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Biocompatible carrier containing L-arginine
L-arginine conjugated to a polymeric matrix is disclosed. The matrix can be used as, for example, a coating for an implantable medical device such as a stent.
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1. Field of the Invention
This invention relates to a biocompatible carrier containing L-arginine and L-arginine oligomers for introduction to a certain target cell population in a vascular region, such as smooth muscle cells or inflammatory cells, requiring modulation to ameliorate a diseased state, particularly for the treatment of stenosis or restenosis following a vascular trauma or disease. Moreover, the invention is directed to a composition containing L-arginine, or L-arginine oligomer thereof combined with a coating on an implantable device.
2. General Background and State of the Art
Percutaneous transluminal coronary angioplasty (PTCA) is a procedure for treating heart disease. A catheter assembly having a balloon portion is introduced percutaneously 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 lumen wall. The balloon is then deflated to a smaller profile to allow the catheter to be withdrawn from the patient's vasculature.
A problem associated with the above procedure includes formation of intimal flaps or torn arterial linings which can collapse and occlude the conduit after the balloon is deflated. Moreover, thrombosis and restenosis of the artery may develop over several months after the procedure, which may require another angioplasty procedure or a surgical by-pass operation. To reduce the partial or total occlusion of the artery by the collapse of arterial lining and to reduce the chance of the development of thrombosis and restenosis, a stent is implanted in the lumen to maintain the vascular patency.
Stents are used not only as a mechanical intervention but also as a vehicle for providing biological therapy. As a mechanical intervention, stents act as scaffoldings, functioning to physically hold open and, if desired, to expand the wall of the passageway. Typically, stents are capable of being compressed, so that they can be inserted through small vessels via catheters, and then expanded to a larger diameter once they are at the desired location. Examples in patent literature disclosing stents which have been successfully applied in PTCA procedures include stents illustrated in U.S. Pat. No. 4,733,665 issued to Palmaz, U.S. Pat. No. 4,800,882 issued to Gianturco, and U.S. Pat. No. 4,886,062 issued to Wiktor.
Biological therapy can be achieved by medicating the stents. Medicated stents provide for the local administration of a therapeutic substance at the diseased site. In order to provide an efficacious concentration to the treated site, systemic administration of such medication often produces adverse or toxic side effects for the patient. Local delivery is a preferred method of treatment in that smaller total levels of medication are administered in comparison to systemic dosages, but are concentrated at a specific site. Local delivery thus produces fewer side effects and achieves more favorable results. One proposed method for medicating stents involves the use of a polymeric carrier coated onto the surface of a stent. A solution which includes a solvent, a polymer dissolved in the solvent, and a therapeutic substance dispersed in the blend is applied to the stent. The solvent is allowed to evaporate, leaving on the stent surface a coating of the polymer and the therapeutic substance impregnated in the polymer.
Local administration of therapeutic agents via stents has shown some favorable results in reducing restenosis. However, development of restenosis remains a persistent problem which has not been significantly alleviated by therapeutic substances which are currently used in the market. Accordingly, there is a great need for better and more effective therapeutic compositions, and methods of administering the compositions, for the effective treatment of restenosis.
Nitric oxide (NO) has many beneficial effects, including vasodilation and inhibiting smooth muscle cell hyperproliferation. However, the temporal, optical and hydrolytic instability of nitric oxide donor moieties has rendered them inefficient for use in reducing restenosis. For example, it is conventionally known that NO is a free radical, has a very short half life and is fast quenching. As a result, long term benefits of reducing restenosis would be difficult to achieve with the use of conventional NO donors.
L-arginine is an amino acid that can be loaded to a higher total effective dose of NO than a conventional NO donor. One of the advantages of using L-arginine as an NO donor is that the rate of NO release from L-arginine is controlled and sustained, which is an improvement over using conventional NO donors. In addition, several molecular components are required in the biosynthesis of nitric oxide from L-arginine including the enzymes iNOS and eNOS, with L-arginine often being the limiting reagent in this reaction scheme. When L-arginine is absorbed by a cell in the presence of eNOS, nitric oxide is produced. In view of the beneficial effects of NO in reducing restenosis, there is a need in the art for a sustained delivery of L-arginine or L-arginine oligomer released from a stent.SUMMARY
The present invention has met the need for a more efficient and sustained method of delivering nitric oxide to a localized area by providing a method of sustained delivery of L-arginine or L-arginine oligomer from the hydrolysis of a polymer matrix from a prosthesis such as a stent.
Accordingly, the present invention is directed to a composition for inhibiting the narrowing of a blood vessel, comprising an oligomer of L-arginine, L-arginine, L-arginine analog, or L-arginine analog oligomer linked through a labile bond to a polymeric matrix, wherein the composition is used for coating an implantation device to inhibit the narrowing of the blood vessel. In this method, the composition may further comprise L-arginine, L-arginine analog, L-arginine oligomer, or L-arginine analog oligomer that is phase dispersed in the polymeric matrix. The oligomer may comprise more than 2 residues of L-arginine or L-arginine analog, or from 2 to 20 residues, from 2 to 15, from 2 to 9, from 2 to 7, or 7 residues. In the composition, the labile bond may be hydrolyzable by water. And the labile bond may be, but not limited to, an anhydride bond, ester bond, or imine bond.
The polymeric matrix may comprise poly(ethylene-co-vinyl alcohol), polyethylene glycol, acryloyl polyethylene glycol, poly(ethylene-co-glycidylmethacrylate), poly(ethylene-co-acrylic acid), poly(ethylene-co-maleic anhydride), hyaluronic acid, heparin, albumin, or glycosaminoglycan. The composition may also comprise a non-linking polymer. The non-linking polymer may be poly-n-butylmethacrylate, polyvinylidenefluoride, polyhexafluoropropylene, polycyclohexylmethacrylate, polyvinyledenefluoride-co-polyhexafluoropropylene, or hyaluronic acid.
