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Medical Patent Abstract
A medical device is adapted for at least partial implantation into
a body and includes first and second sections along the length of
the device. A first therapeutic agent is associated with the first
section and a second therapeutic agent is associated with the second
section. The first therapeutic agent can be one or more antiproliferative,
such as paclitaxel, a paclitaxel derivative, or a paclitaxel pro-drug,
anti-coagulant, antithrombotic, thrombolytic, fibrinolytic, or combination
thereof. The second therapeutic agent can be one or more antimicrobials,
such as one or more antibiotics. Each of the first and second therapeutic
agents can either be posited on one or more surfaces of the respective
section, or impregnated within the section. The device can include
a separator to space the first and second sections. A method of
making a medical device and a method of establishing access to a
vessel within a body are also provided.
Medical Patent Claims
The invention claimed is:
1. A medical device for at least partial implantation, comprising:
a main body having a first end, a second end, and a lumen extending
therebetween, a first section proximal the first end of said main
body and having a first therapeutic agent, said first therapeutic
agent comprising one or more members selected from the group consisting
of antiproliferatives, anticoagulants, antithrombotics, thrombolytics,
and fibrinolytics; and a second section proximal the second end
of said main body and having a second therapeutic agent, said second
therapeutic agent comprising an antimicrobial; said main body having
a length such that when said device is at least partially implanted
said first end accesses a body vessel and at least a portion of
said second section is disposed within a subcutaneous space of a
patient.
2. The medical device of claim 1, wherein the main body comprises
a cannula.
3. The medical device of claim 1, wherein the first therapeutic
agent comprises an antiproliferative.
4. The medical device of claim 3, wherein the antiproliferative
comprises paclitaxel.
5. The medical device of claim 1, wherein the antimicrobial is
a member selected from the group consisting of antibiotics, antiseptics,
and disinfectants.
6. The medical device of claim 5, wherein the antimicrobial is
an antibiotic.
7. The medical device of claim 6, wherein the antibiotic is one
or more members selected from the group consisting of tetracyclines,
rifamycins, macrolides, penicillins, cephalosporins, other beta-lactam
antibiotics, aminoglycosides, chioramphenicol, sufonamides, glycopeptides,
quinolones, fusidic acid, trimethoprim, metronidazole, clindamycin,
mupirocin, polyenes, azoles and beta-lactam inhibitors.
8. The medical device of claim 6, wherein the antibiotic comprises
a combination of rifampin and minocycline.
9. The medical device of claim 1, wherein the main body has an
exterior surface, the first therapeutic agent is impregnated within
the first section, and the second therapeutic agent is posited on
the exterior surface of the second section.
10. The medical device of claim 1, further comprising a separator
spacing the first section from the second section.
11. The medical device of claim 10, wherein the separator comprises
a portion of the main body having a reduced diameter.
12. The medical device of claim 10, wherein the separator comprises
a band surrounding the main body.
13. The medical device of claim 10, wherein the separator comprises
a dye disposed in or on the main body.
14. A medical device for at least partial implantation comprising:
a cannula having first and second ends, interior and exterior surfaces,
and defining a lumen; a first axial section proximal the first end
having a first therapeutic agent; a second axial section proximal
the second end having a second therapeutic agent; and a separator
spacing the first axial section from the second axial section.
15. The medical device of claim 14, wherein the first therapeutic
agent is impregnated within the first section, and the second therapeutic
agent is posited on one of the interior and exterior surfaces of
the second section.
16. The medical device of claim 14, wherein the first therapeutic
agent is impregnated within the first section, and the second therapeutic
agent is posited on the interior surface and the exterior surface
of the second section.
17. A cannula for use in the extracorporeal treatment of a bodily
fluid of a patient, comprising: a main body having first and second
ends, interior and exterior surfaces, and defining a lumen; a first
section proximal the first end; a second section proximal the second
end; said main body sized such that during said extracorporeal treatment
said first end accesses a target body vessel carrying said bodily
fluid and at least a portion of said second section is positioned
within a subcutaneous layer in the body of the patient; an antiproliferative
impregnated within the first section; and an antimicrobial coated
on at least one of the interior and exterior surfaces of the second
section.
18. A method of establishing access to a vessel of a body, comprising:
providing a medical device comprising a cannula having a distal
end, a proximal end, an interior surface, an exterior surface, and
defining a lumen, the cannula further having a length extending
from the proximal end to the distal end, a first section generally
adjacent the distal end with a first therapeutic agent extending
along part of the length, and a second section generally adjacent
the proximal end with a second therapeutic agent extending along
part of the length, said first therapeutic agent comprising one
or more members selected from the group consisting of antiproliferatives,
anticoagulants, antithrombotics, thrombolytics, and fibrinolytics,
and said second therapeutic agent comprising an antimicrobial; implanting
the distal end into the body; and forming an interface between the
distal end and the vessel.
