U.S. patent application number 10/353117 was filed with the patent office on 2003-07-17 for method of drug delivery to interstitial regions of the myocardium.
This patent application is currently assigned to BioCardia, Inc.. Invention is credited to Altman, Peter A., Crockett, K. David.
Application Number | 20030135113 10/353117 |
Document ID | / |
Family ID | 26873622 |
Filed Date | 2003-07-17 |
United States Patent
Application |
20030135113 |
Kind Code |
A1 |
Altman, Peter A. ; et
al. |
July 17, 2003 |
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.
Inventors: |
Altman, Peter A.; (South San
Francisco, CA) ; Crockett, K. David; (Mission Viejo,
CA) |
Correspondence
Address: |
CROCKETT & CROCKETT
24012 CALLE DE LA PLATA
SUITE 400
LAGUNA HILLS
CA
92653
US
|
Assignee: |
BioCardia, Inc.
|
Family ID: |
26873622 |
Appl. No.: |
10/353117 |
Filed: |
January 27, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10353117 |
Jan 27, 2003 |
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09407461 |
Sep 28, 1999 |
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6511477 |
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09407461 |
Sep 28, 1999 |
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09177765 |
Oct 23, 1998 |
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6443949 |
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09177765 |
Oct 23, 1998 |
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08816850 |
Mar 13, 1997 |
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6086582 |
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Current U.S.
Class: |
600/431 |
Current CPC
Class: |
A61M 2025/0089 20130101;
A61B 2017/00247 20130101; A61P 9/06 20180101; A61B 2018/1425
20130101; A61B 2018/1435 20130101; A61B 2018/00351 20130101; A61B
2018/00011 20130101; A61N 1/0575 20130101; A61B 18/1492 20130101;
A61K 9/1676 20130101; A61K 9/5084 20130101; A61P 9/08 20180101;
A61B 2218/002 20130101; A61B 2018/00839 20130101; A61B 2018/00577
20130101; A61K 9/50 20130101; A61K 9/127 20130101; A61B 2018/00392
20130101; A61P 9/00 20180101 |
Class at
Publication: |
600/431 |
International
Class: |
A61B 006/00 |
Claims
We claim:
1. A system for delivering a drug to the heart of a patient, said
system comprising: a catheter capable of delivering a plurality of
liposomes to the heart of the patient; a source of liposomes
adapted for fluid communication with the catheter, said source
containing a plurality of liposomes, and wherein each of the
plurality of liposomes has a half-life within the body of the
patient of less than about sixty minutes; and a drug encased within
at least one of the plurality of liposomes.
2. A system for delivering an agent to the heart of a patient, said
system comprising: a catheter capable of delivering a microsphere
to the heart of the patient; a source of microspheres adapted for
fluid communication with the catheter, said source containing the
microsphere; wherein the agent is disposed within the microsphere;
wherein the agent is adapted to be taken-up by the lymphatic system
of the heart, transported proximally relative to a coronary artery
of the heart, and thereafter to migrate from the lymphatic system
into the coronary artery at a site proximal from a location of
injection.
3. The system of claim 2 wherein the agent comprises a liposome,
wherein a drug is dispersed within the liposome.
4. The system of claim 2 wherein the agent comprises a drug.
5. The system of claim 2 wherein the agent comprises a therapeutic
agent.
6. The system of claim 2 wherein the microsphere comprises a
degradable material and wherein the agent comprises a drug
dispersed within the degradable material, and wherein the
microsphere is degradable within the myocardium, said microsphere
being sized and dimensioned, at the time of injection, to inhibit
take-up into the lymphatic system of the heart, said microsphere
being degradable over time to release the drug into the myocardium,
wherein the molecules of the drug are capable of take-up in the
lymphatic system of the heart.
7. The system of claim 6 wherein the microsphere further comprises:
a first layer and a second layer, said first layer being at or near
the surface of the microsphere, said second layer being inside the
first layer; wherein the drug comprises a first drug disposed
within the first layer.
8. The system of claim 7 further comprising a second drug disposed
within the second layer of the microsphere.
9. The system of claim 8 wherein the first drug comprises an
anti-angiogenic agent and the second drug comprises an angiogenic
agent.
10. A system for delivering a therapeutic agent to the heart of a
patient, said system comprising: a catheter capable of delivering
the therapeutic agent to the heart of the patient; a source of
agents adapted for fluid communication with the catheter, said
source containing the therapeutic agent; wherein the therapeutic
agent is in the form of a plurality of microspheres which are
degradable in the body, said plurality of microspheres comprising a
first group of microspheres sized to permit entry into the
lymphatic system in a first time period, and a second group of
microspheres sized to inhibit entry into the lymphatic system in
the first time period.
11. The system of claim 10 wherein the first group of microspheres
is loaded with an anti-angiogenic agent and the second group of
microspheres is loaded with an angiogenic agent.
12. An infusion system for delivering a drug to the heart of a
patient, said system comprising: an infusion device adapted for
implantation within the body of the patient, said infusion device
capable of delivering a liposome to the heart of the patient, and
said infusion system operably connected to the heart of the
patient; wherein the drug is encased within the liposome, the
liposome having a half-life within the body of the patient of less
than about sixty minutes, the liposome disposed such that the
infusion device may deliver the liposome.
13. The infusion system of claim 12 wherein the liposome is sized
and dimensioned to allow the liposome to be taken-up by the
lymphatic system of the heart.
