Patent Application
20110270226
The present invention relates to medical devices, more particularly, to catheter devices.
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 balloon is inserted through a peripheral blood vessel and then guided via a catheter through the vascular system to the target intravascular site. However, as the balloon travels through the vascular system, the flow of blood may wash away some of the drug coating. In addition, the control of the timing, location, and/or duration of the drug release can be an issue. Therefore, there is a need for improved catheter-based devices for drug delivery to an intravascular site.
In one embodiment, the present invention provides a medical device comprising: a catheter; a balloon mounted on the catheter; one or more sheaths disposed around the balloon, wherein the one or more sheaths are slidable over the balloon; and a therapeutic agent disposed between the surface of the balloon and the one or more sheaths. The therapeutic agent may be formulated to include a pharmaceutically-acceptable lubricant material.
In another embodiment, the present invention provides a medical device comprising: a catheter; a balloon mounted on the catheter; a sheath disposed around the balloon, wherein the sheath has a weakened portion, and wherein the sheath is disrupted at the weakened portion when the balloon is expanded; and a therapeutic agent disposed between the surface of the balloon and the sheath.
In another embodiment, the present invention provides a medical device comprising: a catheter; a balloon mounted on the catheter; a sheath disposed around the balloon, wherein the sheath comprises nanofibers; and a therapeutic agent retained on the medical device by the sheath.
In another embodiment, the present invention provides a medical device comprising: a catheter; a balloon mounted on the catheter; a sheath disposed around the balloon, wherein the sheath comprises a body and a plurality of reservoirs that are in communication with the external surface of the body of the sheath, wherein the reservoirs are longitudinally-extending channels within the body of the sheath; and a therapeutic agent contained in the reservoirs.
In another embodiment, the present invention provides a method for making a medical device, comprising: providing a balloon; disposing over the surface of the balloon, a layer of therapeutic agent; embossing a pattern onto the layer of therapeutic agent; and disposing a sheath over the layer of therapeutic agent.
It is to be noted that certain features in these drawings have been exaggerated to more clearly show details thereof. For example, the diameter of an uninflated balloon relative to the thickness of the catheter shaft may be smaller than what is depicted in the drawings.
Catheter devices of the present invention use an expandable balloon for delivering a therapeutic agent to a target site in the body. The balloon is designed to be insertable in the body via a catheter. The therapeutic agent can be associated with the balloon in any of various ways, as further described below. Any of various mechanisms conventionally used for the delivery, actuation, or expansion (e.g., by inflation) of balloon catheter devices may be used in the present invention. The balloon catheter 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 catheter devices of the present invention may be used in conjunction with other drug delivery devices, such as stents.
In one aspect of the present invention, one or more sheaths are disposed around the balloon. The sheath may be made of various types of materials, and in some cases, the sheath may be formed of a permeable or semi-permeable material to allow the passage of the therapeutic agent through the sheath. For example, the sheath may be made of expanded polytetrafluoro-ethylene (ePTFE), which can be made by expanding PTFE tubing under controlled conditions during the manufacturing process. This expansion process alters the physical properties of the PTFE tubing such that microscopic pores are created in the tube. The sheath can also be made from various other types of polymeric materials, such as polyolefin copolymers, fluoropolymers, noncompliant polyethylene terephthalate (PET), polyimide, nylon, polyethylene, PEBAX, or the like. The sheath may have varying degrees of compliance depending upon the type of balloon being used and the particular application. The sheath may be attached to the surface of the balloon (e.g., at one or more points or continuously) or the sheath may be free of any attachments to the surface of the balloon (e.g., the sheath is “free-floating” over the balloon surface).
Further, a therapeutic agent can be disposed over the sheath, within the sheath, or between the balloon and the sheath. The therapeutic agent can be associated with the sheath in various ways. For example, referring to
In certain embodiments, the sheath is designed to retract away from the balloon as the balloon is expanded. For example, referring to the embodiment shown in
In operation, balloon 84 is inserted into the body via a catheter, with the balloon in an unexpanded condition as shown in
In certain embodiments, the sheath comprises a body and a plurality of reservoirs for containing a therapeutic agent. The reservoirs can be, for example, longitudinally-extending channels within the body of the sheath. As the balloon is expanded within the sheath, the expanding balloon applies pressure against the reservoirs to push the therapeutic agent out of the reservoirs. In some cases, two or more of the reservoirs may be in communication with each other.
