Patent Application
20080065044
Use of the singular herein includes the plural and visa versa unless expressly stated to be otherwise. That is, “a” and “the” refer to one or more of whatever the word modifies. For example, “a bioactive agent” includes one such agent, two such agents, etc.
As used herein, “implantable medical device” refers to any type of appliance that is totally or partly introduced, surgically or medically, into a patient's body or by medical intervention into a natural orifice, and which is intended to remain there after the procedure. The duration of implantation may be essentially permanent, i.e., intended to remain in place for the remaining lifespan of the patient; until the device biodegrades; or until it is physically removed. At present, a preferred implantable medical device for use with this invention includes a open ring-shaped device body that can be employed for the regional or localized delivery of bioactive agents to specific treatment sites or areas in a patient's body.
As used herein, “device body” refers to a fully formed implantable medical device with an outer surface to which no coating or layer of material different from that of which the device itself is manufactured has been applied.
As used herein, “open ring-shaped device body” refers to generally circular shaped device body in which the ends of the circle are not connected. Rings in which the ends overlap or do not overlap are encompassed by the present invention. The terms “open ring-shaped device body”, “device body” and “ring” and will be used interchangeably (unless the context shows otherwise).
As used herein, “adhered to the surface of” means the bioactive agent is covalently or non-covalently attached to the outer surface of the device body.
As used herein, “integrated into the structure of” means the bioactive agent is encapsulated in the material forming the device body.
As used herein, “disposed within pores” means the bioactive agent is located within pores, or holes, that are part of the device body.
As used herein, “tether” refers to any connecting mechanism, e.g., a string, that is flexible and capable of being coupled, either directly or indirectly to a component of the invention.
As used herein, “operatively coupled” refers to the attachment of a tether to the biodegradable spherical member, the biodegradable casing or the device body of the invention through either direct or indirect means. For example, the tether can be directly attached to the surface of the casing or the spherical member by a portion of the tether itself. Alternatively, the device body can encircle the tether, in which case it would be indirectly attached to the tether.
As used herein, “casing” refers to a material that completely encases a device body and optionally a spherical member of the invention. The casing will be readily biodegradable or biosoluble such that once the device body is positioned at a target site in the vasculature it will degrade or dissolve within a few seconds to a few minutes to release the device body within. Preferably, a casing will degrade within 10 seconds to 10 minutes after deployment in vivo. Examples of biodegradable and biosoluble materials include polyethylene glycol, polyvinyl pyrrolidone, polysaccharides, tyrosine-based polycarbonates and amphiphilic block copolymers such as poly ethylene glycol-poly lactic acid. Other suitable biodegradable materials are known to those skilled in the art.
As used herein, “biodegradable” as well as degraded, eroded, and absorbed, are used interchangeably (unless the context shows otherwise) and refer to materials that are capable of being degraded or absorbed when exposed to bodily fluids such as blood, and components thereof such as enzymes, and that can be gradually resorbed, absorbed, and/or eliminated by the body.
As used herein, “spherical member” refers to a generally round end piece attached to the distal end of the tether and on which the ring-shaped device body can be positioned during deployment. It can be biodegradable, biosoluble or biostable. Examples of biodegradable, biosoluble and biostable materials are described below, and others are known to those skilled in the art.
As used herein, “patient” refers to any organism that can benefit from the administration of a bioactive agent. In particular, patient refers to a mammal such as a cat, dog, horse, cow, pig, sheep, rabbit, goat or a human being.
As used herein, “treating” refers to the administration of a therapeutically effective amount of a bioactive agent to a patient known or suspected to be suffering from a disease.
As used herein, “therapeutically effective amount” refers to the amount of bioactive agent that has a beneficial effect, which may be curative or palliative, on the health and well-being of a patient with regard to a disease with which the patient is known or suspected to be afflicted. A therapeutically effective amount may be administered as a single bolus, as intermittent bolus charges, as short, medium or long term sustained release formulations or as any combination of these.