19. The medical device of claim 18, wherein the implanting the
distal end comprises positioning the first section below a subcutaneous
layer of the body.
20. The medical device of claim 19, wherein the implanting the
distal end further comprises positioning the second section comprising
the second therapeutic agent across a subcutaneous layer of the
body.
21. The medical device of claim 19, wherein the implanting the
distal end further comprises positioning the second section comprising
the second therapeutic agent within a subcutaneous layer of the
body.
22. A medical device for at least partial implantation, comprising:
a main body having a first end, a second end, and a length extending
from the first end to the second end; a first axial section along
the length having a first therapeutic agent comprising one or more
members selected from the group consisting of antiproliferatives,
anticoagulants, antithrombotics, thrombolytics, and fibrinolytics;
a second axial section along the length having a second therapeutic
agent, said second axial section distinct from said axial first
section, and a separator for spacing said second axial section from
said first axial section.
Medical Patent Description
FIELD OF THE INVENTION
The present invention relates to medical devices suitable for at
least partial implantation into a body. More specifically, the present
invention relates to medical devices with therapeutic agents. In
preferred embodiments, the invention relates to cannulae, such as
catheters, with therapeutic agents. The present invention also relates
to a method of making a medical device, and a method of establishing
access to a vessel within a body.
BACKGROUND OF THE INVENTION
Many types of medical devices are used in a variety of medical
procedures that include at least partial implantation into a body.
When implanted, medical devices can be in intimate contact with
a variety of cells, tissues, and body systems. For example, cannulae,
such as catheters, are used in a variety of medical procedures to
introduce articles, such as stents, into body vessels. Cannulae
are also used to establish a communicative passageway by which a
body vessel can be accessed from the exterior of the body. These
cannulae are indispensable in procedures that require repeated access
to the vessel, such as hemodialysis procedures that include repeated
extracorporeal treatment of blood.
While implanted medical devices provide several advantages, they
also present an opportunity for infection. Indwelling medical devices,
such as indwelling cannulae used for access ports, are particularly
susceptible to infection due to their long term presence in the
body. In essence, the cannula provides a path from the external
environment into the body along which microorganisms can colonize,
and eventually produce an infection.
The establishment of an infection can require intervention, such
as treatment with a therapeutic agent or even mechanical manipulation
of the medical device to remove the microorganisms. Even worse,
the infection may require removal and replacement of the medical
device. Ultimately, the presence of an infection may outweigh the
benefits of the implantation.
Infections associated with indwelling medical devices are commonly
caused by bacteria or fungi. The most common organisms associated
with infections associated with indwelling devices are Staphylococcus
epidermidis and Staphylococci aureus. Candida albicans, a fungi,
is another significant cause of infections associated with these
devices. No matter the microorganism, establishment of infection
requires colonization along the surface of the medical device, which
depends on a variety of factors, including the formation of glycocalyx
and a fibrin sheath.
Glycocalyx is a polysaccharide produced by adherent microorganisms.
The glycocalyx allows the microorganisms to adhere to the surface,
and contributes to the formation of a biofilm around the medical
device. In addition to the glycocalyx formation, a fibrin sheath
is often produced by the host as a natural result of thrombogenesis.
The fibrin sheath essentially covers the surfaces of the indwelling
device, and provides another agent onto which microorganisms can
adhere.
Considering the importance of implantable medical devices, considerable
attention has been directed toward preventing colonization and/or
infection on these articles. The art contains many examples of medical
devices that incorporate a variety of approaches that attempt to
control colonization and/or infection. For example, U.S. Pat. No.
5,688,516 to Raad et al. discloses medical devices coated with mixtures
of antibiotics and other therapeutic agents. Also, U.S. Pat. No.
5,624,704 to Darouiche et al. discloses medical devices impregnated
with antimicrobials.
As indicated above, the microorganisms commonly associated with
colonization and/or infection from implanted medical devices typically
originate from outside the body, such as on the skin, and progress
into the body along the path of the medical device. Once inside
the body, the microorganisms produce the glycocalyx that facilitates
adherence, and the body produces a fibrin sheath around the device
that facilitates colonization and establishment of an infection.
Thus, two distinct processes are occurring on two distinct portions
of the medical device. Outside the body, microorganisms gain access
to the device and begin to proceed into the body. Inside the body,
microorganisms arriving from the external portion of the device
produce a glycocalyx to facilitate adherence, and the body produces
the fibrin sheath which further facilitates adherence. The prior
art fails to recognize the localization of these processes in the
available devices designed to prevent or inhibit colonization and/or
infection.
