WO2000041763A1

WO2000041763A1 - Tissue localized drug delivery apparatus and process

Info

Publication number: WO2000041763A1
Application number: PCT/US2000/000690
Authority: WO
Inventors: Ascher Shmulewitz
Original assignee: Pharmaspec, Inc.
Priority date: 1999-01-11
Filing date: 2000-01-11
Publication date: 2000-07-20
Also published as: WO2000041763A9

Abstract

This invention is a tissue localized drug delivery device, and method for locally administering a drug substance to a specific vascular bed, the device having an occlusive means (15), and a drug delivery means (14), wherein the occlusive means (15) provides for a period of holding a high concentration of drug within a defined vascular space (4) before release into the general circulation; and significant diluted effects of any drug remaining in the defined vascular space (4). Specifically, the localized drug delivery process provides for increased residence time, control of drug pharmacokinetics, and pharmacodynamics of the drug substance within a defined vasculature or tissue, particularly within the central nervous system, the heart or any vascular location containing proliferative tissue.

Description

TISSUE LOCALIZED DRUG DELIVERY APPARATUS AND PROCESS

Technical Field of the Invention The present invention provides a tissue localized drug delivery apparatus and method for locally administering a drug substance(s) to a specific vascular bed. The localized drug delivery device for localized drug delivery comprises an occlusive means and a drug delivery means, wherein the occlusive means provides for a period of holding a high concentration of drug within a defined vascular space before release into the general circulation and significant dilutive effects of any drug remaining in the defined vascular space. Specifically, the localized drug delivery process provides for increased residence time ( T) and control of drug pharmacokinetics and pharacodynamics of the drug substance within a defined vasculature or tissue, particularly within the central nervous system (CNS), the heart or any vascular location containing proliferaive tissue. The present invention further provides a localized drug delivery device and process for CNS drug delivery for augmented tissue delivery across the CNS blood brain barrier (BBB), wherein the occlusive means is located distal to a catheter drug delivery means to form a region of high drug concentration on the venous side of a CNS vascular bed with increased drug residence time before dilutive wash-out.

Background of the Invention

It has long been a goal in the field of drug delivery to locally deliver drugs to only those tissue that need such exposure and avoid having the drugs exert side effects at other tissues where such exposure would be undesirable. Improving drug delivery techniques can have advantages of (1) continuous maintenance or large bolus of drug levels in a therapeutically desirable range but only to specific target tissues where needed; (2) reduction of side effects due to targeted delivery to a particular cell type or tissue and dilution before exposure to thus tissues where side effects could occur; (3) decreased amounts of drug substance needed; (4) decreased number of dosages, leading to increased patient compliance; and (5) facilitation of drug administration for pharmaceuticals with short in vivo half lives {e.g., oligonucleotides, polypeptides and proteins) or lack of bioavailability. The need for improved drug delivery systems is acute because about 15% of hospital admission in the United States (including about 100,000 deaths per year and about $136 billion in health care costs in the U.S. per year) can be attributed to adverse drug reactions. Moreover, an additional 10% of hospital admission in the U.S. can be attributed to a lack of patient compliance with drug administration schedules and effects. However, the many ways already developed to address the foregoing needs had to overcome problems relating to drug delivery systems, such as (1) toxicity of the materials (or their degradation products) from which the drug is released or other safety concerns such as unwanted rapid release of the drug (dose dumping); (2) discomfort caused by the drug delivery system itself or its means for inserting; and (3) expense of the drug delivery system due to drug encapsulation materials or the manufacturing process. One such attempt was made to address oxygenation of ischemic tissues by Corday (U.S.

Patent 4,689,041) with a catheter with an inflatable balloon on its distal end for insertion into the venous side of coronary vasculature that is ischemic due to impaired flow on the arterial side. Similarly, Aldea (U.S. Patent 5,533,957) provides yet another catheter-based device for retrograde perfusion delivery of therapeutic agents to the venous side of ischemic coronary vasculature due to coronary artery obstruction by a multiple-channeled catheter device. However, each of the two foregoing devices is targeted for venous retrograde delivery of drugs to ischemic myocardial tissue cause by coronary artery obstruction.

