text:
|Publication number
|Publication type
|Application number
|Publication date
|Oct 11, 2005
|Filing date
|Oct 3, 2003
|Priority date
|Sep 28, 2000
|Fee status
|Also published as
|Publication number
|Daniel Castro, Stephen D. Pacetti
|Original Assignee
|Advanced Cardiovascular Systems, Inc.
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (100), Non-Patent Citations (53), Referenced by (109), Classifications (34), Legal Events (3)
|External Links: USPTO, USPTO Assignment, Espacenet
This is a continuation of U.S. patent application Ser. No. 09/676,049 filed Sep. 28, 2000, now U.S. Pat. No. 6,716,444.
1. Field of the Invention
The present invention relates to implantable medical devices that release a drug.
2. Description of the Background
Percutaneous transluminal coronary angioplasty (PTCA) is a procedure for treating heart disease. A catheter assembly having a balloon portion is introduced into the cardiovascular system of a patient via the brachial or femoral artery. The catheter assembly is advanced through the coronary vasculature until the balloon portion is positioned across the occlusive lesion. Once in position across the lesion, the balloon is inflated to a predetermined size to radially compress against the atherosclerotic plaque of the lesion to remodel the arterial lumen. The balloon is then deflated to a smaller profile to allow the catheter to be withdrawn from the patient's vasculature.
In treating the damaged vasculature tissue, and to deter thrombosis and restenosis, drugs are commonly administered to the treatment site. For example, anticoagulants are commonly used to prevent thrombosis of the coronary lumen. Antiplatelets are administered to reduce the incidence of major adverse cardiac events. Cytostatic agents are presently used in clinical trials to reduce post-angioplasty proliferation of the vascular tissue.
Systemic administration of such drugs in sufficient amounts to supply an efficacious concentration to the local treatment site often produces adverse or toxic side effects for the patient. Accordingly, local delivery is a preferred method of treatment since smaller amounts of medication are administered in comparison to systemic dosages, but the medication is concentrated at a specific treatment site. Local delivery thus produces fewer side effects and achieves more effective results.
A common technique for local delivery of drugs involves coating a stent or graft with a polymeric material which, in turn, is impregnated with a drug or a combination of drugs. Once the stent or graft is implanted within a cardiovascular system lumen, the drug(s) is released from the polymer for the treatment of the local tissues. U.S. Pat. No. 5,605,696 to Eury et al., U.S. Pat. No. 5,464,650 to Berg, et al., and U.S. Pat. No. 5,700,286 to Tartaglia, et al. provide examples illustrating the use of a polymeric coating for the local delivery of a drug or substance.
Stents are scaffoldings, usually cylindrical or tubular in shape, which are inserted into an anatomical passageway and operate to physically hold open and, if desired, to expand the wall of a passageway. Stents are capable of being crimped onto balloon catheters for insertion through small cavities, positioned in a desired location, and then expanded to a larger diameter. Stents can be either balloon expandable or self-expanding.
Grafts are typically placed in a blood vessel to either replace a diseased segment that has been removed, or to form a bypass conduit through a damaged segment of the vessel wall as is the case with an aneurysm, for example. The graft has a tubular portion which spans the site of the damaged tissue and through which the blood flows. The graft has sections at both ends of the tube that are used to secure the graft to the inside of a vessel wall. The graft also has an outer surface, portions of which are in contact with an inner surface of the blood vessel wall, and an inner surface in contact with the blood flowing through the vessel.
An equation describing the drug release rate per unit area of device 10 is as follows:
Equation 1 assumes that: (1) all resistance to drug release is determined by the diffusivity of drug 16 in polymer 14; (2) the concentration of drug 16 is uniform throughout; (3) drug 16 does not go into the metallic surface 12; and (4) drug 16 is rapidly removed from the surface of polymer 14 as soon as drug 16 is released from polymer 14.
The diffusivity of drug 16 in polymer 14, Dp, in turn is determined by certain properties of drug 16 (e.g., molecular weight, size) and physical properties of the polymer 14 through which drug 16 is diffusing (e.g., pore size, crystallinity, glass transition temperature, polarity or hydrophobicity).
A problem associated with the use of a polymeric coating as a matrix for carrying the drug is that the rate at which the drug is released is highly variable, typically exhibiting a very high rate of release after the medical device is implanted in the patient, followed by a significantly lower rate of release. This may be undesirable in many applications, since the initial concentrations may be too high (causing undesirable side effects or even cell death), the later concentrations may be too low to have any therapeutic effect, and the overall residence time of the drug in the target area may be too short to provide the desired therapeutic effect.
For example, for certain antiproliferative drugs, a residence time of thirty minutes may be all that is required to achieve a permanent effect, while others may take up to two weeks. Where nitrous oxide (NO) is used as the antiproliferative drug, a residence time of four to eight weeks is desirable, but even longer durations up to twelve weeks may be beneficial, depending on the patient.
With respect to anti-inflammatory drugs, a long residence time (e.g., several weeks) is desirable, because the anti-inflammatory drug should be delivered until some amount of healing has occurred. Anti-thrombogenic drugs also may require a long residence time, for example, up to five months, since that much time may be required for a stent to become endothelialized.
Thus, there is a need for a mechanism for controlling the release rate of drugs from implantable medical devices to increase the efficacy of local drug delivery in treating patients.
The present invention allows for a controlled rate of release of a drug or drugs from a polymer carried on an implantable medical device. The controlled rate of release allows localized drug delivery for extended periods, e.g., weeks to months, depending upon the application. This is especially useful in providing therapy to reduce or prevent cell proliferation, inflammation, or thrombosis in a localized area.
One embodiment of an implantable medical device in accordance with the present invention includes a substrate, which may be, for example, a metal or polymeric stent or graft, among other possibilities. At least a portion of the substrate is coated with a first layer that includes one or more drugs in a polymer carrier. A barrier coating overlies the first layer. The barrier (which may be considered a coating) reduces the rate of release of the drug from the polymer once the medical device has been placed into the patient's body, thereby allowing an extended period of localized drug delivery once the medical device is in situ.
The barrier is necessarily biocompatible (i.e., its presence does not elicit an adverse response from the body), and typically has a thickness ranging from about 50 angstroms to about 20,000 angstroms. It is contemplated that the barrier contains mostly inorganic material. However, some organic compounds (e.g., polyacrylonitrile, polyvinylidene chloride, nylon 6—6, perfluoropolymers, polyethylene terephthalate, polyethylene 2,6-napthalene dicarboxylate, and polycarbonate) may be incorporated in the barrier. Suitable inorganic materials for use within the barrier include, but are not limited to, inorganic elements, such as pure metals including aluminum, chromium, gold, hafnium, iridium, niobium, palladium, platinum, tantalum, titanium, tungsten, zirconium, and alloys of these metals, and inorganic compounds, such as inorganic silicides, oxides, nitrides, and carbides. Generally, the solubility of the drug in the material of the barrier is significantly less than the solubility of the drug in the polymer carrier. Also, generally, the diffusivity of the drug in the material of the barrier is significantly lower than the diffusivity of the drug in the polymer carrier.
The barrier may or may not be biodegradable (i.e., capable of being broken down into harmless compounds by the action of the body). While it is contemplated that non-biodegradable barrier may be preferable, some biodegradable materials may be used as barriers. For example, calcium phosphates such as hydroxyapatite, carbonated hydroxyapatite, tricalcium phosphate, beta-tricalcium phosphate, octacalcium phosphate, amorphous calcium phosphate, and calcium orthophosphate may be used. Certain calcium salts such as calcium phosphate (plaster of paris) may also be used. The biodegradability of the barrier may act as an additional mechanism for controlling drug release from the underlying first layer.
The one or more drugs contained within the polymer may include, but are not limited to, antineoplastic, anti-inflammatory, antiplatelet, anticoagulant, fibrinolytic, thrombin inhibitor, antimitotic, antiallergic, and antiproliferative substances.
In accordance with one embodiment of the present invention, the barrier is a homogeneous layer. A homogeneous layer of barrier may be produced by several methods, depending on the type of materials selected from the barrier. For example, nitride barriers, such as titanium nitride and chromium nitride, may be deposited by cathodic arc physical vapor deposition. Oxide barriers, such as silicon dioxide and aluminum oxide, can be produced by reactive sputtering. Metallic barriers, such as aluminum, gold, tungsten, platinum, or alloys of metals, may be produced by sputtering, thermal evaporation, or electron beam evaporation, as well as electroless deposition.
In accordance with another embodiment of the present invention, the barrier is formed by a number of discrete deposits on the surface of the polymer coating. The release rate of the drug from the polymer coating may be manipulated by controlling the fraction of the surface area covered by the barrier. Such a barrier may be obtained, for example, by cathodic arc sputtering, reactive sputtering, thermal evaporation, and electron beam (e-beam) evaporation of materials such as aluminum, chromium, gold, iridium, niobium, platinum, tantalum, titanium, and tungsten.
In accordance with another embodiment of the present invention, the barrier is intermixed with the first layer at and near the outer surface of the first layer, rather than being a discrete layer atop the first layer. This embodiment may be produced by several techniques, including for example, ion implantation, plasma ion implantation, alkoxide hydrolysis, and electroless deposition. Ion implantation and plasma ion implantation may produce, for example, titanium and palladium barrier coatings. Alkoxide hydrolysis may produce barrier coatings of titanium oxide, zirconium oxide, and aluminum oxide from titanium alkoxides, zirconium alkoxides and aluminum alkoxides, respectively. Electroless deposition may produce, for example, palladium and gold barrier coatings.
These and other embodiments and aspects of the present invention may be better understood in view of the drawings and the following detailed description.
