Patent Application
20070292470
Implantable medical devices comprising polymers and bioactive materials have been created using solvent casting to create thin films which are then structured into appropriate shapes. See, for example, United States patent Number (USPN) U.S. Pat. No. 6,641,831 and United States Patent Application No. 2005/0021131. While these approaches addressed certain drawbacks of the prior art, shaping pre-made films into complex geometric patterns, such as those found in stents, has inherent technical difficulties and drawbacks.
Others have also attempted to create implantable medical devices comprising polymers containing bioactive materials through thermal injection molding. However, the temperatures required for polymers to undergo this process are relatively high and above the temperature at which most bioactive materials remain stable. Therefore, this approach also did not adequately address the issue of providing an implantable medical device constructed of a polymer containing bioactive materials. The present invention provides such implantable medical devices and methods for making the same.
The present invention provides methods to manufacture polymeric implantable medical devices containing bioactive materials. The methods involve dissolving a polymer and a bioactive material in an appropriate volatile co-solvent, and injecting the mixture into a mold ‘cold’ (i.e. at a temperature that does not degrade bioactive materials). The volatile co-solvent can then be removed from the mixture through evaporation. In one embodiment, evaporation can occur through a parting line in the mold. In other embodiments, evaporation can be aided by, without limitation, appropriate venting, vacuuming or low level heating. The mixture viscosity can be easily tuned by adding more or less solvent. Further, the polymer can be bioresorbable or non-resorbable. These methods can provide cost-effective means to manufacture a polymeric drug-eluting stent. Further, the methods are rapid, provide a finished stent in its final shape and can provide any surface texturing that is required. The methods can also facilitate the inclusion of three dimensional topography of a stent and can reduce bioactive materials waste by utilizing 100% of the bioactive material in the mixture.
In one example according to the present invention, instead of melting a polymer using heat, the polymer and a bioactive material are dissolved in a suitable co-solvent. The amount of co-solvent is selected to give an appropriate viscosity to the mixture. In the described example this mixture is then injected into a mold. Following injection into the mold, the co-solvent is allowed to evaporate sufficiently for the mixture (now a shaped implantable medical device) to be removed from the mold without damage or deformation. Co-solvent evaporation can be aided by, without limitation, the opening of evaporation ports in the mold, by the application of a vacuum to evaporation ports and/or by low level heating. Once the implantable medical device has been removed from the mold after sufficient co-solvent evaporation, in certain embodiments evaporation and drying can be further aided by, without limitation, an oven or other appropriate fume hood or chamber.
The following provides non-limiting exemplary polymers, bioactive materials and co-solvents that are especially beneficial for use in accordance with the present invention. Polymers: poly-lactic acid (PLA); poly-glycolic acid (PGA), polycarbonates, polyurethanes, polycapralactone and polyorthoester. Bioactive Materials: Zotarolimus (ABT-578), rapamycin, paclitaxel, dexamethasone, everolimus, tacrolimus, des-aspartate angiotensin I, exochelins, nitric oxide, apocynin, gamma-tocopheryl, pleiotrophin, estradiol, heparin, aspirin and HMG-CoA reductase inhibitors such as atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, abciximab, angiopeptin, colchicines, eptifibatide, hirudin, methotrexate, streptokinase, taxol, ticlopidine, tissue plasminogen activator, trapidil, urokinase, vascular endothelial growth factor, transforming growth factor beta, insulin growth factor, platelet-derived growth factor, fibroblast growth factor, combinations thereof, etc. Co-Solvents: chloroform, acetone, methylene chloride, ethyl acetate and tetrahydrofuran (THF). As will be understood by one of ordinary skill in the art and described further below, however, there are many other appropriate polymers, bioactive materials and cosolvents that can be used.
A more complete listing of polymers that can be used in accordance with the present invention include rapidly bioerodible polymers such as, without limitation, poly[lactide-co-glycolide], polyanhydrides, and polyorthoesters, whose carboxylic groups are exposed on the external surface as their smooth surface erodes. In addition, polymers containing labile bonds, such as, without limitation, polyanhydrides and polyesters can also be used. Representative natural polymers that can be used include, without limitation, proteins, such as zein, modified zein, casein, gelatin, gluten, serum albumin, or collagen, and polysaccharides, such as, without limitation, cellulose, dextrans, polyhyaluronic acid, polymers of acrylic and methacrylic esters and alginic acid. Representative synthetic polymers that can be used in accordance with the present invention include, without limitation, polyphosphazines, poly(vinyl alcohols), polyamides, polycarbonates, polyalkylenes, polyacrylamides, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes and copolymers thereof. Synthetically modified natural polymers that can be used in accordance with the present invention include, without limitation, alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, and nitrocelluloses. Other polymers that can be used in accordance with the present invention include, but are not limited to, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate, cellulose sulfate sodium salt, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly(ethylene terephthalate), poly(vinyl acetate), polyvinyl chloride, polystyrene, polyvinyl pyrrolidone, and polyvinylphenol. Representative bioerodible polymers include polylactides, polyglycolides and copolymers thereof, poly(ethylene terephthalate), poly(butic acid), poly(valeric acid), poly(lactide-co-caprolactone), poly[lactide-co-glycolide], polyanhydrides, polyorthoesters, blends and copolymers thereof.
