CN104784762A - Sents having biodegradable layers - Google Patents

Abstract

The invention relates to sents having biodegradable layers. Provided herein is a coated coronary arterial stent. The coated coronary arterial stent comprises: a, a stent framework, and b, a plurality of layers depositing on the stent framework to form the coated coronary arterial stent; at least one of the layers contains a bioabsorbable polymer, and at least one of the layers contains one or more active agent; and at least part of the active agent is in a crystalline form.

Description

There is the support of biodegradable layers

The application is the applying date is on April 17th, 2008, and application number is 200880020515.0 (international application no is PCT/US2008/060671), and denomination of invention is the divisional application of the application for a patent for invention of " support with biodegradable layers ".

Cross reference

This application claims on April 17th, 2007 submit to U.S. Provisional Application the 60/912nd, on April 17th, No. 408 1 submit to U.S. Provisional Application the 60/912nd, No. 394 and on October 19th, 2007 submission U.S. Provisional Application the 60/981st, the rights and interests of No. 445.Contents of these applications by reference and entirety is attached to herein.

Background of invention

The present invention relates to and form the method for support, what this support comprised powder type on matrix can the polymer of bio-absorbable and medicament or biological preparation.

Expect to have drug-eluting stent, this support has minimum physics, chemistry and treatment after effect in the blood vessel after repulsion time phase.This period is based on effective recovery from illness (current authoritative doctor thinks 6-18 month) of blood vessel after opening obstruction by PCI/ support.

In order to the pliability that (a) launches, (b) enters thin vessels and (c) minimum intrusion blood vessel wall and blood, also expects the drug-eluting stent with minimum cross section thickness.

Summary of the invention

An embodiment provides the coronary stent of coating, this coronary stent comprises: Support frame and rapamycin-polymer coating, wherein at least partly rapamycin is crystal form, and rapamycin-polymer coating comprise one or more can resorbent polymer.

In another embodiment, rapamycin-polymer coating has uniform thickness substantially, and the rapamycin in coating is evenly dispersed in rapamycin-polymer coating substantially.

In another embodiment, one or more can be selected from PLGA (PLGA), DLPLA-poly-(d1-lactide), LPLA-poly-(1-lactide), PGA-PGA, PDO-poly-(two by resorbent polymer alkane ketone), PGA-TMC-Acetic acid, hydroxy-, bimol. cyclic ester-trimethylene carbonate copolymer, PGA-LPLA-1-PLGA, PGA-DLPLA-d1-PLGA, LPLA-DLPLA-1-lactide-d1-lactide copolymer, PDO-PGA-TMC-Acetic acid, hydroxy-, bimol. cyclic ester-trimethylene carbonate-two alkane ketone copolymers and combination thereof.

Going back in another embodiment, polymer is 50/50PLGA.

Going back in another embodiment, at least part of described rapamycin forms the one or more phases be separated formed with described polymer.

In another embodiment, rapamycin is at least 50% crystallization.

In another embodiment, rapamycin is at least 75% crystallization.

In another embodiment, rapamycin is at least 90% crystallization.

In another embodiment, rapamycin is at least 95% crystallization.

In another embodiment, rapamycin is at least 99% crystallization.

In another embodiment, polymer is the mixture of two or more polymer.

In another embodiment, the mixture of polymer forms continuous print film around the granule of rapamycin.

In another embodiment, two or more polymer are mixed fully.

In another embodiment, mixture does not comprise the single polymers territory being greater than about 20nm.

In another embodiment, each polymer in described mixture comprises discontinuous phase.

In another embodiment, the discontinuous phase formed by described polymer in described mixture is greater than about 10nm.

In another embodiment, the discontinuous phase formed by described polymer in described mixture is greater than about 50nm.

In another embodiment, the rapamycin in described support has the bin stability of at least 3 months.

In another embodiment, the rapamycin in described support has the bin stability of at least 6 months.

In another embodiment, the rapamycin in described support has the bin stability of at least 12 months.

In another embodiment, coating is conformal substantially.

In another embodiment, support provides following elution curve: wherein in physiological conditions, the 1st week eluting after compositions implants experimenter is about the rapamycin of 10%-about 50%, be about the rapamycin of 25%-about 75% at the 2nd week eluting, and be about the rapamycin of 50%-about 100% at the 6th week eluting.

In another embodiment, support provides following elution curve: wherein in physiological conditions, the 1st week eluting after compositions implants experimenter is about the rapamycin of 10%-about 50%, be about the rapamycin of 25%-about 75% at the 2nd week eluting, and be about the rapamycin of 50%-about 100% at the 10th week eluting.

In another embodiment, Support frame is stainless steel frame.

Also another embodiment provides the coronary stent of coating, this support comprises support and immunosuppressive macrocyclic lactone (not taking charge of) drug-polymer coating, wherein at least partly medicine is crystal form, and immunosuppressive macrocyclic lactone drug-polymer coating comprise one or more can resorbent polymer.

