Patent Grant
8673334
This invention relates to implantable medical devices such as stents. More particularly, the invention relates to materials that can be used to coat stents.
In the field of medical technology, there is frequently a necessity to administer drugs locally. To provide an efficacious concentration to the treatment site, systemic administration of medication often produces adverse or toxic side effects for the patient. Local delivery is a preferred method of treatment in that smaller total levels of medication are administered in comparison to systemic dosages, but are concentrated at a specific site. For the treatment of vascular lesions, stents can be modified with a polymeric coating to provide local drug delivery capabilities.
Examples of polymers that can be used to coat stents or other implantable devices include hydrophobic polymers, for example, poly(meth)acrylates, such as poly(n-butyl methacrylate) (PBMA) and copolymers or terpolymers having units derived from n-butyl methacrylate (BMA). PBMA and BMA-based coatings can provide effective control of the rate of release of a drug from a stent. In addition, PBMA and BMA-based polymers are biocompatible, have good adhesion to the underlying stent surface, are easily processable, and possess good physical and mechanical properties such as ability to withstand elongation, compression, and shear that the stent undergoes during crimping onto the catheter, delivery to the lesion site, and expansion.
The properties of PBMA and BMA-based stent coatings can be improved, however. For example, permeability of such coatings can be too low, particularly for drugs having higher molecular weights, leading to potentially insufficient supply of the drug to the diseased site. An ability to better regulate the rate of release through the coatings is desired. The present invention provides such coatings.
An implantable medical device comprising a coating is provided, the coating includes a mixture of at least one poly(meth)acrylate and at least one polyalkylene glycol, wherein the macromolecular chains of the poly(meth)acrylate and the polyalkylene glycol form a physically entangled or interpenetrating system. Examples of the poly(meth)acrylate include poly(methyl methacrylate), poly(ethyl methacrylate), poly(n-propyl methacrylate), poly(iso-propyl methacrylate), poly(n-butyl methacrylate), poly(iso-butyl methacrylate), poly(tert-butyl methacrylate), poly(methyl acrylate), poly(ethyl acrylate), poly(n-propyl acrylate), poly(iso-propyl acrylate), poly(n-butyl acrylate), poly(iso-butyl acrylate), and mixtures thereof. Examples of the polyalkylene glycol include poly(ethylene glycol), poly(ethylene oxide), poly(propylene glycol), poly(ethylene oxide-co-propylene oxide), poly(trimethylene glycol), poly(tetramethylene glycol), and mixtures thereof.
An implantable medical device comprising a coating is provided, the coating includes a mixture of at least one hydrophobic polymer and at least one polymeric hydrophilic compound, wherein the macromolecular chains of the hydrophobic polymer and the hydrophilic compound form a physically entangled or interpenetrating system. The hydrophobic polymer can include poly(meth)acrylates, vinyl polymers, polyolefins, halogenanated polymers, polymers having urethane groups, polybutyrals, nylon, silicones, polycarbonate, or polysulfone. The polymeric hydrophilic compound can include polyalkylene glycols, hyaluronic acid, chondroitan sulfate, chitosan, glucosaminoglucans, dextran, dextrin, dextran sulfate, cellulose acetate, carboxymethyl cellulose, hydroxyethyl cellulose, cellulosics, polypeptides, poly(2-hydroxyethyl methacrylate), polyacrylamide, polyacrylimide, poly(ethylene amine), poly(allyl amine), poly(vinyl pyrrolidone), poly(vinyl alcohol), poly(acrylic acid), poly(methacrylic acid), acrylic acid copolymers, methacrylic acid copolymers, polyvinyl alkyl ethers, non-ionic tetrafunctional block-copolymer surfactants, gelatin, collagen, albumin, chitin, heparin, elastin, fibrin, and mixtures thereof.
A medical article comprising an implantable substrate and a coating is provided, the coating includes a bulk polymer, an additive polymer in less quantity in the coating that the bulk polymer, the additive polymer being entangled or interpenetrated with the bulk polymer, and a drug.
A method for fabricating a coating for an implantable medical device is provided, the method comprises forming a coating on the device, the coating including a mixture of at least one hydrophobic polymer and at least one polymeric hydrophilic compound, wherein the macromolecular chains of the hydrophobic polymer and the hydrophilic compound form a physically entangled or intertwined system.
A coating for an implantable medical device, such as a stent, can include an optional primer layer, a drug-polymer layer, and an optional topcoat layer. The drug-polymer layer can be applied directly onto at least a part of the stent surface to serve as a reservoir for an active agent or a drug which is incorporated into the drug-polymer layer. An optional primer layer can be applied between the stent and the drug-polymer layer to improve the adhesion of the drug-polymer layer to the stent. An optional topcoat layer can be applied over at least a part of the drug-polymer layer to reduce the rate of release of the drug from the reservoir.
The topcoat layer, if used, is the outermost layer of the stent coating. If the topcoat layer is not used, the drug-polymer layer is the outermost layer of the stent coating. The drug-polymer and/or topcoat layer of the stent coating can include at least one hydrophobic polymer. To regulate a rate of release of the drug from the drug-polymer layer the hydrophobic polymer(s) can be physically mixed or blended with at least one polymeric hydrophilic additive to form a polymer system where the macromolecular chains of the hydrophobic polymer and the hydrophobic additive are physically entangled, miscible, and/or interpenetrating. This polymer system can be, in one embodiment, the outermost region or layer of the coating.
Hereinafter, the hydrophobic polymer is also referred to as “polymer,” and polymeric hydrophilic additive is also referred to as “additive.” The term “physically entangled” is defined hereinafter as a polymer/additive composition in which neither the polymer nor the additive forms a separate phase domain having a size larger than about 100 nanometers, such as the size larger than about 200 nanometers, for example, larger than about 300 nanometers. The size of the domain is determined by the largest linear dimension of the domain particle, e.g., by the diameter of a particle in case the domain particles are spheres. The definition of “physically entangled” also includes a condition that once the polymer and the additive have become physically entangled, they do not disentangle but remain physically entangled for the duration of the service of the coating or until the drug has been released from the coating.
The hydrophobic polymer and the hydrophobic additive are defined hereinafter as “miscible” if the thermogram of the polymer/additive mixture shows substantially no thermal transitions attributable to either the essentially pure polymer or the essentially pure additive. The thermogram can be obtained by a standard method of thermal analysis known to those having ordinary skill in the art, for example, by the method of differential scanning calorimetry.
The term “interpenetrating” is defined as the polymer/additive system where the polymer and the additive form an interpenetrating polymer network (IPN). The definition of the IPN used by the International Union of Pure and Applied Chemistry (IUPAC) is adopted herein. The IUPAC describes the IPN as a polymer comprising two or more networks which are at least partially interlaced on a molecular scale, to form both chemical and physical bonds between the networks. The networks of an IPN cannot be separated unless chemical bonds are broken. In other words, an IPN structure represents two or more polymer networks that are partially chemically cross-linked and partially physically entangled.
To define the terms “hydrophobic” and “hydrophilic” for the purposes of the present invention, one of the two criteria can be used. According to one criterion, a component in the polymer/additive system (i.e., the polymer or the additive) can be classified by the value of the component's equilibrium water adsorption. Whichever component in the polymer/additive system has the greater value of the equilibrium water adsorption at room temperature is considered hydrophilic and the other component is considered hydrophobic. If more than two components are used in the polymer/additive system, then each can be ranked in order of its equilibrium water adsorption value. In one embodiment, the polymer is considered hydrophobic if it has an equilibrium water adsorption less than 10 mass % at room temperature, and the additive is considered hydrophilic if it has an equilibrium water adsorption at room temperature of 10 mass % or greater.
