

As shown in FIG. 7, FIG. 8 and Table 2, the mechanical properties of the present invention of Example 1-1 were remarkably superior to those of Comparative Examples 1 to 3, and the possibility of controlling the physical properties according to the composition was confirmed.

Experimental Example 2. Measurement of Contact Angle of Polymer Film According to Functional Group

The weight of the copolymer of Examples 1 to 3 was dissolved in a volume of methylene chloride (MC) of 30:70. The polymer solution was spread over a wide area using an applicator having a thickness of 3 mm, dried at low temperature for 2 days, dried at room temperature for 4 days, and cut into a square of 1 × 1 cm ² . 10 [mu] l of distilled water was added to the prepared film, and the degree of hydrophilicity was confirmed by measuring the contact angle. The results are shown in Fig.

As shown in Fig. 9, it was confirmed that the hydrophilicity can be controlled depending on whether the functional group is introduced or not and the type of the functional group.

Experimental Example 3. Biodegradation according to the molecular weight and composition of the copolymer (in vitro)

The film prepared in Experimental Example 2 was placed in a 20 ml vial, and a pH 7.4 phosphate buffered saline (PBS) was added thereto, and the mixture was rotated at 100 rpm at 37 ° C. The sample was freeze-dried at a constant time for 6 weeks while keeping the temperature constant, and the decrease in the molecular weight was confirmed by GPC at each time, and the results are shown in FIG. 10 and Table 3. FIG. 10A is a GPC graph (in vitro) of the biodegradation behavior of Example 1-1, FIG. 10B is a GPC graph (in vitro) of the biodegradation behavior of Example 1-2, FIG. -2 is a biodegradation half-life graph.

Degradation Half-life Behavior of Prepared Films sample Half-life (day) Example 1-1 50 Examples 1-2 20

As shown in Fig. 10 and Table 3, it was confirmed that the decomposition half-life can be controlled according to the molecular weight of the produced film.

Experimental Example 4 Biodegradation according to the molecular weight and composition of the copolymer (in vivo)

The film prepared in Experimental Example 2 was sterilized with ethylene oxide gas, and inserted into a male rat eight-week-old model subcutaneously. At 1, 2, 4, and 6 weeks after the injection, the formulations removed from the subcutaneous tissue of the rats were lyophilized and the decrease in molecular weight at each time was confirmed by GPC. The results are shown in Table 4.

Degradation Half-life Behavior of Prepared Films sample Half-life (day) Example 1-1 40 Examples 1-2 10

As shown in Table 4, it was confirmed that the decomposition half-life can be controlled according to the molecular weight of the produced film.

Experimental Example 5. Histological Evaluation of Film Formulation

The film prepared in Experimental Example 2 was sterilized with ethylene oxide gas, and inserted into a male rat eight-week-old model subcutaneously. At 1, 2, 4, and 6 weeks after the injection, the formulations removed from the subcutaneous rats were fixed in 10% formalin, and the fixed formulations were made into paraffin blocks, cut into 4 μm thickness, H & E and ED1 staining were performed for evaluation. H & E staining is the most basic staining method, using hematoxylin which is specifically stained in the nucleus of cells and eosin which is stained by cytoplasm. It is a staining method which can confirm the nature of nucleus and cytoplasm. Cell morphology and morphology. The decomposition behavior of the hydrophobic part was confirmed by the above H & E staining. The results are shown in FIG.

Expression of ED1 (mouse anti rat CD68; Serotec, UK) was also confirmed to confirm the inflammatory response of the implanted formulation, and the results are shown in FIG.

As shown in FIG. 11 and FIG. 12, it was confirmed that the cardiovascular implanted structure of the present invention has biocompatibility and the degree of immune inflammatory reaction is different according to the proportion of the hydrophobic part, and the immune response is almost not.

Experimental Example 6. Evaluation of Drug Release of Drug-Containing Film (in vitro)

After introducing a carboxyl group into the functional group of Example 1-2, paclitaxel was mixed as a physiologically active substance to prepare a film as in Experimental Example 2, and 3 mg of drug was loaded on the film. The prepared film was placed in a sample tube having a diameter of 2.5 cm and a height of 3.6 cm, placed in a 50 ml tube containing 10 ml of PBS, rotated at 100 rpm at 37 ° C, and the amount of drug released per hour was measured by HPLC. Is shown in Fig.

As shown in FIG. 13, it was confirmed that the drug release rate can be controlled by controlling the functional group, and it was confirmed that the release of the drug can be controlled stepwise in the multi-layer structure of the graft structure.

Claims (11)

(1), comprising a lactide (LA), a caprolactone (CL), a lactide (fLA) having a functional group and a caprolactone (fCL) Block copolymer.
[Chemical Formula 1]

In Formula 1, R is a methyl group, a benzyl ether group, a hydroxyl group, a carboxyl group, an amine group, or a peptide; a, b, c and d are molar ratios of monomers, and a + b + c + d = 1. The polyester block copolymer according to claim 1, wherein the polyester block copolymer has a molecular weight of 1,000 to 3,000,000 g / mole. The polyester block copolymer according to claim 1, wherein the block copolymer has a biodegradation half-life of 1 week to 2 years. (a) drying the alcohol initiator through azeotropic distillation; And
(b) adding lactide (LA), caprolactone (CL), lactide (fLA) having a functional group and caprolactone (fCL) having a functional group to the dried initiator and conducting polymerization, ≪ / RTI > by weight of the block copolymer.
[Reaction Scheme 1]

In the above Reaction Scheme 1, R is a methyl group, a benzyl ether group, a hydroxyl group, a carboxyl group, an amine group or a peptide; n is an integer from 1 to 300; a, b, c and d are molar ratios of the monomers constituting the polyester, respectively, and a + b + c + d = 1. 5. The process according to claim 4, wherein the alcohol initiator is selected from the group consisting of water, methanol, ethanol, ethylene glycol, propylene glycol, carbitol and polyethylene glycol. 6. The method according to claim 5, wherein the polyethylene glycol has a molecular weight of 32 to 50,000 g / mole. 5. The method according to claim 4, wherein the polymerization in step (b) is carried out at a temperature of 50 to 160 DEG C for 12 to 48 hours. A tissue engineering support comprising the polyester block copolymer of any one of claims 1 to 3. An anti-adhesion agent comprising the polyester block copolymer of any one of claims 1 to 3. A drug carrier comprising the polyester block copolymer of any one of claims 1 to 3. A biodegradable stent comprising the polyester block copolymer of any one of claims 1 to 3.

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