U.S. patent application number 10/062788 was filed with the patent office on 2002-07-11 for drug delivery graft.
This patent application is currently assigned to IMPRA, Inc., a subsidiary of C.R. Bard, Inc.. Invention is credited to Calcote, Robert W..
Application Number | 20020091440 10/062788 |
Document ID | / |
Family ID | 23940445 |
Filed Date | 2002-07-11 |
United States Patent
Application |
20020091440 |
Kind Code |
A1 |
Calcote, Robert W. |
July 11, 2002 |
Drug delivery graft
Abstract
An improved drug delivery graft comprises a drug delivery device
coupled to an outer wall of a porous graft. An agent is conducted
by the drug delivery device from a source to the outer wall of the
graft where it is released to diffuse into the lumen of the graft
through porous interstices of the outer wall.
Inventors: |
Calcote, Robert W.;
(Phoenix, AZ) |
Correspondence
Address: |
MORRISON & FOERSTER LLP
755 PAGE MILL RD
PALO ALTO
CA
94304-1018
US
|
Assignee: |
IMPRA, Inc., a subsidiary of C.R.
Bard, Inc.
Tempe
AZ
85280
|
Family ID: |
23940445 |
Appl. No.: |
10/062788 |
Filed: |
January 31, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10062788 |
Jan 31, 2002 |
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09488625 |
Jan 20, 2000 |
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6355063 |
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Current U.S.
Class: |
623/1.42 ;
604/891.1 |
Current CPC
Class: |
A61L 31/048 20130101;
A61L 27/16 20130101; A61L 27/54 20130101; C08L 27/18 20130101; A61L
31/16 20130101; A61L 2300/00 20130101; C08L 27/18 20130101; A61F
2250/0068 20130101; A61L 2300/416 20130101; A61F 2/06 20130101;
A61L 27/16 20130101; A61L 31/048 20130101 |
Class at
Publication: |
623/1.42 ;
604/891.1 |
International
Class: |
A61F 002/06 |
Claims
We claim:
1. A drug delivery graft, comprising: a graft comprising a lumen
defined by an outer wall, wherein the outer wall is characterized
by a microstructure having nodes interconnected by fibrils; and
drug delivery means coupled to the outer wall for delivering a drug
thereto, wherein the drug diffuses into the lumen through the outer
wall.
2. The drug delivery graft according to claim 1, further comprising
a drug source coupled to the drug delivery means.
3. The drug delivery graft according to claim 1, wherein the drug
delivery means comprises a hollow tube.
4. The drug delivery graft according to claim 3, wherein the hollow
tube is arranged substantially parallel to a longitudinal axis of
the graft.
5. The drug delivery graft according to claim 3, wherein the hollow
tube comprises a cutaway portion in communication with the outer
wall.
6. The drug delivery graft according to claim 3, wherein the hollow
tube comprises perforations in communication with the outer
wall.
7. The drug delivery graft according to claim 3, wherein the hollow
tube comprises a porous wall in communication with the outer
wall.
8. The drug delivery graft according to claim 1, wherein the graft
comprises expanded polytetrafluoroethylene.
9. The drug delivery graft according to claim 1, wherein the drug
is selected from the group consisting of a growth factor, a growth
factor inhibitor, growth factor receptor antagonist, a
transcriptional repressor, a translational repressor, an antisense
nucleic acid, a replication inhibitor, an anti-microtubule agent,
an inhibitory antibody, an antibody directed against a growth
factor, a bifunctional molecules comprising a growth factor and a
cytotoxin, and a bifunctional molecule comprising an antibody and a
cytotoxin.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to medical devices, and more
particularly, to a graft for delivering an agent into a natural
tissue conduit, e.g., a blood vessel.
BACKGROUND OF THE INVENTION
[0002] Providing frequent, direct delivery of bioactive agents to a
natural tissue conduit has become a necessity for many medical
treatments such as those requiring frequent intravenous
administration of drugs. To meet this need, many types of devices
including stents and vascular grafts have been used to deliver
agents into natural tissue conduits.
