Patent Application
20070184083
The invention relates generally to intra-luminal devices for the treatment of chronic total occlusions (CTO) in a lumen, and more particularly, to a drug-eluting device and method for the treatment of CTO.
Stenotic lesions may comprise a hard, calcified substance and/or a softer thrombus material, each of which forms on the lumen walls of a blood vessel and restricts blood flow there through. Intra-luminal treatments such as balloon angioplasty (PTA, PTCA, etc.), stent deployment, atherectomy, and thrombectomy are well known and have proven effective in the treatment of such stenotic lesions. These treatments often involve the insertion of a therapy catheter into a patient's vasculature, which may be tortuous and may have numerous stenoses of varying degrees throughout its length. In order to place the distal end of a catheter at the treatment site, a guidewire is typically introduced and tracked from an incision, through the vasculature, and across the lesion. Then, a catheter (e.g. a balloon catheter), perhaps containing a stent at its distal end, can be tracked over the guidewire to the treatment site. Ordinarily, the distal end of the guidewire is quite flexible so that it can be rotatably steered and pushed through the bifurcations and turns of the typically irregular passageway without damaging the vessel walls.
In some instances, the extent of occlusion of the lumen is so severe that the lumen is completely or nearly completely obstructed, which may be described as a total occlusion. If this occlusion persists for a long period of time, the lesion is referred to as a chronic total occlusion or CTO. Furthermore, in the case of diseased blood vessels, the lining of the vessels may be characterized by the prevalence of atheromatous plaque, which may form total occlusions. The extensive plaque formation of a chronic total occlusion typically has a fibrous cap surrounding softer plaque material. This fibrous cap may present a surface that is difficult to penetrate with a conventional guidewire, and the typically flexible distal tip of the guidewire may be unable to cross the lesion.
Thus, for treatment of total occlusions, stiffer guidewires have been employed to recanalize through the total occlusion. However, due to the fibrous cap of the total occlusion, a stiffer guidewire still may not be able to cross the occlusion. Further, when using a stiffer guidewire, great care must be taken to avoid perforation of the vessel wall.
Further, in a CTO, there may be a distortion of the regular vascular architecture such that there may be multiple small non-functional channels throughout the occlusion rather than one central lumen for recanalization. Thus, the conventional approach of looking for the single channel in the center of the occlusion may account for many of the failures. Furthermore, these spontaneously recanalized channels may be responsible for failures due to their dead-end pathways and misdirecting of the guidewires. Once a “false” tract is created by a guidewire, subsequent attempts with different guidewires may continue to follow the same incorrect path, and it is very difficult to steer subsequent guidewires away from the false tract.
Another equally important failure mode, even after a guidewire successfully crosses a chronic total occlusion, is the inability to advance a balloon or other angioplasty equipment over the guidewire due to the fibrocalcific composition of the chronic total occlusion, mainly both at the “entry” point and at the “exit” segment of the chronic total occlusion. Even with balloon inflations throughout the occlusion, many times there is no antegrade flow of contrast injected, possibly due to the recoil or insufficient channel creation throughout the occlusion.
Atherosclerotic plaques vary considerably in their composition from site to site, but certain features are common to all of them. They contain many cells; mostly these are derived from cells of the wall that have divided wildly and have grown into the surface layer of the blood vessel, creating a mass lesion. Plaques also contain cholesterol and cholesterol esters, commonly referred to as fat. This lies freely in the space between the cells and in the cells themselves. A large amount of collagen is present in the plaques, particularly advanced plaques of the type which cause clinical problems. Additionally, human plaques contain calcium to varying degrees, hemorrhagic material including clot and grumous material composed of dead cells, fat and other debris. Relatively large amounts of water are also present, as is typical of all tissue.
Thus, there is a need for a method of treatment of the plaque of a CTO to facilitate guidewire passage through the occlusion as a prerequisite for successful angioplasty.
The present invention is a drug-eluting medical device that is inserted into a chronic total occlusion. After insertion, the medical device elutes a drug that softens or dissolves at least a portion of the plaque of the occlusion. After the medical device has resided in the occlusion for an appropriate period of time, a guidewire can cross the occlusion and a procedure such as PTCA can be performed.
The medical device of the present invention can be made of a material that is bioerodable, such that it dissolves in the vasculature as it releases the drug for softening or dissolving the occlusion. In the alternative, the medical device may not be bioerodable and can be retrieved after the drug dosage has been released.
The medical device of the present invention can take any form that can be implanted into the occlusion, such as a pellet or an open mesh type structure.
The foregoing and other features and advantages of the invention will be apparent from the following description of the invention as illustrated in the accompanying drawings. The accompanying drawings, which are incorporated herein and form a part of the specification, further serve to explain the principles of the invention and to enable a person skilled in the pertinent art to make and use the invention. The drawings are not to scale.