According to another criterion, a component in the polymer/additive system can be classified by the value of the component's Hildebrand solubility parameter δ. The term “Hildebrand solubility parameter” refers to a parameter measuring the cohesion of a substance and is determined as follows:
δ=(ΔE/V)1/2
Whichever component in the polymer/additive system has lower δ value compared to the δ value of the other component in the blend is designated as a hydrophobic component, and the other component with higher δ value is designated as hydrophilic. If more than two components are used in the blend, then each can be ranked in order of its δ value. In one exemplary embodiment, the δ value defining the boundary between the hydrophobic and hydrophilic components of the polymer/additive system can be about 10.7 (cal/cm3)1/2.
Hydrophobic substances typically have a low δ value. In one embodiment, a component in the polymer/additive system that is “hydrophobic” can have a Hildebrand solubility parameter lower than about 10.7 (cal/cm3)1/2. A component in the polymer/additive system that is “hydrophilic” can have a solubility parameter greater than about 10.7 (cal/cm3)1/2.
To make the polymer/additive mixture, the polymer can be blended with the additive and the blend can be dissolved in a solvent or in a system comprising a mixture of solvents. The term “dissolved” means that the polymer/additive blend, when combined with a suitable solvent or a mixture of solvents, is capable of forming a system which can be applied on a stent by a common technique, such as spraying or dipping. The solvent or a mixture of solvents can be selected by those having ordinary skill in the art depending, among other factors, on the nature of the polymer and the additive.
The polymer/additive solution can be then applied on the stent by a commonly known technique known to those having ordinary skill in the art, for example, by spraying or dipping, followed by drying, for example, by baking. The polymer/additive solution can be used to form the topcoat layer and/or the drug-polymer layer of the stent coating.
The combined mass concentration of the polymer and the additive in the polymer/additive solution can be between about 1% and about 10%, for example, about 2%. A ratio between the hydrophobic polymer and the polymeric hydrophilic additive in the polymer/additive solution can be between about 99:1 and about 9:1, such as between about 74:1 and about 14:1, more narrowly between about 49:1 and about 19:1. For example, for a polymer/additive solution containing about 2 mass % of the hydrophobic polymer, the concentration of the polymeric hydrophilic additive can be between about 0.04 and about 0.1 mass % of the total mass of the solution.
The polymer/additive solution can be prepared by various alternative methods. For example, the hydrophobic polymer and the polymeric hydrophilic additive can be dissolved separately to obtain a hydrophobic polymer solution and a polymeric hydrophilic additive solution, followed by combining the two solutions to form the polymer/additive solution. Alternatively, the hydrophobio polymer can be dissolved first to form the hydrophobic polymer solution, followed by adding the polymeric hydrophilic additive to the hydrophobic polymer solution to form the polymer/additive solution. As another alternative, the additive can be dissolved first to form the additive solution followed by adding the polymer to form the polymer/additive solution.
Examples of hydrophobic polymers include poly(meth)acrylates. The term “poly(meth)acrylates” refers to both polymethacrylates and polyacrylates. Examples of poly(meth)acrylates that can be used include homo- and copolymers of butyl methacrylate, for example PBMA, poly(vinylidene fluoride-co butyl methacrylate), or poly(methyl methacrylate-co-butyl methacrylate). Representative examples of other hydrophobic polymers that can be used in practice of the present invention include the following polymers and mixtures thereof:
Representative examples of polymeric hydrophilic additives that can be used in practice of the present invention include hyaluronic acid, chondroitan sulfate, chitosan, glucosaminoglucans, dextran, dextrin, dextran sulfate, cellulose acetate, carboxymethyl cellulose, hydroxyethyl cellulose, cellulosics, poly(ethylene glycol)(PEG), poly(ethylene oxide), poly(propylene glycol), PLURONIC, TETRONIC, poly(trimethylene glycol), poly(tetramethylene glycol), polypeptides, poly(2-hydroxyethyl methacrylate), polyacrylamide, polyacrylimide, poly(ethylene amine), poly(allyl amine), poly(vinyl pyrrolidone), poly(vinyl alcohol), poly(acrylic acid), poly(methacrylic acid), acrylic acid copolymers, methacrylic acid copolymers, polyvinyl alkyl ethers such as poly(vinylmethyl ether) or poly(vinylethyl ether); gelatin, collagen, albumin, chitin, heparin, elastin, fibrin and mixtures thereof. PLURONIC is a trade name of a poly(ethylene oxide-co-propylene oxide). TETRONIC is a trade name of a family of non-ionic tetrafunctional block-copolymer surfactants. PLURONIC and TETRONIC are available from BASF Corp. of Parsippany, N.J.
To achieve the physical entanglement of the hydrophobic polymer and polymeric hydrophilic additive, at least one polymer and at least one additive can be blended together in a common solvent system that includes at least one very volatile solvent, followed by applying the solution onto a stent, for example, by spraying. As used herein, “very volatile solvent” means a solvent that has a vapor pressure greater than 30 Torr at ambient temperature. Examples of very volatile solvent include acetone and methyl ethyl ketone. Alternatively, to physically entangle the hydrophobic polymer and polymeric hydrophilic additive, the polymer and the additive can be blended in the melt, and then applied to the stent from the melt, for example by curtain coating.
One way of forming an interpenetrating system of the hydrophobic polymer and polymeric hydrophilic additive is by blending the polymer and the additive in a solvent, or solvent blend, in which both components are soluble. The solution can be applied onto a stent, for example, by spraying, followed by the removal of the solvent by drying. For the polymer and the additive which are capable of forming an interpenetrating system, the polymers and the additive are expected to interpenetrate while still in solution, and to remain interpenetrated upon solvent removal.
Alternatively, to form an interpenetrating system of the hydrophobic polymer and polymeric hydrophilic additive, the polymer and additive, which can be polymerized according to two different mechanisms, can be selected. For example, the hydrophobic component can be a carbonate urethane that is polymerized by condensation reactions between isocyanate and hydroxyl groups, while the hydrophilic additive can be poly(2-hydroxyethyl methacrylate) that polymerizes by a free radical mechanism. The monomers may be dissolved in a common solvent system, applied to the stent, and then polymerized directly on the stent.
As another alternative way of forming an interpenetrating system of the hydrophobic polymer and polymeric hydrophilic additive, a high molecular weight polymer and additive can be selected, each component having reactive or associative groups that can interact with the reactive or associative groups of the other component. For example, such hydrophilic additive as hydroxy terminated PEG can be blended with a high molecular weight, hydrophobic polyurethane with active isocyanate groups along the backbone. The additive and the polymer can be blended in solution, sprayed onto a stent, followed by curing. Although sometimes the two components may be not miscible, the covalent bonds between them can still prevent phase separation.
