Phosphazene-based polymer for tissue adhesion, a method for preparing the same, and use thereof

1. A phosphazene-based polymer comprising a catechol group,

wherein, on a phosphorous atom of a polyphosphazene backbone represented by the following Formula 1,

a first moiety of an amino acid ester represented by the following Formula 2;

a second moiety of polyethylene glycol represented by the following Formula 3;

a third moiety comprising a functional group; and

a fourth moiety comprising a catechol group linked directly or by a linker to a part of or an entire functional group of the third moiety:

wherein,

the first moiety, the second moiety, the third moiety, and the fourth moiety are present in a molar ratio of a:b:c:d, respectively;

wherein a is 55 mol % to 77 mol %; b is 5 mol % to 30 mol %; a sum of c and d is 10 mol % to 20 mol %; and the c:d ratio is in a range of 1:0.1 to 1:1; and

wherein, in Formulas 1, 2, and 3,

R 1 is C 1-6 alkyl, C 1-6 alkenyl, or C 6-10 aryl-C 1-6 alkyl;

R 2 is hydrogen, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, thiomethyl, methylthioethyl, benzyl, hydroxylbenzyl, or 2-indolylmethyl;

R 3 is C 1-6 alkyl;

n is an integer of 3 to 100,000; and

p is an integer of 1 to 20.

2. The phosphazene-based polymer of claim 1 , wherein the functional group is a hydroxy group or a carboxyl group.

3. The phosphazene-based polymer of claim 1 , wherein R 1 is methyl, ethyl, propyl, butyl, benzyl, or 2-propenyl; and R 3 is methyl.

4. The phosphazene-based polymer of claim 1 , further comprising a fifth moiety, in which at least one functional substance selected from the group consisting of a substance capable of regulating decomposition rate of a polymer, a substituent comprising an ionic group capable of regulating decomposition rate, a substituent capable of cross-linking, an additional compound capable of inducing tissue adhesion, a physiologically active substance, and a composite material formed by linear connection of two or more substances among them is linked directly or by a linker to a part of or an entire functional group of the third moiety.

5. The phosphazene-based polymer of claim 1 , wherein the phosphazene-based polymer comprising a catechol group has a weight average molecular weight of 15,000 to 37,000, and is represented by the formula of poly[isoleucine ethyl ester] a (mino methoxypolyethylene glycol 750) b (amino ethylsuccinate or amino ethyladipic acid) c (amino ethyldopamine) d′ phosphazene] n′ ;

wherein, in the above formula,

a′ is from 1.20 to 1.36;

b′ is from 0.37 to 0.53;

c′ is from 0.13 to 0.26;

d′ is from 0.03 to 0.13;

a′+b′+c′+d′ is 2; and

n′ is an integer from 3 to 100,000.

6. A preparation method of the phosphazene-based polymer of claim 1 , comprising:

a first step of reacting poly(dichlorophosphazene) of Formula 4 with an (amino acid)(C 1-6 alkyl)ester of Formula 5;

a second step of reacting the reaction mixture obtained from the previous step by adding amino(C 1-6 alkoxy)polyethylene glycol and amino(C 1-6 alkanol);

a third step of reacting the reaction mixture of the previous step by further adding a amino(C 1-6 alkoxy)polyethylene glycol solution dropwise;

a fourth step of reacting the product obtained from the previous step with C 1-6 alkanedioic acid or an anhydride thereof, and dimethylaminopyridine; and

a fifth step of reacting the product obtained from the previous step with di(C 1-6 alkyl)carbodiimide, hydroxysuccinimide, and dopamine:

wherein, in Formulas 4 and 5,

R 1 , R 2 , and n are as defined in claim 1 .

7. The preparation method of claim 6 , wherein the first to third steps are carried out in a tetrahydrofuran solution in the presence of triethylamine.

8. The preparation method of claim 6 , wherein the first step is carried out for 24 hours to 60 hours while increasing a temperature from a range of −80° C. to −50° C. to a range of 10° C. to 50° C.

9. The preparation method of claim 6 , wherein the second and third steps are independently carried out at 35° C. to 60° C. for 24 hours to 60 hours.

10. The preparation method of claim 6 , further comprising a step of filtering the resulting reaction mixture; concentrating the filtrate under reduced pressure;

dissolving in methanol; and dialyzing the resulting concentrate with methanol and water after the reaction of the third step.

11. The preparation method of claim 6 , wherein the fourth step is carried out in a dry tetrahydrofuran solution at 35° C. to 60° C. for 24 hours to 60 hours.

12. The preparation method of claim 6 , further comprising a step of filtering the obtained reaction mixture; concentrating the filtrate under reduced pressure; dissolving in methanol; and dialyzing the resulting concentrate with methanol and water after the reaction of the fourth step.

13. The preparation method of claim 6 , wherein the fifth step is carried out in a dry dimethylformamide solution at 10° C. to 35° C.

14. The preparation method of claim 6 , wherein the fifth step is carried out by sequentially adding di(C 1-6 alkyl)carbodiimide, hydroxysuccinimide, and dopamine while reacting for 10 minutes to 60 minutes, 6 hours to 24 hours, and 24 hours to 72 hours, respectively.

15. The preparation method of claim 6 , wherein the (amino acid)(C 1-6 alkyl)ester is isoleucine ethyl ester; the amino(C 1-6 alkoxy)polyethylene glycol is amino methoxypolyethylene glycol; the amino(C 1-6 alkanol) is aminoethanol; the C 1-6 alkanedioic acid or the anhydride thereof is succinic acid, glutaric acid, adipic acid, or an anhydride thereof; and the di(C 1-6 alkyl)carbodiimide is diisopropylcarbodiimide.

16. A tissue-adhesive composition comprising a phosphazene-based polymer comprising a catechol group of claim 1 as an active ingredient.

17. The tissue-adhesive composition of claim 16 , wherein the composition is used for wound healing, adhesion of surgical tissue, or hemostasis.

18. The tissue-adhesive composition of claim 16 , wherein the composition is converted from a sol form to a gel form due to body temperature.