AU727099B2

AU727099B2 - Drug-loaded elastic membrane and method for delivery

Info

Publication number: AU727099B2
Application number: AU70104/98A
Authority: AU
Inventors: Michael S. Williams
Original assignee: Advanced Cardiovascular Systems Inc
Current assignee: Abbott Cardiovascular Systems Inc
Priority date: 1994-11-16
Filing date: 1998-06-11
Publication date: 2000-11-30
Anticipated expiration: 2015-11-14
Also published as: AU7010498A

Description

AUSTRALIA

PATENTS ACT 1990 DIVISIONAL APPLICATION NAME OF APPLICANT(S): Advanced Cardiovascular Systems, Inc.

ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street Melbourne, 3000.

INVENTION TITLE: "Drug-loaded elastic membrane and method for delivery" The following statement is a full description of this invention, including the best method of performing it known to us: Q:OPERUMS37833g5 DIV 91/98 -la- BACKGROUND OF THE INVENTION Field of the Invention This invention relates generally to the treatment of cardiovascular diseases resulting from such conditions restenosis, acute thrombosis, intimal hyperplasia and sub-acute thrombosis. More particularly, the invention relates to an expandable membrane which contains a therapeutic drug intended to be released into a body lumen for treating disease or injury.

Description of Related Art Coronary devices to treat undesirable cardiovascular conditions have, experienced unprecedented growth throughout the 1980's and 1990's such that coronary angioplasty now is S commonplace for treatment of atherosclerotic vascular disease.

15 In a typical percutaneous transluminal coronary angioplasty (PTCA) procedure, a guiding catheter having a pre-formed distal tip is percutaneously introduced into the cardiovascular system through the brachial or femoral arteries and is advanced therethrough until the distal tip is in the ostium of the desired coronary artery. A guidewire and a dilatation catheter having an inflatable balloon on the distal end thereof, are introduced through the guiding catheter with the guidewire slidably-disposed within an inner lumen of the dilatation catheter. The guidewire first is advanced out of the distal 25 end of the guiding catheter and is maneuvered into the coronary vasculature of the patient in which the lesion to be dilated is located, and then is advanced beyond the lesion. Thereafter, the dilatation catheter is advanced over the guidewire until the dilatation balloon is located across the target lesion.

Once in position across the lesion, the balloon of the dilatation catheter is filled with radiopaque liquid at a relatively high pressure greater than about 4.05 bars (4 atmospheres)), and is inflated to a pre-determined size so as SST o radially compress the atherosclerotic plaque of the lesion against the inside of the arterial wall and to thereby dilate the lumen of the artery. The balloon then is deflated so that the dilatation catheter can be removed and blood flow can resume through the dilated artery.

By way of example, further details of the angioplasty procedure and the devices used in such procedures can be found in U.S. Patent 4,323,071 (Simpson-Robert); U.S. Patent No.

4,439,185 (Lindquist); U.S. Patent No. 4,516,972 (Samson);

U.S.

Patent No. 4,538,622 (Samson et U.S. Patent No. 4,554,929 (Samson et U.S. Patent No. 4,616,652 (Simpson);

U.S.

Patent No. 4,638,805 (Powell); and U.S. Patent No. 4,748,982 (Horzewski et al.) A common problem that sometimes occurs after an .angioplasty procedure is the appearance of restenosis at or 15 near the site of the original stenosis in the blood vessel for which treatment was rendered. This problem can require a secondary angioplasty procedure or a bypass surgery. Numerous approaches developed during the late 1980's to treat restenosis of the coronary arteries in an attempt to decrease the incidence of acute complications and the chronic restenosis rate. For example, in the prior art are found mechanical approaches such as atherectomy, stents, laser angioplasty, and the application of pharmacologic agents. Of the mechanical S approaches described, only the stents have been most promising to prevent restenosis and to prevent elastic recoil of the vascular wall.

With regard to expandable stents that are delivered with expandable catheters, such as balloon catheters, the stents are positioned over the balloon portion of the catheter and are expanded from a reduced diameter to an enlarged diameter, greater than or equal to the diameter of the arterial wall, by inflating the balloon from within the stent. Stents of this type can be expanded to an enlarged diameter by deforming the stent and expanding it into engagement with the vascular wall. It is common for stents of this type to experience endothelial growth over and around the stent.

Examples of such expandable catheters and stents are disclosed P:A0PERUJU\;0 10-13 .dr1005 -3in U.S. Patent No. 5,102,417 (Palmaz), U.S. Patent No. 5,123,917 (Lee), and U.S.

Patent No. 5,133,732 (Wiktor). Unfortunately, the stents that currently are being implanted are reported to be affected by a fairly high restenosis rate, in the range of seven to forty percent.

With this relatively high restenosis rate, there has developed a need for some means of reducing the restenosis rate when using a stent, and to limit recurrent stenosis even when a stent is not used. The present invention fulfils this need.

SUMMARY OF THE INVENTION The present invention is directed to an expandable membrane delivery system for use in delivering a therapeutic drug in a body lumen. One of the primary advantages of the invention is to provide local delivery of a therapeutic drug to eliminate the need for systemic delivery of pharmaceuticals which may have undesirable side effects. Local delivery of a drug can be accomplished using a drug- *loaded expandable membrane carried by a perfusion-type catheter system (nonl implantable), or by loading the membrane on a stent for implanting in a vessel. The drug release from the expandable membrane can be controlled to suit a particular clinical need or a specific condition such as restenosis or acute thrombosis.

The expandable sheath delivery system of the present invention includes an :....expandable membrane having a cavity for carrying a drug or which carries the drug in a matrix form. A therapeutic drug is loaded in the expandable membrane so that it can diffuse outwardly into the vessel wall once the expandable membrane is delivered to the site where a PTCA procedure has occurred. The expandable membrane can for example be mounted on the distal end of a catheter, and, more specifically, on an expandable portion, a balloon, by sliding or stretching the expandable membrane around the expandable portion of the catheter.

