KR20040069051A - Thermo-sensitive Polysaccharide Copolymer and Method Thereof - Google Patents

Abstract

PURPOSE: A polysaccharide graft copolymer and its preparation method are provided, to obtain a thermosensitive and water-soluble polysaccharide graft copolymer which has an excellent biocompatibility. CONSTITUTION: The method comprises the steps of adding an oxidation-reduction initiator to a polysaccharide solution to produce a polysaccharide radical; and grafting an acrylamide-based polymer, a copolymer of an acrylamide-based monomer and a vinyl-based monomer or a copolymer of an acrylamide-based monomer and an acryl-based monomer to the polysaccharide radical solution. Preferably the oxidation-reduction initiator is ammonium cerium nitrate. Also the method comprises the steps of treating a polyethylene oxide-polypropylene oxide-polyethylene oxide terpolymer with a substituting agent to carry out tosylation of one terminal hydroxyl group of the terpolymer; and grafting the tosylated terpolymer to a polysaccharide.

Description

Temperature sensitive polysaccharide copolymer and its preparation method {Thermo-sensitive Polysaccharide Copolymer and Method Thereof}

The present invention relates to a temperature sensitive polymer and a method for producing the same, and more particularly, to a chitosan graft copolymer having a temperature sensitivity and a method for producing the same.

Temperature-sensitive polymers (thermo-sensitive polymer) is a material in which a phase transition is reversible due to the difference in the solubility of the polymer with the temperature change in the aqueous solution. That is, the temperature sensitive polymer refers to a material in which the phase transition reversibly from the liquid phase to the hydrogel in accordance with the temperature change.

This phase transition system is divided into a negative temperature sensitive system in which phase transition occurs at a specific low temperature and a positive temperature sensitive system in which phase transition occurs at a specific high temperature. The temperature at which phase transitions occur is referred to as lower critical solution temperature (LCST) in negative temperature sensitive systems and upper critical solution temperature (UCST) in positive temperature sensitive systems, especially for LCST. Much research is being done.

In the negative temperature-sensitive system, the phase transition phenomenon is that the hydrophilic portion contained in the polymer contains water by hydrogen bonding with intermolecular or water, which forms a basic structure at low temperature, so that it is dissolved in water, As the bond breaks, water is released out of the polymer, which intensifies the hydrophobic interaction between molecules and precipitates.

Such temperature-sensitive polymers have recently been researched in various fields such as drug delivery systems, medical materials, biology, environment, textiles, and cosmetics. Temperature-sensitive polymers currently under extensive research include poly (N-isopropylacrylamide, Poly (N-isopropylacrylamide, PNIPAAm)) or polyethylene oxide copolymers, hydroxy polymers, and some polyphosphogen polymers. Can be mentioned. Such a temperature sensitive polymer has a low critical solution temperature that varies with the abundance of hydrophilic or hydrophobic moieties bound to the polymer backbone.In general, as the hydrophilic group increases, the phase transition temperature increases, and as the hydrophobic group increases, the phase transition temperature decreases. .

In particular, poly (N-isopropylacrylamide, hereinafter referred to as 'PNIPAAm') has a low solution temperature of 32-34 ° C., but liquid or sol at room temperature, but in solid state or gel in vivo. Due to these characteristics, much research has been conducted on drug delivery systems using PNIPAAm.

In addition, the PEO-PPO-PEO (polyethylene oxide-polypropylene oxide-polyethylene oxide) triblock copolymer appropriately controls the degree of polymerization of the hydrophilic group PEO portion and the hydrophobic portion PPO portion to adjust the low critical solution temperature according to the purpose. There is an advantage that can be adjusted.

However, the PNIPAAm or PEO-PPO-PEO triple block copolymers have a problem of poor biofunctionality such as mechanical strength.

On the other hand, a biodegradable temperature sensitive polymer has been proposed that has a temperature sensitivity similar to that of the PNIPAAm or the triblock copolymer and can be broken down into small molecules in vivo. For example, US Pat. No. 6,451,346 proposes a temperature sensitive block copolymer composed of polyethylene glycol with a hydrophobic portion and a hydrophilic portion composed of polylactide, polyglycolide or copolymers thereof. . However, the block copolymer has a problem that can be broken down into by-products harmful to the human body through an unexpected reaction in vivo.

