Canadian Patents Database / Patent 2085470 Summary

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(12) Patent Application: (11) CA 2085470
(51) International Patent Classification (IPC):
  • A61M 5/00 (2006.01)
  • A61M 25/00 (2006.01)
(72) Inventors :
  • GRAOR, ROBERT A. (United States of America)
(73) Owners :
(71) Applicants :
(74) Agent: SMART & BIGGAR
(74) Associate agent: SMART & BIGGAR
(45) Issued:
(86) PCT Filing Date: 1991-06-18
(87) Open to Public Inspection: 1991-12-27
(30) Availability of licence: N/A
(30) Language of filing: English

(30) Application Priority Data:
Application No. Country/Territory Date
545,311 United States of America 1990-06-26

English Abstract

2085470 9200113 PCTABS00010
A vascular perfusion catheter (10) includes a catheter body (12)
having a macroporous matrix (40) forming at least a portion of
its distal end (16). A solution carrying a desired therapeutic
agent may be introduced through the catheter (10) and released
through the macroporous matrix (40) under controlled conditions. By
forming a matrix as a tubular element (20), the therapeutic agent
may be released uniformly in all radial directions over a
preselected length within a blood vessel.

Note: Claims are shown in the official language in which they were submitted.

WO 92/00113 PCT/US91/04336


1. A vascular perfusion catheter comprising
an elongate flexible catheter body having a proximal end,
a distal end, and at least one lumen extending axially
therethrough, wherein at least a portion of the catheter
body is formed from a macroporous matrix material which
permits a controlled flow of macromolecules from the

2. A vascular perfusion catheter comprising:
an inner flexible tubular member having a
proximal end, a distal end, and a central lumen extending
between the proximal and distal ends; and
an outer flexible tubular member disposed
coaxially about the inner flexible tubular member and
sealed thereto near the distal end to define an annular
lumen having a closed distal end, wherein at least a
portion of the outer flexible tubular member near the
distal end is formed from a macroporous matrix material
which will allow the controlled diffusion of
macromolecules from the annular lumen.

3. A vascular catheter as in claim 2, wherein
the macroporous matrix is disposed at or near the distal
end of the catheter body.

4. A vascular catheter as in claim 3, wherein
the macroporous matrix extends over a length in the range
from about 2 cm to 50 cm.

5. A catheter as in claim 2, wherein the
macroporous matrix has a molecular weight cutoff above
about 10,000 daltons.

6. A catheter as in claim 2, wherein the
macroporous matrix comprises a woven fabric.

WO 92/00113 PCT/US91/04336


7. A catheter as in claim 2, wherein the
macroporous matrix comprises; a non-woven fabric.

8. A catheter as in claim 2, wherein the
macroporous matrix comprises an organic polymer membrane.

9. A catheter as in claim 2, further
comprising means for partitioning the annular lumen into
at least two isolated regions and means for separately
delivering fluid to each region, wherein the means for
partitioning comprises an annular barrier extending
between the inner flexible tubular member and the outer
flexible tubular member and the means for separately
delivering fluids comprises at least two isolated lumens
extending from the proximal end of the inner tubular
member to the region.

10. A catheter as in claim 2, further
comprising means for providing a bypass flow through a
distal length of the catheter.

11. A method for intravascular administration
of a macromolecule, said method comprising:
introducing a catheter to a blood vessel; and
administering the macromolecule through a
macroporous matrix disposed on the catheter.

12. A method as in claim 11, wherein the
macromolecule is a polypeptide.

13. A method as in claim 11, wherein the
macromolecule is present in a solution which passes
through the macroporous matrix under pressure.

14. A method as in claim 13, wherein the
pressure is in the range from about 0.1 psi to 500 psi.

WO 92/00113 PCT/US91/04336

15. A method as in claim 13, wherein the flow
rate of solution is in the range from about 1 cc/hour to
100 cc/min.

16. A method as in claim 11, wherein the
macromolecule is a thrombolytic polypeptide.

17. A catheter as in claim 11, wherein the
macroporous matrix has a molecular weight cutoff above
about 10,000 daltons.

18. A catheter as in claim 11, wherein the
macroporous matrix comprises a woven fabric.

19. A catheter as in claim 11, wherein the
macroporous matrix comprises a non-woven fabric.

20. A catheter as in claim 11, wherein the
macroporous matrix comprises a fabric having of fibers
composed of a material selected from the group consisting
of polyethylene, polyethyleneterephthalate,
polypropylene, polyester, nylon, polytetrafluoroethylene,
polycarbonate, polystyrene, cellulose, and

21. A catheter as in claim 18, wherein the
macroporous matrix comprises a woven polyethylene
terephthalate fabric.

22. A catheter as in claim 17, wherein the
macroporous matrix comprises an organic polymer membrane.

Note: Descriptions are shown in the official language in which they were submitted.

