KR101249351B1 - POLY(β-AMINOESTER URETHANE)-POLYETHYLENEGLYCOL MULTIBLOCK COPOLYMER HAVING EXCELLENT BIOADEGRADABILITY AND METHOD OF MAKING THE SAME AND INJECTABLE HYDROGELS USING THEREOF - Google Patents

Abstract

The present invention is a poly (β-amino) formed by the Michael reaction of a poly (β-amino ester) starting material having excellent biodegradability to significantly improve the biodegradability that was a disadvantage of the conventional polyurethane hydrogel Ester) A hydrogel that is a poly (β-aminoester urethane) -polyethylene multiblock copolymer prepared by urethane reaction by mixing a polyethylene glycol compound (B) with a polyurethane-based starting material (C) in an oligomer (A). In addition, the polymer hydrogel structure can be formed through amphiphilic properties having both hydrophilic and hydrophobic groups, which are temperature sensitive, and pH sensitive properties of which ionization properties change according to the pH of the surrounding environment. Poly (β-aminoester urethane) -Polyethyleneglycol air that can be used as long-term sustained-release drug delivery system by changing pH in body Body and provides a method of manufacturing the drug delivery system using the same.

Description

Biodegradable poly (β-aminoester urethane) -polyethylene glycol multiblock copolymer and preparation method thereof and injectable hydrogel drug delivery agent using the same MAKING THE SAME AND INJECTABLE HYDROGELS USING THEREOF}

The present invention relates to a biodegradable multiblock copolymer, and more particularly, to a multiblock copolymer molecularly designed to have an ester (ester) bond to have a biodegradability in a urethane bond copolymer, a preparation method thereof, and a drug carrier using the same. .

Polyurethane is a biocompatible polymer and has been widely applied as a biocompatible polymer material in many fields such as artificial organs. However, research on hydrogels has not been carried out very much due to its poor biodegradability.

U.S. Patent No. 5,476,909 describes a triblock copolymer in the form of a biodegradable polyester polymer ABA, wherein the hydrophobic block (A) is polylactide (PLA), polyglycolide (PGA) and copolymers thereof. The hydrophilic block (B) is also limited to polyethylene glycol (PEG) and derivatives thereof.

In addition, US Pat. No. 6,004,573 describes a biodegradable low molecular weight triblock copolymer in which the hydrophobic block is a copolymer of PLA and PGA, and the hydrophilic block is made of PEG. It is present in the form of a sol, which is a liquid, and is automatically transferred into the form of a gel, that is, a semi-solid hydrogel containing water, by body temperature (37 ° C). Amphiphilic block copolymers have been proposed that are insoluble in the form of gels continuously in the human body and are used as drug carriers that reversibly induce thermal gelation to slowly release the drug in the gel.

Even though the above-mentioned technologies are sufficiently injected into the human body, the above-mentioned technologies may be released from tissue due to insufficient bioadhesiveness of the hydrogel, or early over-release of the drug due to biodegradation of the hydrogel may occur at the beginning of human injection. This results in a problem that drug release is not controlled over a period of time.

 The present inventors proposed a method for preparing a block copolymer hydrogel using poly (β-amino ester) as a pH-sensitive component in Korea Patent No. 665672 to synthesize a block copolymer sensitive to temperature as well as pH, similar to the body. It was found that gelation occurred at pH 7.0 to 7.4 and below the above range, so that the gel was formed safely in the body without incidence of clogging of the injection needle, which was found in conventional temperature sensitive hydrogels. It has been suggested that the prepared block copolymer can be applied as a drug-release carrier capable of targeted release at a specific temperature and a specific pH.

In addition, Korean Patent No. 838809 discloses polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), and poly (caprolactone-lactide) random copolymers to have biodegradability in polyurethane. Biodegradable by coupling a polyurethane-based oligomer with a biodegradable polymer consisting of (PCLA), poly (caprolactone-glycolide) random copolymer (PCGA) and poly (lactide-glycolide) random copolymer (PLGA) The potential as block copolymers and drug carriers with sex is presented.

It is an object of the present invention to provide a novel amphiphilic multiblock copolymer having biodegradability sensitive to temperature as well as pH, that is, a temperature and pH sensitive multiblock copolymer having excellent biodegradability and a method of preparing the same.

In addition, the present invention is to provide a hydrogel-type drug carrier comprising a bioactive material that can be encapsulated in the multiblock copolymer.

In addition, the present invention is a gel strength that can be usefully applied by designing a target-oriented design not only for cancer cells but also for genetic variation or other applications by appropriately changing the components of the multiblock copolymer, their molar ratio, molecular weight and / or functional groups in the block It is to provide an excellent temperature and pH sensitive multiblock copolymer, a preparation method thereof and a drug carrier using the same.

The present invention also provides a multiblock copolymer capable of inhibiting initial burst release of the drug and capable of biodegradation, a method for preparing the same, and a drug carrier using the same.

In order to achieve the above object, the present invention provides a multiblock copolymer comprising a first block having an ester bond, a second block having a urethane bond, and an ethylene glycol-based third block.

The present invention also provides a multiblock copolymer wherein the first block having an ester bond is a poly (β-amino ester).

In another aspect, the present invention is the multi-block copolymer consisting of a polyurethane-based the second block is alkyldiaisocyanate starting material.

The present invention also provides a multiblock copolymer in which the multiblock copolymer is represented by the following general formula.

        Where n and m are 2 to 10 repeating units and x is 1 to 20 repeating units.

The present invention also provides a multiblock copolymer in which the copolymer has a molecular weight ratio of 1: 1 to 1: 3 of the hydrophobic block and the hydrophilic block.

The present invention also provides a multiblock copolymer having a number average molecular weight of 8,000 to 20,000 of the copolymer.

The present invention also provides a method for producing a copolymer, comprising: (a) a poly (β-amino ester) oligomeric compound (A); (b) polyethylene glycol series compounds (B); (c) It provides a method for producing a multiblock copolymer formed by polymerizing an alkyl diisocyanate (C) as one of the starting materials of the polyurethane-based oligomer.

The present invention also provides a method for producing a multiblock copolymer in which the poly (β-amino ester) oligomer compound (A) is formed by chelating an amine compound with a hydroxyalkyl acrylate.

In another aspect, the present invention is a block selected from the group consisting of hydroxyethyl acrylate, hydroxybutyl acrylate, hydroxyhexyl acrylate, hydroxyheptyl acrylate, hydroxyoctyl acrylate or a mixture thereof It provides a method for producing a copolymer.

