U.S. patent application number 11/220794 was filed with the patent office on 2006-01-26 for method of drug delivery to interstitial regions of the myocardium.
This patent application is currently assigned to BioCardia, Inc.. Invention is credited to Peter A. Altman.
Application Number | 20060020158 11/220794 |
Document ID | / |
Family ID | 26873623 |
Filed Date | 2006-01-26 |
United States Patent
Application |
20060020158 |
Kind Code |
A1 |
Altman; Peter A. |
January 26, 2006 |
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.
Inventors: |
Altman; Peter A.; (San
Francisco, CA) |
Correspondence
Address: |
CROCKETT & CROCKETT
24012 CALLE DE LA PLATA
SUITE 400
LAGUNA HILLS
CA
92653
US
|
Assignee: |
BioCardia, Inc.
|
Family ID: |
26873623 |
Appl. No.: |
11/220794 |
Filed: |
September 6, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10234300 |
Sep 3, 2002 |
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11220794 |
Sep 6, 2005 |
|
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09177765 |
Oct 23, 1998 |
6443949 |
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10234300 |
Sep 3, 2002 |
|
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08816850 |
Mar 13, 1997 |
6086582 |
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09177765 |
Oct 23, 1998 |
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Current U.S.
Class: |
600/7 |
Current CPC
Class: |
A61B 2018/00392
20130101; A61B 2018/1425 20130101; A61B 2218/002 20130101; A61K
9/5084 20130101; A61B 2017/00247 20130101; A61K 9/50 20130101; Y10S
977/775 20130101; A61K 9/1676 20130101; A61B 2018/00577 20130101;
A61B 2018/1435 20130101; A61B 2018/00011 20130101; A61M 2025/0089
20130101; A61B 2018/00839 20130101; A61N 1/0575 20130101; A61B
2018/00351 20130101; Y10S 977/907 20130101; A61B 18/1492 20130101;
A61K 9/127 20130101 |
Class at
Publication: |
600/007 |
International
Class: |
A61M 36/00 20060101
A61M036/00 |
Claims
1. A method for interventional treatment of a patient having a
lymphatic system and heart with a myocardium comprising: providing
a catheter having a tissue penetrating element disposed on its
distal end and an inner lumen extending from its proximal end to
its distal end; providing a microdrug fluidic delivery system
comprising a plurality of microspheres, said microsperes having an
encapsulating layer and a therapeutic agent within the
encapsulating layer, wherein said encapsulating layer is degradable
when injected into the body tissue; said microspeheres sized and
dimensioned to prevent take up by the lymphatic system for a first
time period; said therapeutic agent comprising a genetic material;
injecting said microdrug interstitially to a depth within the
myocardium to a first treatment site using the catheter; treating
the first treatment site for the first time period; transporting
the microdrug delivery system through a lymphatic system to a
second treament site after the first time period; treating a second
treatment site within the patient with the microdrug delivery
system.
2. The method of claim 1 wherein the microspheres are less than 400
nm in size.
3. The method of claim 1 wherein the microspheres are between about
220 nm to about 250 nm in size.
4. The method of claim 1 wherein the first time period is between
about 5 minutes to about 60 minutes.
5. The method of claim 1 wherin the therapeutic agent is an
angiogenic protein.
6. The method of claim 1 wherein the therpeutic agent is an
antiarrythmic agent.
7. The method of claim 1 wherein the therpeutic agent is an
antirestenosis agent.
8. The method of claim 1 wherein the first treament site it the
ventrical wall and the second treatment site is the atrium
wall.
9. A system for interventional treatment of a patient having a
lymphatic system and a heart with a myocardium comprising: a
catheter having a tissue penetrating element disposed on its distal
end and an inner lumen extending from its proximal end to its
distal end, said tissue penetrating element adapted to penetrate
the endocardium of a chamber of a heart to a depth withing the
myocardium; and a microdrug fluidic delivery system disposed within
the catheter comprising a plurality of microspheres, said
microsperes having an encapsulating layer and a therapeutic agent
within the encapsulating layer, wherein said encapsulating layer is
degradable when injected into the body tissue; said therapeutic
agent comprising a genetic material; said microspeheres sized and
dimensioned to prevent take up by the lymphatic system for a first
time period.
10. The system of claim 9 wherein the microspheres are less than
400 nm in size.
11. The system of claim 9 wherein the microspheres are between
about 220 nm to about 250 nm in size.
12. The system of claim 9 wherein the first time period is between
about 5 minutes to about 60 minutes.
13. The system of claim 9 wherein the therapeutic agent is an
angiogenic protein.
14. The system of claim 9 wherein the therpeutic agent is an
antiarrythmic agent.
15. The system of claim 9 wherein the therpeutic agent is an
antirestenosis agent.
Description
[0001] This application is a continuation of U.S. app. Ser. No.
10/234,300 filed Sep. 3, 2002, now abandoned, which is a
continuation of U.S. app. 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. app. Ser. No. 08/816,850 filed Mar. 13, 1997.
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 applications Ser. No. 08/8816850 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.
DETAILED DESCRIPTION OF THE INVENTION
[0013] 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.
[0014] 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 10 um, preferably about 7.5 um.
Thus 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.
[0015] 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.
[0016] FIG. 2 shows a catheter system 9 with centrally located drug
delivery catheter 20 implanted at a depth within the left
ventricular apex 15. 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.
[0017] 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.
[0018] 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.
[0019] 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
enables 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 Resorbabale 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.
[0020] 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 nanometers, 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.
[0021] 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.
[0022] 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.
[0023] 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.
[0024] 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)].
[0025] 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 antiarrhythmic agents.
[0026] In another embodiment, liposomes of
dimyristoyl-phosphatidylcholine (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.
[0027] 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.
[0028] 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.
[0029] 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. The cardiac lymph
node is closely proximate the atrium of the heart, so that by
natural lymphatic action, the compound injected into the ventricle
wall transported into the atrial 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.)
[0030] The agents to be delivered may include small molecules,
macromolecules, and gene therapy preparations. These will be
briefly defined.
[0031] "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, Suppl. 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.
[0032] 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 anti-angiogenic
agents.
[0033] 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.
[0034] 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, herpes virus, 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.
[0035] 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.
[0036] 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.
[0037] 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.
* * * * *