To facilitate the formation of an entangled and/or interpenetrating hydrophobic polymer-polymeric hydrophilic additive system, the polymer and the additive can be selected in such a way that the chain lengths of the polymer and the additive, as determined by degree of polymerization, are such as to promote the entanglement and/or interpenetration of the macromolecules of the polymer and the additive. The term “degree of polymerization” refers to a number of repeating monomeric units in a single macromolecule. The chain lengths that promote the formation of an entangled and/or interpenetrating network can be such that the contour length of the hydrophilic additive lies in the range of between about 10% and about 100% of the contour length of the hydrophobic polymer, for example, between 50% and 100%, such as 80%. The term “contour length” refers to the combined length of all bonds along the main chain (the backbone) of a macromolecule. The contour length can be approximated as the degree of polymerization multiplied by the number of bonds in the repeat unit. An average bond length of about 1.4 Å can be used for the computation. The following example can be used to illustrate how the molecular weights of the polymer and the additive can be chosen to achieve a proper ratio between the contour lengths of the polymer and the additive.
PBMA with a number-averaged molecular weight (Mn) of about 200,000, has a degree of polymerization of 1,408 and has 2 bonds in the polymer backbone per repeat unit. Thus, a contour length of a PBMA macromolecule is about 3,940 Å. Suitable hydrophilic additive to achieve entanglement can be PEG having contour lengths between about 394 Å and about 3,940 Å. PEG has 3 bonds per repeat unit, so for PEG having contour lengths between about 394 Å and about 3,940 Å, corresponding degree of polymerization is approximately between 131 and 1,313, and the corresponding Mn is between about 5,780 and about 57,800.
Generally, Mn of the hydrophobic polymer can be between about 50,000 and 1000,000 Daltons, for example, about 100,000 Daltons. The molecular weight of the hydrophilic additive can be between about 5,000 and about 100,000 Daltons, for example, about 40,000 Daltons. If PBMA is used as the hydrophobic polymer, the molecular weight of PBMA can be between about 100,000 and about 300,000 Daltons, for example, about 200,000 Daltons. If PEG is used as the hydrophilic additive being mixed with PBMA, the molecular weight of PEG can be between about 10,000 and about 60,000 Daltons, for example, about 20,000 Daltons.
The embodiments of the present invention are described in connection with a stent, e.g., balloon expandable or self-expandable stents; however, other implantable medical devices can also be coated. Examples of such implantable devices include 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 Corp. of Santa Clara, Calif.). 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), “MP35N,” “MP20N,” ELASTINITE (Nitinol), tantalum, nickel-titanium alloy, platinum-iridium alloy, gold, magnesium, or combinations thereof. “MP35N” and “MP20N” are trade names for alloys of cobalt, nickel, chromium and molybdenum available from Standard Press Steel Co. of Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum. Devices made from bioabsorbable or biostable polymers could also be used with the embodiments of the present invention. The device itself can be made in whole or in part from the disclosed polymeric blends.
For the drug-polymer layer, the coating can include an active agent or a drug. The drug can include any substance capable of exerting a therapeutic or prophylactic effect for a patient. The drug may include small molecule drugs, peptides, proteins, oligonucleotides, and the like. The drug could be designed, for example, to inhibit the activity of vascular smooth muscle cells. It can be directed at inhibiting abnormal or inappropriate migration and/or proliferation of smooth muscle cells to inhibit restenosis.
Examples of drugs include antiproliferative substances such as actinomycin D, or derivatives and analogs thereof (manufactured by Sigma-Aldrich of Milwaukee, Wis., or COSMEGEN available from Merck). Synonyms of actinomycin D include dactinomycin, actinomycin IV, actinomycin I1, actinomycin X1, and actinomycin C1. The active agent can also fall under the genus of antineoplastic, anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, antiallergic and antioxidant substances. Examples of such 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. Mutanycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples of such 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 IIb/IIIa platelet membrane receptor antagonist antibody, recombinant hirudin, and thrombin inhibitors such as Angiomax™ (Biogen, Inc., Cambridge, Mass.). Examples of such cytostatic or antiproliferative agents include angiopeptin, angiotensin converting enzyme inhibitors such as captopril (e.g. Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril (e.g. Prinivil® and Prinzide® from Merck & Co., Inc., Whitehouse Station, N.J.); 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, N.J.), 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 donors of nitric oxide. An example of an antiallergic agent is permirolast potassium. Other therapeutic substances or agents which may be appropriate include alpha-interferon, genetically engineered epithelial cells, tacrolimus, dexamethasone, and rapamycin and structural derivatives or functional analogs thereof, such as 40-O-(2-hydroxy)ethyl-rapamycin (known by the trade name of EVEROLIMUS available from Novartis), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.
The molecular weight of the drug can influence the choice of the molecular weights of the polymer and the additive, as well as the ratios between the polymer and the additive, since the release rate of the drugs having higher molecular weights is expected to be slower compared with the release rate of the drugs with lower molecular weights. To illustrate, when the PBMA/PEG topcoat system is used in conjunction with EVEROLIMUS (having molecular weight 958 Daltons), Mn of PBMA can be between about 90,000 Daltons and about 300,000 Daltons, for example, about 190,000 Daltons and Mn of PEG can be between about 6,000 Daltons and about 20,000 Daltons, for example, about 18,000 Daltons, and the mass ratio between PBMA and PEG can be between about 49:1 and about 9:1, for example, about 20:1. At the same time, in the case of estradiol (having molecular weight of 272), Mn of PBMA can be between about 150,000 Daltons and about 900,000 Daltons, for example, about 300,000 Daltons and Mn of PEG can be between about 10,000 Daltons and about 50,000 Daltons, for example, about 30,000 Daltons, and the mass ratio between PBMA and PEG can be between about 99:1 and about 25:1, for example about 49:1.
Embodiments of the present invention are further illustrated by the following examples.
A first polymer solution was prepared, the solution containing:
A second polymer solution was prepared, the solution containing:
The first polymer solution was combined with the second polymer solution to prepare a PBMA/PEG solution. The amount of the first and second polymer solutions were selected to obtain the PBMA/PEG solution having a mass ratio between PBMA and PEG of about 49:1.
The PBMA/PEG solution was cast on a glass slide, and the solvent was removed by drying at room temperature followed by baking at about 80° C. for about 1 hour. As a result, an adhered polymer film was formed on the glass slide. An optical micrograph of the dry PBMA/PEG film was taken in transmitted polarized light, as shown by
A PBMA/PEG solution was prepared as described in Example 1, except the mass ratio between PBMA and PEG in the PBMA/PEG solution was about 19:1. A polymer film was formed on a glass slide out of the PBMA/PEG solution as described in Example 1. An optical micrograph of the dry PBMA/PEG film was taken as described in Example 1. The micrograph is shown by
A PBMA/PEG solution was prepared as described in Example 1, except the mass ratio between PBMA and PEG in the PBMA/PEG solution was about 10:1. A polymer film was formed on a glass slide out of the PBMA/PEG solution as described in Example 1. An optical micrograph of the dry PBMA/PEG film was taken as described in Example 1. The micrograph is shown by
A first composition was prepared by mixing the following components:
(b) the balance, DMAC solvent.
The first composition was applied onto the surface of a bare 18 mm VISION stent (available from Guidant Corp.) by spraying and dried to form a primer layer. A spray coater was used, having a 0.014 fan nozzle maintained at about 60° C. with a feed pressure of about 0.2 atm (about 3 psi) and an atomization pressure of about 1.3 atm (about 20 psi). About 70 μg of the wet coating was applied. The wet coating was baked at about 140° C. for about 2 hours, yielding a dry primer layer.