In the present invention, the amine-based compound is 1-methylamine (1-methylamine), 1-ethylamine (ethylamine), 1-propylamine (1-propylamine), 1-butylamine (1-butylamine), 1-pentyl Amine (1-pentylamine), 1-hexylamine, 1-heptylamine, 1-octylamine, 1-octylamine, 1-nonnaamine, 1-decanamine ( 1-decanamine, 3-isopropylamine, triethyleneamine, 3-methoxypropylamine, 3-ethoxy propylamine, 3- Isopropoxy-1-propanamine, 3-propyl-1-propanamine, 3- (butoxy-1-propanamine) (3-butoxy- 1-propanamine), 1,4-dioxa-1ethoxyamine, 4,4-dimethoxybutylamine, 4,4-die Methoxy-1-butamine) (4,4-diethoxy-1-butanamine), 2-methoxyethanamine, 3-ethoxyethanamine, 3-isopropyl-1- Ethoxy 3-aminepropoxy-1-ethoxyethanamine, 4,4-dimethoxyethylamine, 4,4-diethoxy-1-ethylamine , Tetrahydro-2-furanylmethylamine, 2-phenoxyethanamine, 2- (3,4-dimethoxyphenyl) ethanamine) {2- (3, 4-dimethoxyphenyl) ethanamine}, 2-2,5-dimethoxyphenyl) ethylamine {2- (2,5-dimethoxyphenyl) ethylamine}, 1,2,2-trimethyl-1-1propanamine (1,2, 2, -trimethyl-1-propanamine), 2-methyl-1-butanamine, 3-methyl-1-butanamine, 3-methyl-1-butanamine, 1,3- Dimethyl-1-butanamine (1,3-dimethyl-1-butanamine), 4-methyl-1-pentanamine (4-methyl-1-pentanamine), 3,3-dimethyl-1-butanamine (3,3 -dimethyl-1-butanamine), 1,4-dimethyl-1-pentanamine, 1-methyl-1-hexanamine, 1- Methyl-1-heptanamine, 2-ethyl-1-hexanamine, 2-aminoethanol, 3-amino No-1-propanol (3-amino-1-propanol), (2R) -1amino-2-propanol {(2R) -1-amino-2-propanol}, (2S) -1-amino-2-propanol {(2S) -1-amino-2-propanol}, 2-amino-1-propanol, (2S) -1-amino-2-propanol {(2S) -1-amino 2-propanol}, 2-amino-1,3-propanediol, 2-amino-2-methyl-1,3-propanediol (2-amino-2-methyl -1,3-propanediol), 2-amino-2-methyl-1-propanol, 4-amino-1-butanol, 4-amino-1-butanol, 2-amino-1-propanol, 2-ethylamino-1-butanol, 2- (2-aminoethoxy) ethanol {2- (2 -aminoethoxy) ethanol}, 5-amino-1-pentanol, 3-amino-2,2-1-propanol (3-amino-2,2-dimethyl-1-propanol) , 2-amino-2-ethyl-1,3-propanediol (2-amino-2-ethyl-1,3-propanediol), 2-amino-3-methyl-1-butanol (2-amino-3-methyl -1-butanol), 6-amino-1-hexanol (6-amino-1-hexanol), (1-aminocyclopentyl) methanol {1-aminocyclop entyl) methanol), 4-aminocyclohexanol, 2-aminocyclohexanol, 2-methyl-1-propanamine, 2-methyl-1-propanamine, cyclobutanamine (cyclobutanamine), cyclopropylmethylamine, cyclopentanamine, cyclohexanamine, cyclohexanmethylamine, adamantane-methylamine, silane-methyl- Si-methyl-diethoxy-propylamine, Si-trithoxy-propylamine, 1,4-diazepane, N, N'- Diethyl-1,2-ethanediamine (N, N'-diethyl-1,2-ethane diamine), N, N'-diisopropyl-1,2-ethanediamine (N, N'-diisopropyl-1, 2-ethane diamine), N, N'-dimethyl-1,2-propanediamine (N, N'-dimethyl-1,2-propanediamine), N, N'-dimethyl-1,3-propanediamine (N, N'-dimethyl-1,3-propanediamine), N, N'-diethyl-1,3-propanediamine (N, N'-diethyl-1,3-propanediamine), N, N'-diethyl-1,4-pentanediamine (N, N-diethyl-1,4-pentanediamine), N, N'-bis (2-hydroxyethyl) ethylenediamine (N, N-Bis ( 2-hydroxyethyl) ethylenediamine, N, N'-bis (2-hydroxy) propylenediamine, N, N'-Bis (2-hydroxyethyl) propylenediamine, 4,4'-trimethylenedipiperidine (4,4 -trimethylenepiperidine (TMDP), N, N'-dimethylethylenediamine, piperazine, 2-methylpiperazine, 3-methyl-4- (3-methylphenyl Piperazine {3-methyl-4- (3-methylphenyl) piperazine}, 3-methylpiperazine, 3- (phenylmethyl) piperazine {4- (phenylmethyl) piperazine}, 4- (1 -Phenylethyl) piperazine {4- (1-phenylethyl) piperazine}, 4- (1,1'-dimethoxycarbonyl) piperazine {4- (1,1'-dimethoxycarbonyl) piperazine}, 4- (2 -(Bis-2-propenyl) amino) ethyl) piperazine {4- (2- (bis- (2-prophenyl) amino) ethyl) piperazine}, 1- (2-aminoethyl) piperazine {1- ( 2-aminoethyl) piperazine}, 4- (aminomethyl) piperazine {4- (aminomethyl) pipe razine}, N, N'-dimethyl-1,2-ethanediamine (N, N'-dimethyl-1,2-ethanediamine), N, N'-diethyl-1,2-ethanediamine (N, N ' -diethyl-1,2-ethanediamine), N, N'-diisopropyl-1,2-ethanediamine, N, N'-dimethyl-1,2 -Propylamine (N, N'-dimethyl-1,2-propyldiamine), N, N'-diethyl-1,2-propyldiamine (N, N'-diethyl-1,2-propyldiamine), N, N '-Diisopropyl-1,2-propylamine (N, N'-diisopropyl-1,2-propyldiamine), N, N'-dimethyl-1,2-hexanediamine (N, N'-dimethyl-1, 2-hexanediamine), N, N'-dimethyl-N- (3- (methylamino) propyl] -1,3-propanediamine {N, N'-dimethyl-N- [3- (methylamino) propyl] -1 , 3-propanediamine}, N- [2-methylamino) ethoxyethyl] -N, N'-dimethylamine {N- [2-methylamino) ethoxy ethyl] -N, N'-dimethylamine}, N- [2 -Methylamino) dioxyethyl] -N, N'-dimethylamine, N- [2-methylamino) dioxyethyl] -N, N'-dimethylamine {N- [2-methylamino) dioxyethyl] -N, N'-dimethylamine}, 1,4-diazepane or a mixture thereof Selected from the multi-block provides a process for the preparation of the copolymer.

The present invention also provides a method for producing a block copolymer in which the reaction molar ratio of the hydroxyalkyl acrylate and the amine is 1: 2 to 1: 3.

In another aspect, the present invention provides a method for producing a block copolymer in which the polyethylene glycol compound (B) is represented by the following formula.

Wherein n is a natural number ranging from 10 to 50.

The present invention also provides a method for producing a multiblock copolymer having a number average molecular weight of the polyethylene glycol-based compound in the range of 1,000 to 5,000 g / mol.

The present invention also provides a method for producing a multiblock copolymer formed by polymerizing an alkyl diisocyanate compound with the starting material of the polyurethane-based oligomer.

In another aspect, the present invention provides a method for producing a multiblock copolymer of the alkyl diisocyanate consisting of the following formula.

OCN- (CH ₂ ) _n -NCO

  Where n is the number of repeating units of integers 4-10.

