JP2730702B2 - Device for treating lesions in hollow vessels and other tissue lumens - Google Patents

Description

Description: BACKGROUND OF THE INVENTION The present application relates to the local treatment of lesions in hollow organs such as, for example, blood vessels and other tissue lumens. The method of treatment involves introducing a therapeutic agent into the portion of the tissue lumen defined by the two dilation members. In particular, the present application is used for "bloodless angioplasty" in blood vessels in which blood flow is suppressed by atherosclerotic plaques.

In the body of animals, including humans, there are blood vessels, such as arteries or veins, and hollow or tubular vessels or structures, such as the digestive tract and sac. In addition, there are many "solid" organs that have a natural space, such as a cavity, a cavernous sinus, a lumen, and the like. These "solid" organs include the heart, liver, kidney and pancreas. Finally, ill treatments (eg, necrotic tumors) and trauma can create space in the solid canal.

The lumen created by the various forms of space can be affected in various ways. For example, a lumen may be occluded, restricting or preventing flow through the lumen. Such suppression of flow through the lumen is detrimental because the lumen of many hollow vessels serves an important function, for example, as a transfer conduit for blood, urine, bile or food. A specific example is the occurrence of occluded atheromas (atherosclerotic plaques) in arteries that grow and reduce blood flow through the arteries.

In many cases, the wall of the tissue lumen has a significant barrier function and acts as a fluid transfer tube. For example, in blood vessels, the "intimal" or endothelial lining layer separates the overflowing blood from the intermediate or "media" portion of the underlying blood vessel. Since the media is extremely susceptible to thrombogen formation, such separation is necessary to prevent occlusion of blood vessels in normal blood vessels. further,
When exposed to overflowing blood as a result of a breach of the intima barrier, the media is stimulated by platelets and macrophages in the blood, which can lead to smooth muscle cell proliferation and regenerate stenosis. For example, pathologies such as advanced ulcer atherosclerotic lesions can, in some interventional techniques, break this barrier layer and cause localized blood occlusion, inflammation and, for example, platelet-derived growth factor (PDGF), interleukin- 1, causing proliferation of growth stimulating factors such as macrophage-derived growth factor (MDGF) into the media, and then activating, migrating and proliferating smooth muscle cells in the intima to locally form stenosis There is a possibility to regrow.

The course of the disease may also alter the structure and / or function of the tissue surrounding the lumen. For example, a portion of the tissue can be replaced with a cancerous / tumor or inflammatory portion. In advanced atherosclerosis, the walls of blood vessels are replaced by lipid and inflammatory cell infiltrates, newly grown smooth muscle cells, fibrous collagen, other connective tissues, and dense calcium sediment. This conversion can be (1) vasomotor or expanding and contracting and the ability to alter blood flow in response to metabolic demands of the organs; (2) cellular nutrients into and through blood vessels, ie, fluxes of glucose and oxygen, and Metabolic degradation product / waste efflux, (3) normal release of downstream vascular reactants or endothelium-derived relaxing factor (EDRF), and (4) local action, such as PDGF produced by endothelial cells Doing so alters the ability of the blood vessels to block normal metabolism, altering the ability of the local blood vessel to grow and repair.

Furthermore, even if the appearance of the tissue surrounding the lumen does not change, the metabolism of these cells can change. In this way, the production of necessary mediators such as, for example, growth factors and hormones can be inhibited. This also occurs in atherosclerosis, where the flow of nutrients, oxygen, lipids and growth factors through the walls of blood vessels is typically altered.

Although the types of problems that can occur in hollow vessels and tissue lumens are generally recognized, currently available treatments generally seek to treat symptoms rather than causes. This has a number of disadvantages, as exemplified by atherosclerosis.

