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(12) United States Patent (10) Patent No.: US 8,062,653 B2 Bezwada (45) Date of Patent: Nov

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(12) United States Patent (10) Patent No.: US 8,062,653 B2 Bezwada (45) Date of Patent: Nov US008062653B2 (12) United States Patent (10) Patent No.: US 8,062,653 B2 BeZWada (45) Date of Patent: Nov. 22, 2011 (54) CONTROLLED RELEASE OF NITRICOXIDE 7,629,368 B2 12/2009 Del Soldato et al. AND DRUGS FROM FUNCTIONALIZED 292 s R: $33.9 ES tal MACROMERS AND OLGOMERS 7,858,6654 - B2 12/2010 OnginiSOCO et al. a 7,883,714 B2 2/2011 Earl et al. (75) Inventor: Rao S. Bezwada, Whitehouse Station, 2002fOO28845 A1 3/2002 Ekwuribe et al. NJ (US) 2002.0143047 A1* 10, 2002 Galer et al. .... ... 514,420 2008/0175881 A1* 7/2008 Ippolitietal. ................ 424/423 (73) Assignee: Bezwada Biomedical, LLC, 2008/028817.6 A1 11/2008 Tam et al. Hillborough, NJ (US) 2009/0076174 A1 3, 2009 Bezwada 2l, 2009/0092676 A1* 4/2009 Richard et al. ................ 424,501 (*) Notice: Subject to any disclaimer, the term of this FOREIGN PATENT DOCUMENTS patent is extended or adjusted under 35 CN 101.053662 * 10/2007 U.S.C. 154(b) by 175 days. CN 101.053662 A 10, 2007 WO O1-30334 A2 5, 2001 (21) Appl. No.: 12/508,854 WO 2004-004648 A2 1, 2004 WO WO 2005/05.3685 A1 * 6/2005 WO WO 2007/O25632 A1 * 3, 2007 (22) Filed: Jul. 24, 2009 WO WO 2007/090793 A1 * 8, 2007 WO WO 2008/071421 A1 * 6, 2008 (65) Prior Publication Data k cited. by examiner US 2010/0209469 A1 Aug. 19, 2010 Primary Examiner — Blessing Fubara Related U.S. Application Data (74) Attorney, Agent, or Firm — Moser Taboada (60) Pygal application No. 61/153,349, filed on Feb. (57) ABSTRACT s The present invention provides NO and, optionally, drug (51) Int. Cl. releasing macromers and oligomers wherein the drug mol A6F 2/00 (2006.01) ecule and NO releasing moiety are linked an absorbable mac A63/74 (2006.01) romer or oligomeric chain susceptible to hydrolytic degrada A6 IK3I/21 (2006.01) tion and wherein the macromer or oligomer comprises of (52) U.S. Cl. ...................... 424/423; 424/78.08: 514/509 repeat units derived from Safe and biocompatible molecules (58) Field of Classification Search .................. 424/423, such as glycolic acid, lactic acid, caprolactone and p-diox 424/78.08: 514/509; 525/450, 415 anone. Furthermore, the present invention relates to con See application file for complete search history. trolled release of nitric oxide (NO) and/or drug molecule from a NO and drug releasing macromer or oligomer. More (56) References Cited over, the present invention also relates to medical devices, medical device coatings and therapeutic formulations com U.S. PATENT DOCUMENTS prising of nitric oxide and drug releasing macromers and 7,199,258 B2 4/2007 Del Soldato et al. oligomers of the present invention. 7,279, 176 B1 * 10/2007 West et al. .................... 424/426 7,442,826 B2 10/2008 Rivolta et al. 17 Claims, No Drawings US 8,062,653 B2 1. 2 CONTROLLED RELEASE OF NITRC OXDE Medical research is rapidly discovering therapeutic appli AND DRUGS FROM FUNCTIONALIZED cations for NO including the fields of vascular surgery and MACROMERS AND OLGOMERS interventional cardiology. For example, Stents and DES car diovascular stents have been used clinically for treatment of This Application claims the priority of U.S. Ser. No. 5 occluded cardiac arteries for over fifteen years and their use 61/153,349, filed 18 Feb. 2009. has resulted in substantial clinical benefit for cardiac patients. However, a significant problem with bare-metal stents in FIELD OF THE INVENTION clinical usage is restenosis of the artery, leading to recurrence of the primary cardiac symptoms and effects. Localized NO The present invention relates to NO and, optionally, drug 10 release appears to address Some of the root causes of the molecule releasing macromers and oligomers wherein the restenosis including: 1) the fibrinogen binding-platelet adhe drug molecule and NO releasing moiety are linked a hydro sion-release of platelet derived growth factor cycle and 2) lytically degradable macromer or oligomeric chain compris inflammation and associated release of growth factors. NO ing of repeat units derived from safe and biocompatible mol release also addresses associated problems with undesired ecules such as glycolic acid, lactic acid, caprolactone and 15 smooth muscle cell growth (Raulli et al. WO2007/053578 p-dioxanone. The present invention also relates to controlled A2), and provides a long-term biocompatible solution to the release of NO and, optionally drug molecule from macromers presence of the stent by stimulating rapid endothelialization and oligomers of the present invention. Furthermore, the of the stent itself. Stent endothelialization results in a natural present invention relates to medical devices, medical device cell coating for the stent that essentially seeks to make the coatings and therapeutic formulations comprising nitric stent surface invisible to the blood and its components. oxide and drug releasing macromers and oligomers of the Delayed endothelialization has been linked of late in stent present invention. thrombosis, a potentially