In the present invention, the alkyl diisocyanate is 1,2-diisocyanate ethane, 1,4-diisocyanate butane, 1,3-diisocyanate butane, 1,6-diisocyanate hexane, 1,7-diisocyanate heptane, 1 , 8-diisocyanate octane, 1,9-diisocyanate nona, 1,10-diisocyanate decane, 1,12-diisocyanate decane, bis (4-isocyanate cycloethyl) methane, bis (4-isocyanatephenyl) methane, Multiblock copolymer selected from the group consisting of bis (4-isocyanatephenyl) ether, bis (4-isocyanatephenyl) sulfone, 4,4'-diphenylmethane diisocyanate, hydrogenated 4,4'-diphenylmethane diisocyanate It provides a method of manufacturing.

In another aspect, the present invention is the reaction of the polyethylene glycol (PEG), poly (amino ester) (PHB) and polyurethane oligomer of the starting material (HDI) of 1: 12: 12 to 1: 18: 12 of the multi-block copolymer It provides a manufacturing method.

In another aspect, the present invention provides a method for preparing a multiblock copolymer made of a copolymer, the temperature is 40 to 70 ℃, the time is 1 to 3 hours.

In addition, the present invention, the polymerization is dibutyl diyl dilaurate (dibutyl dilaurate), stannous octoate, tin chloride (stannous chloride), iron oxide (iron oxide), aluminum triisopropoxide (aluminum triisopropoxide), CaH ₂ , Zn, lithim chloride, tris (2,6-di-tert-butylphenolate) can be used at least one catalyst selected from the group consisting of Provided is a method for preparing a multiblock copolymer.

In addition, the present invention is a method for preparing a temperature and pH sensitive block star copolymer having excellent biodegradability, in order to synthesize a poly (β-amino ester) oligomer, 1- (2-hydroxyethyl) piperazine and hydroxy Mitchell reaction with ethyl acrylate; And reacting with 1,6-diisocyanate hexane (HDI) to form polyethylene glycol and polyurethane blocks in the product. And dissolving the reactant in chloroform and dissolving it in excess ethyl ether to remove unreacted poly (β-aminoester urethane) -polyethyleneglycol temperature and pH sensitive multiblock copolymers. Provide a method.

In addition, the present invention (a) a multi-block copolymer according to any one of claims 1 to 6 or a copolymer prepared by the method of any one of claims 7 to 20; And (b) provides a polymer hydrogel-type drug carrier comprising a bioactive material that can be encapsulated in the multiblock copolymer.

In addition, the present invention can be used without particular limitation as a physiologically active substance that can be encapsulated in the polymer hydrogel-type block copolymer, non-limiting examples thereof are paclitaxol, doxorubicin, docetasol ( Anticancer agents such as docetaxol), Chlororambucyl, insulin, exendin-4, human growth hormone (hGH), erythropoietin (EPO), granulocyte colony stimulating factor (G-CSF), Protein drugs, such as granulocyte-macrophage stimulating factor (GM-CSF), and drugs such as antibacterial agents, steroids, anti-inflammatory drugs, sex hormones, immunosuppressants, antiviral agents, anesthetics, antiemetics, or antihistamines, as well as the aforementioned ingredients, At least one selected from the group consisting of known conventional additives such as excipients, stabilizers, pH adjusting agents, antioxidants, preservatives, binders or disintegrants, etc. Provide a drug carrier.

In the present invention, by preparing a poly (β-amino ester) -based oligomer having a tertiary amine group and an ester group exhibiting various ionization degree in order to impart the biodegradability and pH sensitivity, by mixing and reacting polyethylene glycol and polyurethane-based starting material, In addition to temperature sensitivity and pH sensitivity, there is an effect that can solve the problems of the existing polyurethane hydrogel has excellent biodegradability.

 In addition, due to the polyurethane component at the time of human injection, it is excellent in in vivo adhesion, so it can be initially injected into the uterine wall to form a stable hydrogel to form a more stable hydrogel that can enable long-term sustained release of the drug. Can be.

In addition, the temperature- and pH-sensitive block copolymers may be usefully applied to the delivery of imaging agents and therapeutic drugs by guiding cathetering because sol-gel transition does not occur under normal physiological conditions in the human body.

In addition, the hydrogel was formed in the same pH 7.0 to 7.4 range as the normal body conditions and maintained in a sol state at pH 7.0, which is an abnormal condition such as cancer cells, to apply a cancer cell target-oriented design, but the components of the block copolymer, By appropriately modifying their molar ratios, molecular weights and / or functional groups in the block, they can be usefully applied to target-oriented designs not only for cancer cells but also for genetic variations or other applications.

1 is a 20% concentration of a poly (β-aminoester urethane)-polyethylene glycol multiblock copolymer having biodegradability according to temperature and pH changes prepared according to Examples 3 and 5 of one preferred embodiment of the present invention Graph of sol-gel transition behavior in.
Figure 2 is a sol-gel transition behavior according to pH at 37 ℃ of a 20% solution of a poly (β-amino ester urethane)-polyethylene glycol multiblock copolymer prepared according to Example 3 of a preferred embodiment of the present invention Photo.
3 is an NMR graph of a poly (β-aminoester urethane) -polyethylene glycol multiblock copolymer prepared according to Example 3 of a preferred embodiment of the present invention.
4 is an IR graph of a poly (β-aminoester urethane) -polyethylene glycol multiblock copolymer prepared according to Example 3 of a preferred embodiment of the present invention.
5 is a GPC graph of a poly (β-aminoester urethane) -polyethylene glycol multiblock copolymer prepared according to Example 3 of one preferred embodiment of the present invention.
Figure 6 is a graph showing the viscosity change with temperature at various pH of the poly (β-amino ester urethane)-polyethylene glycol multiblock copolymer prepared according to Example 3.
FIG. 7 is a gel-forming image formed over time in a 20% concentration solution of a poly (β-aminoester urethane) -polyethylene glycol multiblock copolymer prepared according to Example 3. FIG.
FIG. 8 shows the cumulative value of the release amount of doxorubicin over time after 500 μg / mL of doxorubicin was added to the poly (β-aminoester urethane) -polyethylene glycol multiblock copolymer prepared according to Examples 3, 5 and 6. FIG. Showing graph.
FIG. 9 is a graph showing biodegradability by molecular weight change of a poly (β-aminoester urethane) -polyethylene glycol multiblock copolymer prepared according to Example 3. FIG.

Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings. First of all, it should be noted that in the drawings, the same components or parts denote the same reference numerals as much as possible. In describing the present invention, detailed descriptions of related well-known functions or configurations are omitted in order not to obscure the subject matter of the present invention.

As used herein, the terms "about", "substantially", and the like, are used at, or in close proximity to, numerical values as are indicative of preparation and material tolerances inherent in the meanings mentioned, and are intended to be accurate or to facilitate understanding of the invention. Absolute figures are used to prevent unfair use by unscrupulous infringers.

The copolymer according to an embodiment of the present invention may include a first block having an ester bond, a second block having a urethane bond, and an ethylene glycol-based third block.

The first block having an ester bond may be made of a poly (β-aminoester) system. Poly (β-amino esters) can exhibit sensitivity to pH in the body by including tertiary amine groups that are ionized at pH 7.0 or below. The poly (β-amino ester) may participate in the reaction in the form of oligomer, and the oligomer more preferably includes functional groups such as hydroxy group (-OH), carboxy group (-COOH) or amine group (-NH ₂ ). This is to easily prepare the block copolymer according to the present invention by polymerization.