In another embodiment, immunosuppressive macrocyclic lactone pharmaceutical pack is containing one or more in following medicine: rapamycin, 40-O-(2-hydroxyethyl) rapamycin (everolimus), 40-O-benzyl-rapamycin, 40-O-(4 '-hydroxymethyl) benzyl-rapamycin, 40-O-[4 '-(1,2-dihydroxy ethyl)] benzyl-rapamycin, 40-O-pi-allyl-rapamycin, 40-O-[3 '-(2,2-dimethyl-1,3-dioxolane-4 (S)-Ji)-propyl-2 '-alkene-1 '-Ji]-rapamycin, (2 ': E, 4 ' S)-40-O-(4 ', 5 '-dihydroxy, penta-2 '-alkene-1 '-Ji)-rapamycin, 40-O-(2-hydroxyl) ethoxycarbonylmethyl group-rapamycin, 40-O-(3-hydroxyl) propyl group-rapamycin, 40-O-(6-hydroxyl) base-rapamycin, 40-O-[2-(2-hydroxyl) ethyoxyl] ethyl rapamycin, 40-O-[(3S)-2,2-dimethyl dioxolane-3-base] methyl-rapamycin, 40-O-[(2S)-2,3-dihydroxy third-1-base]-rapamycin, 40-O-(2-acetoxyl group) ethyl rapamycin, 40-O-(2-nicotinoyl oxygen base) ethyl rapamycin, 40-O-[2-(N-morpholino) acetoxyl group] ethyl rapamycin, 40-O-(2-N-imidazole radicals acetoxyl group) ethyl rapamycin, 40-O-[2-(N-methyl-N '-piperazinyl) acetoxyl group] ethyl rapamycin, 39-O-demethyl-39,40-O, O-ethylidene-rapamycin, (26R)-26-dihydro-40-O-(2-hydroxyl) ethyl rapamycin, 28-O-methyl-rapamycin, 40-O-(2-amino-ethyl)-rapamycin, 40-O-(2-acetamidoethyl)-rapamycin, 40-O-(2-nicotinoyl amino-ethyl)-rapamycin, 40-O-(2-(N-methyl-imidazoles-2 '-base oxethyl formamido group (carbethoxamido)) ethyl)-rapamycin, 40-O-(2-ethoxycarbonylamino group ethyl)-rapamycin, 40-O-(2-tolylsulfonyl-amino-ethyl)-rapamycin, 40-O-[2-(4 ', 5 '-diethoxy carbonyl-1 ', 2 ', 3 '-triazole-1 '-Ji)-ethyl]-rapamycin, 42-table-(tetrazole radical) rapamycin (tacrolimus) and 42-[3-hydroxyl-2-(hydroxymethyl)-2 Methylpropionic acid ester] rapamycin (CCI-779).

In another embodiment, immunosuppressive macrocyclic lactone medicine is at least 50% crystallization.

Another embodiment provides the method for the coronary stent of preparation coating, the method is included on Support frame and forms immunosuppressive macrocyclic lactone (not taking charge of) drug-polymer coating, wherein at least partly medicine is crystal form, and immunosuppressive macrocyclic lactone drug-polymer coating comprise one or more can resorbent polymer.

The invention provides some advantages, these advantages overcome or decrease the restriction of current techniques of Bioabsorbable support.

An embodiment provides the coronary stent of coating, this support comprises: Support frame and rapamycin-polymer coating, wherein at least partly rapamycin is crystal form, and rapamycin-polymer coating comprise one or more can resorbent polymer.

In another embodiment, rapamycin-polymer coating has uniform thickness substantially, and the rapamycin in coating is evenly dispersed in rapamycin-polymer coating substantially.

In another embodiment, one or more can be selected from PLGA (PLGA), DLPLA-poly-(d1-lactide), LPLA-poly-(1-lactide), PGA-PGA, PDO-poly-(two by resorbent polymer alkane ketone), PGA-TMC-Acetic acid, hydroxy-, bimol. cyclic ester-trimethylene carbonate (trimethylene carbonate) copolymer, PGA-LPLA-1-PLGA, PGA-DLPLA-d1-PLGA, LPLA-DLPLA-1-lactide-d1-lactide copolymer, PDO-PGA-TMC-Acetic acid, hydroxy-, bimol. cyclic ester-trimethylene carbonate-two alkane ketone copolymers and combination thereof.

Another embodiment provides the method for the coronary stent of preparation coating, and the method comprises the following steps: provide rustless steel or cobalt-chromium Support frame; Support frame is formed immunosuppressive macrocyclic lactone (not taking charge of) drug-polymer coating, and wherein medicine is crystal form at least partly, and polymer can bio-absorbable.

In another embodiment, Macrocyclolactone lactone kind medicine deposits in dry powder form.

In another embodiment, can the polymer of bio-absorbable deposit in dry powder form.

In another embodiment, polymer is deposited by e-SEDS method.

In another embodiment, polymer is deposited by e-RESS method.

Another embodiment provides further comprising the steps of method: under the condition of form substantially not changing described Macrocyclolactone lactone kind medicine, described coating is sintered.

Also another embodiment provides the coronary stent of coating, and this coronary stent comprises: Support frame; Can the ground floor of polymer of bio-absorbable; With rapamycin-polymer coating, this coating comprises rapamycin and second can the polymer of bio-absorbable, wherein rapamycin is crystal form at least partly, and wherein the first polymer is the polymer slowly absorbed, and the second polymer is the polymer absorbed fast.

Also another embodiment provides the coronary stent of coating, and this coronary stent comprises: Support frame; Can the ground floor of polymer of bio-absorbable; With rapamycin-polymer coating, this coating comprises rapamycin and second can the polymer of bio-absorbable, wherein rapamycin is crystal form at least partly, and wherein the first polymer is the polymer slowly absorbed, and the second polymer is the polymer absorbed fast.

Combine by reference

The all publications mentioned in this manual and patent application are attached to herein all by reference, its degree with each independent publication or patent application respectively also concrete indicate by reference and combine identical.

Detailed Description Of The Invention

The diagram of embodiment selected by the present invention is provided in accompanying drawing 1-12.

Explain the present invention in more detail below.This description is not intended to become and can be implemented all distinct methods of the present invention and maybe can be added to characteristic inventory of the present invention.Such as, the feature set forth about an embodiment can be attached in other embodiment, and can delete from this embodiment about the feature that particular is set forth.In addition, open according to the present invention, many changes and the interpolation of various embodiment in this paper will be apparent to those skilled in the art, and these changes and interpolation do not deviate from scope of the present invention.Therefore, the following description book will illustrate particular more of the present invention, and not exhaustive enumerate its all arrangement, combination and change.

Definition

When used as contemplated in this specification, following word and phrase generally will have the implication of the following stated, unless indicated in addition in the context using them.

When used herein, " matrix " refers to expect any surface of coating being deposited thereon, and this coating is containing polymer and medicament or biological preparation, and wherein coating process does not change the form of medicament or the activity of biological preparation substantially.The present invention is interested in especially biomedical implants; But the present invention does not intend to be limited in such matrix.Person of skill in the art will appreciate that and can benefit from the part of alternative matrix such as drug core as determinator for coating process described herein or the component as diagnostic kit (such as test film).

