Patent Application
20110054396
The present invention relates to medical devices, more particularly, to balloon catheter devices.
Balloon catheters are used in a wide variety of minimally-invasive or percutaneous medical procedures. Balloon catheters having drug coatings may be used to treat diseased portions of blood vessels. Typically, the drug-coated balloon is inserted through a peripheral blood vessel and then guided via a catheter through the vascular system to the target intravascular site. At the target site, the balloon is inflated and the drug is applied to the blood vessel. However, there may be problems with releasing the drug from the balloon. For example, there may be insufficient fragmentation of the drug coating or the drug coating may not sufficiently delaminate off of the balloon. Therefore, there is a need for improved balloon catheter devices for drug delivery to an intravascular site.
In one embodiment, the present invention provides a medical device comprising: (a) a balloon; (b) an expandable sheath disposed around the balloon; and (c) a coating disposed over the expandable sheath, the coating comprising a therapeutic agent, and wherein the coating is less compliant than the expandable sheath.
In another embodiment, the present invention provides a medical device comprising: (a) a balloon having a balloon wall, the balloon wall comprising an outermost layer and an inner layer, the outermost layer being less compliant than the inner layer; and (b) a coating disposed over the outermost layer, the coating comprising a therapeutic agent.
In another embodiment, the present invention provides a method of making a medical device, comprising: (a) providing a balloon having a polymer wall; (b) embrittling the outer surface of the polymer wall to form an outermost layer that is less compliant than the rest of the polymer wall; and (c) disposing a coating over the outermost layer, wherein the coating comprises a therapeutic agent.
Medical devices of the present invention have an inflatable balloon for delivering a therapeutic agent to a target site in a patient's body. The balloon is designed to be insertable in the body using any of various mechanisms conventionally used for the delivery, actuation, or inflation of balloon devices. The balloon device may be designed similar to those that have been known in the art, including but not limited to angioplasty catheters, stent delivery catheters, inflation catheters, and/or perfusion catheters. The medical devices of the present invention may be used in conjunction with other intravascular drug delivery devices, such as vascular stents.
In one embodiment of the present invention, an expandable sheath is disposed around the balloon. The expandable sheath may be made of various types of elastomeric or expandable materials, such as silicone elastomers, fluoropolymer elastomers, or thermoplastic elastomers. Examples of thermoplastic elastomers include thermoplastic polyurethanes, thermoplastic polyesters, and thermoplastic polyamides such as polyether block amide (e.g., PEBAX®). Examples of fluoropolymer elastomers include polymers or copolymers of tetrafluoroethylene, hexafluoropropylene, or vinylidene fluoride. The expandable sheath may or may not have any attachments to the surface of the balloon (e.g., the sheath may without such attachments and be “free-floating” over the balloon surface). The expandable sheath may or may not be elastic (i.e., the deformation of the sheath upon expansion may or may not be reversible).
The balloon may have varying degrees of compliance, depending upon the particular application. For example, the balloon may be a compliant, non-compliant, or a semi-compliant balloon. As used herein, a “non-compliant balloon” means a balloon whose diameter increases by no more than 10% of the rated nominal diameter as the internal pressure in the balloon is increased above the nominal inflation pressure. As used herein, a “semi-compliant balloon” means a balloon whose diameter increases by no more than 20% of the rated nominal diameter as the internal pressure in the balloon is increased above the nominal inflation pressure. As used herein, a “compliant balloon” means a balloon whose diameter increases by more than 20% of the rated nominal diameter as the internal pressure in the balloon is increased above the nominal inflation pressure. For coronary artery balloons, nominal diameters may range from 1.5-7.0 mm, and in the most typical cases, from 2.0-4.0 mm. However, other nominal balloon diameters are also possible, depending upon the intended target site and/or the particular application.
A coating containing a therapeutic agent is disposed over the expandable sheath. The coating may be the therapeutic agent alone, or the therapeutic agent in combination with one or more other materials. For example, the therapeutic agent can be blended with additives or excipient materials (e.g., binders, plasticizers, fillers, etc.) to make the coating more or less brittle. In any case, the coating of therapeutic agent is formulated to be less compliant than the expandable sheath. As such, the coating of therapeutic agent will break apart as the sheath expands. The thickness of the coating will vary depending upon the application, and in some cases, the coating thickness is in the range of 1-10 μm. Thinner or thicker coatings are also possible.
In certain embodiments, the therapeutic agent may be provided in a crystalline form. For some therapeutic agents, such as paclitaxel, the crystalline form is less soluble and has a coarser, grainier texture than the amorphous form. This may allow the therapeutic agent to adhere better to the blood vessel wall, improve tissue penetration, and/or become less susceptible to washing downstream after transfer to the blood vessel wall.
