WO2005053571A2 - Biobeneficial coating compositions and methods of making and using thereof - Google Patents
Biobeneficial coating compositions and methods of making and using thereof Download PDFInfo
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- WO2005053571A2 WO2005053571A2 PCT/US2004/039163 US2004039163W WO2005053571A2 WO 2005053571 A2 WO2005053571 A2 WO 2005053571A2 US 2004039163 W US2004039163 W US 2004039163W WO 2005053571 A2 WO2005053571 A2 WO 2005053571A2
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- 0 CC(*)CCC(C)c1ccccc1 Chemical compound CC(*)CCC(C)c1ccccc1 0.000 description 4
- OUGHBKJRRWUPPH-UHFFFAOYSA-N CC(C)C(CC1)=CC=C1C(C)=O Chemical compound CC(C)C(CC1)=CC=C1C(C)=O OUGHBKJRRWUPPH-UHFFFAOYSA-N 0.000 description 1
- SZTYTCQSBVMJRI-UHFFFAOYSA-N CC(C)C1=CC=CCC1 Chemical compound CC(C)C1=CC=CCC1 SZTYTCQSBVMJRI-UHFFFAOYSA-N 0.000 description 1
- RYSLCLJMTOTVJT-UHFFFAOYSA-O CC(C)c1ccc(C(C)NC(CC2(C)C)CC(C)(C)[NH+]2O)cc1 Chemical compound CC(C)c1ccc(C(C)NC(CC2(C)C)CC(C)(C)[NH+]2O)cc1 RYSLCLJMTOTVJT-UHFFFAOYSA-O 0.000 description 1
Classifications
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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
- 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
- A61L31/08—Materials for coatings
- A61L31/10—Macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
-
- 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
-
- 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
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
-
- 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
- A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs
-
- 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
- A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
Definitions
- This invention generally relates to a polymeric coating composition for coating an implantable device, such as a stent.
- Description of the Background Polymeric coatings have been used for coating stents.
- One of the commercially available polymer coated products is stents manufactured by Boston Scientific.
- U.S. Patent Nos. 5,869,127; 6,099,563; 6,179,817; and 6,197,051, assigned to Boston Scientific Corporation describe various compositions for coating medical devices. These compositions provide to stents described therein an enhanced biocompatibility and may optionally include a bioactive agent.
- a coating composition which includes a bioactive agent, a collagenous material, or a collagenous coating optionally containing or coated with other bioactive agents.
- the nature of the coating polymers plays an important role in defining the surface properties of a coating. For example, very a low T g , amorphous coating material induces unacceptable rheological behavior upon mechanical perturbation such as crimping, balloon expansion, etc. On the other hand, a high T g , or highly crystalline coating material introduces brittle fracture in the high strain areas of the stent pattern.
- a current paradigm in biomaterials is the control of protein adsorption on the implant surface.
- a biomaterials-based strategy for further improving the outcome of drug eluting stents is by the use of biobeneficial materials or surfaces in stent coatings.
- a biobeneficial material is one which enhances the biocompatibility of a device by being non-fouling, hemocompatible, actively non-thrombogenic, or anti-inflammatory, all without depending on the release of a pharmaceutically active agent.
- the composition when coated onto an implantable device, may be covered with a barrier layer of, or blended with, a polymer or material such as polyethylene oxide or hyaluronic acid (see also Pinchuk, et al., "Polyisobutylene-based Thennoplastic Elastomers for Ultra Long-Term Implant Applications," Society for Biomaterials, 6 th World Biomaterials Congress Transactions, 2000, #1452; Drachman DE, et al., J. Amer.
- the biobeneficial composition comprises a first block copolymer and a biobeneficial polymer.
- the biobeneficial polymer may comprise a first block copolymer and a second block copolymer, the second block copolymer comprising a biobeneficial component and another component, which is either water soluble or miscible with the first block copolymer.
- the first block copolymer has a block with a T g below about body temperature and another block that has a T g above about body temperature or has considerable crystallinity with a T m above about body temperature.
- body temperature refers to the normal body temperature of a human, which is about 37 °C, e.g., about 36 °C to 37.5 °C.
- the block with a Tg below about body temperature has an amorphous structure and is elastomeric.
- the composition described herein is elastomeric but very oxidation resistant.
- the high T g block renders the first block copolymer not very permeable, or accessible, to reactive oxygenated species.
