KR20130005902A - Cardiovascular graft structure having elasticity and biodegradation period adjustable copolymer - Google Patents

Abstract

PURPOSE: A cardiovascular transplant structure including a block copolymer in which elastic force and biodegrading period are controlled are provided to enhance flexibility and elastic mechanical physical properties. CONSTITUTION: A cardiovascular transplant structure includes a polyethylene glycol and polyester block copolymer. The polyethylene glycol and polyester block copolymer comprises a hydrophilic part consisting of polyethylene glycol and a hydrophobicity part consisting of polyester containing lactide, glycolide and carprolactone. The molar ratio of lactide, carprolactone and glycolide is in range of 5:5:90 - 47:47:6. [Reference numerals] (AA) Lesion of the cardiovascular system; (BB) Implanting a medicine containing cardiovascular transplant structure; (CC) Medicine releasing of the medicine containing cardiovascular transplant structure; (DD) Expanding the medicine containing cardiovascular transplant structure

Description

Cardiovascular graft structure having elasticity and biodegradation period adjustable copolymer}

The present invention relates to a cardiovascular graft comprising a block copolymer having a modulating elasticity and biodegradation period, and more particularly, to a cardiovascular disease including a copolymer having excellent flexibility and elastic mechanical properties and having a controlled biodegradation half-life. The present invention relates to a drug-releasing implant that can release a therapeutic drug slowly in a human body for long-term delivery.

The lumen of the body may be narrowed or closed due to diseases occurring in the human body. A fistula, esophageal canal, bile duct, urethral canal, prostate, or blood vessel, is a lumen where stenosis or blockage can occur.If the lumen is blocked or narrowed, food, blood, or bile cannot flow smoothly to each organ. Will cause. Therefore, it is necessary to expand the narrowed lumen or prevent the enlarged lumen from narrowing again. As a method for expanding the narrowed lumen passage and maintaining the expanded state, a medical microstructure having an open tube at both ends is opened. Insertion of an intent into the stenosis of the lumen has been performed. Typical methods include inserting a balloon catheter (balloon augmentation) and inserting a metal stent.These methods include high restenosis rates or mechanical vascular damage during expansion and neointimal formation, resulting in restenosis within the stent. This has the disadvantage that will occur. In order to prevent this, drugs to suppress neointimal formation were administered, but since the concentration of drug was not maintained locally in the stent, it could cause serious side effects. In order to overcome this problem, a drug-release stent is introduced to the surface of the stent to release the drug locally, but this also raises a problem in that it cannot control drug release and maintain proper drug concentration. In addition, since the metal stent is an external material of the human body, an inflammatory reaction may occur, and safety may be a problem when used for a long time. For this reason, the stent needs to be removed again after a certain period of time after the procedure on the lesion site. The removal of the stent may not only cause pain and cost to the patient, but also during the insertion and removal of the stent. There is a problem that can cause an inflammatory response by injuring the artery wall.

In order to remedy this problem, the development of biodegradable stents has been proposed. For example, Korean Patent Publication No. 2004-0035434, Korean Patent Publication No. 2003-0059607, Korean Patent Publication No. 2006-0062359, and the like describe a biodegradable stent and a method of manufacturing the same.

However, poly (lactide-co-glycolide) (PLGA), which is widely used in the past, has a very fast disintegration rate and completes the decomposition within one to two months, but it is not easy to manufacture a cardiovascular form that requires excellent mechanical strength. In addition, it is difficult to apply to long-term use that requires decomposition after several months, and there is a difficulty in applying poorly stable drugs such as proteins due to severe pH drop in the substrate due to rapid decomposition. In addition, when using polycaprolactone or polylactide in the form of a single polymer, there is a disadvantage that the degradation products damage the surrounding cells due to the high crystallinity. In addition, in the case of implants containing poly (lactide-co-caprolactone) copolymers, when the lactide content is increased, it is a problem that the human body is greatly influenced by increased acidity due to decomposition products.

Accordingly, the present inventors have studied and tried to solve the above problems, and as a result, the polyethylene glycol / polyester block air including a hydrophilic part made of polyethylene glycol and a hydrophobic part made of polyester containing lactide, glycolide and caprolactone As a result of synthesizing the coalesce and using it as a cardiovascular graft, the present invention was completed by confirming that not only the biodegradation period can be adjusted, but also excellent elasticity and flexibility, and excellent mechanical strength.

Accordingly, an object of the present invention is to provide a drug sustained-release cardiovascular graft comprising a polyethylene glycol / polyester block copolymer is controlled elasticity and biodegradation period.

In order to solve the above problems, the present invention provides a drug sustained-release cardiovascular graft comprising a polyethylene glycol / polyester block copolymer is controlled elasticity and biodegradation period.

The cardiovascular graft structure according to the present invention is capable of controlling tensile strength and elongation, is suitable for living organisms, may contain drugs, and is capable of phased drug release through control of biodegradation period. In addition, after a certain period of time, it is biodegradable and does not require separate removal surgery, minimizes inflammatory reactions, and slowly releases biologically active therapeutic substances, including restenosis suppressing drugs, from the human body for long-term delivery.