[0003] Local delivery is advantageous in that the effective local
concentration of a delivered drug can be much higher than can
normally be achieved by systemic administration. Delivery of agents
to vascular tissue to prevent restenosis is especially useful. U.S.
Pat. No. 5,399,352 to Hanson discloses a device for delivering an
effective concentration of a therapeutic agent locally at a target
site within the body without producing unwanted systemic side
effects. However, the device described in this reference differs
considerably from existing vascular grafts. It would be especially
advantageous to deliver drugs with a device more similar to
currently used vascular grafts.
[0004] Stents and other existing devices are frequently coated with
or impregnated with therapeutic agents for the treatment of
diseases. A concern related to the use of stents and existing
devices for drug delivery is that drug delivery may not be
sustainable. Over time the concentration of drug on the stent or
other similar delivery devices will diminish, through drug
inactivation, degradation, or dilution. Thus, the therapeutic agent
may need to be refreshed or even changed after implant of the
device. Moreover, these existing devices are not capable of
delivering drugs to an internal lumen along the entire length of
the graft.
[0005] Accordingly, it would be desirable to provide a drug
delivery graft capable of delivering a drug or any other agent to
the internal lumen along the entire length of the graft, or
restrict delivery to a finite area on the graft such that the agent
may be renewed or altered after implant of the graft. Furthermore,
a desirable drug delivery graft could be implanted in the same
fashion as regular vascular grafts.
BRIEF SUMMARY OF THE INVENTION
[0006] In accordance with the teachings of the present invention,
an improved drug delivery graft is provided. The invention can be
used, for example, as a vascular graft providing sustained release
of a selected bioactive or diagnostic agent directly into a blood
or other fluid flow pathway. The graft is capable of delivering the
bioactive or diagnostic agent to the internal lumen of a vascular
graft along the entire length, or of restricting delivery to a
finite area of the vascular graft. The graft is preferably made of
expanded polytetrafluoroethylene (ePTFE), but could certainly be
made of any other porous type graft. Various ePTFE grafts that are
reinforced by external beading are well known in the art. However,
unlike previous designs that utilize a solid beading for
reinforcing purposes, one embodiment of the present invention
utilizes a hollow tubing as a drug conduit. The hollow tubing
behaves much like the existing low profile solid beading in that it
has a small diameter and can be readily implanted into the body,
offering advantages as both a spiral support and drug conduit.
[0007] In a preferred embodiment of the present invention, a simple
tubular ePTFE graft is used, which is well known to be extremely
porous. A hollow tubing of non-porous PTFE, fluoroethylene polymer
(FEP) or other implantable polymer is wrapped around the graft and
laminated or adhered in place. The hollow tubing may be wrapped
helically; alternatively other arrangements (e.g., end to end
loops) can be used. Before the wrapping occurs, one surface of the
hollow tubing is cut away (for example, laser cut), punctured
repeatedly or otherwise rendered porous. When an agent such as a
drug is injected into the hollow tubing, e.g., from an infusion
pump or a subcutaneous access port, the drug flows through the
hollow tubing and leaks through the cut or porous region and
diffuses into the outer surface of the ePTFE graft. The drug
diffuses into the graft where it mixes into the blood flowing
therethrough and influences biological processes along the
circulatory system. Depending on the drug used and the precise
configuration of the device the dispensed material could have
either systemic effect or have limited local effect. One
particularly attractive use of the device is to dispense drugs to
limit the restenosis that frequently occurs due to tissue
proliferation at the site of anastimosis of an ePTFE graft to a
blood vessel.
[0008] The invention takes advantage of the well-known porosity of
an ePTFE graft. Impregnation of ePTFE grafts with therapeutic
agents has been previously disclosed. However, the present
invention allows the therapeutic agents to be renewed or altered
following implant of the graft, something that is not possible with
simple drug-impregnated graft materials.
