Source: https://patents.google.com/patent/US8771721B2/en
Timestamp: 2018-11-19 04:22:34
Document Index: 441129556

Matched Legal Cases: ['Application No. 2005', 'Application No. 200580027197', 'Application No. 200580027197', 'Application No. 04750971', 'Application No. 05760224', 'Application No. 05760224', 'Application No. 05760224', 'Application No. 2002', 'Application No. 2002', 'Application No. 2011', 'Application No. 2006', 'Application No. 2006', 'Application No. 552026']

US8771721B2 - Flexible bone composite - Google Patents
US8771721B2
US8771721B2 US13838629 US201313838629A US8771721B2 US 8771721 B2 US8771721 B2 US 8771721B2 US 13838629 US13838629 US 13838629 US 201313838629 A US201313838629 A US 201313838629A US 8771721 B2 US8771721 B2 US 8771721B2
US13838629
US20130209526A1 (en )
This application is a continuation of U.S. patent application Ser. No. 13/539,779 filed on Jul. 2, 2012, which is a continuation of U.S. patent application Ser. No. 13/208,837 filed on Aug. 12, 2011, now U.S. Pat. No. 8,221,782, which is a continuation of U.S. patent application Ser. No. 11/148,193 filed on Jun. 9, 2005, now U.S. Pat. No. 8,012,501, which claims the benefit of prior U.S. provisional application Ser. No. 60/578,610 filed on Jun. 10, 2004, each of which is incorporated herein by reference in its entirety.
When measured for I.V. at a concentration of about 0.1% w/v in chloroform, the polymers according to the invention (before being processed or fabricated into layers) can, in one embodiment, exhibit an inherent viscosity of at least about 1.0 dl/g, for example from about 2.5 dug to about 8 dl/g, from about 3 dug to about 7 dl/g or from about 4 Wig to about 6.5 dl/g. In another embodiment, the inherent viscosity of the poly(L-lactide-co-glycolide) copolymer of the invention can be greater than about 4.5 dl/g. The desired application for which the polymers will be used should generally determine the acceptable range of inherent viscosity values, e.g., a copolymer used for drug delivery, maxillofacial implant, or other application in which enhanced biodegradation or resorbability is paramount, may be preferred to exhibit lower inherent or intrinsic viscosities than those listed above, whereas films used in a composite for a pin, rod, anchor, staple, or other mechanically-intensive and/or load-bearing application may be preferred to exhibit inherent or intrinsic viscosities within, or even above, those listed above.
The polymers can exhibit a wide range of degrees of crystallinity, with preferable values depending upon the desired application for which they are to be used. In one embodiment, the polymeric layers are semicrystalline and can exhibit a degree of crystallinity from about 15% to about 30%, for example from about 20% to about 30%, or for example from about 20% to about 26%. In another embodiment, the layers of the invention can exhibit a degree of crystallinity of less than about 15%. In an alternate embodiment, the layers of the invention can exhibit a degree of crystallinity from about 15% to about 50%. In other alternate embodiments, the layers of the invention can exhibit a degree of crystallinity of less than about 10%, less than about 5%, less than about 1%, or can exhibit substantially no crystallinity (i.e., less than about 0.5%, preferably less than about 0.1%, or at any rate not quantitatively detectable by one or more experimental methods). The “degree of crystallinity” can be measured by a number of well-known experimental techniques and, when the term is used herein, reflects the relative proportion, by volume, cross-sectional area, or linear path through a sample, of crystalline regions in comparison to non-crystalline or amorphous regions of the films. Suitable experimental techniques to measure degree of crystallinity include, but are not limited to, differential scanning calorimetry (DSC), x-ray scattering or diffraction methods (e.g., XRD, WARD, WARS, etc.), or the like.
Values for various mechanical properties of the polymers can vary widely, depending inter alfa upon the desired application for which they are to be used and the process by which they are formed into articles or devices for said applications. For example, in one embodiment, the tensile strength of the polymers can range from about 10 to about 100 MPa. In another embodiment, the elastic modulus of the polymers can range from about 0.1 to about 6 GPa.
In one embodiment, one or more surfaces of the flexible bone composites according to the invention is treated with an oxygen plasma. In another embodiment, one or more surfaces of the flexible bone composites according to the invention is treated with a carbon dioxide plasma. In another embodiment, one or more surfaces of the flexible bone composites according to the invention is treated to form grafted surface(s) according to the HYDROLASTT™ process, commercially available from AST Industries, Inc., of Billerica, Mass., in which the one or more surfaces is exposed to a gas plasma such as oxygen, followed by reaction with a polymeric/oligomeric compound, e.g., a poly(alkylene oxide)/poly(alkylene glycol) such as PEO/PEG or a poly(alkylene imine) such as PEI.