1 is a picture of the action of the cardiovascular graft prepared by the present invention.
Figure 2 is a cross-sectional view of a laminated cardiovascular graft structure prepared according to the properties of the polymer produced by the present invention. The outer wall part of the vessel wall is made of a polymer that is partially dissolved by having a transition temperature in the vicinity of the human body temperature as in Preparation Examples 7 and 8, and the polymer of the outer wall in the three-layer structure has strong adhesiveness and biodegradation period. The short, intermediate layer of the polymer is melted at a temperature higher than the human body temperature, as in Preparation Example 9, and has a relatively weak adhesiveness and longer biodegradation period than the outer wall, and the inner layer in contact with blood has a long biodegradation period.
Figure 3 is a three-dimensional and enlarged cross-sectional view of the cardiovascular graft including a biodegradable vascular adhesive structure made using the biodegradation time difference of the polymer prepared by the present invention. It has a protrusion shape on the surface of the blood vessel-adhesive structure, which is made of the same polymer as the layer in contact with blood in the implant.
4 is a ¹ H-NMR graph of Preparation Examples 1 to 3 produced by the present invention.
5 is a photograph of the tensile strength specimens prepared in Preparation Examples 1 to 3 and Comparative Preparation Examples 1 to 3 prepared by the present invention.
Figure 6 is a graph of the tensile strength measurement results of the specimen prepared by the present invention (a) is Comparative Preparation Examples 1 to 3, (b) is Preparation Examples 1 to 3.
7 is a GPC graph of (a) biodegradation half-life according to the molecular weight, (b) biodegradation half-life according to the composition of the polyester and (c) biodegradation behavior of the block copolymer prepared according to the present invention ( in vitro).
8 is a GPC graph of (a) biodegradation half-life according to molecular weight, (b) biodegradation half-life according to the composition of polyester, and (c) biodegradation behavior of the block copolymer prepared according to the present invention. in vivo).
9 is a picture of H & E staining after extracting the cardiovascular graft constructs of Preparation Examples 2, 3 and 6 after insertion into the subcutaneous rat.
FIG. 10 is a picture obtained by inserting the cardiovascular graft constructs of Preparation Examples 2, 3, and 6 into the subcutaneous rat, and extracting the same.
11 is a graph of in vitro drug release behavior of the cardiovascular graft containing the drugs of Preparation Examples 2, 4 and 5.

The present invention relates to a drug sustained-release cardiovascular graft comprising a polyethylene glycol / polyester block copolymer having a controlled elastic force and biodegradation period, and more specifically, a hydrophilic portion composed of polyethylene glycol (PEG) and an ester-based lock A drug sustained release cardiovascular implant comprising a polyethyleneglycol / polyester (PEG-PLGC) block copolymer comprising a hydrophobic portion consisting of Tide (LA), Glycolide (GA) and Caprolactone (CL) segments.

Hereinafter, the present invention will be described in detail.

The present invention relates to a cardiovascular graft comprising a polyethylene glycol / polyester block copolymer which may contain a drug for cardiovascular disease or a bioactive substance, wherein the polyethylene glycol used as a polymerization initiator in the polyethylene glycol / polyester block copolymer (PEG) is suitable for use in vivo because it can be easily contained and released, non-toxic, and immune-rejecting. In addition, it has the effect of inhibiting protein adsorption, when used as a material of the cardiovascular graft structure has the advantage that it is effective in preventing restenosis. In addition, since mechanical properties vary depending on the degree of polymerization of polyethylene glycol, mechanical properties may be controlled using the same.

Although the molecular weight of the polyethylene glycol in the present invention is not limited, preferably it has a molecular weight of 500 ~ 20,000 g / mole, more preferably 500 ~ 5,000 g / mole, most preferably 750 ~ 2,000 g / It is good to have a molecular weight of mole because the mechanical properties of the polyethylene glycol / polyester block copolymer is better.

In addition, in the present invention, the ester-based biodegradable polymer not only can appropriately control the decomposition period by adjusting the molecular weight and the component ratio, but also excellent mechanical properties of the polylactide by appropriately controlling and polymerizing the composition of lactide and caprolactone. The flexibility of the polycaprolactone is complementary to produce a polymer that is biodegradable, has excellent elasticity and flexibility, and excellent mechanical strength. The present invention also shows the advantage that the use of glycolide together with the hydrophobic moiety allows the biodegradation period to be more effectively controlled than when lactide and caprolactone are used.

In the present invention, the molar ratio of the lactide, glycolide, and caprolactone segments is preferably adjusted in the range of 5: 5: 90 to 47: 47: 6 in the order listed. When the use molar ratio of the lactide is less than the minimum range, there is a problem such that the produced polymer is present in dissolved form at room temperature, and when the maximum range exceeds the maximum range, the produced polymer is too hard to lose flexibility. There is the same problem, and it is preferable to maintain the above range. In addition, when the use molar ratio of the glycolide is less than the minimum range, there is a problem such that the produced polymer is present in dissolved form at room temperature, and when the exceeded maximum range, the prepared polymer is too hard to lose flexibility. There is the same problem, and it is preferable to maintain the above range. In the case of caprolactone, there is a problem such that the prepared polymer is too hard when the molar ratio is less than the minimum range, so that the flexibility is lost, and when the caprolactone is exceeded, the biodegradation is very slow. It is desirable to maintain the range.

The polyester containing the lactide (LA), glycolide (GA) and caprolactone (CL) segments is preferably to have a molecular weight of 10,000 ~ 1,000,000 g / mole. When the molecular weight of the polyester is less than 10,000 g / mole, there is a problem of brittleness when manufacturing a vascular graft structure, and when the molecular weight exceeds 1,000,000 g / mole, the polymer fluidity is very large, so that the vascular graft structure is very difficult to manufacture the above range It is desirable to maintain.

The hydrophobic part made of polyester containing the lactide (LA), glycolide (GA) and caprolactone (CL) segments may be represented by, for example, the following Chemical Formula 1. Each segment of the hydrophobic portion is characterized by being copolymerized irregularly, and can be polymerized in various ratios.