WO '~/()01~ PCr/US'31/0~336
~";,~ ~j

l. Field of the_Invention
The present invention relates generally to
apparatus and methods ~or intravascular drug delivery and
more particularly to a catheter and method ~or the
:~: controlled infusion of therapeutic agents into an
:: extended region within a blood vessel over a prolonged
time period.
Catheter infusion vf drugs and other active
substances may be useful for treating a wide variety o~
disorders. Of particular interest to the present
invention, catheters may be used for the localized
: 15 admLnistration of thrombolytic agents to dissolv~ clots
within the vascular system. Typically, the catheter is
perrutaneously introduced to the vascular system at the
distal end located adjacent to or within the region of
clot or thrombus. The thro~bolytic agent is then
deliv~red through the catheter and released thxough one
`~ or more discrete perfusion ports ~ormed neax the distal
~,- end of the catheter. AlternatiYely , two or more ~:
~ catheters may be utilized si~ultaneously in an attempt to
-~ release the thrombolytic agent throughout the entire
clotted region.
Although generally effective, such catheter
~ designs suffer from certain disadvantages. In
:;l particular, the use of discrete perfusion poxts results
~ in an uneven distribution of the thrombolytic a~ent
.. 30 ~hroughout the region heing treated, and thrombus
adjacent to ~ach port will receive a much higher
e~fective concentration of the thrombolytic agent than
. received by the thrombus located even a short distance
"! away. Suc:h an uneven application of the thrombolytic
`, 3 5 agent increases the hance that the clot w.ill be
fragm~nted as it is dissolved, Qxposing the patient to
th~ rel2ase of emboli. Moreover, uneven distribution

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WO9~/00l13 rCr/US9l/0433

requires that the overall delivery rate of the
thrombolytic agent be increased so that th~ entirP region
of the thrombus may be disso:Lved. The ~eed to incr~ase
the delivery rate is wastefu:L ~nd results in an increased
: 5 release of the thrombolytic agent throughout the
remainder of the vascular system which can have
undesirable side effects. The uneven rel~ase of the
throm~olytic agent further s:Lows the overall dissolution
rate of the thrombus which results in a lengtheniny of
the total time required for ~3ach treatment. As the
.: treatment time can frequently be many hours, any increase
is highly undesirable. Finally, the use oP discrete
:: perfusion ports makes it more difficult to control the
release rate which may be as low as several ml/minO Any
deviation from thQ desired r~lease rate can in turn cause
: the release of excess thro~bolytic agent which is
wasteful or the r~lPase of less than the desired
thrombolytic agent which increases the necessary
: treatment time.
~' 20 For these reasons, it would be desirable to
pro~ide i~proYed apparatus, catheters, and me~hods for
: the localized intravascular delivery of therapeutic
- agents, such as clot dissolving agents. The catheters
should be suitable for percutaneous introduction to a
desired location within the vasculax system, preferably
; utilizing conventional guide wire introduction
techniques. The catheter should further be able to
provide highly uniform an~ controllable delivery rates
.~; over an extended axial length thereof so that the
therapeutic agent may be released within the vascular
fj system under optimum conditions. It would be further
desirable if the catheters were suitable ~or vascular
placement over extended periods of hours.
2~ De~ i~ Ds-eh~-~8oh9~9~h3l
U.S. Patent No. 4,765,339, descr.ibes a catheter
~' having a tubular dialysis me~brane formed th~reon~ The
,i, catheter is intended primarily for ~lood analysis, but it
.,,, -
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W~/nO113 PC'r/USi)1/0433f~
~, 3
is isuggested that it would also be u~e~ul for introducing
medicaments. It would not, however, be useful for
introducing macromolecules as the membrane is macroporous
and selected to blocX protei.ns and other larger
molecules. U.S. Patent No. 4,671,287, describes a
catheter having an oxyg~n p~rm~able bag intended for
gastrointestinal oxygenatiom. U.S. Patent No. 4,274,4l7,
~ describes a blood gas analy~is probe having a permeable
- tip. U.S. Patent No. 4,318,402, describes a liquid
infusion catheter having a per~orated outer tube and an
unper~orated i~ner tube. U.S~ Patent No. 4,717,379,
describes a catheter probe having a plurality o~ radial
capillary openings intended for the release of
: lubricants, washing agents, etc. U.S. Patent No.
4,068,664, descrihes a surgical suction wand having a
perforated tip. U.S. Patent No. 3,528,427, describ~s a
drainage cannula having a per~orated tip and an inner
', tube. U.S. Patent No. 3,593,713, describes an infusion
catheter with a perforated (foraminous) rigid shaft.
United States Catheter, IncO has developed a dilatation
balloon catheter where the balloon has a plurality o~
, laser-drilled holes which allow release of an inflating
:~ 25 The present invention comprises an invention
and method for the intravascular introduction o~
therapeutic agents, particularly high molecular weight
macromolecular therapeutic ag2nt5 such as thrombolytic
: protein~ and other polypeptides. The apparatus comprises
a catheter having an elongate catheter body with proximal
and distal ends. At least one lumen extends axially ~rom
the proximal end of the catheter body to a macroporous
trix which is located on the catheter body, typically
being at or near the distal end o~ the cath~ker body.
~j 35 The macroporous matrix has permeability characteristics
.1 which permit the controlled in~usion ~under a pressure~i~ gradient) of macromol~cules ~rom the lumen to a region