When used herein, " biomedical implants " refers to insert any implant in human or animal's subject, include but not limited to support (such as intravascular stent), electrode, conduit, wire, implanted pacemaker, cardioverter or defibrillator shell, joint, screw, bar, ocular implant, stock nail, blade plate, graft, stapling apparatus, circumvascular strip of paper used for sealing, stitching thread, staple, hydrocephalus diverter, dialysis graft, colostomy bag attachment arrangement, ear drainage tubes, the wire of pacemaker and implantable cardioverter and defibrillator, vertebra dish, spicule, suture anchor, hemostasis spacer, pincers, screw, plate, clip, blood vessel graft, tissue adhesive and sealer, organization bracket, various types of dressing (such as wound dressing), artificial bone, intracavitary unit, vessel support thing etc.

Implant can be formed by any suitable material, include but not limited to organic polymer (comprising the polymer of stable or inertia and biodegradable polymer), metal, inorganic material such as silicon and compositions thereof, comprise the layer structure of one or more coatings of core and the different materials with a kind of material.The matrix be made up of conductive material is easy to electrostatic capture.But the present invention considers electrostatic capture and matrix or the non-conductive body conbined usage with low electric conductivity.When utilizing non-conductive body, in order to strengthen electrostatic capture, by this matrix process, near matrix, maintain highfield simultaneously.

The experimenter that can apply or insert biomedical implants of the present invention comprises the animal subjects (including but not limited to Canis familiaris L., cat, horse, monkey etc.) of people experimenter's (comprising masculinity and femininity experimenter and baby, teenager, youth, adult and aged subjects) and veterinary's object.

In preferred embodiments, biomedical implants is expandable Endoluminal repair thing or support (such as comprising metallic mesh tube), such as at the United States Patent (USP) the 4th of Palmaz Shaz, 733, described in No. 665, this blood vessel graft or support, by the angioplasty sacculus be associated with conduit, can expand at Ink vessel transfusing, expand and expand to make lumen of vessels.