Many of the foregoing problems are being developed with better targeting for localized drug delivery. In its simplest form, localized drug delivery means injecting a particular drug directly to the target tissue, such as an intramuscular injection of a gene therapy product directly into the myocardium to provide for local uptake of the naked DNA and (hopefully) transient expression of the gene product of the administered DNA. In another approach, a drug compound is physically entrapped inside a solid polymer that is then injected systemically throughout the body (not local delivery) or physically implanted in the body. Other delivery systems, such as intelligent delivery systems, are delivered systemically and then use a targeting agent (such as a monoclonal antibody or antibody fragment) to seek out and bind to target organs and target cells. Such systems have failed to deliver on their promises and metabolic complications and liver metabolic function has served to limit exposure at target sites.

Summary of the Invention

The present invention provides a device and process for increasing drug residence time (RT) within a target vascular bed, comprising an occlusive means for blocking blood flow on the venous side of the target tissue vascular bed and a means for immediate-release or sustained- release delivery of the drug located within the arterial or venous side of the vascular bed, wherein the means for immediate-release drug delivery is a catheter having a tip, and the means for sustained-release drug delivery is a biodegradable polymer having drug substance embedded therein or a catheter device communicating with a sustained infusion pump, such as an osmotic pumping device. Preferably, the occlusive means comprises a balloon element of a catheter having a port for inflating and deflating the balloon, wherein the balloon element is placed proximal to the tip of the catheter. The present invention provides a process for local administration of a therapeutic agent(s) to target tissues in specific vascular beds through local retrograde perfusion flow of selected target tissue, wherein the retrograde perfusion flow allows high drug concentrations across a target tissue vasculature capillary bed. Specifically, the present invention provides a process for increased residence time of a drug substance within vasculature of a target tissue, comprising (a) inserting an occlusive means distally to the vasculature of the target tissue, (b) inserting a catheter having an exit tip within the vasculature of the target tissue proximal to the occlusive means, (c) activating the occlusive means to occlude flow, and (d) infusing drug substance through the exit tip of the catheter. Preferably, the occlusive means is an inflatable balloon. Preferably, the occlusive means is located within the vasculature of the target tissue in a more distal location. Preferably, the occlusive device is located from about 2 cm to about 20 cm distal from the exit tip of the catheter. Preferably, the drug substance is infused through the exit tip of the catheter by means of manual infusion or infusion pumping through an entry port of the catheter.

Specifically, the present invention further provides a process for increased residence time and increased duration of a drug substance within vasculature of a target tissue, comprising (a) inserting an occlusive means distally to the vasculature of the target tissue, wherein the occlusive means is capable of forming a conical shape having an outer surface oriented in a proximal direction (meaning facing a direction away from flow toward the heart), and further comprises drug substance(s) contained within a biodegradable matrix coated onto the outer surface of the occlusive means, (b) activating the occlusive means to occlude flow and causing drug substance to diffuse from the polymeric matrix, and (c) removing the occlusive means after completion of drug treatment.

The present invention further provides a drug delivery catheter for increasing drug residence time (RT) within a target vascular bed, comprising (a) a plurality of ports including a flow conduit port, and an occlusive means port, (b) an introducer sheath, (c) an occlusive means, and (d) a catheter tip, wherein the occlusive means is located in an adjustable range of from about 2 cm to about 20 cm from the catheter tip. Preferably, the drug delivery catheter further comprises a pressure transducer port wherein a pressure transducer is inserted at or near the catheter tip. Preferably, the introducer sheath is from about 6 to about 8 French. Preferably, the occlusive means is a balloon device that is inflated or deflated through the occlusive means port.

The present invention further provides drug delivery device for increasing drug residence time (RT) and duration within a target vascular bed, comprising (a) a metallic sheet formed into a cone, sphere or elliptical shape and wrapped around a delivery catheter having an outer surface and an inner surface, wherein the metallic sheet further comprises a collapsible sheet and cable allowing for insertion of the device into the target vascular bed and spreading of the shape to occlude the vein or artery when activated; and (b) drug substance(s) contained within a polymeric matrix and deposited on the outer surface of the metallic sheet.

Detailed Description of the Drawings Figure 1 shows a schematic diagram of the vasculature of target tissue 4 having two venous drainage exits 7, 8.