0 1)2/~)Ol 1:~ P~/USl)l/Oq33f)

within a blood vessel which c;urrounds the matrix. In the
specific embodiment, the macroporous matrix has a tubular
; geometry and forms a portion of the exterior of the
catheter body, extending over a desired axial len~th. In
this way, highly uniform and controlled flow of the
therapeutic agent can be achiLeved over extended lengt~s
- of the catheter body in a manner which is unattainable
: with the per~orate structures heretofore employed.
In the method of the present invention, the
catheter is percutaneously introduced and transluminally
positioned so that the macroporous matrix is located
within or adjacent to a region within a blood vessel
~ which requires therapy, usually ~ re~ion of thrombus. A
- desired therapeutic agent may then be introduced through
the lumen, such as a solution containing a thrombolytic
polypeptide. Therapeutic agents can be introduced at a
concentration and for a time sufficient to achieve the
~ desired therapeutic effect. The controlled and uniform
: delivery rate of tAe therapeutic agent can be carefully
selected to optimize the treatment conditions.
, ~_
Fig. 1 is a perspective view of a controlled
~, perfusion catheter constructed in accordance with the
`' principles of the present invention.
Fig. 2 is a detailed elevaticnal view of the
distal end of the catheter of Fig. 1 shown in eross-
.; .
.~ section.
Fig. 3 is a cross-sectional view taken along
line 3-3 of Fig. 2.
.`~ 30 Fig. 4 is a croc~s-sectional view taken along
: 4-4 of Fig. 2.
.~ Fig. 5 is a cross-sectional view t~ken along
~'. line 5-5 of Fig. 2.
. Fig. 6 illustrates a first alternate ~mbodiment
of the catheter of the present invention.
~, Fig. 7 illustrates a second alternate
embodiment of the catheter of the pres~nt invention.
, .



