CN1301110C - Antimicrobial atresia with tauryl amine derivatives and carboxyl acid and/or its saltAnti - Google Patents

Antimicrobial atresia with tauryl amine derivatives and carboxyl acid and/or its saltAnti Download PDF

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CN1301110C
CN1301110C CNB021087741A CN02108774A CN1301110C CN 1301110 C CN1301110 C CN 1301110C CN B021087741 A CNB021087741 A CN B021087741A CN 02108774 A CN02108774 A CN 02108774A CN 1301110 C CN1301110 C CN 1301110C
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taurolidine
acid
solution
antimicrobial
patient
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CN1448051A (en
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克劳斯·索德曼
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ND Partners LLC
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Abstract

The present invention relates to a method for inhibiting or preventing infection and hematopexis in or near a medical repair device after the device is implanted in a patient. The method comprises the process of offering composition as the effective dose of the medicine of the device, and the composition comprises the following components: (A) at least one kind of tauryl amine derivatives and (B) at least one kind of compounds selected from acids and salts thereof acceptable biologically.

Description

Comprise the antimicrobial locking of tauryl amine derivative and carboxylic acid and/or its salt
Technical field
The present invention relates to be used for the flushing of prevention infection and hemopexis and the compositions and the method for coating conduit.
Background technology
Enter human or animal patient's vascular system, the hemodialysis transit system (hemodialysis accesssystem) that is used for blood exchange between vascular system and external operation device is being known in the art.A kind of method is included in and places the conduit that an end extends to the central vein system among the patient.As any invasion procedure, prevention infection has become problem, particularly in the situation of using the device that must remain on original position for a long time.In conduit and the hemopexis around the conduit also be trouble, therefore need the method for prevention hemopexis, when particularly considering to suppress to reduce or to destroy the conduit obstruction of conduit effectiveness.Carried out big quantity research to alleviate these problems.
With anticoagulant such as heparin irrigating catheter is standard step.Yet heparin is not antimicrobial, and in addition, if not carefully control, its degree that anticoagulant process is carried out is too high, thereby has hemorrhage risk.
United States Patent (USP) 4,096,241 disclose the pharmaceutical composition that is used for the treatment of and prevents tooth and gingival infection, particularly periodontitis, and it comprises the thiadiazine derivatives as active component.
United States Patent (USP) 4,107,305 disclose the method by the Taurolidine compositions opposing endotoxemia that gives effective dose.
United States Patent (USP) 4,337,251 disclose Taurolidine eliminated or reduced tissue adhesion in the human or animal purposes.
United States Patent (USP) 4,587,268 disclose the compositions that is used for the treatment of wound, and it contains can resorbent aqueous gel, dissolving or disperseed one or more water soluble drugs in this aqueous gel, preferably antibiotic or methylol shift antimicrobial.
United States Patent (USP) 4,587,284 disclose the method for preparing the enhanced hydrophilic polymer materials of water absorption, described material is applicable to wound dressing, in the method, permeate moisture organic hydrogel, but described hydrogel comprises polysaccharide and/or the protein or the polypeptide of the gelatine that is scattered with hydrophilic acrylic acid or methacrylic acid derivative polymer with alkali, during with described alkali treatment, the pH of described hydrogel is elevated to is at least 9.
United States Patent (USP) 4,604,39l disclose prophylactically two first diazine chemical compound administration of human or homoiothermic animal with opposing osteitis or osteomyelitis, particularly in the patient of the bone injury of suffering from the wound of coming from.
United States Patent (USP) 4,626,536 disclose the Taurolidine chemical compound resists in people or homoiothermic animal poisonous protein or peptide class is arranged, for example the purposes in venom, mycotoxin and the bacterial endotoxin.
United States Patent (USP) 4,772,468 disclose the pharmaceutical composition that is used to be packed into bone cavity, and it comprises by powder calcium phosphate and antibiotic substance, optionally contains water suspension paste with what one or more binding agents formed.Antibiotic substance is preferably taurolidine, and calcium phosphate is preferably bata-tricalcium phosphate.
