CN1929882A - VEGF receptor tyrosine kinase inhibitor coated stent - Google Patents
VEGF receptor tyrosine kinase inhibitor coated stent Download PDFInfo
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- CN1929882A CN1929882A CNA2005800075100A CN200580007510A CN1929882A CN 1929882 A CN1929882 A CN 1929882A CN A2005800075100 A CNA2005800075100 A CN A2005800075100A CN 200580007510 A CN200580007510 A CN 200580007510A CN 1929882 A CN1929882 A CN 1929882A
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
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- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
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- A61L29/16—Biologically active materials, e.g. therapeutic substances
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61M25/00—Catheters; Hollow probes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/08—Vasodilators for multiple indications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/432—Inhibitors, antagonists
- A61L2300/434—Inhibitors, antagonists of enzymes
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Abstract
The invention relates to the local administration of a vascular endothelial growth factor receptor tyrosine kinase inhibitor or a pharmaceutically acceptable salt, optionally in conjunction with one or more other active ingredients, and a device adapted for such local administration.
Description
The present invention relates to be used for the drug delivery system of prevention and treatment proliferative disease, particularly angiopathy.
Many people suffer the misery of the blood circulation diseases that the carrying out property obstruction by the blood vessel that spreads all over heart and other major organs causes.The serious obstruction of this type of people's medium vessels usually causes ischemia damage, hypertension, apoplexy or myocardial infarction.The atherosclerotic lesions of restriction or obstruction coronary flow or PBF is that the ischemic disease comprises morbidity and the main causes of death that coronary heart disease is relevant with apoplexy.In order to stop to damage the lysis and the more serious morbid state of prevention of cardiac muscle or other organ, used the medical science revascularization to become the art operation, such as blood vessel transplantation operation through percutaneous transluminal coronary angioplasty (PCTA), percutaneous transluminal angio plasty (PTA), atherosclerotic plaque excision, bypass graft or other type.
Atherosclerotic restenosis coronarius after multiple revascularization becomes operation takes place in the operation and the artery position that depend on use in the patient of the 10-80% that stands this treatment.Except opening the tremulous pulse that is blocked by atherosclerosis, revascularization becomes also interior endotheliocyte and the smooth muscle cell of injured blood vessel wall of art, therefore causes thrombosis and inflammatory reaction.Hypertrophy and transport reaction in cell-derived somatomedin such as platelet derived growth factor, wellability macrophage, lymphocyte or the smooth muscle cell autostimulation smooth muscle cell.In the time of with local proliferation and migration, inflammatory cell is also invaded vascular injury site and can be moved to the more deep layer of blood vessel wall.Hypertrophy/migration usually after damage in one to two day beginning and, the revascularization that depends on use becomes the art operation, continues several days to several weeks.
Cell in the atherosclerotic lesions and the cell in the substrate be migration, hypertrophy and/or secrete a large amount of extracellular matrix proteins all.Hypertrophy, migration and extracellular matrix are synthetic to last till that the endodermis of damage obtains repairing, and at this moment hypertrophy slows down in inner membrance.The new tissue that forms is called neointima, intimal thickening or restenosis damage and causes lumen of vessels narrow usually.Because constitutive character is rebuild, reconstructing blood vessel for example, it is narrow that further inner membrance can take place, and causes inner membrance further to thicken or hyperplasia.
Therefore, after needing effectively treatment and drug delivery system to be used for prevention and treatment to damage, blood vessel injury for example, comprise for example surgery damage, for example, revascularization becomes the inductive damage of art, also intimal thickening or the restenosis that for example takes place after the damage in heart or other graft.
The selective depressant 4-pyridylmethyl-2 derivant of VEGF (VEGF) receptor tyrosine kinase has been described in the U.S. Patent number 6,258,812 that for example, is hereby incorporated by.Reported that this compounds is used for the treatment of and the relevant disease of reducing, particularly neoplastic disease (solid tumor) of blood vessel generation, such as breast carcinoma, colon cancer, pulmonary carcinoma, particularly small cell lung cancer, and carcinoma of prostate.
Astoundingly, find when the part is used for damage location the vegf receptor tyrosine kinase inhibitor now, particularly as the chemical compound of the formula I that defines in the literary composition and, particularly PTK787 chooses wantonly and other reactive compound, and for example anti-hypertrophy chemical compound is in conjunction with having advantageous effect.
