(19)
(11)EP 3 370 794 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
09.10.2019 Bulletin 2019/41

(21)Application number: 16806326.1

(22)Date of filing:  04.11.2016
(51)Int. Cl.: 
A61L 29/16  (2006.01)
A01N 37/44  (2006.01)
A01N 31/02  (2006.01)
A01N 43/54  (2006.01)
(86)International application number:
PCT/US2016/060571
(87)International publication number:
WO 2017/079589 (11.05.2017 Gazette  2017/19)

(54)

ANTIMICROBIAL SOLUTIONS WITH ENHANCED STABILITY

ANTIMIKROBIELLE LÖSUNGEN MIT VERBESSERTER STABILITÄT

SOLUTIONS ANTIMICROBIENNES À STABILITÉ AMÉLIORÉE


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 05.11.2015 US 201562251481 P

(43)Date of publication of application:
12.09.2018 Bulletin 2018/37

(73)Proprietor: Board of Regents, The University of Texas System
Austin, TX 78701 (US)

(72)Inventors:
  • ROSENBLATT, Joel
    Pottstown, PA 19465 (US)
  • RAAD, Issam
    Missouri City, TX 77459 (US)

(74)Representative: Rückerl, Florian 
Dehmel & Bettenhausen Patentanwälte PartmbB Herzogspitalstraße 11
80331 München
80331 München (DE)


(56)References cited: : 
US-A1- 2004 110 841
US-B2- 7 601 731
  
  • M. VENKATESH ET AL: "Novel synergistic antibiofilm combinations for salvage of infected catheters", JOURNAL OF MEDICAL MICROBIOLOGY., vol. 58, no. 7, 5 June 2009 (2009-06-05), pages 936-944, XP55345572, GB ISSN: 0022-2615, DOI: 10.1099/jmm.0.009761-0
  • I. RAAD ET AL: "Optimal Antimicrobial Catheter Lock Solution, Using Different Combinations of Minocycline, EDTA, and 25-Percent Ethanol, Rapidly Eradicates Organisms Embedded in Biofilm", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 51, no. 1, 1 January 2007 (2007-01-01), pages 78-83, XP55345631, US ISSN: 0066-4804, DOI: 10.1128/AAC.00154-06
  • I. RAAD ET AL: "Chelator-Based Catheter Lock Solutions in Eradicating Organisms in Biofilm", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 57, no. 1, 1 January 2013 (2013-01-01), pages 586-588, XP55345571, US ISSN: 0066-4804, DOI: 10.1128/AAC.01287-12
  • "Minocin", NDA 50-444/S-047, August 2010 (2010-08),
  
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description

BACKGROUND OF THE INVENTION


1. Field of the Invention



[0001] The present invention relates generally to the field of molecular biology and medicine. More particularly, it concerns antimicrobial compositions such as, e.g., antimicrobial catheter lock solutions.

2. Description of Related Art



[0002] Microbial contamination of medical devices, such as catheters, continues to present a significant clinical problem. Medical devices, such as vascular catheters, have improved the quality of medical care. However, infections resulting from the colonization of organisms embedded in biofilm are the most frequent complication associated with the use of these and other indwelling and/or prosthetic devices. In fact, infections are the most serious complications associated with indwelling central venous catheters (CVCs) (Maki et al., 1998). It is estimated that more than 200,000 catheter-related bloodstream infections (CRBSI) occur annually in the United States alone (Kluger et al., 1999). Staphylococcus epidermidis, Staphylococcus aureus and Candida species are the leading organisms causing CRBSI (Maki et al., 1998; Raad et al., 2002).

[0003] While there is a risk of bacterial colonization of a catheter, use of a catheter lock solution can allow continued use of a catheter, and removal of the catheter from a patient is often problematic in many clinical situations. Antimicrobial catheter lock solutions can provide salvage of colonized vascular catheters in the setting of blood stream infections. For many critically ill patients, removal or exchange of a vascular catheter in the setting of blood stream infection is a poor option. There is a risk of vessel irritation or rupture as well as bleeding. The risk of bleeding is particularly significant in patients with underlying coagulopathies such as cancer patients. There is also a risk of cardiac taponade as well as cost associated with radiologic imaging to verify tip position of the replacement catheter. Antimicrobial catheter lock solutions can also serve the valuable function of preventing a catheter from becoming a source of blood stream pathogens in the setting of blood stream infection.

[0004] Nonetheless, intralumenal colonization is the major source for the migration of organisms leading to bloodstream infections in long-term silicone catheters (Raad et al., 1993). While progress has been made in reducing bacterial infiltration of medical devices or indwelling medical devices, infections resulting from bacterial colonization of medical devices continues. Clearly, there is a need for new and improved antimicrobial solutions, such as improved antimicrobial catheter lock solutions.

SUMMARY OF THE INVENTION



[0005] The present invention overcomes limitations in the prior art by providing, in certain aspects, improved antimicrobial compositions (e.g., improved catheter lock solutions) that display improved stability and storage. The present invention is based, in part, on the observation that some antimicrobial compositions can result in an undesirable precipitation of antimicrobial components from the solution, thus limiting utility of the solution. Improved antimicrobial solutions are provided herein that exhibit reduced precipitation of components in solution and improved stability.

[0006] As shown in the below examples, the inventors have observed that inclusion of both EDTA and an alcohol in an antimicrobial solution with an antibiotic can result in an undesirable precipitation (e.g., of the EDTA and/or antibiotic) from the solution, which may reduce the antimicrobial properties of the antimicrobial solution. Further, this precipitate may produce undersirable consequences in a catheter lock or flush solution since, e.g., the precipitate may clog catheter lumens or create emboli.

[0007] Simply reducing the concentration of EDTA in the antimicrobial solution might be expected to reduce the precipitation of EDTA; however, reducing the concentration of EDTA could also reduce the antimicrobial properties of the resulting antimicrobial composition. In some aspects, the present invention is based, in part, on the surprising discovery that antimicrobial solutions comprising both EDTA and an alcohol (e.g., ethanol), when adjusted to about pH 6-8, can result in compositions that display in little or no undesirable precipitation of the EDTA over extended periods of time (e.g., for at least about 24 hours, at least about 48 hours, or at least 72 hours after mixture with an antibiotic such as minocycline). To the knowledge of the inventors, neither this problem nor this solution is described in the prior art.

[0008] As shown in the below examples, while using of the triple combination minocycline/EDTA/Ethanol (M/EDTA/Ethanol) as described in US7601731, the inventors observed that a precipitate began to form within 24 hours of preparing this triple combination (M/EDTA/Ethanol) lock solution. In clinical usage, in some situations it is impossible or undesirable to immediately use all the prepared lock solution, e.g., when the lumens of a catheter are in service for administering medication, hydration, nutrition or diagnostics. In some cases, the availability of individuals trained to mix the lock may be limited, creating a need for storage. Furthermore, due of the cost of Minocycline, may be economically preferable to store unused lock solutions for limited durations rather than to discard them. As shown in the below examples, antimicrobial solutions observed to provide for at least about 72 hours of stable storage of prepared lock solution prior to use. A stable (e.g., stable for at least 72 hours) lock solution comprising M/EDTA/Ethanol can be prepared, e.g., when a fourth component is added to adjust the pH to the range of about 6-8. Several stable four component/EDTA/Ethanol lock solutions are described. Kit designs for salvage of infected catheters via antimicrobial lock therapy with the stable lock solution are also provided. The scope of the invention is defined by the claims. In some embodiments, the antimicrobial solution or catheter lock solution may contain:
  1. (i) Alcohol + Antimicrobial agent + acidic EDTA (such as disodium EDTA) + sufficient base (such as sodium or potassium hydroxide) to adjust pH to 6-8;
  2. (ii) Alcohol + antimicrobial agent + basic EDTA (such as tetrasodium EDTA) + sufficient acid (such as hydrochloric or acetic acid) to neutralize pH to 6-8; or
  3. (iii) Alcohol + antimicrobial agent + acidic EDTA (such disodium EDTA) + basic EDTA (such as tetrasodium EDTA) in proportion to attain pH 6-8. In some embodiments, a mixture of acidic and basic EDTAs is sometimes sold as trisodium EDTA and can have a pH of 6.5-7.5 depending on the ratio, and may be used in the antimicrobial solution or catheter lock solution.