[Formula 1]

(In Formula 1, x, y and z are the molar ratios of the monomers, x and y are each 0.1 to 0.45, z is 0.1 to 0.8, x + y + z = 1)

The molecular weight of the polyethylene glycol / polyester (PEG-PLGC) block copolymer is preferably in the range of 20,000 ~ 1,000,000 g / mole, but is not limited by the above range. As the molecular weight increases, the biodegradation period increases, so that the biodegradation period can be properly adjusted according to the purpose of use, and the biodegradation period and mechanical properties can be adjusted according to the ratio of each segment used. It is possible to control the fine decomposition period and the mechanical properties.

The polyethyleneglycol / polyester block copolymer may comprise (a) drying the polyethyleneglycol through azeotropic distillation; And (b) adding lactide, glycolide, and caprolactone to the dried polyethylene glycol, and performing polymerization in a range of 130 to 160 ° C. for 12 to 48 hours.

Synthesis of the block copolymer may be represented, for example, as in Scheme 1 below.

[Reaction Scheme 1]

(In Reaction Scheme 1, n is an integer indicating a repeating unit of polyethylene glycol constituting the hydrophilic portion, x, y, z are each a segment constituting a hydrophobic polyester portion, x, y is 0.1 ~ 0.45, z is 0.1 ~ It is preferable to use in molar ratio of 0.8)

In more detail, the reaction is synthesized by ring-opening polymerization of ester-type lactide, glycolide and caprolactone with polyethylene glycol as a hydrophilic moiety. After carrying out azeotropic distillation of polyethyleneglycol as an initiator and drying, it adds ester monomer and toluene which is a reaction solvent, and superposes | polymerizes using Sn (Oct) ₂ as an initiator activator. At this time, the reaction temperature is preferably 130 ~ 160 ℃, the reaction time is about 12 to 48 hours, more preferably about 20 to 28 hours. This produces a polyethylene glycol / polyester block copolymer. Structural analysis and molecular weight measurements of polymers can be determined using hydrogen nuclear magnetic resonance spectroscopy ( ¹ H NMR), differential scanning calorimetry (DSC), gel permeation chromatography (GPC) and the like.

The cardiovascular graft according to the present invention may have a blood vessel attachment structure on its surface, and may be released for a long time by slowly releasing drugs for treating cardiovascular diseases in the human body.

The cardiovascular implant according to the present invention preferably has a thickness of 10 to 500 μm, more preferably 10 to 300 μm, and may have a single layer or a multilayer structure. More specifically, the implant may be comprised of a vascular contact layer, an intermediate layer, and a blood contact layer.

The outer wall portion of the vascular wall of the cardiovascular graft structure is partially dissolved as it has a transition temperature in the vicinity of the human body temperature, and thus has adhesiveness, for example, as in Preparation Example 8 of the present invention. It is preferable that it consists of a block copolymer. In multi-layered cardiovascular grafts, the polymer on the outer wall (vascular contact layer) has strong adhesion and short biodegradation period, and the polymer on the middle layer has a relatively weak adhesion and longer biodegradation period than the outer wall, and the inner layer in contact with blood. (Blood contact layer) is preferably made of a long biodegradation period.

To this end, the blood vessel contact layer is preferably made of a polymer having a molecular weight of polyethylene glycol 2,000 ~ 5,000 g / mole, the ratio of the polymer is in the range of 40:40:20 ~ 35:35:30 biodegradation half-life 2 ~ It can be adjusted in the range of 10 days, and is preferably partially melted and has adhesiveness. In addition, the intermediate layer is preferably made of a polymer having a molecular weight of 750 ~ 5,000 g / mole of polyethylene glycol, the ratio of the polymer is in the range of 45:45:10 ~ 20:20:60 biodegradation half life range of 5 to 20 days It is preferable to adjust to. The blood contact layer is preferably made of a polymer having a molecular weight of 500 ~ 750 g / mole of polyethylene glycol, the ratio of the polymer is in the range of 30:30:60 ~ 10:10:80 biodegradation half-life 10 to 50 days It is preferable because it can adjust to a range.

More preferably, the vascular contact layer includes a vascular adhesion structure having protrusions, which can be prevented from falling off due to the flow of blood when attached to the blood vessel, and the vascular adhesion layer described above. It is preferable to use the same polymer as the polymer used in the present invention. In addition, the blood vessel adhesion structure is preferably manufactured in different directions alternately at an angle of less than 90 degrees perpendicular to the blood vessel, for example, as shown in Figure 3 the direction of the blood vessel adhesion structure is different from each other at an angle of 45 degrees It is preferable to give more resistance to the flow of blood to prepare.

The cardiovascular implant according to the present invention may include a drug, and the drug may include a drug or a bioactive substance for cardiovascular disease. The drug or bioactive substance for cardiovascular diseases may include at least one selected from the group consisting of actinomycin D, cylorilim, tacrolimus everolimus, zotarolimus, paclitaxel, docetaxel, dexamethasone and heparin. have.

The cardiovascular graft structure according to the present invention can be produced by a method such as extrusion, injection using a mold having a protrusion shape.

The cardiovascular graft structure of the present invention prepared according to the above has not only a certain level of mechanical strength and elongation required for use as the graft structure, but also control of tensile strength and elongation. It also has the advantage that staged drug release is possible by controlling the biodegradation period of the copolymer.

Hereinafter, the present invention will be described in detail in the following examples, but the scope of protection of the present invention is not limited to the following examples.