When the therapeutic substance is an antimicrobial agent, one, and usually no more than three, usually no more than two, antimicrobial agents may be present in the flexible bone composite. Non-limiting examples of useful antimicrobial agents include: Antiamebics, e.g. Arsthinol, Bialamicol, Carbarsone, Cephaeline, Chlorbetamide, Chloroquine, Chlorphenoxamide, Chlortetracycline, Dehydroemetine, Dibromopropamidine, Diloxanide, Diphetarsone, Emetine, Fumagillin, Glaucarubin, Glycobiarsol, 8-Hydroxy-7-iodo-5-quinoline-sulfonic Acid, Iodochlorhydroxyquin, Iodoquinol, Paromomycin, Phanquinone, Polybenzarsol, Propamidine, Quinfamide, Scenidazole, Sulfarside, Teclozan, Tetracycline, Thiocarbamizine, Thiocarbarsone, Timidazole; Antibiotics, e.g. Aminoglycosides (such as Amikacin, Apramycin, Arbekacin, Bambermycins, Butirosin, Dibekacin, Dihydrostreptomycin, Fortimicin(s), Gentamicin, Isepamicin, Kaniamycin, Micronomicin, Neomycin, Neomycin Undecylenate, Netilmicin, Paromomycin, Ribostamycin, Sisomicin, Spectinomycin, Streptomycin, Tobramycin, Trospectomycin), Amphenicols (Azidamfenicol, Chloramphenicol, Florfenicol, Thiamphenicol), Ansamycins (Rifamide, Rifampin, Rifamycin, Rifapentine, Rifaximin), .beta.-Lactams (Carbacephems, Loracarbef, Carbapenems (Biapenem, Imipenem, Meropenem, Panipenem), Cephalosporins (Cefaclor, Cefadroxil, Cefamandole, Cefatrizine, Cefazedone, Cefazolin, Cefcapene Povoxil, Cefclidin, Cefdinir, Cefditoren, Cefepime, Cefetamet, Cefixime, Cefinenoxine, Cefodizime, Cefonicid, Cefoperazone, Ceforanide, Cefotaxime, Cefotiam, Cefozopran, Cefpimizole, Cefpiramide, Cefpirome, Cefpodoxime Proxetil, Cefprozil, Cefroxadine, Cefsulodin, Ceftazidime, Cefteram, Ceftezole, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefuroxime, Cefuzonam, Cephacetrile Sodium, Cephalexin, Cephaloglycin, Cephaloridine, Cephalosporin, Cephalothin, Cephapirin Sodium, Cephradine, Pivcefalexin), Cephamycins (Cefbuperazone, Cefmetazole, Cefminox, Cefotetan, Cefoxitin), Monobactams (Aztreonam, Carumonam, Tigemonam), Oxacephens (Flomoxef, Moxalactam), Penicillins (Amdinocillin, Amdinocillin Pivoxil, Amoxicillin, Ampicillin, Apalcillin, Aspoxicillin, Azidocillin, Azlocillin, Bacampicillin, Benzylpenicillic Acid, Benzylpenicillin Sodium, Carbenicillin, Carindacillin, Clometocillin, Cloxacillin, Cyclacillin, Dicloxacillin, Epicillin, Fenbenicillin, Floxacillin, Hetacillin, Lenampicillin, Metampicillin, Methicillin Sodium, Mezlocillin, Naacillin Sodium, Oxacillin, Penamecillin, Penethamate Hydriodide, Penicillin G Benethamine, Penicillin G Benzathine, Penicillin G Benzhydrylamine, Penicillin G Calcium, Penicillin G Hydrabamine, Penicillin G Potassium, Penicillin G Procaine, Penicillin N, Penicillin 0, Penicillin V, Penicllin V Benzathine, Penicillin V Hydrabamine, Penimepicycline, Phenethicillin Potassium, Piperacillin, Pivampicillin, Propicillin, Quinacillin, Sulbenicillin, Sultamicillin, Talampicillin, Temocillin, Ticarcillin), Ritipenem), Lincosamides (Clindamycin, Lincomycin), Macrolides (Azithromycin, Capbomycin, Clarithromycin, Dirithromycin, Erythromycin, Erythromycin Acistrate, Erythromycin Estolate, Erythromycin Glucoheptonate, Erythromycin Lactobionate, Erythromycin Propionate, Erythromycin Stearate, Josamycin, Leucomycins, Midecamycins, Miokamycin, Oleandomycin, Primycin, Rokitamycin, Rosaramicin, Roxithromycin, Spiramycin, Troleandomycin), Polypeptides (Amphomycin, Bacitracin, Capreomycin, Colistin, Enduracidin, Enviomycin, Fusafungine, Gramicidin