S sTY P:\OPER\LKA\70104-252 clns.dmoc/09O40 -4- In one aspect this invention provides an expandable sheath delivery system for delivering a therapeutic drug in a body lumen, comprising: a therapeutic drug; an expandable membrane in the form of a cylindrical member having a first end and a second end and a first layer and a second layer, each layer having an edge, the first and second layers being bonded together along the edges to form a reservoir therebetween adapted to receive and hold the therapeutic drug; the expandable member being configured so that it independently lacks the structural integrity to hold open and maintain the patency of the body lumen; and means for intraluminally delivering and expanding the expandable *o membrane in the body lumen so that the therapeutic drug can be eluted through at *least one of the layers at a specific site in the body lumen.

In an embodiment, the membrane may be in the form of a flat sheet with a first and second edge which edges overlap and are attached to each other so as to form a sleeve around the expandable portion of the catheter. In an alternative embodiment, the membrane is in the form of a seamless tube carried by the catheter.

The catheter then is delivered intraluminally to the area at which the diseased or injured area is presented, and the expandable portion of the catheter is expanded Ssuch that it also expands the expandable membrane. Once expanded, the 0 20 therapeutic drug diffuses into the vessel wall for treating the injured or diseased area. Thereafter, the expandable portion of the catheter is deflated, and the catheter and expandable membrane are withdrawn from the vasculature.

In another aspect this invention provides an expandable sheath delivery system for delivering a therapeutic drug in a body lumen, comprising: an expandable membrane having a first layer and a second layer affixed to each other along their edges to form a drug-containing reservoir therebetween; a plurality of apertures on the first layer through which a therapeutic drug A can diffuse from within the drug-containing reservoir, the plurality of apertures P:\OPER\LKA70104.252 Jhus.doc-0/09/0 remaining open when the first layer is in a stretched condition and the apertures tightly closing when the first layer is in a relaxed condition; the expandable member being configured so that it independently lacks the structural integrity to hold open and maintain the patency of the body lumen; and means for intraluminally delivering and expanding the expandable membrane in the body lumen so that the therapeutic drug can be eluted at a specific site in the body lumen.

In an embodiment of the invention the first elastic layer is stretched and drilled with a plurality of micro-holes or apertures through which the therapeutic drug can pass prior to attaching the two layers. Thereafter, the first layer and second layer are affixed to each other as described, and a therapeutic drug is injected into the cavity between the two layers through any of the plurality of apertures. When the expandable membrane is in its relaxed condition, the plurality of apertures close tightly so that no therapeutic drug can pass therethrough. The 15 expandable membrane then is rolled onto the balloon portion of the catheter to form a cylindrical configuration and is delivered intraluminally as described above. The flat sheet is rolled into a cylinder and the edges are joined by means such as by welding or adhesive, etc. The balloon portion of the catheter is expanded, thereby expanding the expandable membrane and forcing the therapeutic drug through the plurality of apertures and into contact with the vessel wall at the site of the injured or diseased area. After the therapeutic drug has been delivered, the balloon portion of the catheter is deflated, and the catheter and expandable membrane are withdrawn from the vasculature. Instead of forming the expandable membrane from flat sheets, this embodiment also may be achieved with two tubular members, one within the other, to form a cavity between the layers. The ends are sealed and micro-holes are drilled by laser into the outer layer to allow the therapeutic drug to pass therethrough. The tubular members also may have a drug incorporated in the olymer material in the form of a matrix which allows the drug to diffuse into the i ssel wall over time.

P:\OPER\LKA\70104-252 lms.doc-08/09/00 5A In another aspect this invention provides an expandable sheath delivery system for delivering a therapeutic drug in a body lumen, comprising: an expandable membrane in the form of a cylindrical member and having an inner surface and an outer surface; a plurality of micro-pockets disbursed upon the outer surface but not penetrating through to the inner surface; a therapeutic drug for loading into the micro-pockets; the expandable member being configured so that it independently lacks the structural integrity to hold open and maintain the patency of the body lumen; and means for intraluminally delivering and expanding the expandable membrane in the body lumen so that the therapeutic drug can be eluted at a specific :o site in the body lumen.

In an embodiment of the invention, the expandable membrane is in the form S"of a flat sheet and having a thickness in the range of 0.05-0.5 millimeters (0.002- 15 0.020 inch). The plurality of micro-pockets or pores are drilled into the outer surface of the expandable membrane, but are not drilled all the way through that surface so as to form a hole. The micro-pockets are drilled while the membrane is in its stretched position. Thereafter, a therapeutic drug is loaded into the various micro-pockets and the membrane is relaxed so that the pockets close with the S 20 therapeutic drug inside. The elastic membrane then can be rolled into a cylindrical form and mounted on a catheter for delivery to the diseased or injured area. When the expandable membrane is expanded by the balloon portion of the catheter, the micro-pockets open and the therapeutic drug is delivered to the diseased or injured area. After the therapeutic drug has been delivered, the balloon portion of the catheter is deflated and the catheter and expandable membrane are withdrawn from the patient.

In another aspect this invention provides an expandable sheath delivery L system for delivering a therapeutic drug in a body lumen, comprising: P:\OPER\LKA\70104-252 clhs.doc-08/ogloo an expandable membrane in the form of a cylindrical member having a first end, a second end, and a lumen therethrough; a therapeutic drug combined with the expandable membrane; a catheter system for intraluminally delivering and expanding the expandable membrane in the body lumen, the catheter system having a distal end, a proximal end, and a balloon portion at the distal end; the expandable member being configured so that it independently lacks the structural integrity to hold open and maintain the patency of the body lumen; and means for loading the expandable membrane on the balloon portion of the 10 catheter system so that when the balloon portion is inflated, the balloon portion expands radially outwardly to expand the expandable membrane into contact with the body lumen so that the therapeutic drug can be eluted at a specific site in the body lumen.

In an embodiment of the invention, an intravascular stent is mounted on the 15 balloon portion of a catheter so that it may be implanted in a conventional manner within the vasculature. The expandable membrane, having a therapeutic drug contained therein in the form of a matrix, is mounted on the outer surface of the stent, and the catheter, the stent, and the expandable membrane are delivered intraluminally to the injured or diseased area. As the balloon is expanded, the 20 balloon forces the stent radially outward, along with the expandable membrane, and the expandable membrane thus is forced into contact with the vessel wall. The balloon portion of the catheter then is deflated, and the catheter and balloon are withdrawn from the vasculature, leaving the intravascular stent and expandable membrane implanted at the injured or diseased area. Thereafter, the therapeutic drug will diffuse from the matrix into the vessel wall in an effort to reduce the incidence of restenosis.