14. A method of treating cardiac arrhythmia in a patient, said
method comprising the steps of: providing an infusion system for
delivering an anti-arrhythmic agent to the heart of the patient,
said system comprising: an infusion device adapted for implantation
within the body of the patient, said infusion device capable of
delivering a liposome to the heart of the patient, and said
infusion system operably connected to the heart of the patient;
wherein the anti-arrhythmic agent is encased within the liposome,
the liposome having a half-life within the body of the patient of
less than about sixty minutes, the liposome disposed such that the
infusion device may deliver the liposome; implanting the infusion
device within the body of the patient; and delivering the liposome
to the heart of the patient with the infusion system.
15. The method of claim 14 wherein: the step of providing an
infusion system further comprises providing an infusion system
wherein the liposome is sized and dimensioned to allow uptake of
the liposome by the lymphatic system of the heart; the step of
delivering the liposome further comprises delivering the liposome
to the wall of a ventricle of the heart; and the method further
comprises allowing the lymphatic system of the heart to transport
the liposome to the wall of an atrium of the heart.
16. A method of treating the heart of a patient, said method
comprising the steps of: delivering a dose of a first
macromolecular agent to a depth within the heart muscle, said dose
delivered in the form of a first plurality of microspheres
encapsulating molecules of the first macromolecular agent; and
controlling the release of the molecules of the first
macromolecular agent from the first plurality of microspheres.
17. The method of claim 16 wherein the step of delivering a dose of
a first macromolecular agent comprises delivering a dose of an
angiogenic agent.
18. The method of claim 16 comprising the further steps of:
delivering a dose of a second macromolecular agent to a depth
within the heart muscle, said dose delivered in the form of a
second plurality of microspheres encapsulating molecules of the
second macromolecular agent; and controlling the release of the
molecules of the second macromolecular agent from the second
plurality of microspheres.
19. The method of claim 18 wherein the step of delivering a dose of
a first macromolecular agent comprises delivering a dose of an
angiogenic agent and the step of delivering a dose of a second
macromolecular agent comprises delivering a dose of an
anti-inflammatory steroid.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 09/407,461 file 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 sites where they are most
needed, reduce the amount of drug required, increase the
therapeutic index, and control the time course of agent delivery.
These, in turn, improve the viability of the drugs, lower the
amount (and cost) of agents, reduce systemic effects, reduce the
chance of drug-drug interactions, lower the risk to patients, and
allow the physician to more precisely control the effects induced.
Such local delivery may mimic endogenous modes of release, and
address the issues of agent toxicity and short half lives.
[0004] Local drug delivery to the heart is known. In U.S. Pat. No.
5,551,427, issued to Altman, implantable substrates for local drug
delivery at a depth within the heart are described. The patent
shows an implantable helically coiled injection needle which can be
screwed into the heart wall and connected to an implanted drug
reservoir outside the heart. This system allows injection of drugs
directly into the wall of the heart acutely by injection from the
proximal end, or on an ongoing basis by a proximally located
implantable subcutaneous port reservoir, or pumping mechanism. The
patent also describes implantable structures coated with coating
which releases bioactive agents into the myocardium. This drug
delivery may be performed by a number of techniques, among them
infusion through a fluid pathway, and delivery from controlled
release matrices at a depth within the heart. Controlled release
matrices are drug polymer composites in which a pharmacological
agent is dispersed throughout a pharmacologically inert polymer
substrate. Sustained drug release takes place via particle
dissolution and slowed diffusion through the pores of the base
polymer. Pending application Ser. No. 08/881,6850 by Altman and
Altman, and Ser. No. 09/057,060 by Altman describes some additional
techniques for delivering pharmacological agents locally to the
heart. Implantable drug delivery systems, such as controlled
release matrices, have been well described in the literature, as
has the use of delivering particulate delivery systems or
particulate drug carriers such as microcapsules, lipid emulsions,
microspheres, nanocapsules, liposomes, and lipoproteins into the
circulating blood. However, local delivery of such micro drug
delivery systems to a depth within the myocardium using endocardial
catheter delivery and epicardial injection systems have not been
described, and have many advantages that have not been
foreseen.
[0005] Recently, local delivery to the heart has been reported of
therapeutic macromolecular biological agents by Lazarous
[Circulation, 1996, 94:1074-1082.], plasmids by Lin [Circulation,
1990; 82:2217-2221], and viral vectors by French [Circulation, Vol.
90, No 5, November 1994, 2414-2424] and Muhlhauser [Gene Therapy
(1996) 3, 145-153]. March [Circulation, Vol. 89, No 5, May 1994,
1929-1933.] describes the potential for microsphere delivery to the
vessels of the heart, such as to limit restenosis, and this
approach has also been used for the delivery of bFGF by Arras
[Margarete Arras et. al., The delivery of angiogenic factors to the
heart by microsphere therapy, Nature Biotechnology, Volume 16,
February 1998.] These approaches for microsphere delivery obstruct
flow, and will be delivered preferentially to capillary beds which
are well perfused. 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.
[0006] 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. By going rapidly across the capillary wall, the small
molecules are rapidly carried away by the bloodstream. 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.
SUMMARY
[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.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1 illustrates an encapsulated therapeutic agent
designed for injection into the heart.
[0009] FIG. 1a illustrates a microsphere encapsulated therapeutic
agent designed for injection into the heart.
[0010] FIG. 2 illustrates a method for injection of therapeutic
agents into the heart.
[0011] FIG. 3 illustrates the expected transportation of molecules
released from degrading microspheres injected within the
myocardium.
[0012] FIGS. 4a through 4d illustrate the progression of injected
liposome encapsulated small molecules within the heart tissue after
injection.
[0013] FIG. 5 illustrates a method of delivering therapeutic agents
to the coronary arteries through the lymphatic vessels.
