News Column

Patent Issued for Diazeniumdiolated Phosphorylcholine Polymers for Nitric Oxide Release

May 14, 2014



By a News Reporter-Staff News Editor at Biotech Week -- A patent by the inventors Chen, Mingfei (Santa Rosa, CA); Shumaker, David (Santa Rosa, CA); Cheng, Peiwen (Santa Rosa, CA); Udipi, Kishore (Santa Rosa, CA), filed on April 13, 2009, was published online on April 29, 2014, according to news reporting originating from Alexandria, Virginia, by NewsRx correspondents (see also Medtronic Vascular, Inc.).

Patent number 8709465 is assigned to Medtronic Vascular, Inc. (Santa Rosa, CA).

The following quote was obtained by the news editors from the background information supplied by the inventors: "Nitric oxide (NO) is a simple diatomic molecule that plays a diverse and complex role in cellular physiology. Less than 25 years ago NO was primarily considered a smog component formed during the combustion of fossil fuels mixed with air. However, as a result of the pioneering work of Ferid Murad et al. it is now known that NO is a powerful signaling compound and cytotoxic/cytostatic agent found in nearly every tissue including endothelial cells, neural cells and macrophages. Mammalian cells synthesize NO using a two step enzymatic process that oxidizes L-arginine to N-.omega.-hydroxy-L-arginine, which is then converted into L-citrulline and an uncharged NO free radical. Three different nitric oxide synthase enzymes regulate NO production. Neuronal nitric oxide synthase (NOSI, or nNOS) is formed within neuronal tissue and plays an essential role in neurotransmission; endothelial nitric oxide synthase (NOS3 or eNOS), is secreted by endothelial cells and induces vasodilatation; inducible nitric oxide synthase (NOS2 or iNOS) is principally found in macrophages, hepatocytes and chondrocytes and is associated with immune cytotoxicity.

"Neuronal NOS and eNOS are constitutive enzymes that regulate the rapid, short-term release of small amounts of NO. In these minute amounts NO activates guanylate cyclase which elevates cyclic guanosine monophosphate (cGMP) concentrations which in turn increase intracellular Ca.sup.2+ levels. Increased intracellular Ca.sup.2+ concentrations result in smooth muscle relaxation which accounts for NO's vasodilating effects. Inducible NOS is responsible for the sustained release of larger amounts of NO and is activated by extracellular factors including endotoxins and cytokines. These higher NO levels play a key role in cellular immunity.

"Medical research is rapidly discovering therapeutic applications for NO including the fields of vascular surgery and interventional cardiology. Procedures used to clear blocked arteries such as percutaneous transluminal coronary angioplasty (PTCA) (also known as balloon angioplasty) and atherectomy and/or stent placement can result in vessel wall injury at the site of balloon expansion or stent deployment. In response to this injury a complex multi-factorial process known as restenosis can occur whereby the previously opened vessel lumen narrows and becomes re-occluded. Restenosis is initiated when thrombocytes (platelets) migrating to the injury site release mitogens into the injured endothelium. Thrombocytes begin to aggregate and adhere to the injury site initiating thrombogenesis, or clot formation. As a result, the previously opened lumen begins to narrow as thrombocytes and fibrin collect on the vessel wall. In a more frequently encountered mechanism of restenosis, the mitogens secreted by activated thrombocytes adhering to the vessel wall stimulate over-proliferation of vascular smooth muscle cells during the healing process, restricting or occluding the injured vessel lumen. The resulting neointimal hyperplasia is the major cause of a stent restenosis.

"Recently, NO has been shown to significantly reduce thrombocyte aggregation and adhesion; this combined with NO's directly cytotoxic/cytostatic properties may significantly reduce vascular smooth muscle cell proliferation and help prevent restenosis. Thrombocyte aggregation occurs within minutes following the initial vascular insult and once the cascade of events leading to restenosis is initiated, irreparable damage can result. Moreover, the risk of thrombogenesis and restenosis persists until the endothelium lining the vessel lumen has been repaired. Therefore, it is essential that NO, or any anti-restenotic agent, reach the injury site immediately.