The use of the same reference numbers in different drawings indicates similar or identical items.
Barrier 28 acts to reduce the rate of delivery of drug 16 to internal target tissue area 50 by at least one of two mechanisms. First, the solubility of drug 16 in barrier 28 is substantially less (i.e., at least two to three orders of magnitude less) than the solubility of drug 16 in first layer 24. Likewise, the diffusivity of drug 16 in barrier 28 is significantly lower than the diffusivity of drug 16 in first layer 24. Accordingly, drug 16 will diffuse more slowly through barrier 28 than through first layer 24. Secondly, barrier 28, being mostly an inorganic material, is composed of much smaller molecules than those found within the polymer in first layer 24. The barrier molecules are aligned more tightly and in a more orderly fashion than the polymer molecules, thereby leaving less void space through which drug 16 can travel.
Some barriers, especially defect-free metallic films and SiOx films, will be very impermeable, except for microfractures through the barrier coating. While these microfractures may link the top and bottom of the barrier coating, the paths of the microfractures linking the top and bottom of the barrier coating are tortuous, and thus the path that drug 16 must take to exit medical device 11 is much longer than the thickness of barrier 28. Moreover, since the drug is restricted to diffusing only through the microfractures, the area available for diffusion is greatly reduced as well.
A simple model for the embodiment illustrated in
where DI=diffusivity of drug 16 in barrier 28;
This equation assumes that all of the resistance to drug release is in the barrier 28. This is a reasonable assumption since, typically, DI is at least two to three orders of magnitude lower than the diffusivity of drug 16 in first layer 24. As can be seen from Equation 2, variables DI, k, and TI, are the most significant variables affecting drug release. Of course, the present invention does not depend on this equation or the assumptions discussed above.
Suitable inorganic materials for barrier 28 include, but are not limited to, silicides, oxides, nitrides, and carbides. Suitable silicides may include silicides of vanadium, zirconium, tungsten, titanium, niobium, and tantalum. Suitable oxides may include oxides of aluminum, barium, calcium, hafnium, niobium, silicon, tantalum, titanium, tungsten, and zirconium. Suitable nitrides may include nitrides of chromium, silicon, titanium, and zirconium. Suitable carbides may include carbides of silicon and titanium. Other suitable materials may include molybdenum disulfide, amorphous diamond, diamond-like carbon, pyrolytic carbon, ultra-low temperature isotropic (ULTI) carbon, amorphous carbon, strontium titanate, and barium titanate. Also suitable for use are pure metals, such as aluminum, chromium, gold, hafnium, iridium, niobium, palladium, platinum, tantalum, titanium, tungsten, zirconium, and alloys of these metals.
Several methods may be used to deposit barrier 28 on first layer 24, depending on the application. For example, silicide compounds, such as vanadium disilicide, zirconium disilicide, tungsten disilicide, titanium disilicide, niobium disilicide, tantalum disilicide, vanadium silicide, titanium trisilicide, and tantalum trisilicide may be deposited by sputtering or chemical vapor deposition (CVD).
Oxide barrier coatings, such as tantalum oxide, titanium dioxide, zirconium oxide, niobium oxide, tungsten oxide, aluminum oxide, and silicon dioxide can be produced by reactive sputtering. The power source used in this method may be AC or DC, and utilizes the pure element as a target with a sputter gas of argon and low levels of oxygen.
Nitride barrier coatings, such as titanium nitride, titanium carbonitride, chromium nitride, titanium aluminum nitride, and zirconium nitride can be deposited on first layer 24 at relatively low temperatures (i.e., less than 60� C.) by cathodic arc vacuum deposition. Such a method may be chosen where first layer 24 and drug 16 are temperature-sensitive.
Films of pure metals (e.g., aluminum, gold, tungsten, platinum) may be produced by physical vapor deposition (PVD) methods such as sputtering, thermal evaporation, or electron beam evaporation. Alloys of these metals can be deposited by sputtering if, for example, an alloy sputtering target is used or multiple metal targets are simultaneously sputtered. Alloys may also be deposited utilizing thermal evaporation or electron beam evaporation if several evaporation sources are used simultaneously.
Suitable polymer materials for first layer 24 can include, but are not limited to, polyurethanes, polyesterurethanes, silicone, fluoropolymers, ethylene vinyl acetate, polyethylene, polypropylene, polycarbonates, trimethylenecarbonate, polyphosphazene, polyhydroxybutyrate, polyhydroxyvalerate, polydioxanone, polyiminocarbonates, polyorthoesters, ethylene vinyl alcohol copolymer, L-polylactide, D,L-polylactide, polyglycolide, polycaprolactone, copolymers of lactide and glycolide, polymethylmethacrylate, poly(n-butyl)methacrylate, polyacrylates, polymethacrylates, elastomers, and mixtures thereof.
Representative elastomers include, but are not limited to, a thermoplastic elastomer material available under the trade name "C-FLEX" from Concept Polymer Technologies of Largo, Fla., polyether-amide thermoplastic elastomer, fluoroelastomers, fluorosilicone elastomer, sytrene-butadiene rubber, butadiene-styrene rubber, polyisoprene, neoprene (polychloroprene), ethylene-propylene elastomer, chloro-sulfonated polyethylene elastomer, butyl rubber, polysulfide elastomer, polyacrylate elastomer, nitrile, rubber, polyester, styrene, ethylene, propylene, butadiene and isoprene, polyester thermoplastic elastomer, and mixtures thereof.
The choice of the polymer in first layer 24 typically depends on the selection of the particular drug 16. For a drug 16 that is to be dissolved in the polymer, the factors to be considered in selecting an appropriate polymer include the molecular structure of both the polymer and the drug, the crystallinity or amorphousness of the polymer, the molecular weight of the drug (which is indicative of its size on a molecular level), and the solubility of the drug in the polymer. Examples of drug/polymer pairings include dexamethasone in silicone or polyurethanes or fluoroelastomer; taxol in ethylene vinyl acetate or L-polylactide or polycaprolactone or polyurethanes; rapamycin in polymethylmethacrylate or poly(n-butyl)methacrylate; tranilast in polyurethanes or ethylene vinyl acetate; and fluorouracil in polyurethanes.
Examples of drug 16 include antineoplastic, antimitotic, antiinflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antiproliferative, antibiotic, antioxidant, and antiallergic substances as well as combinations thereof. 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., Mutamycin� from Bristol-Myers Squibb Co., Stamford, Conn.). Examples of such antiinflammatory substances include estradiol. Examples of such antiplatelets, anticoagulants, antifibrin, and antithrombins include sodium heparin, low molecular weight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogs, 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 antiallergic substances include permirolast potassium and tranilast. Examples of such cytostatic or antiproliferative agents include actinomycin D as well as derivatives and analogs thereof (manufactured by Sigma-Aldrich, Milwaukee, Wis.; or COSMEGEN� available from Merck & Co., Inc., Whitehouse Station, N.J.), angiopeptin, mitomycin, 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, fibrolast growth factor (FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (an inhibitor of HMB-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 nitric oxide.
Other drugs or agents that may be used include, for example, alpha-interferon, genetically engineered epithelial cells, and dexamethasone. While the preventative and treatment properties of the foregoing drugs or agents are well-known to those of ordinary skill in the art, the substances or agents are provided by way of example and are not meant to be limiting. Other drugs that may be carried in a polymer coating are equally applicable for use with the present invention.
According to the present invention, the release rate of the drug typically will be controlled in part by the material selected for the barrier. For instance, the barrier material may be an inorganic compound, which is typically polar or ionic in nature. Generally, if the selected drug 16 is likewise polar or ionic in nature (e.g., cisplatin, fluoracil), then the solubility of drug 16 in barrier 28 will be higher, resulting in a higher diffusivity, and thus a faster rate of delivery of drug 16 through barrier 28 to internal target tissue area 50. Conversely, if the selected drug 16 is nonpolar, (e.g., TAXOL�, dexamethasone), then the solubility of drug 16 in barrier 28 will be lower, resulting in a lower diffusivity, and thus a lower rate of delivery of drug 16 through barrier 28 to internal target tissue area 50. However, this is not always the case. Titanium dioxide is a polar inorganic compound, but it has such a high degree of crystallinity, and an affinity for itself that other polar compounds (e.g., the drug to be delivered) do not necessarily dissolve into titanium dioxide very well.
In the embodiment illustrated in
The release rate associated with the embodiment of
Release Rate=(1−A)Φ(t) (Equation 3)
Equation 3 assumes that there is no diffusion through nucleation sites 30. Again, this equation is provided as an explanatory aid, and does not in any way limit the invention.
Advantageously, in this embodiment, the rate of drug delivery (and thus, the effective treatment time) may be manipulated by controlling the number of nucleation sites 30 that are permitted to form on surface 29 of first layer 24. The number of nucleation sites may be controlled by controlling various deposition process parameters, such as deposition rate, substrate temperature, energy of the deposited atoms, substrate surface cleanliness and defects, angle of the incident atom flux, and substrate surface roughness.
The embodiment illustrated in
The embodiment illustrated in
The rate of drug delivery from first layer 24 to internal target tissue area 50 may be reduced in large part by at least two mechanisms in this embodiment. First, if drug 16 diffuses through the barrier material in intermixed zone 42, then drug 16 may have to follow a more tortuous diffusion path than drug 16 would otherwise follow, decreasing the diffusion rate. Second, if the barrier material in intermixed zone 42 acts as a complete barrier to diffusion, then the area normal to the direction of diffusion is significantly reduced, thus reducing the diffusion rate, in a manner similar to the nucleation sites in the embodiment illustrated in
Meaningful quantitative or semiquantitative descriptions of drug release rates from the embodiment illustrated in
One of ordinary skill in the art will appreciate that, for all of the embodiments described herein, the thickness of the barrier used may be varied, with a corresponding change in the drug release rate. Generally, the thicker the barrier, the greater the reduction in the drug release rate. However, there is a practical limit on the thickness of the barrier to be applied to first layer 24. If the barrier becomes too thick, then, when subjected to stress from mechanical flexing or changes in temperature, internal stresses will build up within the barrier. When these internal stresses exceed the adhesion between the barrier and the underlying film, the barrier may fracture throughout. Small pieces of the barrier may then be lifted off from first layer 24. The pieces could enter the lumen of a blood vessel, and act as an embolus, with potentially very harmful effects on the patient.