: wn ~2/~ PCr~US91/n~33b

Fig. 8 illustrates the method of the present
:~ invention using the cathet2r of Fig. 1 to introducQ a
:~ thrombolytic polypeptide to a region of thrombus within a
patient's vascular system.
i The present invention is use~ul ~or
- intravasGular delivery of a wide vari~ty of therapeutic
agents including both low molecul~r w~ight druys, such as
antiproliferative drugs, e. g., methotrexate and high
molecular weight macromolecules. The invention is
particularly useful ~or the delivery of high molecular
weight macromolecular therapeutic agen~s such as
proteins, polypeptides, polysaccharides,
.~ mucopolysaccharides, and other biomolecules having a
desired therapeutic activity. Specific ~x~mpl~s 9f
.~ . therapeutic biomolecule include thrombolytic
; polypeptides, blood thinning agents such as heparin (a
`;~ mucopolysaccharide), vasodialators, ~ntibodies,
-~ immunotoxins, and the like. T~e present invention is :.
particularly useful when site-specific delivery o~ a
th~rapautic agent is requir~d, such as treatment of a
' solid tumor with an immunotoxin or antiproli~rative drug
,;~ proximate the tumor site, treatment o~ a stenotic region
~ within the vasc~lar system with a thrombolytic
' 25 polypeptide, and the like. The following discussion will
~3 focus on the treatment of thrombus and plaque within the
;i vascular system using thrombolytic polypeptides, such as
., tissue plasminogen activator ~rTPA), streptokinase ,
urokinase, and the like. The present invention, howe~ver,
:: 30 is not limited to such treatment and instead encompasses
the delivery of okher macromolecules and smaller druys
'~ which may be advantageously released ir.~to the vascular
.: system t~e catheter and me~hod of the present
invention .
~ 35 : The catheter of the present inven~ion comprises
` ~ an elongate, ~lexibl~ catheter body having proximal and
,~ distal encls. The length and diameter of the catheter

! :
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w~ /onl13 PCr/OS'~ 1336

;;;J~ {) 6

body w.ill vary dependiny on the intended application,
typically having a lQ.ngth in the range from about 60 to
150 cm and a diameter in the range from about 3 to 11 F
(one French (F) is equal to 0.33 mml. When the catheter
i~ intended to reach the coronary blood vessels, the~
catheter body will typically have a length i~ the range
from about 120 to 150 cm and a diameter in the range from
about 3 to 8 F. When intended to reach the peripheral
blood vessels, the catheter body will usually have a
- 10 length from about 60 to 150 cm and a diameter from about
3 to 11 F.
The catheter body may include one or more
tubular elements with multiple tubes usually being
arranged coaxially. The tube(s) will typically be formed
by extrusion of an oryanic pol~mer, typically a
thermoplastic such as nylon, polyurethane,
polyethyleneter~phthalate (PET), poly~inylchloride (PVC),
polyethylene, or the like. The tubes s~ formed may be
:~ reinforced or unrein~orced, with reinforcement being
optionally provided ~y metal wires, metal braided cables,
or the like. Processes and techniques ~or forming
intravascular catheter bodies are well known in the art
and well described in the patent, scientific, and medical
The tube(s) will define one or more lumens
~, extending axially within the catheter body from the
proximal end. At least one lumen will be provided for
delivering the therapeutic agent from the proximal end of
the catheter to near the distal end, as described in more
. 30 detail hereina~ter. Additional lumens may be provided
for a variety of purposes, such as to allow introduction
~ and placement of the catheter over a guide wire, and the
.~ like. Alternati~ely, the catheter may employ a fixed
guide wire at its distal end to allow for positioning of
the catheter within the vascular system.
In a particular embodiment, a lumen will be
.' provided in the distal tip of the catheter to allow a
~' .


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W092/00113 Pcr/us() l/0433()

bypass blood flow through the catheter. Such a bypass
blsod ~low is particularly useful when the catheter is
inserted into relatively tight regions of stenosis where
: blood f 1GW would be otherwise blocked and when the
`~ 5 catheter is to be left for extended periods of time. In
`~ . a second particular embodLment, one or more additional
-. lumens are provided to deliver dif~erent therapeutic or
other agents to dif~erent locations on the catheter. For
example, while a thrombolytic agent is being delivered to
the distal end of the catheter, a separate lumen might
: simultaneously deliver an anti-clotting agent along the
r maining length o the c3theter to inhibit clotting
which might otherwise be induced by the catheter.
The catheter of the present invention will
include or be attachable to a proximal housing which
provides for access to the internal lumen(s) within the
.~ catheter body. The proximal housing will include one or
more conYentional fittings, e.g., luer connectors, which
provide ~or attachment of tubes and in~roduetion of guide
wires, as described in more detail h~reinafter.
;1 The therapeutic agent deli~ered by the catheter
will be released under a preselected pressure gradient
,-, through a macroporous matrix disposed along an axial
.. length of the catheter body, usually although not
necessarily disposed near the distal end of the catheter.
; The macroporous matrix will be in Pluid connection with
the lumen which carries the therapeutic agent so that the
matrix provides a rate-controlling barrier for releasing
~: the therapeutic agent from the catheter. Conveniently,
30. the macroporous matrix will form a portion of the outer
suxface of the catheter ~ody with th~ lumen disposed
along the entire interior length o~ the matrix~ In this
way, the therapeutic agent can perfuse outward through
the macroporous matrix to the exterior environment
surrounding the catheter in a highly uniform and
controlled manner, where the rate of perfusion is
controlled both by the characteristics of the matrix and