- the elastomeric, low T g block can be oxidation resistant.
- the composition described herein may further include a bioactive agent.
- the composition described herein can be used for coating an implantable device such as a stent or for controlled delivery of a bioactive agent.
- Figure 1 is a scheme of forming a conjugate of polystyrene-polyisobutylene-polystyrene block copolymer with poly(ethylene glycol) (PEG).
- PEG poly(ethylene glycol)
- Figure 2 is a scheme of forming a conjugate of polystyrene-polyisobutylene-polystyrene block copolymer with 4-amino-2,2,6,6-tetramethylpiperidine-l -oxide (4-amino-TEMPO).
- a biobeneficial composition for coating an implantable device or delivery of a bioactive agent comprises a first block copolymer and a biobeneficial polymer.
- the biobeneficial composition may comprise a first block copolymer and a second block copolymer, the second block copolymer comprising a biobeneficial component and another component that is either water insoluble or miscible with the first block copolymer.
- the first block copolymer has a block with a T g below about body temperature and another block with a T g above about body temperature or that has considerable crystallinity with a T m above about body temperature.
- the block with a T g below about body temperature has an amorphous structure and is elastomeric. Functionally, the elastomeric, low T g block provides for flexibility, and the block with T g or T m above about body temperature acts as a virtual crosslink.
- the composition described herein may further include a bioactive agent.
- T g as used herein generally refers to the temperature at which the amorphous domains of a polymer change from a brittle vitreous state to a plastic state at atmospheric pressure. In other words, T g corresponds to the temperature where the onset of segmental motion in the chains of the polymer occurs, and it is discernible in a heat-capacity-versus-temperature graph for a polymer.
- T g of a given polymer can be dependent on the heating rate and can be influenced by the thermal history of the polymer. Furthermore, polymer chemical structure heavily influences T g by affecting polymer mobility. Generally, flexible main-chain components lower T g and bulky side groups raise T g . Similarly, increasing flexible-side-group length lowers T g and increasing main- chain polarity increases T g . Additionally, the presence of crosslinks can increase the observed T g for a given polymer, and the presence of a drug or therapeutic agent can alter the T g of a polymer due to plasticization effects. The magnitude of these plasticization effects depends on the miscibility and compatibility of the drug and polymer and the loading of drug in the polymer.
- biobeneficial refers to an attribute of a material that increases the biocompatibility and/or bio-responses of a coating on an implantable device.
- water insoluble refers to an attribute of a material having a quality of being insoluble as understood by one of ordinary skill in the art.
- One indication of a material's being insoluble is the material having a solubility in water less than or equal to 1% (w/w) or 10 mg/gm at 37 °C and 1 atm.
- the composition described herein is elastomeric, but very oxidation resistant.
- the high T g block renders the first block copolymer not very permeable, or accessible, to reactive oxygenated species.
- the elastomeric, low T g block can be oxidation resistant.
- the elastomeric, low T g block can be a polyisobutyl block, which is oxidation resistant because every other carbon is a tertiary carbon. Free radicals and oxidants can attach and oxidize the CH 2 moieties of the polyisobutyl block forming hydroxyl and carbonyl groups.
- Free radicals and oxidants can attach and oxidize the CH 2 moieties of the polyisobutyl block forming hydroxyl and carbonyl groups.
- no secondary carbons are adjacent, making it impossible to form carbon-carbon double bonds in the polymer backbone. Consequently, the backbone of the polyisobutyl block will remain intact.
- composition described herein can be used for coating an implantable device such as a stent or for controlled delivery of a bioactive agent.
- the composition can also be used to make an implantable medical device.
- the composition disclosed herein comprises a conjugate of a first block copolymer comprising at least one elastomeric block having a T g below about body temperature and another block having a Tg or Tm above about body temperature with a biobeneficial polymer.
- the block having a T g above about body temperature has a structure of Formula I and the elastomeric block having a T g below about body temperature has a structure of Formula II:
- Formula I Formula II wherein R ls R , R 3 and R 4 are independently hydrogen, phenyl, methyl, ethyl, carboxylate, acrylate, or methacrylate provided that Ri, R 2 , R 3 and R camiot be all hydrogen;
- R 5 and R 7 or R 6 and R 8 are independently methyl, ethyl, propyl, butyl, benzyl, or phenyl; and
- R 6 and R 8 or R 5 and R 7 are independently hydrogen, methyl, ethyl, propyl, benzyl, or phenyl.