The present invention has been proposed to solve the above problems, and an object of the present invention is to provide a temperature-sensitive polymer having excellent biocompatibility by including a material that can be usefully used in vivo.

Another object of the present invention is to use a polysaccharide copolymer having excellent biocompatibility and temperature sensitivity to change the activity of physiologically active substances such as cells, enzymes, proteins, genes, drugs, etc. The present invention aims to provide a temperature sensitive polymer delivery system that maximizes the efficiency of physiologically active substances that can be encapsulated in a polymer simply by injecting it into a solid phase under body temperature by injecting it into a required site.

1 is a schematic diagram of a chitosan-poly (N-isopropylacrylamide) graft copolymer according to one embodiment of the present invention;

2 is a schematic diagram of a chitosan- (PEO-PPO-PEO) graft copolymer according to another embodiment of the present invention;

3 is a phase transition graph of chitosan-poly (N-isopropylacrylamide).

For this purpose, the present invention comprises the steps of adding a redox initiator to the polysaccharide solution to produce a polysaccharide radical; And grafting an acrylamide polymer, a copolymer of acrylamide monomer and vinyl monomer or a copolymer of acrylamide monomer and acryl monomer to the radicalized polysaccharide solution. It provides a method of manufacturing.

The acrylamide polymers include poly (N-methyl-Nn-propylacrylamide), poly (Nn-propylacrylamide), poly (N-methyl-N-isopropylacrylamide), and poly (Nn-propylmethacrylamide). ), Preferably poly (N, n-diethylacrylamide) or alkyl acrylamides such as poly (N-isopropylacrylamide), and most preferably poly (N-isopropylacrylamide). .

The vinyl monomer is selected from vinyl alcohol, N-vinylpyrrolidone, vinyl methyl ether, vinyl acetate, vinyl formate, vinyl propionate, and the acrylic monomer is acrylic acid, methacrylic acid, acrylic ester, hydroxypropyl It is selected from acrylate, hydroxypropyl methacrylate, the redox initiator is characterized in that the cerium ammonium nitrate.

In addition, the present invention comprises the steps of treating the polyethylene oxide-polypropylene oxide-polyethylene oxide triblock copolymer with a substituent to activate a hydroxyl group of one of both ends of the triblock copolymer; A method of preparing a temperature sensitive polysaccharide graft copolymer comprising grafting the activated triblock copolymer to a polysaccharide, preferably the substituent is a temperature sensitive polysaccharide selected from tosyl chloride or carbonyldiimidazole It provides a method for producing a graft copolymer.

On the other hand, the present invention is treated with a carbodiimide-based polyethylene oxide-polypropylene oxide-polyethylene oxide triblock copolymer in which at least one end of both ends is substituted with a carboxyl group, one of both ends of the copolymer Activating the terminal carboxyl group; And it provides a method for producing a temperature-sensitive polysaccharide graft copolymer comprising the step of grafting the activated triblock copolymer to a polysaccharide.

Furthermore, the present invention is a polysaccharide graft copolymer for graft reacting a polymer having temperature sensitivity to a biocompatible polysaccharide, wherein the polymer is an acrylamide-based polymer, a copolymer of an acrylamide-based monomer and a vinyl monomer. Provided are a polysaccharide graft copolymer selected from copolymers of monomers and acrylic monomers or from polyethylene oxide-polypropyleneoxide-polyethylene oxide (PEO-PPO-PEO) triblock copolymers.

The polysaccharide graft copolymer prepared according to the present invention may be used as a material for medical supplies mixed with other substrate molecules and used as a transporter of a bioactive material. For example, by mixing a polysaccharide graft copolymer of the present invention with a drug having a water-soluble or insoluble cell, protein, gene or charge, it can be utilized as a tissue engineering and target-oriented drug delivery system. In addition, the graft copolymer of the present invention may be used as an additive for coating or forming on medical materials.