"One approach for providing a therapeutic level of NO at an injury site is to increase systemic NO levels prophylactically. This can be accomplished by stimulating endogenous NO production or using exogenous NO sources. Methods to regulate endogenous NO release have primarily focused on activation of synthetic pathways using excess amounts of NO precursors like L-arginine, or increasing expression of nitric oxide synthase (NOS) using gene therapy. U.S. Pat. Nos. 5,945,452, 5,891,459 and 5,428,070 describe sustained NO elevation using orally administrated L-arginine and/or L-lysine. However, these methods have not been proven effective in preventing restenosis. Regulating endogenously expressed NO using gene therapy techniques remains highly experimental and has not yet proven safe and effective. U.S. Pat. Nos. 5,268,465, 5,468,630 and 5,658,565, describe various gene therapy approaches.

"Exogenous NO sources such as pure NO gas are highly toxic, short-lived and relatively insoluble in physiological fluids. Consequently, systemic exogenous NO delivery is generally accomplished using organic nitrate prodrugs such as nitroglycerin tablets, intravenous suspensions, sprays and transdermal patches. The human body rapidly converts nitroglycerin into NO; however, enzyme levels and co-factors required to activate the prodrug are rapidly depleted, resulting in drug tolerance. Moreover, systemic NO administration can have devastating side effects including hypotension and free radical cell damage. Therefore, using organic nitrate prodrugs to maintain systemic anti-restenotic therapeutic blood levels is not currently possible.

"Therefore, considerable attention has been focused on localized, or site specific, NO delivery to ameliorate the disadvantages associated with systemic prophylaxis. Implantable medical devices and/or local gene therapy techniques including medical devices coated with NO-releasing compounds, or vectors that deliver NOS genes to target cells, have been evaluated. Like their systemic counterparts, gene therapy techniques for the localized NO delivery have not been proven safe and effective. There are still significant technical hurdles and safety concerns that must be overcome before site-specific NOS gene delivery will become a reality.

"However, significant progress has been made in the field of localized exogenous NO application. To be effective at preventing restenosis an inhibitory therapeutic such as NO must be administered for a sustained period at therapeutic levels. Consequently, any NO-releasing medical device used to treat restenosis must be suitable for implantation. An ideal candidate device is the vascular stent. Therefore, a stent that safely provides therapeutically effective amounts of NO to a precise location would represent a significant advance in restenosis treatment and prevention.

"Nitric oxide-releasing compounds suitable for in vivo applications have been developed by a number of investigators. As early as 1960 it was demonstrated that NO gas could be reacted with amines, for example, diethylamine, to form NO-releasing anions having the following general formula R--R'N--N(O)NO. Salts of these compounds could spontaneously decompose and release NO in solution.

"Nitric oxide-releasing compounds with sufficient stability at body temperatures to be useful as therapeutics were ultimately developed by Keefer et al. as described in U.S. Pat. Nos. 4,954,526, 5,039,705, 5,155,137, 5,212,204, 5,250,550, 5,366,997, 5,405,919, 5,525,357 and 5,650,447 all of which are herein incorporated by reference.

"The in vivo half-life of NO, however, is limited, causing difficulties in delivering NO to the intended area. Therefore NO-releasing compounds which can produce extended release of NO are needed. Several exemplary NO-releasing compounds have been developed for this purpose, including for example a NO donating aspirin derivative, amyl nitrite and isosorbide dinitrate. Additionally, biocompatible polymers having NO adducts (see, for example, U.S. Patent Publications 2006/0008529 and 2004/0037836) and which release NO in a controlled manner have been reported.

"Secondary amines have the ability to bind two moles of NO and release them in an aqueous environment. The general structure of exemplary secondary amines capable of binding two NO molecules is depicted in Formula 1, referred to hereinafter a diazeniumdiolate, (wherein M is a counterion, and can be a metal, with the appropriate charge, or a proton and wherein R.sup.1 and R.sup.2 are generic notation for organic and inorganic chemical groups). Exposing secondary amines to basic conditions while incorporating NO gas under pressure leads to the formation of diazeniumdiolates.

"##STR00001##

"Polymers with diazeniumdiolate functional groups are capable of spontaneous release of nitric oxide under physiological conditions. Diazeniumdiolate is typically formed by a solution diazeniumdiolation process under strong basic conditions. Generally, the diazeniumdiolate polymers have poor solubility in organic solvent.

"Biocompatibility of any medical device which is put inside a patient can present a problem. If the body rejects a medical device, such as a vascular stent, procedures performed to treat vascular diseases may be considered a failure. This is the case even if NO is released in suitable amounts and at proper locations by the medical device. Thus, there is an unmet need in the art to have materials which are NO releasing but also have superior biocompatibility."