[0009] As aspect of the present invention relates to a pharmaceutically acceptable antimicrobial solution comprising: (i) a C1-4 alcohol; (ii) an EDTA; and (iii) a tetracycline antibiotic; wherein said solution has a pH of about 6-8, and wherein said solution comprises a pharmaceutically acceptable excipient or diluent. In some embodiments the antibiotic is trimethoprim or minocycline. In some embodiments, the C1-4 alcohol is ethanol, isopropanol, methanol, or butanol. In some embodiments, the C1-4 alcohol is ethanol. The C1-4 alcohol may be present in the solution at a concentration of about 10-40%. In some embodiments, the C1-4 alcohol is present in the solution at a concentration of about 10-30%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, or any range derivable therein. The C1-4 alcohol may be ethanol. In some embodiments, the solution comprises about 1-5%, 1.5-5% 1-3.5%, 1-3%, or about 3% EDTA. The solution may comprise about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5% EDTA, or any range derivable therein. In some embodiments, the EDTA is EDTA free acid, EDTA 2Na, EDTA 3Na, EDTA 4Na, EDTA 2K, EDTA 2Li, EDTA 2NH4, EDTA 3K, Ba(II)-EDTA, Ca(II)-EDTA, Co(II)-EDTA, Cu(II)-EDTA, Dy(III)-EDTA, Eu(III)-EDTA, Fe(III)-EDTA, In(III-EDTA, La(III)-EDTA, EDTA-OH, or Methyl-EDTA. The solution may comprise about 0.05-0.2% tetracycline antibiotic. In some embodiments, the solution comprises about 0.1% minocycline, about 3% EDTA, and about 25% ethanol. In some embodiments, the EDTA is an acidic EDTA, and wherein the solution further comprises a base. In some embodiments, the acidic EDTA is EDTA free acid, EDTA 2Na, EDTA 2K, EDTA diammonium, or a diacid of EDTA. In some embodiments, the base is sodium hydroxide, potassium hydroxide, ammonia, an amine, or urea. In some embodiments, the EDTA is a basic EDTA, and wherein the solution further comprises an acid. In some embodiments, the basic EDTA is EDTA 4Na, EDTA 4K, or tetra ammonium EDTA. The acid may be hydrochloric acid or acetic acid. In some embodiments, the solution comprises both an acidic EDTA and a basic EDTA. The acidic EDTA may be EDTA free acid, EDTA 2Na, dipotassium EDTA, or diammonium EDTA; and wherein the basic EDTA is EDTA 4Na, tetra potassium EDTA (EDTA 4K), or tetra ammonium EDTA. The solution may comprise a pharmaceutically acceptable saline diluent or a pharmaceutically acceptable diluent. The solution has a pH of about 6.5-7.5, of about 7-7.4, or 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, or any range derivable therein. The solution may further comprise polyethylene glycol. In some embodiments, the solution is further defined as a catheter lock solution. In some embodiments, the fraction of EDTA in the tetravalent form is between about 0.1 and about 0.000001, preferably between about 0.05 and about 0.000005, or more preferably between about 0.01 and about 0.00001, or any range derivable therein (e.g., about 0.0042-0.000018, about 0.001-0.0001, about 0.0025-0.000025, about 0.0025-0.000075, etc.).

[0010] Another aspect of the present invention relates to a syringe, comprising a unit dose of a pharmacologically effective amount of a solution of the present invention (e.g., an antimicrobial solution or catheter lock solution as described herein) or as described above.

[0011] Yet another aspect of the present invention relates to a vial, comprising a unit dose of a pharmacologically effective amount of a solution of the present invention (e.g., an antimicrobial solution or catheter lock solution as described herein) or as described above.

[0012] Another aspect of the present invention relates to a medical device locking solution comprising or consisting of a solution of the present invention (e.g., an antimicrobial solution or catheter lock solution as described herein) or as described above.

[0013] Yet another aspect of the present invention relates to a kit comprising: (i) a tetracycline antibiotic in a first container; (ii) a solution containing an EDTA and an alcohol at a pH of about 6-8 in in a second container; (iii) a suitable connector for mixing the antibiotic and the solution; and (iv) a suitable syringe or container for administering the mixed solution to a catheter. In some embodiments, one or more labels or removable extension-line tags is attached to the catheter. The tags may be symmetric peel-off tags comprising adhesive on one side and optionally having pre-perforated lines (e.g., on about the mid-section of the tags). The mixed solution may be a solution of the present invention (e.g., an antimicrobial solution or a catheter lock solution). The antibiotic may be lyophilized. In some embodiments, the alcohol is ethanol. In some embodiments, the first container is a vial or syringe, and wherein the second container is a vial or syringe. In some embodiments, the antibiotic is a lyophilized antibiotic, and wherein the first container and the second container are each a vial or syringe.

[0014] Another aspect of the present invention relates to a solution for use in flushing or locking a catheter in a subject, wherein the solution is a solution the present invention (e.g., an antimicrobial solution as described above or herein). The catheter may be an intravascular catheter, a urinary catheter, a brain catheter, a nephrostomy tube, or a drain or drainage catheter. In some embodiments, the subject is a human.

[0015] A variety of EDTA chelator molecules may be used with the present invention. In some embodiments, the composition may comprise an additional chelator molecule. The EDTA or chelator may be, e.g., EDTA free acid, EDTA 2Na, EDTA 3Na, EDTA 4Na, EDTA 2K, EDTA 2Li, EDTA 2NH4, EDTA 3K, Ba(II)-EDTA, Ca(II)-EDTA, Co(II)-EDTACu(II)-EDTA, Dy(III)-EDTA, Eu(III)-EDTA, Fe(III)-EDTA, In(III-EDTA, La(III)-EDTA, CyDTA, DHEG, diethylenetriamine penta acetic acid (DTPA), DTPA-OH, EDDA, EDDP, EDDPO, EDTA-OH, EDTPO, EGTA, HBED, HDTA, HIDA, IDA, Methyl-EDTA, NTA, NTP, NTPO, O-Bistren, TTHA, EGTA, DMSA, deferoxamine, dimercaprol, zinc citrate, a combination of bismuth and citrate, penicillamine, succimer or Etidronate. It is contemplated that a chelator that binds barium, calcium, cerium, cobalt, copper, iron, magnesium, manganese, nickel, strontium, or zinc may be included in various embodiments of the present invention.

[0016] Trisodium EDTA is not as commonly available as the other salts and has a pH of 9.5 (e.g., Dissolvine NA3-36 AkzoNobel Industrial Chemicals Amersfoort, Netherlands; CAS 150-38-9). Trisodium EDTA is sometimes sold as a blend of di- and tetra- sodium EDTAs which can have pH depending on the blend ratio. This however is not a single EDTA salt. Some Trisodium EDTAs for cell culture applications are treated with diethyl pyrocarbonate (DEPC), which lowers the pH to 8 (Santa Cruz Biotechnology, Dallas, TX; Millipore, Billerica, MA). The DEPC adjusted Trisodium EDTA is not a pure, single salt form of EDTA and because of the additive would require extensive safety testing for blood contact in humans. EDTA is a tetra-acid. The different anions coexist in solution with fractional presence dependent on solution pH. Between pH 6 and 8 the predominant fractions are di and trivalent, but a small fraction of tetra valent is also present. Harris (2010) reports that at 20 degrees Celsius and 0.1 Molar concentration that the fraction of EDTA that is tetravalent at pH 8 is about 0.0042 and the fraction that is tetravalent at pH 6 is about 0.000018 (1.8 x 10-5). Solutions of EDTA with the desired final pH can be prepared by blending salts with different valences or by adjusting the pH to the desired range by addition of acid or base; however accomplished, the fraction of tetravalent EDTA in the solution (as compared to the other forms of EDTA, i.e., as compared to the mono-, di-, and tri-valent forms of EDTA) may preferably be between about 0.1 and about 0.000001, more preferably between about 0.05 and about 0.000005, and even more preferably between about 0.01 and about 0.00001, or any range derivable therein (e.g., about 0.0042-0.000018, about 0.001-0.0001, etc.).

[0017] A "C1-4 alcohol", as used herein, refers to a small-chain alcohol having 1-4 carbons. In some embodiments the C1-4 alcohol is methanol, ethanol, butanol (n-butanol), isopropanol, n-propanol, 2-butanol, tert-butanol or isobutanol. In some embodiments, the C1-4 alcohol (e.g., ethanol) is present in an antimicrobial solution of the present invention at a concentration of less than about 30%, more preferably less than about 28%. In some embodiments, the C1-4 alcohol (e.g., ethanol) is present in an antimicrobial solution of the present invention at a concentration of about 1-30%, 2.5-25%, 5-25%, 5-15%, 10-15%, 5-10%, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 23, 24, 25 %, or any range derivable therein.

