Systemic and localized drug delivery can be achieved using a wide variety of techniques, including injection, infusion, transdermal delivery, intralumenal delivery, and the like, each of which has associated advantages and disadvantages. Most of these techniques will be useful for both delivering a bolus of the drug and for delivering the drug continuously over time. For example, injection techniques, including intravascular, intramuscular, and subcutaneous injection, are primarily useful for delivering a single bolus of the drug, where the injections must be repeated in order to maintain a desired systemic concentration of the drug. In many cases, it is desirable to deliver a drug continuously in order to maintain a relatively constant in vivo concentration and bioavailability. Continuous delivery can be achieved by infusion, but requires the patient to be attached to a pump or other infusion device. Such attachment over long periods of time is both inconvenient and exposes the patient to risk of infection. Continuous drug delivery may be more conveniently achieved using transdermal patches, but such patches are useful only with a small number of drugs and do not always achieve a sufficient intravascular concentration of the drug to be effective.

At least partly due to the limits on intravascular drug delivery, a number of vascular conditions cannot be

treated pharmacologically and require surgical interventions.

For example, peripheral vascular disease (PVD) is a common atherosclerotic disease of the lower extremities which, in the worse cases, can require amputation. PVD can cause both chronic ischemia and thrombotic occlusion within the arteries of the lower limbs, and treatment by infusion with heparin and thrombolytic agents is not always effective. When such drug therapy is ineffective, surgical intervention including embolectomy, balloon angioplasty, stent placement, atherectomy, and bypass grafting are commonly performed.

For these reasons, it would be desirable to provide improved methods and devices for the intralumenal delivery of bioactive agents. It would be particularly desirable to provide methods and devices for releasing bioactive agents directly into blood vessels and other body lumens continuously for relatively long periods of time, typically on the order of hours, days, or weeks, without the need to connect the patient to external infusion devices. It would be further desirable to provide methods and devices for implanting a drug delivery device which provides for the controlled release of drug from a reservoir to the body lumen over such time. Such devices should be easy to implant, provide little or no risk to the patient, require no connection to external apparatus or components, and be compatible with conventional vascular access procedures, such as percutaneous arterial punctures used in accessing the vasculature for introduction of conventional intravascular catheters. It would be still further desirable to provide methods and devices which are useful in-the treatment of peripheral vascular disease. At least some of these objectives will be met by the invention described herein below.

2. Description of the Background Art U.S. Patent Nos. 5,545,208 and 5,342,348, describe stents for the controlled release of bioactive substance in blood vessels and other lumenal environments. PCT WO 95/01138 describes an implantable system for drug delivery in vascular tissues. U.S. Patent Nos. 4,744,364; 4,852,568; 4,890,612;

5,021,059; 5,061,274; 5,192,302; 5,222,974; 5,306,254; 5,326,350; 5,342,393; and 5,370,660 describe closure devices for percutaneous penetrations into blood vessels. The devices comprise biodegradable disks which may be formed from materials having a clot-inducing agent to accelerate hemostasis. Exposure of the clot-inducing agent to blood flow is limited by coating exposed portions of the disk with a waxy coating. Various drug implants are described in U.S. Patent Nos. 4,588,395; 4,578,061; 4,900,303; and 4,941,874.

Catheters for the localized delivery of drugs and other bioactive agents are described in, for example, U.S. Patent Nos. 5,279,565 and 5,336,178.

SUMMARY OF THE INVENTION The present invention provides improved methods and devices for the continuous delivery of bioactive agents to body lumens, particularly to blood vessels, for a variety of therapeutic and diagnostic purposes. The methods rely on implantation of an eluting element through a percutaneous penetration directly into the body lumen, preferably so that the eluting elements lies against the wall of a body lumen.

The eluting element will usually be positioned using a positioning member which may be introduced through a previously formed tissue penetration or which may be self- introducing, e.g. being a needle or other instrument having a sharpened distal tip. The eluting element releasibly contains one or more bioactive substance(s) and releases such substance(s) into the body lumen in a controlled manner over time. The eluting element will usually be porous to contain the bioactive substance(s) and will more usually be bioerodible so the bioactive substance(s) will be released as the material of the eluting element erodes over time. The use of bioerodible eluting elements and other components of the system is advantageous since the components do not need to be removed after they have been fully eroded.