A second composition was prepared by mixing the following components:
The second composition was applied onto the dried primer layer to form a drug-polymer layer, using the same spraying technique and equipment used for applying the primer layer. About 300 μg of the wet coating was applied, followed by drying, e.g., by baking as described above. The dry drug-polymer layer contained about 130 μg of EVEROLIMUS.
A third composition was prepared by mixing the following components:
The third composition was applied onto the dried drug-polymer layer, to form a topcoat layer, using the same spraying technique and equipment used for applying the primer and the drug-polymer layers. About 200 μg of the wet coating was applied, followed by drying, e.g., by baking as described above. The final amount of the dried topcoat was about 50 μg.
The kinetics of release of EVEROLIMUS in vitro was studied chromatographically (HPLC). To study the kinetics, three stents were coated as described above in this Example. The amount of EVEROLIMUS released from a stent coating having the PBMA-PEG topcoat was measured. The average of the data obtained from the three stents was used to plot a curve 1. As a control, two identical control stents were used, except the topcoat included only pure PBMA instead of PBMA-PEG. A control curve 2 was plotted using the average of the data obtained from the two control stents. The rate of release of EVEROLIMUS through the PBMA-PEG topcoat is about twice the rate of release through the PBMA topcoat.
A primer and drug-polymer layers can be formed on a stent as described in Example 4, but instead of EVEROLIMUS, rapamycin can be used. A topcoat composition can then be prepared by mixing the following components:
If desired, poly(tetramethylene glycol) (PTMG) can be used in the topcoat composition instead of PPG. The Mn of PTMG can also be about 40,000. A PPG/PTMG blend having any ratio between PPG and PTMG can also be optionally used instead of PPG. In this example, in the topcoat composition the mass ratio between PEG and PPG is 1:1. If desired, the amount of PPG or PTMG, or a mixture thereof can be up to about twice amount of PEG. Optionally, all of the PEG in the topcoat composition can be replaced with PPG or PTMG, or with a mixture thereof.
The topcoat composition can be applied onto the dried drug-polymer layer, to form a topcoat layer, using the same spraying technique and equipment used for applying the primer and the drug-polymer layers. About 200 μg of the wet coating can be applied, followed by drying, e.g., by baking as described above. The final amount of the dried topcoat can be about 50 μg.
A primer and drug-polymer layers can be formed on a stent as described in Example 4. A topcoat composition can then be prepared by mixing the following components
F127 PLURONIC is a difunctional poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymer terminating in primary hydroxyl groups. F127 PLURONIC has Mn of about 12,600.
The topcoat composition can be applied onto the dried drug-polymer layer, to form a topcoat layer, using the same spraying technique and equipment used for applying the primer and the drug-polymer layers. About 200 μg of the wet coating can be applied, followed by drying, e.g., by baking as described above. The final amount of the dried topcoat can be about 50 μg.
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.
This application is a divisional of U.S. application Ser. No. 10/431,711 filed 8 May 2003, now U.S. Pat. No. 7,279,174 which is incorporated by reference as if fully set forth, including any figures, herein.
| Number | Name | Date | Kind |
|---|---|---|---|
| 590263 | Henry | Sep 1897 | A |
| 2072303 | Herrmann et al. | Mar 1937 | A |
| 2386454 | Frosch et al. | Oct 1945 | A |
| 3773737 | Goodman et al. | Nov 1973 | A |
| 3849514 | Gray, Jr. et al. | Nov 1974 | A |
| 4226243 | Shalaby et al. | Oct 1980 | A |
| 4329383 | Joh | May 1982 | A |
| 4343931 | Barrows | Aug 1982 | A |
| 4529792 | Barrows | Jul 1985 | A |
| 4611051 | Hayes et al. | Sep 1986 | A |
| 4656242 | Swan et al. | Apr 1987 | A |
| 4733665 | Palmaz | Mar 1988 | A |
| 4752624 | Kim et al. | Jun 1988 | A |
| 4800882 | Gianturco | Jan 1989 | A |
| 4882168 | Casey et al. | Nov 1989 | A |
| 4883699 | Aniuk et al. | Nov 1989 | A |
| 4886062 | Wiktor | Dec 1989 | A |
| 4931287 | Bae et al. | Jun 1990 | A |
| 4941870 | Okada et al. | Jul 1990 | A |
| 4977901 | Ofstead | Dec 1990 | A |
| 5019096 | Fox, Jr. et al. | May 1991 | A |
| 5079272 | Allegrezza et al. | Jan 1992 | A |
| 5100992 | Cohn et al. | Mar 1992 | A |
| 5112457 | Marchant | May 1992 | A |
| 5133742 | Pinchuk | Jul 1992 | A |
| 5163952 | Froix | Nov 1992 | A |
| 5165919 | Sasaki et al. | Nov 1992 | A |
| 5219980 | Swidler | Jun 1993 | A |
| 5258020 | Froix | Nov 1993 | A |
| 5272012 | Opolski | Dec 1993 | A |
| 5292516 | Viegas et al. | Mar 1994 | A |
| 5298260 | Viegas et al. | Mar 1994 | A |
| 5300295 | Viegas et al. | Apr 1994 | A |
| 5306501 | Viegas et al. | Apr 1994 | A |
| 5306786 | Moens et al. | Apr 1994 | A |
| 5328471 | Slepian | Jul 1994 | A |
| 5330768 | Park et al. | Jul 1994 | A |
| 5380299 | Fearnot et al. | Jan 1995 | A |
| 5417981 | Endo et al. | May 1995 | A |
| 5426158 | Mueller et al. | Jun 1995 | A |
| 5447724 | Helmus et al. | Sep 1995 | A |
| 5455040 | Marchant | Oct 1995 | A |
| 5462990 | Hubbell et al. | Oct 1995 | A |