In addition to the background information obtained for this patent, NewsRx journalists also obtained the inventors' summary information for this patent: "The present disclosure addresses the long-felt need for materials which are biocompatible and release therapeutic nitric oxide (NO) from diazeniumdiolated functional groups. Phosphorylcholine (PC) is a cell membrane component. Polymers with PC functional groups have proved to be very biocompatible. Such materials have been used in medical devices such as drug eluting stents and contact lenses. The present disclosure generally relates to methods and related material resulting from the fact that PC can be diazeniumdiolated to release nitric oxide and after NO release, the diazeniumdiolate potentially can revert back to the PC functional group. Thus, even after NO release is completed, medical devices having the present polymers retain superior biocompatibility.

"In one embodiment, the present disclosure relates to a nitric oxide donating polymer comprising a biocompatible polymer having at least one diazeniumdiolated phosphorylcholine functional group. In another embodiment, the biocompatible polymer having at least one diazeniumdiolated phosphorylcholine functional group is a copolymer. Alternatively, the biocompatible polymer is produced from a precursor polymer capable of containing a phosphorylcholine functional group selected from the group consisting of: methacrylate, polyester, polycarbonate, poly(ortho ester), polyamide, polyurethane, polyurea, poly(ester amide), polysulfone, polyketone, silicone, polyphosphazene, poly(amino acid), polyether, polyimide, vinyl polymer, polyacrylate, polymethacrylate, plystyrene, poly(vinyl acetate), poly(vinyl chloride), poly(vinyl ester), poly(vinyl ether), polyacrylonitrile, poly(vinyl ketone), poly(vinyl pyrolidinone), fluorinated polymer, natural or modified biopolymers, collagen, alginate, elastin, chitosan, fibrin, fibrinogen, cellulose, starch, collagen, dextran, dextrin, hyaluronic acid acid, heparin, glycosamino glycan, and polysaccharide; and combinations thereof.

"In another embodiment, the precursor polymer is a methacrylate polymer according to Formula I:

"##STR00002##

"wherein R is C.sub.1 to C.sub.20 straight chain alkyl, C.sub.3 to C.sub.8 cycloalkyl, C.sub.2 to C.sub.20 alkenyl, C.sub.2 to C.sub.20 alkynyl, C.sub.2 to C.sub.14 heteroatom substituted alkyl, C.sub.2 to C.sub.14 heteroatom substituted cycloalkyl, C.sub.4 to C.sub.10 substituted aryl, or C.sub.4 to C.sub.10 heteroatom substituted heteroaryl; and further wherein a is 1 to 10,000 and b is 0 to 10,000.

"The present disclosure also relates to a nitric oxide donating polymer comprising a biocompatible polymer of Formula II having at least one diazeniumdiolated phosphorylcholine functional group:

"##STR00003## wherein a is 1 to 10,000 and b, c and d are each 0 to 10,000.

"The present disclosure also relates to a medical device comprising a biocompatible polymer having at least one diazeniumdiolated phosphorylcholine functional group. In another embodiment of the medical device, the biocompatible polymer is a copolymer. In another embodiment of the medical device, the biocompatible polymer is produced from a precursor polymer capable of containing a phosphorylcholine functional group, said precursor polymer being selected from the group consisting of: methacrylate, polyester, polycarbonate, poly(ortho ester), polyamide, polyurethane, polyurea, poly(ester amide), polysulfone, polyketone, silicone, polyphosphazene, poly(amino acid), polyether, polyimide, vinyl polymer, polyacrylate, polymethacrylate, plystyrene, poly(vinyl acetate), poly(vinyl chloride), poly(vinyl ester), poly(vinyl ether), polyacrylonitrile, poly(vinyl ketone), poly(vinyl pyrolidinone), fluorinated polymer, natural or modified biopolymers, collagen, alginate, elastin, chitosan, fibrin, fibrinogen, cellulose, starch, collagen, dextran, dextrin, hyaluronic acid acid, heparin, glycosamino glycan, and polysaccharide; and combinations thereof.

"In another embodiment of the medical device, the medical device is selected from the group consisting of a vascular stent, stent graft, urethral stent, biliary stent, catheter, suture, ocular device, heart valve, shunt, pacemaker, bone screw, bone anchor, protect plate and prosthetic device. In another embodiment of the medical device, medical device is a vascular stent.