For example, referring to the embodiment shown in
In operation, catheter device 40 is inserted into the body via a catheter. At the target site, as shown in
In certain embodiments, the sheath has a non-linear compliance curve. Balloons having high compliance at smaller inflation diameters and low compliance at larger inflation diameters (i.e., a non-linear or hybrid compliance curve) are described in U.S. Pat. No. 5,348,538 (Wang et al.), which is incorporated by reference herein. Such balloons can be made using the shrunken balloon technique described in Wang et al., which is incorporated by reference herein. In general, a high compliance balloon will undergo a relatively large increase in diameter in response to an increase in inflation pressure, whereas a low compliance balloon will undergo a relatively small increase in diameter in response to an increase in inflation pressure. As such, a sheath of the present invention can be made in the same or similar manner, such that it has high compliance at smaller expansion diameters and low compliance at larger expansion diameters. In some cases, such a sheath can be formed of ePTFE having a porous cell structure. As the sheath expands in diameter with inflation of the balloon, the size of the pores in the sheath increase, making it more permeable to the therapeutic agent.
For example, referring to the embodiment shown in
In operation, balloon 156 is inserted into the body via a catheter. Because therapeutic agent 18 is covered by sheath 154, therapeutic agent 18 is protected while balloon 156 is being guided to the target site. At the target site, as shown in
In certain embodiments, it may be desirable to apply the sheath (e.g., of ePTFE) over a balloon that has been inflated and then deflated. This deflation or shrinking process can allow subsequent over-expansion of the sheath or ePTFE layer to create a larger cell size to allow for burst release of the therapeutic agent. When a relatively non-compliant balloon is used, the shrinking process facilitates the use of higher inflation pressures.
In certain embodiments, the sheath may be elastomeric and expands upon inflation of the balloon. In some cases, the elastomeric sheath may be an elastomeric mesh. With expansion, the widened spaces of the mesh allow for the release of the therapeutic agent. In some cases, the elastomeric mesh may comprise a biodegradable material (e.g., polyglycolic acid, polylactic acid, polyanhydride, etc.). In some cases, the medical device may further include a biodegradable stent (e.g., made of a biodegradable polymer or bioresorbable metal, such as magnesium) disposed over the balloon, with the biodegradable stent being covered by the elastomeric mesh.
For example, referring to the embodiment shown in
In operation, balloon 166 is inserted into the body via a catheter. Because therapeutic agent 18 is covered by sheath 164, therapeutic agent 18 is protected while balloon 166 is being guided to the target site. At the target site, as shown in
In some cases, sheath 164 may further have numerous pili as shown in
In certain embodiments, the sheath is designed to tear, break, or otherwise become disrupted at one or more points when the sheath expands as a result of balloon inflation. The sheath is provided with one or more weakened portions where the tearing, breaking, or disruption occurs. The weakened portions are areas where the sheath has a different structure or composition than other areas of the sheath, wherein the different structure or composition at the weakened portions cause the area to be structurally weaker than the other areas of the sheath. For example, the weakened portions may be slots, slits, grooves, or perforations in the sheath. The weakened portions may have any of various orientations or configurations relative to the balloon, including radial, longitudinal, grid-like, or random. The tearing, breaking, or disruption of the sheath allows the release of the therapeutic agent. In some cases, the weakened portions may be areas where the sheath is attached to the balloon such that disruption of the sheath preferentially occurs at the attachment points. Such attachments can be made by, for example, spot welding of the sheath to the balloon.