BRIEF SUMMARY OF THE INVENTION
The present invention provides a medical device for at least partial
implantation in a body, such as a human body, comprising a main
body having a first end, a second end, and a length extending from
the first end to the second end. The medical device has first and
second sections extending along the length of the medical device.
The first section is near the first or distal end of the device
and the second section is near the second or proximal end of the
device. The first section has a first therapeutic agent, and the
second section has a second therapeutic agent. Once implanted, the
first section is fully implanted in the body, and the second section
is only partially implanted in the body. The second section is at
least partially positioned within a subcutaneous layer of the body,
and may have a section that extends outside of the body.
In a preferred embodiment, the main body comprises a cannula having
an interior surface and an exterior surface. The cannula defines
a lumen. Further, the medical device can include a separator that
separates the first section from the second section.
The first and second therapeutic agents can be associated with
the first and second sections, respectively, in a variety of manners.
For example, the agents can be impregnated into the main body of
the medical device, or can be posited onto the medical device. In
a preferred embodiment, one or more of the therapeutic agents is
coated onto one or more surfaces of the medical device. In a particularly
preferred embodiment, the first therapeutic agent is impregnated
into the first section of the main body and the second therapeutic
agent is coated onto at least one surface of the second section
of the main body.
The first and second therapeutic agents can be any suitable type
of agent. Examples of suitable types of agents include, without
limitation, antiproliferatives, anticoagulants, antithrombotics,
thrombolytics and/or fibrinolytics, and antimicrobials.
In a preferred embodiment, a first therapeutic agent comprises
an antiproliferative. Particularly preferable, the first therapeutic
agent comprises paclitaxel, a paclitaxel derivative, or a paclitaxel
pro-drug. Also preferable, the second therapeutic agent comprises
one or more antimicrobials. The antimicrobial can be an antibiotic,
an antiseptic, and/or a disinfectant. In a particularly preferred
embodiment, the second therapeutic agent comprises a blend of two
or more antibiotics. A desirable blend includes rifampin and minocycline.
The present invention also provides a method of making a medical
device for at least partial implantation. The method comprises providing
a main body having a first end, a second end, a length extending
from the first end to the second end, a first section along the
length, and a second section along the length; exposing the first
section to a solvent so that the first sections swells; soaking
the first section in a solution containing a first therapeutic agent;
drying the first section; and coating at least a portion of the
second section with a second therapeutic agent.
The present invention also provides a method of establishing access
to a vessel of the body. The method comprises providing a medical
device comprising a cannula having a distal end, a proximal end,
an interior surface, an exterior surface, and defining a lumen.
The cannula has a length extending from the proximal end to the
distal end, a first section extending along the length with a first
therapeutic agent, and a second section extending along the length
with a second therapeutic agent. The method also includes implanting
the distal end of the cannula into the body so that the proximal
end remains either substantially outside the body or in a subcutaneous
layer, and forming an interface between the distal end and the vessel.
The interface can be a direct insertion of the distal end into the
vessel or an attachment of the distal end to the vessel, such as
an anastomosis.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic illustration of a medical device according
to an embodiment of the present invention.
FIGS. 1A, 1B, 1C and 1D illustrate various cross-sectional shapes
and lumen configurations for devices according to the present invention.
FIG. 2 is a cross-sectional view taken along line I-I in FIG. 1.
FIG. 3 is a cross-sectional view illustrating an embodiment of
the present invention.
FIG. 4 is a cross-sectional view illustrating an embodiment of
the invention.
FIG. 5 is a cross-sectional view illustrating an embodiment of
the invention.
FIG. 6 is a cross-sectional view taken along line II-II in FIG.
1.
FIG. 7 is a cross-sectional view illustrating an embodiment of
the invention.
FIG. 8 is a cross-sectional view illustrating an embodiment of
the invention.
FIG. 9 is a cross-sectional view illustrating an embodiment of
the invention.
FIG. 10 is a cross-sectional view of a medical device according
to an embodiment of the present invention.
FIG. 11 is a schematic illustration of a medical device according
to the present invention transcutaneously implanted into a body.
FIG. 12 is a schematic illustration of a medical device according
to the present invention implanted subcutaneously into a body.
FIG. 13 is a schematic illustration of a medical device according
to an embodiment of the present invention.
FIG. 14 is a schematic illustration of a medical device according
to an embodiment of the present invention.
FIG. 15 is a schematic illustration of a medical device according
to an embodiment of the invention.
FIG. 16 is a schematic illustration of a medical device according
to an embodiment of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Medical devices according to the present invention can be any of
a variety of medical device types and configurations. The medical
device need only be at least partially implantable within a body.
