CA2085470A1 - Method and catheter for intravascular drug delivery - Google Patents

Method and catheter for intravascular drug delivery

Info

Publication number
CA2085470A1
CA2085470A1 CA 2085470 CA2085470A CA2085470A1 CA 2085470 A1 CA2085470 A1 CA 2085470A1 CA 2085470 CA2085470 CA 2085470 CA 2085470 A CA2085470 A CA 2085470A CA 2085470 A1 CA2085470 A1 CA 2085470A1
Authority
CA
Canada
Prior art keywords
catheter
macroporous matrix
macroporous
distal end
lumen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA 2085470
Other languages
French (fr)
Inventor
Robert A. Graor
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
CARDIOVASCULAR THERAPEUTIC TECHNOLOGIES Inc
Original Assignee
Robert A. Graor
Cardiovascular Therapeutic Technologies, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US54531190A priority Critical
Priority to US545,311 priority
Application filed by Robert A. Graor, Cardiovascular Therapeutic Technologies, Inc. filed Critical Robert A. Graor
Priority to PCT/US1991/004336 priority patent/WO1992000113A1/en
Publication of CA2085470A1 publication Critical patent/CA2085470A1/en
Application status is Abandoned legal-status Critical

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00Catheters; Hollow probes
    • A61M25/0043Catheters; Hollow probes characterised by structural features
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00Catheters; Hollow probes
    • A61M25/0043Catheters; Hollow probes characterised by structural features
    • A61M2025/0057Catheters delivering medicament other than through a conventional lumen, e.g. porous walls or hydrogel coatings

Abstract

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.

Description

WO '~/()01~ PCr/US'31/0~336 ~";,~ ~j ~113T~OD AND ~ATElETElR FOR INTRA~S~ DRUG DE:L: :VlERY
.
BAC~RGROUN~ F THæ IN~ENTION
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 il ~' 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 li m~dium.
S~MMARY 0~ T~ INVENTION
:~ 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.
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: 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.
DESCR PTION OF_T~113 PREE'ERlEæD EMBOD:I:M~S
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 usi.ng 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 ~:3 ! :
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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 literature.
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() ~'~Y~
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 time.
: 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 d '' 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 '''~

~,1 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 .

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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 ~,:

.1 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.

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W092/nO113 PCT/US')l/~J433C
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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.
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Claims (22)

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 lumen.
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.
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.
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 polyacetonitrile.
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.
CA 2085470 1990-06-26 1991-06-18 Method and catheter for intravascular drug delivery Abandoned CA2085470A1 (en)

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US54531190A true 1990-06-26 1990-06-26
US545,311 1990-06-26
PCT/US1991/004336 WO1992000113A1 (en) 1990-06-26 1991-06-18 Method and catheter for intravascular drug delivery

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JP (1) JPH06503972A (en)
CA (1) CA2085470A1 (en)
WO (1) WO1992000113A1 (en)

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WO1992000113A1 (en) 1992-01-09
JPH06503972A (en) 1994-05-12
EP0536296A4 (en) 1993-08-04
EP0536296A1 (en) 1993-04-14

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