Monomers and Polymers with Covalently - Attached Active Ingredients

• US 20090208553A1
• Filed: 02/11/2009
• Published: 08/20/2009
• Est. Priority Date: 02/15/2008
• Status: Abandoned Application

• Current Assignee: University of Southern Mississippi
• Original Assignee: University of Southern Mississippi
• Inventors: Hammond, NIcholas Lee, Kemp, Lisa Kay
• Application Number:
  US12/369,125
• Publication Number:
  US 20090208553A1
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: A61K 31/74 Synthetic polymeric materials
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 29/085 Macromolecular materials
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: C08L 53/02 of vinyl-aromatic monomers and conjugated dienes

Abstract

Methods to form an active agent modified monomer comprising a ring opening cyclic monomer linked to an active agent via a degradable covalent linkage. Methods to form a polymer or copolymer comprising an active agent modified monomer. Methods to form an active agent modified monomer comprising combining a ring opening cyclic monomer with a first functional group (X) and an active agent with a second functional group (Y) to form an active agent modified monomer, wherein the first (X) and second (Y) functional groups are complementary functional groups that form a degradable linkage. The active agent modified monomer can also comprise a non-degradable linkage. The method can form a ring opening cyclic monomer that includes a cyclic carbonate, cyclic epoxide, lactam, lactone, lactide anhydride, cyclic carbamate, cyclic phosphoester, or siloxane. Apparatus that includes a medical device that comprises a polymer or copolymer that comprises an active agent modified monomer.

Claims

1. A method of forming an active agent modified monomer, comprising:

combining a ring opening cyclic monomer with a first functional group (X) and an active agent with a second functional group (Y) to form an active agent modified monomer,

wherein the first (X) and second (Y) functional groups are complementary functional groups that form a degradable linkage.

2. The method of claim 1 wherein the ring opening cyclic monomer is a cyclic carbonate, cyclic epoxide, lactam, lactone, lactide, anhydride, cyclic carbamate, cyclic phosphoester, or siloxane.

3. The method of claim 2 wherein the cyclic epoxide monomer is glycidol, ethyl-2,3-epoxybutyrate, glycidyl methacrylate, or 1,2,7,8-diepoxyoctane.

4. The method of claim 2 wherein the lactam monomer is 4-Oxo-2-azetidinecarboxylic acid, 4-Hydroxy-2-pyrrolidone, 5-(Hydroxymethyl)-2-pyrrolidinone, Pyroglutamic acid, Ethyl 2-oxo-3-piperidinecarboxylate, or alpha-Amino-epsilon-caprolactam.

5. The method of claim 2 wherein the cyclic carbonate monomer is 5-ethyl-5-(hydroxymethyl)-1,3-dioxan-2-one, 5-hydroxy-1,3 -dioxan-2-one, 4-hydroxy-1,3-dioxolan-2-one, 5-methyl-2-oxo-1,3-dioxane-5-carboxylic acid, or 5-ethyl-2-oxo-1,3-dioxane-5-carboxylic acid.

6. The method of claim 1 wherein the first (X) or the second (Y) functional group is independently an amine, aldehyde, ketone, chloroformate, hydrazine, alcohol, carboxylic acid, acid halide, acid anhydride, acid salt, isocyanate, or ester.

7. The method of claim 1, wherein the active agent modified monomer comprises a non-steroidal anti-inflammatory agents, chemotherapeutic agent, anticoagulant, cholinergics, adrenergics, serotonergics, anesthetics, hypnotics, antiseizure therapeutics, antipsychotics, anxiolytics, stimulants, opiods, analgesics, spasmolytics, cardiac glycosides, antianginals, antiarrhythmics, diuretics, angiotensin converting enzyme inhibitors, angiotensin converting enzyme antagonists, calcium blockers, central sympatholytics, peripheral sympatholytics, vasodilators, antihyperlipoproteinemics, cholesterol biosynthesis inhibitors, antithrombotics, thrombolytics, coagulants, plasma extenders, insulin, oral hypoglycemic agents, adrenocorticoids, estrogens, progestins, androgens, thyroid drugs, antihistamines, antiallergenic agents, antiulcer agents, antibiotics, antimicrobials, antiparasitics, antifungals, antimycobacterial agents, cancer chemotherapeutics, antivirals, protease inhibitors, gene therapeutics, antisense therapeutics, or selective estrogen receptor modulators, carbohydrates, proteins, enzymes, RNA, DNA, pesticides, herbicides, anti-fouling agents, aromatic agents, detergents, sequestering agents, preservatives, anti-corrosion agents, or catalysts.

8. The method of claim 1 wherein the first (X) and second (Y) functional groups react to form an ester, urethane, anhydride, carbonate, hydrazone, urea, or amide degradable linkage.

9. A method of forming an active agent modified monomer, comprising:

combining a compound comprising ring-forming complementary groups with a first functional group (X) and an active agent with a second functional group (Y) to form an active agent modified monomer, and

closing the ring-forming complementary groups using a direct condensation reaction or adding a ring-forming reagent to the ring-forming complementary groups;

wherein the first (X) and second (Y) functional groups are complementary functional

groups that form a degradable linkage.