The poly (β-amino ester) -based oligomers have ionization properties such that their solubility in water varies with pH due to the tertiary amine groups present in them, thereby forming a hydrogel or maintaining a sol state according to the pH change in the body. .

The oligomer may be prepared according to various methods, and for example, by polymerizing an amine-based compound to an acrylate compound having a hydroxyl group at one end having a double bond through a Michael reaction, both ends Poly (β-amino ester) -based oligomers having an hydroxy group can be obtained.

As used herein, an acrylate compound having a hydroxy group at one end may be represented by the following Chemical Formula 1, and non-limiting examples thereof include hydroxyethyl acrylate, hydroxybutyl acrylate, hydroxyhexyl acrylate, and hydroxy. Heptyl acrylate, hydroxyoctyl acrylate or mixtures thereof.

Wherein z is an alkyl group having 1 to 5 carbon atoms.

In addition, the amine-based compound may be used without limitation as long as it has an amine group, and particularly preferred is a primary amine represented by the following formula (2), a secondary amine-containing diamine compound represented by the formula (3), or a mixture thereof.

In the above formula, R ₁ and R ₂ are alkyl groups having 1 to 20 carbon atoms.

Non-limiting examples of the primary amine compound is 1-methylamine, 1-ethylamine, 1-propylamine, 1-propylamine, 1-butylamine, 1 1-pentylamine, 1-hexylamine, 1-heptylamine, 1-octylamine, 1-nonnaamine, 1-decane Amine (1-decanamine), 3-isopropylamine, triethyleneamine, 3-methoxypropylamine, 3-ethoxy propylamine, 3-isopropoxy-1-propanamine, 3-propyl-1-propanamine, 3- (butoxy-1-propanamine) (3- butoxy-1-propanamine), 1,4-dioxa-1ethoxyamine, 4,4-dimethoxybutylamine, 4,4 -Diethoxy-1-butamine) (4,4-diethoxy-1-butanamine), 2-methoxyethanamine, 3-ethoxyethanamine, 3-isopropyl 1-ethoxy 3-isopropoxy-1-ethoxyethanamine, 4,4-dimethoxyethylamine, 4,4-diethoxy-1-ethylamine , Tetrahydro-2-furanylmethylamine, 2-phenoxyethanamine, 2- (3,4-dimethoxyphenyl) ethanamine) {2- (3, 4-dimethoxyphenyl) ethanamine}, 2-2,5-dimethoxyphenyl) ethylamine {2- (2,5-dimethoxyphenyl) ethylamine}, 1,2,2-trimethyl-1-1propanamine (1,2, 2, -trimethyl-1-propanamine), 2-methyl-1-butanamine, 3-methyl-1-butanamine, 3-methyl-1-butanamine, 1,3- Dimethyl-1-butanamine (1,3-dimethyl-1-butanamine), 4-methyl-1-pentanamine (4-methyl-1-pentanamine), 3,3-dimethyl-1-butanamine (3,3 -dimethyl-1-butanamine), 1,4-dimethyl-1-pentanamine, 1-methyl-1-hexanamine, 1- Methyl-1-heptanamine, 2-ethyl-1-hexanamine, 2-aminoethanol, 3- Mino-1-propanol, (2R) -1 amino-2-propanol {(2R) -1-amino-2-propanol}, (2S) -1-amino-2-propanol {(2S) -1-amino-2-propanol}, 2-amino-1-propanol, (2S) -1-amino-2-propanol {(2S) -1-amino 2-propanol}, 2-amino-1,3-propanediol, 2-amino-2-methyl-1,3-propanediol (2-amino-2-methyl -1,3-propanediol), 2-amino-2-methyl-1-propanol, 4-amino-1-butanol, 4-amino-1-butanol, 2-amino-1-propanol, 2-ethylamino-1-butanol, 2- (2-aminoethoxy) ethanol {2- (2 -aminoethoxy) ethanol}, 5-amino-1-pentanol, 3-amino-2,2-1-propanol (3-amino-2,2-dimethyl-1-propanol) , 2-amino-2-ethyl-1,3-propanediol (2-amino-2-ethyl-1,3-propanediol), 2-amino-3-methyl-1-butanol (2-amino-3-methyl -1-butanol), 6-amino-1-hexanol (6-amino-1-hexanol), (1-aminocyclopentyl) methanol {1-aminocyc lopentyl) methanol), 4-aminocyclohexanol, 2-aminocyclohexanol, 2-methyl-1-propanamine, 2-methyl-1-propanamine, cyclobutanamine (cyclobutanamine), cyclopropylmethylamine, cyclopentanamine, cyclohexanamine, cyclohexanmethylamine, adamantane-methylamine, silane-methyl- Si-methyl-diethoxy-propylamine, Si-trithoxy-propylamine, 1,4-diazepane, N, N'- Diethyl-1,2-ethanediamine (N, N'-diethyl-1,2-ethane diamine), N, N'-diisopropyl-1,2-ethanediamine (N, N'-diisopropyl-1, 2-ethane diamine), N, N'-dimethyl-1,2-propanediamine (N, N'-dimethyl-1,2-propanediamine), N, N'-dimethyl-1,3-propanediamine (N, N'-dimethyl-1,3-propanediamine), N, N'-diethyl-1,3-propanediamine (N, N'-diethyl-1,3-propanediamin e), N, N'-diethyl-1,4-pentanediamine (N, N-diethyl-1,4-pentanediamine), N, N'-bis (2-hydroxyethyl) ethylenediamine (N, N -Bis (2-hydroxyethyl) ethylenediamine, N, N'-bis (2-hydroxy) propylene diamine (N, N'-Bis (2-hydroxyethyl) propylenediamine) or a mixture thereof.

Further, non-limiting examples of the secondary amine-containing diamine compound are 4,4'-trimethylenedipiperidine (4,4-trimethylenepiperidine, TMDP), N, N'-dimethylethylenediamine (N, N'-dimethylethylenediamine ), Piperazine (piperazine), 2-methylpiperazine, 3-methyl-4- (3-methylphenyl) piperazine {3-methyl-4- (3-methylphenyl) piperazine}, 3-methyl Piperazine (3-methylpiperazine), 4- (phenylmethyl) piperazine {4- (phenylmethyl) piperazine}, 4- (1-phenylethyl) piperazine {4- (1-phenylethyl) piperazine}, 4- (1 , 1'-dimethoxycarbonyl) piperazine {4- (1,1'-dimethoxycarbonyl) piperazine}, 4- (2- (bis-2-propenyl) amino) ethyl) piperazine {4- (2- (bis- (2-prophenyl) amino) ethyl) piperazine}, 1- (2-aminoethyl) piperazine {1- (2-aminoethyl) piperazine}, 4- (aminomethyl) piperazine {4- (aminomethyl) piperazine}, N, N'-dimethyl-1,2-ethanediamine (N, N'-dimethyl-1,2-ethanediamine), N, N'-diethyl-1,2-ethanediamine (N, N ' -diethyl-1,2-ethanediamine), N, N'-diisopropyl-1,2-in Diamine (N, N'-diisopropyl-1,2-ethanediamine), N, N'-dimethyl-1,2-propylamine (N, N'-dimethyl-1,2-propyldiamine), N, N'-di Ethyl-1,2-propyldiamine (N, N'-diethyl-1,2-propyldiamine), N, N'-diisopropyl-1,2-propylamine (N, N'-diisopropyl-1,2- propyldiamine), N, N'-dimethyl-1,2-hexanediamine (N, N'-dimethyl-1,2-hexanediamine), N, N'-dimethyl-N- (3- (methylamino) propyl]- 1,3-propanediamine {N, N'-dimethyl-N- [3- (methylamino) propyl] -1,3-propanediamine}, N- [2-methylamino) ethoxyethyl] -N, N'- Dimethylamine {N- [2-methylamino) ethoxy ethyl] -N, N'-dimethylamine}, N- [2-methylamino) dioxyethyl] -N, N'-dimethylamine, N- [2-methylamino ) Dioxyethyl] -N, N'-dimethylamine {N- [2-methylamino) dioxyethyl] -N, N'-dimethylamine}, 1,4-diazepane or mixtures thereof There is this.