- the high Tg block can be polystyrene, poly(methyl methacrylate), poly(ethyl methacrylate), poly(propyl methacrylate), poly(isopropyl methacrylate), poly(4-methylstyrene), poly(alpha-methyl styrene), poly(benzyl methacrylate), poly(tert-butyl methaciylate), poly(chloro-styrene), or poly(bromo-styrene).
- Useful elastomeric, low T g block includes, poly(isobutylene), poly(n-butyl methacrylate), poly(n- hexyl methacrylate), poly(n-octyl methacrylate), poly(n-lauryl methacrylate), poly(2-ethylhexyl methacrylate), and poly(octadecyl methacrylate).
- the first block copolymer can be an A-B diblock copolymer or A-B-A or B-A-B triblock copolymer. In one embodiment, the first block copolymer has the following structure of formula III:
- the conjugate can have a structure of the following:
- biobeneficial polymers include, but are not limited to, poly(ethylene glycol) (PEG), poly(propylene glycol), PLURONICTM surfactants which are block copolymers based on ethylene oxide and propylene oxide, poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone), polyalkylene oxide, dextran, dextrin, sodium hyaluronate, hyaluronic acid, sulphonated poly(styrene), heparin, Elastin, Chitosan, poly(2-hydroxyethyl methacrylate), poly(3- hydroxypropyl methacrylamide), 4-amino-2,2',6,6'-tetrapiperidine oxide, stable nitroxides, super oxide dimutase mimics, free radical scavengers, and combination thereof.
- PEG poly(ethylene glycol)
- PLURONICTM surfactants which are block copolymers based on ethylene oxide and prop
- the biobeneficial can be conjugated to the high T g block of the block copolymer via a linkage, which can be a direct covalent bond, hydrogen bond, ionic bondor chelate.
- the linkage is covalent such, as through an amino linkage, an ester linkage, an ether linkage, a peptide linkage, an amide linkage, a urethane linkage, a carbonate linkage, via a carbon-carbon bond, a hydrazide linkage, a sulfonate linkage, a sulfone linkage, or a thiol ether linkage.
- the biobeneficial polymer can be attached to the high Tg block of the block copolymer via any method known in the art (see, for example, Michael Smith, Organic Synthesis, 2 nd Edition, McGraw-Hill, 2001).
- PEG is attached to polystyrene-polyisobutylene-polystyrene (SIS) triblock copolymer via reductive amination as shown in Figure 1.
- SIS polystyrene-polyisobutylene-polystyrene
- Figure 1 a Lewis acid catalyst
- the acylated SIS triblock copolymer is then subjected to reductive amination with commercially available mPEG- NH 2 (available from vendors such as Nektar) in the presence of a reducing agent such as sodium cyanoborohydride, forming a SIS-PEG conjugate as shown in Figure 1
- a small molecule such as 4-amino-2,2',6,6'-tetrapiperidine oxide (4- amino-TEMPO) can be attached to a SIS triblock copolymer as shown in Figure 2.
- the SIS triblock copolymer is first subjected to acylation in the presence of a Lewis acid such as A1C1 3 .
- the composition disclosed herein comprises a first block copolymer comprising a block with a T g above about body temperature and an elastomeric block with a T g below about body temperature and a second block copolymer comprising a biobeneficial component and another component which is water insoluble or miscible with the first block copolymer, which is described above.
- the component miscible with the first block copolymer is hydrophobic.
- Representative examples can include polystyrene- polyisobutylene-polystyrene block copolymer (SIS), polystyrene, polyisobutylene, polycaprolactone (PCL), poly(L-lactide), poly(D,L-lactide), poly(lactides), polylactic acid (PLA), poly(lactide-co-glycolide), poly(glycolide), polyalkylene, polyfluoroalkylene, polyhydroxyalkanoate, poly(3-hydroxybutyrate), poly(4-hydroxybutyrate), poly(3- hydroxy valerate), poly(3 -hydroxybutyrate-co-3 -hydroxy valerate), poly(3 -hydroxyhexanoate), poly(4-hyroxyhexanoate), mid-chain polyhydroxyalkanoate, poly (trimethylene carbonate), poly (ortho ester), polyphosphazenes, poly (phosphoester), poly(tyrosine derivedarylates), poly(
- the water insoluble component of the second copolymer includes, for example, polydimethyloxanone (PDMS), polyvinylidene fluoride (PVDF), polyhexafluoropropylene (HFP), polydimethylsiloxane, poly (vinylidene fluoride-co- hexafluoropropylene) (PVDF-HFP), poly (vinylidene fluoride-co-chlorotrifluoroethylene) (PVDF-CTFE), poly(butyl methacrylate), poly(methyl methacrylate), poly(methacrylates), poly(vinyl acetate), poly(ethylene-co-vinyl acetate), poly(ethylene-co-vinyl alcohol), poly(ester urethanes), poly(ether-urethanes), poly(carbonate-urethanes), poly(silicone-urethanes), poly(urea- urethanes) and a combination thereof.