S, Gramicidin(s), Mikamycin, Polymyxin, Pristinamycin, Ristocetin, Teicoplanin, Thiostrepton, Tuberactinomycin, Tyrocidine, Tyrothricin, Vancomycin, Viomycin, Virginiamycin, Zinc Bacitracin), Tetracyclines(Apicycline, Chlortetracycline, Clomocycline, Demeclocycline, Doxycycline, Guamecycline, Lymecycline, Meclocycline, Methacycline, Minocycline, Oxytetracycline, Penimepicycline, Pipacycline, Rolitetracycline, Sancycline, Tetracycline), Cycloserine, Mupirocin, Tuberin; synthetic antibacterial agents, e.g. 2,4-Diaminopyrimidines (Brodimoprim, Textroxoprim, Trimethoprim), Nitrofurans (Furaltadone, Furazolium Chloride, Nifuradene, Nifuratel, Nifurfoline, Nifurpirinol, Nifurprazine, Nifurtoinol, Nitrofirantoin), Quinolones and Analogs (Cinoxacin, Ciprofloxacin, Clinafloxacin, Difloxacin, Enoxacin, Fleroxacin, Flumequine, Grepafloxacin, Lomefloxacin, Miloxacin, Nadifloxacin, Nadilixic Acid, Norflaxacin, Ofloxacin, Oxolinic Acid, Pazufloxacin, Pefloxacin, Pipemidic Acid, Piromidic Acid, Rosoxacin, Rufloxacin, Sparfloxacin, Temafloxacin, Tosufloxacin, Trovafloxacin), Sulfonamides (Acetyl Sulfamethoxpyrazine, Benzylsulfamide, Chloramine-B, Chloramine-T, Dichloramine T, N2-Formylsulfisomidine, N4-β-D-Glucosylsulfanilamide, Mafenide, 4′-(Methylsulfamoyl)sulfanilanilide, Noprylsulfamide, Phthalylsulfacetamide, Phthalylsulfathiazole, Salazosulfadimidine, Succinylsulfathiazole, Sulfabenzamide, Sulfacetamide, Sulfachlorpyridazine, Sulfachrysoidine, Sulfacytine, Sulfadiazine, Sulfadicramide, Sulfadimethoxine, Sulfadoxine, Sulfaethidole, Sulfaguanidine, Sulfaguanol, Sulfalene, Sulfaloxic, Sulfamerazine, Sulfameter, Sulfamethazine, Sulfamethizole, Sulfamethomidine, Sulfamethoxazole, Sulfamethoxypyridazine, Sulfametrole, Sulfamidochrysoidine, Sulfamoxole, Sulfanilamide, 4-Sulfanilamidosalicylic Acid, N4-Sulfanilylsulfanilamide, Sulfanilylurea, N-Sulfanilyl-3,4-xylamide, Sulfanitran, Sulfaperine, Sulfaphenazole, Sulfaproxyline, Sulfapyrazine, Sulfapyridine, Sulfasomizole, Sulfasymazine, Sulfathiazole, Sulfathiourea, Sulfatolamide, Sulfisomidine, Sulfisoxazole), Sulfones (Acedapsone, Acediasulfone, Acetosulfone Sodium, Dapsone, Diathymosulfone, Glucosulfone Sodium, Solasulfone, Succisulfone, Sulfanilic Acid, p-Sulfanilylbenzylamine, Sulfoxone Sodium, Thiazolsulfone), Clofoctol, Hexedine, Methenamine, Methenamine Anhydromethylenecitrate, Methenamine Hippurate, Methenamine Mandelate, Methenamine Sulfosalicylate, Nitroxoline, Taurolidine, Xibomol; leprostatic antibacterial agents, such as Acedapsone, Acetosulfone Sodium, Clofazimine, Dapsone, Diathymosulfone, Glucosulfone Sodium, Hydnocarpic Acid, Solasulfone, Succisulfone, Sulfoxone Sodium, antifungal agents, such as Allylamines Butenafine, Naftifine, Terbinafine, Imidazoles (e.g., Bifonazole, Butoconazole, Cholordantoin, Chlormidazole, Cloconazole, Clotrimazole, Econazole, Enilconazole, Fenticonazole, Flutrimazole, Isoconazole, Ketoconazole, Lanoconazole, Miconazole, Omoconazole, Oxiconazole Nitrate, Sertaconazole, Sulconazole, Tioconazole), Thiocarbamates (Tolcilate, Tolindate, Tolnaftate), Triazoles (Fluconazole, Itraconazole, Saperconazole, Terconazole), Acrisorcin, Amorolfine, Biphenamine, Bromosalicylchloranilide, Buclosamide, Calcium Propionate, Chlorphenesin, Ciclopirox, Cloxyquin, Coparaffinate, Diamthazole Dihydrochloride, Exalamide, Flucytosine, Halethazole, Hexetidine, Loflucarban, Nifuratel, Potassium Iodide, Propionic Acid, Pyrithione, Salicylanilide, Sodium Propionate, Sulbentine, Tenonitrozole, Triacetin, Ujothion, Undecylenic Acid, Zinc Propionate; and the like.