In both the reservoir or matrix form of drug delivery, the therapeutic drug may be retained in various structures including microspheres, sheets, tubes, etc.

The expandable membrane of the present invention may be deployed in a body lumen through a variety of devices, which include but which are not limited to, balloon catheters and specialized devices that can deliver a stent within a body lumen. These and other advantages of the invention will become 15 more apparent from the following detailed description thereof when taken in conjunction with the accompanying exemplary drawings.

a.

BRIEF DESCRIPTION OF THE DRAWINGS FIGURE 1 is a top view of the expandable membrane of the invention, prior to rolling the membrane into a cylindrical configuration; 9 FIG. 2A is a perspective view of the expandable membrane of FIG. 1 in its rolled up condition, with its first edge attached to the second edge in an overlapping relationship; FIG. 2B is a perspective view depicting the elastic membrane, in a hollow tubular form that is seamless; FIG. 3 depicts a partial, cross-sectional elevational view of a rapid-exchange catheter system, having a stent mounted on a balloon with the expandable membrane mounted over the stent; FIG. 4A is a partial cross-sectional view depicting an over-the-wire catheter system, having a stent mounted on the balloon portion of the catheter and an expandable membrane mounted over the stent; FIG. 4B is a partial cross-sectional view of a perfusion-type catheter system, having a stent mounted on the balloon portion of the catheter and an expandable membrane over the stent; FIG. 5 is an elevational view depicting the rapid exchange catheter system of FIG. 3, wherein the stent mounted on the balloon portion of the catheter has a specific configuration and the expandable membrane is mounted over the stent; FIG. 5A is a cross-sectional view taken along line 15 5A-5A depicting the expandable membrane over the stent and balloon portion of the catheter; FIG. 6 is a partial, cross-sectional view of the catheter delivery system and stent with the expandable membrane mounted on the stent being delivered transluminally within the S 20 vasculature of the patient;

S

FIG. 7 is a partial, cross-sectional view of the balloon portion of the catheter expanding the stent and the expandable membrane within the vasculature of the patient; FIG. 8 is a partial, cross-sectional view of an intravascular stent and an expandable membrane implanted against the vessel wall of a patient; FIG. 8A is a cross-sectional view taken along line 8A-8A depicting the expandable membrane and stent expanded and in contact with the vessel wall; FIG. 9 is a perspective view of the expandable membrane, wherein the first layer and the second layer are spaced apart prior to affixing the edges to each other; FIG. 10 is the expandable membrane of FIG. 9, wherein the first layer and the second layer have been joined, and the plurality of holes are closed because the membrane is in its relaxed condition; FIG. 11 is a perspective view of the expandable membrane of FIG. 10 in its rolled-up condition and in an 10 unexpanded state, with the plurality of micro-holes tightly closed to thereby contain the drug within the drug-filled reservoir; FIG. 1 1 A is a perspective view of an expandable membrane, having an inner tube and an outer tube with a drug 15 receiving cavity between the two tubes; FIG. 12 is a perspective view of an expandable membrane having a plurality of micro-pockets, for receiving a therapeutic drug; and FIG. 13 is a perspective view of the expandable membrane of FIG. 12 in its rolled-up condition and in a cylindrical form, with the micro-pockets tightly closed and in an unexpanded condition.

DETAILED DESCRIPTION OF THE PREFERRED

EMBODIMENTS

During PTCA procedures it is common to use a dilatation catheter to expand a diseased area to open the lumen of a patient so as to allow blood to flow freely. In spite of the beneficial aspects of the PTCA procedure and its widespread and accepted use, it has several drawbacks, including restenosis and, possibly, acute thrombosis. Recurrent stenosis -9has been estimated to occur in seventeen to fifty percent of patients even when the initial PTCA procedure has been successful. Restenosis is a complex and not fully understood biological response to the injury of a vessel. It results in chronic hyperplasia of the neointima. Intimal hyperplasia is activated by growth factors which are released in response to an injury to the vessel. Acute thrombosis also can be a result of vascular injury, and treatment of it requires systemic antithrombotic drugs and possibly thrombolytics as well. Such therapy can increase bleeding at the catheter insertion site and may result in a longer hospital stay. Another result of vessel injury is acute closure. It occurs in three to five percent of the patients who have received treatment by PTCA, and is caused by any one or all of three events; namely, 15 thrombosis, vessel dissection, or elastic recoil.

Several procedures have been developed to combat restenosis and acute closure, one of which is the delivery and implanting of an intravascular stent. Stents are in the developmental stage at this point and are being used in clinical trials throughout the United States and are regularly implanted in patients in Europe and other countries.

Generally, stents can take on numerous forms, however, a stent typically comprises a cylindrical hollow tube that holds open Sthe vascular wall at an area which previously has been dilated by dilatation catheter. The use of a stent does not always reduce restenosis and can aggravate the site of treatment by causing acute thrombosis, subacute thrombosis and intimal hyperplasia. In order to address the complications arising from PTCA procedures and the deployment of intravascular stents, the present invention for delivering therapeutic drugs was developed.

In one embodiment of the invention, and referring to FIGS. 1 and 2A, an elastic membrane 5 is depicted wherein it has a first edge 6 and a second edge 7. In FIG. 2A, elastic membrane 5 has been rolled into a cylindrical form with first edge 6 and second edge 7 attached in an overlapping relationship as depicted at point 8. It may be desirable to -i0join first edge 6 and second edge 7 in an abutting relationship (not shown), rather than in an overlapping relationship, in order to reduce the overall profile of the finished membrane In another preferred embodiment, and as is depicted in FIG. 2B, an elastic membrane 5 is shown with a first end 1 and a second end 2. This embodiment substantially is a hollow cylinder. It further has an inner surface 3 and an outer surface 4, and is generally of a unitary nature. That is, it is formed from a continuous material and has no seams or overlapping edges. Various means are described below in which a therapeutic agent is incorporated within the elastic membrane so that it may be delivered into a the vascular system of a patient, for the purpose of diffusing the therapeutic agent at a a controlled rate.