Examples of types of medical devices that can be made according
to the present invention include leads, fasteners, and cannula,
such as catheters.
FIG. 1 illustrates a medical device according to one embodiment
of the present invention. In this embodiment, the medical device
10 comprises a cannula having a main body 12 and defining a lumen
14. The cannula 10 has exterior 16 and interior 18 surfaces, a first
or distal end 20, and a second or proximal end 22.
The length of the cannula extends from the first end 20 to the
second end 22. A first section 24 of the cannula 10 extends along
a portion of the length, and a second section 26 extends along another
axially distinct portion of the length. Both the first 24 and second
26 sections extend circumferentially around the cannula 10 and axially
along a respective portion of the length. As illustrated in the
figures the first section 24 is preferably near the first end 20
and the second section 26 is preferably near the second end 22.
A first therapeutic agent 28 is associated with the cannula 10
at the first section 24, and a second therapeutic agent 30 is associated
with the cannula 10 at the second section 26. Both the first 28
and second 30 therapeutic agents can be associated with the cannula
10 in a variety of manners. Preferably, as illustrated in FIG. 2,
the first therapeutic agent 28 comprises an impregnated agent 36
disposed in the material of the first section 24, such as by bulk
distribution, solvent swelling, or other suitable techniques. Also,
as illustrated in FIG. 6, the second therapeutic agent 30 preferably
comprises a coating layer 38 posited on the external surface 16
of the second section 26 of the cannula 10.
Many alternative arrangements for the first 28 and second 30 therapeutic
agents are within the scope of the present invention. For example,
FIGS. 3-5 illustrate alternative arrangements for the first therapeutic
agent 28 in relation to the first section 24 of the cannula 10,
and FIGS. 7-9 illustrate alternative arrangements for the second
therapeutic agent 30 in relation to the second section 26 of the
cannula 10. As illustrated in FIG. 3, the first therapeutic agent
28 can comprise a coating layer 32 posited on the external surface
16 of the cannula 10. As illustrated in FIG. 4, the first therapeutic
agent 28 can comprise a coating layer 34 posited on the internal
surface 18 of the cannula 10. Also, as illustrated in FIG. 5, the
first therapeutic agent 28 can comprise a coating layer 32 posited
on the external surface 16 and a coating layer 34 posited on the
internal surface 18. The second therapeutic agent 30 can likewise
be associated with the second section 26 in similar ways. Thus,
as illustrated in FIG. 7, the second therapeutic agent 30 can comprise
an impregnated agent 42 disposed in the material of the second section
26 of the cannula 10. As illustrated in FIG. 8, the second therapeutic
agent 30 can comprise a coating layer 40 posited on the interior
surface 18 of the cannula 10. Furthermore, as illustrated in FIG.
9, the second therapeutic agent 30 can comprise a coating layer
38 posited on the external surface 16 and a coating layer 40 posited
on the internal surface 18.
In addition to the various arrangements for each of the first 28
and second 30 therapeutic agents, any suitable combination of arrangements,
i.e., one for each agent 28, 30, can be utilized.
The main body 12 can be formed of any suitable material, and need
only be biocompatible and appropriate for the desired type of medical
procedure in which the device will be utilized. Preferred materials
for the main body 12 include thermoplastic and thermoset materials.
In particularly preferred embodiments, silicone, a thermoset material,
is utilized as the material of the main body 12.
The cross-sectional shape of the medical device can be any shape
suitable for the types of procedures in which the device will be
utilized. A circular cross-sectional shape is particularly preferable
in embodiments in which the device comprises a cannula, such as
that illustrated in FIG. 1. A circular cross-sectional shape maximizes
space within the lumen 14 of the cannula 10 while also providing
a suitable shape for interfacing with a body vessel. Furthermore,
the medical device can have any suitable configuration of lumen(s),
and the chosen configuration will depend on the application for
which the device is used. Single and multi-lumen configurations
can be utilized. FIGS. 1A, 1B, 1C and 1D illustrate various suitable
cross-sectional shapes and lumen configurations for use in medical
devices 10 according to the present invention.
The first 28 and second 30 therapeutic agents can be any suitable
agents, and need only provide the desired effects. Thus, the first
therapeutic agent 28, which is associated with the first section
24 near the first or distal end 20, need only have a negative effect
on the formation of fibrin sheaths. Also, the second therapeutic
agent 30, which is associated with the second section 26 near the
second or proximal end 22, need only have an antimicrobial effect.