[0018] In some embodiments, the antibiotic is trimethoprim and/or minocycline. In various embodiments, one or more additional antimicrobial agent (e.g., an alcohol, EDTA, and trimethoprim and/or minocycline, optionally in combination with one or more antimicrobial agent) may be included in an antimicrobial solution or composition of the present invention.

[0019] An antimicrobial solution (e.g., a catheter lock solution) of the present invention includes member of the tetracycline group of antibiotics such as tigecycline, minocycline, doxycycline, or demeclocycline and/or analogs such as anhydrotetracycline, chlorotetracycline, or epioxytetracycline. In some embodiments, antimicrobial solutions or catheter lock solutions as described herein may include one or more additional antiviral agents and/or antifungal agents.

[0020] Antimicrobial compositions and methods described herein can be used to reduce microbial agents (e.g., bacteria) from the surface of a medical device such as, e.g., a catheter, a drain, an endotracheal tube, a nephrostomy tube, a ventricular catheter or shunt, a biliary stent, an orthopedic device, a prosthetic valve, a medical implant, dental devices or dental implants, cardiac assist devices, vascular grafts, tracheostomy, ventriclulostomy devices, or intrathecal devices. In some aspects, the catheter is an indwelling catheter such as a central venous catheter, a peripheral intravenous catheter, an arterial catheter, a Swan-Ganz catheter, a hemodialysis catheter, a urinary catheter, a peritoneal catheter, an umbilical catheter, a percutaneous nontunneled silicone catheter, a cuffed tunneled central venous catheter or a subcutaneous central venous port. In some embodiments, the medical device is an endotracheal tube, a vascular catheter, a urinary catheter, a nephrostomy tube, a biliary stent, a peritoneal catheter, an epidural catheter, a central nervous system catheter, an intracranial catheter, an intraspinal catheter, an epidural catheter, an orthopedic device, a prosthetic valve, or a medical implant. The catheter may be a vascular catheter such as, e.g., a central venous catheter, an arterial line, a pulmonary artery catheter, and a peripheral venous catheter, an intraarterial catheter, or intravenous (i.v.) tubing.

[0021] The pharmaceutical composition or catheter lock solution of the present invention comprises a pharmaceutically acceptable excipient. The phrases "pharmaceutically acceptable" and "pharmacologically acceptable" refer to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, such as, for example, a human, as appropriate. The preparation of an pharmaceutical composition that contains an antimicrobial solution (e.g., a catheter lock solution) of the present invention and an additional active ingredient will be known to those of skill in the art in light of the present disclosure, as exemplified by Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams and Wilkins, 2005. Moreover, for animal (e.g., human) administration, it will be understood that preparations should typically meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biological Standards. In some embodiments, an antimicrobial solution or catheter lock solution may comprise one or more ingredient as described in U.S. Pat. Nos. 7601731, 5362754, and 5688516. In some embodiments, an antimicrobial composition or catheter lock solution of the present invention may comprise one or more additional antiviral or antifungal agent.

[0022] Other than reduction/eradication of microbes in medical devices, the flush solutions of the present invention are also useful in the eradication of the surfaces of other surfaces that microbes can grow on such as pipes, pipelines (e.g., an oil or water pipeline), ice machines, etc. Fluid pipelines, such as oil and water pipelines, are often obstructed by lumenal biofilm that is produced by microorganisms that colonize the internal surface of these pipelines. In these embodiments, higher concentrations of an alcohol may be used (e.g., 1-80% or higher). In some embodiments, an antimicrobial composition of the present invention may be used for oral hygiene, e.g., as a mouthwash or for topical (skin) disinfection. In some embodiments, an antimicrobial solution as described herein may be used to clean or disinfect a surface, or may be included on a wipe.

[0023] In some aspects, kit designs are provided that may reduce errors in salvaging a catheter in a patient experiencing infection symptoms. This can include salvage of vascular catheters in patients experiencing bacteremia. This is particularly a problem with multilumen catheters, where some lumens need to remain in use while others can be locked for a required disinfecting interval. Following disinfection of the locked lumen(s), the lumens can be rotated where the disinfected lumen becomes used for infusion and the lumen being previously used for disinfection becomes locked. With as many as 5 or more lumens, it can become confusing to keep track of which lumens were treated and which were in use. To overcome this problem, a user-ready kit supplied with Minocycline in dry form (powder or lyophilized) and pH adjusted EDTA-Ethanol as a liquid, may include removable extension-line tags which can be preprinted or filled in by the clinician denoting the time that lock therapy was initiated and the tag may indicate how long that lumen should be left locked, so as not to inadvertently terminate lock therapy before that lumen could be disinfected. Also lock therapy completed tags may also be included. Spaces for writing in the dates and color coding of the tags can be used. Symmetric peel-off tags with adhesive on one side which have pre-perforated lines down their mid-sections may be used for this purpose. In some embodiments, these tags can be folded on themselves such that the pre-perforated line contacts and is axially parallel with the extension line (or luer) and the adhesive sides are folded over on themselves. In some embodiments, the tags can be removed or exchanged by pulling in a direction perpendicular to the perforated line such that the tag readily tears at the perforation and can be discarded are placed in a patient's records.

[0024] An "antimicrobial agent" is defined herein as an agent that has antibiotic properties against bacteria, fungi, viruses and other pathogens and includes antibacterial agents, antifungal agents, antiviral agents and antiseptic agents.

[0025] As used herein, the term "antifungal agent" is defined as a compound having either a fungicidal or fungistatic effect upon fungi contacted by the compound. As used herein, the term "fungicidal" is defined to mean having a destructive killing action upon fungi. As used herein, the term "fungistatic" is defined to mean having an inhibiting action upon the growth of fungi.

[0026] As used herein, the term "antibacterial agent" is defined as a compound having either a bactericidal or bacteriostatic effect upon bacteria contacted by the compound. As used herein, the term "bactericidal" is defined to mean having a destructive killing action upon bacteria. As used herein, the term "bacteriostatic" is defined to mean having an inhibiting action upon the growth of bacteria.

[0027] As used herein, the term "antiviral agent" is defined as a compound that can either kill viral agents or one that stops the replication of viruses upon contact by the compound.

[0028] For the purposes of this disclosure, the phrase "effective amount" or "therapeutically effective amount" is defined as a dosage sufficient to induce a microbicidal or microbistatic effect upon the microbes contacted by the composition on a surface.

[0029] As used herein the terms "contact", "contacted", and "contacting", or "exposed" and "exposure" are used to describe the process by which any of the antimicrobial compositions disclosed in the present invention, comes in contact with or direct juxtaposition with a surface of a medical device or any other surface from which microbial growth is to be reduced or eradicated.

[0030] As used herein in the specification, "a" or "an" may mean one or more. As used herein in the claim(s), when used in conjunction with the word "comprising", the words "a" or "an" may mean one or more than one. As used herein "another" may mean at least a second or more.

[0031] The use of the term "or" in the claims is used to mean "and/or" unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and "and/or." As used herein "another" may mean at least a second or more.

[0032] Throughout this application, the term "about" is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects.

[0033] Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS



[0034] The present invention provides, in various aspects, improved antimicrobial solutions, such as improved antimicrobial catheter lock solutions. An antimicrobial catheter lock solution contains a tetracycline antibiotic, a chelator, and an alcohol, wherein the solution is adjusted to a pH of about 6-8. In some embodiments, the antibiotic is minocycline and/or trimethoprim, the chelator is EDTA, and the alcohol is ethanol. For example, the antimicrobial solution or catheter lock solution may contain about 3% EDTA, about 25% ethanol, and about 0.1% minocycline. In some embodiments, the antimicrobial solution or catheter lock solution may exhibit potency against biofilm, little or no toxic side effects, and blood anticoagulant properties in a human patient.