When used herein, " medicament " refers to be used as activating agent, (represent any treatment of mammalian diseases, comprise and preventing disease with any medicine in prevention or the various medicine of disease therapy or medicinal compound or medicinal compound, namely cause the clinical symptoms of disease not occur; Suppress disease, namely stop the development of clinical symptoms; And/or alleviation disease, namely cause disappearing of clinical symptoms).Also two or more medicines or medicinal compound can may be comprised by medicament of the present invention.Medicament includes but not limited to anti-restenosis medicine, antidiabetic drug, analgesic, anti-inflammatory agent, antirheumatic, antihypotensive, antihypertensive, psychoactive drug, tranquilizer, Bendectin, muscle relaxant, glucocorticoid, the medicine for the treatment of ulcerative colitis or Crohn disease, antiallergic agent, antibiotic, antuepileptic, anticoagulant, antifungal agent, cough medicine, arteriosclerosis curative, diuretic, protein, peptide, enzyme, enzyme inhibitor, gout therapertics, hormone and inhibitor thereof, cardiac glycoside, immunization therapy medicine and cytokine, caccagogue, lipid lowerers, Medicine for treating migraine, mineral article, otology medicine, antiparkinsonian drug, thyroid curative, spasmolytic, anticoagulant, vitamin, cytostatics and transfer inhibitor, plant amedica, chemotherapeutic drug and aminoacid.The example of suitable active component is acarbose, antigen, beta-blocker, NSAID (non-steroidal anti-inflammatory drug) { NSAIDs}, cardiac glycoside, aspirin, viral inhibitors, aclarubicin, acyclovir, cisplatin, D actinomycin D, α-and β-sympathomimetic, (dmeprazole, allopurinol, Alprostadil, prostaglandin, amantadine, ambroxol, amlodipine, methotrexate, S-aminosallcylic acid, amitriptyline, amoxicillin, Anastrozole, atenolol, azathioprine, balsalazide, beclometasone, betahistine, bezafibrate, bicalutamide, diazepam and diazepam derivant, budesonide, bufexamac, buprenorphine, methadone, calcium salt, potassium salt, magnesium salt, Candesartan, carbamazepine, captopril, cephalosporins, cetirizine, chenodeoxycholic acid, ursodesoxycholic acid, theophylline and theophylline derivant, trypsin, cimetidine, clarithromycin, clavulanic acid, clindamycin, clobutinol, clonidine, sulfamethoxine azoles, codeine, caffeine, vitamin D and vitamin D-derivatives, colestyramine, cromoglicic acid, coumarin and coumarin derivative, cysteine, cytosine arabinoside, cyclophosphamide, ciclosporin, cyproterone, cytabarine, dapiprazole, desogestrel, desonide, dihydralazine, diltiazem , peptide, dimenhydrinate, dimethyl sulfoxide, simethicone, domperidone and domperidone derivant, dopamine, doxazosin, doxorubizin, doxylamine, dapiprazole, diazepam, diclofenac, glucosides antibiotic, desipramine, econazole, ACE inhibitor, enalapril, ephedrine, epinephrine, erythropoietin and erythropoietin derivant, morphinan, calcium antagonist, irinotecan, modafinil, orlistat, peptide antibiotics, phenytoin, riluzole, Risedronate, 'Xiduofeng ', topiramate, macrolide antibiotics, estradiol and derivatives of estradiol, progestogen and progestin derivative, testosterone and testosterone derivative, androgen and androgen derivant, ethenzamide, etofenamate, etofibrate, fenofibrate, etofylline, etoposide, famciclovir, famotidine, felodipine, fenofibrate, fentanyl, fenticonazole, gyrase inhibitors, fluconazol, fludarabine, flunarizine, fluorouracil, fluoxetine, flurbiprofen, ibuprofen, flutamide, fluvastatin, follicle stimulating hormone, formoterol, fosfomycin (fosfomicin), furosemide, fusidic acid, gallopamil, ganciclovir, gemfibrozil, gentamycin, Semen Ginkgo, Sheng Yuehanshi grass (Saint John ' s wort), glibenclamide, as the urea derivative of oral antidiabetic, glucagon, glucosamine and aminoglucose sugar derivatives, glutathion, glycerol and glycerol derivatives, hypothalamic hormone, goserelin, gyrase inhibitors, guanethidine, halofantrine, haloperidol, heparin and heparin derivatives, hyaluronic acid, hydralazine, hydrochlorothiazide and hydrochlorothiazide derivant, Salicylate (ester), hydroxyzine, idarubicin, ifosfamide, imipramine, indomethacin, indoramine, insulin, interferon, iodine and iodine derivant, isoconazole, isoproterenol, sorbitol and glucitol derivative, itraconazole, ketoconazole, ketoprofen, ketotifen, lacidipine, lansoprazole, levodopa, levomethadone, thyroxin, thioctic acid and lipoic acid derivatives, lisinopril, lisuride, lofepramine, lomustine, loperamide, loratadine, maprotiline, mebendazole, mebeverine, meclizine, mefenamic acid, mefloquine, meloxicam, mepindolol, meprobamate, meropenem, mesalazine, mesuximide, dipyrone, metformin, methotrexate, methylphenidate, methylprednisolone, methixene, metoclopramide, metoprolol, metronidazole, mianserin, miconazole, minocycline, minoxidil, misoprostol, mitomycin, mizolastine, moexipril, morphine and morphine derivatives, Radix Oenotherae erythrosepalae, nalbuphine, naloxone, tilidate, naproxen, narcotine, natamycin, neostigmine, nicergoline, nikethamide, nifedipine, niflumic acid, nimodipine, nimorazole, nimustine, nisoldipine, epinephrine and epinephrine derivant, norfloxacin, novamine sulfone, narcotine, nystatin, ofloxacin, olanzapine, olsalazine, omeprazole, omoconazole, ondansetron, oxaceprol, oxazacillin, oxiconazole, oxymetazoline, pantoprazole, acetaminophen, paroxetine, penciclovir, oral penicillin class, pentazocine, pentifylline, pentoxifylline, perphenazine, Pethidine, plant extract, phenazone, pheniramine, barbituric acid derivatives, Phenylbutazone, phenytoin, pimozide, pindolol, piperazine, piracetam, pirenzepine, piribedil, piroxicam, pramipexole, pravastatin, prazosin, procaine, promazine, propiverine, Propranolol, isopropylantipyrine, prostaglandin, prothionamide, brontyl, Quetiapine, quinapril, quinaprilat, ramipril, ranitidine, reproterol, reserpine, ribavirin, rifampicin, risperidone, ritonavir, ropinirole, roxatidine, Roxithromycin, ruscogenin, rutin and rutin derivatives, cevadilla, albuterol, salmaterol (salmeterol), scopolamine, selegiline, Sertaconazole, Sertindole, sertralion, silicate, sldenafil, simvastatin, sitosterol, sotalol, spaglumic Acid, Sparfloxacin, spectinomycin, spiramycin, spirapril, spironolactone, stavudine, streptomycin, sucralfate, sufentanil, sulbactam, sulfonamides, sulfasalazine, sulpiride, sultamicillin, Sultiame (sultiam), sumatriptan, Choline Chloride Succinate, tacrine, tacrolimus, taliolol, tamoxifen, taurolidine, tazarotene, temazepam, teniposide, tenoxicam, terazosin, terbinafine, terbutaline, terfenadine, terlipressin, tertatolol, tetracycline, teryzoline, theobromine, theophylline, butizine, thiamazole, phenothiazines, phosphinothioylidynetrisaziridine, tiagabine, tiapride, propanoic derivatives, Ticlopidine, timolol, tinidazole, tioconazole, thioguanine, tioxolone, tiropramide, tizanidine, tolazoline, tolbutamide, tolcapone, tolnaftate, tolperisone, hycamtin, torasemide, antiestrogen, tramadol, tramazoline, trandolapril, tranylcypromine, trapidil, trazodone, triamcinolone and triamcinolone derivant, triamterene, trifluperidol, trifluridine, trimethoprim, trimeprimine, tripelennamine, triprolidine, trifosfamide, tromantadine, trometamol, tropalpin, troxerutin (troxerutine), tulobuterol, tyramine, Tyrothricin, urapidil, ursodesoxycholic acid, chenodeoxycholic acid, valaciclovir, valproic acid, vancomycin, chlorination vecuronium bromide, viagra, venlafaxine, verapamil, vidarabine, vigabatrin, viloazine, vinblastine, vincamine, vincristine, vindesine, vinorelbine, vinpocetine, viquidil, warfarin, xantinol nicotinate, xipamide, zafirlukast, zalcitabine, zidovudine, Zomitriptan, zolpidem, zopiclone (zoplicone), zotepine (zotipine) etc.See such as No. the 6th, 897,205, United States Patent (USP); Also see United States Patent (USP) the 6th, 838, No. 528; United States Patent (USP) the 6th, 497, No. 729.

Rapamycin is comprised with the example of the therapeutic agent of conbined usage of the present invention, 40-O-(2-hydroxyethyl) rapamycin (everolimus), 40-O-benzyl-rapamycin, 40-O-(4 '-hydroxymethyl) benzyl-rapamycin, 40-O-[4 '-(1,2-dihydroxy ethyl)] benzyl-rapamycin, 40-O-pi-allyl-rapamycin, 40-O-[3 '-(2,2-dimethyl-1,3-dioxolane-4 (S)-Ji)-propyl-2 '-alkene-1 '-Ji]-rapamycin, (2 ': E, 4 ' S)-40-O-(4 ', 5 '-dihydroxy, penta-2 '-alkene-1 '-Ji)-rapamycin, 40-O-(2-hydroxyl) ethoxycarbonylmethyl group-rapamycin, 40-O-(3-hydroxyl) propyl group-rapamycin, 40-O-(6-hydroxyl) base-rapamycin, 40-O-[2-(2-hydroxyl) ethyoxyl] ethyl rapamycin, 40-O-[(3S)-2,2-dimethyl dioxolane-3-base] methyl-rapamycin, 40-O-[(2S)-2,3-dihydroxy third-1-base]-rapamycin, 40-O-(2-acetoxyl group) ethyl rapamycin, 40-O-(2-nicotinoyl oxygen base) ethyl rapamycin, 40-O-[2-(N-morpholino) acetoxyl group] ethyl rapamycin, 40-O-(2-N-imidazole radicals acetoxyl group) ethyl rapamycin, 40-O-[2-(N-methyl-N '-piperazinyl) acetoxyl group] ethyl rapamycin, 39-O-demethyl-39,40-O, O-ethylidene-rapamycin, (26R)-26-dihydro-40-O-(2-hydroxyl) ethyl rapamycin, 28-O-methyl-rapamycin, 40-O-(2-amino-ethyl)-rapamycin, 40-O-(2-acetamidoethyl)-rapamycin, 40-O-(2-nicotinoyl amino-ethyl)-rapamycin, 40-O-(2-(N-methyl-imidazoles-2 '-base oxethyl formamido group) ethyl)-rapamycin, 40-O-(2-ethoxycarbonylamino group ethyl)-rapamycin, 40-O-(2-tolylsulfonyl-amino-ethyl)-rapamycin, 40-O-[2-(4 ', 5 '-diethoxy carbonyl-1 ', 2 ', 3 '-triazole-1 '-Ji)-ethyl]-rapamycin, 42-table-(tetrazole radical) rapamycin (tacrolimus) and 42-[3-hydroxyl-2-(hydroxymethyl)-2 Methylpropionic acid ester] rapamycin (CCI-779).