Healthy endothelial cells located along the intima (the innermost layer of cells lining the blood vessels) produce a nearly constant supply of nitric oxide. Nitric oxide molecules signal the surrounding smooth muscle cells. We currently believe nitric oxide molecules also prevent the smooth muscle cells from migrating and/or proliferating, which, it is postulated, would reduce the incidence of restenosis following PTCA. To be effective in local delivery, nitric oxide would ideally be released over a period of weeks (e.g., four to eight weeks, generally, and in some cases, up to twelve weeks, depending on the patient). In accordance with one embodiment of the invention, a homogeneous film of non-stoichiometric silicon dioxide (known as SiOx) is deposited as barrier coating 28 on first layer 24. First layer 24 contains drug 16, which in this case is nitric oxide or a molecule which releases nitric oxide.
Experimental data collected by others has shown that a polycarbonate film having an average molecular weight in the range of 20,000 to 40,000 g/mole has an oxygen (O2) transmission rate of 1000 cm3/m2-atm-day. See, Erlat, et al., "Morphology and Gas Barrier Properties of Thin SiOx Coatings on Polycarbonate: Correlations with Plasma-enhanced Chemical Vapor Deposition Conditions," J. Mater. Res., Vol. 15, No. 3, March 2000. By depositing a SiOx coating having a thickness of approximately 30 nanometers (nm) on the polycarbonate, using plasma-enhanced chemical vapor deposition, the oxygen transmission rate was reduced by one order of magnitude to approximately 100 cm3/m2-atm-day. By increasing the thickness of the SiOx coating deposited to 60 nanometers, the oxygen transmission rate was further reduced by another order of magnitude, to approximately 10 cm3/m2-atm-day. A less dramatic reduction in oxygen transmission was observed with further increases in SiOx coating thickness.
Since oxygen (O2) and nitric oxide (NO) are similar to each other in size and molecular weight, we anticipate that an implanted medical device (e.g., a stent or graft) having a SiOx layer provided atop a polymeric coating containing nitric oxide would cause a similar reduction in the rate at which nitric oxide is released from the polymeric material into a target tissue area. That is, the release rate of nitric oxide from the polymeric carrier could be reduced by a factor of 10 by depositing a SiOx coating that is 30 nanometers thick on the polymeric carrier, and reduced by a factor of 100 by depositing a SiOx coating 60 nanometers thick on the polymeric carrier. As a result, for a given mass of nitric oxide loaded into the polymer carrier, the period of time over which nitric oxide is released could be extended by factors of 10 and 100, respectively. Accordingly, the implantable medical device having such a polymer coating and barrier coating would be useful in providing localized drug delivery for an extended period to a patient after PTCA.
Line A of
Assuming nucleation sites 30 of a barrier material were deposited on the silicone polymer in a manner similar to that illustrated in
Similarly, the process parameters could be controlled so that nucleation sites 30 cover 75% of surface 29 of first layer 24 (which
One method by which the embodiment illustrated in
A solution of titanium ethoxide is created in dry ethanol at concentrations from about 0.1% to 10%. A polymer coated stent is exposed to an environment with controlled relative humidity between 20% and 100% for between 0.5 and 60 minutes. The stent is then immersed in the alkoxide solution for between 1 and 60 seconds, and then removed. The excess alkoxide solution is rinsed off using ethanol or water. The stent is then dried in a suitable environment (temperature from 20� to 70� C. for 1 to 60 minutes).
Another method by which the embodiments illustrated in
Biocompatible inorganic barriers that may be deposited by electroless deposition include palladium (Pd) and gold (Au). Reducing agents for palladium include hypophosphite, amineborane, and hydrazine. Reducing agents for gold include borohydride, amineborane, and hydrazine. The principal reactions that are believed to occur during electroless palladium plating, using hypophosphite as a reducing agent in one commercial application, are shown below.
"Training Course in Electroplating and Surface Finishing," �1998 by American Electroplaters and Surface Finishers Society, Inc., AESF, 12644 Research Parkway, Orlando, Fla. 32826-3298.
According to the authors, the hypophosphite ion is thought of as being catalytically oxidized (dehydrogenated) on the surface to be plated to release hydride ions (H—) which are then available for reduction of palladium ions at the surface. The products of the reactions are thus the palladium-phosphorus deposit, phosphite ions, hydrogen ions, and hydrogen gas. The phosphorus may be codeposited with palladium to the extent of 1 to 15 percent by weight by a mechanism shown in reaction (3) above.
For example, to provide a palladium barrier coating, an implantable medical device having a polymer coating with a finely etched surface is immersed in an aqueous solution of 5 g/L SnCl2 and 5 mL/L HCL for a period of about 5 minutes at 35� C. The implantable medical device is then immersed in a plating solution at a temperature of 50� C., the plating solution including 2 g/L of palladium chloride, 160 mL/L of ammonium hydroxide (27%), 26 g/L of ammonium chloride, and 10 g/L of sodium hyposphosphite.
To provide a gold barrier coating, an implantable medical device having a polymer coating with a finely etched surface is immersed in an aqueous solution of 5 g/L SnCl2 and 5 mL/L HCL for a period of about 5 minutes at 35� C. The implantable medical device is then immersed in a plating solution at a temperature of 75� C., the plating solution including 5.8 g/L of potassium gold cyanide, 13.0 g/L of potassium cyanide, and 21.6 g/L of potassium borohydride.
Codeposition of phosporus and boron may occur in the electroless plating process given above. In another process which is commercially available, a proprietary reducing reagent is used that yields an electroless deposit of pure palladium that is free of phosphorus or boron. The process is known as the Pallatect™ process, and is available from Atotech USA, Inc. of Somerset, N.J. This process reportedly involves the steps of acid cleaning, microetching, activation, and electroless deposition of palladium.
While particular embodiments of the present invention have been shown and described, various changes and modifications can be made without departing from this invention in its broader aspects. For instance, while we have discussed the invention in conjunction with stents and grafts, artisans will appreciate that the invention may be used with any implantable medical device that can be used in conjunction with a drug-loaded polymer for localized drug delivery. For example, such barrier coatings may be applied to drug-loaded polymer coatings on catheters, cerebrospinal fluid shunts, drug delivery pacemaker leads, defibrillation electrodes, artificial hips and bones, breast implants, and other implanted devices. 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.
|Cited Patent
|Filing date
|Publication date
|Jul 21, 1980
|May 11, 1982
|Nippon Zeon Co., Ltd.
|Non-thrombogenic material comprising substrate which has been reacted with heparin
|Nov 7, 1985
|Mar 29, 1988
|Expandable Grafts Partnership
|Expandable intraluminal graft, and method and apparatus for implanting an expandable intraluminal graft
|Mar 13, 1987
|Jan 31, 1989
|Cook Incorporated
|Endovascular stent and delivery system
|Sep 5, 1986
|Nov 21, 1989
|American Cyanamid Company
|Polyesters containing alkylene oxide blocks as drug delivery systems
|Oct 19, 1987
|Dec 12, 1989
|Medtronic, Inc.
|Intravascular radially expandable stent and method of implant
|Jun 14, 1988
|Jun 5, 1990
|University Of Utah
|Heterogeneous interpenetrating polymer networks for the controlled release of drugs
|Dec 30, 1988
|Jul 17, 1990
|Ube-Nitto Kasei Co., Ltd.
|Method for manufacturing a synthetic vascular prosthesis
|Apr 6, 1990
|Dec 18, 1990
|Minnesota Mining And Manufacturing Company
|Article having non-crosslinked crystallized polymer coatings
|Oct 14, 1988
|May 28, 1991
|Trustees Of Columbia University In The City Of New York
|Infection-resistant compositions, medical devices and surfaces and methods for preparing and using same
|Jun 28, 1990
|Nov 12, 1991
|Schneider (Usa) Inc.
|Self-expanding prosthesis having stable axial length
|Apr 12, 1990
|Dec 10, 1991
|Schneider (U.S.A.) Inc.
|Radially expandable fixation member
|May 4, 1990
|Jan 7, 1992
|Interventional Thermodynamics, Inc.
|Method and apparatus for maintaining patency in the body passages
|May 17, 1990
|Mar 3, 1992
|Wayne State University
|Method for treating an arterial wall injured during angioplasty
|Jul 23, 1990
|May 12, 1992
|Case Western Reserve University
|Process for producing hydroxylated plasma-polymerized films and the use of the films for enhancing the compatiblity of biomedical implants
|Sep 14, 1990
|Nov 17, 1992
|Michael Froix
|Expandable polymeric stent with memory and delivery apparatus and method
|Mar 15, 1989
|Nov 24, 1992
|Terumo Kabushiki Kaisha
|Medical material containing covalently bound heparin and process for its production
|Apr 24, 1992
|Nov 2, 1993
|Michael Froix
|Method of using expandable polymeric stent with memory
|Jan 29, 1992
|Dec 21, 1993
|C. R. Bard, Inc.
|Medical apparatus having protective, lubricious coating
|Nov 8, 1991
|Mar 8, 1994
|Mediventures, Inc.
|Body cavity drug delivery with thermoreversible gels containing polyoxyalkylene copolymers
|Jun 9, 1992
|Mar 29, 1994
|Mediventures, Inc.
|Topical drug delivery with polyoxyalkylene polymer thermoreversible gels adjustable for pH and osmolality
|Sep 13, 1991
|Apr 5, 1994
|Mediventures, Inc.
|Ophthalmic drug delivery with thermoreversible polyoxyalkylene gels adjustable for pH
|Nov 8, 1991
|Apr 26, 1994
|Mediventures, Inc.
|Drug delivery by injection with thermoreversible gels containing polyoxyalkylene copolymers
|Aug 4, 1993
|Jul 12, 1994
|Endoluminal Therapeutics, Inc.
|Method and apparatus for treatment of focal disease in hollow tubular organs and other tissue lumens
|Jul 5, 1991
|Jul 19, 1994
|Massachusetts Institute Of Technology
|Controlled drug delivery using polymer/pluronic blends
|Nov 3, 1993
|Sep 6, 1994
|Leonard Bloom
|Method and device for inhibiting HIV, hepatitis B and other viruses and germs when using a catheter in a medical environment
|Feb 6, 1992
|Sep 6, 1994
|Interface Biomedical Laboratories, Corp.
|Intravascular stent and method for conditioning the surfaces thereof
|Aug 30, 1993
|Jan 10, 1995
|Med Institute, Inc.
|Thrombolytic treated intravascular medical device
|Apr 28, 1993
|May 23, 1995
|Terumo Kabushiki Kaisha
|Thermoplastic polymer composition and medical devices made of the same
|Nov 15, 1993
|Sep 5, 1995
|Harbor Medical Devices, Inc.
|Medical device polymer
|Nov 19, 1992
|Oct 3, 1995
|Case Western Reserve University
|Anticoagulant plasma polymer-modified substrate
|Oct 5, 1993
|Oct 31, 1995
|Board Of Regents, The University Of Texas System
|Multifunctional organic polymers