Therefore, the present invention relates to preventative and therapeutic treatment and damage for example blood vessel injury, comprise for example surgery damage, for example revascularization becomes the inductive damage of art, for example comprise the intimal thickening that takes place after the damage in heart or other graft or the method for restenosis, it comprises to its vegf receptor tyrosine kinase inhibitor of homoiothermic animal administering therapeutic effective dose of needs.
Vegf receptor tyrosine kinase inhibitor used among the present invention is passable, particularly be selected from the chemical compound that suppresses vegf receptor tyrosine kinase or antibody or in conjunction with vegf receptor or the chemical compound of VEGF, protein for example, micromolecule or monoclonal antibody, disclosed protein among the WO 98/35958 particularly, micromolecule or monoclonal antibody, 1-(4-chloroanilino)-4-(4-pyridylmethyl) 2 for example, 3-benzodiazine or its officinal salt, or at WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO 00/27819, WO 00/37502, WO 94/10202 and EP 0 769 947, people Cancer Research such as M.Prewett
59(1999) 5209-5218, people Proc.Natl.Acad.Sci.USA such as F.Yuan, the 93rd volume, the 14765-14770 page or leaf, in December, 1996, people Cancer Res.58 such as Z.Zhu, 1998,3209-3214, people ToxicologicPathology such as J.Mordenti, the 27th volume, the 1st phase, 14-21 page or leaf, those of 1999 descriptions, people such as M.S.O ' Reilly, Cell 79,1994, the Angiostatin that 315-328 describes
TM, people such as M.S.O ' Reilly, Cell 88,1997, the Endostatin that 277-285 describes
TM
Preferably, the present invention relates to preventative and the therapeutic treatment damage, blood vessel injury for example, comprise for example surgery damage, for example revascularization becomes the inductive damage of art, for example comprise in heart or other graft the intimal thickening that the damage back takes place or the method for restenosis, it comprises to its homoiothermic animal of needs, the chemical compound of the formula I of preferred people's administering therapeutic effective dose
Wherein
R is 0 to 2,
N is 0 to 2,
M is 0 to 4,
R
1And R
2(i) be low alkyl group or
(ii) form inferior formula I together
*In bridge
Realize combination by two terminal carbons, or
(iii) form inferior formula I together
*In bridge
One of them or two ring members T
1, T
2, T
3And T
4Be nitrogen, and other ring members is CH under every kind of situation, and passes through T
1And T
4Realize combination;
A, B, D and E are N or CH independently of each other, condition be in these groups at the most 2 groups are N;
G is a low-grade alkylidene, by acyloxy or hydroxyl ,-CH
2-O-,-CH
2-S-,-CH
2(O-), thia (S-) or the imino group (NH-) low-grade alkylidene of Qu Daiing for-NH-, oxa-;
Q is a low alkyl group;
R is H or low alkyl group;
X is that imino group, oxa-or sulfur are assorted;
Y is aryl, the pyridine radicals that does not replace or replace, or the cycloalkyl that does not replace or replace; With
Z is amino, single replaces or hydroxyl, nitro, cyano group, carboxyl, the carboxyl of esterification, alkanoyl, the carbamoyl of alkyl, hydroxyl, etherificate or the esterification of dibasic amino, halogen, alkyl, replacement, N-is mono-substituted or N, the dibasic carbamoyl of N-, amidino groups, guanidine radicals, sulfydryl, sulfo group, thiophenyl, phenyl-lower alkylthio, alkyl sulfur-base, phenyl sulfonyl, phenyl-low alkyl group sulfinyl or alkyl phenyl sulfinyl, if there is more than one Z base, substituent group Z is identical or different so;
And if wherein had key, the feature of key would be the wavy line of singly-bound or two keys so;
Or the N-oxide of definite chemical compound, wherein one or more N atoms carry oxygen atom,
Or has the salt, particularly succinate of this compounds of at least one salt forming group.
Group and symbol used in the definition of the chemical compound of formula I have at U.S. Patent number 6,258, disclosed implication in 812.
The chemical compound of preferred formula I is PTK787.
The chemical compound of used term " PTK787 " expression I in the literary composition, wherein r, n and m each be 0, R
1And R
2Form inferior formula I together
*Bridge; Each is CH for A, B, D and E, and G is a methylene, and X is an imino group, and Y is the 4-chlorphenyl, and is that the key of feature is two keys with the wavy line.