Thus, the present invention provides a number of advantages over the art described above. The eluting elements of the present invention may be introduced using minimally

invasive techniques where very small tissue penetrations are percutaneously formed to the target site, e.g. to an artery or the blood vessel. The eluting element may be introduced simultaneously with formation of the penetration, or may be introduced after the penetration is initially formed, optionally for other purposes. In either case, the eluting element may further act as a plug or seal for the penetration, thus preventing loss of lumenal fluids through the tissue penetration and promoting healing. Eluting elements can be introduced relatively close to the desired treatment regions within the patient's body. For example, for the treatment of peripheral vascular disease (PVD), the eluting elements containing appropriate bioactive substances can be introduced to the femoral or other suitable artery so that the bioactive substance is released directly to the arteries of the lower extremities.

In a first aspect of the present inventioii, a method for delivering a bioactive agent to a body lumen comprises forming a percutaneous tissue penetration to a target site within the body lumen. An elution element releasibly containing the bioactive substance(s) is positioned at or near a distal end of the percutaneous tissue penetration, where the elution element releases the bioactive agent as the elution element is exposed to the fluid within the body lumen.

Preferably, the elution element will be folded or otherwise collapsed as it is introduced through the tissue penetration, and the positioning step will further comprise opening the elution element from its folded configuration to an unfolded configuration within the body lumen. In an exemplary embodiment, the elution element is constrained within a needle or delivery sheath, and is deployed by ejecting the elution element therefrom. Once it is released into the body lumen, the elution element will unfold or unfurl due to its resilient nature or as a result of an active deployment step, e.g. inflation, mechanical opening, or the like.

In another specific aspect of the method of the present invention, the elution element will be positioned

against the lumenal wall by pulling back on the elution element, e.g., using a tether which is connected to the elution element and which then passes outwardly through the tissue penetration. In this way, the elution element can be conformed to the interior surface of the body lumen, e.g. to the inner blood vessel wall, in order to reduce blockage of the body lumen. This is particularly important with blood vessels where any intrusion into the blood vessel lumen can be a site for thrombus formation. In the exemplary embodiments, the body lumen is a blood vessel, and the blood vessel is usually an artery. For the treatment of PVP, the preferred blood vessel will be the femoral artery.

The bioactive agent will be selected to treat a coidition of interest. The bioactive agent(s) may be selected çrom the group consisting of angiogenic factors, thrombolytic agents, anti-thrombotic agents, cellular response-mediating agents, anti-restenosis agents, antibiotics, anti-fungal agents, and the like. The bioactive agent(s) may be any form of substance which can be immobilized within the eluting element, including small (low molecular weight) organic molecules, carbohydrates, peptides, proteins, nucleic acids (oligonucleotides), viral vectors, cellular material (such as endothelial cells which have been modified to produce therapeutic proteins), or the like. Any of these agents which can enhance peripheral circulation may be used for treatment of PVD.

The eluting element usually comprises a porous polymeric matrix, where the matrix is a flexible disk having a diameter in the range from 5 mm to 20 mm and a thickness in the range from 0.25 mm to 5 mm. Usually, the porous polymeric matrix degrades in situ (i.e. in the lumenal environment) usually degrading fully over a time period in the range from 3 days to 10 years. The porous polymeric matrix may be composed of a variety of particular polymers which are biocompatible and bioerodible. Exemplary polymer systems include lactic acid/glycolic acid copolymer, carbophenoxy propane/sebacic acid, polycaprolactones, polyanhydrides, polyorthoesters, and

polyosphoesters. Other suitable polymers include silicones, ethylene-vinylacetate copolymer and poly(vinylalcohol).

In a second aspect of the present invention, devices for delivering bioactive agents comprise a bioeluting element, generally as described above, having a tether attached thereto. The tether has a length sufficient to extend through a tissue penetration, typically being in the range from 5 cm to 25 cm, and a proximal end of the tether may secured to a skin surface of the patient proximate the penetration. As described above, the tether is useful for maintaining the bioeluting element within the body lumen and positioning the bioeluting element, preferably by drawing bioeluting element against a wall in the region where the penetration is located.