[0035] In addition to use with catheters (e.g., as a catheter lock solution or a catheter flush solution), an antimicrobial composition or solution of the present invention may be applied to or used with a medical device. The medical device may be, e.g., an endotracheal tube, a nephrostomy tube, a biliary stent, an orthopedic device, a valve, a prosthetic valve, a drainage tube, a drain, a shunt, a staple, a clip, a mesh, a film, a blood exchanging device, a port, a cardiovascular device, a defibrillator, a pacemaker lead, a wire coating, an ocular implant, an auditory implant, a cochlear implant, a dental implant, a stimulator, a drug delivery depot, a filter, a membrane, a vascular access port, a stent, an envelope, a bag, a sleeve, intravenous or other tubing, a bag, a dressing, a patch, a fiber, a pin, a vascular graft, a suture, a cardiovascular suture, or an implantable prosthesis. In some embodiments, the medical device is a catheter such as, e.g., a vascular catheter, a urinary catheter, an intracranial catheter, an intraspinal catheter, a peritoneal catheter, a central nervous system catheter, a cardiovascular catheter, a drainage catheter, a soaker catheter, an aspirating catheter, an intrathecal catheter, a neural catheter, a stimulating catheter, or an epidural catheter. The catheter may be a vascular catheter such as, e.g., a central venous catheter, an arterial line, an pulmonary artery catheter, a peripheral venous catheter, an intravenous catheter, or an intraarterial catheter.

Antimicrobial Agents and Microbes



[0036] Antimicrobial compositions of the present invention may be used to kill, destroy, or reduce the proliferation of a variety of microbes. Some non-limiting exemplary bacterial and fungal microbes that can be reduced or eradicated by the compositions and methods of the invention include Staphyloccous species (such as Staphylococcus epidermidis), Staphylococcus aureus; Aspergllus species (such as Aspergillus flavus, Aspergillus terreus), Enterrococcus faecalis, Pseudomonas aeruginosa, Escherichia coli, Fusarium oxysporum, and Candida species (such as Candida krusei, Candida parapsilosis, Candida tropicalis, Candida albicans and Candida glabrata).

Chelators



[0037] According to the present invention, an antimicrobial solution (e.g., a catheter lock or flush solution) comprises both a C1-4 alcohol and a chelator such as EDTA. Chelators can bind a metal ion, typically involving the central metal ion attached by coordinate links to two or more nonmetal atoms in the same molecule. Heterocyclic rings are typically formed during chelation, with the metal atom as part of the ring. The molecule comprising the nonmetal linking atoms is termed a chelator. Chelators are used in various chemical applications, for example as titrating agents or as metal ion scavengers. Chelators can also be used to remove ions from participation in biological reactions. For example, the well-known chelator ethylenediamine-N,N,N',N',-tetraacetic acid (EDTA) can act as an anticoagulant because it is capable of scavenging ions such as calcium ions from the blood. EDTA may sequester metal ions such as Ca2+ or Fe3+. EDTA can also act as an antimicrobial agent, e.g., by binding iron and/or trace metals that may be important or essential for the microbes to grow and reproduce.

[0038] In some embodiments, the EDTA is present in an antimicrobial solution or composition of the present invention (e.g., in a catheter lock solution) at a concentration of from about 1-5%, 1.5-5%, 1-3.5%, 1-3%, or about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5%, or any range derivable therein.

[0039] A variety of forms of EDTA may be used in various embodiments of the present invention. For example, the EDTA may be: EDTA free (Ethylenediamine-N,N,N',N',-tetraacetic acid), EDTA 2Na (Ethylenediamine-N,N,N',N',-tetraacetic acid, disodium salt), dihydrate EDTA 3Na (Ethylenediamine-N,N,N',N',-tetraacetic acid, trisodium salt, trihydrate), EDTA 4Na (Ethylenediamine-N,N,N',N'-tetraacetic acid, tetrasodium salt), tetrahydrate EDTA 2K Ethylenediamine-N,N,N',N'-tetraacetic acid, dipotassium salt), dihydrate EDTA 2Li (Ethylenediamine-N,N,N',N'-tetraacetic acid, dilithium salt), monhydrate EDTA (2NH4 Ethylenediamine-N,N,N',N'-tetraacetic acid, diammonium salt), EDTA 3K (Ethylenediamine-N,N,N',N'-tetraacetic acid, tripotassium salt), dihydrate Ba(II)-EDTA (Ethylenediamine-N,N,N',N'-tetraacetic acid, barium chelate), Ca(II)-EDTA (Ethylenediamine-N,N,N',N'-tetraacetic acid, calcium chelate), Ce(III)-EDTA (Ethylenediamine-N,N,N',N'-tetraacetic acid, cerium chelate), Co(II)-EDTA (Ethylenediamine-N,N,N',N'-tetraacetic acid, cobalt chelate), Cu(II)-EDTA (Ethylenediamine-N,N,N',N'-tetraacetic acid, copper chelate), Dy(III)-EDTA (Ethylenediamine-N,N,N',N'-tetraacetic acid, dysprosium chelate), Eu(III)-EDTA (Ethylenediamine-N,N,N',N'-tetraacetic acid, europium chelate), Fe(III)-EDTA (Ethylenediamine-N,N,N',N'-tetraacetic acid, iron chelate), In(III)-EDTA (Ethylenediamine-N,N,N',N'-tetraacetic acid, indium chelate), La(III)-EDTA (Ethylenediamine-N,N,N',N'-tetraacetic acid, lanthanum chelate), Mg(II)-EDTA (Ethylenediamine-N,N,N',N'-tetraacetic acid, magnesium chelate), Mn(II)-EDTA (Ethylenediamine-N,N,N',N'-tetraacetic acid, manganese chelate), Ni(II)-EDTA (Ethylenediamine-N,N,N',N'-tetraacetic acid, nickel chelate), Sm(III)-EDTA (Ethylenediamine-N,N,N',N'-tetraacetic acid, samarium chelate), Sr(II)-EDTA (Ethylenediamine-N,N,N',N'-tetraacetic acid, strontium chelate). Zn(II)-EDTA (Ethylenediamine-N,N,N',N'-tetraacetic acid, zinc chelate), CyDTA (trans-1,2-Diaminocyclohexane-N,N,N',N'- tetraaceticacid, monohydrate), EDTA-OH (N-(2-Hydroxyethyl)ethylenediamine-N,N',N'-triacetic acid), or Methyl-EDTA (1,2-Diaminopropane-N,N,N',N'-tetraacetic acid). In some embodiments, the antimicrobial solution or composition may further comprise DHEG (N,N-Bis(2-hydroxyethyl)glycine), DTPA-OH (1,3-Diamino-2-hydroxypropane-N,N,N',N'-tetraacetic acid), DTPA (1,3-Diaminopropane-N,N,N',N'-tetraacetic acid), EDDA (Ethylenediamine-N,N'-diacetic acid), EDDP (Ethylenediamine-N,N'-dipropionic acid dihydrochloride), EDDPO (Ethylenediamine-N,N'-bis(methylenephosphonic acid), hemihydrate), EDTPO (Ethylenediamine-N,N,N',N'-tetrakis(methylenephosponic acid)), EGTA (O,O'-bis(2-aminoetbyl)etbyleneglycol-N,N,N',N'- tetraacetic acid), HBED (N,N-diacetic acid HDTA 1,6-Hexamethylenediamine-N,N,N',N'-tetraacetic acid HIDA N-(2-Hydroxyethyl)iminodiacetic acid), IDA (Iminodiacetic acid), NTA Nitrilotriacetic acid, NTP (Nitrilotripropionic acid), NTPO (Nitrilotris(methylenephosphoric acid), trisodium salt), O-Bistren (7,19,30-Trioxa-1,4,10,13,16,22,27,33-octaabicyclo [11,11,11] pentatriacontane hexahydrobromide), TTHA (Triethylenetetramine-N,N,N',N",N"',N"'-hexaacetic acid), or EDDS (Ethylenediamine-N,N'-disuccinic acid).

[0040] In some embodiments, an antimicrobial solution of the present invention (e.g. a catheter lock solution) may include one or more additional anticoagulants. For example, the anticoagulant may be EGTA, EDTA, heparin, urokinase, streptokinase, low molecular weight heparin, enoxaparin, sodium coumarin, indanedione, anisindione, warfarin, protamine sulfate, anti-thrombin III, nitrilotriacetic acid, potassium sodium tartrate, potassium hydrogen D-tartrate, L-tartaric acid dipotassium salt, L-tartaric acid disodium salt, L-tartaric acid monosodium salt, tris(carboxymethyl)amine, warfarin, acetylsalicylic acid, ibuprofen, indomethacin, prostaglandins, sulfinpyrazone, streptokinase, urokinase, tissue plasminogen activator, coumarin, protamine sulfate, anti-thrombin III, coumadin, protein C/protein S, nicoumalone, phenprocoumon, hirudin, hirulog, or a glycosaminoglycan. Additional chelators, anticoagulants, and/or additional agents useful in the practice of the present invention may be found in U.S. Pat. No. 5,688,516.