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

In the present invention, the temperature sensitivity and biocompatibility can be controlled by grafting a polymer known as a temperature sensitive polymer onto a polysaccharide having excellent biocompatibility. The polysaccharide is preferably chitosan or cellulose, more preferably chitosan.

Polysaccharides such as cellulose or chitosan are biodegradable natural polymeric materials.

Cellulose is a polysaccharide in which D-glucose is linked by ??-1,4 bonds, and is one of the most widely present substances in nature. In addition, chitosan is a basic polysaccharide in which chitin present in shellfish such as shellfish is deacetylated and thus useful properties such as cationic, nontoxic, and biodegradable properties due to the presence of amino groups are found. It is widely used in food additives and the like. In particular, since chitosan itself has pharmacological effects such as cholesterol lowering effect and tumor suppression effect, chitosan or its derivatives have been studied for application to medical materials, artificial skin, and the like.

However, the cellulose, chitosan or derivatives thereof are extremely low in solubility in the organic solvents used in general, and thus are limited to be used as biocompatible materials such as hemodialysis membranes or drug delivery systems. In the present invention, as described below, by grafting a polymer suitable for the polysaccharide or a derivative thereof, mechanical and physical properties are improved and solubility in an organic solvent or water is improved.

Meanwhile, whether or not the chitosan is water-soluble depends on the degree of deacetylation and the degree of polymerization. The chitosan used in the present invention may be used as a base material of a temperature sensitive polymer regardless of the degree of water solubility and deacetylation.

The polysaccharides used for biocompatibility in the present invention are dissolved with gentle stirring under a nitrogen stream in an appropriate solvent to minimize the effects of oxygen.

The polymer grafted to the polysaccharide is a polymer whose temperature is found to be sensitive, and in the present invention, when the polysaccharide is grafted to the polysaccharide after the radicalization reaction of the polysaccharide, the block copolymer in which the terminal substituent is activated is grafted to the polysaccharide. Can be divided into the following cases.

First, the polymer grafted to the polysaccharide after the radicalization reaction of the polysaccharide is a material having compatibility with polysaccharides, particularly chitosan, and acrylamide polymers, copolymers of acrylamide monomers and vinyl monomers or acrylamides. It is selected from the copolymer of a monomer and an acrylic monomer.

The acrylamide polymers include poly (N-methyl-Nn-propylacrylamide), poly (Nn-propylacrylamide), poly (N-methyl-N-isopropylacrylamide), and poly (Nn-propylmethacrylamide). ), Poly (N, n-diethylacrylamide) or alkyl acrylamide such as poly (N-isopropylacrylamide), preferably poly (N-isopropylacrylamide).

The vinyl monomer is selected from vinyl alcohol, N-vinylpyrrolidone, vinyl methyl ether, vinyl acetate, vinyl formate, vinyl propionate, and the acrylic monomer is acrylic acid, methacrylic acid, acrylic ester, hydroxypropyl It is preferred to be selected from acrylates.

FIG. 1 is a schematic diagram showing a process of grafting N-isopropylacrylamide, a monomer of PNIPAAm, a typical temperature sensitive polymer, to chitosan in a polysaccharide.

As shown in Fig. 1, the chitosan solution dissolved in a suitable solvent is radicalized by a redox initiator, and a temperature sensitive polymer (poly (N-isopropylacrylamide in Fig. 1)) is added to the radicalized chitosan. Graft copolymerized.

The redox initiator used in the present invention may be a redox initiator used for the radicalization of polysaccharides including chitosan, but is preferably ceric ammonium nitrate (NH ₄ ) ₂ Ce (NO ₃ ) ₆ ). to be. This is because the cerium ammonium nitrate shows high starting efficiency at room temperature.