The tether is preferably bioerodible, comprising for example of bioerodible suture.

In another aspect of the present invention, a system for delivering a bioactive agent to a body lumen comprises a bioeluting element, generally as described above, and a delivery device for percutaneously positioning the bioeluting element at or near a distal end of a tissue penetration proximate a lumen of the body lumen. The delivery device may comprise a needle having a hollow shaft and a sharpened distal tip, where the bioeluting element is carried within the needle so that it may be ejected from the needle after the needle has been penetrated through tissue to the target site.

Alternatively, the delivery device may comprise a sheath which may be introduced through a previously formed tissue penetration, where the bioeluting element is carried within the sheath and may be deployed from the sheath after the sheath reaches the target site. As a third alternative, the delivery device may comprise a stylet which carries the bioeluting element on its exterior surface. The stylet may be sharpened for self-introduction or may be blunt for introduction through a previously formed tissue penetration.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a perspective view of an elution element constructed in accordance with the principles of the present invention and having a disk-shaped polymeric matrix.

Fig. 2 illustrates the elution element of Fig. 1, shown with the porous matrix in a collapsed configuration.

Fig. 3 illustrates a needle-type delivery device for implanting the eluting element of Figs. 1 and 2 in a body lumen.

Fig. 4 illustrates a sheath-like delivery device for implanting the eluting element of Figs. 1 and 2 in a body lumen.

Fig. 5 illustrates a stylet-type device for implanting the eluting element of Figs. 1 and 2 in a body lumen.

Figs. 6-9 illustrate use of the needle-type delivery device of Fig. 3 for implanting the eluting element of Figs. 1 and 2 into a blood vessel according to the method of the present invention.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS The present invention provides methods and devices for delivering bioactive agents to body lumens, particularly blood vessels, including both arteries and veins. The present invention is particularly useful for treating peripheral vascular disease (PVD) by implanting an eluting element in the femoral artery, but will also find use in treating a wide variety of other vascular conditions by implanting such eluting elements into other arteries and veins. The present invention will also find use in delivering bioactive agents to a wide variety of other natural body lumens, such as the upper and lower gastrointestinal tract, the genitourinary tract, and the like, as well as implantable lumens, such as A/V shunts, vascular prostheses, and the like.

The bioactive agents delivered by the methods and devices of the present invention may be therapeutic agents or diagnostic agents. By "therapeutic agent" it is meant that the bioactive agent will treat some diseased state or

condition of the patient. The treatment may be systemic, i.e.

effecting the entire body or a portion of the body remote from the treatment site, or maybe localized, i.e. located at or near the region of vasculature or other body lumen where the bioactive agent is being released. Exemplary bioactive agents include angiogenic factors, such as vascular endothelial growth factor (VEGF), acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF); thrombolytic agents, such as urokinase, streptokinase, tissue plasminogen activator (tPA), pro-urokinase (P-UK), APSAC; anti-thrombotic agents such as heparin, low molecular weight heparin, thrombin inhibitors (e.g. hirudin, hirulog, PEG-hirudin, PPACK, and argatroban), extrinsic pathway inhibitors (e.g. factor Xa inhibitors, factor VIIa inhibitors, and tissue factor inhibitors) ; platelet inhibitors (e.g., factor IIb/IIIa inhibitors, cycloxygenase inhibitors, and vWf inhibitors; and PAI-1 inhibitors; agents which act on endothelial cells and vasomotion, such as NTG, NO synthase, and L-arginine; anti- restenosis agents; antibiotics; anti-fungal agents; viral vectors; endothelial cells; and other agents which promote regression of atherosclerotic or other diseases.

The present invention relies on forming a percutaneous penetration from outside the patient's body to a target site within a desired body lumen, where the penetration is used to introduce and position the eluting element in a "less invasive" manner. The penetration will usually be formed specifically for the purpose of implanting the eluting element at the lumenal target site. In other cases, however, the penetration could have been made for another purpose, such as an arterial penetration for the introduction of a vascular catheter, an abdominal penetration into the peritoneal cavity for performance of a laparoscopic procedure, or the like. The nature of the penetration is not critical and it is necessary only that it provide sufficient access to permit the introduction, positioning, and release of the eluting element.