Referring to the embodiment shown in
In operation, balloon 204 (enclosed within sheath 206) is inserted into the body via a catheter. Because therapeutic agent 18 is covered by sheath 206, therapeutic agent 18 is protected while balloon 204 is being guided to the target site. At the target site, as shown in
Referring to the embodiment shown in
In operation, balloon 214 enclosed within sheath 216 is inserted into the body via a catheter. Because therapeutic agent 18 is covered by sheath 216, therapeutic agent 18 is protected while balloon 214 is being guided to the target site. At the target site, as shown in FIG. 10B, balloon 214 is inflated, causing sheath 216 to also expand. Expansion of sheath 216 causes tearing of sheath 216 along perforation lines 218 to form tears 219. Tears 219 expose therapeutic agent 18 on the surface of balloon 214 such that therapeutic agent 18 is released.
Referring to the embodiment shown in
In operation, balloon 224 enclosed within sheath 226 is inserted into the body via a catheter. Because therapeutic agent 18 is covered by sheath 226, therapeutic agent 18 is protected while balloon 224 is being guided to the target site. At the target site, as shown in
Referring to the embodiment shown in
In operation, balloon 234 enclosed within sheath 236 is inserted into the body via a catheter. Because therapeutic agent 18 is covered by sheath 236, therapeutic agent 18 is protected while balloon 234 is being guided to the target site. At the target site, as shown in
Referring to the embodiment shown in
As shown in
In certain embodiments, the sheath comprises nanofibers. The nanofibers are formed of any suitable polymer material, including polymers that are elastic. The nanofibers may have diameters (thickness) that are less than 1 μm (e.g., in the range of 200 nm-1 μm). The nanofibers may comprise biodegradable polymers, such as poly(lactic-co-glycolic acid) (PLGA), poly(lactic acid) (PLA), or uncured poly(ethylene oxide) (PEO). The nanofibers may also comprise non-biodegradable polymers, such as poly(styrene-isobutylene-styrene) (SIBS) block copolymers, polyamides (e.g., nylon), polyesters, polyethylene, polyurethane, or carbon fiber.
The nanofibers may be disposed over the balloon in any of various ways. In some cases, the nanofibers are wound circumferentially around the body of the balloon. The nanofibers may be wound around the balloon loosely or under elastic tension. Where the nanofibers are wound around the balloon under elastic tension, the elastic tension may restrain the balloon in its unexpanded or folded configuration.
For example,
In some cases, the nanofibers are deposited as a tangled mat on the balloon. In some of such cases, additional nanofibers may be wound circumferentially around the tangled mat of nanofibers (e.g., to encase the tangled mat of nanofibers).
The nanofibers may be disposed over the balloon with the balloon in any suitable configuration (e.g., inflated or uninflated, folded or unfolded). The nanofibers may be disposed over the entire balloon or over only a portion of the balloon (e.g., between the cones).
The therapeutic agent may be associated with the nanofiber sheath in any of various ways. The therapeutic agent may be provided in any suitable form, including as a liquid, a gel, or a solid. In some cases, the therapeutic agent is contained between the nanofiber sheath and the balloon (i.e., the sheath covers over the therapeutic agent). For example, the therapeutic agent can be deposited on the balloon and the nanofibers are spun (e.g., by electro-spinning) over the therapeutic agent to encase and protect it. Where the sheath comprises a tangled mat of nanofibers, the therapeutic agent may be dispersed within the network of nanofibers. In some cases, the therapeutic agent may be dispersed in the spaces between the nanofibers. In some cases, where the nanofibers are biodegradable (e.g., made of partially cured PEO), the therapeutic agent may constitute part of the composition of the nanofibers and be released upon degradation of the nanofibers. For example, the therapeutic agent may be contained in the nanofiber solution and spun with the nanofibers.
Upon delivery of the balloon to the target site, the therapeutic agent may be released through any of various mechanisms. Where the nanofiber sheath covers over the therapeutic agent, the therapeutic agent may be released through gaps or openings between the nanofibers. For example, as the balloon expands, the therapeutic agent may be squeezed through such gaps or openings. In some cases, stretching of the nanofibers as the balloon expands causes thinning of the nanofibers. This thinning of the nanofibers increases the spacing between the nanofibers, providing openings for the release of the therapeutic agent.