: , . , : ~ . . , : : . ~,

WO 92/110113 PCr/VS(~I/0433fi
'~r.5;,~q~ 8

by th~ level of internal pressurization as described in
more detail hereinafter. It: would be possible, of
course, to provide additlonzll structure on the catheter
to control or direct the flow of therapeutic ayent in
s~me manner. In all cases, however, the macroporous
matrix will act as a rate controlling element in the
delivery system.
In an exemplary eD~odiment~ t~e macroporous
matrix i5 formed as a close~ended tube or cylinder where
the lumen opens into an interior volume within the tube.
-~ Such a structure is particularly advantageous since it
provides for highly uniform diffusion in all radial
, directions along the entire length of the macroporous
:~ membraneO The length of the macroporous membrane may
. 15 vary widely, usually being at least 1 cm in length and
extending up to the entire catheter length, e.g., 160 cm.
~- Usually, the length of the macroporous matrix will be in
the range from about 2 to 50 cm, more usually being in
; the ranse ~rom about 2 to 20 cm, and fr~quently being in
;- 20 the range from 5 to 15 cm.
: Alternatively, the macroporou~ matrix may be
formed as a sheath over an internal tubular structure
which defines one or more therapeutic agent delivery
.. lumens. Such a structure allows the sheath to be divided
2S into two or more delivery zones where different agents
may be simultaneously released from di~erent locations
. on the catheter. The delivery zones may be axially
spaced-apart, radially spaced apart, or spaced-apart both
.; axially and radially. In a particular embodiment, a
.~ 30 first lumen can deliver a therapeutic agent to a
macroporous matrix located near the catheter tip while
second lu~len deli.vers an anti-clotting ~gent, such as
heparin, to a macroporous matrix which exten~s over a
portion o~` or the entire length o~ the catheter shaft.
The abilit:y to inhibit clot formation along the lenyth of
the catheter is particularly advantageous when the

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.'~ .

WO ')2/00113 PCIYUS') I /0'1336
f.'.l',f:.' ;~ ~5;~

catheter is to be le~t in place for extended p~riods of
: The macroporous matrix will be formed from a
material which is sufficient:Ly porous to allow piassage or
diffusion of the active molecular species o~ th~
therapeutic ag~nt while prov:iding su~icient flow
resistance so that the solu~.ion containing the
therapeutic agent can be released at a desired rate
. uniformly across the l~ngth of the matrix. The material
;10 will usually be selected to pass molecules having a
: molecular weight of at least ten kilodaltons (kD), more
~ usually of at least about 25 kD, preferably of at least
; about 50 kD, and more preferably of at least about
100 kD. The release rate o~ the solution which carries
the ~herapeutic agent will depend on a number of factors
in addition to the nature of the matrix ~ater.ial,
including the deliv~ry pressure, ma~rix area, matrix
thickness, functionalization of the matxix material, and
the like. Usually, these charac~eristics will be
`. 20 selected to provide an overall release rate from the
catheter in the range from about 1 cc/hr. to lûO cc/min.,
usually from about lcc/min. to 50 co/min., and more
: usually in the range from about 5 cc/min. to Z5 cc/min.
The macroporous matrix will be eomposed of a
.~, 25 biocompatible material, typically being formed from an
organic pol~mer, although in certain cases it may be
possible to form the matrix ~rom metals, e.g., stainless
steel , or ceramics , e.g., alumina. The macroporous
matrix will usually be a single layer of material,
0 although in certain cases it may be desirable to ~orm the
~`~; matrix as a composite o~ two or more layers where one
layer provides the necessary mechanical strength and
another layer provides for the desired moleculii~r weight
cutoff and ~low resistance. The macroporous matrix may
be ~lexible or rigid, usually being flexible to
acilitate m~nipulation through the vascular system. The
~,~ matrix material w.ill usually not be substantially