Usually, a penetration made with a needle having a gauge in the range from 12 to 20 will be sufficient for most purposes.

As will be further described below, the penetration may be made using a needle, a stylet, or other conventional surgical penetration instrument. In some cases, penetration will be formed initially with a first instrument which is then withdrawn, leaving an access tract through the tissue overlying the body lumen. The elution element may then be positioned using a second, separate positioning instrument which is passed through the previously formed tissue tract.

In other cases, however, a single instrument may be used for both penetrating tissue and positioning the eluting element.

Typically, such instruments will be needles, stylets, or other instruments having sharpened distal tips, where the eluting element is carried in or on the instrument, typically near a distal end thereof, while it is being percutaneously ntroduced. After reaching the target site in the body lumen, the eluting element can be ejected or otherwise removed from the positioning instrument and released into the body lumen.

The eluting element will then be positioned, e.g., by retracting a tether which is attached to a main body portion of the eluting element, so that it is positioned against a lumenal wall of the body lumen.

While the methods and apparatus of the present invention are particularly useful in percutaneous procedures where the eluting element is delivered through skin and tissue overlying the body lumen, they may also find use in open surgical procedures, where the eluting element may be implanted through the wall or membrane of a body organ. In such cases, the tether will typically be attached to an outer surface of the body organ and will thus be enclosed when the open surgical site is closed.

The eluting element will comprise a porous polymeric matrix capable of receiving and holding the bioactive agent therein. Usually, the bioactive agent will initially be present as an aqueous solution or suspension, and may be absorbed into the porous polymeric matrix by conventional techniques. Optionally, the bioactive agent may then be dried, lyophilized, or otherwise immobilized within the porous polymeric or co-polymeric matrix so that its release is

controlled or inhibited. Alternatively, the bioactive agent may be left in an aqueous form so that it may be released into an aqueous lumenal environment after it has been implanted.

In a preferred embodiment, the bioactive agent will be released from the porous polymeric matrix as the polymeric material degrades in the lumenal environment, e.g. vascular environment. The bioactive agent will thus be released together with the erosion of the polymeric matrix, thus carefully controlling the release rate and extending the overall release time.

Thus, the polymeric materials used to form the matrix will often be degradable over time within a vascular or other lumenal environment. That is, the polymers will naturally erode in a physiological environment characteristic of the body lumen into which they are to be delivered. The bioactive agents are entrapped in the polymer are released as the polymer degrades or erodes. Polymers may be synthesized with specific degradation characteristics determining the lifespan of the polymer under the particular physiological conditions to be encountered. The rate of polymer degradation and the concentration of bioactive agent in the polymer together determine the release rate of the bioactive agent to the surrounding lumenal environment. Methods for preparing such degradable polymers are described in the medical and scientific literature. For example, co-polymers of poly[bis(p-carboxyphenoxy) propane anhydride] and sebacic acid may be synthesized to yield desired biodegradation characteristics. Pure poly [bis (p-carboxyphenoxy) propane anhydride has a relatively low erosion rate. Co-polymerizing sebacic acid with poly[bis(p-carboxyphenoxy) propane anhydride] increases the erosion rate. As sebacic acid content increases, the erosion rate may increase by a factor of several hundred. See Leong et al., J. Biomed. Mat. Res.

19:941-955 (1985), incorporated herein by reference. Thus by altering the relative content of each of the components, co- polymers having the desired degradation characteristics may be synthesized.

Many biocompatible polymers are known, including several which are biodegradable. Several are described in Langer, Science 249:1527-1532 (1990) and Langer and Moses J.

Cell. Biochem., 45:340-345 (1991), both of which are incorporated herein by reference. Poly-L-lactide polymers degrade over a period of months under physiological conditions. Lactic acid-glycolic acid copolymers are also well known biodegradable polymers. Other acceptable polymers may contain monomers of hydroxyethylmethacrylate, vinylalcohol, ethylenevinylacetate, lactic acid, or glycolic acid.

Particularly useful polymers in the present invention are polyanhydrides of the general formula - (OOC-C6H4-0 (CH2) x~CO~ ) n where x varies from 1 to 10 or [-(OOC-CH--CH-CO)X-(OOC-R-CO)y~]n as generally described in Chasin et al. "Polyanhydrides as Drug Delivery Systems" in Biodegradable Polymers as Drug Delivery Systems, Langer and Chasin, eds. Mercel Dekker, Inc.