As used herein, “known” to be afflicted with a disease refers first to a condition that is relatively readily observable and or diagnosable. An example, without limitation, of such a disease is atherosclerosis, which is a discrete narrowing of a patient's arteries. Restenosis, on the other hand, while in its latter stages, like atherosclerosis, is relatively readily diagnosable or directly observable, may not be so in its nascent stage. Thus, a patient may be “suspected” of being afflicted or of being susceptible to affliction with restenosis at some time subsequent to a surgical procedure to treat an atherosclerotic lesion.
As used herein, “bioactive agent” can be used interchangeably with therapeutic agent. A bioactive agent of the invention can be an anti-restenosis agent, an antiproliferative agent, an anti-inflammatory agent, an antineoplastic, an antimitotic, an antiplatelet, an anticoagulant, an antifibrin, an antithrombin, a cytostatic agent, an antibiotic, an anti-allergic agent, an anti-enzymatic agent, an angiogenic agent, a cyto-protective agent, a cardioprotective agent, a proliferative agent, an ABC A1 agonist, an antioxidant, or any combination thereof.
Examples of antiproliferative agents include, without limitation, actinomycins, taxol, docetaxel, paclitaxel, rapamycin, 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, or 40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin, everolimus, biolimus, perfenidone and derivatives, analogs, prodrugs, co-drugs and combinations of any of the foregoing.
Examples of anti-inflammatory agents include both steroidal and non-steroidal (NSAID) anti-inflammatory agents such as, without limitation, clobetasol, alclofenac, alclometasone dipropionate, algestone acetonide, alpha amylase, amcinafal, amcinafide, amfenac sodium, amiprilose hydrochloride, anakinra, anirolac, anitrazafen, apazone, balsalazide disodium, bendazac, benoxaprofen, benzydamine hydrochloride, bromelains, broperamole, budesonide, carprofen, cicloprofen, cintazone, cliprofen, clobetasol propionate, clobetasone butyrate, clopirac, cloticasone propionate, cormethasone acetate, cortodoxone, deflazacort, desonide, desoximetasone, dexamethasone dipropionate, diclofenac potassium, diclofenac sodium, diflorasone diacetate, diflumidone sodium, diflunisal, difluprednate, diftalone, dimethyl sulfoxide, drocinonide, endrysone, enlimomab, enolicam sodium, epirizole, etodolac, etofenamate, felbinac, fenamole, fenbufen, fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac, flazalone, fluazacort, flufenamic acid, flumizole, flunisolide acetate, flunixin, flunixin meglumine, fluocortin butyl, fluorometholone acetate, fluquazone, flurbiprofen, fluretofen, fluticasone propionate, furaprofen, furobufen, halcinonide, halobetasol propionate, halopredone acetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol, ilonidap, indomethacin, indomethacin sodium, indoprofen, indoxole, intrazole, isoflupredone acetate, isoxepac, isoxicam, ketoprofen, lofemizole hydrochloride, lomoxicam, loteprednol etabonate, meclofenamate sodium, meclofenamic acid, meclorisone dibutyrate, mefenamic acid, mesalamine, meseclazone, methylprednisolone suleptanate, morniflumate, nabumetone, naproxen, naproxen sodium, naproxol, nimazone, olsalazine sodium, orgotein, orpanoxin, oxaprozin, oxyphenbutazone, paranyline hydrochloride, pentosan polysulfate sodium, phenbutazone sodium glycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicam olamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone, proxazole, proxazole citrate, rimexolone, romazarit, salcolex, salnacedin, salsalate, sanguinarium chloride, seclazone, sermetacin, sudoxicam, sulindac, suprofen, talmetacin, talniflumate, talosalate, tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam, tesimide, tetrydamine, tiopinac, tixocortol pivalate, tolmetin, tolmetin sodium, triclonide, triflumidate, zidometacin, zomepirac sodium, aspirin (acetylsalicylic acid), salicylic acid, corticosteroids, glucocorticoids, tacrolimus, pimecrolimus and derivatives, analogs, prodrugs, co-drugs and combinations of any of the foregoing.
Examples of antineoplastics and antimitotics include, without limitation, paclitaxel, docetaxel, methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride, and mitomycin.