< Manufacturing example  1> molecular weight 20,000 g / mole sign Methoxy polyethylene glycol -( Polylactide - co - Polyglycolide -co-pole Ricapro Lactone) block copolymers [ MPEG -( PLLA - co - PGA - co - PCL )] ( Lactide : Glycolide Caprolactone = 40: 40: 20)

Methoxyethylene glycol (MPEG)-(polylactide (PLLA) -co-polyglycolide (PGA) -co-polycaprolactone (PCL)) block copolymer of molecular weight 20,000 g / mole Oxypolyethylene glycol (0.4 g, 0.533 mmol) and 40 ml of toluene were placed in a well dried 100 ml round flask and subjected to azeotropic distillation at 130 ° C. for 3 hours using a Dean Stark trap. After distillation, 30 ml of toluene was removed, and methoxy polyethylene glycol (MPEG) was cooled to 25 ° C., followed by pre-purified caprolactone (CL) (1.92 g, 16.8 mmol) and lactide (LA) (4.84 g, 33.6 mmol). Glycolide (GA) (3.91 g, 33.7 mmol) was added thereto, and 10 ml of toluene, which was previously purified, was added as a reaction solvent. Then, 0.64 ml of Sn (Oct) ₂ was added as a polymerization catalyst and stirred at 160 ° C. for 24 hours. All procedures were carried out under high purity nitrogen. After the reaction, in order to remove unreacted monomer or initiator, the reactant was precipitated while slowly dropping the reactant into 1,600 ml of hexane and 400 ml of ether. The precipitate was dissolved in methylene chloride (MC), filtered through a filter paper, and the solvent was removed through a rotary evaporator and dried under reduced pressure.

Molecular weight of the constituents of the copolymer synthesized in the above was measured by ¹ H-NMR, molecular weight 21,000 g / mole similar to the theoretical expected value was obtained, for the determination of polydispersity It was confirmed by gel permeation chromatography (GPC) to have a polydispersity of 1.7.

< Manufacturing example  2> molecular weight 50,000 g / mole sign Methoxy polyethylene glycol -( Polylactide - co - Polyglycolide - co - Polycaprolactone ) Synthesis of block copolymers [ MPEG -( PLLA - co - PGA - co - PCL )] ( Lactide : Glycolide : Caprolactone  = 40: 40: 20)

Methoxyethylene glycol (MPEG)-(polylactide (PLLA) -co-polyglycolide (PGA) -co-polycaprolactone (PCL)) block copolymer of molecular weight 50,000 g / mole Oxypolyethylene glycol (0.2 g, 0.267 mmol) and 40 ml of toluene were placed in a well dried 100 ml round flask and subjected to azeotropic distillation at 130 ° C. for 3 hours using a Dean Stark trap. After distillation, 30 ml of toluene was removed, and methoxy polyethylene glycol (MPEG) was cooled to 25 ° C., followed by prepurified caprolactone (CL) (2.40 g, 21.1 mmol) and lactide (LA) (6.05 g, 42.0 mmol). Glycolide (GA) (4.88 g, 42.1 mmol) was added thereto, and 10 ml of toluene, which was previously purified, was added as a reaction solvent. Then, 0.32 ml of Sn (Oct) ₂ was added as a polymerization catalyst and stirred at 160 ° C for 24 hours. All procedures were carried out under high purity nitrogen. After the reaction, in order to remove unreacted monomer or initiator, the reactant was precipitated while slowly dropping the reactant into 1,600 ml of hexane and 400 ml of ether. The precipitate was dissolved in methylene chloride (MC), filtered through a filter paper, and the solvent was removed through a rotary evaporator and dried under reduced pressure.

Molecular weight of the constituents of the copolymer synthesized in the above was measured by ¹ H-NMR, molecular weight 46,000 g / mole similar to the theoretical expected value was obtained, for the determination of polydispersity It was confirmed by gel permeation chromatography (GPC) to have a polydispersity of 1.8.

< Manufacturing example  3> molecular weight is 90,000 g / mole sign Methoxy polyethylene glycol -( Polylactide - co - Polyglycolide -co-pole Ricapro Lactone) block copolymers [ MPEG -( PLLA - co - PGA - co - PCL )] ( Lactide : Glycolide Caprolactone = 40: 40: 20)

Methoxyethylene glycol (MPEG)-(polylactide (PLLA) -co-polyglycolide (PGA) -co-polycaprolactone (PCL)) block copolymer of molecular weight 90,000 g / mole Oxypolyethylene glycol (0.1 g, 0.133 mmol) and 40 ml of toluene were placed in a well dried 100 ml round flask and subjected to azeotropic distillation at 130 ° C. for 3 hours using a Dean Stark trap. After distillation, 30 ml of toluene was removed, and methoxy polyethylene glycol (MPEG) was cooled to 25 ° C., followed by pre-purified caprolactone (CL) (2.16 g, 18.9 mmol) and lactide (LA) (5.45 g, 37.8 mmol). Glycolide (GA) (4.39 g, 37.8 mmol) was added thereto, and 10 ml of pre-purified toluene was added as a reaction solvent. Then, 0.16 ml of Sn (Oct) ₂ was added as a polymerization catalyst and stirred at 160 ° C. for 24 hours. All procedures were carried out under high purity nitrogen. After the reaction, in order to remove unreacted monomer or initiator, the reactant was precipitated while slowly dropping the reactant into 1,600 ml of hexane and 400 ml of ether. The precipitate was dissolved in methylene chloride (MC), filtered through a filter paper, and the solvent was removed through a rotary evaporator and dried under reduced pressure.

Molecular weight to mole ratio of the constituents of the copolymer synthesized above was measured using ¹ H-NMR to obtain a molecular weight of 92,000 g / mole similar to the theoretical expected value, for the determination of polydispersity It was confirmed by gel permeation chromatography (GPC) to have a polydispersity of 1.8.