Upon inflation of the balloon, the unfolding and/or expansion of the balloon will exert outward pressure on the sheath, causing the expandable sheath to expand as well. The sheath may expand in a radial direction, longitudinal direction, a combination thereof, or any other direction. Where radial expansion is involved, the amount of radial expansion that the expandable sheath experiences as the balloon is inflated will vary with different balloon devices. In some cases, the balloon device is designed such that the sheath experiences at least a 1.5-fold increase in diameter (i.e., at least 50% radial elongation), and in some cases, at least a 2.5-fold increase in diameter (i.e., at least 150% radial elongation) as the balloon is inflated from its uninflated state. However, other amounts of radial expansion are also possible, depending upon the particular application. Because the therapeutic agent coating on the sheath is less compliant than the sheath, the coating will break into fragments (e.g., particles) as the sheath expands. The fragments of therapeutic agent may be applied onto the body tissue and/or released from the balloon.
In operation, with balloon 14 in an uninflated condition (as shown in
As shown in
In an alternate embodiment, there is an intermediate release layer between sheath 12 and therapeutic agent coating 16 that facilitates the delamination of therapeutic agent coating 16 off of sheath 12 as coating 16 breaks apart into particles 20. The intermediate release layer can be made in various ways to perform this function. For example, the release layer may comprise a low adhesion material, such as low-adhesion silanes or the above-mentioned fluoropolymer elastomers. In another example, the release layer may comprise a material that dissolves or degrades upon exposure to body fluids (e.g., a sugar or biodegradable polymer). In another example, the release layer may comprise a material that absorbs fluid and swells upon exposure to body fluids (e.g., a hydrogel). In each case, the release layer facilitates the delamination and release of the fragments of therapeutic agent.
The coated elastic sheath was mounted on a 3.0 mm×20 mm angioplasty balloon from a Liberte™ stent system (Boston Scientific). The balloon/sheath was inserted into the hydrophilic polyurethane tube in a water bath at 37° C. The balloon was held in the polyurethane tube for 1 minute and then inflated. The polyurethane tube was sized to give 20% overstretch during balloon deployment. The balloon was maintained in the inflated state for 1 minute, vacuum was pulled for 15 seconds, and the balloon/sheath was withdrawn from the polyurethane tube. The polyurethane tube was then removed from the water bath, dried, and imaged.
During the balloon deployment process, fluid flow around the balloon may wash the therapeutic agent coating on the expandable sheath downstream. Due to the increased fluid velocity around the balloon as the flow volume shrinks with balloon expansion, a considerable portion of this loss may occur during balloon expansion at moments just prior to when the balloon contacts the wall of the blood vessel.
As such, the medical device may be designed to reduce this loss of therapeutic agent coating during balloon expansion. In certain embodiments, the length of the expandable sheath is shorter than the length of the balloon such that one or both ends of the balloon is unconstrained by the sheath. As used herein, the length of the balloon and sheath refers to the length as measured when the balloon is in the nominally inflated state. During expansion of the balloon, this configuration can allow for the unconstrained end(s) of the balloon to begin inflating before the sheath-covered portion of the balloon. The sheath can have various lengths relative to the balloon length. For example, in certain embodiments, the sheath can be 20-80% of the length of the balloon, but other lengths are also possible. One or both ends of the balloon may be left uncovered by the sheath.
For example,
In operation, with balloon 54 in an uninflated state, balloon 54 is inserted into a blood vessel using catheter shaft 58. At the target site, balloon 54 is inflated. As seen in
In another embodiment of the present invention, the wall of the balloon comprises an outermost layer and one or more inner layers. The outermost layer is less compliant than the inner layer(s) such that cracks will form in the outermost layer as the balloon is inflated to its nominal diameter or beyond. A therapeutic agent is disposed as a coating over the relatively less compliant outermost layer. The coating may be the therapeutic agent alone, or the therapeutic agent in combination with one or more other materials (such as the above-described additives or excipient materials). The coating of therapeutic agent breaks apart when the relatively less compliant outermost layer cracks with the inflation of the balloon.
The outermost layer is sufficiently brittle that the amount of surface area elongation required to cause cracks to form is less than 40% at body temperature (i.e., 37° C.) while submerged in a buffered aqueous solution. In other words, up to a 40% increase in the surface area of the outermost layer is sufficient to cause cracks to form in the outermost layer, but this does not mean that the outermost layer necessarily expands to this degree. The amount of brittleness may vary depending upon the compliance characteristics of the balloon. For example, since a non-compliant balloon does not expand as much as a compliant balloon, the outermost layer of the non-compliant balloon may be made to have a higher degree of brittleness (i.e., cracks with less surface area elongation) than for the compliant balloon.