In atherosclerosis, the overall problem is the gradual progression of atherosclerotic plaques at focal locations on the walls of the arteries. The plaques are composed of proliferating smooth muscle cells, stimulated macrophages and other inflammatory cells, chemically modified lipid components, ie, cholesterol, oleic acid: linoleate, rigid connective tissue, ie, collagen, and calcium. Is a composite of a multi-component three-dimensional structure consisting of The distribution of plaques in the walls of the blood vessels is such that the majority of the lesions intervene in a disturbing manner within the lumen of the blood vessel. This reduces blood flow over the spots and subsequently reduces downstream blood flow. If blood flow is so restricted in the body's arterial bed, such as the coronary artery of the heart or the carotid artery of the neck, a decrease in blood flow is due to cardiac angina or a transient ischemic attack in the brain ( TIA). Complete interruption of blood flow can lead to a heart attack or stroke, respectively.

The treatment of atherosclerosis has progressed from coronary artery bypass grafting (CABG) to catheter-based techniques such as, for example, percutaneous transluminal coronary angioplasty (PTCA).
Thus, the state of the art has progressed from simply bypassing the area in question to actually trying to remedy the inhibitory effects of the direct effects and spread of the lesion. These attempts have led to the development of various catheter structures and treatment techniques. For example, U.S. Pat. No. 4,636,195 to Wolinsky describes the use of a catheter with two occlusion balloons and a conduit to deliver a lysing agent to dissolve plaques. A central balloon is included to pump the lysing agent into the plaque. U.S. Pat. No. 4,610,662 to Weikel et al uses a catheter with two inflatable balloons to block the lesion and then break up plaques between the balloons, e.g. And a catheter for introducing such chemicals. A similar approach to the treatment of gallstones is disclosed in US Pat. No. 4,781,677 to Wilcox.

However, these methods, as well as the basic techniques of angioplasty itself, seek to direct the underlying pathophysiology, which acts on the lesion or otherwise biologically affects the lesion. Not. Thus, there is no effort to provide complete disappearance of the lesion due to regressive resorption or healing of the lesion, or replacement of a diseased wall fragment with a healthy wall fragment having normal vascular components and function. The present invention satisfies the above needs by intensive administration of a therapeutic agent to the focal region alone or in conjunction with physical effects on the focal region (eg, PTCA).

A particularly preferred application of the present invention is "bloodless angioplasty". In this application, the occluded lesion area is washed to remove blood prior to introducing the therapeutic agent. The lesion area is then treated with a therapeutic agent to suppress cell proliferation in the lesion area. The rupture is then caused, for example, by conventional balloon angioplasty, Aselectmi, laser plaque removal or resection. Finally, the occluded area may be treated with a drug to promote healing of the blood vessels and coated with a polymeric material. Blood is
The risk of clotting in this technique is reduced because there is no contact with the potentially exposed media ruptured lesions. In addition, restenosis occurs because cells in the "scratched" stimulated and exposed medial smooth muscle are not exposed during expansion immediately after being most sensitive to activity and stimulation by various factors found in the blood. And there is no potential mechanism leading to long-term PTCA failures. Thus, antiproliferative therapies further reduce the potential for long-term restenosis by blocking smooth muscle cell proliferation that is maximal during the first 12 to 24 hours after treatment.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows two views of a catheter device according to the present invention, FIG. 2 shows a catheter device according to the present invention, and FIG. 3 shows steps for performing "bloodless angioplasty" according to the present invention. FIG. 4 shows a catheter device according to the invention, FIG. 5 shows two types of catheter device according to the invention, FIG. 6 shows two types of catheter device according to the invention, FIG. 1 is a diagram showing a catheter device according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION As used herein and in the claims, the term "therapeutic agent" refers to a substance that alters the metabolism of cells and reduces the propensity of thrombosis within a focal area of a tissue. Examples used for coronary arteries include vasodilators, i.e., nitrate and calcium channel blockers, antiproliferative agents, i.e., colchicine and alkylating agents, intercalators, e.g., interleukins, transforming growth factor b, platelet-derived growth factor, and Growth modulators such as synergists with clonal antibody-induced anti-growth factors, such as anti-GI
Antithrombotic agents such as Ib / 3a, trigramin, prostacyclin, and salicylate, eg, streptokinase, urokinase, tissue plasminogen activator (TPA)
And thrombogen-forming agents such as anisolate plasminogen-streptokinase activator complex (APSAC), steriodal and non-steriodal, which can modulate vascular tone, function, arteriosclerosis and post-operative vascular or tracheal healing responsiveness There are both anti-inflammatory and other drugs. Antiproliferative drugs or also for the treatment of focal phlebitis or other inflammatory arteritis such as, for example, granulomatous arteritis, polyarteritis nodosa, temporal arteritis, and Wegna granulomatosis. High potency anti-inflammatory agents are also useful. Anti-inflammatory agents are also useful in connection with indications such as, for example, enteritis, localized ileitis, ulcerative colitis, and focal GI inflammation. In other applications, an adhesive according to the present invention may be introduced to promote healing of anatomical parts, flaps and aneurysms. Examples of adhesives include cyanoacrylate, gelatin / resorcinol / formol, Mussel adhesive protein and self-fibrinogen adhesive. The term "therapeutic agent" does not include lysing agents that break atherosclerotic plaques.

