Localized delivery of cardiac inotropic agents

• US 8,551,961 B2
• Filed: 05/25/2006
• Issued: 10/08/2013
• Est. Priority Date: 05/25/2005
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Edelman, Elazer, Lovich, Mark
• Primary Examiner(s): BLAND, LAYLA D
• Application Number:
  US11/440,529
• Publication Number:
  US 20070021358A1
• Time in Patent Office: 2,693 Days
• Field of Search: None
• US Class Current: 514/26
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/4166 having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
• CPC Class Codes: A61K 31/4168 having a nitrogen attached in position 2, e.g. clonidine
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 38/2242 Atrial natriuretic factor complex: Atriopeptins, atrial natriuretic protein [ANP]; Cardionatrin, Cardiodilatin
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Abstract

The present invention provides novel methods for the localized delivery of inotropic agents to the heart, including specific regions of the heart, such as the ventricles, for example in a subject undergoing cardiothoracic surgery, with the aim of supporting the myocardial contractile function of the heart.

Claims

1. A method of delivering a positive cardiac inotropic agent to the heart of a human subject, comprising:

providing a delivery vehicle which is in the form of an adherent patch which comprises at least one positive inotropic agent and a barrier that is non-permeable to the positive inotropic agent, the barrier being effective to allow release of the positive inotropic agent toward the myocardium and to minimize release into the pericardial fluid;

adhering the delivery vehicle onto an outer surface of the heart away from the sinoatrial node of a subject in need of treatment; and

releasing a therapeutically effective amount of the positive inotropic agent in a controlled manner from the delivery vehicle directly to the heart to increase the force of myocardial contraction.

2. The method of claim 1, wherein the adherent patch is biodegradable.

3. The method of claim 1, wherein the positive inotropic agent is a sympathomimetic compound.

4. The method of claim 1, wherein the inotropic agent is a phosphodiesterase inhibitor.

5. The method of claim 1, wherein the delivery vehicle is placed on the left ventricular wall or apex of the ventricle and away from the sinoatrial node or the right atrium of the heart.

6. The method of claim 1, wherein the inotropic agent is an agent that interacts with the sympathetic nervous system and modulates calcium entry, G-proteins, ATP, or GTP, wherein the inotropic agent is selected from the group consisting of sympathomimetic compounds, phosphodiesterase inhibitors, BNP, ANP, and digitalis glycosides.

7. The method of claim 1, wherein the inotropic agent is a sympathomimetic compound selected from the group consisting of epinephrine, norepinephrine, dobutamine, isoproterenol, salbutamol, salmeterol, terbutaline, phenylephrine, ephedrine, clonidine and dopamine.

8. The method of claim 1, wherein the inotropic agent is a phosphodiesterase inhibitor selected from the group consisting of milrinone, enoximone and amrinone, and derivatives and analogues thereof.

9. The method of claim 1, wherein the subject is a surgical patient and is selected from the group consisting of a cardiac surgery patient, a thoracic surgery patient, and a general surgery patient.

10. The method of claim 1, wherein the subject is a cardiac surgery patient, and wherein the cardiac surgery patient is selected from the group consisting of a cardiac surgical patient requiring support from a cardiopulmonary bypass circuit and a cardiac patient not requiring support from a cardiopulmonary bypass circuit.

11. The method of claim 1, wherein the subject has a condition selected from the group consisting of trauma, shock, acute congestive heart failure, and chronic congestive heart failure.

12. The method of claim 1, wherein the delivery vehicle comprises a polymeric material in which said positive inotropic agent is mixed.

13. The method of claim 1, wherein the delivery vehicle is placed directly onto the heart via an open surgical wound.

14. The method of claim 1, wherein the inotropic agent is administered to said subject during a time period selected from the group consisting of prior to a CPB surgery, during a CPB surgery, subsequent to a CPB surgery, and combinations thereof.

15. The method of claim 1, wherein placement of the delivery vehicle onto the heart comprises passing the delivery vehicle through a catheter or port.

16. The method of claim 1, wherein the delivery vehicle is sufficiently compliant to not impede cardiac contraction.