US 2010O24.9747A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0249747 A1 Mills et al. (43) Pub. Date: Sep. 30, 2010 (54) TRANSDERMAL VENOUS ACCESS Publication Classification LOCKING SOLUTION (51) Int. Cl. A6M 25/00 (2006.01) (75) Inventors: Stanley L. Mills, Goldsby, OK A 6LX 3L/727 (2006.01) (US); Jacqueline L. Mills, A638/17 (2006.01) Goldsby, OK (US); Robert D. A6IP 7/02 (2006.01) Maurer, Elkhorn, NE (US); Gary A6II 3L/20 (2006.01) L. Rayburn, Norman, OK (US); AOIN 37/00 (2006.01) Marvin A. Cuchens, Madison, MS A6IP3L/00 (2006.01) (US) (52) U.S. Cl. ............. 604/506; 514/56; 514/12: 514/558; 514/557; 604/265 Correspondence Address: (57) ABSTRACT Richard G. Gervase Mintz Levin Cohn Ferris Glovsky and Popeo PC Compositions and methods of employing compositions in Chrysler Center, 666 Third Avenue, 24th Floor flushing and coating medical devices are disclosed. The com New York, NY 10017 (US) positions include combinations of a chelating agent, antico agulant, or antithrombotic agent, with a C-C carboxylate antimicrobial agent, such as octanoic acid. Methods of using (73) Assignee: Organic Medical Ventures, these compositions for coating a medical device and for L.L.C., Norman, OK (US) inhibiting catheter infection are also disclosed. Particular combinations of the claimed combinations include, for (21) Appl. No.: 12/383,722 example, octanoic acid or other C-C carboxylate antimicro bial agent together with EDTA, EGTA, DTPA, heparin and/or (22) Filed: Mar. 26, 2009 hirudin in a pharmaceutically acceptable diluent. SOLUTIONY-...-- Patent Application Publication Sep. 30, 2010 Sheet 1 of 10 US 2010/0249747 A1 Patent Application Publication Sep. 30, 2010 Sheet 2 of 10 US 2010/0249747 A1 Patent Application Publication Sep. 30, 2010 Sheet 3 of 10 US 2010/0249747 A1 Patent Application Publication Sep. 30, 2010 Sheet 4 of 10 US 2010/0249747 A1 Patent Application Publication Sep. 30, 2010 Sheet 5 of 10 US 2010/0249747 A1 Patent Application Publication Sep. 30, 2010 Sheet 6 of 10 US 2010/0249747 A1 Patent Application Publication Sep. 30, 2010 Sheet 7 of 10 US 2010/0249747 A1 Patent Application Publication Sep. 30, 2010 Sheet 8 of 10 US 2010/0249747 A1 Patent Application Publication Sep. 30, 2010 Sheet 9 of 10 US 2010/0249747 A1 |ZTZ-ZTZ-Z-Z-ZIZIZIZIZIZIZO Patent Application Publication Sep. 30, 2010 Sheet 10 of 10 US 2010/0249747 A1 FIG. 5 FU US 2010/0249747 A1 Sep. 30, 2010 TRANSIDERMAL VENOUSACCESS Such organisms as Staphylococci and Candida, with an LOCKING SOLUTION enhanced adherence capacity to the catheter Surface. Unlike these particular microbes, gram-negative bacilli do not FIELD OF THE INVENTION adhere well to fibrin and fibronectin. A composition that halts fibrin formation would thus be particularly useful in halting 0001. This invention relates to the field of transdermal the colonization of Staphylococci, Candida, and the like, at indwelling medical devices, such as catheters, as well as to transdermal catheter sites. the field of methods and compositions for flushing, locking 0006 Ethylenediaminetetraacetic acid (EDTA) is an anti and coating these medical devices. The field of this invention coagulant used in blood collection tubes. It is also recognized also relates to microbial-inhibiting pharmaceutical prepara as a calcium chelating agent. EDTA is also recognized to have tions. This invention also relates to pharmaceutical prepara an antibacterial and antistaphylococcal effect (alone or in tions useful in maintaining catheter patency and preventing combination) (Harper & Epis (1987) Microbios. 51:107: Said infection. Methods of using the pharmaceutical preparation et al. (1987) J. Med. Microbiol. 24:267: Root et al. (1988) of the invention in the management and maintenance of trans Antimicrob. Agents Chemother: 32:1627). While those inves dermal vascular access catheters are also related to the present tigators found EDTA to be bacteriocidal, no remedy or sug disclosure. gestion of how the microbial glycocalyx of a device-related infection could be eliminated was provided. BACKGROUND OF THE INVENTION 0007 EGTA (ethylene glycol-bis-beta-aminoethyl 0002 Transdermal medical devices, including vascular ether-N.N.N',N'-tetraacetic acid) is another recognized catheters, have become essential in the management of hos chelating agent. This agent has not been described as antimi pitalized or chronically ill patients. Unfortunately, vascular crobial. Triethylene tetramine dihydrochloride (trientine catheters have become the major source for hospital-acquired 2HCl) (TTH) is a recognized chelating agent that chelates sepsis. Hence, the benefit derived from transdermal medical copper. TTH and other chelating agents, including diethylen devices such as vascular catheters is often upset by