Method of drug delivery to interstitial regions of the myocardium

• US 6,511,477 B2
• Filed: 09/28/1999
• Issued: 01/28/2003
• Est. Priority Date: 03/13/1997
• Status: Expired due to Term

• Current Assignee: BioCardia, Inc
• Original Assignee: BioCardia, Inc
• Inventors: Altman, Peter A., Crockett, K. David
• Primary Examiner(s): Lateef, Marvin M.
• Assistant Examiner(s): MANTIS MERCADER, ELENI M
• Application Number:
  US09/407,461
• Publication Number:
  US 20020062125A1
• Time in Patent Office: 1,218 Days
• Field of Search: 606/41, 606/44, 606/45, 606/48, 606/47, 600/34, 600/508, 607/3, 607/120, 607/121, 607/122, 607/126, 607/127, 607/128, 607/60, 607/32, 607/33, 607/61, 424/450, 424/400, 424/489-490, 604/22, 604/264
• US Class Current: 606/41
• CPC Class Codes: A61B 18/1492 having a flexible, catheter-like structure, e.g. for heart ablation A61B18/1477 takes precedence
• CPC Class Codes: A61B 2017/00247 Making holes in the wall of the heart, e.g. laser Myocardial revascularization
• CPC Class Codes: A61B 2018/00011 with fluids
• CPC Class Codes: A61B 2018/00351 Heart
• CPC Class Codes: A61B 2018/00392 Transmyocardial revascularisation
• CPC Class Codes: A61B 2018/00577 Ablation
• CPC Class Codes: A61B 2018/00839 Bioelectrical parameters, e.g. ECG, EEG
• CPC Class Codes: A61B 2018/1425 Needle
• CPC Class Codes: A61B 2018/1435 Spiral
• CPC Class Codes: A61B 2218/002 Irrigation
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/1676 having a drug-free core with discrete complete coating layer containing drug adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921
• CPC Class Codes: A61K 9/50 Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals A61K9/2081 takes precedence; particles with a single coating comprising drug A61K9/167
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: A61M 2025/0089 Single injection needle protruding axially, i.e. along the longitudinal axis of the catheter, from the distal tip
• CPC Class Codes: A61N 1/0575 with drug delivery
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications

Abstract

A method of treating the heart and other body tissues by injecting a compound comprised of microsphere encapsulated macromolecule therapeutic agents into the myocardium, such that the microsphere size inhibits capillary transport of the compound but may permit lymphatic transport of the compound, and the compound releases therapeutic agents upon degradation of the microsphere. The compounds may be used in a method of treating the coronary arteries in which lymphatic transportable therapeutic agents are injected into the myocardium at a location distal to a target site in the coronary artery, after which they are taken up by the lymphatic vessels and transported proximally relative to the coronary artery, and migrate from the lymphatic vessel to the coronary blood vessel.

Claims

1. A method of treating a coronary artery in a human patient having a heart, said heart having a myocardium and a lymphatic system, said method comprising:

injecting a therapeutic agent into the myocardium of the heart at a location distal to the desired area of entry into the coronary artery, wherein said therapeutic agent is adapted to enter the lymphatic system of the heart, to be transported proximally relative to the coronary artery, and thereafter to migrate from the lymphatic system of the heart into the coronary artery at a site proximal from the location of injection into the myocardium, thereby treating the coronary artery.

2. The method claim 1 further comprising the steps of:

providing the therapeutic agent in microspheres comprising a degradable material with the therapeutic agent dispersed within the degradable material, said microspheres being degradable within the myocardium, said microspheres being sized and dimensioned, at the time of injection, to inhibit take-up into the lymphatic system of the heart, said microspheres being degradable over time to release the therapeutic agent into the myocardium, wherein the molecules of the therapeutic agent are capable of take-up in the lymphatic system of the heart.

3. The method of claim 2 wherein the therapeutic agent comprises an anti-stenosis agent.

4. The method of claim 2 wherein the therapeutic agent comprises an angiogenic agent.

5. The method of claim 2 wherein the therapeutic agent comprises an anti-angiogenic agent.

6. A method of treating a target site in coronary artery in a human patient having a heart, said heart having a myocardium and a lymphatic system, said method comprising:

injecting a therapeutic agent into the myocardium of the heart at a location distal to the target site of the coronary artery, wherein said therapeutic agent is adapted to enter the lymphatic system of the heart, to be transported proximally relative to the coronary artery, and

thereafter to migrate from the lymphatic system of the heart into the coronary artery at a site proximal from the location of injection into the myocardium, thereby treating the coronary artery.

7. The method of claim 6 further comprising:

treating the target site of the coronary artery with balloon angioplasty or a stent; and

providing an angiogenic agent in the therapeutic agent.

8. The method of claim 6 further comprising:

treating the target site of the coronary artery with balloon angioplasty or a stent; and

providing an anti-angiogenic agent in the therapeutic agent.

9. The method of claim 6 further comprising:

treating the target site of the coronary artery with balloon angioplasty or a stent;

providing an anti-angiogenic agent in the therapeutic agent; and

providing an angiogenic agent in the therapeutic agent.

10. The method of claim 9 further comprising:

providing said anti-angiogenic agent in a first time-release formulation, said first time-release formulation degrading to release the anti-angiogenic agent in a first time period after the step of treating the target site; and

providing said angiogenic agent in a second time release formulation, said second time release formulation degrading to release the angiogenic agent in a second time period after the step of treating the target site.

11. The method of claim 10 wherein the second time period begins after the first time period.

12. The method of claim 10 further comprising the steps of:

providing the therapeutic agent in the form of microspheres which are degradable in the body, said microspheres having a first layer and a second layer, said first layer being at or near the surface of the microsphere and said second layer being inside the first layer;

loading the first layer with the anti-angiogenic agent; and

loading the second layer with the angiogenic agent.

13. The method of claim 10 further comprising the steps of:

providing the therapeutic agent in the form of microspheres which are degradable in the body, said microspheres comprising a first group of microspheres sized to permit entry into the lymphatic system in the first time period, and a second group of microspheres sized to inhibit entry into the lymphatic system in the first time period;

loading the first group of microspheres with the antiangiogenic agent; and

loading the second group of microspheres with the angiogenic agent.

14. The method of claim 6 further comprising:

providing an anti-angiogenic agent in the therapeutic agent; and

providing an angiogenic agent in the therapeutic agent.

15. The method of claim 14 further comprising:

providing said anti-angiogenic agent in a first time-release formulation, said first time-release formulation degrading to release the anti-angiogenic agent in a first time period; and

providing said angiogenic agent in a second time release formulation, said second time release formulation degrading to release the angiogenic agent in a second time period.

16. The method of claim 15 wherein the second time period begins after the first time period.

17. The method of claim 14 further comprising the steps of:

providing the therapeutic agent in the form of microspheres which are degradable in the body, said microspheres having a first layer and a second layer, said first layer being at or near the surface of the microsphere and said second layer being inside the first layer;

loading the first layer with the anti-angiogenic agent; and

loading the second layer with the angiogenic agent.

18. The method of claim 14 further comprising the steps of:

providing the therapeutic agent in the form of microspheres which are degradable in the body, said microspheres comprising a first group of microspheres sized to permit entry into the lymphatic system in the first time period, and a second group of microspheres sized to inhibit entry into the lymphatic system in the first time period;

loading the first group of microspheres with the antiangiogenic agent; and

loading the second group of microspheres with the angiogenic agent