< Manufacturing example  4> molecular weight 50,000 g / mole sign Methoxy polyethylene glycol -( Polylactide - co - Polyglycolide - co - Polycaprolactone ) Synthesis of block copolymers [ MPEG -( PLLA - co - PGA - co - PCL )] ( Lactide : Glycolide : Caprolactone  = 30: 30: 40)

Methoxyethylene glycol (MPEG)-(polylactide (PLLA) -co-polyglycolide (PGA) -co-polycaprolactone (PCL)) block copolymer of molecular weight 50,000 g / mole Oxypolyethylene glycol (0.2 g, 0.267 mmol) and 40 ml of toluene were placed in a well dried 100 ml round flask and subjected to azeotropic distillation at 130 ° C. for 3 hours using a Dean Stark trap. After distillation, 30 ml of toluene was removed, and methoxy polyethylene glycol (MPEG) was cooled to 25 ° C., followed by pre-purified caprolactone (CL) (4.92 g, 43.2 mmol) and lactide (LA) (4.66 g, 32.4 mmol). Glycolide (GA) (3.75 g, 32.3 mmol) was added thereto, and 10 ml of toluene, which was previously purified, was added as a reaction solvent. Then, 0.32 ml of Sn (Oct) ₂ was added as a polymerization catalyst and stirred at 160 ° C. for 24 hours. All procedures were carried out under high purity nitrogen. After the reaction, in order to remove unreacted monomer or initiator, the reactant was precipitated while slowly dropping the reactant into 1,600 ml of hexane and 400 ml of ether. The precipitate was dissolved in methylene chloride (MC), filtered through a filter paper, and the solvent was removed through a rotary evaporator and dried under reduced pressure.

Molecular weight of the constituents of the copolymer synthesized above was measured using ¹ H-NMR to obtain a molecular weight of 51,000 g / mole similar to the theoretical expected value, for the determination of polydispersity The gel permeation chromatography (GPC) confirmed that it has a polydispersity of 1.9.

< Manufacturing example  5> molecular weight 50,000 g / mole sign Methoxy polyethylene glycol -( Polylactide - co - Polyglycolide - co - Polycaprolactone ) Synthesis of block copolymers [ MPEG -( PLLA - co - PGA - co - PCL )] ( Lactide : Glycolide : Caprolactone  = 20: 20: 60)

Methoxyethylene glycol (MPEG)-(polylactide (PLLA) -co-polyglycolide (PGA) -co-polycaprolactone (PCL)) block copolymer of molecular weight 50,000 g / mole Oxypolyethylene glycol (0.2 g, 0.267 mmol) and 40 ml of toluene were placed in a well dried 100 ml round flask and subjected to azeotropic distillation at 130 ° C. for 3 hours using a Dean Stark trap. After distillation, 30 ml of toluene was removed, and methoxy polyethylene glycol (MPEG) was cooled to 25 ° C., and then purified caprolactone (CL) (7.57 g, 66.4 mmol) and lactide (LA) (3.19 g, 22.2 mmol) Glycolide (GA) (2.57 g, 22.2 mmol) was added thereto, and 10 ml of toluene, which was previously purified, was added as a reaction solvent. Then, 0.32 ml of Sn (Oct) ₂ was added as a polymerization catalyst and stirred at 160 ° C. for 24 hours. All procedures were carried out under high purity nitrogen. After the reaction, in order to remove unreacted monomer or initiator, the reactant was precipitated while slowly dropping the reactant into 1,600 ml of hexane and 400 ml of ether. The precipitate was dissolved in methylene chloride (MC), filtered through a filter paper, and the solvent was removed through a rotary evaporator and dried under reduced pressure.

Molecular weight to molar ratio of the constituents of the copolymer synthesized above was measured using ¹ H-NMR to obtain a molecular weight of 52,000 g / mole similar to the theoretical expected value, for the determination of polydispersity It was confirmed by gel permeation chromatography (GPC) to have a polydispersity of 1.4.

< Manufacturing example  6> molecular weight 50,000 g / mole sign Methoxy polyethylene glycol -( Polylactide - co - Polyglycolide - co - Polycaprolactone ) Synthesis of block copolymers [ MPEG -( PLLA - co - PGA - co - PCL )] ( Lactide : Glycolide : Caprolactone  = 10: 10: 80)

Methoxyethylene glycol (MPEG)-(polylactide (PLLA) -co-polyglycolide (PGA) -co-polycaprolactone (PCL)) block copolymer of molecular weight 50,000 g / mole Oxypolyethylene glycol (0.2 g, 0.267 mmol) and 40 ml of toluene were placed in a well dried 100 ml round flask and subjected to azeotropic distillation at 130 ° C. for 3 hours using a Dean Stark trap. After distillation, 30 ml of toluene was removed, and methoxy polyethylene glycol (MPEG) was cooled to 25 ° C., followed by pre-purified caprolactone (CL) (10.37 g, 91.0 mmol) and lactide (LA) (1.64 g, 11.4 mmol). Glycolide (GA) (1.32 g, 11.4 mmol) was added thereto, and 10 ml of toluene, which was previously purified, was added as a reaction solvent. Then, 0.32 ml of Sn (Oct) ₂ was added as a polymerization catalyst and stirred at 160 ° C. for 24 hours. All procedures were carried out under high purity nitrogen. After the reaction, in order to remove unreacted monomer or initiator, the reactant was precipitated while slowly dropping the reactant into 1,600 ml of hexane and 400 ml of ether. The precipitate was dissolved in methylene chloride (MC), filtered through a filter paper, and the solvent was removed through a rotary evaporator and dried under reduced pressure.

Molecular weight of the constituents of the copolymer synthesized above was measured using ¹ H-NMR to obtain a molecular weight of 51,000 g / mole similar to the theoretical expected value, for the determination of polydispersity It was confirmed by gel permeation chromatography (GPC) to have a polydispersity of 1.4.