15 The membrane 5 may be formed of any suitable material that is elastic and resilient. Preferably the material is one that has a high degree of non-linearity is plastically deformable) for a wide range of stress and strain values a material that has very low residual stress). In the 20 preferred embodiment, however, any elastic material my be used.

e r Commercially available tubing may be used such as the tubing manufactured under the tradename "C-FLEX" by Concept Polymer :Technologies of Largo, Florida.

In addition, the expandable material should have good "tear strength" to prevent fracturing or splitting when it is expanded and stretched. Other suitable properties for expandable membrane 5 include a low modulus of elasticity, high toughness, a high percentage of elongation (at least three hundred percent), and a minimal residual of stress after expansion. Several preferred materials for the expandable membrane 5 are ethylene vinyl acetate (EVA) and biospan. Other suitable materials for the expandable membrane 5 include latexes, urethanes, polysiloxanes, and modified styreneethylene/butylene-styrene block copolymers (SEBS), and the associated families, as well as elastomeric bioabsorbable materials from the linear aliphatic polyester group.

-11- In keeping with the invention, a therapeutic drug is combined with the expandable membrane 5, for the purposes of diffusing the drug into the vessel wall of the patient. For this purpose, any therapeutic drug for use in the body can be combined with the expandable membrane for treatment. For example, therapeutic drugs for treating an injured or diseased areE. in a vessel and for combination with the expandable membrane can include anti-platelets, anti-thrombins, and antiproliferatives. Examples of anti-platelets and anti-thrombins include sodium heparin, LMW heparin, hirudin, hirulog, argatroban, forskolin, vapiprost, prostacyclin, dextran, D-pher pro-arg-chloromethylketone (synthetic antithrombin) Sdipyridamole, glycoprotein IIb/IIIa platelet membrane receptor antibody, recombinant hirudin, thrombin inhibitor (from the 15 company Biogen) and 7E-3B (an anti-platelet drug from the company Centocor) Examples of anti-proliferatives include angiopeptin (somatostatin analogue from the French company Ibsen), angiotensin-converting enzyme inhibitors (Captopril S (from the Squibb Corporation), Cilazapril (from the Hoffman- LaRoche Corporation) and Lisinopril (from the Merck Company)), oc. calcium channel blockers (Nifedipine), colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega 3-fatty acid) low molecular weight heparin (from the companies Wyeth and Glycomed), histamine antagonists, lovastatin (inhibitor of HMG- SCoA reductase, a cholesterol-lowering drug from the Merck Company), methotrexate, monoclonal antibodies (to

PDGF

receptors, etc.), nitroprusside, phosphodiesterase inhibitors, prostacyclin analogues, prostaglandin inhibitor (from the Glaxo Corporation), seramin (PDGF antagonist), serotonin blockers, steroids, thioprotease inhibitors triazolopyrimidine

(PDGF

antagonist from a Japanese company). While the foregoing therapeutic agents have been used to prevent or treat restenosis and thrombosis, they are provided by way of example and are not meant to be limiting, as other therapeutic drugs may be developed which are equally applicable for use with the present invention.

-12- In keeping with the invention, the therapeutic drug can be combined with the expandable membrane 5 by one of several methods. The therapeutic drug can be loaded into the expandable membrane by known methods such as melt processing, solvent casting, injection molding, extrusion, coating or by diffusion/absorption techniques. Other methods of incorporating a drug into a polymeric material are well known and include heating processes. Such processes must be monitored carefully and controlled at temperatures that are low enough to prevent degrading the drug. It is important that the therapeutic drug be able to diffuse out of the expandable membrane 5 and into the vascular system of the patient at a controlled rate, upon delivery ofthe expandable membrane to the injured or diseased area. Thus, the rate of diffusion is controlled to suit the circumstances and can range from a very rapid diffusion rate to a long term diffusion rate.

In general, the expandable membrane 5 can be delivered within the vascular system of a patient by any catheter system, such as commonly known dilatation catheters 20 having balloon portions at the distal tips thereof. There are a wide range of catheter systems available, three of which are depicted in FIGS. 3, 4A and 4B. In FIG. 3 a rapid-exchange catheter system is depicted; in FIG. 4A an over-the-wire system is depicted, and in FIG. 4B a perfusion catheter is depicted.

25 For purposes of the present invention, any of these systems S: would suffice, and numerous other catheter systems would be appropriate, including dilatation catheters. Typical dilatation catheter and perfusion balloon catheter systems can Sbe found in U.S Patent Nos 4,323,071; 4,516,972; 5,061,273; 5,137,513; 5,195,971. An advantage to using a perfusion balloon catheter system is that the balloon can remain inflated for longer periods of time as it allows blood flow to continue in the vessel while the balloon is inflated.

While the expandable membrane 5 can be mounted directly onto the balloon portion of a catheter for intraluminal delivery, the preferred embodiment involves deploying the expandable membrane 5 in the vascular system of -13a patient by use of an intravascular stent. Thus, FIGS. 4A, 4B, 5 and 5A illustrate a stent delivery system which embodies features of the invention for implanting the expandable membrane Referring to FIG. 3, the rapid-exchange delivery system includes a delivery sheath 10 which has an outer lumen 11 and an intravascular catheter 12 disposed within the outer lumen 11. The intravascular catheter has an elongated catheter body 13 and a balloon 14 on the distal portion of the catheter body. A manipulating device 15 is provided on the distal end of the delivery system which is employed to affect relative axial or longitudinal movement between the delivery sheath and the intravascular catheter 12. An expandable stent 16, which is to be delivered and implanted within a body lumen of a patient, is mounted on the exterior of the balloon 14. The stent disclosed in U.S. Serial No. 08/164,986, which is commonly assigned to Advanced Cardiovascular Syustems, Inc., is suitable for use with the present invention. Such stents are expandable and deform beyond their elastic limit to hold open the vessel wall in which they are implanted.