Alcohols



[0041] The antimicrobial solutions of the present invention comprise an alcohol, such as an antiseptic or disinfectant alcohol. The alcohol is a C1-4 alcohol such as, e.g., ethanol, methanol, butanol, or isopropanol. In some embodiments, the final alcohol concentration is in the range of about 5%-80% (v/v), more preferably in the range of about 10% to 50%, more preferably in the range of about 15% to 40%, more preferably in the range of 20% to 30%, or 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% (v/v), or any range derivable therein, of the alcohol in the preparation of the instant antimicrobial solutions. This includes the use of intermediate concentrations of alcohol such as 11%, 22.5%, 26% and the like. In some embodiments where the antimicrobial solution or composition may be used as a catheter lock or flush solution, it may be desirable to use a concentration of alcohol of about 30% or less such as, e.g., about 5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5%, less than 30%, or about 30%, or any range derivable therein.

Additional Agents



[0042] It is also contemplated that any additional pharmacologically active ingredients or sterilization agents may be comprised in the solutions of the present invention or may be used separately for flushing or treating the devices of the present invention to further reduce or eliminate pathogenic microbes and viruses. Typical pharmacologically active ingredients include antifibrin agents, anti-thrombotic agents, and anti-inflammatory agents. Anti-inflammatory agents include steroids, and nonsteroidal anti-inflammatory agents, and salicylates. Anti-thrombotic drugs including acetylsalicylic acid, dipyridamole, heparin, ibuprofen, indomethacin, prostaglandins, sulfinpyrazone, warfarin, thrombolytic enzymes such as streptokinase, urokinase, or plasminogen activator may be used. Complexing agents such as ammonium-1-pyrrolidine dithiocarbanate may also be used. However, the above examples are not meant to be limiting. In some embodiments, an antimicrobial solution or a catheter lock solution may comprise one or more additional anticoagulant and/or an anti-inflammatory agent.

[0043] Pharmaceutical compositions such as an antimicrobial solution or catheter lock solution, as described herein, may contain an additional agent dissolved or dispersed in a pharmaceutically acceptable carrier. The phrases "pharmaceutical or pharmacologically acceptable" refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, such as, for example, a human, as appropriate. An antimicrobial solution or catheter lock solution as described herein may contain an additional active ingredient, e.g., as exemplified by Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams and Wilkins, 2005. Moreover, for animal (e.g., human) administration, it will be understood that preparations should typically meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biological Standards.

Packaging and Kits



[0044] Various packaging techniques may be employed in providing an antimicrobial solution or catheter lock or flush solution of the invention as part of a commercially available kit. The kit will optionally include an instruction sheet insert to identify how the kit is to be used.

[0045] In some embodiments, the antimicrobial solution comprises minocycline as the antibiotic, EDTA as the chelator/anticoagulant, and ethanol. The kit may comprise of one or two or three or more compartments. The components of the kit may be provided in separate compartments or in the same compartment. The components of the kit may be provided separately or mixed. The mixed components may contain two or more agents such as an antibiotic, a chelator/anticoagulant, or ethanol, or additional component.

[0046] In some embodiments, the kit comprises (i) an antibiotic in a first container; (ii) a solution containing an EDTA and an alcohol at a pH of about 6-8 in in a second container; (iii) a suitable connector for mixing the antibiotic and the solution; and (iv) a suitable syringe or container for administering the mixed solution, e.g., to a catheter. Alternately, the ETDA and the alcohol may be present in separate containers, such that the pH or each of the separate containers or the pH of the resulting mixed solution is about 6-8. The antibiotic (e.g., minocycline) and/or EDTA may be lyophilized or dry. For example, 3-9 mg minocycline (dry), 10-100 mg EDTA (powdered) and one wet component comprising 3 ml diluent (alcohol or diluted in saline or distilled water) at a pH sufficient to achieve a pH of about 6-8. When ready for use, the dry components, minocycline and EDTA, will be allowed to mix with the diluent. In some embodiments, a WET/WET dual chamber container system, available from Becton-Dickinson, may be used in these applications.

[0047] Each container of the kits will generally include at least one vial, test tube, flask, bottle, syringe or other container, into which the antibiotic, EDTA, and/or alcohol may be placed or suitably aliquoted. In some embodiments, the kit may comprise a suitable syringe or container for administering the mixed solution to a catheter.

Examples



[0048] The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. Solutions according to the invention have a pH of 6-8. Solution having a pH outside this range are comparative.

Example 1


Observed Precipitation in Antimicrobial Solutions



[0049] When combining 25% ethanol with pure, single EDTA sodium salts (e.g., as described in US 7601731), the inventors observed either pH or solubility issues. 25% ethanol + 3% pure tetrasodium EDTA yields a pH of 10.9. This pH may be harmful to blood vessels, can induce clot formation and destabilize Minocycline.

[0050] The inventors have found that at 25% ethanol + 3% pure disodium EDTA solutions yields a pH of 4.75. The inventors observed that, within hours, a precipitate forms. In the presence of 0.1% Minocycline the precipitate was observed to still form. This precipitate can be undesirable in a catheter lock or flush because the precipitate can clog catheter lumens or create emboli. Monosodium EDTA is difficult to source commercially but is expected to produce a pH below disodium EDTA. The inventors further observed that pure tetra-acid EDTA is mostly insoluble in water/ethanol which is undesirable for the reasons enumerated above and additionally, yields a pH of 3.1 which is harmful to blood vessels and destabilizing to Minocycline. Disodium EDTA is a commonly used EDTA salt in blood contacting applications because it is water soluble and has better calcium binding capacity than tetrasodium EDTA. However, it still produces an acidic pH and one still needs to overcome a precipitation problem with disodium EDTA in the presence of 25% ethanol.

[0051] To overcome the precipitation problem with 25% Ethanol/3% disodium EDTA /0.1% Minocycline, the inventors surprisingly observed that adjustment to pH greater than 5.5 substantially prolongs stability (minimizes precipitation) without the need to reduce EDTA concentration or form novel grafted chelator chemicals. Excessively basic pH (pH > 8.5) can be detrimental to clotting and endothelial health. The pH adjustment to 6-8 range is used in the Minocycline/EDTA/Ethanol system.

Example 2


Procedure for preparing 0.1% Minocycline, 3% disodium EDTA, 25% Ethanol lock



[0052] A 0.1% Minocycline, 3% disodium EDTA, 25% Ethanol catheter lock solution was made as follows:
  1. 1. Weigh out 660 mg disodium EDTA powder, and dissolve in 11 mL sterile water in a sterile vessel. Shake EDTA and sterile water until completely dissolved. Resulting concentration is 60 mg/mL. Filter with 0.22 micron filter into an empty sterile 30 mL vial to a filtrate volume of 10 mL.
  2. 2. Reconstitute a 100 mg vial of minocycline with 10 mL sterile water using a sterile syringe, and withdraw 2 mL (20 mg). Add to the vial with the EDTA.
  3. 3. Using a sterile syringe, draw up 5 mL of alcohol, and add to the vial with the EDTA and minocycline
  4. 4. QS to total volume of 20 ml with water, representing EDTA 30 mg, minocycline 1 mg, and alcohol 25% per 1 ml.
  5. 5. Prepare 19 syringes with 1 mL in each syringe. (3 mL sterile syringes can be used).
  6. 6. Label the syringes, and store protected from light.

Example 3


pH Measurement and Stability Observations with Storage at 4 °C



[0053] A consistent pH of 4.5 ± 0.1 was recorded for the samples prepared as described in Example 1. Nine of the pH 4.5 Minocycline/EDTA/Ethanol syringes were stored at 25 °C and observed daily for precipitation by removing and rotating the syringes (N indicates NO precipitate observed, Y indicates precipitate observed):
Syringe #Baseline (0hrs)Day 1 (24hrs)Day 2 (48hrs)Day 3 (72hrs)
1 N Y Y Y
2 N Y Y Y
3 N Y Y Y
4 N Y Y Y
5 N Y Y Y
6 N Y Y Y
7 N Y Y Y
8 N Y Y Y
9 N Y Y Y
  0/9 = 0% 9/9 = 100% 9/9 = 100% 9/9 = 100%


[0054] All (100%) of the samples precipitated within 24 hours when stored at 25 °C.