If needed, active component also their pharmaceutically acceptable salt or derivative form can use and (refer to retain biological effectiveness and the characteristic of the compounds of this invention, and its be not biologically or other less desirable salt), and when chiral acti ve composition, optical isomer and racemic modification or non-enantiomer mixture may be used.

When used herein, " stability " refers in its final product form, is deposited on the stability (medicine stability such as, in coated stents) of the polymer coating Chinese medicine on matrix.The drug degradation that term stability will be limited in final product form 5% or lower.

When used herein, " active biological agent " refers to the material that the initial organism by living produces, and this material may be used for prevention or disease therapy (refers to any treatment of mammalian diseases, comprises and preventing disease, namely cause the clinical symptoms of disease not occur; Suppress disease, namely stop the development of clinical symptoms; And/or alleviation disease, namely cause disappearing of clinical symptoms).Also two or more active biological agent or a kind of active biological agent of combining with medicament, stabilizing agent or chemistry or biological entities can may be comprised by active biological agent of the present invention.Although active biological agent may produce by the organism at first by living, of the present invention those also can synthesize preparation, or the method preparation by combining bio-separation and synthetic modification.As limiting examples, nucleic acid can be the form be separated from biogenetic derivation, or is prepared by the conventional art known to the skilled in nucleic acid synthesis field.In addition, nucleic acid can be modified further, to comprise the part that non-natural exists.The limiting examples of active biological agent comprises peptide, protein, enzyme, glycoprotein, nucleic acid (comprise deoxyribonucleotide or the ribonucleotide polymer of strand or double chain form, unless limited otherwise, comprise the mode being similar to naturally occurring nucleotide, hybridize to the known analog of the natural nucleotide of nucleic acid), antisensenucleic acids, fatty acid, anti-microbial agents, vitamin, hormone, steroid, lipid, polysaccharide, carbohydrate etc.They also include but not limited to anti-restenosis medicine, antidiabetic drug, analgesic, anti-inflammatory agent, antirheumatic, antihypotensive, antihypertensive, psychoactive drug, tranquilizer, Bendectin, muscle relaxant, glucocorticoid, the medicine for the treatment of ulcerative colitis or Crohn disease, antiallergic agent, antibiotic, antuepileptic, anticoagulant, antifungal agent, cough medicine, arteriosclerosis curative, diuretic, protein, peptide, enzyme, enzyme inhibitor, gout therapertics, hormone and inhibitor thereof, cardiac glycoside, immunization therapy medicine and cytokine, caccagogue, lipid lowerers, Medicine for treating migraine, mineral article, otology medicine, antiparkinsonian drug, thyroid curative, spasmolytic, anticoagulant, vitamin, cytostatics and transfer inhibitor, plant amedica and chemotherapeutic drug.Preferably, active biological agent is peptide, protein or enzyme, comprises derivant and the analog of native peptides, protein and enzyme.

When used herein, " activity " refers to that the ability of medicament or active biological agent prevention or disease therapy (refers to any treatment of mammalian diseases, comprises and preventing disease, namely cause the clinical symptoms of disease not occur; Suppress disease, namely stop the development of clinical symptoms; And/or alleviation disease, namely cause disappearing of clinical symptoms).Therefore the activity of medicament or active biological agent should have treatment or preventive values.

When used herein, " secondary structure, tertiary structure and quarternary structure " is defined as follows.The activity typically with said preparation is depended on its secondary structure to a certain degree, tertiary structure and/or quarternary structure by active biological agent of the present invention.Exemplarily property, limiting examples, protein has secondary structure, tertiary structure and quarternary structure.Secondary structure refers to the spatial arrangements of amino acid residue adjacent to each other in linear order.Alpha-helix and beta chain are the key elements of secondary structure.Tertiary structure to refer in linear order mutually away from the spatial arrangements of amino acid residue, and refer to disulfide patterns.The protein comprising more than one polypeptide chain shows the structure organization of other level.Each polypeptide chain in such protein is called subunit.Quarternary structure refers to spatial arrangements and the contact property thereof of subunit.Such as hemoglobin is made up of two α chains and two β chains.Know protein function and result from the three-dimensional arrangement (stretch out polypeptide chain lack active) of its conformation or atom.Therefore, one aspect of the present invention is process active biological agent, simultaneously careful its conformation of maintenance, not lose its therapeutic activity.

When used herein, " polymer " refers to the monomeric unit of a series of repetitions being cross-linked or being polymerized.Any suitable polymer may be used for implementing the present invention.Also may can comprise two kinds, three kinds, four kinds or more and plant different polymer by polymer of the present invention.In some embodiments of the present invention, a kind of polymer is only used.In some preferred embodiments, the combination of two kinds of polymer is used.Can by different ratios by combination of polymers, to provide the coating with different qualities.The technical staff in polymer chemistry field will be familiar with the different qualities of polymer.