The delivery sheath 10 has a distal port 17 in its [r *distal end which is in fluid communication with the outer lumen 11 and a proximal port 18 disposed proximally to the distal 2 port. The distal portion of delivery sheath 10 tapers down in 25 a spherical-like manner so that the cross-sectional area is somewhat less in the distal region than the cross-sectional area of the rest of the delivery sheath. A slit 19 extends from the proximal port 18 to a location just proximal to the distal port 17.

The intravascular catheter 12 has a distal port and a proximal port 21 which are in fluid communication with a first inner lumen 22 extending within the distal portion of the catheter 12 and being adapted to slidably receive a guidewire therein. A slit 23 extends from the proximal port 21 to a location 24 proximal to the proximal end of balloon 14. The proximal end of the guidewire-receiving first inner lumen 22 is provided with a ramp 25 to guide the proximal end of a -14guidewire 26 out of the proximal port 21 of an intravascular catheter 12 when the catheter is mounted onto the guidewire, as will be discussed hereinafter. A second, much longer inner lumen 27 is provided within the catheter body 13 to direct inflation fluid from the proximal end of the catheter body to the interior of balloon 14.

Proximal to the proximal port 21 in the catheter body 13 is a stiffening member 28 which is disposed in the third inner lumen 29 provided within the catheter body 13. As shown in the drawings, the third inner lumen 29 and the first inner lumen 22 may be the same lumen with a plug 30 separating the two lumens. The ramp 25 is on the distal side of the plug *In a typical stent deployment, the expandable membrane 5 is loaded onto the stent 16 so that it covers the stent without overlapping the ends of the stent. The expandable membrane and intravascular stent will be implanted in the vascular system of a patient to treat the diseased and injured area and to allow sufficient blood flow through the vessel. Thus, as depicted in FIGS. 5-8 (including FIGS. SA and 8A), the intravascular stent 16 and the expandable membrane S aare implanted in the vascular system of the patient.

Typically, in these situations there usually will be a guidewire 26 (or other guiding member) which extends across the damaged section of the artery such as shown in FIG. 6. The 25 proximal end of the guidewire 26, which extends out of the patient during the entire procedure, is inserted through the distal port 20 in the distal end of the catheter 12 and advanced proximally through the first inner lumen 22 until the proximal end of the guidewire impacts the ramp 25 and is thereby directed through the proximal port 21.

The intravascular catheter 12 preferably is positioned within the outer lumen 11 of the delivery sheath so that at least a significant portion of the proximal port 18 in the sheath is in alignment with the proximal port 21 of the intravascular catheter. In this manner, proximal advancement of the guidewire 26 through the inner lumen 22 also will direct the proximal end of the guidewire out the proximal port 18 in the delivery sheath. The proximal end of the guidewire 26 then may be manually held to maintain the position of the guidewire within the vasculature of the patient, while the stent delivery system is advanced over the guidewire and through the vascular system. The advancement of the stent delivery system with the expandable membrane 5 mounted thereon continues until the distal ends of the catheter and sheath extend adjacent to or across the injured or diseased area. Next, the manipulator on the proximal end of the delivery system is actuated to move sheath 10 proximally with respect to the catheter 12 and to thereby expose the stent 16 and the expandable member 5 which are mounted on balloon 14. Thereafter, inflation fluid is .s directed under substantial pressure through the inflation lumen 27 in the catheter body 13 to the interior of the balloon 14, thereby expanding the balloon and simultaneously expanding the stent 16 and the expandable member 5 against the vessel wall as shown in FIG. 7. After the balloon 14 is deflated, the delivery systems, both the sheath 10 and the catheter 12, are 2 removed from the patient along with the guidewire 26, leaving the expanded the stent 16 pressing against the expandable Smember 5, which is in contact with the vessel wall as is shown in FIGS. 8 and 8A.

The therapeutic drug contained within the expandable membrane 5 then can diffuse directly into the vessel wall at a 4t 25 the area of the injured or diseased vessel to provide treatment.

In another embodiment of the invention, as depicted in FIG. 4A, an over-the-wire catheter system is employed to carry the stent 16 and the expandable membrane 5 within the patient's vasculature to the damaged area. A guidewire 26 is employed to cross a damaged area and locate the position within the patient so that the intravascular catheter can reach the diseased or injured area. As is typical in over-the-wire catheter systems, the intravascular catheter has an outer member 77 and an inner member 78 which are coaxially aligned.

The inner member 78 has an inner lumen 79 which carries the guidewire 26. The guidewire can move freely within the inner -16lumen 79 in an axial direction. The intravascular catheter is slidably-disposed within the sheath 10 in the inner lumen 11.

The port 17 at the distal end of the sheath 10 provides an opening through which the catheter can extend.

The method of deploying the expandable membrane 5 is similar to that which is described for the rapid exchange system explained above and as is depicted in FIGS. 3, 5-8, and and 8A. Generally, a guidewire 26 is positioned at a location just past the injured or diseased area and the catheter system is threaded over the guidewire 26 so that the balloon 14, along with the stent 16 and the expandable membrane are positioned at the injured or diseased area. Thereafter, the balloon 14 is expanded radially outwardly to thereby expand the stent 16 and the expandable membrane 5. The expandable 15 membrane 5 is sandwiched between the vasculature of the patient and the stent 16. The balloon 14 then is deflated and the catheter system is withdrawn from the vasculature of the patient leaving the stent 16 and the expandable membrane securely implanted in the injured or diseased area. The therapeutic drugs within the expandable membrane 5 then diffuse *into the vessel wall of the patient to treat the injured or diseased area.