|Apr 26, 1993
|Nov 7, 1995
|Medtronic, Inc.
|Intravascular stent and method
|Jun 26, 1991
|Dec 12, 1995
|The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services
|Method and device for reversible sterilization
|Jun 7, 1995
|Oct 29, 1996
|Harbor Medical Devices, Inc.
|Medical device polymer
|Apr 1, 1994
|Nov 5, 1996
|Localmed, Inc.
|Method and apparatus for sequentially performing multiple intraluminal procedures
|Feb 1, 1995
|Nov 19, 1996
|Schneider (Usa), Inc.
|Process for producing slippery, tenaciously adhering hydrogel coatings containing a polyurethane-urea polymer hydrogel commingled with at least one other, dissimilar polymer hydrogel
|Sep 16, 1994
|Nov 26, 1996
|Ramot Of Tel Aviv University
|Thromboresistant surface treatment for biomaterials
|Mar 30, 1995
|Feb 25, 1997
|Advanced Cardiovascular Systems, Inc.
|Drug loaded polymeric material and method of manufacture
|Jun 23, 1993
|Mar 4, 1997
|Froix; Michael
|Expandable polymeric stent with memory and delivery apparatus and method
|Jun 7, 1995
|Mar 11, 1997
|Med Institute, Inc.
|Coated implantable medical device
|Apr 19, 1991
|Apr 1, 1997
|Trustees Of Columbia University In The City Of New York
|Infection-resistant compositions, medical devices and surfaces and methods for preparing and using same
|Jun 7, 1995
|Apr 29, 1997
|Medtronic, Inc.
|Intravascular stent and method
|Jul 18, 1994
|May 13, 1997
|Cortrak Medical, Inc.
|Phoretic balloon catheter with hydrogel coating
|Sep 22, 1994
|Jul 22, 1997
|Advanced Cardiovascular Systems, Inc.
|Metal reinforced polymer stent
|Nov 27, 1995
|Aug 19, 1997
|Rutgers, The State University
|Copolymers of tyrosine-based polycarbonate and poly(alkylene oxide)
|Feb 1, 1995
|Sep 2, 1997
|Schneider (Usa) Inc.
|Process for producing slippery, tenaciously adhering hydrogel coatings containing a polyurethane-urea polymer hydrogel commingled with a poly (n-vinylpyrrolidone) polymer hydrogel
|Jul 27, 1995
|Sep 16, 1997
|Micro Therapeutics, Inc.
|Compositions for use in embolizing blood vessels
|Jul 6, 1995
|Sep 23, 1997
|Terumo Kabushiki Kaisha
|Medical instruments that exhibit surface lubricity when wetted
|Nov 15, 1996
|Oct 7, 1997
|Quanam Medical Corporation
|Endoprosthetic device with therapeutic compound
|Jun 22, 1995
|Oct 14, 1997
|Razavi; Ali
|Temporary stent
|Jun 7, 1995
|Oct 21, 1997
|Medtronic, Inc.
|Intravascular stent and method
|Aug 22, 1996
|Dec 23, 1997
|Advanced Cardiovascular Systems, Inc.
|Polymer film for wrapping a stent structure
|Feb 22, 1995
|Dec 30, 1997
|Meadox Medicals, Inc.
|Method of providing a substrate with a hydrophilic coating and substrates, particularly medical devices, provided with such coatings
|Jun 7, 1995
|Feb 10, 1998
|Angiogenesis Technologies, Inc.
|Anti-angiogenic compositions and methods of use
|Dec 19, 1995
|Mar 3, 1998
|Talison Research
|Plasma deposited film networks
|Jun 7, 1995
|Mar 17, 1998
|St. Jude Medical, Inc.
|Bioresorbable heart valve support
|Jan 2, 1997
|Apr 7, 1998
|Scimed Life Systems, Inc.
|Intravascular stent pump
|Aug 8, 1996
|May 5, 1998
|The General Hospital Corporation
|Targeted co-polymers for radiographic imaging
|Feb 14, 1996
|Jun 9, 1998
|Shikani; Alain H.
|Anti-infective and anti-inflammatory releasing systems for medical devices
|Oct 9, 1996
|Jul 7, 1998
|Medtronic, Inc.
|Intravasoular stent and method
|Feb 10, 1997
|Aug 4, 1998
|Inflow Dynamics Inc.
|Biodegradable coating with inhibitory properties for application to biocompatible materials
|Apr 28, 1995
|Aug 11, 1998
|Flex Products, Inc.
|Barrier film having high colorless transparency and method
|May 8, 1996
|Sep 1, 1998
|Emed Corporation
|Microporous catheter
|Jun 7, 1995
|Oct 13, 1998
|Medtronic, Inc.
|Blood-contacting medical device and method
|Oct 9, 1996
|Oct 20, 1998
|Medtronic, Inc.
|Method for delivering a therapeutic substance to a body lumen
|Oct 31, 1996
|Oct 20, 1998
|Med Institute, Inc.
|Coated implantable medical device
|Oct 11, 1996
|Nov 3, 1998
|Micro Therapeutics, Inc.
|Methods for embolizing vascular sites with an emboilizing composition comprising dimethylsulfoxide
|Feb 21, 1995
|Nov 3, 1998
|Imarx Pharmaceutical Corp.
|Cationic lipids and the use thereof
|Apr 27, 1995
|Nov 17, 1998
|Medtronic, Inc.
|Intravascular stent and method
|Jun 13, 1996
|Nov 17, 1998
|Schneider (Usa) Inc
|Drug release stent coating process
|May 6, 1994
|Dec 1, 1998
|Endoluminal Therapeutics, Inc.
|Local polymeric gel cellular therapy
|Apr 28, 1994
|Dec 15, 1998
|Focal, Inc.
|Methods for intraluminal photothermoforming
|May 5, 1997
|Dec 15, 1998
|Schneider (Usa) Inc
|Process for hydrophilicization of hydrophobic polymers
|Feb 14, 1997
|Dec 22, 1998
|Microtherapeutics, Inc.
|Compositions for use in embolizing blood vessels
|Aug 18, 1997
|Dec 29, 1998
|Meadox Medicals, Inc.
|Bioresorbable compositions for implantable prostheses
|Jun 19, 1996
|Jan 5, 1999
|Localmed, Inc.
|Method and apparatus for sequentially performing multiple intraluminal procedures
|Sep 2, 1997
|Jan 5, 1999
|Sitek, Inc.
|Silicon micro machined occlusion implant
|Jan 25, 1995
|Jan 12, 1999
|Board Of Regents, The University Of Texas System
|Gels for encapsulation of biological materials
|Mar 4, 1997
|Jan 12, 1999
|St. Elizabeth's Medical Center
|Fas ligand compositions for treatment of proliferative disorders
|Aug 6, 1997
|Feb 2, 1999
|Medtronic, Inc.
|Blood contacting medical device and method
|Jun 18, 1997
|Feb 9, 1999
|Boston Scientific Corporation
|Method of providing a substrate with a bio-active/biocompatible coating
|Feb 24, 1997
|Feb 23, 1999
|Cook Incorporated
|Silver implantable medical device
|May 29, 1996
|Mar 2, 1999
|Ethicon, Inc.
|Stent and method of varying amounts of heparin coated thereon to control treatment
|Jul 28, 1995
|Mar 2, 1999
|Rutgers, The State University Of New Jersey
|Polymeric drug formulations
|Jan 23, 1997
|Mar 9, 1999
|Focal, Inc.
|Targeted delivery via biodegradable polymers
|Sep 15, 1997
|Apr 20, 1999
|St. Jude Medical, Inc.
|Bioresorbable heart valve support
|Aug 26, 1994
|Apr 27, 1999
|Children's Medical Center Corporation
|Trophic factors for central nervous system regeneration
|Aug 4, 1997
|May 4, 1999
|Schneider (Usa) Inc.
|Balloon expandable braided stent with restraint
|Nov 6, 1997
|Jun 15, 1999
|Heartport, Inc.
|Methods and devices for cannulating a patient's blood vessel
|Feb 1, 1995
|Jul 6, 1999
|Schneider Inc.
|Slippery, tenaciously adhering hydrogel coatings containing a polyurethane-urea polymer hydrogel commingled with a poly(N-vinylpyrrolidone) polymer hydrogel, coated polymer and metal substrate materials, and coated medical devices
|Apr 18, 1996
|Jul 20, 1999
|Kazunori Kataoka
|Heterotelechelic block copolymers and process for producing the same
|Apr 22, 1997
|Aug 3, 1999
|Katoot; Mohammad W.
|Method for modifying the surface of an object
|Aug 1, 1997
|Sep 14, 1999
|Scimed Life Systems, Inc.
|Local application of oxidizing agents to prevent restenosis
|Apr 23, 1997
|Sep 21, 1999
|Board Of Regents, The University Of Texas System
|pH dependent polymer micelles
|Oct 14, 1997
|Oct 5, 1999
|Ali Razavi
|Temporary stent
|Nov 24, 1997
|Oct 5, 1999
|Talison Research, Inc.
|Plasma deposited substrate structure
|Jan 29, 1997
|Oct 26, 1999
|Rochester Medical Corporation
|Method of making catheter
|Jul 29, 1997
|Nov 9, 1999
|Terry; Paul B.
|Implant for preventing conjunctivitis in cattle
|Sep 22, 1997
|Nov 9, 1999
|Schneider (Usa) Inc
|Method of applying drug-release coatings
|Dec 3, 1998
|Jan 1, 2002
|Scimed Life Systems, Inc.
|Polymeric coatings for controlled delivery of active agents
|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).
|Atotech, Atotech Global-Home, http://www.atotech.com/start.php3?cl my id=30574, printed Mar. 17, 2004 (1 page).
|Atotech, Pallatect(TM) A Process For Autocatalytic Deposition of Palladium, http://www.insulectro.com/Pallatect.pdf, printed Mar. 17, 2004 (4 pages).
|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 a heparinizable material, J. Biomed. Mater. Res. 25:1259-1274 (Oct. 1991).
|Baudrand et al., Electroless Palladium, Past and Future, Proceedings of the AESF annual technical conference American Electroplaters and Surface Finishers Society, 1999, pp. 49-51.
|Chemical Business Newsbase, "Headline: Modern Plastics International: New PET barrier technologies show promise in beer bottles", Copyright 2000 FT Asia Intelligence Wire, Mar. 10, 2000 (1 page).
|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).
|DNP Products & Services-Packaging, "Barrier Carton for Liquid L-Carton L-Barrier L-Alumi," http://www.dnp.co.jp.international/pack/carton/carton 2.html, printed Mar. 17, 2004 (2 pages).
|DNP Products & Services-Packaging, "Barrier Carton for Liquid L-Carton L-Barrier L-Alumi," http://www.dnp.co.jp/interantional/pack/carton/carton 3.html, printed Mar. 17, 2004 (1 page).
|DNP Products & Services-Packaging, "Barrier Carton for Liquid L-Carton L-Barrier L-Alumi," http://www.dnp.co.jp/international/pack/carton/carton/carton 1.html, printed Mar. 17, 2004 (1 page).
|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).
|Electro-Coatings of Iowa, Inc., "Kanigen(R) Electroless Nickel Alloy," http://www.platingforindustry.com/electrocoatings/kantech.htm, printed Mar. 17, 2004 (3 pages).
|Erlat et al., Morphology And Gas Barrier Properties Of Thin SiO<SUB>x </SUB>Coatings On Polycarbonate: Correlations With Plasma-Enhanced Chemical Vapor Deposition Conditions, J. Mater. Res., vol. 15, No. 3, Mar. 2000, pp. 704-717.
|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).
|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).
|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).
|Mitsubishi Chemical Kohjin PAX Corporation, "How to Handle and Convert TECHBARRIER(R)," http://www.techbarrier.com/techbarrier/tech-kakou.htm, printed Mar. 17, 2004 (2 pages).
|Mitsubishi Chemical Kohjin PAX Corporation, "TECHBARRIER(R)-S," http://www.techbarrier.com/techbarrier/tech-s.htm, printed Mar. 17, 2004 (2 pages).
|Mitsubishi Chemical Kohjin PAX Corporation, "Transparent Excellent Gas Barrier Plastic Film . . . TECHBARRIER(R)," http://www.techbarrier.com/techbarrier/index.htm, printed Mar. 17, 2004 (3 pages).
|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).
|Modern Plastics, New PET Barrier Technologies Show Promise in Beer Bottle Advances to be on Tap At Industry Event, http://www.modplas.com/news/month 0100/gr01.htm, printed Dec. 3, 2002 (6 pages).
|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).
|Pharmaceutical & Medical Packaging News, "Film Preserves Blood Substitute," http://www.devicelink.com/grabber.php3?URL=http:www.devicelink.com/pmpn/achive, printed Dec. 10, 2003 (3 pages).
|Shigeno, Prevention of Cerebrovascular Spasm By Bosentan, Novel Endothelin Receptor, Chemical Abstract 125:212307 (1996).
|U.S. Appl. No. 09/894,293, filed Jun. 27, 2001, Roorda.
|U.S. Appl. No. 10/176,504, filed Jun. 21, 2002, Roorda et al.
|U.S. Appl. No. 10/176,510, filed Jun. 21, 2002, Hossainy et al.
|U.S. Appl. No. 10/177,117, filed Jun. 21, 2002, Hossainy.
|U.S. Appl. No. 10/177,154, filed Jun. 21, 2002, Hossainy et al.
|U.S. Appl. No. 10/198,912, filed Jul. 19, 2002, Ding et al.
|U.S. Appl. No. 10/320,899, filed Dec. 16, 2002, Shah 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.
|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 dellivery to a solid tumor, Journal of Controlled Release 50:79-92 (1998).
|Citing Patent
|Filing date
|Publication date
|May 17, 2005
|Apr 6, 2010
|Advanced Cardiovascular Systems, Inc.
|Poly(butylmethacrylate) and rapamycin coated stent
|May 16, 2005
|Dec 21, 2010
|Boston Scientific Scimed, Inc.
|Medical devices including metallic films