The polysaccharide containing chitosan is opened by the redox initiator to form radicals, and a chain polymerization reaction is caused through a double bond of an acrylamide- or vinyl-based monomer added to the polysaccharide. In this case, in the present invention, since the acrylamide system grafted to the polysaccharide may have a double bond in the monomer, chain extension triggered by the radicalization reaction may be possible, but a longer chain graft copolymer is desired. Alternatively, in order to increase the rate of the chain extension reaction, a crosslinking agent may be added separately in addition to the component grafted to the polysaccharide, such as an acrylamide polymer. As a crosslinking agent that can be used in connection with the present invention, an acrylic or vinyl salt having a plurality of functional groups may be used, and preferably 1,3-propanediol diacrylate, 1,4-butanediol diacrylate, 1 , 6-hexamethylene diacrylate, 1,3-propanediol dimethacrylate, 1,4-butanediol dimethacrylate, 1,6-dihexamethylene dimethacrylate, 1,4-phenylene diacrylate Ethylene glycol dimethacrylate, triethylene dimethacrylate, glycerol trimethacrylate, divinylpyridine, divinylpyridine, 2,5-divinylpyrazine, 1,4-divinylimidazole, and the like. Can be used.

The reaction of the grafted monomer with the polysaccharide used in the present invention is described in Scheme 1 below.

Scheme 1

As the polymer to be grafted in connection with the present invention, a polymer having temperature sensitivity may be used as the acrylamide-based polymer. However, the phase transition temperature (LCST) in vivo depends on environmental factors such as molecular weight and pH of the polysaccharide. If there is a need for adjustment, a copolymer of acrylamide monomer and vinyl monomer, two or more copolymers such as acrylamide monomer and acrylic monomer, in particular a block copolymer or an altered copolymerization state, may be grafted to the polysaccharide. Can be.

After the graft polymerization reaction to the polysaccharide is terminated as described above, by removing the unreacted homopolymer, a copolymer of the polysaccharide-temperature sensitive polymer having the biocompatibility of the present invention can be obtained.

On the other hand, the temperature-sensitive molecules may be grafted to the polysaccharide as a block copolymer, in the present invention, a hydrophilic group (polyethylene oxide, PEO) and a hydrophobic group (polypropylene oxide, PPO) is a block copolymerized polyethylene oxide-polypropylene Oxide-polyethylene oxide (PEO-PPO-PEO) triblock copolymer was used. The PEO-PPO-PEO triblock copolymer may be prepared according to a conventional method.

In the present invention, the polyethylene oxide (PEO) located at the sock end of the triblock copolymer grafted to the polysaccharide has an effect of preventing the adsorption of proteins in vivo, and the polymer and the biomolecule interaction when injected into the blood. It is possible to prevent the polymer injected into the cell by the cell to be removed, thereby allowing the polymer to stay in the cell for a long time.

However, since the PEO has a small functional group except for the terminal, there is a problem in that the introduction of molecules that can adhere to the cell is limited and the absorption rate of the biological tissue cell is lowered. In the present invention, the polysaccharide having a plurality of functional groups is grafted. This was solved by

Figure 2 is roughly the process of grafting on chitosan after activating the end of the PEO-PPO-PEO triblock copolymer with toluenesulfonyl chloride (TsCl), one of the substituents used in the present invention It is a schematic diagram shown by.

As shown, the hydroxyl group at one terminal of the hydroxyl groups located at both ends of the PEO-PPO-PEO triblock copolymer is reacted with TsCl to tosylate, and then reacted with the primary amine group of chitosan to PEO-PPO to chitosan. -PEO triblock copolymer is grafted. The graft reaction of the triblock copolymer is shown in Scheme 2 below.

Scheme 2

It is also possible to use other activators other than the tosyl chloride according to the functional group located at the end of the triblock copolymer. For example, when at least one of both ends is substituted with a carboxyl group (which can be obtained by using an appropriate oxidizing agent such as potassium permanganate), a carbodiimide-based activator capable of activating the carboxyl group is Can be used, the reaction mechanism is shown in Scheme 3 below.