In some cases, the outermost layer has excavated regions to facilitate cracking of the outermost layer. As used herein, “excavated regions” refers to voids (e.g., fracture lines, holes, slots, grooves, channels, etchings, perforations, pits, etc.) that are created by removal of material using techniques that control the size, shape, and location of the voids. For example, such techniques include direct-write etching using energetic beams (e.g., laser, ion, or electron), micromachining, microdrilling, or lithographic processes.
A balloon having a balloon wall with a relatively less compliant outermost layer can be made using any of a number of different techniques known for making multi-layered balloons. One such way is by embrittling the polymer material on the surface of the balloon wall using any suitable embrittling process. Examples of embrittling processes include processes that cross-link the polymer material, processes that cause degradation of the polymer material, or processes that remove any plasticizers. There are various processes for degrading a polymer, such as exposing the polymer to heat, radiation, or reactive chemicals, and the type of process suitable for use will vary depending upon the type of polymer. For example, polyethylene and polypropylene can degrade and become brittle upon oxidation or exposure to ultraviolet (UV) rays. The polymer material may also be degraded by exposure to reactive chemicals, which may be a chemical solution such as a strong acid solution (e.g., sulfuric acid) or a strong base solution. The reactive chemical may also be a reactive gas such as ozone, chlorine, or plasma. For example, polyethylene terephthalates can degrade and become brittle from hydrolysis by strong acids, while polycarbonates can degrade and become brittle when exposed to strong alkalis. Some of these degradative processes involve chain scissioning of the polymers, particularly where the polymer wall is made from long chain polymers.
As mentioned above, embrittling can also be achieved by cross-linking of the polymers in the polymer wall. There are various processes for cross-linking a polymer, and the type of process suitable for use will vary depending upon the type of polymer. Some of the processes for cross-linking include exposing the balloon to heat, pressure, or radiation (such as UV rays, electron beam, or gamma radiation). There may also be photo-initiated cross-linking additives (e.g., benzophenone) in the balloon wall that can facilitate radiation-induced cross-linking.
As mentioned above, embrittling can also be achieved by removing plasticizers (e.g., by evaporating or leaching) that may be present in the polymer wall. For example, polyvinyl chloride (PVC) can become brittle with the loss of plasticizers. The coating of therapeutic agent could be applied before or after the above-described embrittling processes. Where the coating of therapeutic agent is applied before the embrittling process, the embrittling process may also serve to trap the therapeutic agent within the outermost layer.
Another way of making a multi-layered balloon having a relatively less compliant outermost layer is by using a co-extrusion process with the outermost layer being made of a different material than the inner layer(s) of the balloon wall. For example, the balloon may be made using the co-extrusion processes described in U.S. Pat. No. 5,195,969 (Wang et al.) or U.S. Pat. No. 7,166,099 (Devens), which are both incorporated by reference herein. The material used in making the outermost layer can differ in a variety of ways from the material used in making the inner layer(s). For example, the outermost layer may be made of a material that is relatively less elastic than the material used in the inner layer(s). In another example, the outermost layer may be made of a material that can be further processed to make the outermost layer less compliant. For example, the outermost layer may be made of a material having additives (e.g., benzophenone) that allow for UV-initiated cross-linking of the polymers in outermost layer.
In operation, the catheter device is inserted into a patient's body with the balloon 30 in an uninflated state.
Examples of additives or excipient materials that can be blended with the therapeutic agent include carbohydrates; polysulfones; physiologically acceptable oils, fats, lipids, lipoids, or waxes; bioresorbable or biodegradable polymers; surfactants such as polyethylene glycol (PEG)-fatty acid esters, glycerol fatty esters, or PEG-glyceryl fatty esters; resins such as shellac or its components (e.g., shellolic acid or aleuritic acid); citrate esters such as alkyl acetyl citrates, triethyl acetyl citrate, tributyl acetyl citrate, trihexyl acetyl citrate, alkyl citrates, triethyl citrate, or tributyl citrate; or radiological contrast agents.
Non-limiting examples of carbohydrates include monosaccharides, disaccharides, trisaccharides, oligosaccharides, polysaccharides, and derivatives of sugars (such as sugar alcohols, sugar acids, esterified sugars, and sugar polymers (e.g., Ficoll™)). Examples of sugars include mannitol, sucrose, fructose, mannose, trehalose, and raffinose. Examples of oligosaccharides and polysaccharides include those containing N-acyl glucosamine and uronic acid (e.g., glucuronic acid or iduronic acid) or N-acyl galactosamine and uronic acid.