The present invention is also directed to a coating for a prosthetic device, comprising a composition for inhibiting the narrowing of a blood vessel, comprising an oligomer of L-arginine, L-arginine, L-arginine analog, or L-arginine analog oligomer linked through a labile bond to a polymeric matrix. The prosthesis may be selected from a group of balloon-expandable stents, self-expandable stents, and grafts. The coating additionally may comprise a therapeutically active ingredient to be used in combination with the composition. The therapeutically active ingredient may be selected from a group of antineoplastic, anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antiproliferative, antibiotic, antioxidant substances, and combinations thereof.
In another aspect, the invention is directed to a method of coating a surface of a prosthesis with a coating that comprises a composition for inhibiting the narrowing of a blood vessel, comprising an oligomer of L-arginine or L-arginine analog linked through a labile bond to a polymeric matrix, which method comprises spraying the coating on to a prosthesis or immersing the prosthesis in a solution of the coating.
In another embodiment, the invention is directed to a method of inhibiting restenosis of a blood vessel comprising depositing into a designated region of the blood vessel the L-arginine composition discussed above, wherein the composition is coated on to a prosthetic device.
The present invention is also directed to a stent coated with a coating comprising a composition for inhibiting the narrowing of a blood vessel, comprising an oligomer of L-arginine, L-arginine, L-arginine analog, or L-arginine analog oligomer linked through a labile bond to a polymeric matrix. And the stent further comprises a therapeutically active ingredient to be used in combination with the composition.
These and other embodiments of the invention will be more fully understood from the following referenced drawing attached hereto, description of the invention, and the claims appended hereto.
As used herein, “abnormal” or “inappropriate” proliferation means division, growth or migration of cells occurring more rapidly or to a significantly greater extent than which typically occurs in a normally functioning cell of the same type, i.e., hyperproliferation.
As used herein, “analogs” or “derivatives” refers to L-arginine or any variation of it that retains the biological activity of L-arginine, so long as it is capable of acting as a substrate of nitric oxide production.
As used herein, “inhibiting” cellular activity means reducing, delaying or eliminating smooth muscle cell hyperplasia, restenosis, vascular occlusions, platelet activation, or inflammatory response, particularly following biologically or mechanically mediated vascular injury or trauma or under conditions that would predispose a mammal to suffer such a vascular injury or trauma. As used herein, the term “reducing” means decreasing the intimal thickening that results from stimulation of smooth muscle cell proliferation. “Delaying” means retarding the progression of the hyper-proliferative vascular disease or delaying the time until onset of visible intimal hyperplasia, as observed, for example, by histological or angiographic examination. “Elimination” of restenosis following vascular trauma or injury means completely “reducing” and/or completely “delaying” intimal hyperplasia in a patient to an extent which makes it no longer necessary to surgically intervene, i.e., to re-establish a suitable blood flow through the vessel by, for example, repeat angioplasty, atheroectomy, or coronary artery bypass surgery. The effects of reducing, delaying, or eliminating restenosis may be determined by methods known to one of ordinary skill in the art, including, but not limited to, angiography, ultrasonic evaluation, fluoroscopy imaging, fiber optic visualization, or biopsy and histology. Biologically mediated vascular injury includes, but is not limited to injury caused by or attributed to autoimmune disorders, alloimmune related disorders, infectious disorders including endotoxins and herpes viruses such as cytomegalovirus, metabolic disorders such as atherosclerosis, and vascular injury resulting from hypothermia and irradiation. Mechanical mediated vascular injury includes, but is not limited to vascular injury caused by catheterization procedures or vascular scraping procedures such as percutaneous transluminal coronary angioplasty, vascular surgery, stent placement, transplantation surgery, laser treatment, and other invasive procedures which disrupted the integrity of the vascular intima or endothelium. The active ingredient of the invention is not restricted in use for therapy following vascular injury or trauma; rather, the usefulness of the active ingredient will also be determined by the ingredient's ability to inhibit cellular activity of smooth muscle cells or inhibit the development of restenosis.
As used herein, “L-arginine” includes L-arginine that may be isolated from nature or chemically synthesized. Various forms of L-arginine may be also indicated where L-arginine may be in either a monomeric or an oligomeric form. By derivatives or analogs of “L-arginine,” it is meant to refer to modifications of the compound that do not affect its ability to act as a substrate for nitric oxide production. L-arginine is used hereinafter without explicitly referring to those derivatives and analogs which are modifications. It is understood that by “L-arginine,” those derivatives and analogs that act as a substrate for nitric oxide production may be included.
As used herein, “linking polymer” or “linking type polymer” refers to those polymers, copolymers, etc. that have the capability to bind to L-arginine or oligomers of L-arginine through a bond, e.g., labile bond. Such a labile bond may be generally cleaved by hydrolysis, thus releasing L-arginine or L-arginine oligomer.
As used herein, “migration” of smooth muscle cells means movement of these cells in vivo from the medial layers of a vessel into the intima, such as may also be studied in vitro by following the motion of a cell from one location to another, e.g., using time-lapse cinematography or a video recorder and manual counting of smooth muscle cell migration out of a defined area in the tissue culture over time.
As used herein, “non-linking polymer” or “non-linking type polymer” refers to those polymers that do not generally bind to L-arginine or oligomers of L-arginine.
As used herein, “oligomer” of L-arginine refers to at least two residues of L-arginine linked together. In particular, “R7” refers to a seven residue L-arginine oligomer. Following the same pattern, “R3” refers to a three residue L-arginine oligomer.
As used herein, “proliferation” of smooth muscle cells means increase in cell number.