Examples of suitable therapeutic agents for use as the first therapeutic
agent 28 include anticoagulants, antithrombotics, thrombolytics
and/or fibrinolytics, and antiproliferatives. The type of agent
selected as the first therapeutic agent 28 will depend on several
factors, including the stage of development of the fibrin sheath
at which interference with further development is desired. For example,
antithrombotics, such as heparin, hirudin, hirulog and PPACK, directly
or indirectly bind thrombin to prevent polymerization of fibrin
from fibrinogen, a necessary step in the coagulation process. Anticoagulants,
such as the glycoprotein IIbIIIa inhibitors, attach to platelet
receptors and block activation sites, thereby preventing their degranulation
and release of serotonin. Other anticoagulants block ADP induced
platelet aggregation, such as Ticlopidine and Clopidigrel. Still
other anticoagulants such as warfarin and coumadin inhibit the action
of vitamin K and the production of coagulation factors. Some anticoagulants,
such as aspirin, inhibit platelet aggregation by inhibiting Thromboxane
A2.
Thrombolytics and/or fibrinolytics lyse or break down an organized
thrombus by activating plasmin, which breaks down fibrin. Examples
of suitable thrombolytics and/or fibronolytics include Tissue Plasminogen
Activator (tPA), Urokinase, and Streptokinase.
Certain matrix metalloproteinases, such as collagenase, can break
down the connective tissue of a formed fibrin sheath.
Examples of suitable antithrombotics include heparin, hirudin,
hirulog, and PPACK. Examples of suitable anticoagulants include
glycoprotein IIbIIIa inhibitors, ticlopidine, clopidigrel, warfarin,
coumadin, and aspirin. Examples of suitable thrombolytics and/or
fibrinolytics include tPA, recombinant tPA, urokinase, streptokinase,
Tenecteplase, Alteplase, Activase, Lysatec, Antistreplase, APSAC,
Eminase, Retaplase, Retavase, Hannahpep (Indian King Cobra venom),
and Ancrod (Malayan pit viper venom). Examples of suitable matrix
metalloproteinases include collagenase. Other suitable agents for
the first therapeutic agent include olyeyloxyethyl phosphorylcholine.
Also, combinations of two or more agents can be used as the first
therapeutic agent 28.
In a preferred embodiment, the first therapeutic agent comprises
an antiproliferative. In a particularly preferred embodiment, the
first therapeutic agent 28 comprises natural or synthetic paclitaxel,
a derivative of paclitaxel, and/or a paclitaxel pro-drug.
Paclitaxel is a natural diterpere product isolated from the Pacific
yew tree (Taxus brevifolia). Paclitaxel is a member of the taxane
family of terpenes, and was first isolated by Wani et al. (J. Am.
Chem. Soc., 93:2325, 1971). Paclitaxel has proven efficacious in
the treatment of a variety of neoplasms, and has been approved for
use in the clinical treatment of breast and ovarian cancer in the
United States.
Paclitaxel functions as an antiproliferative agent; i.e., as an
inhibitor of cell replication. It is believed that paclitaxel inhibits
replication by inducing an abnormal polymerization of tubulin. This
results in stabilization of microtubules and disruption of the cell
division process, mitosis. Further, paclitaxel inhibits smooth muscle
cell proliferation both in vitro and in vivo.
Paclitaxel can be used in medical devices of the present invention
in its basic form, as a derivative (see for example U.S. Pat. No.
6,476,242 to Kingston et al. for 2-AROYL4-ACYL PACLITAXEL ANALOGS;
see also U.S. Pat. No. 6,441,025 to Li et al. for WATER SOLUBLE
PACLITAXEL DERIVATIVES), and/or as a PRO-DRUG (i.e., a drug that
yields paclitaxel upon action by an appropriate agent, such as a
naturally occurring enzyme; see U.S. Pat. No. 6,153,756 to Digenis
et al. for SOLUBLE PRODRUGS OF PACLITAXEL). Also, a preparation
of paclitaxel can be utilized. Any suitable preparation can be used,
and should facilitate placement of the paclitaxel into or on the
medical device of the present invention, and should allow its release
from the medical device. Examples of suitable paclitaxel preparations
include those described in U.S. Pat. No. 5,681,846 to Triysel for
EXTRUDED STABILITY FORMULATIONS FOR PACLITAXEL.
Considerable attention has been directed toward the effects of
paclitaxel on a variety of cell types and physiological processes.
Paclitaxel may arrest the migration of fibroblasts and smooth muscle
cells, thereby reducing or preventing connective tissue formation
that often follows fibrin sheath formation. It has also been found
to decrease restenosis of human coronary arteries following stent
use.
The second therapeutic agent 30 can be any suitable antimicrobial
agent. As used herein, the term `antimicrobial` means any agent
that has killing or growth inhibiting effects on one or more microorganisms.
Suitable classes of antimicrobials include antibiotics, disinfectants,
and antiseptics.