Figure 2 shows a schematic illustration of the vasculature of target tissue 4 with atherosclerotic disease having two venous drainage exits 7, 8. There is blockage from atherosclerosis in the arterial side in the main artery feeding the tissue 10 and after its bifurcation 11.

Figure 3 shows a schematic diagram of the target tissue vascular flow, according to the present invention, having blockages on the venous side. The drug delivery device is placed in one of the venous drainage outflows. In Figure 3 the blockage device increases the resistance to flow through vein 4. Figure 4 shows the schematic diagram of the vascular bed of the target tissue having a catheter 14 inserted through the venous tree. Inventive blocking device 15 is placed in vein 7 and a perfusion catheter tip 17 is placed as close as possible 16 to tissue 4.

Figure 5 shows the catheter 14 configure for human use having a side 6-8 Fr introducer sheath with a thin wall to allow high flow. The introducer sheath has multiple ports (at least two) for inserting the perfusion catheter, to flush the system and serve as the flow conduit. The drug is injected through the catheter tip 14.

Figure 6 shows an inventive device 21 with a metallic sheet preloaded in the shape of a cone tightly wrapped around a delivery catheter.

Detailed Description of the Invention

The present invention provides a method for local administration of therapeutic agents to target tissues in specific vascular beds through local high drug concentrations that get significantly diluted out after wash out into the general systemic circulation. Preferably, the inventive local drug delivery device provides locally high concentrations of a single or plurality of drug products either across a capillary bed of a target tissue, such as a solid tumor mass, or within more accessible venous vasculature. In a second embodiment, the present invention provides a localized drug delivery device and method for drug delivery for augmented tissue delivery, such as across the CNS blood brain barrier (BBB), comprising a plugging means and a catheter drug delivery means, wherein the activation of the plugging means (such as inflation of a balloon catheter) forms a region of high drug concentration on the venous side of a vascular bed with increased drug residence time before dilutive wash-out (such as when the balloon catheter is disinflated). Preferably, the plugging means is a balloon-tipped catheter and causing the plugging means to plug is accomplished by inflating the balloon element of the balloon tipped catheter. Preferably, the method involves infusing drug material at the time when the plugging means is activated. Studies with retrograde perfusion of drug solutions into the coronary vasculature have shown that when the vasculature perfusion bed is obstructed (such as due to atherosclerosis) the uptake of drugs through the retrograde approach (through veins draining the perfusion bed) is higher than the antegrade approach. Therefore, the present invention provides a venous occlusive device with a drug delivery device distal (that is, closer to the flow to the heart) to the means for blocking blood flow (i.e., venous occlusive device) to provide a temporary perfusion blockage. Catheter-Based Immediate Drug Delivery Device and Process

The present invention provides a device for drug delivery to the vasculature of a target tissue. The inventive device comprises a passive plugging means designed for plugging the venous tree of the vasculature of the target tissue and a catheter for immediate drug delivery or a biodegradable polymer implanted for sustained-release drug delivery. Instead of the biodegradable polymer, sustained drug deliver can also be achieved by a catheter device having an osmotic pumping means to provide for sustained drug delivery through the end of the catheter.

With regard to Figure 1 , a typical vasculature tree of a target tissue 4 is shown. This design has a main artery 1 with two primary branches 2, 3 that may divide into additional branches and supply oxygenated blood to the tissue 4 through a series of capillaries (not shown). The capillaries are connected to venules (not shown) that drain into larger veins 5. The drainage of blood is done through a network of multiple veins and shunts 6, 9 that connect between these veins. Shunts, such as 9, connect through collateral drainage networks 8.

Figure 2 shows the same vascular network as Figure 1 with the addition of atherosclerotic disease in the arteries. The disease 10 can occur in a main artery 1 or create a partial occlusion 11 in a branch 2. Collateral vessels (not shown) are created over time even with complete blockage 10. Traditional drug delivery techniques are employed on the arterial side and they must assume that a collateral network created is sufficient to supply tissue 4. Most drug substance released, however, is washed out to other organs.

Figure 3 shows the inventive process, wherein a blockage is created on the venous side. The venous side blockage increases the resistance to flow through within target tissue 4. The net result is that any drug substance contained within the blood within tissue 4 during the time of venous side blockage will have vastly increased residence time within tissue 4. Moreover, the longer the residence time (RT) the greater the drug effectiveness because this allows for greater tissue uptake. In addition, the more distal the blockage site (this means closer to the heart, or larger veins), the greater the increasing RT effect. For example, in Figure 3, blockage 13 increases RT of drugs located within capillaries in all regions of tissue 4, whereas blockage 12 has a more limited effect on only a small region of tissue 4.

