Room temperature-curable polymers
Methods of making room temperature-curable polymers. Reactants include siloxane-terminated polymers and silanols. The reactants are mixed, and the polymerization allowed to proceed in air at room temperature. The polymers are exceptionally useful because they allow for the incorporation into the polymers themselves of one or more therapeutic compounds. Thus, medical devices from which controlled drug release is desirable (for either local or systemic delivery) can be coated with therapeutic compound-containing polymers of the invention. In a preferred embodiment, a polymer of poly(MPC w :LAM x :HPMA y :TSMA z ) where w, x, y, and z represent the molar ratios of monomers used in the feed for preparing the polymer; MPC represents the unit 2-methacryoyloxyethylphosphorylcholine, LMA represents the unit lauryl methacrylate, HPMA represents the unit 2-hydroxypropyl methacrylate, and TSMA represents the unit 3-trimethoxysilylpropyl methacrylate is reacted with polydimethylsiloxane. In another preferred embodiment, a therapeutic compound is incorporated into the polymer, such as dexamethasone.
1. A method of preparing a composition, said composition comprising at least one therapeutic compound and a molecule of formula IV:
said method comprising reacting a molecule of formula I:
in situ with a molecule of formula II:
adding the therapeutic compound to reactant (I) or reactant (II) or both prior to the reaction thereof, or adding the therapeutic compound to the reaction mixture of the reactants during the reaction thereof; wherein
R 1 comprises a polymer, the polymer containing at least one group selected from the group consisting of an acyloxy, alkenyl, alkoxyl, alkyl, alkylcycloalkenyl, alkylcycloalky, alkenylcycloalkyl, alkynyl, amino, aralkyl, aryl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, halogen, heterocycle, heterocyclic, ketone, N-acylamino, N-containing heterocycle; and combinations thereof; and
R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are alkyls or silanol-terminated alkyls; and
wherein n is an integer, 1≦n≦100; and
wherein the reaction is carried out at a temperature compatible with the therapeutic compound.
2. The method of claim 1 , wherein the temperature, T, at which the reaction is carried out is 4° C.<T≦100° C.
3. The method of claim 2 , wherein 15° C.≦T≦30° C.
4. The method of claim 2 , wherein 20° C.≦T≦22° C.
5. The method of claim 1 , wherein the therapeutic compound is one selected from the group consisting of sirolimus, zotarolimus, esters, and salts thereof.
6. The method of claim 5 , wherein the therapeutic compound comprises zotarolimus.
7. The method of claim 1 , wherein the therapeutic compound comprises one selected from the group consisting of anti-proliferative agents, anti-platelet agents, anti-inflammatory agents, anti-thrombotic agents and thrombolytic agents.
8. The method of claim 7 , wherein the anti-inflammatory agent is one selected from the group consisting of dexamethasone, hydrocortisone, estradiol, acetaminophen, ibuprofen, naproxen, fluticasone, clobetasol, adalimumab and sulindac.
9. The method of claim 1 , wherein the therapeutic compound comprises an antibody.
10. The method of claim 7 , wherein the therapeutic compound comprises dexamethasone.
11. The method of claim 1 , further comprising applying the polymer to a medical device.
12. The method of claim 11 , wherein the medical device comprises a stent.
13. The method of claim 1 , wherein the composition comprising at least two therapeutic compounds, a first compound comprising zotarolimus or paclitaxel, and a second compound selected from the group consisting of anti-proliferative agents, anti-platelet agents, anti-inflammatory agents, anti-thrombotic agents and thrombolytic agents.
14. A method of preparing a composition, said composition comprising at least one therapeutic compound and a molecule of formula IX:
said method comprising reacting a molecule of formula V:
in situ with a molecule of formula II:
adding the therapeutic compound to reactant (V) or reactant (II) or both prior to the reaction thereof, or adding the therapeutic compound to the reaction mixture of the reactants during the reaction thereof;
wherein n is an integer, 1≦n≦100; where w, x, y, and z represent the molar ratios of monomer used in the feed for preparing the polymer of formula V;
R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are alkyls or alkyl-terminated silanols; and
wherein the reaction is carried out at a temperature compatible with the therapeutic compound.
