Anticoagulant compounds and methods and devices for their use

Patent metadata

Field	Value
Publication number	US-11654036-B2
Application number	US-202117402357-A
Country	US
Kind code	B2
Filing date	Aug 13, 2021
Priority date	May 26, 2020
Publication date	May 23, 2023
Grant date	May 23, 2023

Abstract

Devices, systems, and methods are provided including a structure having one or more surfaces configured for internal use within a patient's body and one or more therapeutic compositions comprising one or more active substances including a direct factor Xa inhibitor, and a direct factor IIa inhibitor disposed in or on the structure. The structure is configured to be positioned adjacent an injury site in the patient's body. The one or more active substances optionally include an anti-proliferative agent. The therapeutic composition is formulated to release the one or more active substances to the injury site to provide one or more of inhibit clot formation, promote clot dissolution, inhibit or dissolute inflammation, inhibit vessel injury, increase time before clotting, and/or inhibit cell proliferation.

First claim

What is claimed is:

1. An implant comprising:
a structure for implantation in a patient's body comprising:
a first therapeutic composition comprising a first drug formulation including at least one drug selected from the group consisting of a direct factor IIa inhibitor and a direct factor Xa inhibitor; and
a second therapeutic composition comprising a second drug formulation including at least one drug selected from the group consisting of a direct factor IIa inhibitor and a direct factor Xa inhibitor;
wherein the first therapeutic composition is formulated for a rapid release of the first drug formulation into an implanted environment and the second therapeutic composition is formulated for an extended release of the second drug formulation into the implanted environment, and
wherein the second therapeutic composition is layered over a surface of the implantable structure and the first therapeutic composition is layered over at least a portion of the second therapeutic composition and
wherein the first and second therapeutic compositions each comprise a polymer and wherein the first therapeutic composition has a first drug-to-polymer weight ratio and the second therapeutic composition has a second drug-to-polymer weight ratio, wherein the first drug-to-polymer weight ratio is in a range from 5:1 to 1:3.

2. The implant of claim 1 , wherein the implantable structure comprises a metal or a polymer scaffold which is non-degradable in the implanted environment.

3. The implant of claim 1 , wherein the implantable structure comprises a metal or polymer scaffold which is degradable in the implanted environment.

4. The implant of claim 1 , wherein at least one of the first drug formulation and the second drug formulation comprises both a direct factor IIa inhibitor and a direct factor Xa inhibitor.

5. The implant of claim 4 , wherein the first drug formulation and the second drug formulation each comprise both a direct factor IIa inhibitor and a direct factor Xa inhibitor.

6. The implant of claim 1 , wherein the first drug formulation is configured to release the at least one drug at a mean rate in a range from 1 μg/day to 10 μg/hour over a first time period in a range from 3 hours to 28 days after implantation.

7. The implant of claim 1 , wherein the second formulation is configured to release the at least one drug of the second formulation at a mean rate not exceeding 2 μg/hour over a 24-hour period following implantation.

8. The implant of claim 4 , further comprising an anti-proliferative agent.

9. The implant of claim 5 , further comprising an anti-proliferative agent.

10. The implant of claim 1 , wherein the first therapeutic composition and the second therapeutic composition are configured to delay start of release of the second drug formulation for a time period after release of the first drug has started.

11. The implant of claim 10 , wherein the first therapeutic composition is configured to dissolve over the time period to expose the second therapeutic composition and allow release of the second drug formulation.

12. The implant of claim 1 , wherein a sacrificial layer is present over at least one of the first therapeutic composition and the second therapeutic composition or between the first therapeutic composition and the second therapeutic composition to delay release of one or more drugs from either or both of the first therapeutic composition and the second therapeutic compositions.

13. The implant of claim 1 , wherein a diffusion-rate controlling layer is present over at least one of the first therapeutic composition and the second therapeutic composition or between the first therapeutic composition and the second therapeutic composition to control a release rate of one or more drugs from either or both of the first therapeutic composition and the second therapeutic compositions.

14. The implant of claim 1 , wherein the polymer of the first and/or second therapeutic composition is degradable when implanted in a patient's body and configured to release the first and/or second drug formulation at least partly by dissolution of the polymer when exposed to the implanted environment.

15. The implant of claim 14 , wherein the polymer of one of the therapeutic compositions dissolves at a faster rate than does the polymer of the other therapeutic composition in the implanted environment.

16. The implant of claim 8 , wherein the polymer of the at least first and/or second therapeutic composition is non-degradable when implanted in the patient's body and configured to release the first and/or second drug formulation at least partly by a diffusion mechanism through the polymer when exposed to the implanted environment.

17. The implant of claim 1 , wherein the polymer is configured to release the first and/or second drug formulation through a combination of dissolution of and diffusion through the polymer when exposed to the implanted environment.

18. The implant of claim 1 , further comprising an anti-proliferative agent.

19. The implant of claim 8 , 9 or 18 , wherein the anti-proliferative agent is present in the first drug formulation, in the second drug formulation and/or a third therapeutic composition or any combination thereof, which composition(s) are formulated to release the anti-proliferative drug into an implanted environment when the structure is present in the implanted environment.

20. The implant of claim 1 , wherein the first drug formulation and/or the second drug formulation comprises a direct factor IIa inhibitor and the direct factor IIa inhibitor comprises at least one of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, bivalirudin, desirudin, and lepirudin.

21. The implant of claim 20 , wherein the direct factor Ha inhibitor comprises argatroban, or a salt, isomer, solvate, derivative, metabolite, or prodrugs thereof.

22. The implant of claim 21 , wherein the first drug formulation and/or the second drug formulation comprise a direct factor Xa inhibitor comprising at least one of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), daraxaban (YM-150), 2-[(7-carbamimidoylnaphthalen-2-yl)methyl-[4-(1-ethanimidoylpiperidin-4-yl)oxyphenyl] sulfamoyl] acetic acid (YM-466 or YM-60828), or eribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 445-(2,6-dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052).

23. The implant of claim 22 , wherein the direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, derivative, metabolite, or prodrugs thereof or rivaroxaban, or a salt, isomer, solvate, derivative, metabolite, or prodrugs thereof.

24. The implant of claim 8 , 9 , or 18 , wherein the anti-proliferative agent comprises an mTOR inhibitor selected from a group consisting of sirolimus, biolimus, everolimus, myolimus, novolimus, ridaforolimus, temsirolimus, zotarolimus, or salts, isomers, solvates, derivatives, metabolites, or prodrugs thereof.

25. The implant of claim 8 , 9 , or 18 , wherein the anti-proliferative agent comprises sirolimus, or a salt, isomer, solvate, derivative, metabolite, or prodrugs thereof or paclitaxel, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof.

26. The implant of claim 8 , 9 , or 18 , furthe

Assignees

• Elixir Medical Corp

Inventors

• Sirhan Motasim
• Zheng Xiaoxia
• Bhat Vinayak D
• Yan John

Classifications

• A61F2220/0008

  Fixation appliances for connecting prostheses to the body · CPC title

• A61L27/507

  for artificial blood vessels (apparatus for applying cells on a blood vessel prosthesis A61F2/062) · CPC title

• A61L27/54

  Biologically active materials, e.g. therapeutic substances {(A61L27/227 takes precedence)} · CPC title

• A61L31/16

  Biologically active materials, e.g. therapeutic substances {(A61L31/047 takes precedence)} · CPC title

• A61L31/04

  Macromolecular materials · CPC title