|Dec 29, 2004
|Mar 8, 2011
|Boston Scientific Scimed, Inc.
|Medical devices including a metallic film and at least one filament
|Jul 27, 2007
|Apr 26, 2011
|Boston Scientific Scimed, Inc.
|Articles having ceramic coated surfaces
|Nov 30, 2004
|Apr 26, 2011
|Endosphere, Inc.
|Method and apparatus for reducing obesity
|Nov 2, 2007
|May 10, 2011
|Boston Scientific Scimed, Inc.
|Deformable underlayer for stent
|Jul 11, 2007
|May 17, 2011
|Boston Scientific Scimed, Inc.
|Endoprosthesis coating
|May 23, 2007
|Jul 12, 2011
|Boston Scientific Scimed, Inc.
|Endoprosthesis with select ceramic morphology
|Sep 24, 2007
|Jul 19, 2011
|Boston Scientific Scimed, Inc.
|Endoprosthesis with coatings
|Jul 30, 2008
|Jul 26, 2011
|Boston Scientific Scimed, Inc.
|Bioerodible endoprosthesis
|May 9, 2008
|Aug 16, 2011
|Boston Scientific Scimed, Inc.
|Sep 13, 2007
|Aug 23, 2011
|Boston Scientific Scimed, Inc.
|Bioerodible metallic ENDOPROSTHESES
|Jul 11, 2007
|Aug 23, 2011
|Boston Scientific Scimed, Inc.
|Endoprosthesis coating
|Sep 17, 2007
|Sep 6, 2011
|Fujifilm Corporation
|Hydrophilic composition and hydrophilic member
|Nov 2, 2007
|Oct 4, 2011
|Boston Scientific Scimed, Inc.
|Stent with embedded material
|Apr 12, 2006
|Nov 1, 2011
|Boston Scientific Scimed, Inc.
|Endoprosthesis having a fiber meshwork disposed thereon
|Aug 2, 2007
|Nov 8, 2011
|Boston Scientific Scimed, Inc.
|Endoprosthesis with three-dimensional disintegration control
|Sep 13, 2007
|Nov 8, 2011
|Boston Scientific Scimed, Inc.
|Medical devices and methods of making the same
|Sep 13, 2007
|Nov 8, 2011
|Boston Scientific Scimed, Inc.
|Sep 14, 2007
|Nov 15, 2011
|Boston Scientific Scimed, Inc.
|Bioerodible endoprostheses and methods of making the same
|May 11, 2010
|Nov 29, 2011
|Boston Scientific Scimed, Inc.
|Drug-releasing stent with ceramic-containing layer
|Apr 5, 2007
|Nov 29, 2011
|Boston Scientific Scimed, Inc.
|Stents with ceramic drug reservoir layer and methods of making and using the same
|Feb 27, 2008
|Dec 6, 2011
|Boston Scientific Scimed, Inc.
|Medical device with a porous surface for delivery of a therapeutic agent
|Mar 4, 2009
|Dec 6, 2011
|Boston Scientific Scimed, Inc.
|Dec 27, 2007
|Dec 20, 2011
|Boston Scientific Scimed, Inc.
|Bioerodible endoprostheses and methods of making the same
|Feb 1, 2006
|Jan 3, 2012
|Boston Scientific Scimed, Inc.
|Bioabsorbable metal medical device and method of manufacture
|Nov 29, 2007
|Feb 21, 2012
|Boston Scientific Corporation
|Medical articles that stimulate endothelial cell migration
|Sep 14, 2007
|Mar 6, 2012
|Boston Scientific Scimed, Inc.
|Bioerodible endoprosthesis with biostable inorganic layers
|Feb 26, 2004
|Mar 20, 2012
|Boston Scientific Scimed, Inc.
|Medical devices
|Dec 15, 2005
|Apr 3, 2012
|Endosphere, Inc.
|Methods and devices to curb appetite and/or reduce food intake
|Apr 23, 2010
|Apr 10, 2012
|Boston Scientific Scimed, Inc.
|Medical devices including metallic films
|Mar 27, 2006
|May 29, 2012
|Boston Scientific Scimed, Inc.
|Medical devices comprising a porous metal oxide or metal material and a polymer coating for delivering therapeutic agents
|Nov 2, 2007
|Jul 10, 2012
|Boston Scientific Scimed, Inc.
|Endoprosthesis coating
|Jul 30, 2008
|Jul 17, 2012
|Boston Scientific Scimed, Inc.
|Medical device coating by laser cladding
|Dec 3, 2009
|Jul 31, 2012
|Boston Scientific Scimed, Inc.
|Medical implants including iridium oxide
|Jun 10, 2008
|Aug 7, 2012
|Boston Scientific Scimed, Inc.
|Bioerodible endoprosthesis
|Jun 17, 2009
|Sep 4, 2012
|Syntach Ag
|Device, a kit and a method for treatment of disorders in the heart rhythm regulation system
|Mar 2, 2010
|Sep 18, 2012
|Boston Scientific Scimed, Inc.
|Self-buffering medical implants
|Apr 24, 2009
|Oct 16, 2012
|Boston Scientific Scimed, Inc.
|May 21, 2010
|Nov 6, 2012
|Remon Medical Technologies Ltd.
|Method and device for electrochemical formation of therapeutic species in vivo
|Nov 16, 2006
|Nov 6, 2012
|Fujifilm Corporation
|Hydrophilic member and process for producing the same
|Sep 10, 2007
|Jan 15, 2013
|Boston Scientific Scimed, Inc.
|Medical devices with drug-eluting coating
|Oct 3, 2008
|Feb 26, 2013
|Boston Scientific Scimed, Inc.
|Medical implant having NANO-crystal grains with barrier layers of metal nitrides or fluorides
|Feb 3, 2010
|Apr 2, 2013
|Syntach Ag
|Electrical conduction block implant device
|Feb 27, 2008
|Apr 30, 2013
|Boston Scientific Scimed, Inc.
|Coated medical devices for abluminal drug delivery
|Aug 13, 2008
|May 7, 2013
|Abbot Cardiovascular Systems Inc.
|Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device
|Jun 17, 2009
|May 28, 2013
|Boston Scientific Scimed, Inc.
|Endoprosthesis coating
|Mar 7, 2006
|May 28, 2013
|Innovational Holdings, Llc
|Implantable medical device with beneficial agent concentration gradient
|May 25, 2010
|Nov 5, 2013
|Boston Scientific Scimed, Inc.
|Medical devices having nanoporous coatings for controlled therapeutic agent delivery
|May 25, 2007
|Nov 19, 2013
|Endosphere, Inc.
|Methods and devices to curb appetite and/or to reduce food intake
|Dec 29, 2004
|Nov 26, 2013
|Boston Scientific Scimed, Inc.
|Medical devices including metallic films and methods for making same
|Mar 14, 2012
|Dec 10, 2013
|Endosphere, Inc.
|Methods and devices to curb appetite and/or reduce food intake
|Apr 13, 2011
|Jan 7, 2014
|Endosphere, Inc.
|Method and apparatus for reducing obesity
|Dec 29, 2004
|Jan 21, 2014
|Boston Scientific Scimed, Inc.
|Flexible medical devices including metallic films
|Mar 22, 2011
|Mar 11, 2014
|Boston Scientific Scimed, Inc.
|Surface treated bioerodible metal endoprostheses
|Nov 21, 2011
|May 6, 2014
|Boston Scientific Scimed, Inc.
|Bioerodible endoprostheses and methods of making the same
|Jun 15, 2007
|Jul 8, 2014
|Boston Scientific Scimed, Inc.
|Medical devices with selective titanium oxide coatings
|Sep 14, 2007
|Aug 19, 2014
|Boston Scientific Scimed. Inc.
|Bioerodible endoprostheses and methods of making the same
|Jul 27, 2007
|Aug 26, 2014
|Boston Scientific Scimed, Inc.
|Drug eluting medical devices having porous layers
|Jun 28, 2006
|Aug 26, 2014
|Boston Scientific Scimed, Inc.
|Coatings for medical devices comprising a therapeutic agent and a metallic material
|Mar 2, 2009
|Sep 23, 2014
|Syntach Ag
|Electrical conduction block implant device
|Jan 5, 2006
|Sep 23, 2014
|Boston Scientific Scimed, Inc.
|Bioerodible endoprostheses and methods of making the same
|Sep 22, 2008
|Sep 30, 2014
|Waldemar Link Gmbh & Co. Kg
|Endoprosthesis component
|Feb 22, 2011
|Oct 21, 2014
|Boston Scientific Scimed, Inc.
|Medical devices including metallic film and at least one filament
|Oct 6, 2009
|Dec 2, 2014
|Boston Scientific Scimed, Inc.
|Coating for medical device having increased surface area
|Oct 12, 2006
|Dec 2, 2014
|DePuy Synthes Products, LLC
|Drug-impregnated encasement
|Apr 17, 2009
|Dec 30, 2014
|Boston Scientific Scimed, Inc.
|Medical devices having a coating of inorganic material
|Apr 23, 2009
|Jan 13, 2015
|Boston Scientific Scimed, Inc.
|Medical devices having inorganic particle layers
|Dec 29, 2004
|Mar 31, 2015
|Boston Scientific Scimed, Inc.
|Medical devices including metallic films
|Dec 29, 2004
|Apr 7, 2015
|Boston Scientific Scimed, Inc.
|Medical devices including metallic films
|Jul 16, 2008
|Jun 23, 2015
|Endosphere, Inc.
|Conformationally-stabilized intraluminal device for medical applications
|Feb 15, 2013
|Jul 7, 2015
|Endosphere, Inc.
|Methods and devices for delivering or delaying lipids within a duodenum
|Nov 19, 2003
|Aug 25, 2015
|Advanced Cardiovascular Systems, Inc.
|Biologically beneficial coatings for implantable devices containing fluorinated polymers and methods for fabricating the same
|Jul 17, 2008
|Mar 15, 2016
|Boston Scientific Scimed, Inc.
|Endoprosthesis having a non-fouling surface
|Jun 17, 2009
|Mar 29, 2016
|Syntach Ag
|Device, a kit and a method for treatment of disorders in the heart rhythm regulation system
|Feb 15, 2013
|May 31, 2016
|Endosphere, Inc.
|Methods and devices to curb appetite and/or reduce food intake
|Dec 27, 2012
|Jul 5, 2016
|DePuy Synthes Products, Inc.
|Films and methods of manufacture
|Jan 17, 2006
|Jul 26, 2016
|Syntach Ag
|Electrical conduction block implant device
|Feb 16, 2006
|Dec 27, 2016
|Boston Scientific Scimed, Inc.
|Medical balloons and methods of making the same
|Oct 1, 2014
|Feb 28, 2017
|DePuy Synthes Products, Inc.
|Drug-impregnated encasement
|Nov 30, 2004
|Sep 1, 2005
|Binmoeller Kenneth F.
|Method and apparatus for reducing obesity
|May 17, 2005
|Sep 22, 2005
|Daniel Castro
|Barriers for polymer-coated implantable medical devices and methods for making the same
|Aug 4, 2005
|Aug 10, 2006
|Arrow International Limited
|Sealing of Plastic Containers
|Dec 15, 2005
|Aug 10, 2006
|Binmoeller Kenneth F
|Methods and devices to curb appetite and/or reduce food intake
|Dec 20, 2006
|Jul 26, 2007
|Cornova, Inc.
|Flexible expandable stent
|Feb 16, 2006
|Aug 16, 2007
|Jan Weber
|Medical balloons and methods of making the same
|Feb 16, 2006
|Aug 16, 2007
|Jan Weber
|Bioerodible endoprostheses and methods of making the same
|Sep 17, 2007
|Jul 24, 2008
|Satoshi Tanaka
|Hydrophilic composition and hydrophilic member
|Aug 22, 2007
|Jul 24, 2008
|Cornova, Inc.
|Implantable devices and methods of forming the same
|Aug 22, 2007
|Sep 4, 2008
|Cornova, Inc.
|Implantable devices having textured surfaces and methods of forming the same
|Mar 11, 2008
|Oct 2, 2008
|Satoshi Hoshi
|Hydrophilic member and undercoating composition
|May 13, 2008
|Jan 29, 2009
|Fujifilm Corporation
|Two-liquid composition, hydrophilic composition and hydrophilic member
|Sep 22, 2008
|Mar 26, 2009
|Waldemar Link Gmbh & Co. Kg
|Endoprosthesis component
|Nov 29, 2007
|Jun 4, 2009
|Boston Scientific Corporation
|Medical articles that stimulate endothelial cell migration
|Mar 2, 2009
|Jul 2, 2009
|Richard Cornelius
|Two-Stage Scar Generation for Treating Atrial Fibrillation
|Apr 25, 2008
|Jul 23, 2009
|Chameleon Scientific Corporation
|Atomic plasma deposited coatings for drug release
|Mar 20, 2009
|Sep 24, 2009
|Makoto Fukuda
|Hydrophilic composition and hydrophilic treated member
|Nov 16, 2006
|Oct 22, 2009
|Satoshi Hoshi
|Surface-hydrophilic structure
|Apr 17, 2009
|Oct 22, 2009
|Boston Scientific Scimed, Inc.
|Medical devices having a coating of inorganic material
|Nov 16, 2006
|Nov 5, 2009
|Satoshi Hoshi
|Hydrophilic member and process for producing the same
|Dec 10, 2009
|Aug 19, 2010
|Harald Zimmermann
|Thermally Sprayed Surface Layer As Well As An Orthopedic Implant
|Mar 24, 2010
|Sep 30, 2010
|Biotronik Vi Patent Ag
|Drug eluting medical implant with porous surface
|Dec 18, 2008
|Mar 3, 2011
|Nanosurface Technologies, Llc
|Nanofilm Protective and Release Matrices
|Dec 6, 2010
|Jun 9, 2011
|Breath Limited
|Sealing of Plastic Containers
|Jul 2, 2009
|Jun 9, 2011
|Mckinley James T
|Methods and devices for delivering or delaying lipids within a duodenum
|Apr 13, 2011
|Aug 4, 2011
|Binmoeller Kenneth F
|Method and apparatus for reducing obesity
|Dec 8, 2014
|Jun 18, 2015
|Mayo Foundation For Medical Education And Research
|Prostacyclin compositions for regulation of fracture repair and bone formation
|Apr 24, 2015
|Oct 22, 2015
|Biocompatible packaging
|Oct 22, 2009
|Jun 23, 2010
|Sulzer Metco AG
|Thermally injected surface layer and orthopaedic implant
|U.S. Classification
|423/423, 623/1.1, 623/1.23, 623/1.15
|International Classification
|Cooperative Classification
|European Classification
|Mar 20, 2009
|Fee payment
Year of fee payment: 4
|Mar 18, 2013
|Fee payment
Year of fee payment: 8
|May 19, 2017
|Maintenance fee reminder mailed