Other antimicrobial agents useful in the present invention include Q-lactamase inhibitors (e.g. Clavulanic Acid, Sulbactam, Tazobactam); Chldramphenicols (e.g. Azidamphenicol, Chloramphenicol, Thiaphenicol); Fusidic Acid; synthetic agents such as Trimethoprim, optionally in combination with sulfonamides) and Nitroimidazoles (e.g., Metronidazole, Timidazole, Nimorazole); Antimycobacterial agents (e.g. Capreomycin, Clofazimine, Dapsone, Ethambutol, Isoniazid, Pyrazinamide, Rifabutin, Rifampicin, Streptomycin, Thioamides); Antiviral agents (e.g. Acryclovir, Amantadine, Azidothymidine, Ganciclovir, Idoxuridine, Tribavirin, Trifluridine, Vidarabine); Interferons (e.g. Interferon α, Interferon β); and antiseptic agents (e.g., Chlorhexidine, Gentian violet, Octenidine, Povidone Iodine, Quaternary ammonium compounds, Silver sulfadiazine, Triclosan).
The therapeutic substance can further include a biological therapeutic substance, such as, e.g., a protein. In one embodiment, bone associated proteins may be added to modify the physical properties of the composition, enhance resorption, angiogenesis, cell entry and proliferation, mineralization, bone formation, growth of osteoclasts and/or osteoblasts, or the like. Proteins of particular interest are the different types of collagen, particularly Type 1. Other proteins include osteonectin, bone sialoproteins (Bsp), alpha-2HS-glycoproteins, bone Gla-protein (Bgp), matrix Gla-protein, bone phosphoglycoprotein, bone phosphoprotein, bone proteoglycan, protolipids, bone morphogenic proteins (e.g., BMP-1, -2A, -2B, -3, -3b, -4, -5, -6, -7, -8, -8b, -9, -10, -11, -12, -13, -14, -15), cartilage induction factor, platelet derived growth factor (PDGF-1, -2), endothelial cell growth factors (ECGF-1, -2a, -2b), skeletal growth factor (SKF=IGF-2), insulin-like growth factors (IGF-1, IGF-2), fibroblast growth factor (ODGF-1, -2, -3, -4, -5, -6, -7, -8, -9, -10, -11, -12, -13, -14, -15, -16, -17, -18, -19, -20, -21, -22, -23), colony stimulating factor, transforming growth factor (e.g., TGF-(3), vascular endothelial growth factors (VEGF), growth/differentiation factors (GDF-1, -3, -5, -6, -7, -8, -9, -9B, -10, -11, -15, -16), osteogenic proteins (OP-1=BMP-7, OP-2=BMP-8, OP-3=BMP-8b), bone growth hormone, parathyroid hormone (PTH), insulin, calcitonin, and the like. The proteins can also include proteins associated with cartilage, such as chondrocalcining protein; proteins associated with dentin, such as phosphosphoryn, glycoproteins and Gla proteins; or proteins associated with enamel, such as amelognin and enamelin. Structural proteins of interest for use in the present invention include, but are not limited to, fibrin, fibrinogen, keratin, tubulin, elastin, and the like. In one embodiment, blood proteins may be employed, individually or together, in plasma or serum, e.g., serum albumin.