"In another embodiment of the medical device, the medical device further comprises at least one bioactive agent. In another embodiment of the medical device, the at least one bioactive agent is selected from the group consisting of zotarolimus, rapamycin or its derivatives, an antisense agent, an antineoplastic agent, an antiproliferative agent, an antithrombogenic agent, an anticoagulant, an antiplatelet agent, an antibiotic, an anti-inflammatory agent, a steroid, a gene therapy agent, a therapeutic substance, an organic drug, a pharmaceutical compound, a recombinant DNA product, a recombinant RNA product, a collagen, a collagenic derivative, a protein, a protein analog, a saccharide, a saccharide derivative, and combinations thereof. In another embodiment of the medical device, the at least one bioactive agent is rapamycin and its derivatives.

"The present disclosure also relates to a medical device comprising a nitric oxide donating polymer whose precursor polymer is a methacrylate polymer according to Formula I:

"##STR00004##

"wherein R is C.sub.1 to C.sub.20 straight chain alkyl, C.sub.3 to C.sub.8 cycloalkyl, C.sub.2 to C.sub.20 alkenyl, C.sub.2 to C.sub.20 alkynyl, C.sub.2 to C.sub.14 heteroatom substituted alkyl, C.sub.2 to C.sub.14 heteroatom substituted cycloalkyl, C.sub.4 to C.sub.10 substituted aryl, or C.sub.4 to C.sub.10 heteroatom substituted heteroaryl; and further wherein a is 1 to 10,000 and b is 0 to 10,000.

"In another embodiment, the medical device comprises a nitric oxide donating polymer comprising a biocompatible polymer of Formula II having at least one diazeniumdiolated phosphorylcholine functional group:

"##STR00005## wherein a is 1 to 10,000 and b, c and d are each 0 to 10,000.

"The present disclosure also relates to a method of making a nitric oxide donating polymer comprising: providing a biocompatible polymer having at least one phosphorylcholine functional group, diazeniumdiolating at least one of said phosphorylcholine functional groups to produce a biocompatible polymer having at least one phosphorylcholine diazeniumdiolated functional group. In another embodiment of the method of making a nitric oxide donating polymer, biocompatible polymer is produced from a precursor polymer capable of containing a phosphorylcholine functional group selected from the group consisting of: methacrylate, polyester, polycarbonate, poly(ortho ester), polyamide, polyurethane, polyurea, poly(ester amide), polysulfone, polyketone, silicone, polyphosphazene, poly(amino acid), polyether, polyimide, vinyl polymer, polyacrylate, polymethacrylate, plystyrene, poly(vinyl acetate), poly(vinyl chloride), poly(vinyl ester), poly(vinyl ether), polyacrylonitrile, poly(vinyl ketone), poly(vinyl pyrolidinone), fluorinated polymer, natural or modified biopolymers, collagen, alginate, elastin, chitosan, fibrin, fibrinogen, cellulose, starch, collagen, dextran, dextrin, hyaluronic acid acid, heparin, glycosamino glycan, and polysaccharide; and combinations thereof. In another embodiment of the present method, the biocompatible polymer is a copolymer.

"In another embodiment of the method of making a nitric oxide donating polymer, the biocompatible polymer is represented by Formula II with at least one diazeniumdiolated phosphorylcholine functional group:

"##STR00006## wherein a is 1 to 10,000 and b, c and d are each 0 to 10,000."

URL and more information on this patent, see: Chen, Mingfei; Shumaker, David; Cheng, Peiwen; Udipi, Kishore. Diazeniumdiolated Phosphorylcholine Polymers for Nitric Oxide Release. U.S. Patent Number 8709465, filed April 13, 2009, and published online on April 29, 2014. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=95&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=4749&f=G&l=50&co1=AND&d=PTXT&s1=20140429.PD.&OS=ISD/20140429&RS=ISD/20140429

Keywords for this news article include: Antianginal Agents, Drugs, Amines, Anions, Elastin, Surgery, Therapy, Arginine, Peptides, Synthase, Chemistry, Silicones, Siloxanes, Cardiology, Fibrinogen, Restenosis, Nitric Oxide, Free Radicals, Heart Disease, Methacrylates, Nitroglycerin, Blood Proteins, Vinyl Chloride, Nitrogen Oxides, Vinyl Compounds.

Our reports deliver fact-based news of research and discoveries from around the world. Copyright 2014, NewsRx LLC


For more stories covering the world of technology, please see HispanicBusiness' Tech Channel



Source: Biotech Week