DETAILED DESCRIPTION OF THE INVENTION
[0014] FIG. 1 illustrates a microdrug delivery system which is
comprised of a compound or substance for use in delivering a
therapeutic agent to the heart. The compound is comprised of
numerous capsules 1 which are made up of an encapsulating layer 2
which may form a microsphere formulated from Prolease.TM. or other
biodegradable microsphere material, or from vesicle forming lipids
which may form a liposome or micelle, and a therapeutic agent 3
within the encapsulating layer. Therapeutic agent may be embedded
in a biodegradable polymer, or in a carrier fluid 4. The
encapsulating layer is typically pharmacologically inactive,
although techniques to make it active to promote cellular uptake
and/or receptor binding are known in the art. The therapeutic agent
may be any of a wide variety of drugs and other compounds used for
treatment of various ailments of the heart. The capsules are
carried within a solution such as pH controlled saline to create a
slurry which can be injected into the heart of a patient. Prior to
injection, the encapsulating layer will protect the macromolecule
from mechanical and chemical degradation within the catheter or
needle used for injection. Once injected into the heart tissue, the
size of the encapsulating layer will inhibit transport of the
compound away from the injection site, either through the cardiac
capillary system and/or the cardiac lymphatic system. Also once
injected, the encapsulating layer will degrade, either due to
chemical conditions, biological conditions, or temperature
conditions within the heart wall, and release the encapsulated
molecule. The time period over which the encapsulating layer
degrades is variable, depending upon its formulation, such
formulations being available in the art. The half-life for
degradation may be selected from several minutes to several days,
depending on the therapy intended. Thus a sustained reservoir of
therapeutic agent is created within the heart tissue near the
injection site, and therapeutic agents are slowly released near the
injection site to treat nearby tissue. The need to flood the entire
heart and/or the entire blood system of the patient is eliminated,
so that very small doses of therapeutic agents are enabled. This
reduces the cost of treatment, and minimizes the otherwise harsh
side effects associated with many effective therapeutic agents.
[0015] FIG. 1a illustrates the formulation of the microdrug
delivery system from a microsphere formulated from Prolease.TM.,
biodegradable polymers, or particulate controlled release matrix
with molecules of therapeutic agent dispersed throughout the
microsphere. The microsphere 5 in FIG. 1a includes numerous
molecules or particles of therapeutic agents 3 dispersed throughout
the solid biodegradable microsphere or particulate controlled
release matrix 6. As the microsphere material degrades, therapeutic
agents are slowly released from the microsphere. This formulation
differs from the capsule formulation, but may be employed to
achieve similar results. In one preferred embodiment, the core 7 of
the solid biodegradable microsphere contains no therapeutic drug at
a radius less then approximately 20 um, preferably about 15 um.
Thus the core of the microsphere, to a radius of up to 20 um,
preferably 15 um, may be devoid of therapeutic agent.
Alternatively, the core of the microsphere, to a radius of up to 10
um, preferably 7.5 um, may be devoid of therapeutic agent. This
prevents problems associated with migration of the potentially
potent depot within the lymphatic system. The core of the
microsphere may also be designed to have a longer degradation
half-life so that essentially all of the drug will be delivered
before the microsphere can substantially migrate through the
lymphatic networks. Thus, the particulate micro delivery systems
includes millispheres, microspheres, nanospheres, nanoparticles,
liposomes and micelles, cellular material and other small
particulate controlled release structures which can be advanced in
a fluid suspension or slurry and be delivered to a depth within the
heart muscle. These small drug delivery systems may deliver
therapeutic agents as diverse as small molecule antiarrhythmics,
agents that promote angiogenesis, and agents that inhibit
restenosis. They may also be combined in cocktails with steroid
agents such as dexamethasome sodium phosphate to prevent
inflammatory response to the implanted materials. Separate
particulate drug delivery systems for delivering different agents
to the same region of the heart may also be used. The release
kinetics of separate micro delivery systems may also be
different.
[0016] Delivery of small drug delivery systems reduce the
likelihood of causing embolic events in the brain, kidneys, or
other organs should these drug delivery systems escape into the
left chambers of the heart. Because the systems are small only very
small arterioles would be occluded should one of them escape into
the blood within the left chambers of the heart. This is not a
problem in the right side of the heart, as the lungs act as a
filter of potentially embolic materials.
[0017] FIG. 2 shows a catheter system 9 with centrally located drug
delivery catheter 20 implanted at a depth within the left
ventricular apex 15 of the heart 10. Hollow penetrating structure
30 has penetrated the heart muscle, and has transported particulate
encapsulated agents 35 such as VEGF, bFGF, or other therapeutic
agent to a depth within the heart muscle. The encapsulated agents
are injected into the heart muscle (the myocardium) in an intact
portion of the heart muscle (that is, not into a vessel such as the
ventricle chamber, a coronary artery or a TMR channel which are
subject to blood flow and immediate transport of the injected
particles from the area). The capsules or microspheres are
suspended within a fluid inside the catheter to facilitate
injection. The use of small drug delivery systems in slurry or
suspension delivered by a fluidic pathway (a needle or catheter) to
a depth within the myocardium can solve different problems in
pharmacokinetics of local cardiovascular drug delivery. Such an
approach can provide for well controlled and easily administered
sustained dosage of therapeutic macromolecules, eliminate the issue
of convective losses of small molecules for local delivery, and
increase the ability of gene therapy preparations to gain access
through the cell membrane.
[0018] Problems exist for macromolecular therapies in the heart
such as short half-lives and the presence of endogenous inhibitors.
Many macromolecular therapies may be improved by providing a
sustained dosage over time to overcome endogenous inhibitors, as
well as encapsulation to protect the macromolecule from
degradation.