United States Patent (USP) 4,797,282 disclose implantable medicine intravital, that be used to control, postpone to discharge cytostatics stores agent (pharmaceutical depot), and it comprises and contains cytostatics and at least a amino acid whose synthetic material based on polyacrylate and/or polymethacrylates.
United States Patent (USP) 4,853,225 disclose the implantable medicine storage agent that is used to resist infection, and it comprises the reactive compound of acceptable excipient of physiology and at least a delay release, and described chemical compound is a kind of chemotherapeutant of gyrase inhibitor type.
United States Patent (USP) 4,882,149 disclose the medicine storage agent formulation that is used to implant alkalescence tissue (basetissue), it comprises the fat of having removed natural connection and the natural bone mineral of bone protein, therefore described bone is aseptic and nonallergenic, is absorbing one or more biological active substanceies on the described bone material and/or in described bone material.This biological active substances is antibiotic or taurolidine or tauroflex or the protein or the polypeptide of auxiliary osteanagenesis advantageously.
United States Patent (USP) 4,905,700 disclose and have been used to transmit ultransonic acoustic coupling medium.This useful in the ultrasonic contrast of human body medium comprises hydrogel layer, and described hydrogel contains and surpasses 90% water, preferably contains and surpasses 95% water.This hydrogel preferably comprises agar, and its chain and polyacrylamide chain are alternately.
United States Patent (USP) 4,960,415 disclose the device that is used for implanting in wound and the wound chamber, this device is made up of the container that contains pharmaceutically active substance, this wall of a container to small part by film, preferably form by semipermeable membrane, described film allows active substance to enter the wound district.More preferably, this container is a Dialysis tubing.In order to discharge wound exudate, contain pharmaceutically active substance, particularly the container of taurolidine links to each other with drainage tube easily.Preferably, use an end that imports wound to split into the drainage tube of filament.
United States Patent (USP) 5,077,281 disclose the Taurolidine chemical compound as the hemopexis inhibitor with as the purposes of aseptic inflammation inhibitor.According to this patent, Taurolidine has the outstanding inhibitory action of solidifying, and it is specially adapted to require the medical symptom of dialysing and blood vessel prosthesis.This patent also discloses these chemical compounds and can use with other anticoagulant such as coumarin or heparin.
United States Patent (USP) 5,167,961 and 5,417,975 disclose the method for preparing the high-purity bone mineral, wherein by heating and degradation of organic substances matter with ammonia or primary amine, it is characterized in that being lower than under 60 ℃ the temperature,, randomly repeat thisly to heat and washing step with primary amine by extracting dissolved catabolite with the flowing water washing, thereby remove all basically organic substances that these steps can be removed that passes through, reach the bone mineral that heating is so handled in air under 700 ℃ in temperature.
United States Patent (USP) 5,210,083 discloses the taurolidine that contains antibacterial valid density and/or tauroflex and the aqueous solution of (parenterallyacceptable) polyhydric alcohol of can non-gastrointestinal giving.It is said that this aqueous solution is particularly suitable for non-gastrointestinal and gives.
United States Patent (USP) 5,362,754 disclose the pharmaceutical composition of minocycline and EDTA (M-EDTA) mixture, and use said composition to keep the open method of catheter channel (catheterport).Also provide and used the inhibition of M-EDTA solution to be rich in the method for glycocalyx (as the staphylococcic glycocalyx) formation of polysaccharide.M-EDTA solution can also be used for the pretreatment medical treatment device to prevent the adhesion of infectious bacterium such as staphylococcus epidermidis (S.epidermis) and staphylococcus aureus (S.aureous).The glycocalyx that polysaccharide was destroyed and prevented to be rich in to said composition forms.
United States Patent (USP) 5,573,771 disclose the granular bone mineral product of purification that is used for medical treatment, and described salt particle is basically without any the endogenous Organic substance and have at least in its surface can resorbent, that the physiology is compatible, natural or synthetic macromolecule material.Especially, provide bone mineral, it floods with the protein that forms gel or polysaccharide such as gelatin, thereby strengthens intensity and the product that comprises bone mineral is provided, and described bone mineral is in collagen fiber and forms in the proteinic substrate of gel.This product is as reinventing implant or repairing bone substitute.
