Tissue-adhesive polymers
The invention is directed to a multi-arm tissue-adhesive polymer wherein at least six or more arms each comprise a reactive functional group that can form a urethane or a urea bond with an amine group present in tissue, as well as to the use thereof for sealing or closing of tissue and use in a medical treatment of a human or animal body. In a further aspect, the invention is directed to a method for the preparation of said multi-arm tissue-adhesive polymer.
1. Multi-arm tissue-adhesive polymer comprising at least six arms, wherein each of the at least six arms comprises a polymeric group and a reactive functional group that can form a thiourethane, a urethane or a urea bond with an amine group present in tissue, wherein the polymer is of formula I
wherein n is an integer of 6 or more;
LG is a leaving group;
X is selected from the group consisting of S, NH and O;
R 1 is a polymeric group; and
Y is a core structure;
such that R 1 —X—C(O)-LG is each arm comprising the reactive functional group X—C(O)-LG; and
wherein Y is based on a polyol of any of structures ii, iii and iv
wherein each R 2 is individually H or the group for connecting to another structure ii, each R 3 is individually H or the group for connecting to another structure iii, and each R 4 is individually H or the group for connecting to another structure iv, depending on the desired amount of hydroxyl groups to yield the at least six arms.
2. The multi-arm tissue-adhesive polymer according to claim 1 , wherein Y is based on hexaglycerol (HG), tripentaerytritol (TP) or dipentaerythritol (DP).
3. The multi-arm tissue-adhesive polymer according to claim 1 , wherein the polymeric group R 1 comprises a polyether, polyester, polycarbonates, polyurethanes, polyetherurethanes, polyurethane urea, poly(vinylpyrrolidone), poly(saccharide), poly(vinyl alcohol), or polyoxazoline, or combinations of distinct R 1 thereof.
4. The multi-arm tissue-adhesive polymer according to claim 1 , wherein the reactive functional group comprises a leaving group LG that is an alcohol radical functioning as an electron-withdrawing group.
5. The multi-arm tissue-adhesive polymer according to claim 1 , wherein n is an integer in the range of 6-12.
6. The multi-arm tissue-adhesive polymer according to claim 1 , wherein Y is based on a polyol comprising n hydroxyl groups, wherein n is defined above.
7. The multi-arm tissue-adhesive polymer according to claim 1 , wherein each arm has a number-average molecular weight in the range of 500 Da to 50 kDa.
8. The multi-arm tissue-adhesive polymer according to claim 1 , wherein the polymer has molecular weight in the range of 5 to 100 kDa.
9. The multi-arm tissue-adhesive polymer according to claim 1 , wherein the polymer has a substitution degree of the arms with the reactive functional group of more than 60% as determined by 1 H-NMR.
10. The multi-arm tissue-adhesive polymer according to claim 1 , wherein the reactive functional group is present in an amount of less than 5% based on the total weight of the tissue-adhesive polymer.
11. Method for the preparation of the multi-arm tissue-adhesive polymer according to claim 1 , comprising reacting a polymer compound having the structure Y—R 1 —XH with a compound having structure of formula III,
to form the multi-arm tissue-adhesive polymer of formula I.
12. A method of sealing or closing tissue comprising applying the multi-arm tissue-adhesive polymer according to claim 1 to tissue in a manner to seal or close the tissue.
13. Medical foam or sheet comprising the multi-arm tissue-adhesive polymer according to claim 1 .
14. The multi-arm tissue-adhesive polymer according to claim 1 , wherein the polymeric group R 1 comprises poly(alkylene glycol), poly(lactic acid), poly(caprolactone), polydioxanone, poly(glycolide) or poly(trimethylene carbonate).
15. The multi-arm tissue-adhesive polymer according to claim 1 , wherein the reactive functional group comprises a leaving group LG that is an alcohol radical, wherein the alcohol is selected from the group consisting of perfluoroalkyl alcohol, p-nitro-phenol, 3,4,5-trichlorophenol, pentafluorophenol, 1-benzotriazolyl alcohol, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, and N-hydroxysuccinimide alcohol or derivatives thereof.
16. The multi-arm tissue-adhesive polymer according to claim 1 , wherein the reactive functional group comprises a leaving group LG that is an alcohol radical, wherein the alcohol is selected from the group consisting of N-hydroxysuccinimide alcohol, N-hydroxymaleimide, N-hydroxyphthalimide, endo-N-hydroxy-5-norbornene-2,3-dicarboximide and a N-hydroxysulfosuccinimide.
17. The multi-arm tissue-adhesive polymer according to claim 1 , wherein n is an integer in the range of 6-8.
18. The multi-arm tissue-adhesive polymer according to claim 1 , wherein each arm has a number-average molecular weight in the range of 1-25 kDa.
19. The multi-arm tissue-adhesive polymer according to claim 1 , wherein the polymer has molecular weight in the range of 10-80 kDa.
20. The multi-arm tissue-adhesive polymer according to claim 1 , wherein the polymer has molecular weight in the range of 20-60 kDa.