ANTIMICROBIAL LOCKING SOLUTIONS COMPRISING TAURINAMIDE DERIVATIVES AND BIOLOGICALLY ACCEPTABLE SALTS AND ACIDS, WITH THE ADDITION OF SMALL CONCENTRATIONS OF HEPARIN

Abstract

The present invention relates to inhibiting or preventing infection and protecting against patency complications after a blood catheter has been in a patient comprising administering to the device a pharmaceutically effective amount of a composition comprising:

(A) at least one taurinamide derivative,

(B) at least one compound selected from the group consisting of biologically acceptable acids and biologically acceptable salts thereof; and

(C) heparin at a low concentration.

Claims

1-24. (canceled)

25. A locking solution composition for treating and reducing infection and flow reduction in blood catheters, wherein the composition comprises a solution of: a. at least one taurinamide derivative; and b. heparin, wherein the heparin concentration is selected so as to (i) permit blood clotting within the blood catheter, and (ii) reduce taurinamide derivative-induced changes to the character of the clots.

26. The composition according to claim 25 wherein the taurinamide derivative is taurolidine.

27. The composition according to claim 25 further comprising a biologically acceptable acid and a biologically acceptable salt of said acid in a combination that brings the pH of the combination into a range that enhances antimicrobial activity of the taurinamide derivative.

28. The composition according to claim 27 wherein the biologically acceptable acid is chosen from the group consisting of citric acid and lactic acid and the biologically acceptable salt is chosen from the group consisting of citrate and lactate.

29. The composition according to claim 27 wherein the taurinamide derivative is taurolidine, the biologically acceptable acid is citric acid and the biologically acceptable salt is citrate.

30. A locking solution composition for treating and reducing infection and flow reduction in blood catheters, wherein the composition comprises a solution of: a. at least one taurinamide derivative; and b. heparin, wherein the heparin concentration is selected so as to (i) permit blood clotting within the blood catheter, and (ii) reduce the formation of methemoglobin by the interaction of the at least one taurinamide derivative with blood.

31. The composition according to claim 30 wherein the taurinamide derivative is taurolidine.

32. The composition according to claim 30 further comprising a biologically acceptable acid and a biologically acceptable salt of said acid in a combination that brings the pH of the combination into a range that enhances antimicrobial activity of the taurinamide derivative.

33. The composition according to claim 32 wherein the biologically acceptable acid is chosen from the group consisting of citric acid and lactic acid and the biologically acceptable salt is chosen from the group consisting of citrate and lactate.

34. The composition according to claim 32 wherein the taurinamide derivative is taurolidine, the biologically acceptable acid is citric acid and the biologically acceptable salt is citrate.

35. A locking solution composition for treating and reducing infection and flow reduction in blood catheters, wherein the composition comprises a solution of: a. at least one taurinamide derivative; and b. heparin, wherein the heparin concentration is selected so as to (i) permit blood clotting within the blood catheter, and (ii) reduce the formation of blood clots of the type which have a tendency to stick to catheter walls.

36. The composition according to claim 35 wherein the taurinamide derivative is taurolidine.

37. The composition according to claim 35 further comprising a biologically acceptable acid and a biologically acceptable salt of said acid in a combination that brings the pH of the combination into a range that enhances antimicrobial activity of the taurinamide derivative.

38. The composition according to claim 37 wherein the biologically acceptable acid is chosen from the group consisting of citric acid and lactic acid and the biologically acceptable salt is chosen from the group consisting of citrate and lactate.

39. The composition according to claim 37 wherein the taurinamide derivative is taurolidine, the biologically acceptable acid is citric acid and the biologically acceptable salt is citrate.

40. A locking solution composition for reducing infection and flow reduction in blood catheters, wherein the locking solution composition comprises a solution of: a. at least one taurinamide derivative; and b. heparin, wherein the heparin concentration is selected so as to (i) permit blood clotting within the blood catheter, and (ii) reduce fragmentation and adherence of clots and clot fragments to the wall of the blood catheter, thereby enhancing removal of clots and clot fragments during preparation of the catheter for use.

41. The composition according to claim 40 wherein the taurinamide derivative is taurolidine.

42. The composition according to claim 40 further comprising a biologically acceptable acid and a biologically acceptable salt of said acid in a combination that brings the pH of the combination into a range that enhances antimicrobial activity of the taurinamide derivative.

43. The composition according to claim 42 wherein the biologically acceptable acid is chosen from the group consisting of citric acid and lactic acid and the biologically acceptable salt is chosen from the group consisting of citrate and lactate.

44. The composition according to claim 42 wherein the taurinamide derivative is taurolidine, the biologically acceptable acid is citric acid and the biologically acceptable salt is citrate.