United States Patent (USP) 5,593,665 disclose the product that contains tumor necrosis factor and taurolidine and/or tauroflex, they are as compound formulation, simultaneously, respectively, use in order and suffer from patient by the medical symptom of tumor necrosis factor mediation with treatment.
United States Patent (USP) 5,603,921 disclose the pastille dental floss that is used to control the bacterial activity relevant with gingivitis.Mix antimicrobial in the dental floss, remove the result of (flossing) action as dental floss, described deposition of antimicrobial agent is distinguished between the tooth of tooth.The slow dissolving of antimicrobial has guaranteed to reach for a long time the Drug therapy of effect level, thereby reduces bacterial activity.
United States Patent (USP) 5,688,516 disclose compositions and used method for compositions in flushing and coated medical device.Said composition comprises the selection combination of chelating agen, anticoagulant or antithrombotic agent and non-glycopeptide antimicrobial such as tetracycline antibiotic.The method of using these compositions coated medical device and suppressing catheter infections is also disclosed.Specific combination is included in minocycline or other non-glycopeptide antimicrobial and EDTA, EGTA, DTPA, TTH, heparin and/or the trematodiasis element in the pharmacy acceptable diluent.
Myers etc.; J.Appl.Bacteriol 48:89-96 (1980) reported Taurolidine-two (1,1-dioxo-perhydro--carotene 1,2; 4-thiadiazine base) methane is Antimicrobe compound, and it forms by bimolecular taurine and termolecular formaldehyde condensation.Taurolidine release formaldehyde when contacting with antibacterial had been proposed in the past.The author presents evidence and shows Taurolidine most of hydrolysis in aqueous solution, discharges formaldehyde and two monomer molecules 1,1-dioxo-perhydro--carotene 1,2,4-thiadiazine and the carbinolamine derivant thereof of a part.According to the narration of this article, stable balance is set up.The author reaches a conclusion, and antibacterial activity is not exclusively owing to the absorption of free formaldehyde, also owing to the reaction of (or potential) formaldehyde of sheltering because the activity of finding Taurolidine is greater than formaldehyde.By contrast, find that monomer only is slightly active.
Gorman etc., J.Clin.Pharm.Ther.12:393-399 (1987) has reported three kinds of antimicrobials, taurolidine, chlorhexidine and povidon iodine are to the tissue adhesion activity of microorganism.Two kinds of adhesion system have been studied: the coliuria isolate of the epithelial Candida albicans mouth of population isolate (isolate) and Urina Hominis epithelial cell (uroepithelialcell).Three kinds of reagent demonstrate significant tissue adhesion activity separately, and it is a concentration dependent.
Root etc., Antimicrobial Agents and Chemotherapy32 (11): 1627-1631 (1998) have reported that the granulocytopenia patient who has catheter in blood vessel has staphylococcus epidermidis (S.epidermis) risk of infection of increase.Interim when conduit is not used in transfusion, the opening that keeps catheter lumen usually with the solution that contains heparin.The author proves that heparin does not suppress the growth of isolating staphylococcus epidermidis (S.epidermis) from the conduit of infected patient.EDTA two sodium solutions of 20mg/ml are proved to be after 24 hours 10 3CFU/ml staphylococcus inoculum first has bactericidal action, the EDTA disodium be a kind of under this concentration effective anticoagulant chelating agen.Also find to be generally used for to treat antibiotic vancomycin that staphylococcus infects under the dosage of 6.7 μ g/ml to 10 3CFU/ml inoculum first has bactericidal action, and 6.7 μ g/ml are the concentration in therapeutic domain.From its low cost, consider that as the angle of the effectiveness of anticoagulant and bactericidal activity the author recommends EDTA is studied as the succedaneum of heparin solution, is used for the maintenance of granulocytopenia patient's vein inner catheter.
Jones etc.; J.Appl.Bacteriol.71:218-227 (1991) has checked three kinds of non-antibiotics, and antimicrobial-taurolidine, chlorhexidine acetate and povidon iodine are to the influence of the surface hydrophilicity of clinical strains escherichia coli, staphylococcus saprophyticus (S.saprophyticus), staphylococcus epidermidis (S.epidermidis) and C.albicans.Under the adherent concentration of being reported of interference microorganism-epithelial cell, find that these three kinds of reagent all change the cell surface hydrophilic.Yet these influences do not show the relation of homogeneous.Usually, the treatment of taurolidine and povidon iodine reduces the hydrophilic of the bacterial strain of being checked, and chlorhexidine acetate depends on the microbe colony of being treated and act on.