text:
- "No man but a blockhead ever wrote except for money." - Dr. Samuel Johnson
Tag Archives: Geico pig
One For The Missus (pat. pending)
Of all the truly excellent Geico spots we've seen over the past half-dozen years, this just might be the best. Cool. Thanks Mr. G. Advertisements
Posted in Uncategorized Tagged Geico pig, The Missus 1 Comment

subset: commoncrawl


text:
Aralsk, Kazakhstan
Aral Sea
Rusting ships sit in a desert where a sea used to be.
A man made environmental disaster has left a once-great sea dry, the land polluted, and the locals inundated with disease.
The destruction of the Aral Sea is a strange legacy of the US Civil War, when the US cut off cotton exports to the outside world. In Russia, the decision was made to irrigate land in the recently assimilated central Asian countries and develop their own cotton industry. At the time, the Aral Sea was the world's fourth largest inland sea.
By 1937, the area had successfully become a major exporter of cotton with little impact on the natural environment. But starting in the 1950s, aggressive Soviet irrigation projects stemming from the Aral Sea started to have an adverse impact. Between 1960 and 1980, the water level dropped by 20 meters, exposing sea beds, and increasing the salinity levels of the lake until the fish population died off.
Today, the sea is nearly dry and has separated into two much smaller seas. Fishing boats sit aground, rusting in a vast contaminated desert wasteland.
To make what is an already horrific situation worse, on the island of Vozrozhdeniye, in the center of the former Aral Sea are the remains of the Soviet Union's extensive bio-warfare experimentation. Experiments with anthrax, plague and smallpox were conducted here in open air tests in the 1950s. The base was hastily abandoned in the 1990s following the breakup of the Soviet Union, the canisters of disease agents buried, and the land coated with bleach. In the years since the abandonment, the island has slowly become part of the mainland.
A US anti-terrorist team visited the remains of the island in 2001, in theory to clean up any remaining bio-warfare agents, but a visit by author Nick Middleton in 2005 showed signs that there is still plenty to be worried about. He found the island crawling with local looters, disturbing old buildings, and wearing no protection. Test tubes and feeding troughs for test animals were still in place. Although some diseases like smallpox can be virtually eliminated by exposure to UV over time, the same can not be said for Anthrax which has a very long and stubborn lifespan, and once inhaled, has a mortality rate of 90%.
The local population suffers from abnormally high cancer rates, tuberculosis, and anemia, made worse by the poverty caused from the death of the formerly lucrative local fishing industry. The causes for the diseases are being traced back to the pesticides used on the cotton crops to the south.
In 2000, UNESCO developed a rescue plan for the area which attempts to reclaim water for the sea by 2025, but it is regarded as unrealistic by many. The people with most ability to directly impact this is the government of Uzbekistan, where the cotton fields are, but they are reluctant to make any changes as their country's delicate economy hinges on the success of the cotton crop. The World Bank funded a small dam that has protected and even raised water levels in the northern portion of the sea, but most agree that the rest could disappear completely within 15 years.
The remains of the sea are remote, reachable after a day's drive through the desert.
Update November 2017: The local Mayor ordered the removal and scrapping of all rusting Aral ships; the only example now remaining is at the Aralsk Port Museum.
Know Before You Go
The old fishing town of Aralsk at the north of the Aral Sea is on the Northern Kazakhstan train line, but is difficult to get to as it is between stops, and is a 36 hour train ride from Almaty.
- Aral Sea Foundation
- http://www.aralsea.org/
- United Nations Environment Programme - Aral Sea
- http://na.unep.net/digital_atlas2/webatlas.php?id=11
- http://en.wikipedia.org/wiki/Aral_Sea
- http://en.wikipedia.org/wiki/Vozrozhdeniya_Island
- A visit to the bio-warfare island - Guardian UK
- http://www.guardian.co.uk/science/2005/apr/21/russia.internationalnews
- Anthrax Island - New York Times
- http://www.nytimes.com/2003/01/12/magazine/anthrax-island.html?sec=&spon=&partner=permalink&exprod=permalink


text:
Click on Thumbnails to see full size images.
Please note that over time links change or are no longer online. This is known as link rot or
link decay.
As such, links may appear that were valid originally, but no longer are.
Images that the Drudge Report links to often expire
after several weeks, consequently we usually only display the original link, not the images
after serveral weeks. You can still click on the link to see if the original image is still available.
DrudgeReportArchive.com © 2017 [DMCA]
CT Inc.
Tag cloud phrases:addresses american american military calls backers contact patients data federal direct contact employee hackers federal employee federal personnel hackers personnel kill list kill military list addresses massive breach military personnel personnel data personnel direct personnel isis personnel posts posts kill


text:
The Navy's new Littoral Combat Ships (LCS), which are supposed to be able to carry out a variety of missions at high speeds in shallow water, have serious design and technical problems that could mean the multi-billion dollar fleet won't deliver its "promised capability," says a report by the Government Accountability Office (GAO).
The report raises questions about the ability of the program's two first ships -- USS Freedom and USS Independence -- to hunt submarines, deal with mines and to launch smaller boats, especially in heavy seas. The GAO also suggests that Freedom was deployed too early, and that the various problems have increased the price of the two ships' seaframes by almost $700 million. Many of the problems, says the report, stem from putting Freedom into service before issues with its frame were resolved and the ship was fully outfitted.
Freedom operates out of San Diego. Independence has been on the East Coast, undergoing upgrades, outfitting and testing. But San Diego is its assigned home port.
"Until mission packages are proven, the Navy risks investing in a fleet of ships that does not deliver promised capability," the GAO report says.
The report was released one week after the Navy announced that it has delayed a decision on which contractor will be chosen to build the next batch of LCS vessels. The contract is worth billions of dollars. The Navy said little about why it chose to postpone the decision until later this year.
Admiral Gary Roughead, Chief of Naval Operations, has acknowledged the large cost overruns on the program. But he said in a speech last year, the LCS "is a ship that is going to serve us very, very well regionally, and in the types of missions that we'll be performing."
Freedom was designed and built by an industry team led by Lockheed Martin. The company pursued a different design than General Dynamics, which led the team that built Independence. The companies and its partners are now building the third (LCS3) and fourth (LCS4) ships in the line. The Navy plans to build as many as 55 of the vessels at a cost of at least $25 billion.
The GAO report discusses a variety of design and technical problems with the frames of Freedom and Independence. It goes on to say that, "Key mine countermeasures and surface warfare systems have encountered technical issues that have delayed their development and fielding. Further, Navy analysis of LCS anti-submarine warfare systems found these capabilities did not contribute significantly to the anti-submarine warfare mission."
The report also says that ,"The Navy deferred testing of (Freedom's) launch, handling, and recovery system -- a system instrumental to deploying and recovering mission package elements (boats and unmanned vehicles) that, if not performing adequately, will impair LCS capability.
"To date, a full demonstration of this system remains incomplete. Navy simulations to date have identified risks in safely launching and recovering mission systems that experience pendulous motion during handling -- such as the remote multi-mission vehicles and unmanned surface vehicle systems."
Independence has encountered similar problems, especially when it comes to recovering boats and unmanned vehicles.
The Navy and its contractors have been trying the fix the various problems, an undertaking that has contributed to a large increase in the cost of the ships. GAO says the initial budget of Freedom's seaframe has grown from $215.5 million to $537 million. The budgeted cost of the Independence seaframe has increased from $256.5 million to $637 million.
San Diego's military payroll highest in the nationCopyright © 2017, The San Diego Union-Tribune