The expandable membrane 5 also can be delivered :intraluminally by loading it onto a perfusion-type dilatation catheter of the type disclosed in U.S. Patent No. 5,195,971 (Sirhan) and as depicted in FIG. 4B. One advantage in using a perfusion catheter is that blood continues to flow on both sides of the balloon while it is inflated thereby allowing longer balloon inflation times. Thus, as shown in FIG. 4B, the expandable membrane 5 may be loaded directly onto the balloon 41, or onto a stent that is carried by the balloon. The balloon 41 is mounted on a tubular extension 40 which is carried by the perfusion catheter. The proximal end of the balloon 41 is attached to the distal section 42 of the catheter. The perfusion catheter has an inflation lumen 43 and a guidewire lumen 44. The inflation lumen 43 will carry inflation fluid to expand the balloon 41 and the expandable 17membrane 5. The guidewire lumen 44 will receive a guidewire (not shown) similar to that which is depicted in FIG. 4A. In order to permit blood to flow continuously while the balloon 41 is expanded, a plurality of perfusion ports are incorporated into the catheter. Thus, proximal perfusion ports 46 and distal perfusion ports 47 permit blood to flow through the guidewire lumen 44 while the balloon 41 and the expandable membrane 5 are in their expanded condition. Intraluminal delivery and implanting are similar to that which is described for the over-the-wire catheter of FIG. 4A. By using a perfusion-type catheter system, the expandable membrane 5 does not have to be implanted because it can be delivered and expanded into contact with the vessel wall for long periods of time without adverse effects to the patient. When the drug has S. 15 diffused, the perfusion balloon is deflated and the elastic oooo membrane 5 elastically contracts along with the deflated balloon. The entire catheter system and the elastic membrane *5 are then removed from the patient.

In another embodiment of the invention, as depicted in FIGS. 9 and 10, the expandable membrane 5 has a first layer 80 and second layer 81 spaced apart. The first layer 80 and second layer 81 are then joined along their edges to form a fluid-tight seal 82 along all of their edges. Both the first •layer 80 and second layer 81 can be formed from any of the 44 25 expandable and elastic materials described above with respect to the elastic membrane depicted in FIG. i.

Before joining the first layer 80 to the second layer 81, a plurality of apertures 84 (holes) are formed in the first layer 80 by known methods, such as using a laser or other means for making micro-holes in an elastic membrane. Holes 84 are formed in a first layer 80 while it is in stretched condition so that when the first layer 80 is in a relaxed condition the holes will close to form a fluid-tight seal.

Once the first layer 80 and second layer 81 have been joined together, the layers are stretched and a therapeutic drug is injected through any of the holes 84 to fill a cavity 83 which has been formed between the two joined layers. After -18the therapeutic drug is injected into the cavity 83, the expandable membrane is relaxed and the holes 84 close so that the therapeutic drug is contained within the structure. The expandable membrane 5 as depicted in FIG. 11 now is ready to be rolled into a cylindrical configuration. It also may be desirable to roll the membrane so that the edges abut rather than overlap so that in order to reduce the profile of the cylindrical shape.

Delivery of the expandable membrane 5 of FIG. 11 is similar to that which is described for the expandable membrane of FIGS. i, 2A and 2B. Again referring to the expandable membrane of FIG. 11, it can be mounted on a stent which is e"00 mounted on the balloon portion of the catheter. Thereafter, the catheter, along with the expandable membrane and stent, is S* 15 delivered intraluminally as described above. Unlike the prior .description relating to the expandable membrane of FIGS. 2A and 2B, expanding the expandable membrane 5 of FIG. 11 will force the therapeutic drug through the holes 84 when the expandable membrane is expanded by the balloon 14 and the stent 16 upon which the membrane is mounted. Thus, as the expandable ~membrane 5 gets larger, the holes 84 begin to open allowing the diffusion of the therapeutic drug into the vessel wall of the patient. As the balloon expands the stent 16 expands, radially •outwardly and it increases the pressure on the expandable **25 membrane 5 and causes yet more of 'he therapeutic drug to diffuse outwardly into the vessel wall of the patient. The expandable membrane 5 then is sandwiched between the vessel wall and the stent 16 when the balloon 14 is fully expanded and the stent is implanted against the vessel wall. Thus, the therapeutic drug is injected at the injured or diseased area to provide maximum treatment at the specific site. The invention eliminates systemic levels of drugs which may well result in negative (undesirable) side effects such as bleeding complications and toxicity. The polymer sleeve also may be loaded in matrix format to allow for sustained release of the same or a different drug.

-19- In another embodiment of the invention, as depicted in FIG. 11A, a pair of seamless cylindrical tubes, concentrically aligned, form the expandable membrane 5. An inner tubular member 100 is surrounded by an outer tubular member i01 and the ends 102,103 are sealed by any known method such as welding or by adhesives. A reservoir 104 is formed between the inner and outer tubular members 100,101 for receiving a therapeutic drug. A plurality of micro-holes 105 is formed in the outer tubular member 101 by a laser or other known method. While the expandable membrane 5 is in a stretched condition, the therapeutic drug is injected into the reservoir 104 through the micro-holes 105, and thereafter the .expandable membrane 5 is relaxed, thereby closing the microholes 105 and trapping the therapeutic drug in the reservoir 15 104. The expandable membrane 5 of FIG. 11A then can be loaded onto a stent 16 and implanted against a vessel wall in the same manner as previously described for FIG. 11ii. Once the expandable membrane 5 is expanded, the therapeutic drug is injected through the micro-holes 105 directly into the vessel wall.

It should be understood that with all of the :*embodiments described herein, the expandable membrane 5 also can carry one or more therapeutic drugs in a matrix format.

For example, again referring to FIG. llA, inner and outer •a 25 tubular members 100,101 each may be loaded with one or more therapeutic drugs in a matrix form. When the expandable membrane 5 is implanted as described above, the therapeutic drug(s) contained in the matrix will release into the vessel wall at a predetermined rate. The therapeutic drug in the reservoir 104, however, will be injected into the vessel wall rapidly as previously described. Thus, by providing a combination of drugs within the reservoir 104 and in matrix form in the inner and outer tubular members 100,101, drugs are continuously administered at a specific site over a long period of time. For example, the inner tubular member I00 can be loaded with a sustained-released antithrombotic drug since the inner tubular member is in direct contact with the blood flow.

The outer tubular member i01, which is pressed against the vessel wall, can be loaded with a sustained-release antiproliferative drug. Depending on the drug and the polymer used, in excess of forty percent by weight of a drug can be loaded into the tubular members 100,101.