infectious etriamine pentaacetic acid (DTPA), are similarly not recog complications. Thrombotic occlusions of the lumenofcentral nized as having antimicrobial activity. venous catheters (CVC) are another complication that will 0008 Although glycopeptide antibiotics (Vancomycin often lead to the removal of catheters. and teicoplanin) are effective against Staphylococci in vitro 0003) To reduce problems associated with thrombus for and in tissue, they are not active against adherent staphylo mation, it is now common to "lock intravascular access cocci embedded in a biofilm layer, such as glycocalyx. While catheters between Successive uses. Locking typically flushing with Such agents may acutely destroy these micro involves first flushing the catheter with saline to remove organisms, the risk of rapid development of tolerant and resis blood, medications, cellular debris and other substances from tant strains in the patient being treated makes this a contrain the catheter lumen. After the catheter has been flushed, a dicated procedure in most cases. locking solution, typically heparin, is then injected to dis 0009 U.S. Pat. No. 5,688,516 to I. Radd, describes com place the Saline and fill the lumen. The heparin locking solu positions for use with catheters that include a tetracycline tion both excludes blood from the lumen and actively inhibits antibiotic, such as minocycline and EDTA. clotting and thrombus formation within the lumen. To address O010 U.S. Pats. No. 4,343,788 and 4,479,795 to R. V. infection, various antimicrobial Substances have been com Mustacich, describe polymer compositions containing car bined with the locking solution in order to inhibit infection at boxylate antimicrobial agents for incorporation into cath the same time that thrombosis is being inhibited. However, eters. U.S. Pat. No. 4,392,848 to D. S. Lucas, describes poly problems with current and continuously emerging resistance mer compositions for incorporation into catheters that are to antimicrobial Substances, as well as the over-use (and permeable to carboxylate antimicrobial agents. U.S. Pat. No. hence the increased risk of developing resistance) of antimi 4,489,097 to R. L. Stone (hereinafter “Stone'), describes crobials, is an ever-growing concern. intravenous Solutions containing carboxylate antimicrobial 0004 Staphylococcus epidermidis and S. aureus account agents, preferably n-hexanoic and n-octanoic acids and phar for 75% of CVC related infections. Candida species account maceutically-acceptable, water-soluble salts thereof. for another 10% to 15% of such infections. The use of anti 0011 A prophylactic agent for catheter maintenance staphylococcal antibiotics to prevent these infections has should both inhibit/eliminate the formation of polysaccha been found to reduce CVC related bacterial infections, but ride-rich glycocalyx and eliminate staphylococci and fungi. only at the expense of the occurrence of higher rates of fungal 0012. In view of the foregoing, there is a need for (Candida) infections. The fibrous glycocalyx material pro improved compositions, kits and methods for flushing, lock duced by staphylococci and Candida helps these organisms ing and disinfecting catheters. Such compositions should adhere and stick to catheter Surfaces. These microbiological have antimicrobial activity against a broad spectrum of biofilm layers are made offibrous glycocalyx material prima microorganisms, preferably including fungi and both gram rily polysaccharide in nature. The protective sheath provided positive and gram-negative bactertia, and preferably be effec by the glycocalyx at the infected site effectively prevents the tive against planktonic (free-floating) and adherent microor elimination and treatment of these infections. As a result, ganisms embedded in a biofilm. The compositions should pharmaceutical preparations are needed that are effective for discourage the development of resistant microbes, be rela reducing or eliminating glycocalyx of infectious microorgan tively inexpensive, non-toxic, compatible with the catheter isms typically associated with catheter colonization and material, safe if inadvertently infused systemically, easy to infection. implement, require minimum or no preparation, and be useful 0005 Transdermal vascular catheters get engulfed by a with most orall types of implanted catheters, including hemo fibrin sheath that subsequently acts to cover the internal and dialysis and hemofiltration catheters, IV catheters, peritoneal external surfaces of a catheter. This fibrin sheath provides dialysis catheters, urinary catheters, chemotherapy catheters, US 2010/0249747 A1 Sep. 30, 2010 and the like. At least some of these objectives are met by 0017. Other embodiments of the compositions can include