When used herein, " form that treatment is expected " refers to once be deposited on matrix, to provide in vitro storage, body overall shape and the structure of the medicament of the optimum condition preserved and/or discharge in body.The rate of release of the effect duration that this type of optimum condition can include but not limited to increase, the body internal stability of increase, good biocompatibility, good bioavailability or improvement.For the present invention, the dosage form of usual expectation will be crystallization or hypocrystalline or amorphous, although this can change in a wide range according to many factors, these factors include but not limited to the holding conditions that the character of medicament, the disease for the treatment of/prevention, matrix are predetermined before the use or any biomedical implants position in vivo.Preferably the medicament of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% is crystallization or hypocrystalline form.

When used herein, " stabilizing agent " refers to any material maintaining or improve biological preparation stability.These stabilizing agents are categorized as generally regarded as safe (GRAS) material by food and drug administration (FDA) ideally.The example of stabilizing agent includes but not limited to carrier protein, such as albumin, gelatin, metal or inorganic salt.The pharmaceutically acceptable excipient that can exist such as can also be found in the following literature: Handbook of Pharmaceutical Additives:An International Guide to More Than 6000Products by Trade Name in relevant document, Chemical, Function, and Manufacturer; Michael and Irene Ash (editor); Gower Publishing Ltd. publishes; Aldershot, Hampshire, England, nineteen ninety-five.

When used herein, " compression fluid " refer to be at standard temperature and pressure gas can the fluid of density measurement (such as > 0.2g/ce).When used herein, " supercritical fluid ", " near critical fluids ", " near supercritical fluid ", " critical fluids ", " fine and close fluid " or " fine and close gas " refer to the compressed fluid that to be at least 80% and pressure of this fluid critical temperature be under the condition of at least 50% of this fluid critical pressure of temperature wherein.

The example being applicable to the material of display supercritical of the present invention or near critical behavior includes but not limited to the material such as Chlorofluorocarbons (CFCs), HCFC, hydrogen fluorohydrocarbon, perfluocarbon (such as perfluoromethane and perfluoropropane, chloroform, Arcton 11, dichlorodifluoromethane, dichlorotetra-fluoroethane) and composition thereof of carbon dioxide, isobutene., ammonia, water, methanol, ethanol, ethane, propane, butane, pentane, dimethyl ether, xenon, sulfur hexafluoride, halo and part halo.

When used herein, " sintering " instigates fraction matrix or whole polymer-matrix to be changed into continuously the process of (such as, the formation of continuous print polymeric film).As discussed below, control sintering process, to produce the continuous print substrate (fully sintered) of complete conformal or to produce continuous coated region or territory, in substrate, produce space (discontinuity) simultaneously.And control sintering process, be separated and/or produce between discontinuous polymer beads be separated to obtain some between different polymer (such as, polymer A and B).By sintering process, improve the adhesiveness of coating, to reduce coating peeling off from Matrix separation during use operation.As described below, in some embodiments, control sintering process to provide the incomplete sintering of polymeric matrix.In the embodiment relating to not exclusively sintering, the polymeric matrix of formation has continuous print territory and space, gap, chamber, hole, passage or gap, and they provide space for the therapeutic agent chelating discharged under controlled conditions.According to the character of polymer, the size of polymer beads and/or other polymer property, Compressed Gas, dense gas, near critical fluids or supercritical fluid can be used.In one embodiment, use carbon dioxide treatment matrix, this matrix has used dry powder and RESS Electrostatic coating methods, with polymer and coated with drug.In another embodiment, in sintering process, isobutene. is used.In other embodiments, the mixture of carbon dioxide and isobutene. is used.

During temperature more than unbodied heating materials to its glass transition temperature, or when crystalline material is heated to the temperature of more than phase transition temperature, the molecule comprising material has more mobility, and this represents that they have more activity conversely, and be therefore easier to reaction be such as oxidized.But when amorphous materials maintains the temperature lower than its glass transition temperature, its molecule is fixed substantially, and be therefore comparatively not easy to reaction.Equally, when at the temperature that crystalline material maintains lower than its phase transition temperature, its molecule is fixed substantially, therefore more not easily reacts.Therefore, under the condition such as deposition as herein described and sintering condition of gentleness, process drug component, makes cross reaction and the minimum degradation of drug component.By process of the present invention, the reaction of a minimized type relates to the ability avoiding Conventional solvents, be exposed to free radical, residual solvent and autoxidation initiator by reducing it, it makes again to be no matter amorphous, hypocrystalline or the autoxidation of the medicine of crystal form minimizes.

When used herein, " rapid expanding of supercritical solution " or " RESS " relate to dissolution of polymer in compressed fluid, normally supercritical fluid, and then at lower pressure, normally close under atmospheric condition, rapid expanding is in room.Supercritical fluid solution rapid expanding is by little opening, and the reduction of its density adjoint, reduce the dissoluble capacity of fluid, and cause the coring and increment of polymer beads.By maintaining the gas " cloud " of isolation in room, the atmosphere of room is made to maintain electric neutrality state.Carbon dioxide or other suitable gas is used to prevent electric charge to be transferred to surrounding from matrix.

" bulk property " characteristic comprising the coating of medicament or biological preparation that can be improved by method of the present invention comprises such as: the mixing of adhesiveness, slickness, conformality, thickness and composition.

When used herein, " static electrification lotus " or " electromotive force " or " electrostatic capture " refers to that the powder collection of spraying generation is on the matrix with the electrostatic potential different from spraying granule.Therefore, matrix is in leave away attractive electromotive force to granule, and this causes catching granule on matrix, the electric charge that namely matrix is contrary with granule band, and by electrostatic attraction, promotes that granule is transported on the surface of matrix through the fluid media (medium) of catching blood vessel.Some other methods easily expected by making particle charge and making matrix ground connection or make matrix charged and make granule ground connection on the contrary, or are realized by the technical staff in electrostatic capture field by this.

Can the method for polymer+drug matrices-formation resulting device of bio-absorbable upper formation of supporting structure (form):

As undertaken by Micell method (e-RESS, e-DPC, Compressed Gas sinter), spraying has the supporting structure of medicine and polymer.