text: On Sat, May 22, 2004 at 10:03:37AM +0800, Jason Lim wrote: > > > Checking `lkm'... You have 3 process hidden for readdir command > > > You have 3 process hidden for ps command > > > Warning: Possible LKM Trojan installed > > > > > > Sometimes chkrootkit returns nothing detected and every time rkhunter > > > tells me nothing is wrong. Is this a false positive with chkrootkit > and > > > debian woody? chkrootkit on nearly anything occasionally gives this false positive. I believe it is something to do with normal processes terminating or spawning at the time chkrootkit is looking for hidden processes. Hence the word "Possible" in its report. If you run chkrootkit again, you will probably not see the message again. If you repeatedly see that message every time you run chkrootkit, then you can start panicing. ---------------------------------------------------------------- Donovan Baarda http://minkirri.apana.org.au/~abo/ ----------------------------------------------------------------


text:
I like how crispy they are and the flavor, and I also like that they are perfect for not only eating alone, but for dipping, putting some cheese and meats on, and even packing while we head out on our road trips this summer. With the flavors, we were able to try four different ones, and as a family we found the Cheddar Cheese Baked Crackers to be the favorite for everyone. Though I found the Multi-Grain to be a close second for me.
Then when it comes to bringing out the Milton's Gluten Free Baked Crackers when we have guests over, I like that we can put all four out, giving people a variety of crackers to choose from for eating alone, dipping, and more! In all, making the Milton's Gluten Free Baked Crackers a must have to add to the menu when entertaining this summer, and a must have to add to the packing list when you head out with the family for those summer road trips as well! And to help make your summer a little better, the wonderful people from Milton's Craft Bakers' would like to give one of my amazing readers their own prize pack!
Product received, thank you to Milton's Craft Bakers' as well as the PR for supplying me with a product for this review, all opinions are my own.
Widget by Css Reflex | TutZone


text:
Bitcoin prizes are now available in the GiftHulk Store! Now you can get free Bitcoins without spending any of your own money! Here are examples of the last payments to users that were made by GiftHulk:
Following many questions from our users we have decided to provide some explanation regarding Bitcoin, answering questions such as "What is Bitcoin?" and "What can I buy with Bitcoin?"
What is Bitcoin?
Bitcoin(or Bit Coin) is an online financial network that people use to send payments from one person to another.
In many ways, Bitcoin is similar to conventional payment networks like Visa credit cards or Paypal. While Paypal and Visa conduct transactions in conventional currencies, the Bitcoin network conducts transactions in a new monetary unit – called Bitcoin.
U.S. government sees a lot of potential in Bitcoin market. Earlier this month, Federal Reserver Chairman Ben Bernanke told Congress that, while there are potential problems with Bitcoin, he believes the currency "may hold long-term promise, particularly if the innovations promote a faster, more secure and more efficient payment system." Other government officials echoed this positive sentiment during a Senate hearing early this week.
Where do bitcoins come from?
In a conventional financial system, new money is created by a central bank, such as the Federal Reserve. But the Bitcoin network doesn't have a central bank. In Bitcoin – hundreds of computers(called "bitcoin miners") scattered around the Internet work together to process Bitcoin transactions(this process is called "bitcoin mining").
Every 10 minutes, on average, a Bitcoin miner wins a computational race and gets a prize – 25 bitcoins, worth around $20,000(at the current Bitcoin exchange rate).
There are almost 12 million bitcoins in existence, so the total Bitcoin value is now around $10 billion.
Where to buy bitcoins?
* One option is to mine them yourself, but that's a very poor choice for beginners as you will have to compete in "bitcoin mining" of the same Bitcoin with hundreds thousands of other users.
* There is also an option to buy Bitcoins them with a conventional currency or trade Bitcoins with other users at Bitcoin exchanges.
* The best option – buy Bitcoins for Hulk Coins at the GiftHulk Store without hassle and without dealing with Bitcoin exchanges fees! This is your only place on the Web for fast and free Bitcoins, no Bitcoin faucet will give you this!
Okay, I bought some Bitcoins at the GiftHulk Store. Now what?
Bitcoins are stored in "Bitcoin wallets," which in this case are just files that contain encryption keys, or secret codes that allow you to transfer your bitcoins to other people.
There are several options:
* One is to store them yourself using one of the Bitcoin programs available for Mac, PC and Android.
* Another option is to entrust them to a third-party Web site known as "online Bitcoin wallet."
* A third option is what's known as a "paper wallet," where you print out your encryption keys and store them in a safe place, such as a safe deposit box.
Okay, I have some bitcoins and found a secure way to keep them. What do I do with them now?
* If you're using Bitcoin to buy stuff, you'll often deal with a third-party service, like Bitpay (supports 10,000+ merchants), which will process the Bitcoin transaction and convert Bitcoin to USD(ot other local currency) for vendors. For you, it'll work almost exactly the same as paying with a credit or debit card; just put in your wallet address, the item's amount, and hit "pay." Easy.
* You can also spend bitcoins in "real life." To spend them in person, you need a Bitcoin mobile app. Generally, the store you're buying from will show you a QR code representing the Bitcoin transaction. You then scan this QR code with your phone, and the mobile app will send the required number of Bitcoins to the store. Then you walk out the door with your purchases.
We hope that this blog post helped you understand what is Bitcoin, how you can buy Bitcoins at GiftHulk and what you can do with your Bitcoins. You are welcome to ask questions in the comments below!
If you are not GiftHulk user yet – you can sign up here


text:
The TideNation's power rankings look at the top 10 Alabama players raising their game:
Every week, we'll update these rankings to reflect how specific areas of the Alabama football program are improving.
Here's this week's power rankings:
1. LB C.J. Mosley: After pitching two shutouts and failing to allow a single point in nine quarters of play, the Alabama defense is back in the conversation of being the best in the country. Mosley, the heart and soul of the unit and the team's leading tackler, has been a constant. Against Arkansas, he had five tackles and forced a key fumble.
2. QB AJ McCarron: His numbers won't blow you away -- 11-for-16 for 189 yards and one touchdown passing against Arkansas -- but his effectiveness is without question. The junior quarterback has thrown seven touchdowns and no interceptions this season. His quarterback efficiency rating is an otherworldly 196.6.
3. LB Adrian Hubbard: Whether it was Tyler Wilson quarterbacking the Razorbacks or not, Hubbard was going to get after him. The sophomore outside linebacker was a menace in the backfield in Arkansas, pulling down three tackles, two for loss and one sack. His skill in pass rush is becoming more evident with each passing week.
4. WR Christion Jones: Could the fleet-footed slot receiver be McCarron's favorite target? After going without a catch against Michigan, Jones has had three catches in each of the last two games. He's used his speed to run away from linebackers and safeties, racking up 121 yards and two touchdowns.
5. RB T.J. Yeldon: Pretty soon we'll stop referring to Yeldon as a true freshman. The way he plays is beyond his years. Against Arkansas, he did just enough, carrying the ball 13 times for 57 yards and a touchdown. He also had an 18-yard reception. He is tied for second on the team in catches with six.
6. S Vinnie Sunseri: Sunseri has wasted no time transitioning from special teams star to impact defender in his sophomore season. He continued to make big plays against Arkansas, recording three tackles, helping on a tackle for loss and snatching a key interception that the offense turned into six points.
7. LB Nico Johnson: The senior leader on defense turned up his play in the SEC opener, keeping Arkansas' underneath passing game from ever materializing. He led the team in tackles with six and contributed to a tackle for loss.
8. K Cade Foster: Whatever Foster is doing differently this season, it's working. The kicker has turned a corner in 2012, both on kickoffs and field goals. He hit his second 50-plus yard attempt against Arkansas and put eight of nine kickoffs into the end zone for touchbacks.
9. C Barett Jones: The offensive line responded to a poor performance against WKU the week before. Against Arkansas, the line helped produce 225 yards rushing and 438 total yards of offense. And on a slick field, Jones was flawless at snapping the football. Not bad for a guy making his third career start at center.
10. WR Kevin Norwood: Norwood stays in the top 10 after a subpar performance against Arkansas, catching one pass for 14 yards and dropping another. The junior's body of work this season -- leading the team in receptions, yards and tied for first in touchdown grabs -- is enough to keep him on our rankings.
Honorable mention: CB Dee Milliner, NG Jesse Williams, S Ha'Sean Clinton-Dix, S Robert Lester, WR Amari Cooper, P Cody Mandell, RB Eddie Lacy.


text:
Senior Management Team Over the past few months, there have been some changes to NSCAD's senior management team. The administration of the university is led by NSCAD President Dianne Taylor-Gearing, along with:
• Sharon Johnson Legere, Vice President Finance and Administration • Dr. Ann-Barbara Graff, Vice President Academic and Research • Linda Hutchison, Associate Vice President University Relations • Terry Bailey, Acting Associate Vice President, Student Experience & RegistrarPolicy Framework Since July 2015, members of the senior management team along with the Directors of Facilities, Computer Services, and Human Resources, have been working on a policy framework for NSCAD. Kathy Connor, Executive Assistant, Governance and the President's Office, is charged with the stewardship of the policy development process and coordinating policy-related activity of the senior management team and Board of Governors.
Working with a policy review consultant, team members reviewed and identified gaps in NSCAD's existing policies.
The 60 policies on the books include everything from a Space Use Policy and Attendance Policy to the Code of Conduct. Twenty-three policies were identified as being in need of review, while other policies were created where gaps were acknowledged.
For example, policies developed include an Emerita Policy, Confidentiality and Privacy Policy, and Employee Recognition Policy.
As policies are developed, the next stage is review and approval, first by the senior management team and then by the Board of Governors on the recommendations of its four standing committees: Governance and Human Resources, Advancement, Financial and Physical Resources and Audit and Risk Oversight. As the policies are approved, they are being posted on the NSCAD University website in the section "About the University." The Policy Framework and template format are approved by the Board of Governors and have been posted. Newly developed policies and revised policies are in the final stages of approvals, although new policy development is ongoing.