In preparing a poly (β-amino ester) exhibiting pH sensitivity, the reaction molar ratio of the amine compound and the hydroxyalkyl acrylate compound is preferably in the range of 1: 2 to 1: 3. When the molar ratio of the amine-based compound is less than 1: 2, the probability of producing a poly (β-amino ester) oligomer having a hydroxyl group at both ends is lowered, and when it exceeds 1: 3, the block length of the block copolymer is controlled. This becomes difficult. The molecular weight of the poly (β-amino ester) oligomer is not particularly limited but is preferably in the range of 5,000 to 15,000. If the molecular weight is less than 5,000, the sol-gel transition behavior does not appear according to the pH change, and if it exceeds 15,000, the temperature sensitivity becomes difficult to appear simultaneously.

 It may be formed by polymerizing an alkyl diisocyanate compound as one component of the urethane-based starting material forming the second block of the present invention. The alkyl diisocyanate may be composed of the following formula (4).

Where n is the number of repeating units of the integer 2-2.

In the present invention, the diisocyanate is 1,2-diisocyanate ethane, 1,4-diisocyanate butane, 1,3-diisocyanate butane, 1,6-diisocyanate hexane (HDI), 1,7-diisocyanate heptane , 1,8-diisocyanate octane, 1,9-diisocyanate nona, 1,10-diisocyanate decane, 1,12-diisocyanate decane, bis (4-isocyanate cycloethyl) methane, bis (4-isocyanatephenyl) Methane, bis (4-isocyanatephenyl) ether, bis (4-isocyanatephenyl) sulfone, 4,4'-diphenylmethane diisocyanate (MDI), hydrogenated 4,4'-diphenylmethane diisocyanate (HMDI) Provided are block copolymers selected from the group consisting of:

Meanwhile, the ethylene glycol series compound forming the third block of the present invention may be a polyethylene glycol series compound represented by Formula 5 below.

Wherein n is a natural number ranging from 10 to 50.

The polyethylene glycol-based compound may be polyethylene glycol (PEG), it is preferable that the number average molecular weight is in the range of 1,000 to 5,000 g / mol.

The multi-block copolymer according to the present invention is a polyethylene glycol-based compound and a polyurethane-based starting material in a poly (β-amino ester) oligomer formed by Michael reaction of the poly (β-amino ester) starting material. It may be formed of a poly (β-aminoester urethane) -polyethylene glycol multiblock copolymer prepared through a urethane reaction by mixing an alkyl diisocyanate, which is one of, and may be represented by the following formula (6).

   Here, n and m are the number of repeating units of the integer 2-10, x is the number of repeating units of 1-20.

In the multiblock copolymer, when the molecular weight ratio of the hydrophilic block and the hydrophobic block is less than 1: 1 and greater than 1: 3, not only is sol-gel transition difficult but gel strength is weak even if a gel is formed. It is difficult to use as a sex drug carrier.

In addition, the number average molecular weight of the multiblock copolymer may be 8,000 to 20,000. If the gel strength is lower than the above range, and if the gel strength is higher than the above range, there is difficulty in controlling drug release.

Hereinafter, the manufacturing method of the copolymer of the present invention will be described.

The copolymer according to an embodiment of the present invention may be prepared including a first block having an ester bond, a second block having a urethane bond, and an ethylene glycol-based third block.

Specifically, a poly (β-aminoester) having excellent biodegradability by reacting (a) a poly (β-aminoester) -based oligomer, (b) a polyethylene-based compound and (c) an alkyl diisocyanate as one component of the polyurethane-based starting material Urethane) -polyethylene glycol multiblock copolymers may be prepared.

The temperature and pH sensitive multiblock copolymers according to the present invention may include other components or additives commonly used in addition to the aforementioned components.

To prepare a temperature and pH sensitive multiblock copolymer according to the present invention using the poly (β-amino ester) compound (A), polyethylene glycol compound (B) and the starting material (C) of the polyurethane-based oligomer For this purpose, any one of various polymerization methods known in the art, such as radical polymerization, cationic polymerization, anionic polymerization, condensation polymerization and addition polymerization, can be used.

In one embodiment thereof, a method of preparing a star block copolymer includes a) alkyl diisocyanate as a starting material of a polyethylene glycol compound (B) and a polyurethane oligomer in a poly (β-amino ester) oligomer (A). (C) may be reacted.

First, a poly (β-amino ester) oligomer is formed through a Mitchell reaction of a poly (β-amino ester) starting material, and a urethane polymerization is performed by mixing a polyethylene glycol compound and an alkyl diisocyanate which is a component of the polyurethane starting material. To form a copolymer, which may be, for example, represented by Scheme 1 below.

[Reaction Scheme 1]

Where n and m are 2 to 10 repeating units and x is 1 to 20 repeating units.

Specifically, by reacting hydroxybutyl acrylate (HBA) with 1- (2-hydroethylethylpiperazine (HP), which is a starting material of the poly (β-amino ester) oligomer, hydroxybutyl acrylate (HBA), the poly (β-amino ester) oligomer After forming the copolymerization reaction of hexyl diisocyanate (HDI) as a starting material of the polyethylene glycol compound (PEG) and the polyurethane-based oligomer is preferably a urethane reaction, the polymerization temperature and time is not particularly limited, but 40 to A temperature of 70 ° C. and 1 to 3 hours is preferable, and catalysts may be used for reactivity, and available catalysts include dibutyltin dilaureate, stannous octoate, and tin chloride. chloride), iron oxide (iron oxide), GeO _2, Sb ₂ O _3, SnO ₂ or the like, aluminum triisopropoxide (aluminum triisopropoxide), CaH _2, Zn, lithium chloride (lithim chloride), bit 'S (2,6-di-tertiary-butyl and the like phenolate (tris (2, 6-di-tert-butylphenolate)).

Indeed, poly (β-aminoester urethane) -polyethyleneglycol (PEG-PAEU) _x multiblock copolymers prepared in this way employ FT-IR and 1H-NMR to introduce the respective functional groups and react the end groups. By increasing the molecular weight of the block copolymer using gel permeation chromatography (GPC), it was confirmed that the poly (β-amino ester) oligomer, polyethylene glycol-based compound and polyurethane-based oligomer is a multi-block polymerized structure . In addition, in order to confirm the pH sensitivity, the change in the sol-gel transition properties were measured while changing the pH with temperature, and through this, it was confirmed that the multiblock copolymer of the present invention possesses pH sensitivity properties.