As used herein, “smooth muscle cells” include those cells derived from the medial and adventitia layers of the vessel which proliferate in intimal hyperplastic vascular sites following vascular trauma or injury. Under light microscopic examination, characteristics of smooth muscle cells include a histological morphology of a spindle shape with an oblong nucleus located centrally in the cell with nucleoli present and myofibrils in the sarcoplasm. Under electron microscopic examination, smooth muscle cells have long slender mitochondria in the juxtanuclear sarcoplasm, a few tubular elements of granular endoplasmic reticulum, and numerous clusters of free ribosomes. A small Golgi complex may also be located near one pole of the nucleus.
L-arginine Linked Polymeric Matrix
L-arginine and oligomers thereof may be covalently linked by a hydrolyzable bond to various polymers so that sustained release of nitric oxide can be effectuated. In the practice of the invention, various polymers possessing the capability to form hydrolyzable bonds with L-arginine or derivatives thereof may be used. In this regard, L-arginine may be linked to large biological molecules such as albumin, hyaluronic acid and glycosaminoglycans, as well as other large molecules such as heparin. Moreover, the L-arginine and L-arginine oligomers may bind to natural or synthetic polymers.
Examples of such polymers may be ones that form esters, anhydrides, or imines. It is understood that any polymer may be used in linking the L-arginine or L-arginine derivative to the polymer so long as the bond that is formed is hydrolyzable. Specifically useful polymers may include poly (ethylene-co-vinyl alcohol), commercially known as EVAL, and poly(ethylene-co- glycidylmethacrylate (EGMA). Both of these polymers exemplify polymers that may form ester bonds with L-arginine or oligomers thereof. Another useful polymer is poly(ethylene-co-acrylic acid) (EAA) and poly(ethylene-co-maleic anhydride) (EMA), which may form an anhydride linkage with L-arginine or an L-arginine oligomer. In the instance where anhydride bonds are formed, the resultant stable polymer may undergo hydrolysis, thus releasing L-arginine.
In yet another embodiment of the invention, polymers having no functional groups to form any linkage with L-arginine may be also included in the polymeric matrix. Such polymers may include, but not limited to, poly-n-butylmethacrylate (PBMA), polyvinylidenefluoride (KYNAR) (PVDF), polyhexafluoropropylene (HFP), polycyclohexylmethacrylate (PCMA), poly(vinyledenefluoride-co-hexafluoropropylene), hyaluronic acid, and combinations thereof.
Sufficient amounts of an active agent can also be included in the matrix. The active agent should inhibit the activity of vascular smooth muscle cells. More specifically, the active agent is aimed at inhibiting abnormal or inappropriate migration and proliferation of smooth muscle cells. Examples of the active or therapeutic agents that may be used in the invention in addition to L-arginine include antiproliferative substances such as actinomycin D, or derivatives and analogs thereof (manufactured by Sigma-Aldrich 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233; or COSMEGEN available from Merck). Synonyms of actinomycin D include dactinomycin, actinomycin IV, actinomycin I1, actinomycin X1, and actinomycin C1. The active agent can also fall under the genus of antineoplastic, antiinflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, antiallergic and antioxidant substances. Examples of such antineoplastics and/or antimitotics include paclitaxel (e.g. TAXOL® by Bristol-Myers Squibb Co., Stamford, Conn.), docetaxel (e.g. Taxotere®, from Aventis S.A., Frankfurt, Germany) methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g. Adriamycin® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g. Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.) Examples of such antiplatelets, anticoagulants, antifibrin, and antithrombins include sodium heparin, low molecular weight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor antagonist antibody, recombinant hirudin, and thrombin inhibitors such as Angiomax™ (Biogen, Inc., Cambridge, Mass.) Examples of such cytostatic or antiproliferative agents include angiopeptin, angiotensin converting enzyme inhibitors such as captopril (e.g. Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril (e.g. Prinivil® and Prinzide® from Merck & Co., Inc., Whitehouse Station, N.J.); calcium channel blockers (such as nifedipine), colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand name Mevacor® from Merck & Co., Inc., Whitehouse Station, N.J.), monoclonal antibodies (such as those specific for Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors, suramin, serotonin blockers, steroids, thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), and nitric oxide. An example of an antiallergic agent is permirolast potassium. Other therapeutic substances or agents which may be appropriate include alpha-interferon, genetically engineered epithelial cells, rapamycin, dexamethasone and functional analogs or structural derivatives thereof.
The dosage or concentration of the active ingredient required to produce a favorable therapeutic effect should be less than the level at which the active ingredient produces toxic effects and greater than the level at which non-therapeutic results are obtained. The dosage or concentration of the active ingredient required to inhibit the desired cellular activity of the vascular region can depend upon factors such as the particular circumstances of the patient; the nature of the trauma; the nature of the therapy desired; the time over which the ingredient administered resides at the vascular site; and if other therapeutic agents are employed, the nature and type of the substance or combination of substances. Therapeutic effective dosages can be determined empirically, for example by infusing vessels from suitable animal model systems and using immunohistochemical, fluorescent or electron microscopy methods to detect the agent and its effects, or by conducting suitable in vitro studies. Standard pharmacological test procedures to determine dosages are understood by one of ordinary skill in the art.
The use of the matrix is not limited to stents and the coating can also be used with a variety of other medical devices. Examples of implantable medical devices, that can be used in conjunction with the embodiments of this invention include stent-grafts, grafts (e.g., aortic grafts), artificial heart valves, cerebrospinal fluid shunts, pacemaker electrodes, axius coronary shunts and endocardial leads (e.g., FINELINE and ENDOTAK, available from Guidant Corporation). The underlying structure of the device can be of virtually any design. The device can be made of a metallic material or an alloy such as, but not limited to, cobalt-chromium alloys (e.g., ELGILOY), stainless steel (316L), “MP35N,” “MP20N,” ELASTINITE (Nitinol), tantalum, tantalum-based alloys, nickel-titanium alloy, platinum, platinum-based alloys such as, e.g., platinum-iridium alloy, iridium, gold, magnesium, titanium, titanium-based alloys, zirconium-based alloys, or combinations thereof. Devices made from bioabsorbable or biostable polymers can also be used with the embodiments of the present invention. “MP35N” and “MP20N” are trade names for alloys of cobalt, nickel, chromium and molybdenum available from Standard Press Steel Co. of Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum.
