Contact-killing, QAC functionalized thermoplastic polyurethane for catheter applications
In various embodiments, the present invention provides a functionalized thermoplastic polyurethane (TPU) containing bulk incorporated or surface-grafted quaternary ammonium compounds (QAC)s for contact-killing of a variety of microbes, where the QACs are on the surface of TPU to provide a sterile surface material that prevents bacteria commonly involved in device-associated infections (DAIs) from proliferating. The functionalized TPUs of the present invention can be formed into a wide variety of 3-dimensional shapes, such as catheters, medical tubing, laryngeal or tracheal stents, sutures, prosthetics, wound dressings, and/or a coating for medical devices and contains the residue of either a QAC containing diol monomer or an alkene functional diol monomer, which then allows the TPU to be functionalized with a QAC containing disulfide or free thiol compound, to form a quaternary ammonium functionalized thermoplastic polyurethane compound having antimicrobial properties for use in medical devices.
1. A quaternary ammonium functionalized thermoplastic polyurethane having antimicrobial properties for use in medical devices comprising:
a polyurethane polymer backbone, said polyurethane polymer backbone comprising the residues of one or more diisocyanates, one or more soft segment diols, one or more functionalized diols, and one or more diol chain extenders;
a plurality of side chains, said side chains extending from said polyurethane polymer backbone and comprising a quaternary ammonium functional group;
wherein said plurality of side chains are covalently bonded to said one or more functionalized diol residues via a thioether bond.
2. The quaternary ammonium functionalized thermoplastic polyurethane of claim 1 wherein the residues of one or more functionalized diols comprises from 0.5 to 50 mole percent of said polyurethane polymer backbone.
3. The quaternary ammonium functionalized thermoplastic polyurethane of claim 1 , wherein said one or more functionalized diols are allyl functionalized diols selected from the group consisting of 3-allyloxy-1,2-propanediol, 2-allyloxy-2-ethyl-1, 3-propanediol, 1-(allyloxy)-1,2-propanediol, pentaerythritol allyl ether, trimethylolpropane diallyl ether, trimethylolpropane allyl ether, 1,5-hexadiene-3,4-diol, 2-methylene-1,3-propanediol, 7-Octene-1,2-diol, 5-norbornene-2-endo, 3-endo-dimethanol, 5-norbornene-2-exo,3-exo-dimethanol, 5-Norbornene-2, 2-dimethanol, and combinations thereof.
4. The quaternary ammonium functionalized thermoplastic polyurethane of claim 1 wherein said one or more functionalized diol comprises 3-allyloxy-1,2-propanediol.
5. The quaternary ammonium functionalized thermoplastic polyurethane of claim 1 wherein said side chains further comprise a spacer comprising from about 2 to about 18 atoms selected from the group consisting of carbon, oxygen, nitrogen and sulfur atoms connecting said quaternary ammonium functional group to said polyurethane polymer backbone.
6. The quaternary ammonium functionalized thermoplastic polyurethane of claim 1 wherein said quaternary ammonium functional group comprises at least one alkyl chain having from about 1 to about 18 carbon atoms.
7. The quaternary ammonium functionalized thermoplastic polyurethane of claim 1 comprising the reaction product of:
an allyl functionalized polyurethane polymer; and
a disulfide or thiol compound containing at least one quaternary ammonium functional group.
8. The quaternary ammonium functionalized thermoplastic polyurethane of claim 7 wherein said allyl functionalized polyurethane polymer has a formula selected from:
where a is an integer from 2 to 50; b is an integer from 2 to 50; x is a mole fraction from 0.01 to 0.8; y is a mole fraction from 0.01 to 0.8; and z is a mole fraction ranging from 0.01 to 0.8; and the sum of x, y, and z is equal to 1.
9. The quaternary ammonium functionalized thermoplastic polyurethane of claim 7 wherein said disulfide or thiol compound is a disulfide compound synthesized from a compound selected from the group consisting of 3,3′-dithiodipropionic acid, 4,4′-dithiodibutyric acid, dithiodiglycolic acid, 2-hydroxyethyl disulfide, cystamine dihydrochloride, and combinations thereof.