- PDMS polydimethylo
- the second block copolymer comprising a biobeneficial component is SIS-PEG, polystyrene-PEG, polyisobutylene-PEG, PCL-PEG, PLA-PEG, PMMA-PEG, PDMS- PEG, PVDF-PEG, SIS-hyaluronic acid (HA), polystyrene-HA, polyisobutylene-HA, PCL-HA, PLA-HA, PMMA-HA, PVDF-HA, SIS-heparin, polystyrene-heparin, polyisobutylene-heparin, PCL-heparin, PLA-heparin, PMMA-heparin, or PVDF-heparin.
- SIS-PEG SIS-PEG, polystyrene-PEG, polyisobutylene-PEG, PCL-PEG, PLA-PEG, PMMA-PEG, PDMS- PEG, PVDF-PEG, SIS-hyaluronic acid (HA), poly
- a conjugate is formed by combining one material, e.g., a polymer, with one or more other materials, e.g., a polymer of different nature, by ionic interaction, hydrogen bonding, or covalent bonding.
- the conjugate can be, for example, a block copolymer, an adduct, ion pair, polyelectrolyte complex, or chelate.
- Active Agents In accordance with a further embodiment of the invention, the composition described herein may optionally include one or more active agents.
- the active agent can be for inhibiting the activity of vascular smooth muscle cells. More specifically, the active agent can be aimed at inhibiting abnormal or inappropriate migration and/or proliferation of smooth muscle cells for the inhibition of restenosis.
- the active agent can also include any substance capable of exerting a therapeutic, prophylactic or diagnostic effect.
- the active agent can be for enhancing wound healing in a vascular site or improving the structural and elastic properties of the vascular site.
- active agents include antiproliferative substances such as actinomycin D, or derivatives and analogs thereof (manufactured by Sigma-Aldrich 1001 West Saint Paul Avenue, Milwaukee, WI 53233; or COSMEGEN available from Merck). Synonyms of actinomycin D include dactinomycin, actinomycin IV, actinomycin I 1 ⁇ actinomycin Xi, and actinomycin .
- the active agent can also fall under the genus of antineoplastic, anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, antiallergic and antioxidant substances.
- antineoplastics and/or antimitotics include paclitaxel (e.g. TAXOL ® by Bristol-Myers Squibb Co., Stamford, Conn.), docetaxel (e.g. Taxotere ® , from Aventis S.A., Frankfurt, Germany) methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.
- Adriamycin ® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin e.g. Mutamycin ® from Bristol-Myers Squibb Co., Stamford, Conn.
- antiplatelets, anticoagulants, antifibrin, and antithrombins include sodium heparin, low molecular weight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein Ilb/IIIa platelet membrane receptor antagonist antibody, recombinant hirudin, and thrombin inhibitors such as Angiomax a (Biogen, Inc., Cambridge, Mass.).
- cytostatic or antiproliferative agents examples include angiopeptin, angiote ⁇ sin converting enzyme inhibitors such as captopril (e.g. Capoten ® and Capozide ® from Bristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril (e.g.
- calcium channel blockers such as nifedipine), colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand name Mevacor ® from Merck & Co., Inc., Whitehouse Station, NJ), monoclonal antibodies (such as those specific for Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors, suramin, serotonin blockers, steroids, thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), and nitric oxide.
- PDGF Platelet-Derived Growth Factor
- an antiallergic agent is permirolast potassium.
- Other therapeutic substances or agents which may be appropriate include alpha-interferon, and genetically engineered epithelial cells. The foregoing substances are listed by way of example and are not meant to be limiting. Other active agents which are currently available or that may be developed in the future are equally applicable.