WO~2/~1l3 P~T/U5~1/04336
~æ~ O, ~

expandable, i.e., it will not dilate substantially in
response to internal pressurization, but in some cases
may be expandable.
Th~ macroporous matrix may be formed as a woven
fabric, non-woven fabric, polymeric ~ilm or membrane, or
the like. Woven fabrics will t~pically be formed ~rom
organic polymer fibers, such as polyethylene,
polypropylene, polyester, nylnn, polytetra~luoroethylene
(PTFE), polycarbonate, polystyrene, cellulose,
~ 10 polyacetonitrile, and the like. Individual fibers or
;~ bundles of fibers (yarns) may be woven into the fabric by
conventional techniques, including weaving, braiding,
knitting, and the like. The porosity of woven fabrics
will be determined primarily by thP interstitial spaces
between the woven fiber~ or yarns, with tiyhter weaves
providing a greater flow resistance. Mosk woven fabrics
will have a ~ery high molecular weight cutoff since the
interstices in the weave pattern will be large relative
to molecular dimensions. The flow resistance, however,
will depend primarily on the thickness o~ the ~abric and
can be controlled accordingly~ Thus, for many
~`- applications, the use of woven fabrics as the macroporous
matrix material will be preferred. Particularly
preferred will be the use of woven
polyethyleneterephthalate (PET) fabrics, available under
the tradename Dacron~.
~' Non-woven fabrics, typically spunbonded
fabrics, may also find use as the macroporous matrix
material. Non-woven fabrics can be prepared ~rom most oE
the fiber materials listed abov~ with a wide range of
porosity and rasistance to flow.
The macroporous matrix layers may al~o be
, formed from macroporou~ me~branes produced from a wide
i variety of organic polymers. The preparation of porous
membranes having desired characteristics is well
described in the technical and patenk literature. See,
~or exa~ple, Kirk-Othmer, Encyclopedia o~ Chemical

;! .
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W~92/nOll3 PCr/US91/~433f)

?r ~ ~
Technology, 3rd ed., Vol. 15, John Wiley ~ Sons, New York
(1979), pp. 93-131, the disc:Losure of which i~
incorporated herein by reference. ~xemplary organic
membrane materials include polyethylene, polypropylene,
polystyrene, nylon, poly(methacrylates), polyvinyl
chlorides, and the like.
In some cases, ~or any o~ the organic polymers
.~ described above, it may be desirable to provide
- functional groups on tha pol~meric backbone in order to
achieve a desired effect, typically governing the
controlled release of the therapeutic agent. For
example, hydrophilic or hydrophobic groups mi~ht be
introduced in order to affect the release rate of
therapeutic agents haYing either hydrophobic or
~ 15 hydrophilic characteristics. Similarly, cationic and/or
:~ anionic ~unctionalities may be introduced in order to
affect the release of charged therapeutic agents.
~ It is particularly preferred that the
- m~croporous matrix be "wettable" and capable of reta ning
.~ 20 a residual volume of therapeutic agent with its
' structure, such as woven and non-woven fabrics composed
:: of hydrophilic materials, surh as
~., polyethyleneteraphthalate, and the like. By xetaining
.~ the therapeutic agent within the matrix, regions within
-~ 25 the blood vessel which contact the matrix will be
constantly exposed to the agent, even i~ such contact
inhibits active ~low through that region. Catheters
which employ discrete perfusion ports, in contrast,
frequently su~er from blocked ports which can cause a
highly uneven release and exposure of therapeutic agent.
. Re~erring now to ~i~s~ 1-5, the construction of
; a first exemplary catheter lO constructed in accordance
~- with the principles of the present invention will be
~ described. The catheter 10 compri~es a c~theter body 12
,"~ 35 having a proximal end 14 and a distal end 16. The
catheter b~dy 12 include~ an inner ~lexible tubular
member 18 and an outer ~lexible tubular member 20. The