The catheter device according to the present invention may include various changes and modifications described in detail below. However, in general, the catheter body used in the present invention can be made of any known material, including metals such as steel, and thermoplastic polymers, for example, as continuous tubes or woven spring-like structures. Good. The balloon of the expanding member may be made of an extensible material such as latex or silicone, or polyethylene terephthalate (PET), polyvinyl chloride (P
VC), made from a non-extensible material such as polyethylene or nylon. Also, the catheter may include markers at one or more locations for its positioning. These markers may be, for example, fluoroscopic, radiopaque bands secured to the tubular body by heat sealing.

As used herein and in the claims, the term "paving" refers to applying a coating of a compatible polymeric material to the surface of a tissue lumen.
Thus, at the time of "paving", the polymeric material in the form of a monomer or prepolymer solution or at least partially preformed polymeric material is introduced into the vessel lumen and located at the point of the original stenosis. The polymeric article is then shaped to conform to, and maintain intimate contact with, the interior surface of the blood vessel to achieve the paving and seal coating. Polymeric paving and sealing materials can be used to accelerate the healing process, for example, by incorporating drugs, drug-producing cells, cell regeneration factors, or even ancestral cells that are the same as or histologically different from the target trachea. Can be. Paving is disclosed in U.S. Patent Application Serial No. 07 / 235,998 and International Application No.PCT / US89, both of which are incorporated herein by reference.
/ 03593.

FIG. 1 shows a six lumen catheter device according to the present invention. In FIG. 1, there are two enlarged members 150 and 151, both connected to a conduit 152. Enlargement member 15
0 and 151 fix the position of the tubular body 100 within the tissue lumen and block between them the focal portion of the tissue lumen that supplies the therapeutic agent. The expansion member 153 may be a standard angioplasty balloon, or may be used in a polymer paving arrangement, or both.
And the flow is circulated through conduits 154,155. When using the expandable member 153 to place the polymeric paving, conduits 154 and 155 may be used to control the temperature of the blocked portion of the tissue lumen, or a polymeric sleeve or other sleeve fitted to the expandable member 153. Enlarged molds can act to form polymeric coatings. Therapeutic agent is provided from reservoir 159 via conduit 156, which acts as a drain line to allow fluid to flow through the blocked portion of the tissue lumen ("hypermelt"), or vice versa. However, although a drain line is not required and perfusion is preferred, a simple digestion catheter, similar to the five lumen configuration shown in FIG.
One of 156 or 157 can be omitted. A sixth conduit 158 is optional, but may be advantageously used for guidewires, passages in diagnostic or therapeutic devices, or for distal fluid perfusion. If conduit 158 has an opening in proximity to balloon 151, it can be used as a branch conduit for passive perfusion during occlusion.