Traub etc., Chemotherapy 39:322-330 (1993) checked taurolidine to representative number in meat soup and the bactericidal activity of the many antibiotic drug tolerant bacteria isolate in the presence of cattle and human serum and the fresh human blood of defibrinating.The author proposes this antimicrobial material and can be used for being transplanted in vivo the also patient's of growth or surface infection topical therapeutic by the enterobacteria of glycopeptide endurance strain (GRMRSA) of E.faecium, staphylococcus aureus (S.aureus) or generation wide spectrum beta-lactamase.
Willatts etc.; Crit.Care Med.23 (6): 1033-1039 (1995) has reported that the development of using clinical, bacteriology result, endotoxemia, organ failure's elimination and 28 days mortality rates are as terminal point; to the unitary patient that the comprehensive card of sepsis is arranged of the intensive treatment of accepting university teaching hospital, taurolidine does not have effective therapeutic effect.
Darouiche etc., Nutrition 13 (4) are (suppl): 26S-29S (1997) has reported that the prevention of the infection relevant with vessel catheter mainly concentrates on and has suppressed to derive from the adhesion of the microorganism of skin or catheter adapter (catheter hub) to conduit.They have described two kinds and can not exclusively use, and are used for successfully preventing two kinds of common methods of the infection relevant with vessel catheter.First method is without antimicrobial and comprise following means, as placing and safeguard vessel catheter by skilled injection treatment group, and uses maximum sterile barrier.Second method is used antimicrobial and is comprised application partly sterilised's agent such as chlorhexidine, use the subcutaneous cover capsule (as the short-term central venous catheter) of silver dipping, with the combination irrigating catheter of antimicrobial and anticoagulant, and with antiseptic (chlorhexidine and silver sulfadiazine) or antimicrobial (minocycline and rifampicin) coating conduit.
At the San of Texas Antonio, in the 30th annual meeting of the American Society of Nephrology (American Society of Nephrology) that carries out on November 2nd to 5,1997, the speech of Sodemann etc. has reported that relevant gentamycin/sodium citrate mixture is used to remedy tests in 4 years of the infection relevant with conduit with prevention as antibiotic locking (lock) technology.They reach a conclusion, and can the routine by dense gentamycin/citrate mixt use and avoid infection, and even the conduit that pollutes of inner chamber and to remedy also be possible.
Although above-mentioned contribution to prior art is arranged, but still need safety and effective, the method for prevention infection and hemopexis in the patient of its disease requirement implantation room dummy pipe.
Summary of the invention
According to the present invention, provide antimicrobial/anticoagulant compositions of using in medical prosthetic device, particularly conduit and the passage (port) washing and being coated with.
Particularly, the present invention relates in medical prosthetic device or near it, in described device is implanted the patient after, the method for inhibition or prevention infection and hemopexis, described method comprise the compositions that comprises following ingredients that gives this device medicine effective quantity:
(A) at least a tauryl amine derivative and
(B) at least a be selected from acceptable acid biology and biology acceptable salt chemical compound.
More particularly, the present invention relates in medical prosthetic device or near it, in described device is implanted the patient after, the method for inhibition or prevention infection and hemopexis, described method comprise the compositions that comprises following ingredients that gives this device medicine effective quantity:
(A) the following Antimicrobe compound of at least a molecular formula
R wherein 1Be hydrogen or alkyl, and R 2It is the following group of hydrogen, alkyl or molecular formula
And
(B) at least a be selected from acceptable acid biology and biology acceptable salt chemical compound.
In another embodiment, the present invention relates to use the medical prosthetic device of the compositions coating that comprises following ingredients:
(A) the following Antimicrobe compound of at least a molecular formula
Figure C0210877400103
R wherein 1Be hydrogen or alkyl, and R 2It is the following group of hydrogen, alkyl or molecular formula
Figure C0210877400104
And
(B) at least a be selected from acceptable acid biology and biology acceptable salt chemical compound,
Wherein the amount of the said composition that is comprised is to be used to prevent or to suppress to infect medicine effective quantity with hemopexis.