10. The method of claim 9, wherein the ring-forming complementary groups comprise an alcohol and chloroformate, an alcohol and an acid, an amine and an alcohol, amine and acid, acid halide and an alcohol, an acid halide and an amine, chloride and alcohol, two alcohols, or two acids.

11. The method of claim 9, wherein the ring-forming complementary groups form an epoxide, a cyclic carbonate, a lactone, an anhydride, a cyclic carbamate, or a lactam.

12. A method of forming an active agent modified monomer, comprising

combining a ring opening monomer with a functional group (L), an active agent with a functional group (Y), and a linker with a functional group (X) and a functional group (M) to form an active agent modified monomer,

wherein the functional groups (X) and (Y) are complementary functional groups that form a degradable linkage and

wherein the functional groups (L) and (M) are complementary functional groups that form a stable or degradable linkage.

13. The method of claim 12 wherein the ring opening cyclic monomer is a cyclic carbonate, cyclic epoxide, lactam, lactone, lactide, anhydride, cyclic carbamate, cyclic phosphoester, or siloxane.

14. The method of claim 13 wherein the cycle epoxide is epichlorohydrin.

15. The method of claim 13 wherein the cyclic carbonate is

16. The method of claim 13 wherein the cyclic carbonate is

17. The method of claim 12 wherein the functional group (L) or (M) is an alkyne, alkene, alkyl halide, azide, thiol, or amine.

18. The method of claim 12 wherein the functional groups (L) and (M) react to form a thiolene, triazole, disulfide, or substituted amine.

19. The method of claim 12 wherein the functional group (X) or (Y) is an amine, alcohol, carboxylic acid, acid halide, acid anhydride, acid salt, isocyanate, aldehyde, ketone, chloroformate, hydrazine, or ester.

20. The method of claim 12 wherein the functional groups (X) and (Y) react to form an ester, urethane, carbonate, hydrazone, anhydride, urea, or amide bond.

21. The method of claim 12 wherein the active agent modified monomer is a non-steroidal anti-inflammatory agents, chemotherapeutic agent, anticoagulant, cholinergics, adrenergics, serotonergics, anesthetics, hypnotics, antiseizure therapeutics, antipsychotics, anxiolytics, stimulants, opiods, analgesics, spasmolytics, cardiac glycosides, antianginals, antiarrhythmics, diuretics, angiotensin converting enzyme inhibitors, angiotensin converting enzyme antagonists, calcium blockers, central sympatholytics, peripheral sympatholytics, vasodilators, antihyperlipoproteinemics, cholesterol biosynthesis inhibitors, antithrombotics, thrombolytics, coagulants, plasma extenders, insulin, oral hypoglycemic agents, adrenocorticoids, estrogens, progestins, androgens, thyroid drugs, antihistamines, antiallergenic agents, antiulcer agents, antibiotics, antimicrobials, antiparasitics, antifungals, antimycobacterial agents, cancer chemotherapeutics, antivirals, protease inhibitors, gene therapeutics, antisense therapeutics, or selective estrogen receptor modulators, carbohydrates, proteins, enzymes, RNA, DNA, pesticides, herbicides, anti-fouling agents, aromatic agents, detergents, sequestering agents, preservatives, anti-corrosion agents, or catalysts.

22. A method of forming an active agent modified monomer, comprising

combining a compound comprising ring-forming complementary groups with a functional group (L), an active agent with a functional group (Y), and a linker with a functional group (X) and a functional group (M) to form an active agent modified monomer,

closing the ring-forming complementary groups using a direct condensation reaction or adding a ring-forming reagent to the ring-forming complementary groups;

wherein the functional groups (X) and (Y) are complementary functional groups that form a degradable linkage and

wherein the functional groups (L) and (M) are complementary functional groups that form a stable or degradable linkage.

23. The method of claim 22, wherein the ring-forming complementary groups comprise an alcohol and chloroformate, an alcohol and an acid, an amine and an alcohol, amine and acid, acid halide and an alcohol, an acid halide and an amine, chloride and alcohol, two alcohols, or two acids.

24. The method of claim 22, wherein the ring forming complementary groups form an epoxide, a cyclic carbonate, a lactone, an anhydride, a cyclic carbamate, or a lactam.

25. An active agent modified monomer comprising a ring opening cyclic monomer linked to an active agent via a degradable covalent linkage.

26. The monomer of claim 25, wherein the ring opening cyclic monomer is a cyclic carbonate, cyclic epoxide, lactam, lactone, lactide, anhydride, cyclic carbamate, cyclic phosphonate, or siloxane.

27. The monomer of claim 26, wherein the cyclic epoxide is 3,4-Epoxy-1-butene, 2-Methyl-2-vinyloxirane, epichlorohydrin, epibromohydrin, 1,2-epoxy-5-hexene, glycidol propargyl ether, or methyl-2-methylglycidate.