According to the present invention, the vegf receptor tyrosine kinase inhibitor can be used as that unique active component uses or and immunosuppressant, calcinerin inhibitor for example, cyclosporin for example, spore rhzomorph A for example, or FK506, the EDG-receptor stimulating agent, FTY720 for example, antiinflammatory, steroid for example, corticosteroid for example, for example dexamethasone or prednisone, NSAID, cyclooxygenase-2 inhibitor for example, cox 2 inhibitor for example, celecoxib for example, rofecoxib, etoricoxib or valdecoxib, or ascosin, ASM981 for example, antithrombotic forms or anticoagulant, heparin for example, IIb/IIIa inhibitor etc., anti-proliferative agent, for example microtubule stabilizer or destabilizing agent, include but not limited to taxane, paclitaxel for example, docetaxel or docetaxel, vinca alkaloids, vinblastine for example, vinblastine sulfate particularly, vincristine is vincristine sulfate particularly, and vinorelbine, discodermolides or Epothilones or derivatives thereof, epothilone B or derivatives thereof for example, it or not the tyrosine kinase inhibitor of VEGF inhibitor, for example star born of the same parents rhzomorph and relevant micromolecule, UCN-01 for example, BAY43-9006, Bryostatin 1, perifosine, Limofosine, midostaurin, RO318220, RO320432, GO 6976, Isis 3521, LY333531, LY379196, SU5416, SU6668, AG1296 etc., suppress the chemical compound of pdgf receptor tyrosine kinase or antibody or in conjunction with PDGF or reduce the chemical compound that pdgf receptor is expressed, STI571 for example, CT52923, RP-1776, GFB-111, pyrrolo-[3,4-c]-B-carboline-diketone, Deng, suppress the chemical compound of EGF receptor tyrosine kinase or antibody or in conjunction with EGF or reduce the chemical compound of EGF expression of receptor, disclosed chemical compound in WO97/02266 for example, the chemical compound of embodiment 39 for example, tretinoin, ZD1839 (Iressa), α-, γ-or Delta-Tocopherol or α-, γ-or δ-tocotrienol or influence GRB2, IMC-C225, the chemical compound of inhibin, the chemical compound that for example has the HMG-CoA reductase active, fluvastatin for example, lovastatin, simvastatin, pravastatin, his spit of fland is cut down in holder, simvastatin, Pitavastatin, rosuvastatin or nivastatin, chemical compound, protein, the chemical compound that the somatomedin of the endothelial regeneration of somatomedin or stimulation enhancing intracavity skin tissue produces, FGF for example, IGF, matrix metallo-proteinase inhibitor, batimastat (batimistat) for example, marimastat (marimistat), Trocade, CGS 27023, RS 130830 or AG3340, kinase whose regulator (for example, antagonist or agonist), JNK for example, ERK1/2, MAPK or STAT, or the chemical compound or the NO donor that stimulate (NO) to discharge, for example diazeniumdiolate (diazeniumdiolate), S-nitrosothiol, mesoionic triazole, the isosorbide compositions is used in combination.
The present invention also provides and for example above disclosed calcinerin inhibitor, for example above disclosed EDG-receptor stimulating agent, for example above disclosed microtubule stabilizer or destabilizing agent, the chemical compound of for example above disclosed inhibition pdgf receptor tyrosine kinase or antibody or in conjunction with PDGF or reduce the chemical compound that pdgf receptor is expressed, the chemical compound of for example above disclosed inhibition EGF receptor tyrosine kinase or antibody or in conjunction with EGF or reduce the chemical compound of EGF expression of receptor, for example above disclosed inhibin, for example above disclosed chemical compound, protein, the chemical compound that the somatomedin of the endothelial regeneration of somatomedin or stimulation enhancing intracavity skin tissue produces, for example above disclosed matrix metallo-proteinase inhibitor, for example above disclosed kinase modulator (for example, antagonist or agonist) inhibitor, or the chemical compound that discharges of for example above disclosed stimulation (NO) or NO donor are in conjunction with local application or send the vegf receptor tyrosine kinase inhibitor.
According to concrete discovery of the present invention, provide:
1. smooth muscle cell proliferation and migration in prevention or the treatment hollow pipe in its mammal of needs, or strengthen cell proliferation or reduce programmed cell death or the method for increase apposition, it comprises the optional and for example vegf receptor tyrosine kinase inhibitor of the above bonded treatment effective dose of disclosed one or more other active component of local application.