[0019] The interstitial (intramuscular or intra-myocardial)
delivery of particulate drug delivery systems for sustained release
such as biodegradable microspheres solves these problems.
Particulate systems, such as microspheres, enable the time course
of delivery and area of treatment to be controlled. In addition,
such particulate systems may be delivered to the target site by a
fluid pathway within a drug delivery catheter such as those
described in the prior art. The advantages of these particulate
delivery systems is that they are implanted at a depth within the
heart tissue and the implanted catheter device can be removed
immediately. Thus, a very quick procedure may be performed on an
outpatient basis to deliver particulate drug delivery systems to a
depth within a patient's heart for sustained delivery measured in
days to weeks.
[0020] The microspheres to be used in this treatment are
manufactured to be large enough to prevent migration within the
myocardial interstitium, but also small enough to be deliverable by
a catheter fluid pathway to a depth with the myocardium.
Microspheres such as Alkerme's (Cambridge, Mass.) Prolease system
enable freeze dried protein powder to be homogenized in organic
solvent and sprayed to manufacture microspheres in the range of 20
to 90 um (microns). Development of such microsphere depots for
sustained release of proteins with unaltered integrity requires
methods to maintain stability during purification, storage, during
encapsulation, and after administration. Many of these techniques
have been recently summarized in the literature. See, e.g., Scott
D. Putney, and Paul A. Burke: Improving protein therapeutics with
sustained release formulations, Nature Biotechnology, Volume 16,
February 1998, 153-157. Issues associated with degradation for
biodegradable polymers used in such microspheres are also well
known [Robert Miller, John Brady, and Duane E. Cutright:
Degradation Rates of Oral resorbable Implants {Polylactates and
Polyglycolates}: Rate Modification and Changes in PLA/PGA Copolymer
Ratios, J. Biomed. Mater. Res., Vol. II, PP. 711-719 (1977). The
value of delivering microsphere encapsulated macromolecular agents
such as proteins bFGF and VEGF to a depth within the heart muscle
for controlled release have not been described, and have
substantial unrecognized benefits over other delivery
approaches.
[0021] FIG. 3 shows a schematic description of microsphere
encapsulated agents for delivery. Macromolecule angiogenic agents
336 such as VEGF and bFGF are delivered with biodegradable
microspheres 335 in combination with biodegradable microspheres 302
enclosing dexamethasone sodium phosphate or other anti inflammatory
steroid. In other embodiments the anti-inflammatory agents may be
combined with a particular therapeutic within the same
encapsulation. The microspheres are injected through the
endocardium 338 and into the myocardium 339 so that they reside
interstitially within the heart tissue. Both microspheres 335 and
302 are too large to be transported away by either the capillary
system or the lymphatic system from the injection site within the
myocardium. Where the microspheres are greater than about 15
micrometers in diameter, they will remain at the injection site and
will not migrate. Where the microspheres have a diameter less than
about 1 micrometer they will migrate in the cardiac lymphatic
system, but will not enter the cardiac capillary system. As the
microspheres degrade over time, their components and the
therapeutic molecules will be transported away from the injection
site by the myocardial lymphatic system which has been described in
relation to the transport of extravasated proteins from the
endocardium 338 to the epicardium 340, and from the apex of the
heart 345 towards the base of the heart 350. [Albert J. Miller,
Lymphatics of the Heart, Raven Press, New York, 1982.] Here the
microspheres are delivered endocardially and inferiorly (that is,
upstream in the lymphatic system) to the region to be treated,
identified here schematically by window 355. Clearly regions within
window 355 and regions directly adjacent to the window will all
result in effective delivery of agents to the desired target, and
are viable approaches as well. The large molecules delivered in
such a fashion will be transported through the lymphatics far more
slowly than small molecules which would be more rapidly convected
away from the delivery region by the blood supply. But approaches
exist to minimize the issues associated with convective losses of
small molecules.
[0022] The method of packaging the small molecule so that it cannot
be convected away by the blood, yet will be distributed locally in
the tissue, and then effecting its action on the tissue can be
accomplished with liposomal encapsulation. The term "liposome"
refers to an approximately spherically shaped bilayer structure, or
vesicle, comprised of a natural or synthetic phospholipid membrane
or membranes, and sometimes other membrane components such as
cholesterol and protein, which can act as a physical reservoir for
drugs. These drugs may be sequestered in the liposome membrane or
may be encapsulated in the aqueous interior of the vesicle.
Liposomes are characterized according to size and number of
membrane bilayers. Vesicle diameters can be large (>200 nm) or
small (<50 nm) and the bilayer can have unilamellar,
oligolamellar, or multilamellar membrane.
[0023] Liposomes are formed from standard vesicle forming lipids,
which generally include neutral and negatively charged
phospholipids with or without a sterol, such as cholesterol. The
selection of lipids is generally guided by considerations of
liposome size and ease of liposome sizing, and lipid and water
soluble drug release rates from the site of liposome delivery.
Typically, the major phospholipid components in the liposomes are
phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidyl
serine (PS), phosphatidylinositol (PI) or egg yolk lecithin (EYL).
PC, PG, PS, and PI having a variety of acyl chains groups or
varying chain lengths are commercially available, or may be
isolated or synthesized by known techniques. The degree of
saturation can be important since hydrogenated PL (HPL) components
have greater stiffness than do unhydrogenated PL components; this
means that liposomes made with HPL components will be more rigid.
In addition, less saturated Pls are more easily extruded, which can
be a desirable property particularly when liposomes must be sized
below 300 nm.