In addition, the present invention can prepare a polymer hydrogel-type drug carrier comprising the prepared multiblock copolymer and a physiologically active substance that can be enclosed in the multiblock copolymer.

Bioactive materials that can be encapsulated in the polymer hydrogel-type block copolymer can be used without particular limitation, and non-limiting examples thereof include paclitaxol, doxorubicin, docerubicin, docetasol, chloro Anticancer agents such as Chlororambucyl, insulin, exendin-4, human growth hormone (hGH), erythropoietin (EPO), granulocyte colony stimulating factor (G-CSF), GM Protein drugs such as granulocyte-macrophage stimulating factor (CSF) and antimicrobial agents, steroids, anti-inflammatory drugs, sex hormones, immunosuppressants, antiviral agents, anesthetics, antiemetic or antihistamines. In addition to the above components, conventional additives known in the art can be included, such as excipients, stabilizers, pH adjusters, antioxidants, preservatives, binders or disintegrants. In this case, the carrier may further include other additives, solvents, and the like known in the art.

In addition, the polymer hydrogel drug carrier may be formulated in the form of oral or parenteral preparations, and may be prepared by intravenous, intramuscular or subcutaneous injection.

In addition, the present invention provides a method of using the temperature and pH sensitive multi-block copolymer as a carrier for drug delivery or disease diagnosis. In this case, the material contained in the block copolymer is not particularly limited as long as it is a material for treating, preventing or diagnosing a disease.

Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples. However, the following examples are merely illustrative of the present invention, and the scope of the present invention is not limited thereto.

Example 1-2. Synthesis of Poly (β-Amino Ester) Oligomer]

Example 1

2.62 g (20 mmol) of 1- (2-hydroethylethylpiperazine (HP), a starting material of the poly (β-amino ester) oligomer, was placed in a 250 mL round bottom flask and 40 mL of anhydrous dichloromethane was added. After complete dissolution at room temperature, 2.88 mL (20 mmol) of hydroxybutyl acrylate (HBA) was added, followed by Mitchell reaction at 45 ° C. for 2 hours, followed by precipitation in excess of n-hexane to give a poly (β-amino ester) series. Oligomers (HPB) were prepared.

Example 2

2.62 g (20 mmol) of 1- (2-hydroethylethylpiperazine (HP), a starting material of the poly (β-amino ester) oligomer, was placed in a 250 mL round bottom flask and 40 mL of anhydrous dichloromethane was added. After complete dissolution at room temperature, 2.45 mL (20 mmol) of hydroxyethyl acrylate (HEA) was added, followed by Mitchell reaction at 45 ° C. for 2 hours, followed by precipitation in excess of n-hexane to give a poly (β-amino ester) series. Oligomers (HPE) were prepared.

Synthesis of Poly (β-Aminoester Urethane) -Polyethylene Glycol Multiblock Copolymer]

Example 3

Into a 250 mL round bottom flask, 2.0 g (1 mmol) of polyethylene glycol compound (PEG) and 0.002 g of dibutyltin dilaurate as a catalyst were placed in a reactor and vacuum dried at 100 ° C. for 2 hours to remove moisture. I was. After dropping the flask temperature to 60 ° C., 3.29 g (12 mmol) of HPB prepared in Example 1 was added and then dried under vacuum for 30 minutes. After nitrogen was added while breaking vacuum, 80 mL of anhydrous chloroform was added to completely dissolve the reactants, and 2.0 mL (12 mmol) of hexyl diisocyanate (HDI), which is a component of the starting material of the polyurethane-based oligomer, was added to the urethane for 3 hours. The reaction was carried out. Meanwhile, the product prepared above was cooled to room temperature and then precipitated in excess ethyl ether to remove unreacted material, followed by filtration to obtain (PEG-PAEU) _n multiblock copolymer having a molecular weight of 8,670 grams / mole. Was over 90%.

Example 4

In a 250 mL round-bottom flask, 2.0 g (1 mmol) of polyethylene glycol compound and 0.002 g of dibutyltin dimethyl aureate as catalyst were placed in a reactor and vacuum dried at 100 ° C. for 2 hours to remove moisture. After dropping the flask temperature to 60 degrees, 2.90 g (12 mmol) of HPE prepared in Example 2 was added and then dried under vacuum for 30 minutes. After nitrogen was added while breaking vacuum, 80 mL of anhydrous chloroform was added to completely dissolve the reactants, and 2.0 mL (12 mmol) of hexyl diisocyanate (HDI), which is a component of the starting material of the polyurethane-based oligomer, was added to the urethane for 3 hours. The reaction was carried out. Meanwhile, the product prepared above was cooled to room temperature, and then precipitated in excess ethyl ether to remove unreacted material, followed by filtration to obtain (PEG-PAEU) _n multiblock copolymer having a molecular weight of 8,500. The yield was 90. It was more than%.

Example 5

(PEG-PAEU) _n multiblock copolymer having a molecular weight of 8,600 was obtained in the same manner as in Example 3, except that the molar ratio of PEG: HPB: HDI was 1:15:12 mmol. It was more than%.

Example 6

(PEG-PAEU) _n multiblock copolymer having a molecular weight of 8,650 was obtained in the same manner as in Example 3, except that the molar ratio of PEG: HPB: HDI was 1:18:12 mmol. It was more than%.

Example 7

(PEG-PAEU) _n multiblock copolymer having a molecular weight of 8,400 was obtained by the same method as Example 4, except that the molar ratio of PEG: HPE: HDI was 1: 15: 12 mmol. It was more than%.

Example 8

(PEG-PAEU) _n multiblock copolymer having a molecular weight of 8,450 was obtained in the same manner as in Example 4, except that the molar ratio of PEG: HPE: HDI was 1: 18: 12 mmol. It was more than%.

Experimental Example 1 . Evaluation of Sol-Gel Transition Behavior with pH Change

Evaluation of the sol-gel transition behavior according to the temperature and pH change of the block copolymer prepared according to the present invention was performed.

30 wt% of the multiblock copolymer (PEG-PAEU) _n prepared in Example 3 was dissolved in a buffer solution, and then titrated with NaOH solution at 50 ° C. to adjust pH 5.5, 6.0, 6.5, 7.0, and 7.5, respectively. Multiblock copolymer solutions having respective pHs were allowed to equilibrate under constant temperature for 10 minutes while raising the temperature by 2 ° C., and then sol-gel transition behavior was measured by tilting each solution.

1 is a graph of the sol-gel transition behavior of a multiblock copolymer hydrogel according to temperature and pH changes according to an embodiment of the present invention.

More specifically, FIG. 1 is a poly (β-aminoester urethane) -polyethylene glycol multiple composed of poly (β-amino ester) having pH sensitivity and polyethylene glycol and polyurethane-based oligomer compound having temperature sensitivity according to Examples 3 and 5. It is a graph showing the sol-gel transition behavior according to the temperature and pH change of the block copolymer.

As shown in FIG. 1, the multiblock copolymer of the present invention has a sol-gel transition behavior depending on pH as well as temperature due to a change in the degree of ionization of the poly (β-aminoester urethane) -based oligomer in the copolymer. It was confirmed that this is done reversibly.

