Method of drug delivery to interstitial regions of the myocardium

• US 6,443,949 B2
• Filed: 10/23/1998
• Issued: 09/03/2002
• Est. Priority Date: 03/13/1997
• Status: Expired due to Term

• Current Assignee: BioCardia, Inc
• Original Assignee: BioCardia, Inc
• Inventors: Altman, Peter A.
• Primary Examiner(s): Lateef, Marvin M.
• Assistant Examiner(s): MANTIS MERCADER, ELENI M
• Application Number:
  US09/177,765
• Publication Number:
  US 20020010462A1
• Time in Patent Office: 1,411 Days
• Field of Search: 607/3, 607/120, 604/19, 604/27, 604/93, 604/21, 606/41
• 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: Y10S 977/775 Nanosized powder or flake, e.g. nanosized catalyst
• CPC Class Codes: Y10S 977/907 Liposome

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.

Claims

1. A method of delivering a therapeutic molecule to myocardial interstitium to achieve local therapy to the heart muscle, said method comprising the steps of:

encasing the therapeutic molecule within a liposome, the liposome having a half-life within mammal myocardial tissue of less than about thirty minutes; and

injecting the liposome into the myocardial interstitium.

2. The method of claim 1 wherein the injecting step comprises providing a catheter system that delivers the stable liposomal preparation through an endocardial hollow penetrating delivery system.

3. The method of claim 1 wherein the injecting step comprises an epicardial injection.

4. The method of claim 1 wherein the therapeutic molecule is a small molecule with a molecular weight less than about 2000 daltons.

5. The method of claim 1 wherein the therapeutic molecule is a macromolecule.

6. The method of claim 1 wherein the therapeutic molecule is a gene therapy preparation.

7. A method of delivering a therapeutic agent to myocardium comprising the steps of:

providing a liposomal delivery catheter with a fluid lumen, the fluid lumen having a different physicochemical state than the mammal myocardium; and

injecting liposomes into said myocardium, the liposomes being stable in the fluid lumen and unstable in the mammal myocardium.

8. A method of delivering therapeutic macromolecules locally to the myocardial interstitium to achieve local therapy to the heart muscle, said method comprising the steps of:

encasing the macromolecules within an intact controlled release particle between 15 and 150 micrometers in diameter; and

injecting the controlled release particle into the myocardial interstitium.

9. The method of claim 8 wherein the injecting step comprises providing a catheter system that delivers the controlled release particle through an endocardial hollow penetrating delivery system.

10. A method of treating the heart of a patient by injecting a therapeutic agent into the tissue of the heart, said method comprising the step of:

forming a plurality of capsules by encapsulating molecules of the therapeutic agent within an encapsulating layer, said encapsulating layer being degradable within the heart tissue, said capsules being of sufficient size to prevent capillary transport of the capsules after injection into the heart tissue;

injecting the capsules into the heart tissue;

allowing the encapsulating layer to degrade within the heart tissue and thereby release molecules of therapeutic agent within the heart tissue.

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

formulating the capsules so that they are stable in a storage environment and unstable in a physiological environment, and storing the capsules in the storage environment prior to injection into the heart tissue.

12. The method of claim 10 wherein:

the encapsulating layer comprises a liposome.

13. The method of claim 10 wherein:

the encapsulating layer comprises a micelle.

14. The method of claim 10 wherein:

the encapsulating layer comprises a liposome having a diameter in the range of about 50 nm to about 400 nm

the therapeutic agents comprise at least one of;

macromolecules, gene therapy preparations, antiarrhythmic agents.

15. The method of claim 10 further comprising:

determining a site of intended treatment within the heart tissue;

injecting the capsules into the heart tissue at a point upstream in the lymphatic system relative to an area of intended treatment.

16. The method of claim 10 wherein the capsules are of sufficient size to prevent lymphatic transport of the capsule after injection into the heart tissue.

17. A substance for treatment of body tissue comprising:

a plurality of capsules comprising an encapsulating layer and a therapeutic agent within the encapsulating layer, wherein

said encapsulating layer is degradable when injected into the body tissue;

the half life of said encapsulating layers being between five and sixty minutes;

said capsules having an outer diameter less than about 400 nanometers;

said therapeutic agent having a pharmacological effect on the body tissue upon degradation of the encapsulating layer.

18. The substance of claim 17 wherein the capsules further comprise a core of about 7.5 μ

m diameter which is substantially devoid of therapeutic agent.

19. A substance for treatment of body tissue comprising:

a plurality of capsules comprising an encapsulating layer and a therapeutic agent within the encapsulating layer, wherein said encapsulating layer is degradable when injected into the body tissue;

said capsules having an outer diameter between about 15 and 150 microns, the capsules also having a core of about 7.5 μ

m diameter which is substantially devoid of therapeutic agent;

said therapeutic agent having a pharmacological effect on the body tissue upon degradation of the encapsulating layer.

20. A substance for treatment of body tissue comprising:

a plurality of microspheres comprising an outer layer and an inner core, the outer layer incorporating a therapeutic agent, the inner core comprising a substantially inert agent, the outer layer being degradable when injected into the body tissue thereby releasing the therapeutic agent to the body tissue;

said therapeutic agent having a pharmacological effect on the body tissue.