In addition to their role in delivery of the therapeutic agent, the nanofibers may also serve other functions. For example, elastic nanofibers may serve to control the folding or re-folding of the balloon or control the shape or dimensions of the expanded balloon.
In another aspect of the present invention, the balloon includes a micro-electromechanical system (MEMS) for drug delivery. Various types of drug delivery systems using MEMS are known in the art, such as microfluidic devices that incorporate micropumps, valves, or flow channels; microfabricated porous membranes for drug encapsulation; microparticles for carrying drugs; and the microchip devices for drug delivery described in U.S. Pat. No. 6,656,162 (Santini et al.).
Referring to
In operation, the balloon is inserted into the body via a catheter. At the target site, as shown in
In certain embodiments of the invention, as described above, the configuration of the balloon and the sheath can be controlled such as to allow release of the therapeutic agent only at the desired time. For example, the device may be designed such that a certain pressure within the balloon is required for the sheath to release the therapeutic agent (e.g., by retracting, fracturing, fragmenting, opening pores, etc.). In this way, the therapeutic agent can be held in the folds while the device is delivered through the blood vessel to the target site. Then, at the target site, the balloon is inflated to the pressure and/or diameter at which the sheaths are designed to release the therapeutic agent. In this way, for example, the therapeutic agent release can be controlled such that it is released only if the balloon is in contact with or in close proximity to the vessel wall. This helps to prevent loss of the therapeutic agent during catheter placement and balloon inflation. Also, because deflation of the balloon can, in some instances, stop or substantially reduce therapeutic agent release, certain embodiments of the invention can control the duration of release after the initial release of therapeutic agent.
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, bioerodible, or biodegradable.
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. The contrast agent 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 non-genetic therapeutic agent, a biomolecule, a small molecule, or cells. Example drugs include anti-proliferative agents or anti-restenosis agents such as paclitaxel, sirolimus (rapamycin), tacrolimus, everolimus, and zotarolimus.
Exemplary non-genetic therapeutic agents include anti-thrombogenic agents such heparin, heparin derivatives, prostaglandin (including micellar prostaglandin E1), urokinase, and PPack (dextrophenylalanine proline arginine chloromethylketone); anti-proliferative agents such as enoxaparin, angiopeptin, sirolimus (rapamycin), tacrolimus, everolimus, zotarolimus, monoclonal antibodies capable of blocking smooth muscle cell proliferation, hirudin, and acetylsalicylic acid; anti-inflammatory agents such as dexamethasone, rosiglitazone, prednisolone, corticosterone, budesonide, estrogen, estrodiol, sulfasalazine, acetylsalicylic acid, mycophenolic acid, and mesalamine; anti-neoplastic/anti-proliferative/anti-mitotic agents such as paclitaxel, epothilone, cladribine, 5-fluorouracil, methotrexate, doxorubicin, daunorubicin, cyclosporine, cisplatin, vinblastine, vincristine, epothilones, endostatin, trapidil, halofuginone, and angiostatin; anti-cancer agents such as antisense inhibitors of c-myc oncogene; anti-microbial agents such as triclosan, cephalosporins, aminoglycosides, nitrofurantoin, silver ions, compounds, or salts; biofilm synthesis inhibitors such as non-steroidal anti-inflammatory agents and chelating agents such as ethylenediaminetetraacetic acid, O,O′-bis (2-aminoethyl) ethyleneglycol-N,N,N′,N′-tetraacetic acid and mixtures thereof; antibiotics such as gentamycin, rifampin, minocyclin, and ciprofloxacin; antibodies including chimeric antibodies and antibody fragments; anesthetic agents such as lidocaine, bupivacaine, and ropivacaine; nitric oxide; nitric oxide (NO) donors such as linsidomine, molsidomine, L-arginine, NO-carbohydrate adducts, polymeric or oligomeric NO adducts; anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, an RGD peptide-containing compound, heparin, antithrombin compounds, platelet receptor antagonists, anti-thrombin antibodies, anti-platelet receptor antibodies, enoxaparin, hirudin, warfarin sodium, Dicumarol, aspirin, prostaglandin inhibitors, platelet aggregation inhibitors such as cilostazol and tick antiplatelet factors; vascular cell growth promoters such as growth factors, transcriptional activators, and translational promoters; vascular cell growth inhibitors such as growth factor inhibitors, growth factor receptor antagonists, transcriptional repressors, translational repressors, replication inhibitors, inhibitory antibodies, antibodies directed against growth factors, bifunctional molecules consisting of a growth factor and a cytotoxin, bifunctional molecules consisting of an antibody and a cytotoxin; cholesterol-lowering agents; vasodilating agents; agents which interfere with endogenous vascoactive mechanisms; inhibitors of heat shock proteins such as geldanamycin; angiotensin converting enzyme (ACE) inhibitors; beta-blockers; βAR kinase (βARK) inhibitors; phospholamban inhibitors; protein-bound particle drugs such as ABRAXANE™; structural protein (e.g., collagen) cross-link breakers such as alagebrium (ALT-711); any combinations and prodrugs of the above.