In a preferred embodiment, the second therapeutic agent 30 comprises
one or more antibiotics having activity against the common microorganisms
associated with colonization and/or infection with indwelling cannulae.
Examples of suitable classes of antibiotics include tetracyclines,
rifamycins, macrolides, penicillins, cephalosporins, other beta-lactam
antibiotics, aminoglycosides, chloramphenicol, sulfonamides, glycopeptides,
quinolones, fusidic acid, trimethoprim, metronidazole, clindamycin,
mupirocin, polyenes, azoles and beta-lactam inhibitors.
Examples of specific antibiotics that can be used as the second
therapeutic agent 30 include minocycline, rifampin, erythromycin,
nafcillin, cefazolin, imipenem, aztreonam, gentamicin, sulfamethoxazole,
vancomycin, ciprofloxacin, trimethoprim, metronidazole, clindamycin,
teicoplanin, mupirocin, azithromycin, clarithromycin, ofloxacin,
lomefloxacin, norfloxacin, nalidixic acid, sparfloxacin, pefloxacin,
amifloxacin, enoxacin, fleroxacin, temafloxacin, tosufloxacin, clinafloxacin,
sulbactam, clavulanic acid, amphotericin B, fluconazole, itraconazole,
ketoconazole, and nystatin.
The second therapeutic agent 30 can comprise a combination of two
or more antimicrobials. In these embodiments, the two or more antimicrobials
can be located in or on discrete locations within the second section
26, or the two or more antimicrobials can be blended together and
uniformly distributed within or on the second section 26.
In a preferred embodiment, rifampin and minocycline are used as
the second therapeutic agent 30. The rifampin and minocycline preferably
are blended together and evenly distributed either in or on the
second section 26. In a particularly preferred embodiment, discussed
below, blended rifampin and minocycline are coated onto the surfaces
of second section 26.
FIG. 10 is a cross-sectional illustration of a medical device according
to a preferred embodiment of the present invention. In this embodiment,
the medical device comprises a cannula 10 having a main body 12
and defining a lumen 14. The cannula 10 has an exterior 16 and an
interior surface 18. The cannula 10 has a first or distal end 20
and a second or proximal end 22, and a length extending between
the two ends 20, 22. A first section 24 extends along a portion
of the length, and a second section 26 extends along a different
portion of the length. Each of the first 24 and second 26 sections
preferably extends circumferentially around the cannula 10. A first
therapeutic agent 28 comprises paclitaxel impregnated into the main
body 12 of the first section 24. A second therapeutic agent 30 comprises
a blend of rifampin and minocycline coated on the exterior 16 and
interior 18 surfaces of the second section 26.
In one application medical devices according to the present invention
can be used to establish access to a vessel within a body. As discussed
above, medical devices according to preferred embodiments of the
invention comprise cannulae that define a lumen. The distal end
of the cannula can be interfaced with a vessel to establish a communicative
passageway between the vessel and the lumen of the cannula. In this
configuration, the medical device is particularly well suited for
allowing convenient access to the vessel. These devices can be used
advantageously in procedures that require repetitive access to the
vessel, such as repetitive introduction of an agent into the blood
stream or the repetitive extracorporeal treatment of blood, such
as in hemodialysis procedures.
The medical devices according to the present invention can be completely
implanted within the body, or only partially implanted within the
body. In each scenario, however, at least a portion of the second
section of the device remains within the subcutaneous space. FIG.
11 illustrates a schematic of a medical device 10 according to the
present invention that is transcutaneously implanted into a body.
In this embodiment, the medical device 10 traverses the skin through
the epidermis 52, derma 54 and subcutaneous 56 layers to a vessel
58. An interface 60 is formed between the vessel 58 and the device
10. The interface defines a communicative passageway between the
vessel 58 and the lumen of the device 10. The interface 60 can be
a direct insertion of the distal end 20 of the device 10 into the
vessel 58, or can comprise an attachment of the distal end 20 to
the vessel 58, such as an anastomosis.
Because the device 10 is implanted transcutaneously, the device
10 in this embodiment includes a portion 61 that remains external
to the body. This portion 61 provides the desired access to the
lumen which is in communication with the vessel 58. Thus, in this
embodiment, the vessel 58 can be accessed without further disruption
to the skin 50.
The second section 26, which includes the second therapeutic agent
30, preferably is positioned across the subcutaneous layer 56. As
illustrated in the FIGURES the second section 26 can extend beyond
the subcutaneous layer and toward and through the derma 54 and epidermis
52. The first section 24, which includes the first therapeutic agent
28, preferably is positioned below the subcutaneous layer 56, and
is preferably approximately adjacent the interface 60.