WO ~2/0~ 1 Pcir/uss~ 4:7;?J6

inner flexible tube 18 has a central lumen 22 extending
from proximal end 14 to dis~aL1 end 16, while the inner
tube 18 and outer tube 20 together define an annular
lumen 24 which also extends f`rom the proximal end to the
distal end of the catheter.
A proximal housing 30 is secured to the
proximal end 14 of catheter body 12. The housing 30
includes a central port 32 which communicates with the
ceintral lumen 22 of the inner flexi~le tube 18. The
housing further includes a side port 34 which
co~municates with the annular lumen 24. Typically, the
~ central lumen 22 and port 3~ will be used to introduce
`: the catheter 10 ov~r a movable guide wire 36 ~shown in
broken line) in a conventional manner. The side port 34
will ~e used to introduce a solution carrying the
.: therapeutic agen~ of interest.
Catheter 10 includes a tubular macroporous
matrix 40 formed near the distal end 16. The distal end
:~ o~ tubular m~croporous matrix 40 is attached to the outer
~ 20 surface of tubular member 18 in order to close the end of
~ .,
.'. the annular lumen 24. The tubular macroporous matrix
forms a continuous surface with the outer flexiblP
tubular member 20 so that9 in Pffect, the catheter body
includes a single continuous outer tubular member having
a non-porous or impermieable portion and a second porous
portion defined by the tubul~ir matrix 40. In this way,
the solution carryin~ the therapeutic agent may be
introduced through port 34, travel through the amlular
lumen 24, and be released under controlled conditions
through th~ macroporous matrix 40.
~, The length of the tubular macroporous matrix 40
~i can vary wide~ly within the limits set forth above. The
porosity characteristics of the m2trix 40 will generally
~; be uniform over the entire sur~ace area ~o that the
~' 35 r~ilease ral:e of the therapeutic solution will be the same
i~: at all loc~itions. I~ would, of course, ~e possi~le to
modi~y the porosity and other characteristics o~ the


WO~2/00113 Pcr/us~l/o~336
13 2~
: matrix 40 in cases where it is desired to provide a n~n-
uniform release rate of the therapeutic solution.
~; A second exemplary catheter 50 is illustrated
in Fig. 6 and includes an inner flexible tubular memb~r
52 having four i~olated axial lumens 54a, b, c, and d
~ extending therethrough~ A fifth entral lumen 56 is also
:~ provided for introducing the catheter 50 over a gu.ide
wire (not illustrated~ in a c:onventional manner.
~ The catheter 50 further includes a tubular
:~ lO macroporous matrix 58 disposed coaxially about the inner
flexible tubular member 52 so that an annular lumen 60
remains therebetween. The annular lumen 60 is divided
into a proximal region 62 and a distal region 64 by a
partition 66 so that the different lumens 54a, b, c, and
` lS d may b~ used to deliver different therapeutic agents to
:~ each region. In particular, ports 64 are provided in
;. lumen 54d and lumen 54b ~the latter are not visible in
Fig. 6~ in order to deliver a therapeutic agent to the
distal region 64 o~ the annular lumen 60. From this
region, the therapeutic agent i~ able to i~fu~e in a
~ uni~orm, controlled manner into the surrounding blood
- vessel. A second set of ports 70 are provided in lumen
~., 54a and lumen 54c (the latter ports are not visible in
;~ Fig. 6) in order to deliver a second therapeutic or other
~' 25 agent to the proximal re~ion 62 o~ thP annular lumen 60.
` In this way, the second agent can be administered to a
.~ dif~erent region of the hlood vessel simultaneously with
the first agent.
Thta use of multiple delivery lumens and
partitions can be extended to form any number of delivery
:~ regions along the length of the catheter. The regions
may be continuous or separated and may extend over the
3 entire length or only a portion of the length of ~he
catheter. The embodiment illustrated in Fig. 6 will be
particular:Ly use~ul for delivering an anti-clokting
age~t, such as heparin, along the sha~t of the catheter
~;. while the desired th~rapeutic agent is being delivered at