| 5464650 | Berg et al. | Nov 1995 | A |
| 5485496 | Lee et al. | Jan 1996 | A |
| 5516881 | Lee et al. | May 1996 | A |
| 5569463 | Helmus et al. | Oct 1996 | A |
| 5578073 | Haimovich et al. | Nov 1996 | A |
| 5584877 | Myiake et al. | Dec 1996 | A |
| 5605696 | Eury et al. | Feb 1997 | A |
| 5607467 | Froix | Mar 1997 | A |
| 5609629 | Fearnot et al. | Mar 1997 | A |
| 5610241 | Lee et al. | Mar 1997 | A |
| 5616338 | Fox, Jr. et al. | Apr 1997 | A |
| 5624411 | Tuch | Apr 1997 | A |
| 5628730 | Shapland et al. | May 1997 | A |
| 5644020 | Timmermann et al. | Jul 1997 | A |
| 5649977 | Campbell | Jul 1997 | A |
| 5658995 | Kohn et al. | Aug 1997 | A |
| 5667767 | Greff et al. | Sep 1997 | A |
| 5670558 | Onishi et al. | Sep 1997 | A |
| 5674242 | Phan et al. | Oct 1997 | A |
| 5679400 | Tuch | Oct 1997 | A |
| 5700286 | Tartaglia et al. | Dec 1997 | A |
| 5702754 | Zhong | Dec 1997 | A |
| 5711958 | Cohn et al. | Jan 1998 | A |
| 5716981 | Hunter et al. | Feb 1998 | A |
| 5721131 | Rudolph et al. | Feb 1998 | A |
| 5723219 | Kolluri et al. | Mar 1998 | A |
| 5735897 | Buirge | Apr 1998 | A |
| 5746998 | Torchilin et al. | May 1998 | A |
| 5759205 | Valentini | Jun 1998 | A |
| 5776184 | Tuch | Jul 1998 | A |
| 5783657 | Pavlin et al. | Jul 1998 | A |
| 5788979 | Alt et al. | Aug 1998 | A |
| 5800392 | Racchini | Sep 1998 | A |
| 5820917 | Tuch | Oct 1998 | A |
| 5824048 | Tuch | Oct 1998 | A |
| 5824049 | Ragheb et al. | Oct 1998 | A |
| 5830178 | Jones et al. | Nov 1998 | A |
| 5837008 | Berg et al. | Nov 1998 | A |
| 5837313 | Ding et al. | Nov 1998 | A |
| 5849859 | Acemoglu | Dec 1998 | A |
| 5851508 | Greff et al. | Dec 1998 | A |
| 5854376 | Higashi | Dec 1998 | A |
| 5858746 | Hubbell et al. | Jan 1999 | A |
| 5865814 | Tuch | Feb 1999 | A |
| 5869127 | Zhong | Feb 1999 | A |
| 5873904 | Ragheb et al. | Feb 1999 | A |
| 5876433 | Lunn | Mar 1999 | A |
| 5877224 | Brocchini et al. | Mar 1999 | A |
| 5879713 | Roth et al. | Mar 1999 | A |
| 5902631 | Wang et al. | May 1999 | A |
| 5902875 | Roby et al. | May 1999 | A |
| 5905168 | Dos Santos et al. | May 1999 | A |
| 5910564 | Gruning et al. | Jun 1999 | A |
| 5914387 | Roby et al. | Jun 1999 | A |
| 5919893 | Roby et al. | Jul 1999 | A |
| 5925720 | Kataoka et al. | Jul 1999 | A |
| 5932299 | Katoot | Aug 1999 | A |
| 5955509 | Webber et al. | Sep 1999 | A |
| 5958385 | Tondeur et al. | Sep 1999 | A |
| 5962138 | Kolluri et al. | Oct 1999 | A |
| 5962620 | Reich et al. | Oct 1999 | A |
| 5964744 | Balbierz et al. | Oct 1999 | A |
| 5971954 | Conway et al. | Oct 1999 | A |
| 5980928 | Terry | Nov 1999 | A |
| 5980972 | Ding | Nov 1999 | A |
| 5993972 | Reich et al. | Nov 1999 | A |
| 5997517 | Whitbourne | Dec 1999 | A |
| 6010530 | Goicoechea | Jan 2000 | A |
| 6011125 | Lohmeijer et al. | Jan 2000 | A |
| 6015541 | Greff et al. | Jan 2000 | A |
| 6030634 | Wu et al. | Feb 2000 | A |
| 6033582 | Lee et al. | Mar 2000 | A |
| 6034204 | Mohr et al. | Mar 2000 | A |
| 6042875 | Ding et al. | Mar 2000 | A |
| 6051576 | Ashton et al. | Apr 2000 | A |
| 6051648 | Rhee et al. | Apr 2000 | A |
| 6054553 | Groth et al. | Apr 2000 | A |
| 6056993 | Leidner et al. | May 2000 | A |
| 6060451 | DiMaio et al. | May 2000 | A |
| 6060518 | Kabanov et al. | May 2000 | A |
| 6080488 | Hostettler et al. | Jun 2000 | A |
| 6096070 | Ragheb et al. | Aug 2000 | A |
| 6099562 | Ding et al. | Aug 2000 | A |
| 6110188 | Narciso, Jr. | Aug 2000 | A |
| 6110483 | Whitbourne et al. | Aug 2000 | A |
| 6113629 | Ken | Sep 2000 | A |
| 6120491 | Kohn et al. | Sep 2000 | A |
| 6120536 | Ding et al. | Sep 2000 | A |
| 6120788 | Barrows | Sep 2000 | A |
| 6120904 | Hostettler et al. | Sep 2000 | A |
| 6121027 | Clapper et al. | Sep 2000 | A |
| 6129761 | Hubbell | Oct 2000 | A |
| 6136333 | Cohn et al. | Oct 2000 | A |
| 6143354 | Koulik et al. | Nov 2000 | A |
| 6153252 | Hossainy et al. | Nov 2000 | A |
| 6156344 | Kim et al. | Dec 2000 | A |
| 6159978 | Myers et al. | Dec 2000 | A |
| 6165212 | Dereume et al. | Dec 2000 | A |
| 6172167 | Stapert et al. | Jan 2001 | B1 |
| 6177523 | Reich et al. | Jan 2001 | B1 |
| 6180632 | Myers et al. | Jan 2001 | B1 |
| 6203551 | Wu | Mar 2001 | B1 |
| 6211249 | Cohn et al. | Apr 2001 | B1 |
| 6214901 | Chudzik et al. | Apr 2001 | B1 |
| 6224893 | Langer et al. | May 2001 | B1 |
| 6231600 | Zhong | May 2001 | B1 |
| 6240616 | Yan | Jun 2001 | B1 |
| 6245753 | Byun et al. | Jun 2001 | B1 |
| 6245760 | He et al. | Jun 2001 | B1 |
| 6248129 | Froix | Jun 2001 | B1 |
| 6251136 | Guruwaiya et al. | Jun 2001 | B1 |
| 6254632 | Wu et al. | Jul 2001 | B1 |
| 6258121 | Yang et al. | Jul 2001 | B1 |
| 6258371 | Koulik et al. | Jul 2001 | B1 |
| 6262034 | Mathiowitz et al. | Jul 2001 | B1 |
| 6270788 | Koulik et al. | Aug 2001 | B1 |
| 6277449 | Kolluri et al. | Aug 2001 | B1 |
| 6283947 | Mirzaee | Sep 2001 | B1 |
| 6283949 | Roorda | Sep 2001 | B1 |
| 6284305 | Ding et al. | Sep 2001 | B1 |
| 6287628 | Hossainy et al. | Sep 2001 | B1 |
| 6299604 | Ragheb et al. | Oct 2001 | B1 |
| 6306176 | Whitbourne | Oct 2001 | B1 |
| 6331313 | Wong et al. | Dec 2001 | B1 |
| 6331578 | Turner et al. | Dec 2001 | B1 |
| 6335029 | Kamath et al. | Jan 2002 | B1 |
| 6344035 | Chudzik et al. | Feb 2002 | B1 |
| 6346110 | Wu | Feb 2002 | B2 |
| 6358556 | Ding et al. | Mar 2002 | B1 |
| 6379381 | Hossainy et al. | Apr 2002 | B1 |
| 6384046 | Schuler et al. | May 2002 | B1 |