In fact, as shown in Figure 2, the prepared multiblock copolymer exhibits sol-gel transition properties at a specific pH, thereby gelling at pH 7.0 to 7.4, similar to the body, and solzing below the above range, thereby inducing conventional It was found that the gel is formed safely in the body without the occurrence of clogging of the needle, which can be seen in the temperature sensitive hydrogel, and the block copolymer prepared for the drug release can be released at a specific temperature and at a specific pH. It has been found that it can be applied as a carrier. On the other hand, a relatively formed hydrogel due to the use of a biodegradable poly (β-aminoester urethane) -based oligomer may be suitable as a drug carrier for releasing drugs in the long term by stably sticking to tissues such as the uterine wall.

Experimental Example  2. Biodegradability Evaluation

The biodegradability evaluation was performed from the change in molecular weight over time after the sol-gel transition occurred in the temperature and pH change of the block copolymer prepared according to the present invention. (See Figs. 4 to 9).

20 wt% of (PEG-PAEU) _n prepared in Example 3 was dissolved in a buffer solution, and then titrated with NaOH solution at 50 ° C., adjusted to pH 6.8, 7.0, and 7.4, to increase the temperature while allowing gel transition to fully equilibrate. The biodegradability was evaluated by measuring the change in molecular weight over time while making the state.

The temperature and pH sensitive multiblock copolymers of the present invention form stable hydrogels at certain pHs, such as pH 7.0 to 7.4, the pH range of normal cells in the body, and pH ranges 6.0 to 7.0 indicated by abnormal cells, such as cancer cells. If less, it can be used as a target-oriented drug-release carrier for cancer cells by keeping it in a sol state. That is, due to the increased degree of ionization of the tertiary amine present in the poly (β-aminoester urethane) -based oligomer at low pH (less than pH 7.0), the entire poly (β-aminoester urethane) becomes water soluble to form a hydrogel. At pH 7.0 and above, the degree of ionization of the poly (β-aminoester urethane) is lowered to show hydrophobic properties.

Due to the above properties, the multiblock copolymers of the present invention may exhibit pH-sensitive sol-gel transition properties as well as temperature.

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 inventions. It will be clear to those who have knowledge of.

Claims (22)

In the copolymer,
A multiblock copolymer comprising a first block having an ester bond, a second block having a urethane bond, and an ethylene glycol-based third block,
The multiblock copolymer is a multiblock copolymer represented by the following general formula.

Where n and m are 2 to 10 repeating units and x is 1 to 20 repeating units.
The method of claim 1,
The multiblock copolymer having the ester bond is a poly (β-amino ester). The method of claim 1,
The second block is a multiblock copolymer made of a polyurethane based on alkyldiaisocyanate as a starting material. delete The method of claim 1,
The copolymer is a multiblock copolymer having a molecular weight ratio of hydrophobic block and hydrophilic block of 1: 1 to 1: 3. The method of claim 1,
The number average molecular weight of the copolymer is 8,000 to 20,000 multiblock copolymer. In the manufacturing method of the copolymer,
(a) a poly (β-amino ester) oligomeric compound (A);
(b) polyethylene glycol series compounds (B);
(c) is formed by polymerizing alkyldiaisocyanate (C) as one of the starting materials of the polyurethane-based oligomer,
The poly (β-amino ester) oligomer compound (A) is a method for producing a multiblock copolymer formed by Mitchell reaction of an amine compound and hydroxyalkyl acrylate. delete The method of claim 7, wherein
The hydroxyacrylate compound is a block copolymer selected from the group consisting of hydroxyethyl acrylate, hydroxybutyl acrylate, hydroxyhexyl acrylate, hydroxyheptyl acrylate, hydroxy octyl acrylate or mixtures thereof Way. The method of claim 7, wherein
The amine compound is 1-methylamine (1-methylamine), 1-ethylamine (ethylamine), 1-propylamine (1-propylamine), 1-butylamine (1-butylamine), 1-pentylamine (1- pentylamine, 1-hexylamine, 1-heptylamine, 1-octylamine, 1-octylamine, 1-nonaamine, 1-decanamine , 3-isopropylamine, triethyleneamine, 3-methoxypropylamine, 3-ethoxy propylamine, 3-isopropoxy- Isopropoxy-1-propanamine, 3-propyl-1-propanamine, 3-butoxy-1-propanamine , 1,4-dioxa-1ethoxyamine (1,4-dioxa-1-ethoxyamine), 4,4-dimethoxybutylamine, (4,4-diethoxy-1- Butamine) (4,4-diethoxy-1-butanamine), 2-methoxyethanamine, 3-ethoxyethanamine, 3-isopropyl-1-ethoxyethanamine (3-isoprop oxy-1-ethoxyethanamine), 4,4-dimethoxyethylamine, 4,4-diethoxy-1-ethylamine, tetrahydro-2 Tetrahydro-2-furanylmethylamine, 2-phenoxyethanamine, 2- (3,4-dimethoxyphenyl) ethanamine) {2- (3,4-dimethoxyphenyl) ethanamine }, 2-2,5-dimethoxyphenyl) ethylamine {2- (2,5-dimethoxyphenyl) ethylamine}, 1,2,2-trimethyl-1-1propanamine (1,2,2, -trimethyl- 1-propanamine), 2-methyl-1-butanamine, 3-methyl-1-butanamine, 3-methyl-1-butanamine, 1,3-dimethyl-1-butane Amine (1,3-dimethyl-1-butanamine), 4-methyl-1-pentanamine, 4-methyl-1-pentanamine, 3,3-dimethyl-1-butanamine butanamine), 1,4-dimethyl-1-pentanamine, 1-methyl-1-hexanamine, 1-methyl-1-heptane Amine (1-methyl-1-heptanamine), 2-ethyl-1-hexanamine, 2-aminoethanol, 3-amino-1-propanol (3 -amino-1-propanol), (2R) -1amino-2-propanol {(2R) -1-amino-2-propanol}, (2S) -1-amino-2-propanol {(2S) -1- amino-2-propanol}, 2-amino-1-propanol, (2S) -1-amino-2-propanol {(2S) -1-amino-2-propanol}, 2 2-amino-1,3-propanediol, 2-amino-2-methyl-1,3-propanediol (2-amino-2-methyl-1,3-propanediol) 2-amino-2-methyl-1-propanol, 4-amino-1-butanol, 4-amino-1-butanol, 2-amino-1-propanol (2-amino-1-propanol), 2-ethylamino-1-butanol, 2- (2-aminoethoxy) ethanol {2- (2-aminoethoxy) ethanol}, 5 5-amino-1-pentanol, 3-amino-2,2-1-propanol, 2-amino-2- 2-amino-2-ethyl-1,3-propanediol, 2-amino-3-methyl-1-butanol, 6 -Amino-1-hexanol (6-amino-1-hexanol), (1-aminocyclopentyl) methanol (1-aminocyclopentyl) methanol), 4-a Minocyclohexanol, 2-aminocyclohexanol, 2-methyl-1-propanamine, cyclobutanamine, cyclopropylmethyl Amine (cyclopropylmethylamine), cyclopentanamine, cyclohexanamine, cyclohexanmethylamine, adamantane-methylamine, silane-methyl-deethoxy-propylamine ( Si-methyl-diethoxy-propylamine), Si-trithoxy-propylamine, 1,4-diazepane, N, N'-diethyl-1,2- Ethanediamine (N, N'-diethyl-1,2-ethane diamine), N, N'-diisopropyl-1,2-ethanediamine (N, N'-diisopropyl-1,2-ethane diamine), N , N'-dimethyl-1,2-propanediamine (N, N'-dimethyl-1,2-propanediamine), N, N'-dimethyl-1,3-propanediamine (N, N'-dimethyl-1, 3-propanediamine), N, N'-diethyl-1,3-propanediamine (N, N'-diethyl-1,3-propanediamine), N, N'-diethyl-1,4-pen Tandiamine (N, N-diethyl-1,4-pentanediamine), N, N'-bis (2-hydroxyethyl) ethylenediamine (N, N-Bis (2-hydroxyethyl) ethylenediamine), N, N'- Bis (2-hydroxy) propylenediamine (N, N'-Bis (2-hydroxyethyl) propylenediamine), 4,4'-trimethylenedipiperidine (4,4-trimethylenepiperidine (TMDP), N, N'-dimethyl Ethylenediamine (N, N'-dimethylethylenediamine), piperazine (piperazine), 2-methylpiperazine, 3-methyl-4- (3-methylphenyl) piperazine {3-methyl-4- (3 -methylphenyl) piperazine}, 3-methylpiperazine (3-methylpiperazine), 4- (phenylmethyl) piperazine {4- (phenylmethyl) piperazine}, 4- (1-phenylethyl) piperazine {4- (1- phenylethyl) piperazine}, 4- (1,1'-dimethoxycarbonyl) piperazine {4- (1,1'-dimethoxycarbonyl) piperazine}, 4- (2- (bis-2-propenyl) amino) ethyl ) Piperazine {4- (2- (bis- (2-prophenyl) amino) ethyl) piperazine}, 1- (2-aminoethyl) piperazine {1- (2-aminoethyl) piperazine}, 4- (aminomethyl Piperazine {4- (aminomethyl) piperazine}, N, N'-dimethyl- 1,2-ethanediamine (N, N'-dimethyl-1,2-ethanediamine), N, N'-diethyl-1,2-ethanediamine (N, N'-diethyl-1,2-ethanediamine), N, N'-diisopropyl-1,2-ethanediamine, N, N'-dimethyl-1,2-propylamine (N, N'-dimethyl -1,2-propyldiamine), N, N'-diethyl-1,2-propyldiamine (N, N'-diethyl-1,2-propyldiamine), N, N'-diisopropyl-1,2- N, N'-diisopropyl-1,2-propyldiamine, N, N'-dimethyl-1,2-hexanediamine (N, N'-dimethyl-1,2-hexanediamine), N, N'- Dimethyl-N- (3- (methylamino) propyl] -1,3-propanediamine {N, N'-dimethyl-N- [3- (methylamino) propyl] -1,3-propanediamine}, N- [2 -Methylamino) ethoxyethyl] -N, N'-dimethylamine {N- [2-methylamino) ethoxy ethyl] -N, N'-dimethylamine}, N- [2-methylamino) dioxyethyl] -N , N'-dimethylamine, N- [2-methylamino) dioxyethyl] -N, N'-dimethylamine {N- [2-methylamino) dioxyethyl] -N, N'-dimethylamine}, 1,4- Diazephan (1,4-diazepane) or mixtures thereof The method of the block copolymer. The method of claim 7, wherein
The reaction molar ratio of the hydrocyalkyl acrylate and the amine is 1: 2 to 1: 3 method of producing a block copolymer. The method of claim 7, wherein
The polyethylene glycol-based compound (B) is a method for producing a block copolymer represented by the following formula.