WO 92/0()113 PC'r/US~l/0'~336

the di~tal end. The abili~y to delivery an anti-clotting
agent at relatively low controlled rates for extended
periods of timP is advantageous since catheters can
initiate clot formatlon when present in the vascular
: 5 system.
Referring now to F:ig. 7, the catheter of the
present invention can be adapted to allow for bypass
blood flow. A5 illustrated, a catheter 80 may be
provided with a plurality of ports 82 which communicate
~ 10 with an internal lumen which allows blood to flow through
;~ the catheter. Such a structure is advantageous if the
~: catheter tip is to ~e inserted into a tight stenotic
region where blood flow would othe2~ise be greatly
impeded or blocked entirely. The catheter 80 employs a
central lumen 84 to provide the bypass ~low path, where
the central lumen is open at its distal end 86. Other,
; ~eparate lumens might also be provided.
Referring now to Fig. 8, use of the the~apeutic
~, catheter 10 in treating a region o~ thrombus T in a
- 20 patient's superficial femoral artery SF will b~
described. The guide wire 36 is introduced through the
'~ left iliac ar,tery IL into the right iliac artery IR and
~-~ then into the superficial ~emoral artery SF using an
- introducer catheter 50 in a conventional manner. The
,~` 25 guide wire 36 is positioned so that its distal end passes
in~o ~he deep femoral axtery D~ to reach the region of
thrombus ~. A11 such positioning steps can be performed
., under fluoroscopic guidance.
~;i After the guide wire 36 has been properly
positioned, the catheter 10 may be introduced by passage ~.
over the guide wire until the macroporous membrane 40
. lies within the region of thrombus.T. A perfusa~e
solukion co2ltaining the therapeutic agent of interest,
typically a thrombolytic polypeptide, is then introduced
. 35 through port 34 at a rate and for a time sufficient to at
least part:Ly dissolve the thrombus T.


W092/nO113 PCT/US')l/~J433C
2 ~J~

The perfusate is typically delivered ~ro~ a
r~servoix lO0, such as a flexible pouch, through a pump
102 which is connected to inlet port 34 by tubing 104.
The pump will typically be capable of delivering a
preselected volumetric flow :rate over a wide range of
pressures. Treatment conditions for two of the most
commonly employed thrombolytic agents are as follows.

Thrombolytic Volumetric Concentration; Treatment
A~ent _ Delivery R~te _eferred CQncentration _ Time
TPA 5-150cc/hr 60 IU/cc to 106IU/cc; 1 ~o 36 hr.
250,000 t~ 106IU/cc
15 Urokinase 5-150cc/hr 0.1 to 25 mg/hr; 1 to 36 hr.
5 to 15 mg/hr

The pressure of the perfusate in the catheter
:~ 20 will be determined primarily by the resistance to flow
.. provided by the macroporous membrane 40, and may vary
~`; Prom about 0.1 psi to 500 psi, usually being in the range
from about 25 psi to 100 psi. The back pr~ssure on the
macroporouC membrane 40 provides for highly uniform and
controlled release of the thrombolytic agent throughout
the region of thrombus T so that dissolution occurs at a
: constant rate, minimizing the total amount of agent
required and reducing the chance that port.ions of the
thrombus will be broken off and released as emboli.
Although the foregoing inventiQn has been
described in detail for purposes of clarity of
understanding, it will be obvious that certain
modifications may be practiced within the scope of the
appended claims.
", .
, .',:
, .

A single figure which represents the drawing illustrating the invention.

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Admin Status

Title Date
Forecasted Issue Date Unavailable
(86) PCT Filing Date 1991-06-18
(87) PCT Publication Date 1991-12-27
(85) National Entry 1992-12-15
Dead Application 1994-12-19

Abandonment History

There is no abandonment history.

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Filing $0.00 1992-12-15
Maintenance Fee - Application - New Act 2 1993-06-18 $100.00 1993-05-17
Registration of Documents $0.00 1993-10-26
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Abstract 1991-12-27 1 62
Drawings 1991-12-27 3 143
Claims 1991-12-27 3 160
Abstract 1991-12-27 1 69
Cover Page 1991-12-27 1 36
Representative Drawing 1999-01-25 1 17
Description 1991-12-27 15 1,048
Fees 1993-05-17 1 19
Assignment 1993-06-22 5 241
Assignment 1993-05-04 1 55
Assignment 1992-12-15 3 104
PCT 1992-12-15 31 1,133
Correspondence 1993-08-10 1 39
Correspondence 1993-03-08 1 27
Correspondence 1993-06-25 1 52
Correspondence 1994-08-05 1 23