- Such other active agents include, for example, any anti-cancers, anti-genesis, antibiotics, anti-fungal agents and antibodies, proteins, peptides, anti-inflammatory agents, steroidal anti-inflammatory agents, antivirals, anticancer drugs, free radical scavengers, Everolimus, sirolimus, sirolimus derivatives, paclitaxel, estradiol, nitric oxide donors, super oxide dismutases, super oxide dismutases mimics, 4-amino-2,2,6,6-tetramethylpiperidine-l-oxyl (4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2- hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin, ABT-578, clobetasol, cytostatic agents, and a combination thereof.
- any anti-cancers
- the dosage or concentration of the active agent required to produce a favorable therapeutic effect should be less than the level at which the active agent produces toxic effects and greater than the minimum level at which therapeutic results are obtained.
- the dosage or concentration of the active agent required to inhibit the desired cellular activity of the vascular region can depend upon factors such as the particular circumstances of the patient; the nature of the trauma; the nature of the therapy desired; the time over which the administered ingredient resides at the vascular site; and if other active agents are employed, the nature and type of those agents or combinations of those agents.
- Therapeutic effective dosages can be determined empirically in vivo, for example by infusing vessels from suitable animal model systems and using immunohistochemical, fluorescent or electron microscopy methods to detect the agent and its effects, or by conducting suitable in vitro studies.
- radiopaque elements include, but are not limited to, gold, tantalum, and platinum.
- An example of a radioactive isotope is 32 P.
- Sufficient amounts of such substances may be dispersed in the composition such that the substances are not present in the composition as agglomerates or floes.
- the coating involves dissolving or suspending the composition, or one or more components thereof, in a solvent or solvent mixture to form a solution, suspension, or dispersion of the composition or one or more components thereof, applying the solution or suspension to an implantable device, and removing the solvent or solvent mixture to form a coating or a layer of coating.
- Suspensions or dispersions of the composition described herein can be in the form of latex or emulsion of microparticles having a size between 1 nanometer and 100 microns, preferably between 1 nanometer and 10 microns.
- Heat and/or pressure treatment can be applied to any of the steps involved herein.
- the coating described here can be subjected to further heat and/or pressure treatment.
- the composition can be coated onto the implantable device in the form of a single layer of coating or components of the composition can be coated onto the device in the form of separate layers of coating.
- solvent refers to a liquid substance or composition that is compatible with the polymer and is capable of dissolving or suspending the polymeric composition or one or more components thereof at a desired concentration.
- solvents include chloroform, acetone, water (buffered saline), dimethylsulfoxide (DMSO), propylene glycol monomethyl ether (PM,) iso-propylalcohol (IP A), n-propyl alcohol, 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
- implantable devices include self-expandable stents, balloon-expandable stents, stent-grafts, grafts (e.g., aortic grafts), artificial heart valves, cerebrospinal fluid shunts, pacemaker electrodes, and endocardial leads (e.g., FINELINE and ENDOTAK, available from Guidant Corporation, Santa Clara, CA).
- the underlying structure of the device can be of virtually any design.
- the device can be made of a metallic material or an alloy such as, but not limited to, cobalt chromium alloy (ELGILOY), stainless steel (316L), high nitrogen stainless steel, e.g., BIODUR 108, cobalt chrome alloy L-605, "MP35N,” “MP20N,” ELASTINITE (Nitinol), tantalum, nickel-titanium alloy, platinum-iridium alloy, gold, magnesium, or combinations thereof.
- ELGILOY cobalt chromium alloy
- 316L stainless steel
- high nitrogen stainless steel e.g., BIODUR 108, cobalt chrome alloy L-605, "MP35N,” “MP20N,” ELASTINITE (Nitinol), tantalum, nickel-titanium alloy, platinum-iridium alloy, gold, magnesium, or combinations thereof.
- BIODUR 108 cobalt chrome alloy L-605, "MP35N,” “MP20N,” ELASTINITE (Nitinol), tantalum, nickel-tit
- the implantable device is a stent.
- the compositions described herein can be coated onto a bare metallic or polymeric implantable device or on top of a drug eluting coating on the implantable device. Method of Use In accordance with embodiments of the invention, a composition in the various embodiments as described above can be applied to an implantable device or prosthesis, e.g., a stent.
- the agent will remain on the medical device such as a stent during delivery and expansion of the device, and released at a desired rate and for a predetermined duration of time at the implantation site.
- the medical device is a stent.