< Manufacturing example  7> molecular weight 50,000 g / mole sign Methoxy polyethylene glycol -( Polylactide - co - Polyglycolide - co - Polycaprolactone ) Synthesis of block copolymers [ MPEG -( PLLA - co - PGA - co - PCL )] ( Lactide : Glycolide : Caprolactone  = 35: 35: 30)

Methoxyethylene glycol (MPEG)-(polylactide (PLLA) -co-polyglycolide (PGA) -co-polycaprolactone (PCL)) block copolymer of molecular weight 50,000 g / mole Oxypolyethylene glycol (0.1 g, 0.133 mmol) and 40 ml of toluene were placed in a well dried 100 ml round flask and subjected to azeotropic distillation at 130 ° C. for 3 hours using a Dean Stark trap. After distillation, 35 ml of toluene was removed, and methoxy polyethylene glycol (MPEG) was cooled to 25 ° C., and then purified caprolactone (CL) (1.82 g, 16.0 mmol) and lactide (LA) (2.69 g, 18.7 mmol) And glycolide (GA) (2.16 g, 18.6 mmol) were added thereto, and 10 ml of toluene, which had been previously purified, was added as a reaction solvent. Then, 0.16 ml of Sn (Oct) ₂ was added as a polymerization catalyst and stirred at 160 ° C for 24 hours. All procedures were carried out under high purity nitrogen. After the reaction, in order to remove unreacted monomer or initiator, the reactant was slowly precipitated in 800 ml of hexane and 200 ml of ether. The precipitate was dissolved in methylene chloride (MC), filtered through a filter paper, and the solvent was removed through a rotary evaporator and dried under reduced pressure.

The copolymer synthesized above had adhesiveness. Molecular weight relative to the molar ratio of the constituents was determined using ¹ H-NMR, yielding a molecular weight of 58,000 g / mole similar to the theoretical expected value, and gel permeation chromatography (GPC) for the determination of polydispersity. As a result, it was confirmed that the polydispersity of 1.9.

< Manufacturing example  8> Of methoxy polyethylene glycol  Molecular weight 2,000 g / mol ego, Polyester  Molecular weight of 50,000 g / mole Methoxy polyethylene glycol -( Polylactide - co - Polyglycolide - co - Polycaprolactone ) Synthesis of block copolymers [ MPEG -( PLLA - co - PGA - co - PCL )] ( Lactide : Glycolide : Caprolactone  = 40: 40: 20)

Methoxyethylene glycol (MPEG)-(polylactide (PLLA) -co-polyglycolide (PGA) -co-polycaprolactone (PCL)) block copolymer of molecular weight 50,000 g / mole Oxypolyethylene glycol (0.2 g, 0.100 mmol) and 40 ml of toluene were placed in a well dried 100 ml round flask and subjected to azeotropic distillation at 130 ° C. for 3 hours using a Dean Stark trap. After distillation, 35 ml of toluene was removed, and methoxy polyethylene glycol (MPEG) was cooled to 25 ° C, and then purified caprolactone (CL) (0.90 g, 7.9 mmol) and lactide (LA) (2.27 g, 15.8 mmol) Glycolide (GA) (1.83 g, 15.8 mmol) was added thereto, and 10 ml of toluene, which had been previously purified, was added as a reaction solvent. Then, 0.12 ml of Sn (Oct) ₂ was added as a polymerization catalyst and stirred at 160 ° C for 24 hours. All procedures were carried out under high purity nitrogen. After the reaction, in order to remove unreacted monomer or initiator, the reactant was slowly precipitated in 800 ml of hexane and 200 ml of ether. The precipitate was dissolved in methylene chloride (MC), filtered through a filter paper, and the solvent was removed through a rotary evaporator and dried under reduced pressure.

The copolymer synthesized above had adhesiveness. Molecular weight to mole ratio of the components measured by ¹ H-NMR yielded a molecular weight of 46,000 g / mole, similar to the theoretical expected value, and gel permeation chromatography (GPC) for the determination of polydispersity. As a result of confirming that the polydispersity of 1.7 was confirmed.

< Manufacturing example  9> Of methoxy polyethylene glycol  Molecular weight of 5,000 g / mol ego, Polyester  Molecular weight of 50,000 g / mole Methoxy polyethylene glycol -( Polylactide - co - Polyglycolide - co - Polycaprolactone ) Synthesis of block copolymers [ MPEG -( PLLA - co - PGA - co - PCL )] ( Lactide : Glycolide : Caprolactone  = 45: 45: 10)

Methoxyethylene glycol (MPEG)-(polylactide (PLLA) -co-polyglycolide (PGA) -co-polycaprolactone (PCL)) block copolymer of molecular weight 50,000 g / mole Oxypolyethylene glycol (0.5 g, 0.100 mmol) and 40 ml of toluene were placed in a well dried 100 ml round flask and subjected to azeotropic distillation at 130 ° C. for 3 hours using a Dean Stock trap. After distillation, 35 ml of toluene was removed, and methoxy polyethylene glycol (MPEG) was cooled to 25 ° C., and prepurified caprolactone (CL) (0.45 g, 3.9 mmol) and lactide (LA) (2.54 g, 17.6 mmol) Glycolide (GA) (2.01 g, 17.6 mmol) was added thereto, and 10 ml of toluene, which had been previously purified, was added as a reaction solvent. Then, 0.12 ml of Sn (Oct) ₂ was added as a polymerization catalyst and stirred at 160 ° C. for 24 hours. All procedures were carried out under high purity nitrogen. After the reaction, in order to remove unreacted monomer or initiator, the reactant was slowly precipitated in 800 ml of hexane and 200 ml of ether. The precipitate was dissolved in methylene chloride (MC), filtered through a filter paper, and the solvent was removed through a rotary evaporator and dried under reduced pressure.

