Siloxane polymer containing tethered levofloxacin
A polymer that is a polysiloxane polymer has Levofloxacin groups, or pharmaceutically acceptable salts thereof, attached via linkers. The linkers may be hydrolytically labile thereby providing a manner of releasing the Levofloxacin from the polymer.
1. A polymer formed by
(a) reaction of a polyhydrosiloxane of general formula
R 1 R 2 R 3 SiO—(SiR 4 R 5 —O) y (SiR 6 H—O) x (SiR 7 R 8 —O) z SiR 9 R 10 R 11
with a reactive compound to provide a functionalized polysiloxane, wherein the reactive compound comprises (1) a first reactive group, which is capable of reacting with an Si—H group, at one end, and (2) a second reactive group, which is capable of reacting with Levofloxacin, at its other end;
(b) reaction of the functionalized polysiloxane with Levofloxacin or a pharmaceutically acceptable salt thereof to provide a Levofloxacin-functionalized polysiloxane;
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , R 10 , and R 11 are independently C 1 -C 20 alkyl, benzyl, tolyl, xylyl, or phenyl;
R 7 is a C 1 -C 20 alkyl, benzyl, tolyl, xylyl, phenyl, texturizing moiety, a cross-linkable group, or a combination thereof;
x is 1 to 100;
y is 0 to 100;
z is 0 to 100;
at least one of y and z is greater than 0; and
the polymer contains at least one Levofloxacin group.
2. The polymer of claim 1 , wherein the polyhydrosiloxane is selected from the group consisting of poly(methylhydro-co-dimethyl)siloxane, polymethylhydrosiloxane, polyethylhydrosiloxane, polyphenyl-(dimethylhydro) siloxane, methylhydrosiloxane-phenylmethylsiloxane copolymer, methylhydrosiloxane-octylmethylsiloxane copolymer, or blends of any two or more thereof.
3. The polymer of claim 1 , wherein the reactive compound includes 3 to 20 carbon atoms.
4. The polymer of claim 1 , wherein the reactive compound includes at least one ether linkage.
5. The polymer of claim 1 , wherein the Levofloxacin-functionalized polysiloxane includes at least one Levofloxacin group linked to the polymer by a hydrolytically labile linkage.
6. The polymer of claim 5 , wherein the hydrolytically labile linkage is an ester moiety.
7. The polymer of claim 5 , wherein the hydrolytically labile linkage is an anhydride moiety.
8. The polymer of claim 1 , comprising about 0.1 wt % to about 10 wt % of the Levofloxacin groups.
9. The polymer of claim 1 , wherein the weight average molecular weight of the polymer is about 500 g/mol to 65,000 g/mol.
10. The polymer of claim 1 , wherein the cross-linkable group includes a pendent epoxy group, a pendent anhydride group, or a mixture thereof.
11. A method of preparing a Levofloxacin-functional polysiloxane comprising: reacting a polysiloxane polymer with Levofloxacin or a pharmaceutically acceptable salt thereof to form a polysiloxane polymer having grafted Levofloxacin groups.
12. The method of claim 11 , further comprising reacting the polysiloxane polymer with an allyl epoxy ether to form an polysiloxane polymer having pendent epoxy groups.
13. The method of claim 12 , wherein the allyl epoxy ether is allyl glycidyl ether.
14. The method of claim 11 , further comprising reacting the polysiloxane polymer with an anhydride functional vinyl compound to form an anhydride-functional polysiloxane.
15. The method of claim 14 , wherein the anhydride functional vinyl compound is norbornene anhydride.
16. The method of claim 11 , further comprising curing the polysiloxane polymer by addition of a multifunctional amine cross-linker.
17. The method of claim 16 , wherein the multifunctional amine cross-linker is selected from the group consisting of diethylenetriamine; 1,4-diaminobutane; bis(dimethylamino)-dimethylsilane; 1,3-dipyridyl propane; 1,3-bis(N,N-dimethylamino) -butane; 1,n-bis(N,N-dialkylamino)-alkane where N,N-dialkyl groups are ethyl or methyl, and the 1,n-substituted alkane backbone has from 2 to 10 carbon atoms; 1,4-bis(N, N-dimethylaminomethyl)-benzene; 1,3-di-(aminoethyl)-benzene; 1,4-bis(N,N-dimethylamino)-cyclohexane; 1,4-bis(N,N-dimethylaminomethyl)-cyclohexane; 1,3-dipyridyl butane; 1,6-dipyridyl hexane; 1,4-dipyridyl cyclohexane; N,N,N′,N″,N″-pentamehtyldiethylenetriamine, tetraethylenetriamine, N,N,N′,N′-tetramethylpropylenediamine; N,N,N′,N′-tetramethyl-1,4-butanediamine; N,N,N′N′-tetramethyl-ethylenediamine; N,N,N′N′-tetramethyl-1,6-hexanediamine; N,N,N′N′-tetramethylbenzidine; N,N,N′,N′-tetraethylethylenediamine; 2,2′-dipyridyl; 4,4′-dipyridyl; and a mixture of any two or more thereof.
18. A method of releasing Levofloxacin groups from a Levofloxacin-functional polysiloxane comprising:
contacting a Levofloxacin-functional polysiloxane with an aqueous medium;
wherein, the Levofloxacin-functional polysiloxane comprises:
a polysiloxane;
Levofloxacin groups; and
wherein the Levofloxacin groups are connected to the polysiloxane via a linker.
19. The method of claim 18 , wherein the linkers contain a hydrolytically labile linkage.
20. The method of claim 19 , wherein the hydrolytically labile linkage is an ester or anhydride linkage.
21. A coating composition comprising the polymer of claim 1 .
22. The coating composition of claim 21 further comprising a multifunctional amine cross-linker.
23. A substrate coated with a cured polymer, wherein the cured polymer is formed by curing a mixture comprising the polymer of claim 1 , and a multifunctional amine cross-linker.
24. The substrate of claim 23 , wherein the substrate is a medical device.
25. A polymer formed by
(a) reaction of a polyhydrosiloxane of general formula
R 1 R 2 R 3 SiO—(SiR 4 R 5 —O) y (SiR 6 H—O) x (SiR 7 R 8 —O) z SiR 9 R 10 R 11
with a reactive compound to provide a functionalized polysiloxane, wherein the reactive compound comprises (1) a vinylic group, and (2) an epoxy group or an anhydride group;
(b) reaction of the functionalized polysiloxane with Levofloxacin or a pharmaceutically acceptable salt thereof to provide a Levofloxacin-functionalized polysiloxane;
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , R 10 , and R 11 are independently C 1 -C 20 alkyl, benzyl, tolyl, xylyl, or phenyl;
R 7 is a C 1 -C 20 alkyl, benzyl, tolyl, xylyl, phenyl, texturizing moiety, a cross-linkable group, or a combination thereof;
x is 1 to 100;
y is 0 to 100;
z is 0 to 100;
at least one of y and z is greater than 0; and
the polymer contains at least one Levofloxacin group.