[0009] A more complete understanding of the ePTFE drug delivery
graft will be afforded to those skilled in the art, as well as a
realization of additional advantages and objects thereof, by a
consideration of the following detailed description of the
preferred embodiment. Reference will be made to the appended sheets
of drawings that will first be described briefly.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] FIG. 1 is a side view of a drug delivery graft according to
an embodiment of the present invention;
[0011] FIG. 2 is a side view of a hollow tubing according to an
embodiment of the present invention;
[0012] FIG. 3 is a cross-sectional view of the drug delivery graft
showing a cut portion of the hollow tubing according to an
embodiment of the present invention.
[0013] FIG. 4 is a cross-sectional view of the drug delivery graft
showing a porous hollow tubing according to an embodiment of the
present invention.
[0014] FIG. 5 is a side view of an alternate embodiment of the drug
delivery graft of the present invention.
[0015] FIG. 6 is a side view of another alternate embodiment of the
drug delivery graft of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0016] The following detailed description illustrates the invention
by way of example, not by way of limitation, the principles of the
invention. This description will clearly enable one skilled in the
art to make and use the invention, and describes several
embodiments, adaptations, variations, alternatives and uses of the
invention, including what we presently believe is the best mode of
carrying out the invention.
[0017] The present invention satisfies the need for an improved
drug delivery graft capable of delivering bioactive agents,
including drugs, to an internal lumen of a graft, either along its
entire length or in a localized area, through the use of hollow
tubing on the outside of the graft. In the detailed description
that follows, it should be appreciated that like reference numerals
are used to identify like elements illustrated in one or more of
the figures.
[0018] Referring first to FIG. 1, a side view of a drug delivery
graft 10 in accordance with an embodiment of the present invention
is illustrated. The drug delivery graft 10 comprises a graft 2, a
hollow tubing 4, and a drug source 6. The hollow tubing 4 is
wrapped (spiraled) in a helical fashion around an abluminal surface
of the graft 2. The drug source 6 is connected to one end 14 of the
hollow tubing 4.
[0019] The graft 2 may be a standard clinical vascular graft of any
shape or size comprised preferably of expanded
polytetrafluoroethylene (ePTFE), which material consists of a
porous network of nodes and fibrils created during the expansion
process. This porous network provides a somewhat permeable wall for
the graft 2. The graft 2 can be constructed in a variety of sizes
to allow a surgeon to select the appropriate size to accommodate a
particular vascular application. Likewise, the porosity (internodal
distance) of the graft can be varied to affect the rate of drug or
agent release.
[0020] The drug delivery graft 10 injects a drug or other agent
into the bore of the hollow tubing 4 from the drug source 6. The
drug source 6 can be any of a variety of commercially and
technologically available systems that provide constant controlled
rate delivery of an agent, such as a biologically activated mini
pump that is either subcutaneously or extracorporeally located, an
external mechanical pump, or an access port. For example, an open
end 14 of the hollow tubing 4 may be connected via a micro-catheter
to a subcutaneous or other drug source.
[0021] The agent delivered to the natural tissue conduit can be any
substance, including any drug, and the device can be used for local
or systemic delivery of such substances to prevent or treat a
variety of disease syndromes or to promote or enhance desired
activity within the body. A bioactive or diagnostic agent may
include, for example, therapeutic or prophylactic agents, such as a
drug, protein, enzyme, antibody or other agent, or cells that
produce a drug, protein, enzyme, antibody, or other agent. The
diagnostic material can include, for example, a radiolabeled
antibody or antigen.
[0022] The natural tissue conduit into which the agent is
ultimately delivered may include any structure of a body that
functions to transport substances and includes, but is not limited
to, e.g., blood vessels of the cardiovascular system (arteries and
veins), the lymphatic system, the intestinal tract (esophagus,
stomach, the small and large intestines, and colon), the portal
system of the liver, the gall bladder and bile duct, the urinary
system (bladder, and urethra), the respiratory system (trachea,
bronchi and bronchioles), and ducts and ductules connecting
endocrine organs to other areas of the body. The device of the
present invention can be used in any mammal or in any animal in
which natural tissue conduits are found. Suitable dosage
requirements and treatment regimens for any agent delivered can be
determined and will vary depending upon the tissue targeted for
therapy and upon the particular agent utilized.