| 6387379 | Goldberg et al. | May 2002 | B1 |
| 6395326 | Castro et al. | May 2002 | B1 |
| 6419692 | Yang et al. | Jul 2002 | B1 |
| 6451373 | Hossainy et al. | Sep 2002 | B1 |
| 6482834 | Spada et al. | Nov 2002 | B2 |
| 6494862 | Ray et al. | Dec 2002 | B1 |
| 6503538 | Chu et al. | Jan 2003 | B1 |
| 6503556 | Harish et al. | Jan 2003 | B2 |
| 6503954 | Bhat et al. | Jan 2003 | B1 |
| 6506437 | Harish et al. | Jan 2003 | B1 |
| 6524347 | Myers et al. | Feb 2003 | B1 |
| 6527801 | Dutta | Mar 2003 | B1 |
| 6527863 | Pacetti et al. | Mar 2003 | B1 |
| 6528526 | Myers et al. | Mar 2003 | B1 |
| 6530950 | Alvarado et al. | Mar 2003 | B1 |
| 6530951 | Bates et al. | Mar 2003 | B1 |
| 6540776 | Sanders Millare et al. | Apr 2003 | B2 |
| 6544223 | Kokish | Apr 2003 | B1 |
| 6544543 | Mandrusov et al. | Apr 2003 | B1 |
| 6544582 | Yoe | Apr 2003 | B1 |
| 6555157 | Hossainy | Apr 2003 | B1 |
| 6558733 | Hossainy et al. | May 2003 | B1 |
| 6565659 | Pacetti et al. | May 2003 | B1 |
| 6572644 | Moein | Jun 2003 | B1 |
| 6585755 | Jackson et al. | Jul 2003 | B2 |
| 6585765 | Hossainy et al. | Jul 2003 | B1 |
| 6585926 | Mirzaee | Jul 2003 | B1 |
| 6605154 | Villareal | Aug 2003 | B1 |
| 6616765 | Hossaony et al. | Sep 2003 | B1 |
| 6623448 | Slater | Sep 2003 | B2 |
| 6625486 | Lundkvist et al. | Sep 2003 | B2 |
| 6645135 | Bhat | Nov 2003 | B1 |
| 6645195 | Bhat et al. | Nov 2003 | B1 |
| 6656216 | Hossainy et al. | Dec 2003 | B1 |
| 6656506 | Wu et al. | Dec 2003 | B1 |
| 6660034 | Mandrusov et al. | Dec 2003 | B1 |
| 6663662 | Pacetti et al. | Dec 2003 | B2 |
| 6663880 | Roorda et al. | Dec 2003 | B1 |
| 6666880 | Chiu et al. | Dec 2003 | B1 |
| 6673154 | Pacetti et al. | Jan 2004 | B1 |
| 6673385 | Ding et al. | Jan 2004 | B1 |
| 6689099 | Mirzaee | Feb 2004 | B2 |
| 6695920 | Pacetti et al. | Feb 2004 | B1 |
| 6706013 | Bhat et al. | Mar 2004 | B1 |
| 6709514 | Hossainy | Mar 2004 | B1 |
| 6712845 | Hossainy | Mar 2004 | B2 |
| 6713119 | Hossainy et al. | Mar 2004 | B2 |
| 6716444 | Castro et al. | Apr 2004 | B1 |
| 6723120 | Yan | Apr 2004 | B2 |
| 6733768 | Hossainy et al. | May 2004 | B2 |
| 6740040 | Mandrusov et al. | May 2004 | B1 |
| 6743462 | Pacetti | Jun 2004 | B1 |
| 6749626 | Bhat et al. | Jun 2004 | B1 |
| 6753071 | Pacetti et al. | Jun 2004 | B1 |
| 6758859 | Dang et al. | Jul 2004 | B1 |
| 6759054 | Chen et al. | Jul 2004 | B2 |
| 6764505 | Hossainy et al. | Jul 2004 | B1 |
| 6861503 | Shalaby | Mar 2005 | B2 |
| 7005137 | Hossainy et al. | Feb 2006 | B1 |
| 7008635 | Coury et al. | Mar 2006 | B1 |
| 7094256 | Shah et al. | Aug 2006 | B1 |
| 7217426 | Hossainy | May 2007 | B1 |
| 7247313 | Roorda et al. | Jul 2007 | B2 |
| 20010007083 | Roorda | Jul 2001 | A1 |
| 20010014717 | Hossainy et al. | Aug 2001 | A1 |
| 20010018469 | Chen et al. | Aug 2001 | A1 |
| 20010020011 | Mathiowitz et al. | Sep 2001 | A1 |
| 20010027340 | Wright et al. | Oct 2001 | A1 |
| 20010029351 | Falotico et al. | Oct 2001 | A1 |
| 20010273640 | Wright et al. | Oct 2001 | |
| 20010037145 | Guruwaiya et al. | Nov 2001 | A1 |
| 20010051608 | Mathiowitz et al. | Dec 2001 | A1 |
| 20020005206 | Falotico et al. | Jan 2002 | A1 |
| 20020007213 | Falotico et al. | Jan 2002 | A1 |
| 20020007214 | Falotico | Jan 2002 | A1 |
| 20020007215 | Falotico et al. | Jan 2002 | A1 |
| 20020009604 | Zamora et al. | Jan 2002 | A1 |
| 20020016625 | Falotico et al. | Feb 2002 | A1 |
| 20020032414 | Ragheb et al. | Mar 2002 | A1 |
| 20020032434 | Chudzik et al. | Mar 2002 | A1 |
| 20020051730 | Bodnar et al. | May 2002 | A1 |
| 20020065551 | Koole et al. | May 2002 | A1 |
| 20020071822 | Uhrich | Jun 2002 | A1 |
| 20020077693 | Barclay et al. | Jun 2002 | A1 |
| 20020082679 | Sirhan et al. | Jun 2002 | A1 |
| 20020087123 | Hossainy et al. | Jul 2002 | A1 |
| 20020091433 | Ding et al. | Jul 2002 | A1 |
| 20020094440 | Llanos et al. | Jul 2002 | A1 |
| 20020111590 | Davila et al. | Aug 2002 | A1 |
| 20020120326 | Michal | Aug 2002 | A1 |
| 20020123801 | Pacetti et al. | Sep 2002 | A1 |
| 20020133183 | Lentz et al. | Sep 2002 | A1 |
| 20020142039 | Claude | Oct 2002 | A1 |
| 20020150549 | Vogt et al. | Oct 2002 | A1 |
| 20020155212 | Hossainy | Oct 2002 | A1 |
| 20020165608 | Llanos et al. | Nov 2002 | A1 |
| 20020176849 | Slepian | Nov 2002 | A1 |
| 20010188037 | Chudzik et al. | Dec 2002 | |
| 20020183581 | Yoe et al. | Dec 2002 | A1 |
| 20020188277 | Roorda et al. | Dec 2002 | A1 |
| 20030004141 | Brown | Jan 2003 | A1 |
| 20030028243 | Bates et al. | Feb 2003 | A1 |
| 20030028244 | Bates et al. | Feb 2003 | A1 |
| 20030031780 | Chudzik et al. | Feb 2003 | A1 |
| 20030032767 | Tada et al. | Feb 2003 | A1 |
| 20030036794 | Ragheb et al. | Feb 2003 | A1 |
| 20030039689 | Chen et al. | Feb 2003 | A1 |
| 20030040712 | Ray et al. | Feb 2003 | A1 |
| 20030040790 | Furst | Feb 2003 | A1 |
| 20030059520 | Chen et al. | Mar 2003 | A1 |
| 20030060877 | Falotico et al. | Mar 2003 | A1 |
| 20030065377 | Davila et al. | Apr 2003 | A1 |
| 20030065382 | Fischell et al. | Apr 2003 | A1 |
| 20030072868 | Harish et al. | Apr 2003 | A1 |
| 20030073961 | Happ | Apr 2003 | A1 |
| 20030083646 | Sirhan et al. | May 2003 | A1 |
| 20030083739 | Cafferata | May 2003 | A1 |
| 20030097088 | Pacetti | May 2003 | A1 |
| 20030097173 | Dutta | May 2003 | A1 |
| 20030099712 | Jayaraman | May 2003 | A1 |
| 20030105518 | Dutta | Jun 2003 | A1 |