[0024] Current methods of drug delivery by liposomes require that
the liposome carrier will ultimately become permeable and release
the encapsulated drug. This can be accomplished in a passive manner
in which the liposome membrane degrades over time through the
action of agents in the body. Every liposome composition will have
a characteristic half-life in the circulation or at other sites in
the body. In contrast to passive drug release, active drug release
involves using an agent to induce a permeability change in the
liposome vesicle. In addition, liposome membranes can be made which
become destabilized when the environment becomes destabilized near
the liposome membrane (Proc. Nat. Acad. Sci. 84, 7851 (1987);
Biochemistry 28: 9508, (1989).) For example, when liposomes are
endocytosed by a target cell they can be routed to acidic endosomes
which will destabilize the liposomes and result in drug release.
Alternatively, the liposome membrane can be chemically modified
such that an enzyme is placed as a coating on the membrane which
slowly destabilizes the liposome (The FASEB Journal, 4:2544 (1990).
It is also well known that lipid components of liposomes promote
peroxidative and free radical reactions which cause progressive
degradation of the liposomes, and has been described in U.S. Pat.
No. 4,797,285. The extent of free radical damage can be reduced by
the addition of a protective agent such as a lipophilic free
radical quencher is added to the lipid components in preparing the
liposomes. Such protectors of liposome are also described in U.S.
Pat. No. 5,190,761, which also describes methods and references for
standard liposome preparation and sizing by a number of techniques.
Protectors of liposomal. integrity will increase the time course of
delivery and provide for increased transit time within the target
tissue.
[0025] Liposomal encapsulation of small molecules makes local
delivery possible. By having a liposomal preparation which is
unstable in the body, it will collapse after it is delivered.
Liposomes can be constructed in varying size, including the size
range less than 400 nm, preferably 200-250 nm. Between the time of
delivery and the time of collapse, the liposomes in the size range
less than 400 nm will be transported into and through the
lymphatics and provide for redistribution of small molecules.
Delivery of liposomes that degrade rapidly once delivered to the
body in a matter of minutes goes against the typical approaches for
liposomal delivery and design. Typically pH sensitive liposomes
involves the destabilization of the liposome in the endosome as the
pH falls from physiological 7.4 to 5.0, while here we are
describing liposomes which become destabilized near pH 7.4.
[Chun-Jung Chu and Francis C. Szoka: pH Sensitive Liposomes,
Journal of Liposome Research, 4(1), 361-395 (1994)].
[0026] FIG. 4a shows a schematic of the delivery of small molecules
within liposomes which are unstable at physiological pH (the pH of
the heart tissue or the physiological environment into which the
molecules are delivered). A guiding catheter 401 is shown with a
single lumen needle drug delivery catheter 402 containing liposome
encapsulated small molecules 403 which are delivered through needle
404 by way of needle fitting 404. Here the penetrating needle 405,
crosses the endocardium 410 to deliver liposomes 415 to a depth
within the heart wall 420. Although the liposomes could be various
sizes and have a number of lipid bilayers, in the preferred
embodiment they are small unilamellar liposome vesicles (SUVs) to
augment their rapid uptake by the cardiac lymphatic system. The
drug delivery catheter 402 contains liposomes bathed in a solution
at their stable pH so that they do not collapse prematurely. FIG.
4b shows that the catheter has been removed and that the uptake of
the SUVs 415 by a lymphatic vessel 425 at some time t2 later than
the time they were delivered t1 to the myocardial interstitium,
such as the subendocardial interstitium. Of course, other
physiochemical properties could be used such that the liposomal
preparations are delivered from a system in which they are stable
to a system at a depth within the heart with different
physio-chemical properties in which they are unstable. Temperature
is another possible property that could be varied. Arrows near 407
show that lymphatic transport is from endocardium to epicardium and
from apex to base in the heart. The lymphatic transport will carry
the encapsulated small molecules a distance which will be governed
by their stability and mean time to liposomal degradation. FIG. 4c
shows the same tissue in a larger view at time t3 later than time
t2 in which SUVs 415 are degrading and releasing small molecule
drugs 430 within the lymphatics. The spread of the released drug in
the degraded liposomes 430 provides therapeutic treatment to a
large region of heart tissue while systemic effects are minimized.
FIG. 4d shows that upon degradation, the small molecules 430 will
be transported through the lymphatic vessel wall 435 to the
adjacent myocytes, and be convected rapidly away from the region.
This transport through the lymphatic walls is shown schematically
by the large arrows at the site of the degraded liposome with
released small molecules. Because of the inability of the small
molecules to be convected away rapidly until the liposome
collapses, a much larger region of tissue will be able to be
treated locally than by local infusion of the small molecules
themselves. In one embodiment, oleic acid (OA) and
dioleoylphosphatidyl-ethanolamine (DOPE) devoid of cholesterol
which have been shown to be extremely unstable in the presence of
body fluid plasma [Liu, D. and Huang, L., Role Of Cholesterol In
The Stability Of pH Sensitive, Large Unilamellar Liposomes Prepared
By The Detergent-Dialysis Method, Biochim Biophys. Act, 981,
254-260 (1989)] and could be used to encapsulate small molecule
gene regulators such as hormones or anti-arrhythmic agents.
[0027] In another embodiment, liposomes of
dimyristoylphosphatidylcholine (DMPC) or
dipalmitoylphosphatidylcholine (DPPC), cholesterol (CHOL) and
dicetylphosphate (DCP) containing Amiodarone are prepared at pH 4.5
using DMPC:CHOL:DCP (3:1:2 mol ratio) and are stable at this pH,
and are less stable at the neutral pH of the heart. Because the
stability of the liposome can be varied, and even triggered by
external inputs, a specific size of tissue may be treated locally
with small molecules in this fashion.
