Method of drug delivery to interstitial regions of the myocardium

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.

Description

[0001] This application is a continuation of U.S. application Ser. No. 10 / 353,117 filed Jan. 27, 2003, now abandoned, which is a continuation of U.S. application Ser. No. 09 / 407,461 filed Sep. 28, 1999, now U.S. Pat. No. 6,511,477, which is a continuation-in-part of U.S. application Ser. No. 09 / 177,765 filed Oct. 23, 1998, now U.S. Pat. No. 6,443,949, which is a continuation-in-part of U.S. application Ser. No. 08 / 816,850 filed Mar. 13, 1997, now U.S. Pat. No. 6,086,582.FIELD OF THE INVENTION [0002] The present invention relates to the interstitial delivery of particulate drug delivery systems for large and small molecule therapeutic agents within the heart. BACKGROUND OF THE INVENTION [0003] Local drug delivery provides many advantages. Approaches for local controlled release of agents at a depth within a tissue such as the heart, pancreas, esophagus, stomach, colon, large intestine, or other tissue structure to be accessed via a controllable catheter will deliver drugs to the site...

AI Technical Summary

Benefits of technology

[0007] The therapeutic compounds described below comprise very small capsules which can be injected into body tissue, particularly the heart. The capsules include an encapsulating layer which surrounds a therapeutic agent. After injection, the encapsulating layer degrades or dissolves, and the therapeutic agent is released within the heart. The therapeutic agent may be one of any number of known agents such as anti-arrhythmic drugs, gene therapy solutions, and macromolecules intended to have either acute or long-term effects on the heart. While some of these therapeutic agents are used to treat the heart by injecting them into the heart, they are of such small size that they readily enter the cardiac capillary system and the cardiac lymphatic system, and are quickly transported away from the injection site. Thus, in prior treatment methods, relatively large doses and repeated dosed are required to provide therapeutic effect at the injection site. To provide a solution to this problem, the capsules described below are provided in sizes that are too large to permit capillary transport or lymphatic transport. Thus, injected capsules are immobile within the heart tissue, and upon degradation they will release a therapeutic agent very near the site of injection. The capsules may also be provided in sizes that are too large to permit capillary transport, but small enough to enter the lymphatic system and be transported away from the injection site in the cardiac lymphatic system, so that the therapeutic effect is provided at some distance from the injection site. The encapsulating layer may be made from various materials including biodegradable polymers in the form of microspheres, or from standard vesicle forming lipids which form liposomes and micelles.

Problems solved by technology

Further, these approaches do not deliver therapeutic agents to the interstitial spaces.

None of this work recognizes the potential to use particulate drug delivery system to optimize local drug delivery at a depth within the myocardium.

This art also does not recognize the potential such delivery systems have in treating disease substrates in the myocardium if delivered to an appropriate region of the myocardial interstitium.

Problems exist for delivering small molecules or lipophilic molecules which rapidly transport through the capillary wall, to well-perfused tissues such as the myocardium.

These problems are due to the convective losses of the agents to the systemic circulation.

Local delivery of an easily transported molecule is difficult because local delivery concentrations are rapidly reduced at very small distances from the delivery site due to convective losses.

Such easily transported agents cannot treat an effective area of tissue locally without raising the systemic concentrations of the agents to a therapeutic level.

Thus, in prior treatment methods, relatively large doses and repeated dosed are required to provide therapeutic effect at the injection site.

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