28. The monomer of claim 26, wherein the lactam is bromocaprolactam, vinylcaprolactam, 5-chloromethyl-2-pyrrolidinone, 4-(2-propenyl)-2-pyrrolidinone, or 5-iodo-azocan-2-one.

29. The monomer of claim 26 wherein the cyclic carbonate is 5-ethyl-5-(hydroxymethyl)-1,3-dioxan-2-one, 5-hydroxy-1,3-dioxan-2-one, 4-hydroxy-1,3-dioxolan-2-one, 5-methyl-2-oxo-1,3-dioxane-5-carboxylic acid, or 5-ethyl-2-oxo-1,3-dioxane-5-carboxylic acid.

30. The monomer of claim 25 wherein the active agent is a non-steroidal anti-inflammatory agents, chemotherapeutic agent, anticoagulant, cholinergics, adrenergics, serotonergics, anesthetics, hypnotics, antiseizure therapeutics, antipsychotics, anxiolytics, stimulants, opiods, analgesics, spasmolytics, cardiac glycosides, antianginals, antiarrhythmics, diuretics, angiotensin converting enzyme inhibitors, angiotensin converting enzyme antagonists, calcium blockers, central sympatholytics, peripheral sympatholytics, vasodilators, antihyperlipoproteinemics, cholesterol biosynthesis inhibitors, antithrombotics, thrombolytics, coagulants, plasma extenders, insulin, oral hypoglycemic agents, adrenocorticoids, estrogens, progestins, androgens, thyroid drugs, antihistamines, antiallergenic agents, antiulcer agents, antibiotics, antimicrobials, antiparasitics, antifungals, antimycobacterial agents, cancer chemotherapeutics, antivirals, protease inhibitors, gene therapeutics, antisense therapeutics, or selective estrogen receptor modulators, carbohydrates, proteins, enzymes, RNA, DNA, pesticides, herbicides, anti-fouling agents, aromatic agents, detergents, sequestering agents, preservatives, anti-corrosion agents, or catalysts.

31. The monomer of claim 25, further comprising a non-degradable covalent linkage (Z) extending between the ring opening cyclic monomer and the degradable covalent linkage.

32. The monomer of claim 31, wherein the non-degradable covalent linkage (Z) comprises thiolene, triazole, disulfide, or substituted amine.

33. The monomer of claim 25 wherein the degradable covalent linkage is an ester, urethane, anhydride, carbonate, hydrazone, urea, or amide bond.

34. A polymer produced by the ring opening polymerization of the monomer of claim 25.

35. A polymer produced by the ring opening polymerization of the monomer of claim 25 and one or more other ring opening monomers.

36. The polymer of claim 35 wherein the one or more other ring opening monomers comprise cyclic carbonates, cyclic epoxides, lactams, lactones, lactides, anhydride, cyclic carbamate, cyclic phophoesters, siloxanes, or combinations thereof.

37. A block-polymer formed by ring opening polymerization of the monomer of claim 25 with at least one other ring opening monomer using a polymer macroinitator.

38. The polymer of claim 37, wherein the polymer macroinitiator comprises polystyrene, polybutylene, polyolefins, polyacrylates, polycarbonates, polyesters, polyamides, polyurethanes, polyethers, polyamideimides, polyaramide, polyarylate, polylactams, polylactones, polysiloxanes, polyesteramides, polyetherimides, polyetheretherketones, polyetherketones, polyethersulfones, polysulfides, polyketones, polyimides, polyols, polyphosphates, polypyrroles, polysilanes, polysilynes, polysilylenes, polysulfones, polycyclics, or natural polymers.

39. A block-polymer formed by a reaction of the polymer of claim 34 with at least one other polymer.

40. The polymer of claim 39, wherein the at least one other polymer comprises polystyrene, polybutylene, polyolefins, polyacrylates, polycarbonates, polyesters, polyamides, polyurethanes, polyethers, polyamideimides, polyaramide, polyarylate, polylactams, polylactones, polysiloxanes, polyesteramides, polyetherimides, polyetheretherketones, polyetherketones, polyethersulfones, polysulfides, polyketones, polyimides, polyols, polyphosphates, polypyrroles, polysilanes, polysilynes, polysilylenes, polysulfones, polycyclics, or natural polymers.

41. A block-polymer comprising a reaction product produced by reacting the polymer of claim 35 with one or more polymers comprising polystyrene, polybutylene, or polyethylene glycol.

42. A medical device comprising the polymer of claim 37.

43. The medical device of claim 42, wherein the device is a stent, a catheter, a guide wire, a balloon, a filter, a stent graft, a vascular graft, a vascular patch, and a shunt.

44. The medical device of claim 43, wherein the device is adapted for implantation or insertion into the coronary vasculature, peripheral vascular system, esophagus, trachea, colon, biliary tract, urinary tract, prostate, or brain.

45. A medical device coated by the polymer of claim 37.