FIG. 12 illustrates a cannula 10 according to the present invention
that is completely implanted within a body. In this embodiment,
the cannula 10 includes an access port 62. The access port 62 defines
a chamber that can receive a communicative member, such as a needle,
for either withdrawing fluid from or directing fluid into the vessel
58. Typically, the access port 62 includes a section of resealable
material 64 that prevents escape of fluid from the cannula 10 when
a communicative member is not received by the access port 62. The
resealable material can comprise silicon or any other suitable material.
In this embodiment, the second section 26, and therefore the second
therapeutic agent 30, is completely contained within the subcutaneous
layer 56. The first section 24, and therefore the first therapeutic
agent 28, is positioned below the subcutaneous layer 56 and is preferably
adjacent the interface 60 between the cannula 10 and the vessel
58.
FIG. 13 illustrates another embodiment of the present invention.
A medical device according to this embodiment is identical to the
embodiment illustrated in FIG. 1, except as detailed below. Thus,
the medical device of this embodiment comprises a cannula 10 that
has a main body 12 and defines a lumen 14. The cannula 10 has an
exterior surface 16, an interior surface 18, a first or distal end
20, and a second or proximal end 22. The cannula 10 has a length
that extends from the first end 20 to the second end 22. A first
section 24 extends along a portion of the length, and a second section
26 extends along a different portion of the length. Each of the
first 24 and second 26 sections preferably extend circumferentially
around the main body 12 of the cannula 10. A first therapeutic agent
28 is associated with the first section 24, and a second therapeutic
agent 30 is associated with the second section 26.
The cannula 10 of this embodiment includes a separator 70 that
spaces the first section 24 from the second section 26. The separator
70, in addition to physically separating the first 24 and second
26 sections, provides a visual indicator of the transition between
these sections, which can aid fabrication and implantation procedures.
The separator 70 can be any suitable separator that provides a separation
between the first 24 and second 26 sections. The separator 70 need
only not interfere with implantation in the body. Thus, as illustrated
in FIG. 13, the separator 70 preferably comprises a portion of the
main body 12 that has a reduced diameter as compared to the diameters
of the first 24 and second 26 sections.
Examples of other suitable separators include markers, such as
bands and dyes disposed within or on the main body 12 and other
visual indicators. Also, the separator 70 can comprise an altered
region of the main body 12, such as the reduced diameter section
described above.
FIG. 14 illustrates a medical device according to another embodiment
of the present invention. In this embodiment, the medical device
comprises a cannula 100 and includes first 102 and second 104 tubes.
The second tube 104 is positioned within a lumen 106 of the first
tube 102. This configuration forms an annular space 108 between
the interior surface of the first tube 102 and the exterior surface
of the second tube 104. The first tube 102 can be formed of a porous
material. In this embodiment, the first 110 and second 112 therapeutic
agents are associated with the first 114 and second 116 sections
along the length of the cannula 100. The first therapeutic agent
110 can be positioned within the annular space 108 between the tubes
102, 104. The second therapeutic agent 112 can be positioned within
or on the first tube 102. The first therapeutic agent 110 escapes
from the annular space 108 and through the main body of the first
tube 102 due to its porous nature. A seal 113 can be positioned
between a first end of the first tube 102 and a first end of the
second tube 104 to prevent escape of the first therapeutic agent
110 directly from the annular space 108.
FIG. 15 illustrates a medical device according to another embodiment
of the present invention. The medical device according to this embodiment
comprises a cannula 200 and includes first 202 and second 204 tubes.
The second tube 204 is positioned within a lumen 206 of the first
tube 202. The second tube 204 also defines a lumen 208. An annular
space 210 is formed between the interior surface of the first tube
202 and the exterior surface of the second tube 204. An access line
214 provides communication with the annular space 210. A seal 212
is positioned proximal to the access line 214 and prevents fluid
within the annular space 210 from moving up the cannula away from
the body. In this embodiment, the first cannula 202 is preferably
porous and the first therapeutic agent is preferably contained within
the annular space 210 and escapes from the annular space 210 through
the first tube 202 due to its porosity. The access line 214 allows
for replacement of the first therapeutic agent that has escaped
from the annular space 210 through the first tube 202. A seal (not
illustrated) can close the annular space 210 at the distal end of
the device 200 to prevent escape of the first therapeutic agent
through the distal end. The second therapeutic agent can be placed
in the annular space 210 proximal to the seal 212, thereby being
separated from the first therapeutic agent. Similar to the first
therapeutic agent, the second therapeutic agent will escape from
the annular space 210 through the first tube 202 due to its porosity.