Description

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] The most preferred embodiment of the invention is a combination of a taurolidine or taurultam based antibacterial solution in combination with an anticoagulant and/or calcium chelating substance such as citrate also in solution, the solution having a pH that enhances the antimicrobial activity of the taurolidine, with a low concentration of heparin, said concentration being so low that the threat of systemic anticoagulation of the patient is minimized or eliminated.

[0038] The therapeutic heparin concentration in the systemic circulation even in patients with severe clotting tendencies rarely exceeds 1 unit/ml over the entire blood stream. More typically, concentrations are maintained in the range of 0.2 units per ml of blood to 0.4 units per ml of blood.

[0039] Hemodialysis patients, on the other hand, more typically have low platelet counts and other blood deficiencies that inhibit clotting rather than promote it. Thus the upper limit for blood concentration should be conservative. The current invention assumes that 0.5 units heparin per ml of blood, in the total blood supply, is a safe upper limit for prevention of adverse consequences from infusing heparin into a patient's blood stream. However, the preferred upper limit would be based on the minimum value typically cited for antithrombotic effect, namely the 0.2 units per ml of blood cited above.

[0040] Various means exist for estimating total blood volume for patients. The inventor herein used the following formulas:

[0041] For men:

V.sub.B=0.3669×(H).sup.3+0.03219×W+0.604

[0042] For women:

V.sub.B=0.3561×(H).sup.3+0.03308×W+0.1833,

Where H is patient height in meters and W is patient total body weight in kilograms. The resulting blood volume is in liters (multiplied by 1000 to obtain volume in ml). Using test values for typical patients, a range of blood volumes of 5000 to 6000 ml for males, 4000 to 5000 ml for females, is obtained. A mid-range value of 5000 ml is used in the calculations that follow, but the wide variability from gender to gender and from patient to patient should be kept in mind.

[0043] A typical hemodialysis catheter volume is approximately 3 ml. Typical unavoidable spillage of catheter lock solution into the patient is about ⅓ of that value, or 1 ml. If the concentration of heparin in the catheter lock solution is L.sub.concentration, loss of that much heparin into the patient would produce a vascular concentration of:

(L.sub.concentration)(spilled catheter volume)=(blood concentration)×(blood volume)

[0044] (where, in the most routine case, spilled catheter volume=1 ml and blood volume=5000 ml).

Using the safe upper limit set forth above 0.5 units/ml) and the typical blood volume of 5000 ml, the nominal upper limit of 2500 units of heparin per ml in the catheter lock solution is obtained.

[0045] However, four factors militate in favor of a lower limit. First, patient blood volumes range as low as 3500 ml. Second, sometimes a practitioner inadvertently pushes the entire catheter volume of catheter lock solution into a patient. Third, hemodialysis patients have, as previously noted, a tendency to insufficient clotting. Fourth, the minimum heparin concentration for therapeutic anti-thrombotic effect is 0.2 units per ml in patients with a tendency to form clots. Accordingly, one preferred embodiment of the current invention carries an upper limit for heparin concentration of 1750 units heparin per ml. Another preferred embodiment carries an upper limit for heparin concentration of 1000 units heparin per ml. A third preferred embodiment carries an upper limit of 833 units heparin per ml. A fourth preferred embodiment has an upper limit of 583 units per ml. a highly preferred embodiment for the upper limit is 500 units per ml. Combining factors produces a most highly preferred embodiment of 150 units per ml. As will be appreciated by one skilled in the art, various concentrations of heparin up to 2500 units per ml can be safe for specific patients.

[0046] Some time after the tests referred to above were completed, an additional test specimen comprising the taurolidine formulation with a low concentration heparin (final concentration of about 125 units heparin per ml) was evaluated clinically in Germany. Work was undertaken at Dr. Sodemann's clinics to evaluate the taurolidine formulation modifications to determine if they might affect flow resistance. The modifications to the taurolidine locking solution included an increase in the pH, the addition of PVP to taurolidine, and the incorporation of minimal amounts of heparin (e.g., 125 units per ml) to the taurolidine based catheter lock solution.

[0047] Dr Sodemann was not able to observe any difference regarding flow resistance or any other clinical parameter. However, this observation was in the context that Dr. Sodemann had never seen a decrease in catheter patency using taurolidine-based locks as compared to high concentration heparin-based locks in the first place.

[0048] Clinical testing was then performed in French clinics on patients who had previously experienced flow resistance problems. In this group of patients it was observed that the addition of low concentration heparin reduced the need for flow resistance intervention, i.e., lysing, to low rates, comparable to those experienced with high concentration heparin lock solutions.

[0049] Subsequently other patients who had patency complications in Finland and Austria were tested with the taurolidine plus citrate locking solution with low concentration heparin added. In these cases also, an improvement over the original taurolidine formulation was noted and achieved patency rates similar to the patency rates patients for patients whose catheters were locked with high concentration heparin alone. In various experimental circumstances, concentrations of heparin as low as 50 units heparin per ml of catheter locking solution were found to have the beneficial effect of the current invention.