The catheter shown in FIG. 1 can be used to perform a procedure such as "bloodless angioplasty", as schematically illustrated in FIG. In this technology,
The catheter 1 is inserted into a partially occluded blood vessel 2,
It enters the area of lesion 3 (FIG. 3a). The catheter is positioned such that the dilation members 150,151 are located on both sides of the lesion 3, and then the dilation members 150,151 are dilated to occlude the compartment 4 around the lesion 3. Next, the blocked compartment 4 is washed to remove blood from the area to be treated. This means
It is performed by supplying saline or other biologically compatible material while removing blood (No.
3b). After the blood has been washed from the blocking compartment 4, a therapeutic agent, such as an antiproliferative, is introduced from the reservoir of the catheter (FIG. 3c). Suitable therapeutic agents include nucleic acid compounds (eg, actinomycin D) or drugs that interfere with cell division (eg, cytochalasin B). Next, after a lapse of time sufficient to make the therapeutic agent effective, the angioplasty balloon 153 is inflated, and the lesion 3 is broken according to a known balloon angioplasty process. At this point, additional or other therapeutic agents may be added. Next, the angioplasty balloon 153 is deflated (FIG. 3e). At this stage,
It is preferred to provide another therapeutic agent or polymer coating with or without a mixed antithrombotic or antiproliferative agent to the broken lesion area to promote healing.
The polymeric coating also provides a barrier over the exposed portion of the media. Finally, the expansion members 150 and 151 contract, and the catheter is released to restore normal blood flow (3f
Figure).

In treating restenosis, the preferred therapeutic agents are antiproliferative agents. Useful antiproliferative drugs vary in structure and mode of action, and it is generally believed that many are unsuitable for treatment during coronary surgery in other circumstances. For example, chemotherapeutic drugs that have significant toxic side effects if administered via conventional routes (ie, intestinal (oral) or parenteral (muscular, IV or subcutaneous)) can be used with the present invention. These chemotherapeutic drugs include actinomycin D, adriamycin, methotrexate such as colchicine,
Includes vinca alkaloids such as vincristine and vinblastine, 5-fluorouracil, and nitrogen mustard.

Heparin in both anticoagulated and non-anticoagulated forms,
Antiproliferative vasodilators such as adenosine, cyclic GPM-elevating vasodilators, angiotensin converting enzyme inhibitors, calcium channel blockers and prostaglandin E1, prostacyclin, trapidyl, terbinafine, protein kinase C-active phorbol Other antiproliferative drugs, including esters and dimethyl sulfoxide (DmSO), may be used. Fish oil can also be used as an antiproliferative to block the endothelial formation of platelet-derived growth factor (PDGF). Fish oil cannot be administered in the conventional IV mode due to its insolubility, but can be used according to the present invention. Suramin, a PDGF antagonist with a high antiproliferative profile but clinically toxic, may be employed.

Antiproliferative antibodies against PDGF, or IL-1, TGFb, alpha and gamma interferon, angiopeptin (BI
M23034) and other peptides can also be used in the present invention. However, they are not generally medicated due to the danger of an immune response.

Lesion treatment with an anticoagulant is also desirable in restenosis treatment to reduce the tendency for clot formation at the PTCA site. These materials may be introduced with a solvent and penetrate the blood vessel wall or be deposited as a gel or surfactant coating that adheres to the blood vessel wall.

As an alternative to the angioplasty balloon shown in FIG. 1, US Patent No. 4,799,479 to Spears or US Patent No. to Ginsburg et al.
A heated balloon for dissolving broken tissue as described in US Pat. No. 4,754,752 is disclosed in U.S. Pat.
Woven fibrous tubing as described in US Pat. No. 4,650,466 or US Pat. No. 4,445,892 to Hussein et al.
No. 4,448,188 to Loeb or US Pat. No. 4,627,436 to Leckrone.
The plaque breaking can be performed using the laser beam described in the above item. Solubilizing agents may be employed as disclosed by Weikl et al, Wilcox and Wolinsky.