Carry out coating-sintering step that is multiple and order, wherein can at the different material of each step deposition, therefore cambium layer laminated structure, this laminar structure has multiple thin layers of medicine, polymer or the medicine+polymer building final support.

Polymer+medicine lamination deposition of material (chamber) surface in support of shelter (mask) will be comprised.This shelter can be simple as the non-conductive axle inserted through supporting structure internal diameter.This is sheltered and can carry out before adding any layer, or on purpose inserts constantly which floor deposits around whole supporting structure after.

Another advantage of the present invention to form the support with control (dialling in (dialed-in)) drug elution profile.By having ability and the independent ability controlling the position of medicine in these layers of different materials in each layer of laminar structure, the method enables support by very specific elution curve, procedure order and/or parallel elution curve release medicine.The present invention also allows the eluting controlling a kind of medicine, and does not affect the eluting of the second medicine (or various dose of same medicine).

The embodiment adding supporting structure or framework is provided in radiography in expansion and monitors the ability of support.In embodiment for subsequent use, the internal diameter (such as, by non-conductive axle) of support can be sheltered.This shelter by prevent other layer at support internal diameter (outside chamber (abluminal)) on the surface.For the preferential eluting of the blood vessel wall chamber of the support (surface) that provides medicine to expect anti-restenosis response to treatment wherein, and on the outer surface of chamber, do not provide same anti-proliferative drugs, the configuration obtained may be desirable, they there can delayed healing, and this suspects it is the reason of current DES later stage safety issue conversely.

The invention provides many advantages.The present invention advantageously allows to utilize platform, and this platform is by based on the combination of the layer formation method of compressed fluid technology, electrostatic capture and sintering method.Platform causes having the treatment of enhancing and the drug-eluting stent of mechanical property.The especially favourable part of the present invention is that it utilizes the laminated polymeric thing technology optimized.Especially, the present invention allows the discontinuity layer of certain drug platform to be formed.

Conventional method for spraying support requires, before spraying can occur, medicine and polymer to be dissolved in solvent or mutual solvent.Platform provided herein, makes medicine and polymer-coated on Support frame in discontinuous step, and this can or alternately carry out simultaneously.This allows position activity agent discontinuously (such as medicine) in polymeric matrix, therefore allows to be placed on single medical treatment device more than a kind of medicine, insertion or not insertion polymerization nitride layer.Such as, platform of the present invention provides two drug-eluting stent.

Advantages more provided by the invention comprise the fluid (such as supercritical fluid, such as, based on the method for E-RESS) utilizing compression; Solvent-free deposition method; Allow to process at a lower temperature the platform of the quality therefore keeping activating agent and polymeric matrix; Mix the ability of two kinds, three kinds or multi-medicament, the illeffects coming from direct interaction between various medicine and/or its excipient is minimized simultaneously in the manufacture of drug-eluting stent and/or duration of storage; Dry deposition; The adhesion of the enhancing on Support frame upper strata and mechanical property; Accurate deposition and Rapid Batch process; With the ability forming labyrinth.

In one embodiment, the invention provides the drug release platform producing firm, flexible and pliability drug-eluting stent, what it comprised anti-restenosis drugs (such as not taking charge of (limus) or taxol) and anti-thrombosis drug (such as heparin or its analog) and abundant sign can the polymer of bio-absorbable.Drug-eluting stent part provided herein, by reducing or eliminating thrombosed polymer and minimizing completely or eliminate the left drug that can suppress to heal completely, makes thrombotic minimizing possibility.

Platform provides the optimization of drug therapy such as early treatment's (restenosis) and treatment of late stage (thrombosis) to discharge.

Platform also provides coating of adhesiveness, and this coating can enter through bending damage, and does not have the damaged risk of coating.

Another advantage of platform of the present invention is to provide the ability of the elution curve (such as curve shown in Figure 14-16) of high expectations.

Advantage of the present invention comprises the ability reducing or eliminate completely the thrombosed polymer of possibility and may remain the medicine that can suppress long-term healing.The present invention also provides support easily, if coating allows again to enter complicated lesion and reduces or eliminate layering completely, then this support has optimization intensity and elasticity.The layer of lamination of polymer of bio-absorbable can allow the control eluting of one or more medicines.

Platform provided herein reduces or eliminates the shortcoming relevant to conventional drug-eluting stent completely.Such as, platform provided herein allows to adjust better time of activating agent eluting and polymeric matrix absorbs the necessary time again, therefore makes the thrombosis relevant to poor Drug controlled release and other illeffects minimize.

The invention provides overcome or weaken can bioresorbable support current techniques restriction some advantages.Such as, conventional can bio-absorbable polymeric material inherent limitations with to form the difficulty in firm, pliability, deformable (such as can sacculus launch) support relevant, this support has low profile (profile).Polymer generally lacks the intensity of high-performance metal.The present invention overcomes these restrictions by cambium layer laminated structure in polymer support substantially.Undesirably be subject to the constraint of any particular theory or inference, by by the strength ratio of the intensity of plywood and ply comparatively, be appreciated that the intensity of the increase that support of the present invention provides.

The embodiment that the present invention relates to thin metal rack-framework provides the advantage comprising the intrinsic elastic ability overcoming most polymers.General in the polymer, be difficult to obtain high plastic deformation rate (such as 100%) (have with wherein material ' rebound ' to the elastic deformation of original form compare).In addition, do not wish to be bound by any theory, the metal rack framework at center (itself is too little and too weak to such an extent as to can not be used as support) will play effect wiry in plastics, deformable support, substantially overcome polymer any ' elastic memory '.