[0050] The taurinamide derivatives referred to are antimicrobial compounds which have been chemically described in earlier applications referenced above, which are incorporated by reference herein. The most preferred substance in this family is taurolidine. These compounds, condensation products of taurinamide and formaldehyde, are active not only against both gram-positive and gram-negative bacteria but also against exotoxins and endotoxins. For the purposes of this application these compounds are generically and collectively referred to as taurolidine.

[0051] The concentration of taurolidine in such solutions is preferably in the range of from about 0.4 to about 5% by weight, depending upon the solubility of the compound. Recent experiments have shown that addition of citrates and citric acid in combination, or alternatively the addition of citric acid and adjustment of the pH with sodium hydroxide, such that the pH of the end solution is in the vicinity of 5.2 to 6.5, substantially increases the biocidal effectiveness of taurolidine solution. The approach creates a buffer system of citric acid/sodium citrate by adjustment of pH using sodium hydroxide. This buffer system also resists changes in the pH due to the oxidation of formaldehyde to formic acid.

[0052] In addition, citric acid is a known antioxidant. Thus the use of citric acid and sodium citrate in this combination thus increases the stability and solubility of taurolidine in solution and prevents or severely slows down the precipitation out of solid taurolidine and reaction products frequently seen in taurolidine solution prepared with PVP. Long term stability tests have verified this result. The composition employed in the practice of the present invention preferably also contains a pharmacologically acceptable carrier solution, such as, water, Ringer's solution, or saline.

[0053] Other biologically acceptable acids and biologically acceptable salts thereof are possible for combination with taurolidine. Other possible such acids are acetic acid, dihydroacetic acid, benzoic acid, citric acid, sorbic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, hydrochloric acid, malic acid, phosphoric acid, sulfurous acid, vanillic acid, tartaric acid, ascorbic acid, boric acid, lactic acid, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis-{β-aminoethyl ether}-N,N,N′,N′-tetraacetic acid, and diethylenetriamine pentaacetic acid, esters of p-hydroxybenzoic acid (Parabens), and the like, and biologically acceptable salts of the foregoing, such as, ammonium phosphate, potassium citrate, potassium metaphosphate, sodium acetate, sodium citrate, sodium lactate, sodium phosphate, and the like. A blood anticoagulating amount of an acid selected from the group consisting of citric acid, phosphoric acid, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis-{β-aminoethyl ether}-N,N,N′,N′-tetraacetic acid, and diethylenetriamine pentaacetic acid and biologically acceptable salts thereof is preferred. It is preferred that the acid employed in the practice of the present invention be an organic acid, especially one having at least one carboxyl group, particularly citric acid or EDTA. It is more preferred that the acid be citric acid and most preferred that it be used in combination with a citrate salt, e.g., sodium citrate, since, in addition to its pH lowering and anticoagulation capabilities, it is also known to be an antiseptic at the 3% level.

[0054] Since calcium is one factor that is known to have a role in the coagulation of blood, it is believed possible that at least part of EDTA's efficacy in anticoagulant activity may be brought about by this means. Sodium citrate is also believed to have anticoagulation properties by virtue of its ability to generate insoluble calcium citrate.

[0055] The acid and/or salt will be used in a concentration effective to bring about the desired volume anticoagulation effect and, at the same time, bring about, or help to bring about, an appropriate pH for biocidal effect. Heparin is added in low concentrations, preferably 50 units per ml to 150 units per ml. Typically, the combined antimicrobial, heparin and anticoagulant composition of the present invention will have a pH in the range of from about 3.0 to about 7, preferably from about 3.5 to about 6.5 and, most preferably from about 4.5 to about 6.5. Methods for adjusting the pH, familiar to those of skill in the art, can be employed. Where, as is preferred, trisodium citrate and citric acid are employed in the practice of the present invention, the trisodium citrate will typically be used in a concentration range of from about 5 to about 50 grams per liter. The citric acid will then be added in sufficient amount to bring the pH to the desired level. The formulation which is a preferred embodiment comprises about 1.35% Taurolidine, 4% citrate and acidic pH, generally in the range of 5 to 6.

[0056] Although the process of the present invention is primarily and preferably directed to maintaining the patency and asepsis of implanted hemodialysis catheters, beneficial effects may also be obtained in applying the process to other, similar, devices, such as, central venous catheters, peripheral intravenous catheters, arterial catheters, Swan-Ganz catheters, umbilical catheters, percutaneous non-tunneled silicone catheters, cuffed tunneled central venous catheters as well as with subcutaneous central venous ports.

[0057] Various features and aspects of the present invention are illustrated further in the examples that follow. While these examples are presented to show one skilled in the art how to operate within the scope of the invention, they are not intended in any way to serve as a limitation upon the scope of the invention.