2. the method that is used for the treatment of intimal thickening in the blood vessel wall, it comprise from arbitrarily based on the device of conduit or intraluminal medical devices controllably send optional with for example more than the vegf receptor tyrosine kinase inhibitor of the bonded treatment effective dose of disclosed one or more other active component.
Preferably, disease to be treated becomes narrow, restenosis after art or the neovascularization and/or inflammation and/or thrombosis for revascularization for example.
3. drug delivery device or system, it comprises the medical apparatus that a) is suitable for the interior topical application of hollow pipe or uses, for example based on the delivery apparatus or the intracavity medical apparatus of conduit, and b) the vegf receptor tyrosine kinase inhibitor of therapeutic dose, choose wantonly with for example above disclosed one or more other active component of therapeutic dose and combine every kind of delivery apparatus or medical apparatus that is fixed to releasedly based on conduit.
This kind local delivery device or system can be used as at any vessel position, comprise coronary artery, carotid artery, renal artery, peripheral arterial, cerebral arteries or arbitrarily the revascularization that carries out of other tremulous pulse or venous locations become the adnexa of art, bypass or graft procedure to be used to reduce narrow or restenosis, with reduce such as have or do not have politef transplant and have or unsupported artery-vein dialyzing access in converge (anastomic) restenosis, or with arbitrarily other heart or graft procedure, or congenital blood vessel is got involved combination.
The vegf receptor tyrosine kinase inhibitor will be called " medicine " hereinafter.Can will be generically and collectively referred to as " adjuvant " hereinafter with other active component that for example above disclosed vegf receptor tyrosine kinase inhibitor is used in combination.Medicine represents that medicine or medicine add adjuvant.
Local application preferably occurs near vascular injury site or the vascular injury site.
Use and can be undertaken by one or more following approach: by in conduit or other intravenous delivery system, intranasal, the bronchus, intraperitoneal (interperitoneal) or through esophagus (eosophagal).Hollow pipe comprises that cyclic system is under the overall leadership such as blood vessel (tremulous pulse or vein), tissue cavity, lymph path, digestive tract, comprises digestive tube, respiratory tract, Excretory system pipe, reproductive system conduit and conduit, coelomic duct or the like.The local application of medicine or application provide the concentrated of described medicine to send, and reach by what other route of administration can not obtain to organize level in target tissue.
The method that is used for to the hollow pipe localized drug delivery can be to hollow pipe inside or external physical delivering drugs.Localized drug delivery comprises catheter delivery system, local injection device or system or inherent device.This kind device or system include but not limited to, (paving) or other endovascular device, embolus delivery of particles, the cellular targets of filming in the support of support, coating, intracavity sleeve pipe, stent-grafts, liposome, controlled release matrix, the polymer cavity is fixed, such as film based on the inside patch around the sending of affinity, the hollow pipe, outside patch, hollow bush capsule, outside around the hollow pipe, outside support sleeve pipe or the like.Referring to, quote people such as Eccleston (1995) InterventionalCardiology Monitor 1:33-40-41 and Slepian in the literary composition as this paper reference, N.J. (1996) Intervente.Cardiol.1:103-116, or Regar E, Sianos G, Serruys PW.Stent development and localdrug delivery.Br Med Bull 2001,59:227-48.
" biocompatible " expression does not cause or causes minimum unfavorable tissue reaction, comprises the material of thrombosis for example and/or inflammation.
Can send or drug application with support or sleeve pipe or sheath (sheathes).Can use intracavity stent, it is made up of polymer or other biocompatible materials or is coated with polymer or other compatibility material, and for example, porous ceramics, nanoporous pottery for example, described polymer or other compatibility material have soaked into or mixed medicine.This type of support can be biodegradable maybe can be with metal or alloy for example Ni and Ti when being used for life-time service when meaning, or other stabilizing material is made.Medicine also can be trapped in the improved support or the intravital metal of graft that contains micropore or passage.Also can be with for example being used for local delivery by the chamber of above disclosed polymer that contains medicine or the preparation of other biocompatible materials and/or ablumenal coating or outer cover.
Support is usually as staying in the catheter lumen to alleviate the tubular structure that blocks.Can be inserted in catheter lumen with non-unfolded form they and expansion (self-deploying support) or original position expansion under the help of second kind of device automatically then, the angioplasty air bag of conduit for example is installed, the chamber that it expands with shearing and the destruction obstruction relevant with the wall fraction of blood vessel and obtains to increase in narrow vascular or body passage.