[0028] If the small molecule has a very short half-life, or
antagonists have been delivered systematically to prevent the drug
from having systemic effects, such an approach will enable local
delivery of small molecules to regions of varying sizes within the
myocardium. Alternatively, some small molecules may be delivered
transiently only when needed, such as to terminate a cardiac
arrhythmia, and so that systemic effects are minimized. Such
systems could involve a permanently implantable infusion system for
either continuous or transient local delivery as has been described
in the art.
[0029] Liposomal encapsulated agents delivered to the myocardium
will also provide advantages to other therapeutic agents. Liposomal
encapsulation can improve transfection of gene therapy
preparations, and cytosolic delivery of macromolecules. Liposomal
delivery systems can be used to alter macromolecule and gene
therapy pharmacokinetics and improve their ability to enter the
cell cytosol. Delivery vehicles capable of delivering agents to the
cell cytosol have been created in fusogenic liposomes, which enable
them to cross the cell membrane in a lipophilic vesicle. Newer
techniques for triggering the liposomes so that their contents may
be released within the cytosol have been developed, and a brief
review of this work has appeared in the literature [Oleg Gerasimov,
Yuanjin Rui, and David Thompson, "Triggered release from liposomes
mediated by physically and chemically induced phase transitions",
in Vesicles, edited by Morton Rosoff, Marcel Dekker, Inc., New
York, 1996.] Because the liposome is not stable at the
physicochemical conditions within the body, it can be designed to
degrade in a time period less than it takes to get to the cardiac
lymph node. Once the liposome is degraded, the body can address the
liposomal contents and break them up. Liposomes within the systemic
circulation can then be minimized, as will endocytosis of the
macromolecules and gene therapy preparations outside the target
region. No approach for delivering such liposomal encapsulated
agents to a depth within the myocardium has been described.
[0030] As described, the endocardial to epicardial, and apex to
base lymphatic transport pathways can be used to deliver
macromolecules and particulate drug delivery systems to the
targeted region in need of therapy. The increased risk of ischemia
in the subendocardium implies that it is the tissue in need of
therapeutic intervention. This has been hypothesised as being due
to the higher interstitial pressures during cardiac systole, which
may limit perfusion of this tissue region as opposed to
subepicardial tissue. In order to treat this region with
therapeutic agents from a locally delivered depot site, delivery
should be such that endogenous transport pathways deliver agents to
the target regions. This can be accomplished by delivering agents
on the endocardial side of the ischemic zone, and towards the apex
of the heart. Such an approach has not been previously described.
The internal lymphatic system of the heart can also be used to
control delivery of the therapeutic agents throughout the heart.
For example, liposome encapsulated or micelle encapsulated
amiodarone, or other anti-arrhythmic agents can be injected into
the ventricle wall, (and the liposomes formulated for a half life
of about five minutes to sixty minutes), whereupon the lymphatic
system will transport the liposomes upward toward the atrium of the
heart to the vicinity of the cardiac lymph node. Lymphatic vessels
flow adjacent to the atrium of the heart, such that agents
delivered into the ventricular wall will migrate to the atrium and
the atrium wall. This transport happens within minutes, so that the
release of the therapeutic molecules will occur in the walls of the
atrium. This has potential for treating atrial arrhythmias. (Thus
it can be appreciated that variation of the size of the
encapsulated therapeutic agent can be employed in remarkable new
therapies.)
[0031] The agents to be delivered may include small molecules,
macromolecules, and gene therapy preparations. These will be
briefly defined.
[0032] "Small molecules" may be any smaller therapeutic molecule,
known or unknown. Examples of known small molecules relative to
cardiac delivery include the antiarrhythmic agents that affect
cardiac excitation. Drugs that predominantly affect slow pathway
conduction include digitalis, calcium channel blockers, and
beta-blockers. Drugs that predominantly prolong refractoriness, or
time before a heart cell can be activated, produce conduction block
in either the fast pathway or in accessory AV connections including
the class IA antiarrhythmic agents (quinidine, procainimide, and
disopyrimide) or class IC drugs (flecainide and propefenone). The
class III antiarrhythmic agents (sotolol or amiodorone) prolong
refractoriness and delay or block conduction over fast or slow
pathways as well as in accessory AV connections. Temporary blockade
of slow pathway conduction usually can be achieved by intravenous
administration of adenosine or verapamil. [Scheinman, Melvin:
Supraventricular Tachycardia: Drug Therapy Versus Catheter
Ablation, Clinical Cardiology Vol. 17, Supp. II 11-II-15 (1994).]
Many other small molecule agents are possible, such as poisonous or
toxic agents designed to damage tissue that have substantial
benefits when used locally such as on a tumor. One example of such
a small molecule to treat tumors is doxarubicin.
[0033] A "macromolecule" is any large molecule and includes
proteins, nucleic acids, and carbohydrates. Examples of such
macromolecules include the growth factors, Vascular Endothelial
Growth Factor, basic Fibroblastic Growth Factor, and acidic
Fibroblastic Growth Factor, although others are possible. Examples
of macromolecular agents of interest for local delivery to tumors
include angiostatin, endostatin, and other antiangiogenic
agents.
[0034] A "gene therapy preparation" is broadly defined as including
genetic materials, endogenous cells previously modified to express
certain proteins, exogenous cells capable of expressing certain
proteins, or exogenous cells encapsulated in a semi-permeable micro
device. This terminology is stretched beyond its traditional usage
to include encapsulated cellular materials as many of the same
issues of interstitial delivery of macrostructures apply.