In another embodiment, the present invention relates to medical prosthetic device is exposed to the medical prosthetic device that the method for compositions that comprises following ingredients prepares by comprising:
(A) the following Antimicrobe compound of at least a molecular formula
R wherein 1Be hydrogen or alkyl, and R 2It is the following group of hydrogen, alkyl or molecular formula
Figure C0210877400112
And
(B) at least a be selected from acceptable acid biology and biology acceptable salt chemical compound,
Wherein the amount of the said composition that is comprised is to be used to prevent or to suppress to infect medicine effective quantity with hemopexis.
The specific embodiment
As mentioned above, the present invention relates in medical prosthetic device or near it, in described device is implanted the patient after, the method for inhibition or prevention infection and hemopexis, described method comprise the compositions that comprises following ingredients that gives this device medicine effective quantity:
(A) the following Antimicrobe compound of at least a molecular formula
Figure C0210877400113
R wherein 1Be hydrogen or alkyl, and R 2It is the following group of hydrogen, alkyl or molecular formula
Figure C0210877400121
And
(B) at least a be selected from acceptable acid biology and biology acceptable salt chemical compound.
In British patent 1,124, the preparation of representative example of the chemical compound of molecular formula I has been described in 285.Basically, these chemical compounds are condensation products of tauryl amine and formaldehyde, so these chemical compounds are called as " tauryl amine derivative " in this article.They not only present activity to gram-positive bacteria and gram-negative bacteria, and the extracellular toxin and the endotoxin of these microorganisms presented activity.
If R 1And/or R 2Be alkyl, then they can be the straight or branched alkyl, and preferably are independently selected from those alkyl with 1 to 8 carbon atom, that is, and and methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group and isomer thereof; More preferably, if R 1And/or R 2Be alkyl, then they are independently selected from those alkyl with 1 to 6 carbon atom, that is, and and methyl, ethyl, propyl group, butyl, amyl group, hexyl and isomer thereof; Most preferably, be alkyl with 1 to 4 carbon atom, that is, and methyl, ethyl, propyl group, butyl and isomer thereof.Yet, R most preferably 1Be hydrogen, and R 2It is the group of hydrogen or molecular formula II.
In the present invention, in the chemical compound of molecular formula I, particularly preferably be taurolidine (R 1=H; R 2=molecular formula II) and tauroflex (R 1=R 2=H).Taurolidine is two-(1,1-dioxo-perhydro--carotene 1,2,4-thiadiazine-4-yl) methane.
The Antimicrobe compound that adopts in practice of the present invention is the formaldehyde carrier,, contains the non-toxic derivant of formaldehyde that is.
The model of action that has proved taurolidine comprises to be transferred to methylol on the hydroxyl or amino that exist on the above toxin or on the murein of bacteria cell wall.In solution, taurolidine and tauroflex and N-methylol tauroflex balance exist, and taurolidine is in the great majority.Tauroflex itself exists with methylol tauryl amine balance, and balance helps tauroflex widely.When above hydroxymethyl derivative, when the methylol tauroflex contacted with toxin or antibacterial with methylol tauryl amine, methylol shifted.Thereby make the methylol tauroflex be converted into tauroflex, and methylol tauryl amine is converted into taurine, taurine is a kind of naturally occurring sulfamic acid that has toleration in human body.Therefore it should be understood that taurolidine acts on and produce identical end-product basically in the same manner with tauroflex.
The bacterial infection that gram-negative bacteria causes that is to say usually with endotoxemia, with the endotoxic reaction of patient to this biology release.
Endotoxin is the complex liped polysaccharide component of zero-somatic antigen, and its loosely is connected in the cell wall of gram-negative bacteria.Irrelevant with bacterial origin, all endotoxins all show similar toxicity-contrast with the gram-positive bacteria of bringing into play independent effect miscellaneous.In the people, when being dissolved with a large amount of gram-negative bacteria, it may produce the endotoxin shock syndrome.This syndrome occurs in about 30% the patient that the Gram-negative septicemia is arranged.Known endotoxin can be by the deactivation of tauryl amine derivative.