For example, medicine can be incorporated into or in many ways and with any biocompatible materials attached to support; For example it can be incorporated on polymer or the polymeric matrices and be injected on the outer surface of support.The mixture of medicine and polymeric material can be prepared in solvent or in the solvent mixture and also be applied to rack surface, allow solvent evaporates to stay the film of packaging medicine by coating of dip coated, brush and/or dipping/rotary coating.For support, polymer solution can be used as extraly outer with control drug release from micropore, minor connector or passage delivering drugs; Alternatively, pharmaceutical pack can be contained in micropore, minor connector or the passage and adjuvant can be incorporated in the skin, or vice versa.Also can with medicine attached to the internal layer of support and with adjuvant attached to skin, or vice versa.Also can be with medicine by covalent bond, for example ester, amide or acid anhydride comprise that chemical derivatization is attached to rack surface.Also medicine can be incorporated into biocompatibility porous ceramics coating, for example in the nanoporous ceramic coating.
The example of polymeric material comprises biocompatible degradation material, for example based on the polyester or the copolyesters of lactone, and polylactide for example; Polylactide-co-glycolide; Polycaprolactone-Acetic acid, hydroxy-, bimol. cyclic ester; Poe; Polyanhydride; Polyamino acid; Polysaccharide; Polyphosphazene; Poly-(ether-ester) copolymer, for example PEO-PLLA, or its mixture; With the non-degradable material of biocompatibility, for example polydimethylsiloxane; Poly-(ethane-acetic acid ethyenyl ester); Based on the polymer or the copolymer of acrylate, for example polybutyl methacrylate, poly-(ethoxy methyl methacrylate); Polyvinylpyrrolidone; Fluorinated polymer is such as politef; Cellulose esters.
When using polymeric matrix, it can comprise 2 layers, for example mixes the basal layer of medicine, for example ethylene and polybutyl methacrylate and do not have the top layer of drug combination in the control drug diffusion, for example polybutyl methacrylate.Alternatively, medicine can be included in the basal layer and adjuvant can be incorporated in the skin, or vice versa.The gross thickness of polymeric matrix can be about 1 to 20 μ m or bigger.
The method according to this invention or in device of the present invention or system, medicine can be passive, initiatively or activation down, eluting under the photoactivation for example.
Medicine is in time from the polymeric material eluting and enter surrounding tissue, for example up to about 1 month to 1 year.Allow have high concentration medicine to have the circulation chemical compound of low concentration according to local delivery of the present invention at disease location.The amount that is used for the medicine that local delivery uses depends on the effect of used chemical compound, state to be treated and needs and changes.For purpose of the present invention, with the administering therapeutic effective dose.The treatment effective dose is for enough suppressing cell proliferation and the amount that causes the prevention and the treatment of morbid state.Especially, become the prevention or the treatment of the restenosis behind art or the antineoplaston for for example revascularization, local delivery need be less than the chemical compound of systemic administration.
For example according to method described below, the effectiveness of medicine can animal test method and clinical in confirm.Following examples are examples of the present invention and do not limit the present invention.
The inhibition of rat carotid artery air bag damage model middle and advanced stage neointima damage in A1.28 days
Show that multiple chemical compound suppresses inner film injury formation in the rat airbag neck artery model when 2 weeks, and only several chemical compound proved effectively when 4 weeks.In following rat model, detected the chemical compound of formula I.
Rat oral is used placebo or vegf receptor tyrosine kinase inhibitor, for example chemical compound of formula I, for example PTK787.Began to use daily dose in preceding 3 days and continue 31 days in operation.With by people such as Clowes, Lab.Invest.1983; 49; The method that 208-215 describes is carried out the air bag damage with rat carotid artery.Air bag damages put to death rat in back 28 days, carotid artery was removed and handled be used for histology and somatometry of physique assessment.The ability that significantly reduces the neointima damage formation of air bag damage back at this chemical compound of measuring Chinese style I can be confirmed.