- a stent having the above-described coating is useful for a variety of medical procedures, including, by way of example, treatment of obstructions caused by tumors in bile ducts, esophagus, trachea/bronchi and other biological passageways.
- a stent having the above- described coating is particularly useful for treating occluded regions of blood vessels caused by atherosclerosis, or abnormal or inappropriate migration and proliferation of smooth muscle cells, thrombosis, and restenosis.
- Stents may be placed in a wide variety of blood vessels, both arteries and veins. Representative examples of sites include the iliac, renal, and coronary arteries.
- the implantable device comprising a coating described herein can be used to treat an animal having a condition or disorder that requires a treatment. Such an animal can be treated by, for example, implanting a device described herein in the animal. Preferably, the animal is a human being.
- Exemplary disorders or conditions that can be treated by the method disclosed herein include, but not limited to, occlusive atherosclerotic lesions in the coronary vasculature, neointimal hyperplasia in the coronary arteries, restenosis in the coronary arteries, vulnerable plaques of the coronary arteries, atherosclerosis in the renal arteries, atherosclerosis in the carotid arteries, atherosclerosis in the neurovasculature, atherosclerosis in the iliac arteries, atherosclerosis in the femoral arteries, atherosclerosis in the popliteal arteries, atherothrombosis, and occlusive tumors of the prostate, liver, or gastrointestinal tract.
- Example 1 The polymer of Formula IV as a topcoat in a drug eluting stent coating for the controlled release of paclitaxel from a stent.
- a first composition is prepared by mixing the following components:
- the first composition is applied onto the surface of bare 12 mm small VISIONTM stent (available from Guidant Corporation). Coating is sprayed and dried to form a primer layer.
- a spray coater is used having a 0.014 round nozzle maintained at about body temperature with a feed pressure 2.5 psi (0.17 atm) and an atomization pressure of about 15 psi (1.02 atm). Coating is applied at 20 ⁇ g per pass, in between which the stent is dried for 10 seconds in a flowing air stream at 50C. Approximately 110 ⁇ g of wet coating is applied.
- the stents are baked at 50C for one hour, yielding a primer layer composed of approximately 100 ⁇ g of PBMA.
- a drug reservoir layer is applied onto the primer layer, using the same spraying technique, equipment, and formulation used for the applying the primer.
- a second composition is prepared by mixing the following components:
- Example 2 The polymer of Formula IV is used as a matrix in a drug eluting stent coating for the controlled release of paclitaxel from a stent.
- a first composition is prepared by mixing the following components:
- the first composition is applied onto the surface of bare 12 mm small VISIONTM stent (available from Guidant Corporation). Coating is sprayed and dried to form a primer layer.
- a spray coater is used having a 0.014 round nozzle maintained at about body temperature with a feed pressure 2.5 psi (0.17 atm) and an atomization pressure of about 15 psi (1.02 atm). Coating is applied at 20 ⁇ g per pass, in between which the stent is dried for 10 seconds in a flowing air stream at 50C. Approximately 110 ⁇ g of wet coating was applied.
- the stents are baked at 50C for one hour, yielding a primer layer composed of approximately 100 ⁇ g of PBMA.
- a drug reservoir layer is applied onto the primer layer, using the same spraying technique, equipment, and formulation used for the applying the primer.
- grafting of PEG is carried out using an amino-terminated mPEG of molecular weight of 550 Daltons. Enough PEG derivative is conjugated so that the final composition is 5% by weight PEG.
- this composition namely: (a) 2.0 mass% of (IV) as described above,
- This composition can be applied onto the primer layer to form a drug reservoir layer. Using the same spraying technique and equipment used for applying the drug reservoir layer. Approximately 280 ⁇ g of wet is applied followed by baking at 50 °C for one hour, yielding a 250 ⁇ g reservoir layer of the polymer of Formula IV to act as a reservoir polymer with higher drug permeability than the polymer of formula III.
- Example 3 The polymer of Formula IV as a topcoat in a drug eluting stent coating for the controlled release of everolimus from a stent.
- a first composition is prepared by mixing the following components:
- the first composition is applied onto the surface of bare 12 mm small VISIONTM stent
- a spray coater is used having a 0.014 round nozzle maintained at about body temperature with a feed pressure 2.5 psi (0.17 atm) and an atomization pressure of about 15 psi (1.02 atm). Coating is applied at 10 ⁇ g per pass, in between which the stent is dried for 10 seconds in a flowing air stream at 50C. Approximately 120 ⁇ g of wet coating was applied. The stents are baked at 140C for one hour, yielding a primer layer composed of approximately 100 ⁇ g of EVAL.