Examples of antiplatelet, anticoagulant, antifibrin, and antithrombin drugs include, without limitation, sodium heparin, low molecular weight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin, prostacyclin dextran, D-phe-pro-arg-chloromethylketone, dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor antagonist antibody, recombinant hirudin and thrombin, thrombin inhibitors such as Angiomax ä, calcium channel blockers such as nifedipine, colchicine, fish oil (omega 3-fatty acid), histamine antagonists, lovastatin, monoclonal antibodies such as those specific for Platelet-Derived Growth Factor (PDGF) receptors, nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors, suramin, serotonin blockers, steroids, thioprotease inhibitors, triazolopyrimidine, nitric oxide or nitric oxide donors, super oxide dismutases, super oxide dismutase mimetic, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO) and derivatives, analogs, prodrugs, codrugs and combinations thereof.
Examples of cytostatic or antiproliferative agents include, without limitation, angiopeptin, angiotensin converting enzyme inhibitors such as captopril, cilazapril or lisinopril, calcium channel blockers such as nifedipine; colchicine, fibroblast growth factor (FGF) antagonists; fish oil (ω-3-fatty acid); histamine antagonists; lovastatin, monoclonal antibodies such as, without limitation, those specific for Platelet-Derived Growth Factor (PDGF) receptors; nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors, suramin, serotonin blockers, steroids, thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist) and nitric oxide.
Examples of antiallergic agents include, without limitation, permirolast potassium.
Other compounds that may be used as bioactive agents of this invention include, without limitation, alpha-interferon, genetically engineered epithelial cells, dexamethasone, antisense molecules which bind to complementary DNA to inhibit transcription, and ribozymes, antibodies, receptor ligands, enzymes, adhesion peptides, blood clotting factors, inhibitors or clot dissolving agents such as streptokinase and tissue plasminogen activator, antigens for immunization, hormones and growth factors, oligonucleotides such as antisense oligonucleotides and ribozymes and retroviral vectors for use in gene therapy; antiviral agents; analgesics and analgesic combinations; anorexics; antihelmintics; antiarthritics, antiasthmatic agents; anticonvulsants; antidepressants; antidiuretic agents; antidiarrheals; antihistamines; antimigrain preparations; antinauseants; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations including calcium channel blockers and beta-blockers such as pindolol and antiarrhythmics; antihypertensives; diuretics; vasodilators including general coronary; peripheral and cerebral; central nervous system stimulants; cough and cold preparations, including decongestants; hypnotics; immunosuppressives; muscle relaxants; parasympatholytics; psychostimulants; sedatives; tranquilizers; naturally derived or genetically engineered lipoproteins; and derivatives, analogs, prodrugs, codrugs and combinations of any of the foregoing.
Other bioactive agents include a corticosteroid, everolimus, zotarolimus, sirolimus, and derivatives thereof, paclitaxel, biolimus A9, a bisphosphonate, ApoA1, a mutated ApoA1, ApoA1 milano, an ApoA1 mimetic peptide, an ABC A1 agonist, an anti-inflammatory agent, an anti-proliferative agent, an anti-angiogenic agent, a matrix metalloproteinase inhibitor and a tissue inhibitor of metalloproteinase.
The present invention relates to an implantable medical device that includes a ring having a first and second end and one or more bioactive agents adhered to a surface of, integrated into the structure of or disposed within pores in the ring. Methods of adhering to a surface of, integrating into the structure of and disposing within pores of an implantable medical device are known to those skilled in the art.
A ring of the invention will necessarily be made of a material that has the ability to be compressed and to subsequently expand to its original shape. Exemplary ring materials include nitinol, biodegradable materials, polymeric materials and any combination thereof. A presently preferred ring material includes a polymeric material with a nitinol core. The polymeric material will allow for efficient bioactive agent loading and subsequent release while the nitinol core will allow for efficient compression and subsequent expansion of the ring.
Polymeric materials of the invention will be generally biocompatible and can be biodegradable or biostable as well as hydrophobic or hydrophilic.
As used herein, “biocompatible” refers to a polymer that both in its intact, as synthesized state and in its decomposed state, i.e., its degradation products, is not, or at least is minimally, toxic to living tissue; does not, or at least minimally and reparably, injure(s) living tissue; and/or does not, or at least minimally and/or controllably, cause(s) an immunological reaction in living tissue.