A.2 the inhibition of restenosis 28 days time the in the rabbit iliac artery support model
In the New Zealand white rabbit tremulous pulse, make up the operation of angioplasty and support.Then carry out the damage of iliac artery air bag by 3.0 * 9.0mm angiopoiesis air bag that expands at the iliac artery middle part by 1 air bag length of " retracting " conduit.The air bag damage is repeated 2 times, and the support of 3.0 * 12mm launched 30 seconds with 6 atmospheric pressure in iliac artery.Carry out air bag damage and support placement at the iliac artery of offside in the same manner then.Carry out the angiography after support launches.All animal per os every day are accepted the aspirin of 40 mg/day as Antiplatelet therapy and feeding standard low cholesterol rabbit feedstuff.Support was placed back 28 days, with Animal Anesthesia and euthanasia and with arterial tree with containing of 100mmHg Lactated Ringer's solution perfusion a few minutes, the formalin with 10% 100mmHg poured into 15 minutes then.Blood vessel sections between aorta far away and the nearly femoral artery is downcut and cleaning adventitia week tissue.The section that the brace sections of tremulous pulse is embedded in the plastics and gets near-end, centre and the extremity of each support.All section hematoxylin-eosin staining and Movat pentachrome dyeings.Carry out the computerized method of quadrature to determine the area in internal elastic membrane (IEL), external elastic membrane (EEL) and chamber.Measure neointima and neointima thickness between support minor connector place and the support minor connector.The blood vessel area estimation is the area in the EEL.Data are expressed as average ± SEM.Since every zoometry two support tremulous pulsies, produced the average of every animal, so finish the statistical analysis of histological data with variance analysis (ANOVA).Think that P＜0.05 has significance,statistical.
In placing rack the previous day, PTK787, used behind placing rack 27 days with 50% of placing rack initial dose that day by the gavage dosage forms for oral administration then with initial dose.Can show that in this model the degree that the restenosis damage forms when having PTK787 significantly reduces, and at 28 days, neointima formation is widely arranged in the animal of placebo treatment, and damage is made up of smooth muscle cell abundant in Dan Baijutang/collagen stroma and obviously whole endothelium healing.
A.3 the preparation of support
With support weigh be fixed for then the coating.When support rotates, will be in methanol and tetrahydrofuran compound PTK787 and the 0.0015mg/ml2 of dissolved polylactide Acetic acid, hydroxy-, bimol. cyclic ester, 0.75mg/ml, 6-two-tert-butyl group-4-cresol liquor is sprayed on above the support.On aerosol apparatus, take off the support of coating also air-dry.Determine to be coated on the amount on the support after weighing at last.
A.4 in the aqueous solution PTK787 from the release of polymer coating
The coating of 4 2cm as described above propped up to be placed on pH be in 7.4 the 100mL phosphate buffer (PBS).To be placed in 100mL Polyethylene Glycol (PEG)/aqueous solution (40/60v/v, the molecular weight of PEG=400) from other 4 of each series.With support on agitator 37 ℃ hatch.Exchange buffering every day liquid carries out the different PTK787 concentration that discharge to determine of measuring with PEG solution and on solution.Can show that by this kind method stable PTK787 discharges from the support of coating.Term " stable PTK787 discharges " expression is observed the drug release rate variation and is lower than 10%.
A.5 in the blood plasma PTK787 from the release of polymer coating
Also can study the release of PTK787 in the blood plasma.With in the human plasma that contains citrate (from Helena Labs) of the 1mL that is placed on freeze-dried of the coating of 1cm and by adding the reconstruct of 1mL sterile deionized water.Blood plasma is hatched and changed every day to three pack support plasma solutions at 37 ℃.To carrying out the different PTK787 concentration that discharge to determine of measuring on the solution.Can confirm to discharge from the stable PTK787 of the support of coating in the blood plasma by this kind method.The variation that drug release rate is observed in term " stable PTK787 discharges " expression is lower than 10%.
A.6 the stability of PTK787 in the pharmaceutically acceptable polymer under the body temperature
Can carry out receptor tyrosine kinase algoscopy that PDGF-stimulates to determine the activity of PTK787 to last of each sample.Can carry out similar test with free PTK787.By E.Andrejauskas-Buchdunger and U.Regenass at Cancer Research
52, the similar methods of describing among the 5353-5358 (1992) can be measured the inhibitory action of the receptor tyrosine kinase activity that external PDGF-stimulates with the pdgf receptor immunocomplex of BALB/c 3T3 cell.By can relatively the dissociate stability of PTK787 in PTK787 and the polymer coating of this kind method.