[0023] Referring now to FIG. 2, a side view of the hollow tubing 4
used in an embodiment of the present invention is illustrated. The
hollow tubing 4 may be manufactured from a non-expanded or
partially expanded small diameter PTFE tube or any other
implantable polymer (e.g. FEP). The hollow tubing 4 may be
manufactured in very small diameters (less than 1 mm) and long
lengths (more than 10 feet) to accommodate all sizes of grafts.
Whereas the prior art beading used solely for support purposes is a
solid filament, the hollow tubing 4 has a bore to provide fluid
delivery to the graft 2. Preferably, the hollow tubing 4 has an
uncut portion 16 and a partially cut portion 12 (or a porous and
less or non-porous region arrange circumferentially) that allows
communication between the lumen of the hollow tubing 4 and the
outside surface of the graft 2. Alternatively, communication
between the lumen of the hollow tubing 4 and the outside surface of
the graft 2 may be achieved by using a porous hollow tubing or a
hollow tubing with mechanical or laser perforations. While the
hollow tubing 4, is shown generally cylindrical in shape, it should
be appreciated that alternative designs are possible including a
hollow tubing that is tapered along its length as well as one that
has a stepped configuration or has other, non-circular
cross-sections. Similarly the graft may be tapered or stepped or of
a special shape, such as cuffed, as is known in the art.
[0024] In a preferred embodiment, to manufacture the hollow tubing
4, a specified length of a tube made of PTFE, FEP or other any
other implantable polymer may be loaded on a mandrel to secure the
tube in a rigid fashion. The loaded tube may be placed in a cutting
device where a defined portion of the tube is cut in the
longitudinal direction. A semi-circular "half-tube" C-shaped
section 12 may be created in the middle of the tube to create the
hollow tubing 4. The cutting device may comprise a LASER cutting
device. Alternatively, the tube may be punctured repeatedly or
otherwise rendered porous to allow release of the agent into the
ePTFE of the graft. One end 18 of the hollow tubing 4 may be sealed
mechanically, for example by a crimp, or by a heating process to
terminate the lumen. The terminated end 18 may also be sealed with
a silicon or other self-sealing material that can advantageously
serve as a primer port for infusing an agent through, for example,
a syringe.
[0025] Referring now to FIG. 3, a cross-sectional view of the drug
delivery graft showing a cut portion of hollow tubing according to
an embodiment of the present invention is illustrated. Hollow
tubing 4 is wound spirally around the graft 2. During the spiraling
process, a cutaway portion 12 of the hollow tubing 4 is laminated
and secured against the outer surface of the graft 2, creating a
drug outflow surface that communicates with the outer lumen of the
graft 2. Alternatively, FIG. 4 shows a cross-sectional view of the
drug delivery graft showing a porous hollow tubing 24 according to
an alternative embodiment of the present invention. The porous
hollow tubing 24 comprises perforations or pores 22 through which
an agent or drug is dispensed onto and into the graft 2. The agent
or drug is evenly distributed and diffuses into the graft 2 through
the interstices of an agent infusion area 8. The rate at which the
drug or other agent penetrates the porous wall of the graft 2 is
determined by several factors, including the size and number of the
pores and the size of the drug molecule.
[0026] The graft 2 is capable of delivering drugs or any other
agents to the internal lumen along the entire length of the graft
2, or of restricting delivery to a finite area on the graft 2. In
addition, it should be appreciated that the spacing of the hollow
tubing 4 along the graft 2 can be varied to concentrate dosages in
certain areas of need. Moreover, the spiraling of the hollow tubing
4 around the graft 2, as shown in FIG. 1, could be combined with a
traditional support beading spiraled around the graft 2 for
additional support.