Exemplary biomolecules include peptides, polypeptides and proteins; 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. Nucleic acids may be incorporated into delivery systems such as, for example, vectors (including viral vectors), plasmids or liposomes.
Non-limiting examples of proteins include serca-2 protein, monocyte chemoattractant proteins (MCP-1) and bone morphogenic proteins (“BMP's”), such as, for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (VGR-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15. Preferred BMP's are any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, and BMP-7. These BMPs can be provided as homodimers, heterodimers, or combinations thereof, alone or together with other molecules. Alternatively, or in addition, molecules capable of inducing an upstream or downstream effect of a BMP can be provided. Such molecules include any of the “hedgehog” proteins, or the DNA's encoding them. Non-limiting examples of genes include survival genes that protect against cell death, such as anti-apoptotic Bcl-2 family factors and Akt kinase; serca 2 gene; and combinations thereof. Non-limiting examples of angiogenic factors include acidic and basic fibroblast growth factors, vascular endothelial growth factor, epidermal growth factor, transforming growth factors α and β, platelet-derived endothelial growth factor, platelet-derived growth factor, tumor necrosis factor α, hepatocyte growth factor, and insulin-like growth factor. A non-limiting example of a cell cycle inhibitor is a cathespin D (CD) inhibitor. Non-limiting examples of anti-restenosis agents include p15, p16, p18, p19, p21, p27, p53, p57, Rb, nFkB and E2F decoys, thymidine kinase and combinations thereof and other agents useful for interfering with cell proliferation.
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, and smooth muscle cells. Cells can be of human origin (autologous or allogenic) or from an animal source (xenogenic), or genetically engineered. Non-limiting examples of cells include side population (SP) cells, lineage negative (Lin−) cells including Lin− CD34−, Lin−CD34+, Lin−cKit+, mesenchymal stem cells including mesenchymal stem cells with 5-aza, cord blood cells, cardiac or other tissue derived stem cells, whole bone marrow, bone marrow mononuclear cells, endothelial progenitor cells, skeletal myoblasts or satellite cells, muscle derived cells, go cells, endothelial cells, adult cardiomyocytes, fibroblasts, smooth muscle cells, adult cardiac fibroblasts +5-aza, genetically modified cells, tissue engineered grafts, MyoD scar fibroblasts, pacing cells, embryonic stem cell clones, embryonic stem cells, fetal or neonatal cells, immunologically masked cells, and teratoma derived cells. 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 is a divisional of application Ser. No. 12/399,386 filed Mar. 6, 2009, which claims the benefit of provisional application Ser. No. 61/034,328 filed Mar. 6, 2008, both of which are incorporated by reference herein.
| Number | Date | Country | |
|---|---|---|---|
| 61034328 | Mar 2008 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 12399386 | Mar 2009 | US |
| Child | 13179054 | US |