15. The method of claim 14 , wherein the temperature, T, at which the reaction is carried out is 4° C.≦T≦100° C.
16. The method of claim 15 , wherein 15° C.≦T≦30° C.
17. The method of claim 14 , wherein 20° C.≦T≦22° C.
18. The method of claim 14 , wherein the therapeutic compound is one selected from the group consisting of sirolimus, zotarolimus, esters, and salts thereof.
19. The method of claim 18 , wherein the therapeutic compound comprises zotarolimus.
20. The method of claim 14 , wherein the therapeutic compound comprises one selected from the group consisting of anti-proliferative agents, anti-platelet agents, anti-inflammatory agents, anti-thrombotic agents and thrombylytic agents.
21. The method of claim 20 , wherein the anti-inflammatory agent is one selected from the group consisting of dexamethasone, hydrocortisone, estradiol, acetaminophen, ibuprofen, naproxen, fluticasone, clobetasol, adalimumab and sulindac.
22. The method of claim 14 , wherein the therapeutic compound comprises an antibody.
23. The method of claim 20 , wherein the therapeutic compound comprises dexamethasone.
24. The method of claim 14 , further comprising applying the polymer to a medical device.
25. The method of claim 24 , wherein the medical device comprises a stent.
26. The method of claim 14 , wherein the composition comprising at least two therapeutic compounds, a first compound comprising zotarolimus or paclitaxel, and a second compound selected from the group consisting of anti-proliferative agents, anti-platelet agents, anti-inflammatory agents, anti-thrombotic agents and thrombolytic agents.
27. The method of claim 14 , wherein R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are methyl groups.
28. A method of preparing a composition, said composition comprising at least one therapeutic compound and a molecule of formula VII
said method comprising reacting a molecule of formula V:
in situ with a molecule of formula VI:
adding the therapeutic compound to reactant (V) or reactant (VI) or both prior to the reaction thereof, or adding the therapeutic compound to the reaction mixture of the reactants during the reaction thereof;
wherein n is an integer, 1≦n≦100;
where w, x, y, and z represent the molar ratios of monomers used in the feed for preparing the polymer of formula VI; and
wherein the reaction is carried out at a temperature compatible, with the therapeutic compound.
29. The method of claim 28 , wherein the temperature, T, at which the reaction is carried out is 4° C.≦T≦100° C.
30. The method of claim 29 , wherein 15° C.≦T≦30° C.
31. The method of claim 29 , wherein 20° C.≦T≦22° C.
32. The method of claim 28 , wherein the therapeutic compound is one selected from the group consisting of sirolimus, zotarolimus, and derivatives, esters, and salts thereof.
33. The method of claim 32 , wherein the therapeutic compound comprises zotarolimus.
34. The method of claim 28 , wherein the therapeutic compound comprises one selected from the group consisting of anti-proliferative agents, anti-platelet agents, anti-inflammatory agents, anti-thrombotic agents and thrombylytic agents.
35. The method of claim 34 , wherein the anti-inflammatory agent is one selected from the group consisting of dexamethasone, hydrocortisone, estradiol, acetaminophen, ibuprofen, naproxen, fluticasone, clobetasol, adalimumab and sulindac.
36. The method of claim 28 , wherein the therapeutic compound comprises an antibody.
37. The method of claim 34 , wherein the therapeutic compound comprises dexamethasone.
38. The method of claim 28 , further comprising applying the polymer to a medical device.
39. The method of claim 38 , wherein the medical device comprises a stent.
40. A composition made by any of claims 1 , 14 and 28 .
41. A medical device comprising a composition made by any of claims 1 , 14 and 28 .
42. A stent comprising a composition made by any of claims 1 , 14 and 28 .