Scheme 3

In Scheme 3, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (1-ethyl-3- (3-dimethylaminopropyl) carbodiimde, EDC) is represented as a representative carbodiimide, but in addition, 1-ethyl- 3- (3- (trimethyl) ammoniopropyl) carbodiimide (1-ethtyl-3- (3- (trimethyl) ammoniopropyl) carbodiimide, ETC), 1-cyclohexyl-3- (2-morphinoethyl) Bodyimide (1-cyclohexyl-3- (2-morphinoethyl) carbodiimide (CMC), dimethylcarbodiimide, dicyclohexylcarbodiimide, diisopropylcarbodiimide, diisobutylcarbodiimide Aliphatic dicarbodiimides such as carbodiimides and aromatic carbodiimides such as diphenylcarbodiimide and dinaphthylcarbodiimide can be used.

On the other hand, when at least one end of the sock end of the triblock copolymer is hydroxy, in addition to the above-described toric chloride, it is reacted with a carbonyldiimidazole (CDI) system, which is a hydroxyl group activator, and then reacted with a primary amine group of chitosan. The chitosan can be grafted with PEO-PPO-PEO triblock copolymer. This reactor field is shown in Scheme 4.

Scheme 4

The temperature sensitive polymer of the present invention exhibits water solubility or water dispersibility at room temperature depending on the concentration of the monomer or triblock copolymer added as described above, the reaction temperature, and the concentration of the initiator, so that the temperature sensitivity of the aqueous solution and the low critical solution temperature are changed. do. However, in consideration of the low critical solution temperature of the temperature sensitive monomer or triblock copolymer used in the present invention, the reaction is preferably performed at a temperature of 4 to 30 ° C. This is because at lower temperatures, the reaction rate is too slow to expect efficiency, and at higher temperatures, the monomers or triblock copolymers added to the polysaccharides are present in the gel and cannot be grafted to the polysaccharides.

In addition, the polymer grafted to the polysaccharide is preferably reacted at 2 to 8 parts by weight based on 100 parts by weight of the total graft copolymer. 3 is a diagram showing the phase transition temperature of the temperature sensitive polymer of the present invention according to the weight ratio of the polymer grafted to the polysaccharide. In FIG. 3, A and B are sol states, respectively, and C and D are gels. As can be seen in Figure 3, when the polysaccharide is grafted polymer 3 to 7% by weight it can be seen that the temperature of the phase transition from the sol (sol) to the gel (gel) phase is 31 to 32 degrees. This shows that there is no significant difference compared to PNIPAAm, which is a representative temperature sensitive polymer, and it shows that the polysaccharide-temperature sensitive polymer prepared according to the present invention can be used in drug delivery systems and the like.

Hereinafter, the present invention will be described in more detail with reference to preferred embodiments. However, the present invention is not limited by the following examples.

Example 1

Chitosan was dissolved in 10% by weight acetic acid to prepare a chitosan solution. The chitosan solution was added to a 500 ml reactor, and stirred slowly for 10 minutes under a nitrogen stream. At a reaction temperature of 30 ° C., 5 × 10 ⁻³ M of cerium nitrate as a redox initiator was added to the chitosan solution, and 3% by weight of monomer N-isopropylacrylamide was added to the chitosan solution. Subsequently, polymerization was carried out with stirring at a rate of 100 rpm for 4 hours at 30 ° C. under a nitrogen stream. After the prepared mixture of chitosan-g-poly (N-isoproylacrylamide), poly (N-isopropylacrylamide) which is a homopolymer, and unreacted monomer was added to acetone to precipitate, a homopolymer and an unreacted monomer Was removed to obtain pure chitosan-g-poly (N-isopropylacrylamide).

Example 2

Chitosan-g-poly (N-isopropylacrylamide) was obtained in the same manner as in Example 1 except that the aqueous chitosan was dissolved in distilled deionized water instead of acetic acid.

Example 3

7 wt% of N-isopropylacrylamide was added to the chitosan solution, and the reaction temperature was changed to 25 ° C. to prepare chitosan-g-poly (N-isopropylacrylamide) having a different graft ratio using the same method as in Example 1. To induce a change in phase transition temperature.