In another embodiment of the invention, as depicted at FIGS. 12 and 13, the expandable membrane 5 is substantially thicker than previously described, and on the order of the 0.25-1.3 millimeters (0.010-0.050 inch). In this embodiment, an elastic sheet 90 contains a plurality of micro-pockets 91 which have a depth of several millimeters, but which do not extend entirely through the sheet 90. Thus, the micro-pockets 91 each have a bottom 92 and are hollow for receiving a therapeutic drug. The micro-pockets 91 can be formed by laser 15 drilling or conventional drilling while the expandable membrane 5 is in a stretched condition, as depicted in FIG. 12.

Thereafter, the expandable membrane 5 is relaxed and the micropockets 91 close tightly thereby containing the therapeutic drug therein. As depicted in FIG. 13, the sheet 90 is rolled into a cylindrical form so that it may be delivered intraluminally in the same manner as the expandable membrane depicted in FIGS. 9-11. In the preferred form, the micropockets 91 are filled with a therapeutic drug in the form of micro-spheres as described herein. The micro-pockets 91 (FIG.

0 13) may be covered with a thin film that will act as a ratelimiting membrane (not shown). Such rate-limiting membranes are well known and can be of the perfusion membrane type, or can be a hydrophilic coating that dissolves quickly upon exposure to the vessel of the patient. Commonly known hydrophilic coatings include hydrogel, glucose, acetate, agar and starch. Until expandable membrane 5 is expanded, the therapeutic drug in the micro-pockets 91 is sealed in by the rate-limiting membrane. Upon expansion of the membrane 5, the drug diffuses from the micro-pockets 91 through the ratelimiting membrane at a predetermined rate. The rate-limiting membrane can be laminated to the sheet 90 as herein described.

-21- The expandable membrane 5 depicted in FIG. 12 need not be formed solely from a flat sheet but also can be formed from a seamless tubular member similar to that shown in FIG.

2B. In this embodiment as well as with FIGS. 12-13, a therapeutic drug can be in the form of a matrix combined with the polymer comprising the expandable membrane 5. By loading the drug into matrix form, the time during which the drug diffuses into the vessel wall can be controlled to allow for various stages of disease treatment and recovery. Further, multiple drugs in the matrix can be diffused at rates that coordinate with the particular injury or disease to provide optimal treatment. The matrix can be dispersed in the expandable membrane 5 by known methods including solvent casting, coating, absorption or melt processing.

15 The membrane 5 as described herein also can be made from bioabsorbable materials which will completely absorb into the vascular system of the patient over time. The membrane **can be made from members or co-members of the linear aliphatic polyester family, polyurethanes, and composites.

The dimensions of the intravascular catheter 0°4. described herein generally will follow the dimensions of 44intravascular catheters used in angioplasty procedures in the same arterial location. Typically, the length of a catheter •for use in the coronary arteries is about 150 centimeters, the outer diameter of the catheter shaft is about 0.89 millimeters (0.035 inch), the length of the balloon is typically about 2 centimeters, and the inflated diameter is approximately 1 to about 8 millimeters.

The materials of construction may be selected from those used in conventional balloon angioplasty catheters. The delivery sheath enerally will be slightly shorter than the intravascular catheter, by about the length of the manipulating device 15, with an inner diameter large enough to accommodate the intravascular catheter and to allow the catheter free longitudinal movement therein. The sheath and the catheter shaft can be made of conventional polyethylene tubing, or any other suitable material.

-22- While the present invention has been described herein in terms of delivering an expandable membrane and intravascular stent to a desired location within a vascular system of a patient, the delivery system can be employed to deliver expandable membranes and/or stents to locations within other body lumens, such as peripheral arteries and vessels, the urethra, or the fallopian tubes, so that the stents can bexpanded to maintain the patency of these body lumens. Other areas in which an expandable membrane might be implanted on the iliac arteries, the aorta, or virtually any other body lumen.

Various changes and improvements also may be made to the invention without departing from the scope and spirit thereof.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgement or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Claims

1. An expandable sheath delivery system for delivering a therapeutic drug in a body lumen, comprising: a therapeutic drug; an expandable membrane in the form of a cylindrical member having a first end and a second end and a first layer and a second layer, each layer having an edge, the first and second layers being bonded together along the edges to form a reservoir therebetween adapted to receive and hold the therapeutic drug; the expandable member being configured so that it independently lacks the structural integrity to hold open and maintain the patency of the body lumen; and means for intraluminally delivering and expanding the expandable membrane in the body lumen so that the therapeutic drug can be eluted through at least one of the layers at a specific site in the body lumen.

2. The expandable sheath delivery system of claim 1, wherein the expandable membrane is made from materials taken from the group of materials consisting of the linear aliphatic S polyester family, polyurethanes, latexes, urethanes, 0 5 polysiloxanes, ethylene vinyl acetate, and modified styrene- ethylene/butylene-styrene block copolymers (SEBS). 0*S* S• 3. The expandable sheath delivery system of claim 1, wherein the therapeutic drug is taken from the group of drugs consisting of antiplatelets, antithrombins, and antiproliferatives.

4. The expandable sheath delivery system of claim 3, wherein the therapeutic drug is combined with the expandable membrane in a matrix by any process of solvent casting, coating, melt processing, or absorption. -24- The expandable sheath delivery system of claim 1, wherein the means for intraluminally delivering and expanding the expandable membrane is a catheter system having a proximal end, a distal end, and a balloon portion at the distal end with the expandable membrane affixed to the balloon portion.

6. The expandable sheath delivery system of claim wherein the catheter system includes a perfusion balloon to permit fluids to flow on both sides of the perfusion balloon when the perfusion balloon is fully expanded.

7. The expandable sheath delivery system of claim 1, wherein the means for intraluminally delivering and expanding the expandable membrane is a catheter having a proximal end, a distal &Pao end, and a balloon portion at the distal end with an 5 intravascular stent mounted on the balloon, the expandable Smembrane being attached to the stent to form a cylinder around the stent.

8. The expandable sheath delivery system of claim 1, g wherein the cylindrical member is seamless. 0

9. The expandable sheath delivery system of claim 1, wherein a plurality of apertures are provided in the first layer. The expandable sheath delivery system of claim 9, wherein the plurality of apertures provided in the first layer are formed by a laser when the expandable membrane is in a ST3tretched condition.