Accompanying drawing explanation

Fig. 1 shows to utilize supercritical fluid (E-RESS) can prepare the figure of new equipment;

Fig. 2 is the Technology figure of step 1 " electrostatic applications " and step 2 " sintering ";

Fig. 3 is the figure of use and the mechanical activity coating without parylene coating;

Fig. 4 is the figure of characteristic in simple layer;

Fig. 5 is the figure of another characteristic in simple layer;

Fig. 6 is thin, the conformal of target thickness, flawless coating characteristic figure;

Fig. 7 is the medicine standing properties figure controlled;

Fig. 8 is the coronary stent figure of drug-polymer coating;

Fig. 9 is the optical microscope figure of the support of rapamycin/PEVA/PBMA coating;

Figure 10 is the optical microscope figure of the support of another rapamycin/PEVA/PBMA coating;

Figure 11 is the optical microscope figure that the support of rapamycin/PEVA/PBMA coating after the sintering amplifies 100 times;

Figure 12 is the scanning electron microscope diagram of the support of rapamycin/PEVA/PBMA coating;

Figure 13 is average coating quality figure;

Figure 14 is the comparison diagram of scaffold polymer coating;

Figure 15 be stir with the elution curve compared of static state;

Figure 16 is the figure that 5% ethanol/water compares with the elution media of phosphate buffered saline(PBS).

Embodiment

Provide following examples, enable those skilled in the art to more clearly understand and put into practice the present invention.They should not be regarded as and limit the scope of the invention, but only as its example and representative.

Embodiment

In this embodiment, describe the embodiment of the coronary stent that coating is provided, this coronary stent comprises: Support frame and rapamycin-polymer coating, wherein at least part of rapamycin is crystal form, and rapamycin-polymer coating comprise one or more can resorbent polymer.

In these experiments, make use of two kinds of different polymer:

Polymer A :-50:50PLGA-ester terminal, MW ~ 90kD, degradation rate ~ 70 day.

Polymer B :-50:50PLGA-carboxlyate end groups, MW ~ 29kD, degradation rate ~ 28 day.

Metal rack coating is as follows:

AS1: polymer A/rapamycin/polymer A/rapamycin/polymer A

AS2: polymer A/rapamycin/polymer A/rapamycin/polymer B

AS1 (B): polymer B/rapamycin/polymer B/rapamycin/polymer B

AS1b: polymer A/rapamycin/polymer A/rapamycin/polymer A

AS2b: polymer A/rapamycin/polymer A/rapamycin/polymer B

Eluting result as shown in figures 13-16.

Noted earlier is example of the present invention, and should not be construed as is its restriction.Although shown herein and described embodiment of the present invention, to those skilled in the art, this type of embodiment provides by means of only embodiment will be apparent.To those skilled in the art, much can change now, change and replace and do not deviate from the present invention.Should be understood that various the substituting of embodiment of the present invention described herein can be used for putting into practice the present invention.Claim will limit scope of the present invention, and method and structure in these right and equivalent thereof will be included.

Claims (9)

1. prepare a method for coronary stent, described method comprises:

A. Support frame is provided;

B. be deposited upon on described Support frame by many, to form described coronary stent; At least one of wherein said layer comprises can the polymer of bio-absorbable, the medicament of the upper form expected of at least one treatment and/or at least one active biological agent; Wherein respectively being deposited upon on described Support frame of described many layers is comprised the following steps:

I. by the first hole, medicament and/or at least one active biological agent of the upper form expected of described at least one treatment is released in dry powder form;

Ii forms the supercritical or nearly supercritical fluid solution that comprise at least one supercritical fluid solvent and at least one polymer, and under the condition being enough to the solid particle forming described polymer, by the second hole, release described supercritical or nearly supercritical fluid solution;

Iii. by described polymer and medicament and/or active biological agent particle deposition to described framework, wherein between described framework and described polymer and medicament and/or active biological agent granule, maintain electromotive force, thus form described layer; With

Iv., under the condition of the activity of the form and/or described biological preparation that do not change described medicament, described layer is sintered.

2. prepare a method for coronary stent, described method comprises:

A. Support frame is provided;

B. be deposited upon on described Support frame by many, to form described coronary stent; At least one of wherein said layer comprises can the polymer of bio-absorbable, the medicament of the upper form expected of at least one treatment and/or at least one active biological agent; Wherein respectively being deposited upon on described Support frame of described many layers is comprised the following steps:

I. the supercritical comprising at least one supercritical fluid solvent and one or more medicaments and/or at least one active biological agent or nearly supercritical fluid solution is formed, under the condition being enough to the solid particle forming one or more medicaments described and/or at least one active biological agent, by the first hole, release described supercritical or nearly supercritical fluid solution;

Ii forms the supercritical or nearly supercritical fluid solution that comprise at least one supercritical fluid solvent and at least one polymer, and under the condition being enough to the solid particle forming described polymer, by described first hole or by the second hole, release described supercritical or nearly supercritical fluid solution;

Iii. by described polymer and medicament and/or active biological agent particle deposition to described framework, wherein between described framework and described polymer and medicament and/or active biological agent granule, maintain electromotive force, thus form described layer; With

Iv., under the condition of the activity of the form and/or described biological preparation that do not change described medicament, described layer is sintered.

3. the method any one of claim 1-2, described method also comprises releasing the 3rd dry powder, described 3rd dry powder comprises the second medicament and/or the active biological agent of the last inspection of the body statue and movements for the treatment of of dry powder form, being deposited upon on described framework of at least two kinds of different medicaments and/or active biological agent will be comprised thus, or at least two one of in each self-contained two kinds of different medicaments and/or active biological agent are deposited upon on described framework.

4. the method any one of claim 1-2, wherein said frame strip electrostatic charge.

5. the method any one of claim 1-2, wherein the described medicament of powder type of at least 50% is crystallization or hypocrystalline.

6. the method any one of claim 1-2, wherein saidly the polymer of bio-absorbable can be selected from PGA poly-(Acetic acid, hydroxy-, bimol. cyclic ester), LPLA poly-(1-lactide), poly-(e-caprolactone) PDO of DLPLA poly-(d1-lactide), PCL, poly-(dioxolane) PGA-TMC, 85/15 DLPLG (d1-lactide coglycolide) copolymer, 75/25 DLPL, 65/35 DLPLG, 50/50 DLPLG, TMC poly-(carbonate), p (CPP:SA) (1,3-two-p-(carboxyphenoxy) propane-decanedioic acid) copolymer.

7. the method any one of claim 1-2, described method comprises deposition 4,10,20,50 or 100 layers.

8. the method any one of claim 1-2, wherein said layer comprises medicine alternately and polymeric layer.

9. the method for claim 8, wherein said medicine layer is not containing polymer, and described polymeric layer not drug containing.