1990, pp. 43-70, incorporated herein by reference. Polymers comprising monomers such as carboxyphenoxyacetic acid, carboxyphenoxyvaleric acid, carboxyphenoxyoctanoic acid, terephthalic acid, and carbophenoxy propane-sebacic acid are examples of polymers acceptable for use in the present invention. Polyosphoesters are another suitable polyanhydride-based polymer.

Polymers containing bioactive compounds may be formulated by a variety of methods well known in the art. For example, polymer matrices having the bioactive compounds incorporated within the matrices may be formulated by molding procedures. Briefly, polymer is ground and sieved to a desired particle size, usually about 90-150 ym. The bioactive compounds are ground and sieved to the same particle size and mixed with the polymer particles. The mixture is injection molded in commercially available molders.

Porous polymeric matrix may have any of a wide variety of geometries, but will typically be in the form of a planar membrane, typically having a thickness in the range

from 0.25 mm to 5 mm. More usually, the porous polymeric matrix will be formed as a flexible disk having dimensions which facilitate percutaneous introduction, as described in more detail below. Exemplary disks will have a diameter in the range from 5 mm to 20 mm, preferably from 10 mm to 15 mm, and a thickness in the range set forth above, preferably from 1 mm to 2 mm. Disks having these dimensions and composed of the materials above may be formed to degrade over a wide range of times, typically being the range from 3 days to 10 years, usually from 2 weeks to 1 year.

The porous polymeric matrix will typically be connected to a flexible tether which can be maintained in the percutaneous tissue tract as the eluting element is being positioned within the body lumen. The tether is desirable for at least two reasons. First, it allows manipulation of the porous matrix and helps assure that the eluting element is not lost in the body lumen. Second, it allows the elutiag element to be drawn back toward the entry point into the body lumen, i.e. the point where the percutaneous penetration reaches the body lumen. Thus, the porous matrix may be used to help cover and inhibit blood or other fluid loss from the blood vessel or other body lumen.

The tether will preferably be resorbable (biodegradable) so that it does not need to be removed after the bioeluting element has self-degraded from the body lumen.

Preferably, the tether can be a biodegradable suture material which can be left in the percutaneous tissue penetration and will be resorbed as the tissue heals. Other suitable materials include the same resorbable materials described above in connection with the eluting element.

The systems of the present invention will comprise the bioeluting element together with a delivery device for percutaneously positioning the bioeluting element at or near the tissue penetration into the body lumen. The delivery device will typically comprise an elongate element which can be used to form the tissue penetration and/or to carry the eluting element through the tissue penetration. In a first exemplary embodiment, the delivery device is a needle having a

hollow shaft with a sharpened distal tip where the bioeluting element is carried within the needle and may be injected from the needle to the target site in the body lumen. The needle will typically have a gauge in the range from 14 to 20, and at length the range from 3 cm to 15 cm. The needle can thus be used to directly penetrate the tissue overlying the target site in the body lumen. For example, for introduction into the femoral artery, the needle can be similar to those needles used perform the Seldinger technique for introducing vascular catheters. After penetrating into the blood vessel, the eluting element can be ejected from the distal end of the needle and withdrawn over the tether which remains in the tissue tract.

Alternatively, the delivery device may comprise a sheath which is introduced through a previously formed tissue penetration. The sheath will carry the bioeluting element in a lumen, where the bioeluting element can be released from the sheath after it has been positioned in the body lumen. The positioning of sheaths through tissue penetrations is a well known surgical procedure that need not be described further.

As a third example, a stylet may be used to carry the eluting element to the target site within the body lumen.

Typically, the eluting element can be placed over an exterior surface of the stylet and the stylet thereafter introduced through a previously formed tissue penetration.

As yet another alternative, the eluting element could be configured to be self-penetrating. For example, the eluting element could be collapsed into a tapered or sharpened tip which could be advanced directly through tissue to the target location in the blood vessel or other body lumen. In such cases, the tether could be in a relatively rigid form (which could optionally become soft when exposed to the fluids in the tissue environment) , or could be a tube or other delivery device could be used for advancing the eluting element directly through the tissue.