Example 4

In one reactor, chitosan was dissolved in 10% by weight acetic acid to prepare a chitosan solution. In another reactor, one terminal hydroxy group of the PEO-PPO-PEO triblock copolymer was tosylated by reacting tosyl chloride (TsCl) in a molar ratio of 1: 1. PEO-PPO-PEO triblock copolymer in which one end is tosylated is added by 5% by weight based on chitosan solution and reacted with the primary amine group of chitosan at 30 ° C. to PEO-PPO-PEO triblock copolymer. Copolymers were prepared by grafting the copolymers. The yield of the reaction was about 50%.

Example 5

Chitosan-g-PEO with different graft rates was used in the same manner as in Example 4 except that 7 wt% of PEO-PPO-PEO triblock copolymer was added to the chitosan solution and the reaction temperature was 20 ° C. A -PPO-PEO graft copolymer was prepared to induce a change in phase transition temperature.

Example 6

A 10 wt% chitosan solution was prepared by dissolving in 0.5% acetic acid. After stirring by adding 1-ethyl-3- (3-di-methylaminopropyl) carbodiimide (EDC) to the prepared solution, the PEO-PPO-PEO triblock copolymer in which the terminal functional group was substituted with a carboxyl group was used as a chitosan solution. 5 wt% was added, and the reaction temperature was 30 ° C. or less and reacted at room temperature for at least 3 hours to prepare a chitosan-g-PEO-PPO-PEO graft copolymer by grafting PEO-PPO-PEO triblock copolymer to the chitosan primary amine group. It was.

Example 7

A chitosan-g-PEO-PPO-PEO graft copolymer having a different graft ratio was prepared in the same manner as in Example 6 except that 7 wt% of the PEO-PPO-PEO triblock copolymer was added to the chitosan solution. The change of phase transition temperature was induced.

Example 8

In one reactor, PEO-PPO-PEO triblock copolymer having a hydroxy group and N, N ??-carbonyldiimidazole (CDI) were reacted in a molar ratio of 1: 1 to activate the PEO-PPO-PEO triblock copolymer. In another reactor, 10 wt% chitosan solution was prepared by dissolving 0.5% acetic acid. 5 wt% of the activated PEO-PPO-PEO triblock copolymer was added based on the chitosan solution to react with the primary amine group of chitosan at room temperature to graf the PEO-PPO-PEO triblock copolymer to the amine group of the chitosan main chain. Copolymers were prepared.

Example 9

A chitosan-g-PEO-PPO-PEO graft copolymer having a different graft ratio was prepared in the same manner as in Example 8 except that 7 wt% of the PEO-PPO-PEO triblock copolymer was added to the chitosan solution. The change of phase transition temperature was induced.

Experimental Example

Phase transition temperatures (LCST) were compared with respect to the temperature sensitive polysaccharide graft copolymers prepared in Examples 1-9. The phase transition temperature based on the weight ratio of the monomer or PEO-PPO-PEO triblock copolymer added to the chitosan solution is shown in FIG. 3.

As shown in FIG. 3, when the weight ratio of the acrylamide-based polymer or the triblock copolymer to the chitosan solution is 3 to 7%, the phase transition temperature of the resulting temperature sensitive polysaccharide graft copolymer was 29 to 32 ° C. .

In the above description of the preferred embodiment of the present invention, it will be apparent to those skilled in the art that various modifications and changes are possible. Also, it will be apparent from the appended claims that such variations and modifications fall within the scope of the present invention without departing from the spirit of the invention.

The polysaccharide graft copolymer prepared according to the present invention has no significant difference from the sol phase to the gel phase phase and the PNIPAAm or PEO-PPO-PEO triblock copolymer, which is a temperature sensitive polymer used in the related art. It can be applied to medical fields such as grafted plants or drug delivery systems.

Furthermore, unlike the PNIPAAm or the PEO-PPO-PEO triblock copolymer, the temperature-sensitive polymer of the present invention contains a material such as chitosan or cellulose, and has excellent biocompatibility and bioactive substances (cells, proteins, enzymes, genes, etc.). As a transporter in the body, it can be used as a mechanochemical material such as oral drug delivery system, artificial blood vessel, artificial organ. In particular, the temperature-sensitive polymer of the present invention can be easily applied by simply mixing the temperature-sensitive polymer and the physiologically active substance in an aqueous solution at room temperature and injecting the mixed solution to the required area without surgery.