Changes in tensile strength for a 60:14:26 poly(glycolide-co-dioxanone-co-
trimethylene carbonate)copolymer maintained in a phosphate buffer
solution (pH 7.4).
1. A multilayer flexible bone composite comprising:
a first polymeric layer comprising a flexible polymer and having a first side and a second side;
a first calcium-containing layer comprising granules of a calcium compound affixed to the first side of the first polymeric layer, wherein a majority of the external surface of the granules of the first calcium-containing layer is not covered with polymer; and
a second calcium-containing layer comprising granules of a calcium compound affixed to the second side of the first polymeric layer.
2. The multilayer flexible bone composite of claim 1, further including a second polymeric layer comprising a flexible polymer, wherein the second calcium-containing layer is disposed between the first polymeric layer and the second polymeric layer.
3. The multilayer flexible bone composite of claim 2, wherein the second polymeric layer has a first side and a second side and wherein the granules of the second calcium-containing layer are affixed to the first side of the second polymeric layer.
4. The multilayer flexible bone composite of claim 2, wherein the first polymeric layer and/or the second polymeric layer is substantially free of calcium compounds.
5. The multilayer flexible bone composite of claim 2, wherein the first polymeric layer and/or the second polymeric layer comprises a resorbable polymer.
6. The multilayer flexible bone composite of claim 2, wherein the first polymeric layer and/or the second polymeric layer comprises a synthetic polymer.
7. The multilayer flexible bone composite of claim 2, wherein the flexible polymer of the first polymeric layer and/or the second polymeric layer comprises repeat units selected from the group consisting of L-lactic acid, D-lactic acid, L-lactide, D-lactide, D,L-lactide, glycolide, a lactone, a lactam, ε-caprolactone, trimethylene carbonate, a cyclic carbonate, a cyclic ether, para-dioxanone, beta-hydroxybutyric acid, beta-hydroxypropionic acid, beta-hydroxyvaleric acid, and combinations thereof.
8. The multilayer flexible bone composite of claim 2, wherein the flexible polymer of the first polymeric layer and/or the second polymeric layer has a glass transition temperature between about 30 degrees C. and about 100 degrees C.
9. The multilayer flexible bone composite of claim 2, wherein the first polymeric layer and/or the second polymeric layer has a thickness ranging from about 0.01 mm to about 1.0 mm.
10. The multilayer flexible bone composite of claim 2, wherein the first polymeric layer and/or the second polymeric layer includes one or more perforations.
11. The multilayer flexible bone composite of claim 2, wherein the first polymeric layer and/or the second polymeric layer includes one or more cuts or slits.
12. The multilayer flexible bone composite of claim 11, wherein the one or more cuts or slits has a length ranging from about 0.5 mm to about 10 mm.
13. The multilayer flexible bone composite of claim 1, wherein first calcium-containing layer and/or the second calcium-containing layer is substantially free of polymer.
14. The multilayer flexible bone composite of claim 1, wherein the calcium compound of the first calcium-containing layer and/or the second calcium-containing layer are selected from the group consisting of CaHPO4.nH2O, α-Ca3(PO4)2, α-bar-Ca3(PO4)2, β-Ca3(PO4)2, Ca5(PO4)3OH, Ca10(PO4)6(OH)2, Ca4O(PO4)2, CaP4 O11, Ca2P2O7, Ca(H2PO4)2.nH2O, Ca8H2(PO4)6 nH2O, and combinations thereof, where n is a number ranging from 0 to 5.
15. The multilayer flexible bone composite of claim 1, wherein the calcium compound of the first calcium-containing layer and the second calcium-containing layer is β-Ca3(PO4)2.
16. The multilayer flexible bone composite of claim 1, wherein the calcium compound of the first calcium-containing layer and/or the second calcium-containing layer is substantially free of hydroxyapatite.
17. The multilayer flexible bone composite of claim 1, wherein the granules of the first calcium-containing layer and/or the second calcium-containing layer have a mean diameter of about 0.05 mm to about 10 mm.
18. The multilayer flexible bone composite of claim 1, wherein each granules of the first calcium-containing layer and/or the second calcium-containing layer has a surface area of about 0.1 m2/g to about 100 m2/g.
19. The multilayer flexible bone composite of claim 1, further comprising bone marrow cells in an interior of the multilayer flexible bone composite prior to implantation.
20. The multilayer flexible bone composite of claim 1, wherein the multilayer flexible bone composite is soaked in aspirated bone marrow.
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