Devices and systems for local delivery of inotropic agents to the epicardium

• US 8,562,586 B2
• Filed: 08/26/2009
• Issued: 10/22/2013
• Est. Priority Date: 08/26/2008
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Lovich, Mark, Edelman, Elazer
• Primary Examiner(s): Sirmons, Kevin C
• Assistant Examiner(s): HAYMAN, IMANI N
• Application Number:
  US12/547,959
• Publication Number:
  US 20100057039A1
• Time in Patent Office: 1,518 Days
• Field of Search: 604/500, 604/502, 604/93.01, 604/151, 60428801-28804, 424/423, 424/427
• US Class Current: 604/502
• CPC Class Codes: A61F 2/0063 Implantable repair or support meshes, e.g. hernia meshes
• CPC Class Codes: A61F 2250/0067 Means for introducing or releasing pharmaceutical products into the body
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/703 characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
• CPC Class Codes: A61K 9/7084 Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
• CPC Class Codes: A61M 2210/125 Heart
• CPC Class Codes: A61M 31/002 Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time artificial gland structures or devices A61F2/022; intra-uterine contraceptive devices A61F6/14; tampons for introducing into the vagina A61F13/20, A61L15/00; suppositories or bougies for intra-vaginal or intra-uterine application A61K9/02; physical forms of medicinal preparations for sustained or differential drug release A61K9/20, A61K9/50
• CPC Class Codes: A61M 5/14276 specially adapted for implantation

Abstract

Devices and methods are provided for delivery of a positive inotropic agent to the heart of a patient in need thereof. An epicardial patch includes (i) a backing layer which is impermeable to the positive inotropic agent; and (ii) a drug release layer attached to the backing layer and including the positive inotropic agent and a polymeric membrane material. The polymeric membrane material provides controlled release of the positive inotropic agent to the epicardium to a region of the myocardium and in an amount effective to increase contractility. At least one of the backing layer or the drug release layer includes a tissue coupling portion for affixing the epicardial patch to an area of the epicardial surface. The epicardial patch is dimensioned and compliant to substantially avoid impeding myocardial functionality when affixed to the area of the epicardial surface.

Claims

1. A preformed epicardial patch for delivery of a positive inotropic agent to the heart of a patient, comprising:

a backing layer which is substantially impermeable to the positive inotropic agent; and

a drug release layer attached to the backing layer and comprising the positive inotropic agent and a polymeric membrane material, which, upon placement of the epicardial patch onto a portion of the epicardial surface of the heart, the polymeric membrane material comprising a diffusion-controlling material configured to provide controlled release of the positive inotropic agent to the epicardium to a region of the myocardium and in an amount effective to increase contractility by providing a myocardial concentration of the positive inotropic agent in the range of 10 ng/ml to 100 ng/ml while maintaining plasma concentrations of the inotropic agent below 5 ng/ml,

wherein at least one of the backing layer or the drug release layer comprises a tissue coupling portion for affixing the epicardial patch to an area of the epicardial surface, and

wherein the epicardial patch is dimensioned and compliant to avoid impeding myocardial functionality when affixed to the area of the epicardial surface, the epicardial patch having a surface area of at least 12 cm².

2. The patch of claim 1, wherein, upon the placement of the epicardial patch onto the portion of the epicardial surface of the heart, the epicardial patch is configured to restrict the release of the inotropic agent from the drug release layer such that only a unidirectional release of the inotropic agent from the drug release layer is permitted, wherein the direction of the unidirectional release is toward the region of the myocardium.

3. The patch of claim 1, wherein the positive inotropic agent and the polymeric membrane material are combined in the drug release layer a monolithic, matrix form.

4. The patch of claim 1, wherein the positive inotropic agent in the drug release layer is disposed in at least one discrete reservoir defined between the backing layer and the polymeric membrane material.

5. The patch of claim 4, wherein the discrete reservoir is fillable, or refillable, after affixation to the epicardial surface.

6. The patch of claim 1, which resorbable in vivo.

7. The patch of claim 1, wherein the positive inotropic agent comprises a sympathomimetic agent, a phosphodiesterase inhibitor, a calcium sensitizer, or a combination thereof.