| 20030113439 | Pacetti et al. | Jun 2003 | A1 |
| 20030144727 | Rosenthal et al. | Jul 2003 | A1 |
| 20030150380 | Yoe | Aug 2003 | A1 |
| 20030157241 | Hossainy et al. | Aug 2003 | A1 |
| 20030158517 | Kokish | Aug 2003 | A1 |
| 20030190406 | Hossainy et al. | Oct 2003 | A1 |
| 20030207020 | Villareal | Nov 2003 | A1 |
| 20030211230 | Pacetti et al. | Nov 2003 | A1 |
| 20040018296 | Castro et al. | Jan 2004 | A1 |
| 20040029952 | Chen et al. | Feb 2004 | A1 |
| 20040047911 | Lyu et al. | Mar 2004 | A1 |
| 20040047978 | Hossainy et al. | Mar 2004 | A1 |
| 20040047980 | Pacetti et al. | Mar 2004 | A1 |
| 20040052858 | Wu et al. | Mar 2004 | A1 |
| 20040052859 | Wu et al. | Mar 2004 | A1 |
| 20040054104 | Pacetti | Mar 2004 | A1 |
| 20040060508 | Pacetti et al. | Apr 2004 | A1 |
| 20040062853 | Pacetti et al. | Apr 2004 | A1 |
| 20040063805 | Pacetti et al. | Apr 2004 | A1 |
| 20040071861 | Mandrusov et al. | Apr 2004 | A1 |
| 20040072922 | Hossainy et al. | Apr 2004 | A1 |
| 20040073298 | Hossainy | Apr 2004 | A1 |
| 20040086542 | Hossainy et al. | May 2004 | A1 |
| 20040086550 | Roorda et al. | May 2004 | A1 |
| 20040096504 | Michal | May 2004 | A1 |
| 20040098117 | Hossainy et al. | May 2004 | A1 |
| 20040127978 | Sparer et al. | Jul 2004 | A1 |
| 20050191332 | Hossainy | Sep 2005 | A1 |
| Number | Date | Country |
|---|---|---|
| 42 24 401 | Jan 1994 | DE |
| 0 301 856 | Feb 1989 | EP |
| 0 396 429 | Nov 1990 | EP |
| 0 514 406 | Nov 1992 | EP |
| 0 604 022 | Jun 1994 | EP |
| 0 623 354 | Nov 1994 | EP |
| 0 665 023 | Aug 1995 | EP |
| 0 701 802 | Mar 1996 | EP |
| 0 716 836 | Jun 1996 | EP |
| 0 809 999 | Dec 1997 | EP |
| 0 832 655 | Apr 1998 | EP |
| 0 850 651 | Jul 1998 | EP |
| 0 879 595 | Nov 1998 | EP |
| 0 910 584 | Apr 1999 | EP |
| 0 923 953 | Jun 1999 | EP |
| 0 953 320 | Nov 1999 | EP |
| 0 970 711 | Jan 2000 | EP |
| 0 982 041 | Mar 2000 | EP |
| 1 023 879 | Aug 2000 | EP |
| 1 192957 | Apr 2002 | EP |
| 1 273 314 | Jan 2003 | EP |
| 2001-190687 | Jul 2001 | JP |
| 2002-506369 | Feb 2002 | JP |
| 2002-315823 | Oct 2002 | JP |
| 872531 | Oct 1981 | SU |
| 876663 | Oct 1981 | SU |
| 905228 | Feb 1982 | SU |
| 790725 | Feb 1983 | SU |
| 1016314 | May 1983 | SU |
| 811750 | Sep 1983 | SU |
| 1293518 | Feb 1987 | SU |
| WO 9112846 | Sep 1991 | WO |
| WO 9409760 | May 1994 | WO |
| WO 9510989 | Apr 1995 | WO |
| WO 9524929 | Sep 1995 | WO |
| WO 9640174 | Dec 1996 | WO |
| WO 9710011 | Mar 1997 | WO |
| WO 9745105 | Dec 1997 | WO |
| WO 9746590 | Dec 1997 | WO |
| WO 9808463 | Mar 1998 | WO |
| WO 9817331 | Apr 1998 | WO |
| WO 9832398 | Jul 1998 | WO |
| WO 9836784 | Aug 1998 | WO |
| WO 9858690 | Dec 1998 | WO |
| WO 9901118 | Jan 1999 | WO |
| WO 9938546 | Aug 1999 | WO |
| WO 9963981 | Dec 1999 | WO |
| WO 0002599 | Jan 2000 | WO |
| WO 0012147 | Mar 2000 | WO |
| WO 0018446 | Apr 2000 | WO |
| WO 0064506 | Nov 2000 | WO |
| WO 0101890 | Jan 2001 | WO |
| WO 0115751 | Mar 2001 | WO |
| WO 0117577 | Mar 2001 | WO |
| WO 0145763 | Jun 2001 | WO |
| WO 0149338 | Jul 2001 | WO |
| WO 0151027 | Jul 2001 | WO |
| WO 0174414 | Oct 2001 | WO |
| WO 0203890 | Jan 2002 | WO |
| WO 0226162 | Apr 2002 | WO |
| WO 0234311 | May 2002 | WO |
| WO 02056790 | Jul 2002 | WO |
| WO 02058753 | Aug 2002 | WO |
| WO 02102283 | Dec 2002 | WO |
| WO 03000308 | Jan 2003 | WO |
| WO 03022323 | Mar 2003 | WO |
| WO 03028780 | Apr 2003 | WO |
| WO 03037223 | May 2003 | WO |
| WO 03039612 | May 2003 | WO |
| WO 03080147 | Oct 2003 | WO |
| WO 03082368 | Oct 2003 | WO |
| WO 2004000383 | Dec 2003 | WO |
| WO 2004009145 | Jan 2004 | WO |
| WO 2004010975 | Feb 2004 | WO |
| Entry |
|---|
| Kamath et. al, Advanced Drug Delivery Reviews, 58 (2006) 4112-436. |
| Tesfamariam, Journal fo Cardiovascular Pharmacology, 51 (2008) 118-125. |
| Polyethylene Amine (en.wikipedia.org/wiki/Polyethylene—amine) (downloaded Dec. 16, 2011). |
| Polyethylenimine (en.wikipedia.org/wiki/Polyethylenimine) (downloaded Dec. 16, 2011). |
| Online Conversion (www.onlineconversion.com/energy.htm) (downloaded Dec. 16, 2011). |
| “Additive” Definition at http://www.thefreedictionary.com/ additive) (retireved from the internet May 4, 2013). |
| U.S. Appl. No. 09/894,293, filed Jun. 27, 2001, Roorda et al. |
| U.S. Appl. No. 10/198,912, filed Jul. 19, 2002, Ding et al. |
| U.S. Appl. No. 10/177,154, filed Jun. 21, 2002, Hossainy et al. |
| U.S. Appl. No. 10/251,111, filed Sep. 19, 2002, Hossainy et al. |
| U.S. Appl. No. 10/376,348, filed Feb. 26, 2003, Ding et al. |
| U.S. Appl. No. 10/428,691, filed May 1, 2003, Pacetti. |
| International Search Report mailed May 10, 2004, for PCT application No. PCT/US2004/009011, filed Mar. 23, 2004, 8 pgs. |
| Anonymous, Cardiologists Draw—Up the Dream Stent, Clinica 710:15 (Jun. 17, 1996), http://www.dialogweb.com/cgi/document?req=1061848202959, printed Aug. 25, 2003 (2 pages). |
| Anonymous, Heparin-coated stents cut complications by 30%, Clinica 732:17 (Nov. 18, 1996), http://www.dialogweb.com/cgi/document?req=1061847871753, printed Aug. 25, 2003 (2 pages). |
| Anonymous, Rolling Therapeutic Agent Loading Device for Therapeutic Agent Delivery or Coated Stent (Abstract 434009), Res. Disclos. pp. 974-975 (Jun. 2000). |
| Anonymous, Stenting continues to dominate cardiology, Clinica 720:22 (Sep. 2, 1996), http://www.dialogweb.com/cgi/document?req=1061848017752, printed Aug. 25, 2003 (2 pages). |