- a drug reservoir layer is applied onto the primer layer, using the same spraying technique, equipment, and polymer as used in applying the primer: (a) 2.0 mass% of EVAL E-151 A as described above,
- This composition can be applied onto the primer layer to form a drug reservoir layer. Using the same spraying technique and equipment used for applying the drug reservoir layer. Approximately 240 ⁇ g of wet is applied followed by baking at 80C for 30 minutes, yielding a 223 ⁇ g reservoir layer. A polymer of the current invention is used as a topcoat layer. Starting with the same polymer of Formula III used in the drug reservoir, grafting of PEG is carried out using an amino-terminated mPEG of molecular weight of 500 Daltons. Enough PEG derivative is conjugated so that the final composition is 20% by weight PEG. Using this composition, namely: (a) 2.0 mass% of (IV) as described above, and
- This composition can be applied onto the drug reservoir layer to form a topcoat layer. Using the same spraying technique and equipment used for applying the drug reservoir layer. Approximately 120 ⁇ g of wet topcoat is applied followed by baking at 50C for one hour, yielding a 100 ⁇ g topcoat layer of Formula IV to act as a biobeneficial topcoat. While particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that changes and modifications can be made without departing from this invention in its broader aspects. Therefore, the appended claims are to encompass within their scope all such changes and modifications as fall within the true spirit and scope of this invention.
Abstract
Description
Claims
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US8871883B2 (en) | 2002-12-11 | 2014-10-28 | Abbott Cardiovascular Systems Inc. | Biocompatible coating for implantable medical devices |
JP2009525812A (en) * | 2006-02-07 | 2009-07-16 | テファ, インコーポレイテッド | Polymer degradable drug eluting stent and coating |
US9592325B2 (en) | 2006-02-07 | 2017-03-14 | Tepha, Inc. | Polymeric, degradable drug-eluting stents and coatings |
JP2009538700A (en) * | 2006-05-31 | 2009-11-12 | アボット カーディオヴァスキュラー システムズ インコーポレイテッド | Method of manufacturing an implantable medical device that reduces the probability of delayed inflammatory reaction |
JP2010501264A (en) * | 2006-08-25 | 2010-01-21 | ボストン サイエンティフィック リミテッド | Medical device with improved mechanical performance |
JP2010520781A (en) * | 2007-03-05 | 2010-06-17 | ボストン サイエンティフィック サイムド,インコーポレイテッド | Medical device with improved performance |
JP2010528766A (en) * | 2007-06-05 | 2010-08-26 | アボット カルディオバスキュラー システムズ インコーポレーテッド | Implantable medical device having an elastomeric block copolymer coating |
JP2010532216A (en) * | 2007-06-29 | 2010-10-07 | アボット カーディオヴァスキュラー システムズ インコーポレイテッド | Biodegradable triblock copolymers for implantable devices |
US9090745B2 (en) | 2007-06-29 | 2015-07-28 | Abbott Cardiovascular Systems Inc. | Biodegradable triblock copolymers for implantable devices |
US8961591B2 (en) | 2008-08-07 | 2015-02-24 | Tepha, Inc. | Polymeric, degradable drug-eluting stents and coatings |
EP4056207A4 (en) * | 2019-11-26 | 2023-12-13 | Shanghai MicroPort Medical (Group) Co., Ltd. | Drug-loaded implanted medical device and preparation method therefor |
Also Published As
Publication number | Publication date |
---|---|
US8426476B2 (en) | 2013-04-23 |
EP1686924A2 (en) | 2006-08-09 |
US20050112172A1 (en) | 2005-05-26 |
US20100330145A1 (en) | 2010-12-30 |
US8784859B2 (en) | 2014-07-22 |
US20130330390A1 (en) | 2013-12-12 |
EP1686924A4 (en) | 2011-09-14 |
US20130259911A1 (en) | 2013-10-03 |
US7807722B2 (en) | 2010-10-05 |
WO2005053571A3 (en) | 2006-04-27 |
US20100330259A1 (en) | 2010-12-30 |
US8530526B2 (en) | 2013-09-10 |
US20100331969A1 (en) | 2010-12-30 |
US8501211B2 (en) | 2013-08-06 |
JP2007520260A (en) | 2007-07-26 |
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