L-arginine may be present in the matrix as a phase dispersion, or it may be linked to a polymer described above through a hydrolyzable bond. L-arginine may be present as a monomer, or it may be present as an oligomer. Thus, either of the monomeric or oligomeric form of L-arginine may be phase dispersed or linked to a polymer through a labile bond. It is also understood that a combination of phase dispersed monomer and/or oligomer of L-arginine may be mixed with polymer bound monomer and/or oligomer of L-arginine. The oligomeric version of L-arginine has a particularly advantageous feature. Without being bound by theory, it is believed that the oligomeric form is readily absorbed by the tissue, hence this form is effective in delivering nitric oxide to vessel walls.
L-arginine oligomer may comprise 2 or more L-arginine residues. Usefully, the oligomeric form may comprise from 2 to 20 L-arginine residues. Or, the oligomeric form may comprise from 2 to 15 residues. Still yet, the oligomeric form may comprise from 2 to 9 residues. Also, the oligomeric form may comprise from 2 to 7 residues. In particular, the oligomer has 7 residues. However, it is understood that the number of residues in the oligomer may be modified and optimized depending on the degree of control of the release rate that is desired.
It is also understood that multiple layers of coating may be used, so long as at least one of the layers contains a form of L-arginine linked through a hydrolyzable bond to the linking polymer. For example, a layer may be added to the L-arginine bearing layer and may include an active ingredient mixed with a non-linking polymer or a linking polymer linked to L-arginine. Alternatively, the layer may not have any active ingredient at all, and instead may comprise various polymers, which in effect would be used either as a primer layer or a barrier layer. By way of example only, and without limiting the scope of the invention, in one embodiment of the invention, the first coating layer may contain an active ingredient and a linking type polymer linked with L-arginine or an oligomer thereof. The second coating layer may contain either the same linking type polymer used in the first coating layer, or it may contain a different linking polymer linked with the L-arginine or oligomer thereof, with or without the presence of the active ingredient.
Another exemplary configuration may be that the first coating layer may contain an active ingredient along with a linking type polymer bound through a hydrolytically degradable bond with L-arginine or an oligomer thereof. The second coating layer may contain a non-linking type polymer with either the presence or absence of an active ingredient. In still another example, the first coating layer may contain an active ingredient and a linking type polymer linked to L-arginine, or an oligomer thereof, and the second coating layer may contain a mixture of non-linking polymers and linking polymers linked to various forms of L-arginine.
Further, in another configuration, the first coating layer may contain an active ingredient together with a non-linking polymer. The second coating layer may contain either the same non-linking type polymer used in the first coating layer, or it may contain a different non-linking polymer, with or without the presence of the active ingredient. Phase dispersed L-arginine may be interspersed in either or both of the layers.
Another exemplary configuration may be that the first coating layer may contain an active ingredient along with a non-linking type polymer. The second coating layer may contain a linking type polymer bound through a hydrolytically degradable bond with L-arginine or an oligomer thereof in either the presence or absence of an active ingredient. In still another example, the first coating layer may contain an active ingredient and a non-linking type polymer, and the second coating layer may contain a mixture of non-linking polymers and linking polymers linked to L-arginine and/or oligomers thereof.
It is understood that while in the above exemplifications, where only two coating layers are discussed, it is contemplated that many layers of coating comprising variations in the amount of active ingredient, non-linking polymers, linking polymers, and L-arginine and oligomers thereof, may be used in the practice of the invention as is desired, according to the nitric oxide release profile that is desired.
In one embodiment, it is contemplated that various forms of L-arginine, and in particular, the R7 oligomeric form of L-arginine, are phase dispersed in a polymeric matrix so that they are released first from the polymeric matrix upon contact with vessel walls. Thereafter, the L-arginine forms that are linked to the linking type polymers are released in a controlled manner as a result of cleavage of the labile bonds.
It is also contemplated that L-arginine or an oligomer thereof bound to linking polymers through various labile bonds may be released from the polymers in correlation to the type of labile bond that is being broken. Thus, a rate of release profile may be obtained according to the type of labile bonds that are present in the polymeric matrix. For instance, anhydride labile bonds are quickly broken upon contact with water. Imine bonds have an intermediate level of stability in the presence of water. Among the three exemplified labile bond types—anhydride, imine and ester bond—ester bonds are the most resistant to breakage in the presence of water. Thus, depending on the desires of the practitioner, a polymeric matrix may be formed comprising a mixture of these types of bonds to provide controlled release of L-arginine or oligomers thereof or any other active ingredient associated in the polymeric matrix. For example, if a quick release of the ligands from the polymeric matrix is desired, then the polymeric matrix should be composed of mostly anhydride bonds with the ligands. If a slow release of the ligands is desired, then the polymeric matrix should be comprised of mostly ester bonds.
An example of a polymeric matrix system would include a polymeric matrix comprising non-linking polymers and/or linking polymers. In particular, a copolymer such as acrylic-PEG-L-arginine may be blended with a matrix polymer such as EVAL, EVAL-PEG blend, or polyurethane. In addition, various forms of unbound L-arginine may be dispersed into the matrix so that a fast initial release rate of L-arginine is effected. This initial fast release rate may be followed by a more sustained and controlled delivery of L-arginine by hydrolytic cleavage of the labile bond according to the order of degradability of the bonds, resulting in the release of the ligands from the coupled copolymers.