In a preferred embodiment of the inventive process shown in Figure 4, a catheter 14 is inserted through the venous tree (preferably under some form of imaging, many such processes are widely practiced). An occluder means 15 is placed in vein 7 and a perfusion catheter tip 17 is placed as close as possible 16 to target tissue 4. This allows for increased RT within target tissue 4 and for having the tip of the perfusion catheter deliver drug substance to target tissue 4 with much higher concentrations than in the general circulation and with significantly increased RT.

With regard to the inventive apparatus, Figure 5 shows a preferred embodiment for human use. The essential components of the inventive localized drug delivery catheter are multiple catheter ports for (1) inserting the localized drug delivery catheter, (2) a port for flushing the localized drug delivery catheter, and (3) a port to serve as a flow conduit. Preferably, the inventive localized drug delivery catheter comprises an introducer sheath with a thin wall to induce high flow. Most preferably, the introducer sheath is from about 6 to about 8 French (one French or Fr is 0.33 mm). The inventive localized drug delivery catheter further comprises an occluder means 15 for blockage of blood flow within a blood vessel, preferably a more distal vein. Preferably, the occluder means is a balloon connected to a side port (not shown in Figure 5) for inflation and deflation to control the occluder means. The inventive localized drug delivery catheter further comprises a catheter end 14 perfusion means for injection of the drug substance(s). Drug injection can be done manually through an injection port, or if longer times of administration are required, an external flow pump can be administered.

It is important that the pressure in the venous tree not exceed 35 mm Hg. Therefore, preferably a pressure sensor is inserted in one of the channels of the catheter 14 (not shown). The location of the pressure sensor is preferably as close to the tip 16 as possible. Preferably, the occluder means is mounted on the same catheter as the perfusion means, as this configuration enables an increase in size of the perfusion means. When the integrated catheter is provided, the occlusion means (e.g., balloon) is placed from about 2 to about 20 cm from the tip such that the occlusion means will be located distally (i.e., closer to the heart) from the perfusion tip. Preferably, the occlusion means can be adjusted within a range of distances to provide for a custom fit of the target tissue venous vasculature based upon angiographic images.

An integrated drug delivery device for localized drug delivery having a drug delivery mechanism proximal to the occlusive means (e.g., balloon) can be, for example, a catheter that is implanted as shown in Figure 4. A second means for a drug delivery device is a biodegradable matrix impregnated with drug and implanted in relation to the local tissue vascular bed to be treated as shown in Figure 6. The drug release from the implanted device will reach high concentrations in the immediately adjacent tissue and the vaso-vasorum of the adjacent arteries. In the case of CNS administration, further increases in venous pressures and residence time of the released drugs will further assist in transport across the blood brain barrier.

In the case of chemotherapy of solid tumor masses it is most important to achieve high local drug concentrations. Such drug concentrations will be diluted significantly before such cytotoxic drugs can reach cells and tissues that are rapidly dividing and sites of typical chemotherapeutic side effects (e.g., the bone marrow and the epithelial lining of the gut). In an enhanced effect for chemotherapy of solid tumor masses (as illustrated in Figure 4 when the target tissue 4 is a solid tumor). Moreover, blood in the venous perfusion bed is often recirculated when there is obstruction of the drainage path (Figure 4). Figure 4, the selective obstruction of venous drainage without changing the antegrade flow, results in an enhanced effect of chemotherapeutic drugs. Device with Implanted Polymeric Material-Containing Therapeutic Agent(s)