Example 4


Stability Observations with Storage at 4 °C



[0055] Nine of the pH 4.5 Minocycline/EDTA/Ethanol syringes were stored at 4 °C and observed daily for precipitation by removing and rotating the syringes and by observing through a magnifying glass (N indicates NO precipitate observed, Y indicates precipitate observed):
Syringe #Baseline (0hrs)Day 1 (24hrs)Day 2 (48hrs)Day 3 (72hrs)
1 N Y Y Y
2 N Y Y Y
3 N Y Y Y
4 N Y Y Y
5 N Y Y Y
6 N Y Y Y
7 N Y Y Y
8 N Y Y Y
9 N Y Y Y
  0/9 = 0% 9/9 = 100% 9/9 = 100% 9/9 = 100%


[0056] All (100%) of the samples precipitated within 24 hours when stored at 4 °C.

Example 5


Procedure for pH Adjusted Disodium EDTA Using Base



[0057] A solution containing disodium EDTA that was pH adjusted using base was prepare by the following method:
1. Weigh out 300 mg disodium EDTA powder in 30 ml vial, and dissolve in 9.3 mL sterile water. Shake EDTA and sterile water until completely dissolved. QS to 10 ml with water. Resulting concentration is 30 mg/mL (3%).
2. Measure pH, Add 1M NaOH recording volume added and remeasure pH.
Volume 3% disodium EDTATotal Volume 1M NaOH addedpH
10 ml 0 4.5
  0.5 ml 4.9
  1.0 ml 5.4
  1.5 ml 6.9
  1.7 ml 7.4

Example 6


Procedure for pH Adjusted Tetrasodium EDTA Using Disodium EDTA



[0058] A solution containing tetrasodium EDTA pH adjusted with disodium EDTA was prepared by the following method:
  1. 1. Weigh out 300 mg disodium EDTA powder in 30 ml vial, and dissolve in 9.3 mL sterile water. Shake EDTA and sterile water until completely dissolved. QS to 10 ml with water. Resulting concentration is 30 mg/mL (3%).
  2. 2. Weigh out 300 mg tetrasodium EDTA powder in 30 ml vial, and dissolve in 9.3 mL sterile water. Shake EDTA and sterile water until completely dissolved. QS to 10 ml with water. Resulting concentration is 30 mg/mL (3%).
  3. 3. Measure pH of tetrasodium EDTA and add disodium EDTA recording volume added and pH after each addition


[0059] The following solutions were produced:
Total volume 3% tetrasodium EDTA addedTotal volume 3% disodium EDTA addedpH
5 ml 0 10.9
  1 ml 10.2
  2 ml 9.5
  3 ml 9.0
  4 ml 8.8
  5 ml 8.1
  6 ml 7.1

Example 7


Consistency of pH adjustment of Minocycline/disodium EDTA/Ethanol using 1 M sodium hydroxide



[0060] The consistency of pH adjustment of a minocycline/disodium EDTA/Ethanol solution was evaluated using 1 M sodium hydroxide, as follows:
  1. 1. Weigh out 660 mg disodium EDTA powder, and dissolve in 9.3 mL sterile water in a sterile vessel. Shake EDTA and sterile water for 10 minutes. It will completely dissolve but it takes a while. Resulting concentration is 60 mg/mL.
  2. 2. add 1.7 mL of 1M NaOH to the disodium EDTA solution.
  3. 3. Filter with 0.22 micron filter into an empty sterile 30 mL vial to a volume of 10 mL.
  4. 4. Reconstitute a 100 mg vial of minocycline with 10 mL sterile water using a sterile syringe, and withdraw 2 mL (20 mg). Add to the vial with the EDTA.
  5. 5. Using a sterile syringe, draw up 5 mL of alcohol, and add to the vial with the EDTA and minocycline.
  6. 6. QS to total volume of 20 ml with water, representing EDTA 30 mg, minocycline 1 mg, and alcohol 25% per 1 ml.
  7. 7. Prepare 19 syringes with 1 mL in each syringe. (1-3 mL sterile syringe can be used) Label the syringes and protect from light.


[0061] The pH from seven syringes, sampled randomly, were measured using a pH meter. The following results were observed:
Syringe #pH final solution
1 7.29
2 7.30
3 7.27
4 7.26
5 7.30
6 7.31
7 7.29
Average pH 7.29
Standard deviation 0.02

Example 8


Observation of Stability of Samples Prepared in Example 6



[0062] Nine syringes from the samples prepared in Example 6 were stored at 25 °C and observed daily for precipitate formation by rotating them and by observing through a magnifying glass (N indicates No precipitate observed; Y indicates a precipitate was observed):
Syringe #Baseline (0hrs)Day 1 (24hrs)Day 2 (48hrs)Day 3 (72hrs)
1 N N N N
2 N N N N
3 N N N N
4 N N N N
5 N N N N
6 N N N N
7 N N N N
8 N N N N
9 N N N N
  0/9 = 0% 0/9 = 0% 0/9 = 0% 0/9 = 0%

Example 9


Observation of Stability of samples prepared as in Example 6 at 4 °C and 25 °C



[0063] Sample preparation described in Example 6 was repeated. Nine syringes were stored at 25 °C and 9 at 4 °C. The syringes were observed daily for precipitate formation by rotating them and by observing through a magnifying glass (N indicates No precipitate observed; Y indicates a precipitate was observed):
4 C storage Syringe #Baseline (0hrs)Day 1 (24hrs)Day 2 (48hrs)Day 3 (72hrs)
1 N N N N
2 N N N N
3 N N N N
4 N N N N
5 N N N N
6 N N N N
7 N N N N
8 N N N N
9 N N N N
  0/9=0% 0/9 = 0% 0/9 = 0% 0/9 = 0%
25 C storage Syringe #Baseline (0hrs)Day 1 (24hrs)Day 2 (48hrs)Day 3 (72hrs)
1 N N N N
2 N N N N
3 N N N N
4 N N N N
5 N N N N
6 N N N N
7 N N N N
8 N N N N
9 N N N N
  0/9 = 0% 0/9 = 0% 0/9 = 0% 0/9 = 0%


[0064] As shown above, solutions of Minocycline (1 mg/ml), 3% EDTA, and 25% Ethanol were observed to be much more shelf-stable at pH 6-8 than at more acidic pHs.

REFERENCES



[0065] The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference.

U.S. 7,601,731

U.S. 8,541,472

U.S. 5,362,754

U.S. 5,688,516

U.S. 6,350,251

WO2012/167368

EP1245247

Harris, DC. EDTA Titrations. Chap 11 in Quantitative Chemical Analysis 8th edition. WH Freeman and Co, NY NY 2010

Kluger et al., In: Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) Abstracts of the 39th Meeting, 514, 1999.

Maki et al., In: Hospital Infections. Bennett J V, Brachman P S, eds. Lippincott-Raven, Philadelphia, Pa., pp 689-94, 1998.

Raad et al., J. Infect. Dis. 168:400-407, 1993.

Raad et al., Antimicrob. Agents Chemother., 46(2):327-332, 2002.

Raad et al., Arch. Intern. Med. 162:871-878, 2002.

Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams and Wilkins, 2005

Sheretz et al., "In vitro efficacy of minocyline (M)/EDTA (MEDTA) as a catheter lock solution," Shea Merck Healthcare Epidemiology Search Abstracts, 2002.




Claims

1. A pharmaceutically acceptable antimicrobial solution comprising:

(i) a C1-4 alcohol;

(ii) an EDTA; and

(iii) an antibiotic;

wherein said solution has a pH of about 6-8, and wherein said solution comprises a pharmaceutically acceptable excipient or diluent, wherein the antibiotic is a tetracycline such as minocycline or trimethoprim.
 
2. The solution of claim 1, wherein the C1-4 alcohol is ethanol, isopropanol, methanol, or butanol, in particular ethanol.
 
3. The solution of any one of claims 1-2, wherein the C1-4 alcohol is present in the solution at a concentration of about 10-40%, in particular at a concentration of about 10-30%, in particular at a concentration of about 25%.
 
4. The solution of any one of claims 1-3, wherein the solution comprises about 1-5% EDTA, in particular about 1.5-5% EDTA, in particular about 1-3.5% EDTA, in particular about 1-3% EDTA, in particular about 3% EDTA.
 