In addition, by controlling the concentration of the monomer or the triblock copolymer added to the polysaccharide in the preparation process of the present invention, the reaction temperature, the concentration of the initiator has the advantage that it is easy to change the phase transition temperature.

Claims (14)

Adding a redox initiator to the polysaccharide solution to produce a polysaccharide radical; And Grafting the acrylamide polymer, the copolymer of acrylamide monomer and vinyl monomer or the copolymer of acrylamide monomer and acrylic monomer to the radicalized polysaccharide solution Method for producing a temperature sensitive polysaccharide graft copolymer comprising. The method of claim 1, The acrylamide polymers include poly (N-methyl-Nn-propylacrylamide), poly (Nn-propylacrylamide), poly (N-methyl-N-isopropylacrylamide), and poly (Nn-propylmethacrylamide). ), A process for producing a temperature sensitive polysaccharide graft copolymer selected from alkyl acrylic amides such as poly (N, n-diethylacrylamide) or poly (N-isopropylacrylamide). The method of claim 1, The vinyl monomer is selected from vinyl alcohol, N-vinylpyrrolidone, vinyl methyl ether, vinyl acetate, vinyl formate, vinyl propionate Method for producing a temperature sensitive polysaccharide graft copolymer. The method of claim 1, The acrylic monomer is selected from acrylic acid, methacrylic acid, acrylic ester, hydroxypropyl acrylate, hydroxypropyl methacrylate Method for preparing a temperature sensitive polysaccharide graft copolymer. The method of claim 1, The redox initiator is a method of producing a temperature-sensitive polysaccharide graft copolymer is ammonium cerium nitrate. Treating the polyethylene oxide-polypropylene oxide-polyethylene oxide triblock copolymer with a substituent to tosylate a hydroxyl group at one of both ends of the triblock copolymer; Grafting the tosylated triblock copolymer to polysaccharide Method for producing a temperature-sensitive polysaccharide graft copolymer comprising. The method of claim 6, The substituent is selected from toluenesulfonyl chloride (TsCl) or carbonyldiimidazole (carbonyldiimidazole) Method for producing a temperature sensitive polysaccharide graft copolymer. A polyethylene oxide-polypropylene oxide-polyethylene oxide triblock copolymer in which at least one of both ends is substituted with a carboxyl group is treated with a carbodiimide system to activate a carboxyl group at one of both ends of the copolymer. Doing; Grafting the activated triblock copolymer to polysaccharide Method for producing a temperature-sensitive polysaccharide graft copolymer comprising. The method according to any one of claims 1 to 8, The polysaccharide is chitosan or cellulose is a method of producing a temperature-sensitive polysaccharide graft copolymer. A polysaccharide graft copolymer for graft reacting a polymer having temperature sensitivity to a biocompatible polysaccharide. The method of claim 10, The polymer grafted to the polysaccharide may be an acrylamide polymer, a copolymer of an acrylamide monomer and a vinyl monomer, a copolymer of an acrylamide monomer and an acrylic monomer, or polyethylene oxide-polypropylene oxide-polyethylene oxide (PEO -PPO-PEO) triblock copolymer selected from Polysaccharide graft copolymers. The method of claim 10, The polymer grafted to the polysaccharide is bonded to 2 to 8 parts by weight based on 100 parts by weight of the total graft copolymer Temperature sensitive polysaccharide graft copolymers. The method of claim 10, The temperature sensitive polysaccharide graft copolymer is used as a material for medical supplies utilized as a transporter of a bioactive material Temperature sensitive polysaccharide graft copolymers. The method of claim 13, The medical supplies are selected from the cardiovascular system, nervous system, drug delivery and diagnostic reagents, artificial tissues and artificial organs. Temperature sensitive polysaccharide graft copolymers.