Method of Use
In accordance with the above described method, the active ingredient and L-arginine or L-arginine oligomer can be applied to a prosthesis, e.g., a stent, retained on the stent during delivery and expansion of the stent, and released at a desired control rate and for a predetermined duration of time at the site of implantation. The release rate of the active ingredient can be controlled by modifying release parameters such as the amount of the comonomer content of the copolymer and the initial active ingredient content in the copolymer. The rate of release can also be adjusted by the addition of a second polymeric layer, with or without the active ingredient. A stent having the above described medicated coating is useful for a variety of medical procedures, including, by way of example, treatment of obstructions caused by tumors in bile ducts, an esophagus, trachea/bronchi and other biological passageways. A stent having the above described medicated coating is particularly useful for treating occluded regions of blood vessels caused by abnormal or inappropriate migration and proliferation of smooth muscle cells, thrombosis, and restenosis. Stents may be placed in a wide array of blood vessels, which include both arteries and veins. Representative examples of sites include the iliac, renal, and coronary arteries.
Briefly, an angiogram is first performed to determine the appropriate positioning for stent therapy. Angiography is typically accomplished by injecting a radiopaque contrasting agent through a catheter inserted into an artery or vein as an x-ray is taken. A guidewire is then advanced through the lesion or proposed site of treatment. Over the guidewire is passed a delivery catheter which allows a stent in its collapsed configuration to be inserted into the passageway. The delivery catheter is inserted either percutaneously or by surgery into the femoral artery, brachial artery, femoral vein, or brachial vein, and advanced into the appropriate blood vessel by steering the catheter through the vascular system under fluoroscopic guidance. A stent having the above described coating may then be expanded at the desired area of treatment. A post insertion angiogram may also be utilized to confirm appropriate positioning.EXAMPLES Example 1 Synthesis
To a 100 ml roundbottom flask is added a stirbar, condenser and nitrogen bubbler. Nitrogen is bubbled through the reaction flask. The EVAL is added to the flask and purged with nitrogen. Anhydrous DMAC is added to the flask using a cannula and nitrogen to push the nitrogen into the reaction flask. The flask is heated to 60° C. for 3 hours to dissolve the EVAL polymer. The polymer solution is then cooled to room temperature and the Nα-9-fluorenylmethoxycarbonyl (FMOC)-L-arginine is added and after about 2 minutes of stirring went into solution. The solution is then cooled to 0° C. and the 1 M dicyclohexylcarbodiimide (DCC) solution in methylenechloride (MeCl2) is added dropwise. After the DCC is added, a crystal of dimethylaminopyridine (DMAP) is added to catalyze the esterification process. The solution is then stirred at 0° C. for 2 hours and allowed to warm to room temperature. The solution is then stirred under nitrogen for overnight. After stirring overnight, a significant concentration of white precipitate is formed in the reaction media. The reactants and amounts are shown in Table 1.
The suspension is then added to a separatory funnel. To a flask is added 450 ml of water, 450 ml of methanol with 25 ml of 1N HCI. To the flask is then added the precipitate suspension in a dropwise manner. A white polymer is precipitated from the acidic methanol/water media, which is stirred for 15 minutes and then filtered under vacuum. The polymer is then re-dissolved in DMSO, filtered through a glass frit filter and re-precipitated into methanol/water forming a white fluffy precipitate. The sample is then dried under vacuum for overnight. The sample is extracted with methanol to remove residual DMAP and urea and dried under vacuum.Example 3 Deprotection of FMOC from EVAL-(FMOC-L-arginine) Ester
To a roundbottom flask with a condenser and nitrogen source is added anhydrous N,N-dimethylacetamide, EVAL-(FMOC-L-arginine) ester and tetrabutylammonium fluoride. In the reaction of the deprotection, it is assumed that the yield for the esterification step is 100%. The calculations are shown in Table 2.
To a reaction flask is added the EVAL-(FMOC-L-arginine) ester and anhydrous DMAC under nitrogen. The sample is stirred and heated to 60° C. for 3 hours until the derivatized EVAL polymer went into solution. The solution is then cooled to room temperature. After the solution is cooled to room temperature, tetrabutylammonium fluoride is then added at room temperature, after which the solution turned a pink-red color. The solution is then stirred for 30 minutes.Example 4 Purification of EVAL-Arginine Ester
The reaction solution is then added to 350 ml of deionized water while being vigorously stirred. The white polymer precipitate is then filtered and dried under vacuum. The polymer is re-dissolved into DMAC and then precipitated into methanol:ethanol (75:25). The suspension was then filtered and dried under vacuum. See
A method of obtaining an anhydride linkage between poly(butyl methacrylate-co-acrylic acid) and L-arginine or L-arginine oligomer is described. L-arginine is reacted with protecting groups to block the amino group of arginine. L-arginine is then reacted with thallium alkoxide to form a thallium salt to which polyethylene-co-acryloyl chloride is added. Then, the carboxylic acid moiety of poly (ethylene-co-acrylic acid) is converted to the acid chloride with thionyl chloride. After the completion of these reactions, the modified polymer is precipitated with anhydrous methanol, and then the L-arginine amine groups is are deprotected. After the deprotection of the amine, the polymer is extracted with anhydrous methanol to remove trace contaminants. See the reaction scheme in
An acryloyl-PEG-OH group is reacted with the carboxy group of L-arginine to produce a polymer with a hydrolytically labile ester bond. This product is then further processed by copolymerizing with ethylmethacrylate, hydroxyethylmethacrylate, methylmethacrylate, or butylmethacrylate. The reaction product is then mixed with a matrix linking polymer and polymerized in situ on the stent to form an interpenetrating network, or alternatively, the acrylate group is polymerized separately in solution and mixed with a coating matrix and then applied to the stent.Example 7 Ester Coupling of L-arginine or Oligomer Thereof
EVAL is linked to L-arginine or an L-arginine oligomer by forming an ester linkage. EVAL-L-arginine is then blended with a matrix polymer coating such as EVAL, EVAL-PEG blend, polyurethane and the like.Example 8 A Labile Linkage Between L-arginine and EVAL
EVAL-L-arginine copolymer is blended with coating matrices comprising a PEG-superoxide dismutase donor or an EVAL-superoxide dismutase conjugate. EVAL-L-arginine copolymer may be also blended with coating matrices comprising an active ingredient.Example 9 An Imine Linkage Between L-arginine and Polyethyleneimine
Glycidol is used to modify polyethyleneimine (PEI), an amine-containing compound. A diamine spacer is first lengthened through the epoxide coupling of glycidol. So modified, the compound contains a spacer that terminates in vicinal diols. Periodate oxidation provides a formyl function at the end of the spacer.