[0027] Turning now to FIG. 5, an alternate embodiment of the
present invention is shown. Drug delivery graft 30 includes graft
32 and hollow tubing 34. In this embodiment, the hollow tubing 34
is arranged longitudinally along the graft 32, rather than wrapped
around spirally as in FIG. 1. The hollow tubing 34 is arranged in a
snake-like fashion, longitudinally along the outside of the graft
32, and is connected to the drug source 6 at one end. The
longitudinally arranged strips of hollow tubing 34 loop back at the
ends of the graft so that a single continuous piece of hollow
tubing is employed. In a second alternate embodiment illustrated in
FIG. 6, hollow tubing 44 is arranged longitudinally along a graft
42 in a slightly different configuration to make up a drug delivery
graft 40. In this embodiment, the longitudinally arranged hollow
tubing 44 is connected to manifolds 46 and 48 at each end. The
manifold 46, located at a proximal end of the graft 42, is
circumferentially arranged around the graft 42 and is also
connected to the drug source 6. The manifold 48, located at a
distal end of the graft 42 is circumferentially arranged around the
graft 42 in a closed loop. The drug provided from the drug source 6
flows into the manifold 46 where it is distributed to the
longitudinally placed hollow tubing 44, flowing through the hollow
tubing 44 and along the manifold 48, being distributed to the graft
42 in one of the above-mentioned methods shown in FIGS. 2-4. It
should be appreciated that in both embodiments shown in FIGS. 5 and
6, the hollow tubing can be spaced equidistant or varied depending
on the required application.
[0028] The spiraled or longitudinally-placed hollow tubing is
sintered to the graft to adhere the hollow tubing to the graft in
the same manner as existing standard grafts, adhering the cut
(C-shaped) portion 12 and uncut hollow tubing portion 16 as shown
in FIG. 3, or the porous hollow tubing 24 as shown in FIG. 4, along
the length of the graft 2. Alternatively, any of a number of known
adhesive agents can be used to attach the hollow tubing. Further,
the hollow tubing may be produced from a plastic material such as
polypropylene, which can be adhered to the graft through a partial
melting process. Thus, the design may use the existing low profile
hollow tubing on existing grafts, for example IMPRAFlex.RTM.
grafts, manufactured by IMPRA (Tempe, Ariz.), a Division of C. R.
Bard, Inc., and can be implanted in the same fashion as regularly
used existing vascular grafts.
[0029] The devices of the present invention can function as
improved vascular grafts such that the agent or drug to be
delivered prevents or treats complications associated with
conventional vascular graft placement, including but not limited to
platelet deposition, coagulation, thrombosis, neointimal
hyperplasia and fibrosis. One particularly attractive use of the
drug delivery graft would be to dispense drugs or any other agent
to limit the stenosis that frequently occurs at the site of
anastimosis of an ePTFE graft to a blood vessel. Examples of agents
that prevent restenosis of a blood vessel include, but are not
limited to, a growth factor, a growth factor inhibitor, growth
factor receptor antagonist, transcriptional repressor,
translational repressor, antisense DNA, antisense RNA, replication
inhibitor, anti-microtubule agents, inhibitory antibodies,
antibodies directed against growth factors or their receptors,
bifunctional molecules comprising a growth factor and a cytotoxin,
and bifunctional molecules comprising an antibody and a
cytotoxin.
[0030] The present invention has been described above in terms of a
presently preferred embodiment so that an understanding of the
present invention can be conveyed. However, there are many
alternative arrangements for an expanded PTFE drug delivery graft
not specifically described herein but with which the present
invention is applicable. The scope of the present invention should
therefore not be limited by the embodiments illustrated, but rather
it should be understood that the present invention has wide
applicability with respect to drug delivery grafts generally. All
modifications, variations, or equivalent elements and
implementations that are within the scope of the appended claims
should therefore be considered within the scope of the
invention.
* * * * *