[0035] The term "genetic material" generally refers to DNA which
codes for a protein, but also encompasses RNA when used with an RNA
virus or other vector based upon RNA. Transformation is the process
by which cells have incorporated an exogenous gene by direct
infection, transfection, or other means of uptake. The term
"vector" is well understood and is synonymous with "cloning
vehicle". A vector is non-chromosomal double stranded DNA
comprising an intact replicon such that the vector is replicated
when placed within a unicellular organism, for example by a process
of transformation. Viral vectors include retroviruses,
adenoviruses, herpesvirus, papovirus, or otherwise modified
naturally occurring viruses. Vector also means a formulation of DNA
with a chemical or substance which allows uptake by cells. In
addition, materials could be delivered to inhibit the expression of
a gene. Approaches include: antisense agents such as synthetic
oligonucleotides which are complimentary to RNA or the use of
plasmids expressing the reverse compliment of a gene, catalytic
RNA's or ribozymes which can specifically degrade RNA sequences, by
preparing mutant transcripts lacking a domain for activation, or
over express recombinant proteins which antagonize the expression
or function of other activities. Advances in biochemistry and
molecular biology in recent years have led to the construction of
recombinant vectors in which, for example, retroviruses and
plasmids are made to contain exogenous RNA or DNA respectively. In
particular instances the recombinant vector can include
heterologous RNA or DNA by which is meant RNA or DNA which codes
for a polypeptide not produced by the organism susceptible to
transformation by the recombinant vector. The production of
recombinant RNA and DNA vectors is well understood and need not be
described in detail.
[0036] Many delivery systems could be used to deliver these agents
to a region of the myocardial interstitium. During surgical
procedures, a syringe may suffice, but it is more likely that a
transvascular delivery catheter such has been called out would be
used to deliver the appropriate therapeutic agents to the
appropriate sites. Essentially, a steerable catheter would be
advanced to a location within the heart chamber and placed adjacent
to the heart wall. The drug delivery catheter would be advanced so
that it penetrates the heart wall and the desired volume of
particulate delivery slurry or suspension (0.05 ml to 2.0 ml) would
be infused. The penetrating structure would be disengaged, and the
drug delivery catheter would be pulled back a short distance within
the delivery catheter. The steerable catheter would be reposition,
and the process may be repeated a number of times if so
desired.
[0037] The benefits of the different controlled systems may also be
combined. For example, to provide for local small molecule delivery
that is sustained over time, and does not require an indwelling
drug delivery system in the heart chamber, the SUV liposomes
containing the small molecules could be delivered within
biodegradable microdrug delivery systems such as larger more stable
liposomes or other fully encapsulated controlled release system,
such as a biodegradable impermeable polymer coatings. The time
course of release is governed then by the additive time delay of
the barriers that separate the therapeutic agent from the host, as
well as their combined transport pathways. Microsphere delivery
systems could also be used.
[0038] The ability to deposit therapeutic agents in to the
myocardium for uptake into the cardiac lymphatic system, combined
with the ability of some of the molecules discussed above to
migrate from the lymphatic ducts into parallel running arteries,
permits introduction of therapeutic agents for the coronary
arteries to be introduced through this pathway. The result is a
very low flow environment for the introduction of anti-stenotic
compounds and other arterial therapeutic agents, as compared to the
infusion of therapeutic agents into the high flow environment of
the coronary arteries themselves. The method illustrated in FIG. 5
is useful to deliver therapeutic agents to the coronary arteries,
such as the left coronary artery and its branches, including the
left anterior descending coronary artery, and the right coronary
artery and its branches. As illustrated in FIG. 5, catheter system
9 with centrally located drug delivery catheter 20 implanted at a
depth within the left ventricular apex 15 of the heart 10. Hollow
penetrating structure 30 has penetrated the heart muscle from the
endocardial side. The artery to be treated, in this case the
circumflex branch of the left coronary artery 500, courses over the
surface of the heart (chosen for illustration purposes only). A
corresponding epicardial lymphatic vessel 501 runs nearby, and many
sub-epicardial lymphatic vessel such as vessel 502 drain into the
epicardial lymphatic vessel. (It should be noted that the cardiac
lymphatic vessels are both numerous and largely uncharted, and may
be highly variable from person to person). The artery is occluded
by an arterial plaque, cholesterol or stenotic mass 505 which is
amendable to treatment with drug therapies. The artery may have
been previously treated with angioplasty, or a stent may have been
placed across the occlusion. In any case, several drugs are
available to either ameliorate the blockage or prevent restenosis
or re-occlusion after balloon angioplasty and/or stent placement.
The delivery catheter is navigated into the endocardial space of
the left ventricle 510, and secured in place with penetrating
structure 30. A small dose of therapeutic agent, indicated by the
molecules 35, is injected into the myocardium, and the penetrating
structure is withdrawn. (Withdrawal of the penetrating structure
may be delayed as necessary to prevent the therapeutic agent from
draining back into the ventricular space.) The molecules of the
therapeutic agent are taken up by the lymphatic system, entering
into vessels 501 and 502, and transported upwardly. The molecules
also migrate out of the lymphatic system and then migrate into the
nearby coronary artery, following multiple paths indicated by the
arrows in FIG. 5. The molecules penetrate the adventicia, or outer
layer, of the coronary artery, and thus enter the coronary artery.
Molecules enter the coronary artery along the entire length that
runs near the lymphatic vessels which initially take up the
molecules. Thus, therapeutic agent enters the coronary blood vessel
at the site of occlusion and proximally to the occlusion, after
having been injected into a more distal location (relative to the
coronary artery). The term entering the artery may include entering
the arterial wall without entering the lumen of the artery, or
passing through the arterial wall into the lumen of the artery.