5. The solution of claim 4, wherein the EDTA is EDTA free acid, EDTA 2Na, EDTA 3Na, EDTA 4Na, EDTA 2K, EDTA 2Li, EDTA 2NH4, EDTA 3K, Ba(II)-EDTA, Ca(II)-EDTA, Co(II)-EDTA, Cu(II)-EDTA, Dy(III)-EDTA, Eu(III)-EDTA, Fe(III)-EDTA, In(III-EDTA, La(III)-EDTA, EDTA-OH, or Methyl-EDTA.
 
6. The solution of claim 1, wherein the solution comprises about 0.05-0.2% antibiotic, in particular wherein the solution comprises about 0.1% minocycline, about 3% EDTA, and about 25% ethanol.
 
7. The solution of any one of claims 1-6, wherein: i) the EDTA is an acidic EDTA, such as EDTA free acid, EDTA 2Na, EDTA 2K, EDTA diammonium, or a diacid of EDTA, and wherein the solution further comprises a base, such as sodium hydroxide, potassium hydroxide, ammonia, an amine, or urea, ii) the EDTA is a basic EDTA such as EDTA 4Na, EDTA 4K, or tetra ammonium EDTA, and wherein the solution further comprises an acid such as hydrochloric acid or acetic acid, or iii) the solution comprises both an acidic EDTA and a basic EDTA, in particular wherein the acidic EDTA is EDTA free acid, EDTA 2Na, dipotassium EDTA, or diammonium EDTA; and wherein the basic EDTA is EDTA 4Na, tetra potassium EDTA (EDTA 4K), or tetra ammonium EDTA.
 
8. The solution of any one of claims 1-7, wherein the solution i) comprises a pharmaceutically acceptable saline diluent, ii) has a pH of about 6.5-7.5, in particular of about 7-7.4, iii) further comprises polyethylene glycol, and/or iv) is further defined as a catheter lock solution.
 
9. The solution of any one of claims 1-8, wherein the fraction of EDTA in the tetravalent form is between about 0.1 and about 0.000001, preferably between about 0.05 and about 0.000005, or more preferably between about 0.01 and about 0.00001.
 
10. A syringe, or vial comprising a unit dose of a pharmacologically effective amount of a solution in accordance with any one of claims 1-9 or a medical device locking solution comprising or consisting of a solution in accordance with any one of claims 1-9.
 
11. A kit comprising:

(i) an antibiotic in a first container, in particular wherein the antibiotic is lyophilized;

(ii) a solution containing an EDTA and an alcohol at a pH of about 6-8 in in a second container;

(iii) a suitable connector for mixing the antibiotic and the solution; and

(iv) a suitable syringe or container for administering the mixed solution to a catheter.


 
12. The kit of claim 11, wherein one or more labels or removable extension-line tags is attached to the catheter, in particular wherein the tags are symmetric peel-off tags comprising adhesive on one side and pre-perforated lines on about the mid-section or the tags.
 
13. The kit of claims 11, wherein the mixed solution is the solution of a solution of any one of claims 1-8.
 
14. The kit of claim 11, wherein the alcohol is ethanol.
 
15. The kit of any one of claims 11-14, wherein the first container is a vial or syringe, and wherein the second container is a vial or syringe.
 
16. The kit of claim 11, wherein the antibiotic is a lyophilized antibiotic, and wherein the first container and the second container are each a vial or syringe.
 
17. A solution of any one of claims 1-9 for use in a method of treatment of the human or animal body by therapy or surgery, wherein the method comprises flushing or locking a catheter in a subject, comprising administering the solution of any one of claims 1-9.
 
18. A solution for use according to claim 17, wherein the catheter is an intravascular catheter, a urinary catheter, a brain catheter, a nephrostomy tube, or a drain or drainage catheter.
 
19. A solution for use according to claim 18, wherein the subject is a human.
 


Ansprüche

1. Eine pharmazeutisch verträgliche antimikrobielle Lösung, umfassend

(i) einen C1-4-Alkohol;

(ii) eine EDTA; und

(iii) ein Antibiotikum;

wobei besagte Lösung einen pH von etwa 6-8 besitzt und wobei besagte Lösung einen pharmazeutisch verträglichen Träger oder Verdünnungsmittel umfasst, wobei das Antibiotikum ein Tetracyclin wie Minocyclin oder Trimethoprim ist.
 
2. Die Lösung nach Anspruch 1, wobei der C1-4-Alkohol Ethanol, Isopropanol, Methanol oder Butanol, insbesondere Ethanol ist.
 
3. Die Lösung nach einem der Ansprüche 1 bis 2, wobei der C1-4-Alkohol in der Lösung in einer Konzentration von etwa 10-40%, insbesondere in einer Konzentration von etwa 10-30%, insbesondere in einer Konzentration von etwa 25% vorliegt.
 
4. Die Lösung nach einem der Ansprüche 1 bis 3, wobei die Lösung etwa 1-5% EDTA, insbesondere etwa 1,5-5% EDTA, insbesondere etwa 1-3,5% EDTA, insbesondere etwa 1-3% EDTA, insbesondere etwa 3% EDTA umfasst.
 
5. Die Lösung nach Anspruch 4, wobei die EDTA freie EDTA-Säure, EDTA 2Na, EDTA 3Na, EDTA 4Na; EDTA 2K, EDTA 2Li, EDTA 2NH4, EDTA 3K, Ba(II)-EDTA, Ca(II)-EDTA, Co(II)-EDTA, Cu(II)-EDTA, Dy(III)-EDTA, Eu(III)-EDTA, Fe(III)-EDTA, In(III)-EDTA, La(III)-EDTA, EDTA-OH oder Methyl-EDTA ist.
 
6. Die Lösung nach Anspruch 1, wobei die Lösung etwa 0,05-0,2% Antibiotikum umfasst, insbesondere wobei die Lösung etwa 0,1% Minocyclin, etwa 3% EDTA und etwa 25% Ethanol umfasst.
 
7. Die Lösung nach einem der Ansprüche 1 bis 6, wobei: i) die EDTA eine saure EDTA wie freie EDTA-Säure, EDTA 2Na, EDTA 2K, EDTA Diammonium oder eine Disäure von EDTA ist und wobei die Lösung außerdem eine Base wie Natriumhydroxid, Kaliumhydroxid, Ammoniak, ein Amin oder Harnstoff umfasst, ii) die EDTA eine basische EDTA wie EDTA 4Na, EDTA 4K oder Tetraammonium-EDTA ist und wobei die Lösung außerdem eine Säure wie Salzsäure oder Essigsäure umfasst oder iii) die Lösung sowohl eine saure EDTA als auch eine basische EDTA umfasst, insbesondere wobei die saure EDTA freie EDTA-Säure, EDTA 2Na, Dikalium-EDTA oder Diammonium-EDTA ist; und wobei die basische EDTA EDTA 4Na, Tetrakalium-EDTA (EDTA 4K) oder Tetraammonium-EDTA ist.
 
8. Die Lösung nach einem der Ansprüche 1 bis 7, wobei die Lösung i) ein pharmazeutisch verträgliches kochsalzhaltiges Verdünnungsmittel umfasst, ii) einen pH von etwa 6,5-7,5, insbesondere von etwa 7-7,4 besitzt, iii) außerdem Polyethylenglycol umfasst und/oder iv) außerdem als eine Katheter-Locklösung definiert ist.
 
9. Die Lösung nach einem der Ansprüche 1 bis 8, wobei der EDTA-Anteil in der vierwertigen Form zwischen etwa 0,1 und etwa 0,000001, bevorzugt zwischen etwa 0,05 und etwa 0,000005 oder bevorzugter zwischen etwa 0,01 und etwa 0,00001 beträgt.
 
10. Eine Spritze oder Ampulle, umfassend eine Einzeldosis einer pharmazeutisch wirksamen Menge einer Lösung gemäß einem der Ansprüche 1 bis 9 oder eine Locklösung für eine medizinische Vorrichtung, umfassend oder bestehend aus einer Lösung gemäß einem der Ansprüche 1 bis 9.
 
11. Ein Kit umfassend:

(i) ein Antibiotikum in einem ersten Behälter, insbesondere wobei das Antibiotikum lyophilisiert ist;

(ii) eine Lösung, enthaltend eine EDTA und einen Alkohol, mit einem pH von etwa 6-8 in einem zweiten Behälter;

(iii) ein geeignetes Verbindungsteil zum Mischen des Antibiotikums und der Lösung; und

(iv) eine geeignete Spritze oder Behälter zur Abgabe der gemischten Lösung an einen Katheter.