Alternatively, the second therapeutic agent can be coated onto one
or more surfaces of the first 202 and/or second 204 tubes. The lumen
208 of the second tube 204 is placed in communication with a body
vessel. This double tube structure allows for the establishment
of access to a body vessel and for the replenishment of the first
therapeutic agent, which facilitates the use of the medical device
as an indwelling cannula.
FIG. 16 illustrates a medical device according to another embodiment
of the invention. In this embodiment, the medical device comprises
a catheter 300 that includes first 302 and second 304 lumens. A
first section 306 of the catheter 300 is coated with paclitaxel,
and a second section 308 is coated with a blend of rifampin and
minocycline. In this embodiment, the separator 310 comprises a visual
distinction between the first 306 and second 308 sections. Also,
the separator 310 defines a slight increase in the diameter of the
medical device. The separator 310 includes a taper 312 from the
smaller diameter of the first section 306 to the larger diameter
of the second section 308. The extracorporeal portion 312 of the
catheter includes various connectors 314, 316 that are in individual
communication with the first 302 and second 304 lumen, respectively.
The invention also includes medical devices having a single therapeutic
agent. In these embodiments, the medical devices are preferably
devices suitable for partial implantation in a body. Preferably,
the devices have a therapeutic agent in or on a section of the device
that will be implanted in the body. For example, a hemodialysis
catheter can be coated with an antiproliferative agent, such as
paclitaxel, along the portion of the device that will be implanted
into the body. Alternatively, the therapeutic agent can be distributed
within the material of the device in the section that will be implanted
into the body. In these embodiments, no second therapeutic agent
is utilized.
The first and second therapeutic agents can be associated with
the respective portions of the medical device in any suitable manner.
For example, if an agent(s) is bulk distributed in the material
of the device, a swelling method can be utilized. Alternatively,
the agent(s) can be added to a melt of bulk material. Once extruded,
the device will include the agent(s) in the material. Also, if a
coating layer is desired, the agent(s) can be dip-coated, spray-coated,
or coated onto the device using any other suitable coating technique.
Further, if different portions of the device have agents associated
in different manners (e.g., bulk distribution versus coating layer),
a combination of suitable techniques can be utilized. For example,
Paclitaxel can be associated with a first portion by a swelling
process, and rifampin/minocycline can be associated with a second
portion of the device by a coating process. A separator between
the first and second sections of devices according to these embodiments,
as described above, can advantageously be used to isolate different
techniques during fabrication.
EXAMPLES
Example 1
Loading of Silicone Tubing Devices with Paclitaxel
Silicon tubing segments (approximately 0.8 mm i.d., 1.7 mm O.D.,
50 mm length, 120 mg weight) cut from silicone catheter samples
(5FR single lumen) were swelled by soaking for approximately 20
hours in either freon or hexane. The samples were then loaded with
paclitaxel by soaking for approximately 7 hours in one of the following
solutions containing 4 mg/ml paclitaxel: 100% ethanol, 50/50% freon/ethanol,
50/50% hexane/ethanol. After loading, the tubing segments were allowed
to dry for approximately 24 hours. The amount of paclitaxel loaded
into each segment was determined by extracting the tubing in ethanol
for approximately 12 hours, and assaying the extract by HPLC.
The results are summarized in Table I below:
TABLE-US-00001 Paclitaxel HPLC HPLC Loading Measured Measured Solution
Paclitaxel Paclitaxel Original Swelling Paclitaxel Concen- Loading
Drying Mass Mass per Sample Swelling Time Loading tration Time Time
Total Length Number Solvent (hr) Solvent (mg/ml) (hr) (hr) (ug)
(ug/cm) 1 Freon ~20 100% Ethanol 4 ~7 ~24 44 8.8 2 Freon -20 100%
Ethanol 4 ~7 ~24 48 9.5 3 Freon ~20 50% 4 ~7 ~24 94 18.7 Freon/Ethanol
4 Freon ~20 50% 4 ~7 ~24 76 15.3 Freon/ Ethanol 7 Hexane ~20 100%
4 ~7 ~24 55 11.0 Ethanol 8 Hexane ~20 100% 4 ~7 ~24 34 6.8 Ethanol
9 Hexane ~20 50% Hexane/ 4 ~7 ~24 66 13.2 Ethanol 12 Hexane ~20
50% Hexane/ 4 ~7 ~24 71 14.1 Ethanol AVG 61 12 STDS 19 4
On average the tubing segments yielded approximately 61.+-.19 .mu.g
paclitaxel. For comparison, 3.0 mm.times.15 mm long VFlexPlus coronary
stents, which appeared effective in inhibiting restonosis in clinical
trial studies, were loaded with approximately 60 .mu.g paclitaxel.
All references cited herein, including all U.S. patents and other
cited references, are hereby incorporated into this disclosure in
their entirety. |