With regard to Figure 6, the inventive localized drug delivery catheter 21 is in the form of a "conical" embodiment. The conical embodiment (which encompasses spherical shapes and elliptical shapes as well) is specifically designed for sustained release of drug substance in the form of drug contained within a biodegradable polymeric matrix. The conical inventive localized drug delivery device embodiment comprises an occlusive means in the form of a metallic sheet preloaded in the shape of a cone that is tightly wrapped around a delivery catheter 24. The conical embodiment has a small opening 23 that is directed, when inserted, toward a distal vein and the shaft of the catheter 24. The conical element is held in place on the inventive localized drug delivery device by a collapsible cap 26 and cable 25. Releasing cable 25 and pulling the collapsible cap 26 releases the conical embodiment device 21. A retrieval system (not shown in Figure 6) can be used to remove the device after completion of treatment. The conical embodiment device self-expands to tightly fit the walls of vein 18. The surface area of the conical element facing the vein side 20 (closer to target tissue 4) is coated with drug substance in a polymeric matrix to create a large surface area exposed to blood that has a long RT within target tissue 4. The flow distally (toward the heart and away from target tissue 4) is restricted.

Drug delivery through polymeric coating of stents is well known in the art. For example, anti-restenosis drugs added to bioactive or bioinert coating polymeric materials that are applied onto metallic stents via electrochemical surface polymerization in a hydrophihc solvent. Stent adherence is preferably improved by pre-treating the metallic stent with a chemical treatment to roughen the surface. Similar techniques as those used for stents can add a layer of drug substance to the conical embodiment of the inventive localized drug delivery device. The drug substances most suitable for localized administration with the conical embodiment of the inventive localized drug delivery device include cancer chemotherapeutic agents that are highly toxic to all rapidly- dividing cells, and molecules with poor bioavailability, such as polypeptides. Preferably, the target tissue is a solid tumor mass and the drug or drugs impregnated in the solid matrix are drugs having a mechanism of action of being cytotoxic to rapidly dividing cells. In this embodiment of the invention, preferably suited for CNS drug administration, the device can be located on either the arterial side or the venous side of a target vascular bed. In the CNS, there are tight junctions between endothelial cells that are pronounced in the arterial vasculature and even across capillary beds. This gives rise to the blood brain barrier (BBB). However, those junctions are not as tight on the venous side of CNS circulation and locally high concentrations of drug product in the venous circulation for long duration times can provide an opportunity for greater tissue concentrations of drug product that typical iv-type administration. Advantages of Either the Immediate Release or the Sustained Release Devices

It is also possible to couple both the immediate release device embodiment with the sustained release device embodiment. This results in controlled delivery of a drug(s) to a target tissue to optimize local tissue pharmacodynamics. All of the foregoing effects increase drug residence time (RT) within the target tissue to augment the extent and rate of drug penetration across biological barriers and into tissue spaces and ultimately within cells of target tissues. This is especially important for those drug products that act intracellularly, such as oligonucleotides that form the basis of gene therapy techniques. This is also important for hydrophihc drugs and large molecules, such as polypeptide therapeutics, that often have short plasma half lives when in the general circulation (i.e., high rates of liver metabolism). An additional advantage of the present invention, particularly a sustained release embodiment, is the ability to deliver drugs embedded within polymeric systems into tissue at a controlled rate or in response to physiologic or disease specific triggers. For example, a catheter can deliver a bioresponsive polymer delivery system into a tissue vasculature. This is followed by an immediate release catheter with a distal plugging means that perfuses immediate release perfusing agents (instead of drug substances) that act to release drug from the previously implanted polymer.

Preferably, the target tissue is a solid tumor mass and the drug or drugs are drugs having a mechanism of action of being cytotoxic to rapidly dividing cells. Either embodiment of the invention is better suited for solid tumor therapy wherein highly cytotoxic drugs that tend to be cytotoxic for rapidly dividing cells in general, are infused either in a rapid release or a sustained release schedule. An immediate release means of such drug(s) causes a slight retrograde flow within the tumor tissue vasculature, combined with some hydrostatic pressure exerted on the now closed vasculature of a targeted tumor mass, will create locally high concentration of cytotoxic drug within the vasculature of the tumor mass and across its capillary beds. When, the blood flow is restored, the cytotoxic drug will incur a significant dilution to greatly lessen exposure to other tissues where the negative side effect can occur. Preferably, the plugging means is a balloon catheter and causing the plugging means to plug is accomplished by inflating the balloon element of the catheter. Preferably, the method involves infusing drug material at the time when the plugging means is activated.