The therapeutic agent can be introduced in the form of a solution as described above. However, alternatively, the therapeutic agent may be administered in gaseous or finely divided form. For example, as a gas, ethylene oxide, mustard gas, or chloroform may be administered in a limited dose as an antiproliferative drug. The fine powder may for example be treated in combination with a biodegradable polymer such as polylactic acid, polyglycolic acid, polycaprolactone, polydioxanone, starch, gelatin and polyanhydride or a non-biodegradable polymer such as styrene or acrolein. Can be formed from drugs. Alternatively, a liposome containing a drug may be employed. The preferred size of the fine powder is 4 cyclones or less, more preferably 1 cyclone or less (ie, nanoparticles).

FIG. 4 shows another catheter of the present invention. In this catheter, the expansion members 401 and 40 for backup are used.
2 are located outwardly from the main obstruction enlarging members 150,151. This back-up magnifying member creates a safety compartment that prevents the therapeutic agent from spilling out of the blocking compartment 4 into the blood stream.

Various other modifications to the basic configuration of the catheter shown in FIG. 1 are also contemplated within the scope of the present invention. For example,
A "weeping" balloon can be employed instead of a standard angioplasty balloon so that material can be conveyed to the isolation compartment via perforations in the balloon. Similarly, a guide wire may be incorporated into the catheter of the present invention, or two occlusion balloons may be placed on the catheter portion that slidably interlock to adjust the distance between the balloons. Finally, one or both of the balloons may be provided with injection ports or nozzles for delivering gaseous or particulate therapeutic agents to the isolation compartment.

Further, the catheter device of the present invention may include a pump or a vacuum device for delivering a therapeutic agent from the reservoir to the tissue lumen. Such a pump may be servo-controlled to dynamically pressurize the isolation compartment to allow the lesion to diffuse and / or actively penetrate. Alternate cycling of pressure and vacuum to promote penetration into the lesion or vessel wall may also be advantageously employed.

Another feature that may be included in the catheter of the present invention is that one or more of the catheter bodies are heated to heat the conduit to facilitate instillation of a polymer or surfactant that is solid at room temperature but dissolves upon slight heating. Include a heating element such as, for example, a coaxial heating element. Such heating elements are particularly applicable where a polymeric coating is formed during the introduction of a therapeutic agent or as part of a post-rupture procedure. The catheter may also incorporate a high frequency ultrasonic crystal or ultrasonic or other acoustic vibration element between the two expansion elements to facilitate fluid penetration into the lesion. Such a device may also facilitate vibration or ultrasonic welding (ie, coalescence) of the polymer solvent or fine powder leading to the formation of a coating on the surface of the blood vessel.

Further, those skilled in the art will appreciate that the number of lumens in the catheter body can be varied without departing from the present invention. For example, FIG. 5 shows a seven-lumen catheter, wherein the dilation members to occlude the lesion area are individually controlled via lumens 50 and 51. FIG. 6 shows a five lumen hyperlysis catheter, wherein the expansion of the angioplasty balloon is controlled by a single lumen.

The present invention is ideally suited for, but not limited to, bloodless angioplasty. In fact, the intensive introduction of therapeutic agents at the lesion site using a double balloon catheter is useful for a wide range of applications. In this case, the angioplasty balloon or other rupture means may be omitted between the two occlusion balloons, and the catheter may be connected to a reservoir containing a therapeutic agent, such as shown in FIG. It can be a two lumen dual balloon catheter.
Such catheters can be used to deliver intensive care in the case of bladder tumors, GI polyps, liver tumors, bronchial tumors, and urethral tumors. In addition, it proves to be valuable in treatments that apply anti-inflammatory or wound healing components such as inflammatory bowel disease, focal ileitis, ulcerative colitis, and focal GI inflammation.