Wherein n is a natural number ranging from 10 to 50. The method of claim 12,
Method for producing a multiblock copolymer having a number average molecular weight of the polyethylene glycol-based compound ranges from 1,000 to 5,000 g / mol. The method of claim 7, wherein
Starting material of the polyurethane-based oligomer
A method for producing a multiblock copolymer formed by polymerizing an alkyl diisocyanate compound. 15. The method of claim 14,
The alkyl diisocyanate is a method for producing a multiblock copolymer consisting of the following formula.
OCN- (CH ₂ ) _n -NCO
Where n is the number of repeating units of integers 4-10. 15. The method of claim 14,
The alkyl diisocyanate is 1,2-diisocyanate ethane, 1,4-diisocyanate butane, 1,3-diisocyanate butane, 1,6-diisocyanate hexane, 1,7-diisocyanate heptane, 1,8-di Isocyanate octane, 1,9-diisocyanate nona, 1,10-diisocyanate decane, 1,12-diisocyanate decane, bis (4-isocyanate cycloethyl) methane, bis (4-isocyanatephenyl) methane, bis (4- A method for producing a multiblock copolymer selected from the group consisting of isocyanatephenyl) ether, bis (4-isocyanatephenyl) sulfone, 4,4'-diphenylmethane diisocyanate, hydrogenated 4,4'-diphenylmethane diisocyanate. The method of claim 7, wherein
The reaction molar ratio of the starting material of the polyethylene glycol, poly (β-amino ester) and the polyurethane oligomer is 1:12:12 to 1:18:12. The method of claim 7, wherein
In synthesizing the copolymer, the temperature is 40 to 70 ℃, the time is a method for producing a multiblock copolymer made for 1 to 3 hours. The method of claim 7, wherein
The polymerization is dibutyl diyl laurate (dibutyl dilaurate), stannous octoate, tin oxide (stannous chloride), iron oxide (iron oxide), aluminum triisopropoxide (aluminum triisopropoxide), CaH ₂ , Zn, Lithium chloride, tris (2,6-di-tert-butylphenolate) multi-block copolymer that can use at least one catalyst selected from the group consisting of Manufacturing method. In the method for producing a biodegradable copolymer,
Mitchell reacting 1- (2-hydroxyethyl) piperazine with hydroxyethylacrylate to synthesize a poly (β-amino ester) family oligomer; And reacting with 1,6-diisocyanate hexane (HDI) to form polyethylene glycol and polyurethane blocks in the product. And dissolving the reactant in chloroform and dissolving it in an excess of ethyl ether to remove the unreacted compound. (a) a multiblock copolymer according to any one of claims 1 to 3, 5 and 6 or an air produced by the method of any one of claims 7 or 9 to 20. coalescence; And
(b) a polymer hydrogel-type drug carrier comprising a physiologically active substance that can be encapsulated in the multiblock copolymer. The method of claim 21,
As a physiologically active substance that can be encapsulated in the polymer hydrogel-type block copolymer, paclitaxol, doxorubicin, docetasol, docetaxol, chlororambucil, insulin, exendin-4, Human growth hormone (hGH), erythropoietin (EPO), granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage stimulating factor (GMCSF), antimicrobial agents, steroids, anti-inflammatory analgesics, sex hormones, At least one drug delivery agent selected from the group consisting of immunosuppressants, antiviral agents, anesthetics, antiemetics, antihistamines, additives, excipients, stabilizers, pH adjusters, antioxidants, preservatives, binders and disintegrants.

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