Claims (13)
1. drug delivery device or system, it comprises the medical apparatus that a) is adapted at topical application in the hollow pipe or uses, for example based on the delivery apparatus or the intracavity medical apparatus of conduit, with b) be releasably attached to the vegf receptor tyrosine kinase inhibitor of the therapeutic dose of medical apparatus.
2. according to the device of claim 1, it comprises PTK787.
3. according to the device of claim 1 or 2, it is catheter delivery system, local injection device, inherent device, support, stent-grafts or sleeve pipe.
4. according to the device of claim 1 or 2, it is the support of coating.
5. be used to prevent or treat in its mammal of needs the method for the apposition of the programmed cell death of the cell proliferation of smooth muscle cell proliferation and migration or increase in the hollow pipe or reduction or increase, it comprises VEGF (VEGF) receptor tyrosine kinase inhibitors of local application treatment effective dose.
6. the method that is used for the treatment of the blood vessel wall intimal thickening, it comprises from based on the device of conduit or the intracavity medical apparatus VEGF of delivery treatments effective dose (VEGF) receptor tyrosine kinase inhibitors controllably.
7. claim 5 or 6 method, wherein the vegf receptor tyrosine kinase inhibitor is the chemical compound of formula I
Wherein
R is 0 to 2,
N is 0 to 2,
M is 0 to 4,
R
1And R
2(i) be low alkyl group or
(ii) form inferior formula I together
*In bridge
Realize combination by two terminal carbons, or
(iii) form inferior formula I together
*In bridge
One of them or two ring members T
1, T
2, T
3And T
4Be nitrogen, and other ring members is CH under every kind of situation, and passes through T
1And T
4Realize combination;
A, B, D and E are N or CH independently of each other, condition be in these groups at the most 2 groups are N;
G is a low-grade alkylidene, by acyloxy or hydroxyl ,-CH
2-O-,-CH
2-S-,-CH
2(O-), thia (S-) or the imino group (NH-) low-grade alkylidene of Qu Daiing for-NH-, oxa-;
Q is a low alkyl group;
R is H or low alkyl group;
X is that imino group, oxa-or sulfur are assorted;
Y is aryl, the pyridine radicals that does not replace or replace, or the cycloalkyl that does not replace or replace; With
Z is amino, single replaces or hydroxyl, nitro, cyano group, carboxyl, the carboxyl of esterification, alkanoyl, the carbamoyl of alkyl, hydroxyl, etherificate or the esterification of dibasic amino, halogen, alkyl, replacement, N-is mono-substituted or N, the dibasic carbamoyl of N-, amidino groups, guanidine radicals, sulfydryl, sulfo group, thiophenyl, phenyl-lower alkylthio, alkyl sulfur-base, phenyl sulfonyl, phenyl-low alkyl group sulfinyl or alkyl phenyl sulfinyl, if there is more than one Z base, substituent group Z is identical or different so;
And if wherein had key, the feature of key would be the wavy line of singly-bound or two keys so;
Or the N-oxide of definite chemical compound, wherein one or more N atoms carry oxygen atom,
Or has the salt of this compounds of at least one salt forming group.
8. according to the method for claim 5 or 6, wherein use or send be in intravenous, intranasal, the bronchus, intraperitoneal or use or send through esophagus (eosophagal).
9. according to the method for claim 5 or 6, wherein with filming in the support of catheter delivery system, local injection device, inherent device, support, coating, sleeve pipe, stent-grafts, the polymer cavity or controlled release matrix is used or sent.
10. according to the method for claim 5, wherein use the vegf receptor tyrosine kinase inhibitor from support or from the coating that is applied to support.
11., wherein send the vegf receptor tyrosine kinase inhibitor from support or from the coating that is applied to support according to the method for claim 6.
12. according to the method for claim 5, it is used for the treatment of narrow, restenosis or inflammation.