Step 1. Dissolve 0.13 grams EVAL in 3.6 grams DMAC.
Step 2. Dissolve 0.085 grams R7 in 1.6 grams methanol.
Step 3. While stirring the EVAL solution with a magnetic stir bar, add the R7/Methanol solution drop-wise. A stable, clear solution results. When sprayed onto a stent and dried, the resultant coating is clear and has high gloss, indicating a lack of gross phase separation in the dried film.Example 11 Compatible Single Phase Solution of R7 and EVAL
Step 1. Dissolve 0.13 grams EVAL in 3.6 grams DMAC
Step 2. Dissolve 0.065 grams R7 in 1.5 grams methanol.
Step 3. While stirring the EVAL solution with a magnetic stir bar, add the R7/Methanol solution drop-wise. A stable, clear solution results. When sprayed onto a stent and dried, the resultant coating is clear and has high gloss, indicating a lack of gross phase separation in the dried film.Example 12 Compatible Single Phase Solution of R7 and Poly n-butylmethacrylate (PBMA)
Step 1. Dissolve 0.2 grams PBMA in 3.3 grams DMAC.
Step 2. Dissolve 0.1 grams R7 in 1.4 grams methanol.
Step 3. While stirring the EVAL solution with a magnetic stir bar, add the R7/Methanol solution drop-wise. A stable, clear solution results. When sprayed onto a stent and dried, the resultant coating is clear and has high gloss, indicating a lack of gross phase separation in the dried film.
While particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that changes and modifications can be made without departing from this invention in its broader aspects and, 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.
1. A composition for inhibiting the narrowing of a blood vessel, comprising an oligomer of L-arginine, L-arginine, an L-arginine analog, or an L-arginine analog oligomer linked through a labile bond to a polymeric matrix, wherein the composition is used for coating an implantation device to inhibit the narrowing of the blood vessel.
2. The composition according to claim 1, wherein the L-arginine, the L-arginine analog, the L-arginine oligomer, or the L-arginine analog oligomer is phase dispersed in the polymeric matrix.
3. The composition according to claim 1, wherein the oligomer comprises from 2 to 20 residues of L-arginine or an L-arginine analog.
4. The composition according to claim 1, wherein the oligomer comprises from 2 to 9 residues of L-arginine or an L-arginine analog.
5. The composition according to claim 1, wherein the labile bond is hydrolyzable by water.
6. The composition according to claim 1, wherein the labile bond comprises an anhydride bond, ester bond, or imine bond.
7. The composition according to claim 1, wherein the polymeric matrix comprises poly(ethylene-co-vinyl alcohol), polyethylene glycol, acryloyl polyethylene glycol, poly(ethylene-co-glycidylmethacrylate), poly(ethylene-co-acrylic acid), poly(ethylene-co-maleic anhydride), hyaluronic acid, heparin, albumin, or a glycosaminoglycan.
8. The composition according to claim 1, wherein the composition comprises a non-linking polymer.
9. The composition according to claim 8, wherein the non-linking polymer is poly-n-butylmethacrylate, polyvinylidenefluoride, polyhexafluoropropylene, polycyclohexylmethacrylate, polyvinyledenefluoride-co-polyhexafluoropropylene, or hyaluronic acid.
10. A coating for a prosthetic device comprising a composition, the composition comprising an oligomer of L-arginine, L-arginine, an L-arginine analog, or an L-arginine analog oligomer linked through a labile bond to a polymeric matrix.
11. The coating according to claim 10, wherein the prosthesis is comprises a component selected from a group consisting of balloon-expandable stents, self-expandable stents, and grafts.
12. The coating of claim 10, additionally comprising an active agent carried by the polymeric matrix.
13. The coating of claim 12, wherein the active agent is effective for the treatment of restenosis.
14. A method of coating a prosthesis comprising coating the prosthesis with a composition comprising an oligomer of L-arginine, L-arginine, L-arginine analog, or L-arginine analog oligomer linked through a labile bond to a polymeric matrix.
15. The method of claim 14, wherein the prosthesis is comprises a component selected from a group consisting of balloon-expandable stents, self-expandable stents, and grafts.
16. The method of claim 14, wherein the coating additionally comprises an active agent effective for the treatment of restenosis.
17. A method of inhibiting restenosis of a blood vessel comprising depositing into a designated region of the blood vessel the composition according to claim 1, wherein the composition is coated on to a prosthetic device.
18. A stent coated with a coating comprising a composition for inhibiting the narrowing of a blood vessel, the composition comprising an oligomer of L-arginine, L-arginine, an L-arginine analog, or an L-arginine analog oligomer bonded linked through a labile bond to a polymeric matrix.
19. The stent according to claim 18, wherein the oligomer comprises from 2 to 20 residues of L-arginine or an L-arginine analog.
20. The stent according to claim 18, wherein the oligomer comprises from 2 to 9 residues of L-arginine or an L-arginine analog.