While the method is illustrated in relation to the left circumflex
coronary artery, it may be used with all the coronary arteries.
Also, while endocardial access is preferred for the method as
applied to the coronary arteries located on the anterior surface of
the heart (left and right coronary arteries). Therapeutic agents
may be deposited into the myocardium through catheters delivered
into the coronary sinus, the coronary veins, and even the coronary
arteries, including the coronary artery subject to treatment by
angioplasty or stent placement. Additionally, while it is
preferable to accomplish the therapy percutaneously, the method may
be accomplished by injection into the heart, epicardially, during
open surgery, or during endoscopic or key-hole surgery through the
chest.
[0039] Various therapeutic agents can be delivered to the coronary
arteries using this approach. Anti-restenosis agents may include
agents which inhibit smooth muscle proliferation, endothelial cell
proliferation, and growth of other components of arterial plaque
and stenosis, antioxidant drugs, anti-inflammatory drugs, platelet
derived growth factor antagonists, and numerous other proposed
compounds. Anti-restenosis agents also include anti-neoplastic
agents such as taxol, statins (such as Lovastatin and Provastatin),
Pemirolast, Tranilast, Cilostrazol, INOS, ENOS, ECNOS, and gene
therapy formulations. All of these agents may be formulated as
time-release or controlled release formulations for delivering
these molecules by deposition in the myocardium in position for
uptake and eventual migration into a target site in the coronary
arteries. The therapeutic agents may be incorporated into
biodegradable microspheres with a diameter larger than 15 um (and
preferably greater that 50 um) in diameter so that a depot can be
placed distal to the region of the vessel where treatment is
desired for sustained delivery to the target vessel for extended
periods, such as several hours or several of weeks. The
microspheres would elute agents into the myocardium slowly over a
period of time in order to enable the sustained delivery through
the lymphatics of the heart. In many cases the molecules may be
linked to other molecules such as carbohydrates to prevent their
intravasation and convective losses to the blood. The microspheres,
which are sized to restrict their migration, degrade within the
myocardium near the deposition site and release agents which then
migrate through the lymphatics and migrate from the lymphatics to
the adventicia and cells within the vascular wall within the target
region of the coronary vessel. For other therapies, gene therapy
preparations are delivered to infect the cardiac myocytes in order
to transfect the RNA for production of the therapeutic proteins
locally which will then migrate through the lymphatic walls to
treat the target vessel peri-adventicially.
[0040] The microspheres used in this method are preferably sized to
inhibit migration and immediate uptake by the lymphatic vessels,
and are preferably 50 um in diameter and greater, but perhaps as
small as 30 um. Agents could be encapsulated in liposomal
structures with diameters ranging from 50 to 600 nm which are
transported by the lymphatics and designed to break up at
physiological pH such that agents are released which are able to
diffuse through the lymphatic and arterial walls.
[0041] Anti-angiogenic agents could also be used to limit the
angiogenic response which has been recently associated in the
literature with atherosclerotic plaques. The hypothesis that
anti-angiogenic agents may limit restenosis could be used during a
revascularization procedure in which angiogenic agents are
delivered along with anti-angiogenic agents at the time of stent
placement. By having the anti-angiogenic agents be the first
delivered they would transport through the lymphatics and to the
region of injury caused by balloon angioplasty or stent placement
and minimize the restenosis. Although the reservoir of microspheres
containing angiogenic agents may be delivered at the same
catheterization procedure used to accomplish angioplasty to stent
placement, and potentially at the same location, they would be
released after the anti-angiogenic and anti-neoplastic agents have
had their effect for limiting restenosis. Thus dosage forms for
anti-angiogenic agents and angiogenic agents could be placed in the
heart simultaneously. One way of doing this would be to have a
microsphere in which the core contains angiogenic agents and the
outer shell contains anti-angiogenic agents. Another method of
doing this is to supply anti-angiogenic agents in solution or in
small microspheres which are immediately taken up in the lymphatic
vessels, while supplying the angiogenic agents in larger
microspheres which will not be taken up. The method thus comprises
treating a coronary blood vessel with stent placement, balloon
angioplasty, or both, and delivering a dose of therapeutic agent to
the site of treatment, where the therapeutic agent is delivered to
the myocardium at a location distal to the site of treatment, and
the therapeutic agent includes anti-angiogenic agent to be released
in a time frame shortly after treatment and angiogenic agent to be
released in a time frame after release of the anti-angiogenic
agent. Alternately, the anti-angiogenic agent can be delivered to
the target site with the angioplasty balloon or stent, by coating
the balloon or stent with the anti-angiogenic agent, while the
angiogenic agent is deposited in the myocardium for delayed
transport to the target site.
[0042] Thus, the method allows the use of the lymphatic vessels and
endogenous lymphatic transport to carry agents from the
myocardially located depot of therapeutic agents to the target
coronary arteries such that agents are delivered through the target
vessel walls peri-adventicially. This provides a means of
delivering therapeutic agents peri-adventicially to the vessels of
the heart that is far superior to surgical placement of a
peri-adventicial controlled release devices, and delivery of agents
to the space between the pericardial space between the parietal and
visceral pericardium.
[0043] While the inventions have been described in relation to the
treatment of cardiac tissue, it should be appreciated that the
compounds and methods of treatment may be applied to various body
tissues. Thus, while the preferred embodiments of the devices and
methods have been described in reference to the environment in
which they were developed, they are merely illustrative of the
principles of the inventions. Other embodiments and configurations
may be devised without departing from the spirit of the inventions
and the scope of the appended claims.
* * * * *