The copolymer synthesized above showed a T _m between 40 and 60 ^o C. Molecular weight to mole ratio of the constituents was determined using ¹ H-NMR, yielding a molecular weight of 48,000 g / mole similar to the theoretical expected value, and gel permeation chromatography (GPC) for determination of polydispersity. As a result, it was confirmed that the polydispersity of 1.8.

<Comparison Manufacturing example  1 to 3> Lactide and Glycolide  Copolymer

The molecular weight of the poly (lactide-co-glycolide) (lactide: glycolide = 25: 75) (boehringer Ingelheim Co.) which is commonly used is 20,000 g / mole, 50,000 g / mole and 90,000 g / mole. It was used as a comparative material of the polymer material prepared in Preparation Example (Table 1).

Comparative Production Example 1 Comparative Production Example 2 Comparative Production Example 3 Name of sample RG752 RG755 RG756 Molecular Weight (g / mole) 20,000 50,000 90,000

<Comparison Manufacturing example  4-7> Lactide and Caprolactone  Copolymer of (50:50)

A methoxy polyethylene glycol (MPEG)-(polylactide (PLLA) -co-polycaprolactone (PCL)) block copolymer of molecular weight 100,000 g / mole, 300,000 g / mole, 700,000 g / mole and 1,000,000 g / mole In order to synthesize | combine, superposition | polymerization was performed by the method similar to the said preparation example. Toluene was added, and caprolactone (CL) (1.77 g, 15.5 mmol) and lactide (LA) (2.23 g, 15.5 mmol), which had been previously purified, were added to methoxy polyethylene glycol (MPEG) distilled using a Dean Stock trap. 30 ml of pre-purified toluene was added as a solvent, and then Sn (Oct) ₂ was added as a polymerization catalyst and stirred at 130 ° C. for 24 hours. All procedures were carried out under high purity nitrogen. After the reaction, in order to remove unreacted monomer or initiator, the reactant was precipitated while slowly dropping the reactant into 1,600 ml of hexane and 400 ml of ether. The precipitate was dissolved in methylene chloride (MC), filtered through a filter paper, and the solvent was removed through a rotary evaporator and dried under reduced pressure.

Through the above method, polyethylene glycol- (polylactide-co-polycaprolactone) as a comparative example was obtained and used as a comparative example with the preparation example (Table 2).

Comparative Production Example 4 Comparative Preparation Example 5 Comparative Preparation Example 6 Comparative Production Example 7 Name of sample PCLA 100K PCLA 300K PCLA 700K PCLA 1000K Molecular Weight (g / mole) 120,000 270,000 610,000 910,000

To summarize the results of Preparation Examples 1 to 8 and Comparative Preparation Examples 1 to 7 are shown in Table 3 below.

polymer Molecular Weight
(g / mole) Monomer molar ratio Transition temperature Tg (℃) Lactide Glycolide Caprolactone Production Example 1 21,000 40 42 18 9 Production Example 2 46,000 39 43 18 20 Production Example 3 92,000 38 39 23 3 Production Example 4 54,000 29 31 40 -8 Production Example 5 52,000 16 18 66 -26 Production Example 6 51,000 5 8 87 -49 Production Example 7 58,000 31 34.5 34.5 18 Production Example 8 46,000 39 44 17 41 Production Example 9 48,000 42 46 12 12 Comparative Production Example 1 20,000 25 75 - - Comparative Production Example 2 50,000 25 75 - - Comparative Production Example 3 90,000 25 75 - - Comparative Production Example 4 120,000 53 - 47 -18 Comparative Preparation Example 5 270,000 52 - 48 -16 Comparative Preparation Example 6 610,000 53 - 47 -18 Comparative Production Example 7 910,000 57 - 43 -15

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

< Example  1> Mechanical Properties of Cardiovascular Graft Material according to Copolymer Molecular Weight

Tensile strength specimens were prepared as shown in FIG. 5 by filling a polymer of Preparation Examples 1 to 6 and Comparative Preparation Examples 1 to 3 to a silicon mold having a size of 1 cm x 5 cm and a thickness of 1 mm.

The prepared specimen was measured by pulling at a rate of 3 mm / min using UTM (H5KT) to observe the tensile strength and elongation according to the molecular weight change.

Tensile strength measurement result of manufactured specimen sample Tensile Strength (MPa) Elongation (%) Comparative Production Example 1 0.6 710 Comparative Production Example 2 8.7 140 Comparative Production Example 3 18 230 Production Example 1 0.8 1500 Production Example 2 0.1 1400 Production Example 3 0.4 1700

As can be seen from the above results, it can be confirmed that the mechanical properties of the present invention are superior to the comparative preparation.

< Example  2> Preparation of Polymer Film

The polymers of Preparation Examples 1 to 6 were dissolved in a polymer weight: methylene chloride (MC) volume = 30:70. The polymer solution was opened using an applicator having a thickness of 1 mm, dried at low temperature for 4 days, and dried at room temperature for 2 days, and cut into a disk shape of 1.6 cm in diameter. The resulting disc-shaped film was sterilized with ethylene oxide gas to obtain a film having a thickness of 300 μm.

< Example  3> Biodegradation according to copolymer molecular weight and composition in vitro ) Experiment

The disk prepared by the film production method of Example 2 was placed in a 20 ml vial, phosphate buffer solution (PBS) of pH 7.4 was put at 37 ℃, 100 rpm was rotated. The sample was lyophilized at a predetermined time up to 6 weeks while maintaining the temperature, and it was confirmed through GPC that the molecular weight decreased each time (FIG. 7).