21. The stent according to claim 18, wherein the composition further comprises a labile bond that is hydrolyzable by water.
22. The stent according to claim 21, wherein the labile bond comprises an anhydride bond, an ester bond, or an imine bond.
23. The stent according to claim 18, wherein the polymeric matrix comprises poly(ethylene-co-vinyl alcohol), polyethylene glycol, acryloyl polyethylene glycol, poly(ethylene-co-glycidylmethacrylate), poly(ethylene-co-acrylic acid), poly(ethylene-co-maleic anhydride), hyaluronic acid, heparin, albumin, a glycosaminoglycan, poly-n-butylmethacrylate, polyvinylidenefluoride, polyhexafluoropropylene, polycyclohexylmethacrylate, polyvinyledenefluoride-co-polyhexafluoropropylene, or hyaluronic acid.
24. The coating according to claim 10, wherein the oligomer comprises from 2 to 20 residues of L-arginine or an L-arginine analog.
25. The coating according to claim 10, wherein the oligomer comprises from 2 to 9 residues of L-arginine or an L-arginine analog.
26. The coating according to claim 10, wherein the composition further comprises a labile bond that is hydrolyzable by water.
27. The coating according to claim 26, wherein the labile bond comprises an anhydride bond, an ester bond, or an imine bond.
28. The coating according to claim 10, wherein the polymeric matrix comprises poly(ethylene-co-vinyl alcohol), polyethylene glycol, acryloyl polyethylene glycol, poly(ethylene-co-glycidylmethacrylate), poly(ethylene-co-acrylic acid), poly(ethylene-co-maleic anhydride), hyaluronic acid, heparin, albumin, a glycosaminoglycan, poly-n-butylmethacrylate, polyvinylidenefluoride, polyhexafluoropropylene, polycyclohexylmethacrylate, polyvinyledenefluoride-co-polyhexafluoropropylene, or hyaluronic acid.
29. The method according to claim 14, wherein the oligomer comprises from 2 to 20 residues of L-arginine or an L-arginine analog.
30. The method according to claim 14, wherein the oligomer comprises from 2 to 9 residues of L-arginine or an L-arginine analog.
31. The method according to claim 14, wherein the composition further comprises a labile bond that is hydrolyzable by water.
32. The method according to claim 31, wherein the labile bond comprises an anhydride bond, an ester bond, or an imine bond.
33. The method according to claim 14, wherein the polymeric matrix comprises poly(ethylene-co-vinyl alcohol), polyethylene glycol, acryloyl polyethylene glycol, poly(ethylene-co-glycidylmethacrylate), poly(ethylene-co-acrylic acid), poly(ethylene-co-maleic anhydride), hyaluronic acid, heparin, albumin, a glycosaminoglycan, poly-n-butylmethacrylate, polyvinylidenefluoride, polyhexafluoropropylene, polycyclohexylmethacrylate, polyvinyledenefluoride-co-polyhexafluoropropylene, or hyaluronic acid.
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|WO 00/12147||March 2000||WO|
|WO 00/18446||April 2000||WO|
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- Inoue et al., An AB block copolymer of oligo(methyl methacrylate) and poly(acrylic acid) for micellar delivery of hydrophobic drugs, Journal of Controlled Release 51:221-229 (1998).
- Kataoka et al., Block copolymer micelles as vehicles for drug delivery, Journal of Controlled Release 24:119-132 (1993).
- Katsarava et al., Amino Acid-Based Bioanalogous Polymers. Synthesis and Study of Regular Poly(ester amide)s Based on Bis(α-amino acid)α,ω-Alkylene Diesters, and Aliphatic Dicarbolic Acids, Journal of Polymer Science, Part A: Polymer Chemistry, 37(4), 391-407 (1999).
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Filed: Jun 21, 2002
Date of Patent: Feb 7, 2006
Assignee: Advanced Cardiovascular Systems, Inc. (Santa Clara, CA)
Inventors: Syed F A Hossainy (Fremont, CA), Eugene T Michal (San Francisco, CA), Charles D. Claude (San Jose, CA)
Primary Examiner: Carlos A. Azpuru
Attorney: Squire, Sanders & Dempsey LLP
Application Number: 10/176,499

domain: chemistry


It’s 1977 and “Stayin’ Alive” is playing on everyone’s radios. Do you remember?
This fabulous and funky disco song was written and performed by none other than the Bee Gees from the Saturday Night Fever motion picture soundtrack and we know you can already feel the beat, can’t you?
“Stayin’ Alive” was released on 13 December 1977 as the second single from the original movie soundtrack. The Bee Gees co-produced the song with the help of two very talented musicians, Albhy Galuten and Karl Richardson.
I don’t need to tell you this is the Bee Gees’ signature song. It’s a timeless classic that’s never going away. In 2004, “Stayin’ Alive” was placed at number 189 on the list of Rolling Stone’s 500 Greatest Songs of All Time.
In 2004, it ranked No. 9 on all time top memorable songs from the top 100 movies in American cinema. A Madly Odd fact for our UK friends: In a UK television poll on ITV in December 2011 it was voted fifth in “The Nation’s Favourite Bee Gees Song”.
When it was released, “Stayin’ Alive” climbed the charts to hit the number one spot on the Billboard Hot 100 the week of 4 February 1978, staying there for four whole weeks. I know you remember this. I sure do.
In the process, “Stayin’ Alive” became one of the Bee Gees most recognizable tunes because of its place at the beginning of hit movie Saturday Night Fever with John Travolta.
In the United States, it would go on to become the second of six consecutive number-one singles, tying the record with THE BEATLES!!! Yes, tied for most consecutive number ones in the US at the time. A piece of trivia for you: This record was broken by Whitney Houston who achieved an amazing seven consecutive number-ones).