10. The quaternary ammonium functionalized thermoplastic polyurethane of claim 7 wherein said disulfide or thiol compound is a disulfide or thiol compound having a formula selected from:
wherein l is an integer from 1 to 3, m is an integer from 1 to 18, and n is an integer from 1 to 19.
11. The quaternary ammonium functionalized thermoplastic polyurethane of claim 1 having a shore durometer hardness of from about 50 to about 100 as measured by a shore A durometer.
12. The quaternary ammonium functionalized thermoplastic polyurethane of claim 1 having a formula selected from:
where a is an integer from 2 to 50; b is an integer from 2 to 50; x is a mole fraction from 0.01 to 0.8; y is a mole fraction from 0.01 to 0.8; and z is a mole fraction ranging from 0.01 to 0.8; the sum of x, y, and z is equal to 1; m is an integer from 1 to 18, n is an integer from 1 to 19, and l is an integer from 1 to 4.
13. A method for making the quaternary ammonium functionalized thermoplastic polyurethane of claim 1 comprising:
A) preparing an allyl functionalized polyurethane polymer;
B) preparing a bi-quaternary ammonium functionalized disulfide compound or a quaternary ammonium functionalized thiol compound;
C) combining said allyl functionalized polyurethane polymer, said bi-quaternary ammonium functionalized disulfide compound or quaternary ammonium functionalized thiol compound, and an initiating catalyst under an inert atmosphere;
D) activating said initiating catalyst to produce the quaternary ammonium functionalized thermoplastic polyurethane of claim 1 .
14. The method of claim 13 wherein said allyl functionalized polyurethane has a formula selected from:
where a is an integer from 2 to 50; b is an integer from 2 to 50; x is a mole fraction from 0.01 to 0.8; y is a mole fraction from 0.01 to 0.8; and z is a mole fraction ranging from 0.01 to 0.8; and the sum of x, y, and z is equal to 1.
15. The method of claim 13 wherein said bi-quaternary ammonium functionalized disulfide compound comprises two quaternary ammonium functional groups each attached to a disulfide group by a spacer or said quaternary ammonium functionalized thiol compound comprises a quaternary ammonium functional group attached to a thiol group by a spacer, wherein said spacer comprises from about 2 to about 20 atoms selected from the group consisting of carbon, nitrogen and oxygen atoms.
16. The method of claim 13 wherein said bi-quaternary ammonium functionalized disulfide compound or said quaternary ammonium functionalized thiol compound is a disulfide or thiol compound having a formula selected from:
wherein l is an integer from 1 to 3, m is an integer from 1 to 18, and n is an integer from 1 to 19.
17. The method of claim 13 wherein the step of preparing an allyl functionalized polyurethane polymer (step A) further comprises forming said allyl functionalized polyurethane polymer into a three dimensional shape, film, or coating prior to said step of combining (step C).
18. The method of claim 17 wherein said three dimensional shape comprises a catheter, medical tubing, or a coating for medical devices.
19. The method of claim 13 wherein said quaternary ammonium functionalized thiol compound is prepared by the method comprising:
a) reacting a chlorinated alcohol with a tri-substituted amine to form a chlorinated quaternary ammonium alcohol intermediate;
b) combining 3,3′-dithiodipropionic acid, 4,4′-dithiodibutyric acid, or dithiodiglycolic acid with an excess of thionyl chloride or oxalyl chloride in a suitable container under an inert atmosphere and heating the combination to reflux for from about 4 to about 24 h to produce the corresponding acid chloride;
c) dissolving said chlorinated quaternary ammonium alcohol intermediate in a solvent;
d) cooling the solution of step (c) to a temperature of from about 25° C. to about 0° C. and adding said acid chloride disulfide under an inert atmosphere;
e) heating the combination of step (d) to reflux for from about 12 to about 24 h to produce the bi-quaternary ammonium functionalized disulfide compound;
f) and reacting said bi-quaternary ammonium disulfide compound with a solution of tris(2-carboxyethyl) phosphine hydrochloride at a pH from about 4 to about 7.
20. A medical device for use in the body of a patient comprising the quaternary ammonium functionalized thermoplastic polyurethane of claim 1 .