text:
Ssangyong Korando Wagon 2016 for sale
1,271 Views
Silver 5 Door Petrol 2WD Sport A6
Translate this page :
- Vehicle
- 2016 Ssangyong Korando
- Body
- Silver 5 Door Wagon
- Engine
- 2000cc 6 Speed Tiptronic Petrol Engine
- Odometer
- Please contact seller for details.
- Stock Number
- 1075
- Fuel Economy
- 4/6 Star Rating, Yearly Cost: $2210, 7.9 litres/100km (source: Fuelsaver)
Seller Details
- Dealership:
- Dealer
- Address
- Otago
Brand New Korando Sport Auto... Great Buying At $31,990 + ORC, The New Korando Sport Automatic Includes The Ssangyong 5yr/100,000km Warranty Programme.
Aspiring Auto Court are proud to be Central Otago & Southern Lakes Ssangyong agents. We stock a large range of hatches, sedans, wagons & SUVs between our three branches.
If you are after a specific vehicle please let us know as we may be able to source it through our network of suppliers & buyers.
We can offer MTF finance hire purchase and lease options to approved customers with flexible terms to meet your needs along with Mechanical Breakdown Insurance.
Our team can supply a large range of parts & accessories including Ssangyong Genuine, Mont Blanc roof racks, roof boxes, bike racks, ski racks & more.
Contact us anytime for more information on See Call Now Number .
Air Conditioning
CD Player
Central Locking
Child seat anchor points
iPod Dock
MP3 Player
Steering Wheel Controls
Alloy Wheels
Electric Mirrors
Face Lift Model
Rear Wiper
Remote Central Locking
ABS Brakes
Electric Mirrors
Electric Windows
Fuel Injected
Power Steering


text:
- About
Who We Are
- Admissions
Join Fletcher
- Academics
Degrees + Programs
- Career Services
For Students + Employees
- Students
Life at Fletcher
- Research
Faculty + Centers
- News + Media
Fletcher Updates
- Alumni
Stay Connected
- About
Fletcher Summer Institute 2014
By Jessica Daniels On June 17, 2014 · Leave a Comment · In About Fletcher
It has been good to have the 15 Armenian students keeping us company at Fletcher for the past few weeks. Yesterday a new, and larger, group moved in to ensure that the building remains vibrant: the Fletcher Summer Institute for the Advanced Study of Non-Violent Conflict. The Institute is organized jointly by Fletcher and the International Center on Nonviolent Conflict.
Those who want to connect with the ideas being presented and discussed can review presentations from 2013, and can keep up with this year's program via the FSI Twitter feed.
Comments are closed.
Archives by Date
TagsApplication Boston Boston Marathon Business competitions Capstone Career CIERP Class of 2010 Coffee Hours Commencement Community Conferences Cool stuff! deadlines Dean Stavridis Dear Ariel decisions DME Early Notification Essays Faculty Spotlight First-Year Alumni Five-Year Updates Fletcher Forum Gender Ginn Library GRE Hall of Flags IBGC Internships Interview ISSP MIB OCS On the road Outside the classroom Paying for Grad School Professors suggest Recommendations Roxanne Social List Somerville Student Stories thesis waitlist


text:
Item #148-2626 (1 customer reviews)
Fit for royalty, our King and Queen flutes feature an elegant crown design on each flute … a masculine crown on one and a feminine crown on the other. Engraved personalization is available; please see details below. More details…
|We apologize but this product is no longer available. We are sorry for the inconvenience.
You may be interested in some of these related selections:
Twin Hearts Toasting Flutes
view all Wedding Toasting Flutes
Made of nickel plate and glass.
10-1/4" tall
Shipping Options:
We offer flat rate & expedited/next day shipping.
Click here for rates.
Rush Processing:
Because we understand that you may need your items sooner than the indicated timeframe, we offer Rush Processing for select items. If you are concerned that your order will not arrive in time for your wedding, please contact us so we can work with you personally.
Click here for more information
Drop Shipped Items:
There are a few items on the Web site that will be shipped to you directly from the manufacturer and will arrive separately from the rest of your order. These items typically include edibles, personalized ribbon, and some personalized embroidery.
International Shipping:
We can now ship internationally via our international shipping agent. We have partnered with Bongo International to fulfill our international orders.
5 out of 5 - May 2017 Wedding -
Anonymous (Wilmington)
Perfect for our theme.
Recommend: Yes, I would recommend this to a friend.
You will receive your first email shortly


text:
aldactone 50
ORDER Aldactone >>>> Click Here !<<<<
Click Image >>>>> >>>> Click Here <<<< ORDER Aldactone
aldactone for acne, , 25mg - 90 pills, Honduras.
aldactone 25 mg, , 25mg - 180 pills, France.
aldactone 100, , 25mg - 360 pills, Slovenia.
remedio aldactone, , 25mg - 60 pills, Czech Republic.
aldactone bodybuilding, , 25mg - 120 pills, Portugal.
medicamento aldactone, , 25mg - 360 pills, St. Maarten.
aldactone vs accutane, , 25mg - 60 pills, Uruguay.
aldactone vs accutane, , 25mg - 120 pills, Chile.
spironolactone aldactone, , 25mg - 120 pills, St. Maarten.
buy cheap aldactone pills, , 25mg - 180 pills, Angola.
aldactone and pregnancy, , 25mg - 360 pills, Ireland.
buy aldactone without rx, , 25mg - 60 pills, Saudi Arabia.
aldactone vs accutane, , 25mg - 120 pills, Hungary.
aldactone and pregnancy, , 25mg - 180 pills, Thailand.
aldactone 50, , 25mg - 360 pills, China (Fuzhou).
If any of the following symptoms of overdose manifest itself while enchanting spironolactone, be afflicted with predicament assistants straight away:buy cheapest online viagra does levitra work Symptoms of overdoseUnsystematic heartbeatnervousness stopping effexor xr buy viagra where numbness or tingling in the hands, feet, or lips cialis soft tabs cheap cialis generic order madcap with explicit lesions or minute raised lesions on the skinreddened peltclomid ovulation calendar boy alcohol and clomid weak point or heaviness of the legsSome of the side effects that can manifest itself with spironolactone may not requirement medical attention. As your stiff adjusts to the medicine during treatment these side effects may fail away. Your health heedfulness proficient may also be masterful to portray you in all directions ways to reduce or prevent some of these side effects. If any of the following side effects be prolonged, are bothersome or if you deliver any questions hither them, log in investigate with your vigorousness care skilful: bextra celebrex prescription vioxx cheap cialis tadalafil MetabolicJoined of the most quarrelsome and quickest tests in behalf of hyperkalemia is the electrocardiogram (ECG), which mostly demonstrates out-and-out, "tented", or "peaked" T-waves, if not QRS widening. The first genealogy of treatment on hyperkalemia with ECG changes is intravenous calcium. A defective stock therapy is move treatment with intravenous glucose 20% to 50% and patron insulin 0.25 to 0.50 units as regards every gram of glucose given. Alleviate hyperkalemia can every so often be successfully treated with sodium polystyrene sulfonate barter resin.Results of a case-controlled analyse revealed that sensibility breakdown patients who develop hyperkalemia while receiving spironolactone (the brisk ingredient contained in Aldactone) be biased to be older, likely to clothed diabetes, enjoy higher baseline potassium levels, and are receiving a beta-blocker. In this on, hyperkalemia requiring discontinuation of remedial programme occurred in 3.6% of patients and the speed of serious hyperkalemia (i.e., greater than 6.0 mEq/L) was 1.6%. In deviate from, another study reported that 24% of their courage breakdown patients developed hyperkalemia and 12% developed humourless hyperkalemia while receiving spironolactone. Also, 31% of patients developed hyponatremia.celebrex for back pain aldactone side effects aldactone acne Hyperchloremic metabolic acidosis is associated with spironolactone remedy in patients with liver infection and/or taxing renal dysfunction.[Ref]Metabolic side effects buy celebrex where have been the most tired side effects of spironolactone. Hyperkalemia has been reported in around 10% of patients, which has caused random muscle paralysis and death in rare cases. Hyperkalemia is particularly likely in patients with renal dysfunction. Hyponatremia has been reported in 12% of patients, and may be more likely in patients with liver disease scheduled to the nonosmotic loosing of antidiuretic hormone (ADH). Electrolyte disturbances contain been reported postmarketing.[Ref]EndocrineEndocrinologic side effects have been due to the antiandrogenic properties of spironolactone (the strenuous ingredient contained in Aldactone) Five percent to 30% of virile patients complained of gynecomastia, inefficacy or diminished libido. Female patients reported hirsutism, oligomenorrhea, amenorrhea, menorrhagia, and chest tenderness. These side effects appeared to be dose-related, and were more likely during long-term therapy. Gynecomastia may be more likely in some male patients with liver disability owing to the increased conversion of androgens to estrogens in unsmiling liver disease.[Ref]Spironolactone interferes with 17-hydroxylase vigour, buy aldactone without rx which causes a decrease in testosterone synthesis. It also inhibits the intracellular binding of dihydrotestosterone to its receptor.Rare cases of uninitiated women with liver condition who developed menarche contrariwise after spironolactone was discontinued are reported. Since estradiol union is to a limited dependent on testosterone synthesis, spironolactone may cause primary or secondary amenorrhea in adolescents.Renal side effects prescription drug celebrex celebrex dose aldactone 500 Results of a case-controlled study tell that guts decay patients who developed renal insufficiency while receiving spironolactone (the lively ingredient contained in Aldactone) tended to have a modulate baseline body burden, a higher baseline serum creatinine, required higher doses of ring diuretics, and were also apposite to be receiving a thiazide diuretic. In this on, the incidence of renal insufficiency requiring discontinuation of psychoanalysis was 3.7%. In place against, another study reported that 25% of their tenderness insolvency patients developed renal insufficiency while receiving spironolactone.[Ref]How should this medicament be used?Spironolactone comes as a tablet to consider as through mouth. It regularly is enchanted some time ago or twice a day. To refrain from you reminisce over to grab spironolactone, experience it wide the even so period(s) every day. Lay hold of spironolactone at almost the for all that time(s) every day. Follow the directions on your prescription categorize carefully, and require your doctor or posologist to rationalize any be involved in you do not understand. Take spironolactone undeniably as directed. Do not interpret more or less of it or fool it more over than prescribed nearby your doctor.celebrex purchase aldactone 50 celebrex manufacturer Your doctor may start you on a low dose of spironolactone and mark broaden your dose.Spironolactone controls order aldactone online high blood weight, edema, marrow failure, and hyperaldosteronism, but does not cure these conditions. It may take around 2 weeks or longer before the full upshot of spironolactone occurs. Proceed to take spironolactone orderly if you manipulate well. Do not halt irresistible spironolactone without talking to your doctor.
Website URL: http://palmiraecologica.com/component/k2/itemlist/user/93095 Email: Этот адрес электронной почты защищен от спам-ботов. У вас должен быть включен JavaScript для просмотра.


text:
Dallas Cowboys Womens My Cowboys Crew Tee
The Official Shop of the Dallas Cowboys presents the Dallas Cowboys Womens My Cowboys Crew Tee. Do you love the Cowboys? Show it off in this new women's t-shirt!
- 100% Cotton crew neck tee
- Screen print graphics with foil accents
- Officially licensed NFL product
Write a Review
Fields marked* are required
Please enter your review