These described polymers can be obtained from sources such as Sigma Chemical Co., St. Louis, Mo., Polysciences, Warrenton, Pa., Aldrich, Milwaukee, Wis., Fluka, Ronkonkoma, N.Y., and BioRad, Richmond, Calif. or else synthesized from monomers obtained from these suppliers using standard techniques.
In addition, a variety of bioactive materials can be appropriate for use in accordance with the present invention. Some of these bioactive materials include, without limitation, drugs such as altretamin, fluorouracil, amsacrin, hydroxycarbamide, asparaginase, ifosfamid, bleomycin, lomustin, busulfan, melphalan, chlorambucil, mercaptopurin, chlormethin, methotrexate, cisplatin, mitomycin, cyclophosphamide, procarbazin, cytarabin, teniposid, dacarbazin, thiotepa, dactinomycin, tioguanin, daunorubicin, treosulphan, doxorubicin, tiophosphamide, estramucin, vinblastine, etoglucide, vincristine, etoposid, vindesin, penicillin, ampicillin, nafcillin, amoxicillin, oxacillin, azlocillin, penicillin G, carbenicillin, penicillin V, dicloxacillin, phenethicillin, floxacillin, piperacillin, mecillinam, sulbenicillin, methicillin, ticarcillin, mezlocillin, cefaclor, cephalothin, cefadroxil, cephapirin, cefamandole, cephradine, cefatrizine, cefsulodine, cefazolin, ceftazidim, ceforanide, ceftriaxon, cefoxitin, cefuroxime, cephacetrile, latamoxef, cephalexin, amikacin, neomycin, dibekacyn, kanamycin, gentamycin, netilmycin, kanamycin, tobramycin, amphotericin B, novobiocin, bacitracin, nystatin, clindamycin, polymyxins, colistin, rovamycin, erythromycin, spectinomycin, lincomycin, vancomycin, chlortetracycline, oxytetracycline, demeclocycline, rolitetracycline, doxycycline, tetracycline, minocycline, chloramphenicol, rifamycin, rifampicin, thiamphenicol, sulfadiazine, sulfamethizol, sulfadimethoxin, sulfamethoxazole, sulfadimidin, sulfamethoxypyridazine, sulfafurazole, sulfaphenazol, sulfalene, sulfisomidin, sulfamerazine, sulfisoxazole, trimethoprim with sulfamethoxazole, sulfametrole, methanamine, norfloxacin, cinoxacin, nalidixic acid, nitrofurantoine, nifurtoinol, oxolinic acid; metronidazole; aminosalicyclic acid, isoniazide, cycloserine, rifampicine, ethambutol, tiocarlide, ethionamide, viomycin; amithiozone, rifampicine, clofazimine, sodium sulfoxone, diaminodiphenylsulfone, amphotericin B, ketoconazole, clotrimazole, miconazole, econazole, natamycin, flucytosine, nystatine, griseofulvin, aciclovir, idoxuridine, amantidine, methisazone, cytarabine, vidarabine, ganciclovir, chloroquine, iodoquinol, clioquinol, metronidazole, dehydroemetine, paromomycin, diloxanide, furoatetinidazole, emetine, chloroquine, pyrimethamine, hydroxychloroquine, quinine, mefloquine, sulfadoxine/pyrimethamine, pentamidine, sodium suramin, primaquine, trimethoprim, proguanil, antimony potassium tartrate, niridazole, antimony sodium dimercaptosuccinate, oxamniquine, bephenium, piperazine, dichlorophen, praziquantel, diethylcarbamazine, pyrantel parmoate, hycanthone, pyrivium pamoate, levamisole, stibophen, mebendazole, tetramisole, metrifonate, thiobendazole, niclosamide, acetylsalicyclic acid, mefenamic acid, aclofenac, naproxen, azopropanone, niflumic acid, benzydamine, oxyphenbutazone, diclofenac, piroxicam, fenoprofen, pirprofen, flurbiprofen, sodium salicyclate, ibuprofensulindac, indomethacin, tiaprofenic acid, ketoprofen, tolmetin, colchicine, allopurinol, alfentanil, methadone, bezitramide, morphine, buprenorfine, nicomorphine, butorfanol, pentazocine, codeine, pethidine, dextromoramide, piritranide, dextropropoxyphene, sufentanil, fentanyl, articaine, mepivacaine, bupivacaine, prilocaine, etidocaine, procaine, lidocaine, tetracaine, amantidine, diphenhydramine, apomorphine, ethopropazine, benztropine mesylate, lergotril, biperiden, levodopa, bromocriptine, lisuride, carbidopa, metixen, chlorphenoxamine, orphenadrine, cycrimine, procyclidine, dexetimide, trihexyphenidyl, baclofen, carisoprodol, chlormezanone, chlorzoxazone, cyclobenzaprine, dantrolene, diazepam, febarbamate, mefenoxalone, mephenesin, metoxalone, methocarbamol, tolperisone, levothyronine, liothyronine, carbimazole, methimazole, methylthiouracil and propylthiouracil and/or natural or synthetic hormones such as, without limitation, cortisol, deoxycorticosterone, flurohydrocortisone, beclomethasone, betamethasone, cortisone, dexamethasone, fluocinolone, fluocinonide, fluocortolone, fluorometholone, fluprednisolone, flurandrenolide, halcinonide, hydrocortisone, medrysone, methylprednisolone, paramethasone, prednisolone, prednisone, triamcinolone (acetonide), danazole, fluoxymesterone, mesterolone, dihydrotestosterone methyltestosterone, testosterone, dehydroepiandrosetone, dehydroepiandrostendione, calusterone, nandrolone, dromostanolone, oxandrolone, ethylestrenol, oxymetholone, methandriol, stanozolol methandrostenolone, testolactone, cyproterone acetate, diethylstilbestrol, estradiol, estriol, ethinylestradiol, mestranol, quinestrol chlorotrianisene, clomiphene, ethamoxytriphetol, nafoxidine, tamoxifen, allylestrenol, desogestrel, dimethisterone, dydrogesterone, ethinylestrenol, ethisterone, ethynadiol diacetate, etynodiol, hydroxyprogesterone, levonorgestrel, lynestrenol, medroxyprogesterone, megestrol acetate, norethindrone, norethisterone, norethynodrel, norgestrel, progesterone, inhibin, antidiuretic hormone, proopiomelanocortin, follicle stimulating hormone, prolactin, angiogenin, epidermal growth factor, calcitonin, erythropoietin, thyrotropic releasing hormone, insulin, growth hormones, human chorionic gonadotropin, luteinizing hormone, adrenocorticotropic hormone (ACTH), lutenizing hormone releasing hormone (LHRH), parathyroid hormone (PTH), thyrotropin releasing hormone (TRH), vasopressin, and corticotropin releasing hormone.
In certain embodiments, volatile solvents are those that have atmospheric boiling points below about 90° C., below about 80° C., below about 60° C. or below about 40° C. A more complete list of solvents that can be used in accordance with the present invention include, without limitation, chloroform, acetone, dimethylsulfoxide (DMSO), propylene glycol methyl ether (PM,) iso-propylalcohol (IPA), n-propylalcohol, methanol, ethanol, tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl acetamide (DMAC), benzene, toluene, xylene, hexane, cyclohexane, heptane, octane, nonane, decane, decalin, ethyl acetate, butyl acetate, isobutyl acetate, isopropyl acetate, butanol, diacetone alcohol, benzyl alcohol, acetone, 2-butanone, cyclohexanone, dioxane, methylene chloride, carbon tetrachloride, tetrachlroro ethylene, tetrachloro ethane, chlorobenzene, 1,1,1-trichloroethane, formamide, and combinations thereof.
Thus, as should be evident from the preceding disclosure, a variety of polymers, bioactive materials, co-solvents, mold and evaporation systems and drying devices can be used in accordance with the present invention. Specific embodiments will include at a minimum forming an implantable medical device by dissolving a polymer and a bioactive material in a co-solvent to form a mixture; injecting the mixture into a mold that is part of a system comprising at least one evaporation port; allowing the co-solvent to evaporate from the mixture while the mixture is in the mold; and removing the mixture from the mold after the evaporation.
Other embodiments according to the present invention can modify or add steps or features to this basic embodiment by, without limitation: (i) accelerating the rate of co-solvent evaporation and/or by (ii) further drying or treating the mixture once it is removed from the mold. Accelerating the rate of co-solvent evaporation can be achieved by, without limitation, opening one or more evaporation ports; applying a vacuum to said one or more evaporation ports; heating the system to a temperature below that which would degrade the bioactive material; and combinations thereof. After removal from the mold, the mixture can be further dried by, without limitation, placing the mixture in at least one device selected from the group consisting of an oven, a vacuum oven, a vacuum chamber, a fume hood and a laminar flow hood. Further treatments can include, without limitation, adding additional drug layers or coatings to the surface of the created medical device.
The present invention provides methods to produce a variety of medical devices. In one embodiment, these methods are used to produce stents. The methods can be used to create a variety of other medical devices, however, including, without limitation, those described in the preceding provided definition of “medical devices.”
Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.
While certain embodiments according to this invention are described herein, variations of those embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description.
Furthermore, numerous references have been made to patents and printed publications throughout this specification. Each of the above cited references and printed publications are herein individually incorporated by reference in their entirety.