In the case of thrombolytic therapy, for example, a catheter, would infuse a thrombolytic agent (such as a clot-dissolving enzyme such as tPa or streptokinase) selectively to the perfusion bed of the obstructed artery. This will provide for local high concentrations of the thrombolytic agent without the danger of excessive bleeding elsewhere. Moreover, the selective uptake of ischemic regions (Ryden et al., J. Amer. Col. Cardiol. 18:603-612, 1991) enhances the effect of such thrombolytic agents. In the case of the CNS, the venous side of the blood brain barrier is less pronounced, which will allow for much greater delivery to brain tissue of drugs delivered through the inventive methods using the inventive devices by circumventing those regions of greater barrier properties.

The pump means communicating with one or a plurality of channels within the catheter can be standard intravenous infusion pump using an external power source and commonly found in hospitals and clinics, or it can be a pump micromotor and housed within the catheter. A pressure sensor is optionally coupled to a second or third channel within the catheter. The channel designated for monitoring pressure may contain a pressure transducer which converts the blood pressure at the transducer tip located within the closed segment of target tissue vasculature between the distal plugging means and the proximal catheter, into a readable output signal. If the readable output signal indicates a pressure reading that meets or exceeds a preset safety pressure limit (for example 35 mm Hg), the pressure sensor automatically signal the pumping means to shut down until pressure is reduced. Alternatively, a low-pressure reading will likely indicate failure of the plugging means.

Claims

I claim:

1. A process for increased residence time of a drug substance within vasculature of a target tissue, comprising (a) inserting an occlusive means distally to the vasculature of the target tissue, (b) inserting a catheter having an exit tip within the vasculature of the target tissue proximal to the occlusive means, (c) activating the occlusive means to occlude flow, and (d) infusing drug substance through the exit tip of the catheter.

2. The process for increased residence time of a drug substance within vasculature of a target tissue of claim 1 wherein the occlusive means is an inflatable balloon.

3. The process for increased residence time of a drug substance within vasculature of a target tissue of claim 1 wherein the occlusive means is located within the vasculature of the target tissue in a more distal location.

4. The process for increased residence time of a drug substance within vasculature of a target tissue of claim 1 wherein the occlusive device is located from about 2 cm to about 20 cm distal from the exit tip of the catheter.

5. The process for increased residence time of a drug substance within vasculature of a target tissue of claim 1 wherein the drug substance is infused through the exit tip of the catheter by means of manual infusion or infusion pumping through an entry port of the catheter.

6. A process for increased residence time and increased duration of a drug substance within vasculature of a target tissue, comprising (a) inserting an occlusive means distally to the vasculature of the target tissue, wherein the occlusive means is capable of forming a conical shape having an outer surface oriented in a proximal direction (meaning facing a direction away from flow toward the heart), and further comprises drug substance(s) contained within a biodegradable matrix coated onto the outer surface of the occlusive means, (b) activating the occlusive means to occlude flow and causing drug substance to diffuse from the polymeric matrix, and (c) removing the occlusive means after completion of drug treatment.

7. A drug delivery catheter for increasing drug residence time (RT) within a target vascular bed, comprising (a) a plurality of ports including a flow conduit port, and an occlusive means port, (b) an introducer sheath, (c) an occlusive means, and (d) a catheter tip, wherein the occlusive means is located in an adjustable range of from about 2 cm to about 20 cm from the catheter tip.

8. The drug delivery catheter for increasing drug residence time (RT) within a target vascular bed of claim 7, wherein the drug delivery catheter further comprises a pressure transducer port wherein a pressure transducer is inserted at or near the catheter tip.

9. The drug delivery catheter for increasing drug residence time (RT) within a target vascular bed of claim 7, wherein the introducer sheath is from about 6 to about 8 French.

10. The drug delivery catheter for increasing drug residence time (RT) within a target vascular bed of claim 7, wherein the occlusive means is a balloon device that is inflated or deflated through the occlusive means port.

11. A drug delivery device for increasing drug residence time (RT) and duration within a target vascular bed, comprising (a) a metallic sheet formed into a cone shape and wrapped around a delivery catheter having an outer surface and an inner surface, wherein the metallic sheet further comprises a collapsible sheet and cable allowing for insertion of the device into the target vascular bed and spreading of the cone shape to occlude the vein or artery when activated; and (b) drug substance(s) contained within a polymeric matrix and deposited on the outer surface of the metallic sheet.