8. The patch of claim 7, wherein the sympathomimetic agent is selected from the group consisting of epinephrine, norepinephrine, dobutamine, isoproterenol, salbutamol, salmeterol, terbutaline, phenylephrine, ephedrine, clonidine, dopamine, and any combination thereof.

9. The patch of claim 7, wherein the phosphodiesterase inhibitor is selected from the group consisting of milrinone, enoximone, amrinone, and any combination thereof.

10. The patch of claim 7, wherein the calcium sensitizer is selected from the group consisting of levosimendan, pimobendan, and any combination thereof.

11. The patch of claim 1, wherein the polymeric membrane material comprises a hydrogel.

12. The patch of claim 1, wherein the polymeric membrane material comprises a poly(lactic-co-glycolic) acid, a polylactide, a poly(orthoester), a poly(aminoester), a polyanhydride, a polyorganophosphazene, a polyacrylate, a poly(ethylene glycol), or a combination thereof.

13. The patch of claim 1, wherein the polymeric membrane material comprises micro-perforations.

14. The patch of claim 1, wherein said release is zero-order over the period of release.

15. The patch of claim 1, wherein:

the positive inotropic agent comprises dobutamine, and

the epicardial patch is configured and dimensioned to cover a sufficient area of the epicardial surface of the heart to deliver a therapeutically effective amount of the dobutamine to the myocardiwn at a released dose of 0.5 to 1.0 mcg/kg/min.

16. The patch of claim 1, wherein:

the positive inotropic agent comprises dobutamaine, and

the epicardial patch is configured and dimensioned to cover a sufficient area of the epicardial surface of the heart to increase myocardial contractility by at least 50% at a released dose of 0.5 to 1.0 mcg/kg/min dobutamine.

17. The patch of claim 1, wherein:

the positive inotropic agent comprises levosimendan, and

the epicardial patch is configured and dimensioned to cover a sufficient area of the epicardial surface of the heart to deliver a therapeutically effective amount of the levosimendan to the myocardium at a released dose of about 0.05 mcg/kg/min.

18. The patch of claim 1, wherein:

the positive inotropic agent comprises levosimendan, and

the epicardial patch is configured and dimensioned to cover a sufficient area of the epicardial surface of the heart to increase myocardial contractility by at least 50% at a released dose of about 0.05 mcg/kg/min levosimendan.

19. The patch of claim 1, wherein:

the positive inotropic agent comprises milrinone, and

the epicardial patch is configured and dimensioned to cover a sufficient area of the epicardial surface of the heart to deliver a therapeutically effective amount of the milrinone to the myocardium at a. released dose of about 0.1 mcg/kg/min.

20. The patch of claim 1, wherein:

the positive inotropic agent comprises milrinone, and

the epicardial patch is configured and dimensioned to cover a sufficient area of the epicardial surface of the heart to increase myocardial contractility by at least 50% at a released dose of about 0.1 mcg/kg/min milrinone.

21. The patch of claim 1, wherein the epicardial patch has a thickness from 0.5 mm to 5 mm.

22. The patch of claim 1, wherein the epicardial patch is in the form of a sleeve configured to cover from 80% to 100% of the ventricular epicardial surface.

23. A method of administering a positive inotropic agent to a heart of a patient in need thereof comprising:

providing an implantable epicardial patch which is affixable to an area of an epicardial surface of the heart, the epicardial patch comprising (i) a backing layer which is impermeable to the positive inotropic agent, and (ii) a drug release layer attached to the backing layer, wherein the drug release layer comprises the positive inotropic agent and a polymeric membrane material;

placing the epicardial patch onto a portion of the epicardial surface of the heart; and

providing via the polymeric membrane material controlled release of the positive inotropic agent from the epicardial patch to the epicardium to a region of the myocardium in an amount effective to increase contractility by providing a myocardial concentration of the positive inotropic agent in the range of 10 ng/ml to 100 ng/ml while maintaining plasma concentrations of the inotropic agent below 5 ng/ml.

24. The method of claim 23, wherein the patch is applied directly to the epicardium percutaneously, via an endovascular catheter, or via a pericardial window or subxiphoid approach.