Referring now to Figs. 1 and 2, an exemplary eluting device 10 comprising a disk-shaped polymeric matrix 12 and a tether 14 attached to the center of the disk is illustrated.

The disk will have dimensions generally set forth above and is shown in its deployed (unconstrained) configuration in Fig. 1.

The disk 12 may be collapsed, as shown in Fig. 2, to facilitate introduction through a percutaneous tissue penetration, as will be described below.

Referring now to Fig. 3, a needle-type deployment device 20 is illustrated. The needle comprises a hollow shaft 22 having a sharpened distal tip 24 and a proximal handle 26.

The eluting element 10 may be carried within the hollow lumen of the needle 20 with the collapsed disk 12 near the distal end and the tether 14 running outwardly through the proximal end,- as illustrated. Use of the needle-type delivery device 20 for implanting the elution element 10 within a blood vessel is shown below in Figs. 6-9.

A sheath-type delivery device is illustrated in Fig.

4. The sheath-like delivery device comprises a sheath 32 and a plunger 34. The elution element 10 is carried with the collapsed disk 12 positioned near a distal end of the sheath 32 and the tether 14 extending outwardly through the plunger 34. A sheath-type device 30 may be positioned through a previously formed tissue penetration, optionally a tissue penetration having a sheath therein which has already been implanted. After the distal end of the sheath 32 reaches the target site in the body lumen, the plunger 34 may be used to eject the disk 12 into the body lumen. After reaching the body lumen, the disk will open to the configuration shown in Fig. 1. The tether 14 may then be used to draw the disk 12 back against the lumenal wall in the region of the tissue penetration.

Referring now to Fig. 5, a stylet-type delivery device is illustrated. The stylet includes a rod 42, a conical element 44 at its distal end, and a handle 46 at its proximal end. The disk 12 of elution element 10 may be wrapped around the exterior of the shaft 42 with the tether 14 lying generally parallel to the proximal portions of the shaft. The stylet-type device may then be used to introduce the elution element through a previously formed percutaneous tissue penetration.

Referring now to Figs. 6-9, use of the needle-type delivery device 20 for implanting the disk 12 (not shown) in the lumen L of a blood vessel BV will be described. The sharpened distal tip 24 of the needle-type device 20 is introduced through the tissue T overlying the blood vessel BV in a conventional manner. Typically, the needle will be introduced until blood reflux is noted, indicating that the distal tip has penetrated into the blood vessel lumen L. A rod 28 or other elongate element may then be used to push the disk element 12 out of the interior of the device 20, as shown in Fig. 7. The disk will begin to deploy as it leaves the open distal end of the shaft of device 20. After the disk 12 is fully deployed, the needle-type device 20 may be withdrawn proximally over the tether 14, as shown in Fig. 8. The tether 14 remains in a tissue tract TT. The tether 14 may then be drawn proximally outwardly through the tissue tract TT, drawing the deployed disk 12 against the lumenal wall over the tissue tract, as shown in Fig. 9. The proximal end of the tether may then be taped or otherwise secured, and the tissue tract may be left in place as the disk 12 releases the bioactive agent into blood flow, as shown by the arrows in Fig. 9.

As described thusfar, the specific embodiments of the present invention have relied primarily on the deployed disk (eluting element) for blocking or occluding the tissue penetration through which it has been introduced. In some cases, however, it may be desirable to employ additional materials or elements for filling and blocking the tissue penetration. For example collagen plugs and other devices, such as those described in U.S. Patent Nos. 4,744,364; 4,852,568; 4,890,612; 5,021,059; 5,061,274; 5,192,302; 5,222,974; and 5,306,254, could be employed in combination with the bioactive agent eluting elements of the present invention. The full disclosures of each of these U.S. Patents are incorporated herein by reference. The collagen or other plug materials which are disposed in the tissue tract or penetration could also be used as a reservoir for supplying additional amounts of the bioactive agent(s) to the eluting element over time, and/or could deliver bioactive agents directly to the tissue surrounding the plug.

Although the foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity of understanding, it will be obvious that certain changes and modifications may be practiced within the scope of the appended claims.