fatal event. Thus, the use of nitric The present invention relates to NO and, optionally, drug oxide eluting stent coatings has many advantages over anti molecule releasing macromers and oligomers wherein the proliferatives drugs, especially at the very early stages in the drug molecule and NO releasing moiety are linked to a hydro 25 stent placement pathophysiology. One of the key benefits of lytically degradable macromer or oligomeric chain compris NO is the stimulation of endothelialization which is a primary ing of repeat units derived from safe and biocompatible mol measure of healing. Thus, rapid division of endothelial cells ecules such as glycolic acid, lactic acid, caprolactone and and their rapid colonization of the stent material may be an p-dioxanone. The present invention also relates to controlled ultimate safety feature in DES development. Hence, there release of NO and drug molecule from macromers and oligo 30 exists a need for better technology addressing the release of mers of the present invention. Furthermore, the present inven NO and, optionally, additional drugs in drug-eluting stents. tion relates to medical devices, medical device coatings and Researchers have sought various ways to deliver NO to therapeutic formulations comprising nitric oxide and drug damaged tissue and to tissues and organs at risk of injury. One releasing macromers and oligomers of the present invention. approach for providing a therapeutic level of NO at an injury Nitric oxide (referred to herein as “NO”) is a vital biologi 35 site is to increase systemic NO levels prophylactically. This cal molecule. It plays a significant role in diverse biological can be accomplished by Stimulating endogenous NO produc processes such as host defense, cardiovascular regulation, tion or using exogenous NO sources. Methods to regulate signal transduction, neurotransmission and woundhealing. In endogenous NO release have primarily focused on activation addition to helping body cells to communicate with each of synthetic pathways using excess amounts of NO precursors other by transmitting signals throughout the entire body, NO 40 like L-arginine, or increasing expression of nitric oxide Syn assists the immune system at fighting offbacteria and defend thase (NOS) using gene therapy. U.S. Pat. Nos. 5.945,452, ing against tumors. Furthermore, it helps reduce inflamma 5,891.459 and 5,428,070 describe sustained NO elevation tion and regulate blood pressure by dilating arteries. More using orally administrated L-arginine and/or L-lysine. How over, NO assist in gastric motility and alleviating erectile ever, these methods have not been proven effective in pre dysfunction. 45 venting restenosis. Regulating endogenously expressed NO NO is a well known inhibitor of platelet adhesion and using gene therapy techniques remains highly experimental activation. Continuous release of NO from surface of endot and has not yet proven safe and effective. U.S. Pat. Nos. helial cells effectively prevents the adhesion/activation of 5,268,465, 5,468,630 and 5,658,565, describe various gene platelets on normal blood vessel walls. Furthermore, NO is therapy approaches. also a potent inhibitor of smooth muscle cell proliferation, 50 Exogenous NO sources Such as pure NO gas are highly and agents that release or generate NO locally have been toxic, short-lived and relatively insoluble in physiological proposed as Systematic drugs to prevent and/or treat resteno fluids. Consequently, systemic exogenous NO delivery is sis and thrombus formation when delivered to treatment sites generally accomplished using organic nitrate pro-drugs such inside an individual that have come in contact with medical as nitroglycerin tablets, intravenous Suspensions, sprays and devices such as cardiovascular drug-eluting stents, diagnostic 55 transdermal patches. The human body rapidly converts nitro catheters, guide wires, guide catheters, PTCA balloon cath glycerin into NO; however, enzyme levels and co-factors eters (for percutaneous transluminal coronary angioplasty) in required to activate the pro-drug are rapidly depleted, result blood vessels, in-dwelling sheaths (venous and arterial), ing in drug tolerance. Moreover, systemic NO administration intraaortic balloon pump catheters, intravascular sensors, can have devastating side effects including hypotension and extracorporeal blood loop circuits, intravenous grafts/shunts 60 free radical cell damage. Therefore, using organic nitrate and adhesion prevention barriers including meshes. Further pro-drugs to maintain systemic anti-restenotic therapeutic more, NO released from wound resident cells also play an blood levels is not currently possible. important role in unique cell signaling pathways and the Ideally, NO should be delivered in a controlled manner re-establishment of the microcirculation as newly vascular specifically to those tissues and organs that have been injured ized tissue is formed. Moreover, NO is anti-inflammatory, 65 or are at risk of injury. Furthermore, topical NO delivery may which would be of value for in dwelling urethral or TPN also be a crucial component of a new generation of wound catheters.
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