Biocompatible, biostable polymers include, without limitation, parylene, poly(D,L-lactide-co-glycolide), poly(1-lactide-co-glycolide) poly(3-hydroxybutyrate), poly(4-hydroxybutyrate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate), polyorthoester, polyanhydride, poly(glycolic acid), poly(glycolide), poly(L-lactic acid), poly(L-lactide), poly(D,L-lactic acid), poly(D,L-lactide), poly(L-lactide-co-D,L-lactide), poly(caprolactone), poly(L-lactide-co-caprolactone), poly(D,L-lactide-co-caprolactone), poly(glycolide-co-caprolactone), poly(trimethylene carbonate), polyester amide, poly(glycolic acid-co-trimethylene carbonate), co-poly(ether-esters) (e.g. PEO/PLA), polyphosphazenes, polyurethanes, silicones, polyesters, polyolefins, polyisobutylene and ethylene-alphaolefin copolymers, acrylic polymers and copolymers other than polyacrylates, vinyl halide polymers and copolymers (such as polyvinyl chloride), polyvinyl ethers (such as polyvinyl methyl ether), polyvinylidene halides (such as polyvinylidene chloride), poly(vinylidene fluoride), poly(vinylidene fluoride-co-hexafluoropropylene), polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics (such as polystyrene), polyvinyl esters (such as polyvinyl acetate), acrylonitrile-styrene copolymers, ABS resins, polyamides (such as Nylon 66 and polycaprolactam), polycarbonates including tyrosine-based polycarbonates, polyoxymethylenes, polyimides, polyethers, polyurethanes, rayon, rayon-triacetate, fullerenes and lipids.
Biocompatible, biodegradable polymers include, without limitation, naturally-occurring polymers such as, without limitation, collagen, chitosan, alginate, fibrin, fibrinogen, cellulosics, starches, dextran, dextrin, hyaluronic acid, heparin, glycosaminoglycans, polysaccharides and elastin.
Synthetic biocompatible, biodegradable polymers include, without limitation, polylactic acid, polyglycolic acid, polyethylene glycol, polycaprolactone, polyanhydrides, polyvinyl alcohol and poly(ester-amides).
As used herein, a synthetic polymer refers to one that is created wholly in the laboratory while a semi-synthetic polymer refers to a naturally-occurring polymer than has been chemically modified in the laboratory. Examples of synthetic polymers include, without limitation, polyphosphazines, polyphosphoesters, polyphosphoester urethane, polyhydroxyacids, polyhydroxyalkanoates, polyanhydrides, polyesters, polyorthoesters, polyamino acids, polyoxymethylenes, poly(ester-amides) and polyimides.
A ring of the invention will also necessarily have an open structure so that it can effectively be compressed when positioned within a catheter or within a casing of the invention as well as expand to the circumference of a vessel after it is deployed
Another aspect of the invention relates to a method for treating or preventing a disease using a bioactive agent-containing ring of the invention. The method involves compressing a ring and positioning it at the distal end of a catheter, inserting the catheter into a blood vessel of a patient upstream of a disease site locale and deploying the ring into the bloodstream of the patient, wherein the ring expands to the circumference of the blood vessel in which it is positioned.
A preferred method of deploying the ring involves using a deployment plunger having a longitudinally-oriented cylindrical member on which the compressed implantable medical device is positioned.
Once the ring is deployed, bioactive agent that was adhered to a surface of, integrated into the structure of or disposed within pores in the ring will diffuse into the vessel wall or into the bloodstream, thereby providing a means for the regional treatment of disease. In specific aspects, the disease to be treated is a vascular disease including, but not limited to, atherosclerosis, restenosis, vulnerable plaque or peripheral arterial disease.
While vascular diseases are presently preferred targets of the composition and methods herein, a host of other diseases are expected to be amenable to treatment or prevention such as, without limitation, cancer, coronary artery disease, kidney disease, liver disease, respiratory disease, infectious diseases and autoimmune diseases.
Cancer refers to malignant neoplasms, which, in turn relate to a large group of diseases that can arise in virtually any tissue composed of potentially dividing cells. The basic characteristic of cancer is a transmissible abnormality of cells that is manifested by reduced control over growth and function leading to serious life-threatening effects on the host through invasive growth and metastases.