Claims (19)

(57) [Claims] 1. A catheter device including a tubular body having a distal end and a proximal end, a conduit for controlling delivery of a polymeric coating to a tissue lumen surface near a distal end of the catheter, and the device. In fluid communication with an opening at the distal end of the
A catheter device comprising a combination of a therapeutic agent different from the material forming the polymer coating. 2. The apparatus of claim 2, further comprising an expanding member at a distal end of the device, wherein the conduit controls delivery of the polymeric coating to an area of a tissue lumen adjacent the expanding member. The catheter device according to claim 1. 3. The apparatus of claim 2, further comprising at least two dilation members at a distal end of the device, wherein the conduit controls delivery of the polymeric coating to a region of the tissue lumen between the at least two dilation members. The catheter device according to claim 1, wherein: 4. The method of claim 1, further comprising a material forming a polymeric coating at a proximal end of the conduit and fluidly connected to the conduit. The catheter device according to any one of the preceding claims. 5. The method according to claim 1, wherein said therapeutic agent alters the metabolism of cells or reduces the propensity of thrombosis, stenosis, obstruction, inflammation or restenosis in a diseased part of a tissue. Item 5. The catheter device according to any one of Items 4 to 4. 6. The catheter device according to claim 5, wherein said therapeutic drug is an antiproliferative agent. 7. The catheter according to claim 3, further comprising means for removing body fluid by washing a region between the at least two magnifying members with a washing solution. apparatus. 8. The method of claim 1, wherein the conduit controls delivery of the polymeric coating by expanding a polymeric delivery expander that expands the polymeric coating against a tissue lumen surface. Items 1 to 7
The catheter device according to any one of the above items. 9. The conduit controls delivery of a polymeric coating by delivering a monomer or prepolymer fluid to a tissue lumen surface, and wherein the device polymerizes the monomer or prepolymer fluid at the tissue lumen surface. The catheter device according to any one of claims 1 to 8, further comprising means for performing. 10. A catheter device comprising a tubular body having a distal end and a proximal end for providing localized treatment to a diseased area in a tissue lumen, wherein the device alters cell metabolism or reduces tissue metabolism. Thrombosis, stenosis,
A reservoir containing a therapeutic agent that reduces the likelihood of obstruction, inflammation or restenosis, and a therapeutic agent remote from the device, provided that the therapeutic agent is not the only solubilizer or solubilizer that breaks the atherosclerotic plaque. At least one feeding
A catheter device comprising two conduits. 11. The apparatus of claim 11, further comprising an expansion member at a distal end of the device, wherein the conduit controls delivery of the polymeric coating to an area of a tissue lumen adjacent the expansion member. 11. The catheter device according to claim 10, wherein: 12. The apparatus further comprising at least two dilation members at a distal end of the device, wherein the conduit controls delivery of the polymeric coating to a region of a tissue lumen between the at least two dilation members. 11. The catheter device according to claim 10, wherein: 13. The catheter of claim 1, further comprising a material at a proximal end of said conduit and fluidly connected to said conduit that forms a polymeric coating on a tissue lumen at a distal end of a catheter. 13. The catheter device according to claim 12. 14. The method according to claim 10, wherein said therapeutic agent is selected from the group consisting of vasodilators, calcium channel blockers, antiproliferative agents, intercalators, growth modulators and anti-inflammatory agents. 14. The catheter device according to claim 13. 15. The method according to claim 1, wherein the therapeutic drug is actinomycin D, adriamycin, methotrexate, vinca alkaloid, 5-fluorouracil, nitrogen mustard, heparin, an antiproliferative vasodilator, fish oil, suramin, prostacyclin, dimethyl sulfoxide, trapidil, terbina. 15. The catheter device according to any one of claims 10 to 14, wherein the catheter device is an antiproliferative drug selected from the group consisting of fine and phorbol esters. 16. The catheter device according to claim 10, wherein the antiproliferative drug is selected from the group consisting of an antiproliferative antibody, a peptide and a growth factor. . 17. The catheter device according to any one of claims 10 to 16, wherein the reservoir contains an anti-inflammatory agent. 18. The catheter device according to any one of claims 10 to 17, further comprising means for providing a drug between said at least two dilation members to facilitate treatment of a tissue wall. 19. The apparatus of claim 19, further comprising a second conduit acting as a drain line for flowing fluid through a portion of the tissue lumen separated by said at least two expanding members.
19. The catheter device according to any one of items 10 to 18.