I know all that music talk is hard to handle for some and to be frank, we all know why we’re here. Boys, hit it!
EDITOR’S NOTE: Wooo! Didn’t that take you back?! Now look, I admit watched that about six times, but who’s counting? Now, you can’t go yet before watch this. It’s a quickie:
How old where you when you remember hearing and seeing these flashes from the past?


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text:
The Most Beautiful Palaces In Europe
Many cities in Europe have a beautiful palace (or two) to draw in the tourists. That’s why it’s hard to agree about what the five most beautiful palaces in Europe are. Let’s have a look at our selection of The Most Beautiful Palaces In Europe:…
Provence – What To See And How To Get There
If it’s a slower pace of life you’re looking for, then you’re in the right place. Picture; Fields of lavender, sunflowers and olive trees… A Sunday lunch under the shade of plane trees in a village square, a cafe creme at a sidewalk cafe coupled…
Magnificent Architecture And Where To See It?
Looking to see some superb architecture on your next vacation? If so, there probably is no better place than Europe for you. Whether you’re interested in classical architecture styles or hoping to find some lesser-known jewels, European cities have you covered. Let’s have a look…
Charming Book Stores in Europe
There are plenty of reasons why people like to travel. One of the ones you can hear most often is the ability to have new and exciting experiences. What makes travelling so beautiful is that different personalities will be excited by different things. Adrenaline junkies…
5 Less Crowded Cities To Explore In France
France is a popular tourist hotspot thanks to its beautiful cities and renowned landmarks. The country is a dream destination famous around the world for its incredible culture and delicious food. While many tourists flock to Paris, the city can often become very overcrowded, especially…
Fascinating Street Art and Where to See It?
Street art is a modern form of artistic expression that makes our cities more beautiful. A good street mural might also inspire you to think about a socially important subject or remind you of the works of classical masters. Cities of Europe are full of…
The Best Amusement Parks in Europe
If you’re not sure of which amusement parks in Europe are the best, then look no further. This article is a list of some of the best amusement parks you can visit in Europe right now! We will give you detailed descriptions of each and how…
Best Vintage Stores In Europe And Where To Find Them
When in search of the best vintage stores in Europe, you’re not only on the lookout for those timeless pieces. You’re also taking a trip down memory lane and exploring history. A vintage store is akin to a fashion museum, indicative of a city’s culture…
10 Charming Castles In France By Train
Do you like traveling by train? Do you like seeing amazing castles in countries like France? If that’s the case, then you have reached the right place. That’s because this article “10 Charming Castles In France By Train” will give you a definitive list of…
What is the quickest mode of travel in Europe?
The first thing people think when you wonder What is the quickest mode of travel in Europe is flying. But we would disagree! While the actual flying may be faster, there’s nothing slower than airports to limit the amount of travel time you actually save….
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- The Most Beautiful Palaces In Europe
- Provence – What To See And How To Get There
- Magnificent Architecture And Where To See It?
- What Are The Best National Parks In Europe
- Charming Book Stores in Europe
- Best Destinations In Europe To Travel During A Weekend
- 5 Less Crowded Cities To Explore In France
- What Is The Biggest Advantage Of Train Tickets Online?
- Fascinating Street Art and Where to See It?
- Underground Art – Fascinating Subway Stations
- Business Travel by Train
- car travel tips
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- train teens
- Train travel
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domain: travel


“Slow Times is a song that is as old as our band itself,” said the band. “The Norwegian prom is way less flashier than the American prom. It’s always in an odd, unfitting place, it’s winter and it’s minus -20 degrees Celsius. The suits are too big, the dresses have too big bust, the cool kids bring mouthwash as alcohol and there’s a lot of stiff dancing. Middle school prom is a Norwegians first clumsy step into adulthood, and that is a lot of what our upcoming album is about.”
Look for Slow Times as a track on Iffy Orbit’s debut album, out in September.


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2001-2010 - Ghana - Evaluation of Public Financial Management Reform - Final Country Case Study Report
This Country Report has been prepared by Fiscus Limited, UK, in collaboration with Mokoro Ltd, Oxford, as one of three country reports in the Joint Evaluation of Public Financial Management Reform, managed by the African Development Bank, Denmark and Sweden. The evaluation looked at two main questions: (i) where and why do Public Finance Management (PFM) reforms deliver results and (ii) where and how does donor support to PFM reform efforts contribute most effectively to results? Our overall conclusions are presented in the Summary Matrix contained in Annex A, which summarises, for the overall Ghana PFM reform programme 2001 -2010 and for four component areas within the reform programme, our answers to the 12 Evaluation Questions, posed within the study.

domain: finance


A government judge in New York denied a demand on Tuesday to enable unvaccinated kids to come back to school.
U.S. Area Court Judge Vincent Briccetti decided that 44 students were not permitted to come back to class at Green Meadow Waldorf School in Rockland County, New York, refering to a unprecedented measles outbreak, as indicated by the Rockland/Westchester Journal News.
Briccetti ruled against a legal advisor speaking to the students' parents, who have documented a lawsuit challenging the Rockland Health Department and its official for not enabling the unvaccinated kids to attend school.
The claim contended that the health department?s choice to ban the students from campus violates the families' privilege not to immunize their kids for religious reasons.
The plaintiffs have not demonstrated that public interest weighs in favor of granting an injunction, Briccetti said in court Tuesday, according to the paper.
Parents of the unvaccinated children say none of them have contracted measles.
The district has been managing a measles flare-up since the previous fall.
The news outlet noticed that there have been 145 instances of measles reported in the region since October, with three increasingly presumed cases currently being investigated.
The Rockland Health Department issued a request in December that certain schools in explicit postal codes with vaccination rates under 95 percent must prohibit unvaccinated children from going to school.