Coronary artery disease refers to a narrowing of the coronary arteries cause by atherosclerosis that, when sufficiently severe, limits, or, in its most serious form completely occludes, the flow of blood to the myocardium (heart muscle).
Respiratory disease refers to a disease in which the lungs do not work properly so that breathing is affected. Examples of respiratory diseases include, without limitation, asthma, tuberculosis, cystic fibrosis and pneumonia.
Kidney disease refers to any disease or disorder that affects the function of the kidneys such as, without limitation, acute nephritic syndrome, atheroembolic renal disease, chronic nephritis, kidney cancer, Goodpasture's syndrome, interstitial nephritis and lupus nephritis.
Liver disease refers to any disease that affects the function of the liver such as, without limitation, hepatitis (A, B, C, D or autoimmune), liver cancer and cirrhosis.
Infectious disease refers to any disease transmitted by a microorganism such as, without limitation, a bacterium, a virus, a prion, a fungus, an amoeba or a protozoon. In general, infectious diseases are communicable in nature and may be transmitted from one individual to another and are capable of producing serious illness in the other individual.
Autoimmune disease refers to diseases and disorders (and related diseases and disorders) involving an abnormal immune response such as, without limitation, Hashimoto's thyroiditis, diabetes, rheumatoid arthritis, systemic lupus erythematosus, Sjogren syndrome, multiple sclerosis, myasthenia gravis and Grave's disease.
In another aspect of the invention, a ring of the invention is compressed and encased in a degradable casing. Suitable casing materials include biodegradable, biosoluble and biocompatible polymeric materials and are described above. Methods of encasing a device are known to those skilled in the art. In this aspect of the invention, the degradable casing can also contain a spherical member, which can be biodegradable or biostable, to which the distal end of a tether is directly attached. Suitable biodegradable and biostable materials are described above. In this aspect of the invention, the degradable casing can also be adjacent to a spherical member.
Another aspect of the invention relates to a method for treating or preventing a disease using a ring encased in a biodegradable casing as described above. The method involves positioning the encased ring, i.e., device, in the distal end of a catheter, inserting the catheter into a blood vessel of a patient upstream of a disease site locale and deploying the device into the bloodstream of the patient such that the device is allowed to move in the direction of blood flow. Using the attached tether, the encased ring can be positioned at or near a disease site locale while the proximal end of the tether remains operatively coupled to the catheter.
Once encased ring 360 is positioned upstream of a disease site locale, casing 350 will degrade. During this time ring 300 which abuts spherical member 320 will begin to slowly expand as casing 350 degrades. Once casing 350 has completely degraded, ring 300 will expand fully to match the circumference of blood vessel 340. Spherical member 320 will then be able to be pulled back into catheter 310 by tether 330 or will degrade on its own. In either case, tether 330 will be pulled back into catheter 310.
While vascular diseases are presently preferred targets of these methods, other diseases are expected to be amenable to treatment or prevention and are described above.
It is to be understood that multiple rings and multiple tethers can be used concurrently with any of the above aspects of the invention and are encompassed by the present invention. Indeed, in various aspects, the implantable medical device includes a plurality of tethers wherein one open ring-shaped device encircles each tether and abuts a spherical member. In other aspects, the implantable medical device includes two or more open-ringed shaped devices encircling at least one tether. In this aspect, the two or more open-ringed shaped devices can each individually abut a spherical member coupled to the tether thereby forming a ‘beads on a string’ sort of formation.
When multiple rings are used in a single casing, the segments may be open-ended such that the ring edges are overlapping. Alternatively, the rings may be shaped so as to separate from each other upon expansion.
While particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that changes and modifications can be made without departing from this invention in its broader aspects. Therefore, the claims are to encompass within their scope all such changes and modifications as fall within the true spirit and scope of this invention.
This application claims benefit of and incorporates by reference U.S. Provisional Patent Application No. 60/843,022 which was filed on Sep. 8, 2006.
| Number | Date | Country | |
|---|---|---|---|
| 60843022 | Sep 2006 | US |