Specific embodiments of the present invention are now described with reference to the figures, where like reference numbers indicate identical or functionally similar elements. The terms “distal” and “proximal” are used in the following description with respect to a position or direction relative to the treating clinician. “Distal” or “distally” are a position distant from or in a direction away from the clinician. “Proximal” and “proximally” are a position near or in a direction toward the clinician.
The present invention is directed to a drug-eluting device for treatment of chronic total occlusions.
Referring to
As shown in
Implant 32 shown in
Implant 32 can be made of metals including, but not limited to, gold, platinum, tantalum, iridium, tungsten, stainless steel, cobalt-chromium super alloy, titanium and alloys thereof. Such materials are not bioerodable and thus may need to be retrieved after implant 32 has been implanted for a pharmaceutically effective time. Alternatively, implant 32 can be made of a bioerodable metal, for example, magnesium and magnesium alloys such that implant 32 would not need to be retrieved. Instead, the implant 32 would dissolve in the vessel as it treats occlusion 14. Implant 32 can thus comprise various combinations of bioerodable, biodegradable or non-bioerodable or non-biodegradable materials to make coating layer 38 and base 40.
Although implant 32 has been shown as a stent-like structure, implant 32 can take on different forms, such as a sphere, a cylinder, a cone, a body having multiple prongs emanating from a center, an open geodesic structure such as a sphere or ovoid, or a solid polyhedral pellet shown in
The therapeutic formulation incorporated into implant 32 should be a drug that softens or dissolves the material of occlusion 14. The drug should be non-toxic or minimally toxic considering the small dosage delivered, and should not cause clotting of the blood. An example of the therapeutic formulation incorporated into implant 32 includes, but is not limited to, so-called “proteolytic enzyme-containing formulation” as described in U.S. Published Patent Application Publication No. 2005/0053548. The proteolytic enzyme may be selected from: matrix metalloproteinases, serine elastases, trypsin, neutral protease, chymotrypsin, aspartase, cysteinase and clostripain. Matrix metalloproteinases (MMPs) is a group of zinc-containing enzymes that are responsible for degradation of extracellular matrix (ECM) components, including fibronectin, collagen, elastin, proteoglycans and laminin. These ECM components are important components of the occluding atherosclerotic plaque. MMPs play an important role in normal embryogenesis, inflammation, wound healing and tumour invasion. These enzymes are broadly classified into three general groups: collagenases, gelatinases and stromelysins. Collagenase is the initial mediator of the extracellular pathways of interstitial collagen degradation, with cleavage at a specific site in the collagen molecule, rendering it susceptible to other neutral proteases (e.g. gelatinases) in the extracellular space. In one embodiment, the proteolytic enzyme containing formulation includes a matrix metalloproteinase selected from: collagenase, type 1A collagenase, gelatinases, and stromelysins. In another embodiment, the proteolytic enzyme containing formulation includes collagenase, whether alone or in combination with other enzymes.
The therapeutic formulation incorporated into implant 32 can be a solubilizing agent, such as those discussed in U.S. Pat. No. 4,636,195 to Wolinsky, which is incorporated in its entirety by reference herein. For example, a therapeutic formulation including isotonic aqueous buffers containing phospholipids at a pH of from about 7.2 to 7.6 may be useful. Phospholipids are naturally available compounds that on hydrolysis yield fatty acids; phosphoric acid; an alcohol, usually glycerol; and a nitrogenous base such as choline or ethanolamine. They include lecithins, cephalins and sphingomyelins. Lecithins, particularly egg lecithin, are preferred because of their easy availability and efficiency. The efficiency of a formulation may be improved by the addition of bile acids such as cholic, deoxycholic, chenodeoxycholic, lithocholic, glycocholic and taurocholic acid. Addition of a collagenase, typically a mammalian collagenase, or one derived from bacteria may improve efficacy of the formulation. The collagenase cleaves the collagen that is the main supportive structure of the plaque, so that the plaque body then collapses. This result together with the solubilization of the fat and other components of the plaque serves to decrease markedly the total volume of the plaque. Other proteases such as papain, or chymotrypsin may also be employed together with the collagenase or as an alternative thereto. Other enzymes such as chondroitinase or hyaluronidase may also be employed alone or as one of the active components in the formulation liquid to assist in the removal of other plaque components.
While various embodiments of the present invention have been described above, it should be understood that they have been presented by way of illustration and example only, and not limitation. It will be apparent to persons skilled in the relevant art that various changes in form and detail can be made therein without departing from the spirit and scope of the invention. Thus, the breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the appended claims and their equivalents. It will also be understood that each feature of each embodiment discussed herein, and of each reference cited herein, can be used in combination with the features of any other embodiment. All patents and publications discussed herein are incorporated by reference herein in their entirety.