| Aoyagi et al., Preparation of cross-linked aliphatic polyester and application to thermo-responsive material, Journal of Controlled Release 32:87-96 (1994). |
| Barath et al., Low Dose of Antitumor Agents Prevents Smooth Muscle Cell Proliferation After Endothelial Injury, JACC 13(2): 252A (Abstract) (Feb. 1989). |
| Barbucci et al., Coating of commercially available materials with a new heparinizable material, J. Biomed. Mater. Res. 25:1259-1274 (Oct. 1991). |
| Chung et al., Inner core segment design for drug delivery control of thermo-responsive polymeric micelles, Journal of Controlled Release 65:93-103 (2000). |
| Dev et al., Kinetics of Drug Delivery to the Arterial Wall Via Polyurethane-Coated Removable Nitinol Stent: Comparative Study of Two Drugs, Catheterization and Cardiovascular Diagnosis 34:272-278 (1995). |
| Dichek et al., Seeding of Intravascular Stents with Genetically Engineered Endothelial Cells, Circ. 80(5):1347-1353 (Nov. 1989). |
| Eigler et al., Local Arterial Wall Drug Delivery from a Polymer Coated Removable Metallic Stent: Kinetics, Distribution, and Bioactivity of Forskolin, JACC, 4A (701-1), Abstract (Feb. 1994). |
| Helmus, Overview of Biomedical Materials, MRS Bulletin, pp. 33-38 (Sep. 1991). |
| Herdeg et al., Antiproliferative Stent Coatings: Taxol and Related Compounds, Semin. Intervent. Cardiol. 3:197-199 (1998). |
| Huang et al., Biodegradable Polymers Derived from Aminoacids, Macromol. Symp. 144, 7-32 (1999). |
| Inoue et al., An AB block copolymer of oligo(methyl methacrylate) and poly(acrylic acid) for micellar delivery of hydrophobic drugs, Journal of Controlled Release 51:221-229 (1998). |
| Kataoka et al., Block copolymer micelles as vehicles for drug delivery, Journal of Controlled Release 24:119-132 (1993). |
| Katsarava et al., Amino Acid-Based Bioanalogous Polymers. Synthesis and Study of Regular Poly(ester amide)s Based on Bis(α-amino acid)α,ω-Alkylene Diesters, and Aliphatic Dicarbolic Acids, Journal of Polymer Science, Part A: Polymer Chemistry, 37(4), 391-407 (1999). |
| Levy et al., Strategies for Treating Arterial Restenosis Using Polymeric Controlled Release Implants, Biotechnol. Bioact. Polym. [Proc. Am. Chem. Soc. Symp.], pp. 259-268 (1994). |
| Liu et al., Drug release characteristics of unimolecular polymeric micelles, Journal of Controlled Release 68:167-174 (2000). |
| Marconi et al., Covalent bonding of heparin to a vinyl copolymer for biomedical applications, Biomaterials 18(12):885-890 (1997). |
| Matsumaru et al., Embolic Materials for Endovascular Treatment of Cerebral Lesions, J. Biomater. Sci. Polymer Edn 8(7):555-569 (1997). |
| Miyazaki et al., Antitumor Effect of Implanted Ethylene-Vinyl Alcohol Copolymer Matrices Containing Anticancer Agents on Ehrlich Ascites Carcinoma and P388 Leukemia in Mice, Chem. Pharm. Bull. 33(6) 2490-2498 (1985). |
| Miyazawa et al., Effects of Pemirolast and Tranilast on Intimal Thickening After Arterial Injury in the Rat, J. Cardiovasc. Pharmacol., pp. 157-162 (1997). |
| Nordrehaug et al., A novel biocompatible coating applied to coronary stents, European Heart Journal 14, p. 321 (P1694), Abstr. Suppl. (1993). |
| Ohsawa et al., Preventive Effects of an Antiallergic Drug, Pemirolast Potassium, on Restenosis After Percutaneous Transluminal Coronary Angioplasty, American Heart Journal 136(6):1081-1087 (Dec. 1998). |
| Ozaki et al., New Stent Technologies, Progress in Cardiovascular Diseases, vol. XXXIX(2):129-140 (Sep./Oct. 1996). |
| Pechar et al., Poly(ethylene glycol) Multiblock Copolymer as a Carrier of Anti-Cancer Drug Doxorubicin, Bioconjucate Chemistry 11(2):131-139 (Mar./Apr. 2000). |
| Peng et al., Role of polymers in improving the results of stenting in coronary arteries, Biomaterials 17:685-694 (1996). |
| Saotome, et al., Novel Enzymatically Degradable Polymers Comprising α-Amino Acid, 1,2-Ethanediol, and Adipic Acid, Chemistry Letters, pp. 21-24, (1991). |
| Shigeno, Prevention of Cerebrovascular Spasm by Bosentan, Novel Endothelin Receptor, Chemical Abstract 125:212307 (1996). |
| van Beusekom et al., Coronary stent coatings, Coronary Artery Disease 5(7):590-596 (Jul. 1994). |
| Wilensky et al., Methods and Devices for Local Drug Delivery in Coronary and Peripheral Arteries, Trends Cardiovasc. Med. 3(5):163-170 (1993). |
| Yokoyama et al., Characterization of physical entrapment and chemical conjugation of adriamycin in polymeric micelles and their design for in vivo delivery to a solid tumor, Journal of Controlled Release 50:79-92 (1998). |
| Amendment and Response to OA of a related U.S. Appl. No. 11/903,011, mailed Mar. 18, 2009, 13 pgs. |
| IUPAC Compendium of Chemical Terminology 2nd Ed. (1997), 1 pg. |
| Kamath et al., “The Taxus™ drug-eluting stent: A new paradigm in controlled delivery”, Advanced Drug Delivery Reviews 58, pp. 412-436 (2006). |
| Tesfamariam, “Drug Release Kinetics from Stent Device-Based Delivery Systems”, Journal of Cardiovascular Pharmacology 51, pp. 118-125 (2008). |
| Notification of Refusal, issued by JPO on Aug. 17, 2010, in connection with Appl. No. 2006-532338, 3 pgs. |
| Translation of a Notification of Refusal, issued by JPO on Aug. 17, 2010, in connection with Appl. No. 2006-532338, 3 pgs. |
| Number | Date | Country | |
|---|---|---|---|
| 20080118543 A1 | May 2008 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10431711 | May 2003 | US |
| Child | 11903176 | US |