 
12. Das Kit nach Anspruch 11, wobei ein oder mehrere Etiketten oder entfernbare Verlängerungsleitungs-Aufkleber an dem Katheter angebracht sind, insbesondere wobei die Aufkleber symmetrische abziehbare Aufkleber sind, umfassend Klebstoff auf einer Seite und perforierte Linien in etwa der Mitte der Aufkleber.
 
13. Das Kit nach Anspruch 11, wobei die gemischte Lösung die Lösung einer Lösung nach einem der Ansprüche 1 bis 8 ist.
 
14. Das Kit nach Anspruch 11, wobei der Alkohol Ethanol ist.
 
15. Das Kit nach einem der Ansprüche 11 bis 14, wobei der erste Behälter eine Ampulle oder Spritze ist und wobei der zweite Behälter eine Ampulle oder Spritze ist.
 
16. Das Kit nach Anspruch 11, wobei das Antibiotikum ein lyophilisiertes Antibiotikum ist und wobei der erste Behälter und der zweite Behälter jeweils eine Ampulle oder Spritze sind.
 
17. Eine Lösung nach einem der Ansprüche 1 bis 9 zur Verwendung in einem Verfahren zur Behandlung des menschlichen oder tierischen Körpers mittels Therapie oder Operation, wobei das Verfahren Spülen oder Verschließen eines Katheters in einer Person umfasst, umfassend Verabreichen der Lösung nach einem der Ansprüche 1 bis 9.
 
18. Eine Lösung zur Verwendung gemäß Anspruch 17, wobei der Katheter ein intravaskulärer Katheter, ein Blasenkatheter, ein Gehirnkatheter, ein Nephrostomiekatheter oder ein Abfluss- oder Drainagekatheter ist.
 
19. Eine Lösung zur Verwendung gemäß Anspruch 18, wobei die Person ein Mensch ist.
 


Revendications

1. Solution antimicrobienne pharmaceutiquement acceptable comprenant :

(i) un alcool en C1 à C4 ;

(ii) de l'EDTA ; et

(iii) un antibiotique ;

laquelle solution a un pH d'environ 6-8, et laquelle solution comprend un excipient ou diluant pharmaceutiquement acceptable, dans laquelle l'antibiotique est une tétracycline telle que la minocycline ou le triméthoprime.
 
2. Solution selon la revendication 1, dans laquelle l'alcool en C1 à C4 est l'éthanol, l'isopropanol, le méthanol ou le butanol, en particulier l'éthanol.
 
3. Solution selon l'une quelconque des revendications 1 et 2, dans laquelle l'alcool en C1 à C4 est présent dans la solution à une concentration d'environ 10 à 40 %, en particulier à une concentration d'environ 10 à 30 %, en particulier à une concentration d'environ 25 %.
 
4. Solution selon l'une quelconque des revendications 1 à 3, laquelle solution comprend environ 1 à 5 % d'EDTA, en particulier environ 1,5 à 5 % d'EDTA, en particulier environ 1 à 3,5 % d'EDTA, en particulier environ 1 à 3 % d'EDTA, en particulier environ 3 % d'EDTA.
 
5. Solution selon la revendication 4, dans laquelle l'EDTA est l'EDTA sous forme d'acide libre, l'EDTA 2Na, l'EDTA 3Na, l'EDTA 4Na, l'EDTA 2K, l'EDTA 2Li, l'EDTA 2NH4, l'EDTA 3K, le Ba(II)-EDTA, le Ca(II)-EDTA, le Co(II)-EDTA, le Cu(II)-EDTA, le Dy(III)-EDTA, l'Eu(III)-EDTA, le Fe(III)-EDTA, l'In(III)-EDTA, le La(III)-EDTA, l'EDTA-OH, ou le méthyl-EDTA.
 
6. Solution selon la revendication 1, laquelle solution comprend environ 0,05 à 0,2 % d'antibiotique, en particulier laquelle solution comprend environ 0,1 % de minocycline, environ 3 % d'EDTA, et environ 25 % d'éthanol.
 
7. Solution selon l'une quelconque des revendications 1 à 6, dans laquelle : i) l'EDTA est de l'EDTA acide, tel que l'EDTA sous forme d'acide libre, l'EDTA 2Na, l'EDTA 2K, l'EDTA diammonium, ou un diacide d'EDTA, et laquelle solution comprend en outre une base, telle que l'hydroxyde de sodium, l'hydroxyde de potassium, l'ammoniac, une amine, ou l'urée, ii) l'EDTA est de l'EDTA basique, tel que l'EDTA 4Na, l'EDTA 4K, ou le tétraammonium-EDTA, et laquelle solution comprend en outre un acide tel que l'acide chlorhydrique ou l'acide acétique, ou iii) la solution comprend à la fois de l'EDTA acide et de l'EDTA basique, en particulier dans laquelle l'EDTA acide est l'EDTA sous forme d'acide libre, l'EDTA 2Na, l'EDTA dipotassique, ou le diammonium-EDTA ; et dans laquelle l'EDTA basique est l'EDTA 4Na, l'EDTA tétrapotassique (EDTA 4K), ou le tétraammonium-EDTA.
 
8. Solution selon l'une quelconque des revendications 1 à 7, laquelle solution i) comprend un diluant de type solution saline pharmaceutiquement acceptable ; ii) a un pH d'environ 6,5 à 7,5, en particulier d'environ 7 à 7,4, iii) comprend en outre du polyéthylèneglycol, et/ou iv) est en outre définie comme une solution de remplissage de cathéter.
 
9. Solution selon l'une quelconque des revendications 1 à 8, dans laquelle la fraction d'EDTA sous forme tétravalente est comprise entre environ 0,01 et environ 0,000001, de préférence entre environ 0,05 et environ 0,000005, ou mieux encore entre environ 0,01 et environ 0,00001.
 
10. Seringue ou flacon comprenant une dose unitaire d'une quantité efficace du point de vue pharmacologique d'une solution selon l'une quelconque des revendications 1 à 9 ou une solution de remplissage de dispositif médical comprenant ou consistant en une solution selon l'une quelconque des revendications 1 à 9.
 
11. Kit comprenant :

(i) un antibiotique dans un premier récipient, en particulier lequel antibiotique est lyophilisé ;

(ii) une solution comprenant de l'EDTA et un alcool à un pH d'environ 6 à 8 dans un deuxième récipient ;

(iii) un connecteur adapté pour mélanger l'antibiotique et la solution ; et

(iv) une seringue ou un récipient adapté pour l'administration de la solution mélangée à un cathéter.


 
12. Kit selon la revendication 11, dans laquelle une ou plusieurs vignettes ou étiquettes de prolongateur détachables sont attachées au cathéter, en particulier dans laquelle les étiquettes sont des étiquettes détachables symétriques comprenant un adhésif sur un côté et des lignes pré-perforées au niveau de la section médiane des étiquettes.
 
13. Kit selon la revendication 11, dans laquelle la solution mélangée est une solution de l'une quelconque des revendications 1 à 8.
 
14. Kit selon la revendication 11, dans laquelle l'alcool est l'éthanol.
 
15. Kit selon l'une quelconque des revendications 11 à 14, dans laquelle le premier récipient est un flacon ou une seringue, et dans laquelle le deuxième récipient est un flacon ou une seringue.
 
16. Kit selon la revendication 11, dans laquelle l'antibiotique est un antibiotique lyophilisé, et dans laquelle le premier récipient et le deuxième récipient sont chacun un flacon ou une seringue.
 
17. Solution selon l'une quelconque des revendications 1 à 9 pour une utilisation dans une méthode de traitement thérapeutique ou chirurgical du corps humain ou animal, dans laquelle la méthode comprend le rinçage ou le remplissage d'un cathéter chez un sujet, comprenant l'administration de la solution de l'une quelconque des revendications 1 à 9.
 
18. Solution pour une utilisation selon la revendication 17, dans laquelle le cathéter est un cathéter intravasculaire, un cathéter urinaire, un cathéter cérébral, un tube de néphrostomie, ou un cathéter de drain ou de drainage.
 
19. Solution pour une utilisation selon la revendication 18, dans laquelle le sujet est un humain.
 




REFERENCES CITED IN THE DESCRIPTION



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Patent documents cited in the description




Non-patent literature cited in the description