13. according to the method for claim 6, it is used for the treatment of narrow, restenosis or inflammation.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US55915004P | 2004-04-02 | 2004-04-02 | |
| US60/559,150 | 2004-04-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1929882A true CN1929882A (en) | 2007-03-14 |
Family
ID=34962708
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2005800075100A Pending CN1929882A (en) | 2004-04-02 | 2005-04-01 | VEGF receptor tyrosine kinase inhibitor coated stent |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP1735026A1 (en) |
| JP (1) | JP2007530633A (en) |
| KR (1) | KR20070004795A (en) |
| CN (1) | CN1929882A (en) |
| AU (1) | AU2005229566A1 (en) |
| BR (1) | BRPI0509566A (en) |
| CA (1) | CA2559756A1 (en) |
| WO (1) | WO2005094916A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101925451B (en) * | 2008-01-23 | 2013-08-21 | 诺瓦提斯公司 | Method for coating silicone hydrogels |
| TWI482757B (en) * | 2013-10-07 | 2015-05-01 | Luminescence Technology Corp | Inhibitor of vegf-2/3 receptor and protein kinase and pharmaceutical use thereof |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8057815B2 (en) | 2004-04-19 | 2011-11-15 | Portola Pharmaceuticals, Inc. | Methods of treatment with Syk inhibitors |
| KR102044064B1 (en) * | 2006-09-26 | 2019-11-12 | 노파르티스 아게 | Pharmaceutical compositions comprising an s1p modulator |
| CA2720887A1 (en) * | 2008-04-09 | 2009-10-15 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Inhibitors of stim1 for the treatment of cardiovascular disorders |
| ES2477498T3 (en) | 2010-01-20 | 2014-07-17 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Protein 4 of the angiopoietin type (ANGPTL4) for the maintenance of the integrity of the cellular barrier of the vascular endothelium |
| WO2012110843A1 (en) | 2011-02-18 | 2012-08-23 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for promoting fibrinolysis and thrombolysis |
| EP2741777B1 (en) | 2011-08-12 | 2017-01-18 | INSERM - Institut National de la Santé et de la Recherche Médicale | Methods and pharmaceutical compositions for treatment of pulmonary hypertension |
| WO2013050441A1 (en) | 2011-10-05 | 2013-04-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical composition for inhibiting or preventing platelet aggregation |
| US20140328893A1 (en) | 2011-10-11 | 2014-11-06 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Nutlin compounds for use in the treatment of pulmonary hypertension |
| US20150105329A1 (en) | 2012-03-26 | 2015-04-16 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods and Pharmaceutical Compositions for Prevention or Treatment of Ischemia Related Organ Damage |
| US9504732B2 (en) | 2013-01-14 | 2016-11-29 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods for treating myocardial infarction comprising administering sonic hedgehog |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100455275C (en) * | 2002-02-06 | 2009-01-28 | 祥丰医疗有限公司 | Medical device with coating that promotes endothelial cell adherence and differentiation |
| WO2004010900A1 (en) * | 2002-07-25 | 2004-02-05 | Avantec Vascular Corporation | Devices delivering therapeutic agents and methods regarding the same |
| AU2004273619A1 (en) * | 2003-09-23 | 2005-03-31 | Novartis Ag | Combinations of a VEGF receptor inhibitor with other therapeutic agents |
| WO2005051229A2 (en) * | 2003-11-24 | 2005-06-09 | Avantec Vascular Corporation | Devices delivering therapeutic agents and methods regarding the same |
-
2005
- 2005-04-01 JP JP2007505513A patent/JP2007530633A/en active Pending
- 2005-04-01 CA CA002559756A patent/CA2559756A1/en not_active Abandoned
- 2005-04-01 AU AU2005229566A patent/AU2005229566A1/en not_active Abandoned
- 2005-04-01 WO PCT/EP2005/003459 patent/WO2005094916A1/en not_active Application Discontinuation
- 2005-04-01 KR KR1020067020310A patent/KR20070004795A/en not_active Application Discontinuation
- 2005-04-01 EP EP05716501A patent/EP1735026A1/en not_active Withdrawn
- 2005-04-01 BR BRPI0509566-2A patent/BRPI0509566A/en not_active Application Discontinuation
- 2005-04-01 CN CNA2005800075100A patent/CN1929882A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101925451B (en) * | 2008-01-23 | 2013-08-21 | 诺瓦提斯公司 | Method for coating silicone hydrogels |
| TWI482757B (en) * | 2013-10-07 | 2015-05-01 | Luminescence Technology Corp | Inhibitor of vegf-2/3 receptor and protein kinase and pharmaceutical use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2007530633A (en) | 2007-11-01 |
| BRPI0509566A (en) | 2007-09-25 |
| WO2005094916A1 (en) | 2005-10-13 |
| AU2005229566A1 (en) | 2005-10-13 |
| EP1735026A1 (en) | 2006-12-27 |
| KR20070004795A (en) | 2007-01-09 |
| CA2559756A1 (en) | 2005-10-13 |
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