11. The expandable sheath delivery system of claim wherein the therapeutic drug is loaded into the reservoir through the plurality of apertures when the membrane is in the stretched condition.

12. The expandable sheath delivery system of claim 11, wherein the expandable membrane retains the therapeutic drug within the reservoir when the membrane is in a relaxed condition.

13. The expandable sheath delivery system of claim 12, wherein the first edge and the second edge overlap and are attached to each other.

14. The expandable sheath delivery system of claim 12, wherein the first edge and the second edge abut and are attached to each other. oooo ooi ~15. The expandable sheath delivery system of claim 12, wherein the means for intraluminally delivering and expanding the expandable membrane is a catheter having a proximal end, a distal end, and a balloon portion at the distal end with the expandable membrane attached to the balloon portion for intravascular transport and delivery to a specific site in the body lumen.

16. The expandable sheath delivery system of claim wherein the balloon portion expands, thereby expanding the expandable membrane and forcing the therapeutic drug in the reservoir to diffuse through the apertures and into the lumen all. -26-

17. The expandable sheath delivery system of claim 1, wherein the first layer has an outer surface loaded with a sustained release therapeutic drug so that when the outer surface contacts the body lumen the drug diffuses into the body lumen at a predetermined rate.

18. The expandable sheath delivery system of claim 17, wherein the sustained release therapeutic drug is an antiproliferative drug.

19. The expandable sheath delivery system of claim 1, wherein the second layer has an inner surface in contact with blood flow that is loaded with a sustained release antithrombotic drug for diffusing into the blood at a predetermined rate. oeo.

20. The expandable sheath delivery system of claim 1, wherein the expandable membrane is bioabsorbable.

21. An expandable sheath delivery system for delivering a Stherapeutic drug in a body lumen, comprising: an expandable membrane having a first layer and a second layer affixed to each other along their edges to form a drug-containing reservoir therebetween; a plurality of apertures on the first layer through which a therapeutic drug can diffuse from within the drug- containing reservoir, the plurality of apertures remaining open when the first layer is in a stretched condition and the apertures tightly closing when the first layer is in a relaxed condition; the expandable member being configured so that it independently lacks the structural integrity to hold open and maintain the patency of the body lumen; and means for intraluminally delivering and expanding the expandable membrane in the body lumen so that the therapeutic drug can be eluted at a specific site in the body lumen. -27-

22. The expandable sheath delivery system of claim 21, wherein the therapeutic drug within the drug-containing reservoir is taken from the group consisting of antiplatelets, antithrombins, and antiproliferatives.

23. The expandable sheath delivery system of claim 21, wherein the means for intraluminally delivering and expanding the expandable membrane is a catheter having a proximal end, a distal end, and an expandable balloon portion at the distal end with an intravascular stent mounted thereon, the expandable membrane being affixed to the stent by rolling the expandable membrane to form a cylinder around the intravascular stent.

24. The expandable sheath delivery system of claim 23, wherein the expandable balloon expands from a first diameter to a second enlarged diameter, thereby expanding the stent and the expandable membrane so that the stent and the expandable membrane are implanted in the body lumen.

25. The expandable sheath delivery system of claim 21, wherein the plurality of apertures on the first layer open when the expandable membrane is expanded by the expandable balloon and intravascular stent, so that as the plurality of apertures open the therapeutic drug diffuses from within the drug-containing reservoir into the body lumen. .S S

26. The expandable sheath delivery system of claim 21, wherein the first layer has an outer surface loaded with a sustained release therapeutic drug so that when the outer surface contacts the body lumen the drug diffuses into the body lumen at a predetermined rate. -28-

27. The expandable sheath delivery system of claim 26, wherein the sustained release therapeutic drug is an antiproliferative drug.

28. The expandable sheath delivery system of claim 21, wherein the second layer has an inner surface in contact with blood flow that is loaded with a sustained release antithrombotic drug for diffusing into the blood at a predetermined rate.

29. An expandable sheath delivery system for delivering a therapeutic drug in a body lumen, comprising: mm an expandable membrane in the form of a cylindrical member having a first end, a second end, and a lumen 5 therethrough; a therapeutic drug combined with the expandable membrane; a catheter system for intraluminally delivering and expanding the expandable membrane in the body lumen, the catheter :0 system having a distal end, a proximal end, and a balloon portion at the distal end; the expandable member being configured so that it independently lacks the structural integrity to hold open and maintain the patency of the body lumen; and means for loading the expandable membrane on the balloon portion of the catheter system so that when the balloon portion is inflated, the balloon portion expands radially outwardly to expand the expandable membrane into contact with the body lumen so that the therapeutic drug can be eluted at a specific site in the body lumen. The expandable sheath delivery system of claim 29, wherein the balloon portion of the catheter is a perfusion balloon permitting blood flow on either side of the perfusion lloon when the perfusion balloon is fully expanded. 1! -29-

31. The expandable sheath of claim 29, wherein the expandable membrane has a low modulus of elasticity and can expand to at least 300% of its initial size.

32. An expandable sheath delivery system for delivering a therapeutic drug in a body lumen, comprising: an expandable membrane in the form of a cylindrical member and having an inner surface and an outer surface; a plurality of micro-pockets disbursed upon the outer surface but not penetrating through to the inner surface; a therapeutic drug for loading into the micro-pockets; the expandable member being configured so that it independently lacks the structural integrity to hold open and maintain the patency of the body lumen; and means for intraluminally delivering and expanding the expandable membrane in the body lumen so that the therapeutic drug can be eluted at a specific site in the body lumen.

33. The expandable sheath of claim 32, wherein the plurality of micro-pockets are covered by a rate-limiting membrane so that as the expandable membrane is expanded, the therapeutic drug diffuses from the micro-pockets and through the rate-limiting membrane at a predetermined rate.

34. An expandable sheath for delivering a therapeutic drug substantially as hereinbefore described with reference to the drawings. An expandable sheath delivery system for delivering a therapeutic drug substantially as hereinbefore described with reference to the drawings. DATED this 25th day of September,

2000. Advanced Cardiovascular Systems, Inc. by DAVIES COLLISON CAVE S/.S ent Attorneys for the Applicant