Non-limiting examples of biodegradable or bioresorbable polymers include polycarboxylic acid, polyanhydrides including maleic anhydride polymers; polyorthoesters; poly-amino acids; polyethylene oxide; polyphosphazenes; polylactic acid, polyglycolic acid and copolymers and mixtures thereof such as poly(L-lactic acid) (PLLA), poly(D,L-lactide), poly(lactic acid-co-glycolic acid), 50/50 (DL-lactide-co-glycolide); polydioxanone; polypropylene fumarate; polydepsipeptides; polycaprolactone and co-polymers and mixtures thereof such as poly(D,L-lactide-co-caprolactone) and polycaprolactone co-butyl acrylate; polyhydroxybutyrate valerate and blends; polycarbonates such as tyrosine-derived polycarbonates and acrylates, polyiminocarbonates, and polydimethyltrimethylcarbonates; cyanoacrylate; polyglycosaminoglycans; macromolecules such as polysaccharides (including hyaluronic acid; cellulose and hydroxypropyl methyl cellulose; gelatin; starches; dextrans; alginates and derivatives thereof), proteins and polypeptides; and mixtures and copolymers of any of the above.
Contrast agents that can be blended with the therapeutic agent may be suitable for X-ray imaging, CT scan imaging, or magnetic resonance imaging (MRI) and may contain barium, iodine, manganese, iron, lanthanum, cerium, or gadolinium. Non-limiting examples of contrast agents include iodinated X-ray contrast agents such as iodixanol, iopromide, iohexyl, iopamidol; and paramagnetic chelates such as gadolinium-DPTA (diethylenetriamine penta-acetic acid) or gadobutrol.
The fatty acids can be in triglyceride form. Non-limiting examples of polyunsaturated fatty acids include omega-3 fatty acids, such as α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Other examples of additives or excipient materials that can be blended with the therapeutic agent include polyurethane-urea/heparin; polyurethane; or naturally occurring materials (e.g., collagen, laminin, heparin, fibrin, or cellulose).
Medical devices of the present invention may also include a vascular stent mounted on the balloon. The vascular stent may be any of those known in the art, including those with or without coatings that elute a therapeutic agent. The stent may also be biostable, bioerodable, or biodegradable. The stent may be a bare stent or may have a drug coating.
The balloons of the present invention may also be coated with a low-molecular weight carbohydrate, such as mannitol. The carbohydrate may be a separate coating or be blended with the therapeutic agent. The balloons of the present invention may also be coated with a radiocontrast agent (ionic or non-ionic), such as iopromide, bismuth subcarbonate, bismuth oxychloride, bismuth trioxide, barium sulfate, tungsten, and mixtures thereof. The contrast agent may be a separate coating or be blended with the therapeutic agent. The balloons of the present invention may also be coated with a water-soluble polymer, such as polyvinylpyrrolidone (PVP). The polymer may be a separate coating or be blended with the therapeutic agent.
The therapeutic agent used in the present invention may be any pharmaceutically acceptable agent (such as a drug), a biomolecule, a small molecule, or cells. Exemplary drugs include anti-proliferative agents such as paclitaxel, sirolimus (rapamycin), tacrolimus, everolimus, biolimus, and zotarolimus. Exemplary biomolecules include peptides, polypeptides and proteins; antibodies; oligonucleotides; nucleic acids such as double or single stranded DNA (including naked and cDNA), RNA, antisense nucleic acids such as antisense DNA and RNA, small interfering RNA (siRNA), and ribozymes; genes; carbohydrates; angiogenic factors including growth factors; cell cycle inhibitors; and anti-restenosis agents. Exemplary small molecules include hormones, nucleotides, amino acids, sugars, and lipids and compounds have a molecular weight of less than 100 kD. Exemplary cells include stem cells, progenitor cells, endothelial cells, adult cardiomyocytes, bone marrow cells, and smooth muscle cells. Other therapeutic agents that may be used in the present invention include those listed in U.S. Pat. No. 7,572,625 (Davis et al., “Medical devices coated with drug carrier macromolecules”), which is incorporated by reference herein. Any of the therapeutic agents may be combined to the extent such combination is biologically compatible.
The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Each of the disclosed aspects and embodiments of the present invention may be considered individually or in combination with other aspects, embodiments, and variations of the invention. Modifications of the disclosed embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art and such modifications are within the scope of the present invention.
This application claims the benefit of U.S. Provisional Applications No. 61/237,437 filed on Aug. 27, 2009 and No. 61/291,100 filed on Dec. 30, 2009, both of which are incorporated by reference herein in their entirety.
| Number | Date | Country | |
|---|---|---|---|
| 61237437 | Aug 2009 | US | |
| 61291100 | Dec 2009 | US |