Degradation Half-Life Behavior of Manufactured Films sample Half-life (day) Production Example 1 5 Production Example 2 6 Production Example 3 7 Production Example 4 11 Production Example 5 24 Production Example 6 59

< Example  4> Biodegradation according to copolymer molecular weight and composition in vivo ) Experiment

The disk made by the film production method of Example 2 was sterilized with ethylene oxide gas and inserted into the male subcutaneous 8-week-old model. At 1, 2, 4, and 6 weeks, the formulations removed from the subcutaneous rats were lyophilized to confirm that the molecular weight was reduced at each hour through GPC (FIG. 8).

Degradation Half-Life Behavior of Manufactured Films sample Half-life (day) Production Example 1 7 Production Example 2 7 Production Example 3 7 Production Example 4 9 Production Example 5 14 Production Example 6 92

< Example  5> Histological Evaluation of Film Formulations

The disk made by the film production method of Example 2 was sterilized with ethylene oxide gas and inserted into the male subcutaneous 8-week-old model. At 1, 2, 4, and 6 weeks, the formulations removed from the subcutaneous of rats were fixed in 10% formalin, the fixed formulations were made into paraffin blocks, cut to 4 μm thickness, fixed on slides and histologically H & E and ED1 staining was performed for evaluation. H & E staining is the most basic staining method using hematoxylin, which is specifically stained at the nucleus of cells, and eosin, which is stained at the cytoplasm. Proceed to confirm cell behavior and morphology. Decomposition behavior according to the ratio control of the hydrophobic portion was confirmed through the H & E staining (FIG. 9). In addition, ED1 (mouse anti rat CD68; Serotec, UK) expression was confirmed to confirm the inflammatory response of the implanted formulation (Fig. 10).

The experiment confirmed that the cardiovascular graft of the present invention is biocompatible and has almost no immune response.

< Example  6> for cardiovascular grafts containing drugs Film  Drug release assessment ( in vitro )

In Example 2, 4 and 5, paclitaxel was mixed with a bioactive material to prepare a film as in Example 2. The amount of drug contained in the disc was adjusted to 1, 3 and 5 mg. The prepared film was placed in a sample container having a diameter of 2.5 cm and a height of 3.6 cm, placed in a 50 ml tube containing 10 ml PBS, rotated at 37 ° C. and 100 rpm, and the drug release was measured by HPLC every hour.

The experiment confirmed that the drug release rate can be controlled by adjusting the content of caprolactone (FIG. 11), and it was confirmed that the drug release can be controlled step by step in the multilayer structure of the cardiovascular implant.

Claims (16)

A drug sustained release cardiovascular graft comprising a polyethylene glycol / polyester block copolymer with controlled elasticity and biodegradation duration.
The method of claim 1, wherein the polyethylene glycol / polyester block copolymer
Hydrophilic part made of polyethylene glycol and
Hydrophobic moiety consisting of polyester containing lactide, glycolide and caprolactone
Cardiovascular implant, characterized in that it comprises a.
3. The cardiovascular implant of claim 2, wherein the molar ratio of lactide, glycolide, and caprolactone is in the range of 5: 5: 90 to 47: 47: 6.
The cardiovascular implant of claim 2, wherein the hydrophobic portion is represented by the following Chemical Formula 1:
[Formula 1]

(In Formula 1, x, y and z are the molar ratios of the monomers, x and y are each 0.1 to 0.45, z is 0.1 to 0.8, x + y + z = 1)
3. The cardiovascular implant of claim 2, wherein the polyethylene glycol has a molecular weight of 500 to 20,000 g / mole.
3. The cardiovascular implant of claim 2, wherein the polyester has a molecular weight of 10,000 to 1,000,000 g / mole.
The method of claim 1, wherein the polyethylene glycol / polyester block copolymer
(a) drying the polyethylene glycol through azeotropic distillation; And
(b) adding lactide, glycolide and caprolactone to the dried polyethylene glycol and performing polymerization for 12 to 48 hours in the range of 130 to 160 ° C.
Cardiovascular graft structure characterized in that it comprises a.
The cardiovascular implant of claim 1, wherein the cardiovascular implant has a thickness of 10 to 500 μm.
2. The cardiovascular implant of claim 1, wherein the cardiovascular implant has a monolayer or multilayer structure.
The cardiovascular graft of claim 1, wherein the graft is comprised of a vascular contact layer, an intermediate layer, and a blood contact layer.
The method of claim 10, wherein the vascular contact layer is polyethylene glycol has a molecular weight of 2,000 to 5,000 g / mole, the ratio of the polymer is in the range of 40:40:20 ~ 35:35:30, the intermediate layer is polyethylene The molecular weight of the glycol is 750 ~ 5,000 g / mole, the ratio of the polymer is composed of 45: 45: 10 ~ 20: 20: 60, the blood contact layer is a polyethylene glycol of 500 ~ 750 g / mole And, the ratio of the polymer is a cardiovascular graft structure, characterized in that consisting of in the range of 30:30:60 ~ 10:10:80.
11. The cardiovascular implant of claim 10, wherein the biodegradation half-life is 2-10 days for the vascular contact layer, 5-20 days for the intermediate layer, and 10-50 days for the blood contact layer.
11. The cardiovascular implant of claim 10, wherein the vascular contact layer comprises a vascular attachment structure with protrusions formed thereon.
14. The cardiovascular implant of claim 13, wherein the vascular adherent structures are alternately produced in alternate directions at an angle less than 90 degrees perpendicular to the vessel.
The cardiovascular graft of claim 1, wherein the drug is a cardiovascular drug or a bioactive substance.
15. The method of claim 14, wherein the cardiovascular drug or bioactive agent is selected from the group consisting of actinomycin D, cylorilimus, tacrolimus everolimus, zotarolimus, paclitaxel, dexamethasone, and heparin. Cardiovascular graft.

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