Toxic protein such as extracellular toxin can be inactivated similarly, and can give methylol transfer antibiotics, opposing toxic protein when not having the lipopolysaccharide toxin.The toxin that may relate to comprises the extracellular toxin of this gram-negative bacteria such as escherichia coli and bacteroides fragilis.Known intravenous gives 20% taurolidine solution that mice 0.2ml is dissolved in the 5% aseptic polyvinylpyrrolidone can reduce the mortality rate that intraperitoneal gives escherichia coli and two kinds of pathogenic strains of B.fragilis very significantly.
Other toxic protein comprises venom such as peak venom (mellitin) and mycotoxin such as amanitine and α-bungarotoxin, has proved that they are by taurolidine detoxification basically.
The peculiar advantage of taurolidine is its extremely low toxicity; Proved that it is non-teratogenesis in mice, its intraperitoneal LD 50The order of magnitude at 1.5g/kg.As mentioned above, these compound exhibits methylol transfer activities, this activity causes the generation of in human body natural discovery and nontoxic especially taurine.Another advantage of taurolidine is its stability in aqueous solution, and this makes this solution and to store relatively chronically by pre-packing.
The tauryl amine derivative that adopts in practice of the present invention gives by being expelled in the medical prosthetic device with the form of aqueous solution usually.This solution is except containing given tauryl amine derivative; can also contain gentamycin sulfate or chondroitin sulfate; can also contain solubilizing agent such as polyvinylpyrrolidone (PVP) routinely, with help the tauryl amine derivative be remained in the solution, and the isotonicity of solution is worked.The concentration of the tauryl amine derivative in this solution can be for greater than 0, to about 2% (weight); About 0.01 to about 1.5% (weight) concentration be preferred; Optimum for selecting about 1% (weight) concentration.The concentration higher than these concentration is useful, but in the case, dissolubility becomes problem.
If in solution, mix PVP, then, adopt the concentration of 4-7% (weight) usually in order to reach the high relatively concentration of low tauryl amine derivative, particularly taurolidine of water solublity.The molecular weight of PVP should be greater than about 30000 and preferably less than 10000, and for example about 200 to about 3500.The Kollidone that BASF sells The 17th, suitable especially.This PVP at a good pace is absorbed and passes through renal excretion.
The amount that is expelled to the tauryl amine derivative solution in the medical prosthetic device should be enough to fill this medical treatment prosthetic device.When this device is hemodialysis catheter, its internal capacity usually at about 0.1ml to the scope of about 10ml; Certainly this numerical value will change with the length and the diameter of the pipe that installs, and it can be the function of each patient's size (size) especially.
Preferably about 0.4 to the scope of about 5% (weight), maximum depends on the dissolubility of chemical compound to the concentration of the tauryl amine derivative in this solution.Particularly preferably be about 0.4 taurolidine solution to about 2.0% (weight), that is, and about taurolidine solution of 4 to about 20g/l.
In several patents, for example United States Patent (USP) 4,337, occurred describing the embodiment of the preparation of taurolidine stock solution in 251.
In 25 liters of glass containers that agitator and powerful reflux be housed, be packed into 15 liters of pyrogen-free distilled waters, and under agitation be heated to 50 ℃.After adding taurolidine (400g), (Kollidone 17 then to add PVP; 1000g).After the dissolving, cooling solution also is transferred to 6.0 with several 0.1N hydrochloric acid with pH.Then with flow of solution through the absorption filter, removing microorganism and pyrogen, and the sterilization Millipore filter of flowing through before being packed into the 100ml bottle, bottle is after autoclaving.
Look required, can replace some or all PVP with the polyhydric alcohol that can non-gastrointestinal gives.This purposes of polyhydric alcohol is at United States Patent (USP) 5,210, and open in 083, the document is incorporated herein for referencial use.Be pointed out that, under higher concentrations of taurolidine, crystallization may take place, and crystallization may cause solution unavailable.
Under antibacterial and endotoxin and ectotoxic situation, have been found that as mentioned above, after methylol shifts, there is other the irreversible step that comprises dehydration.Therefore, be under the situation of bacterial endotoxin of lipopolysaccharide at endotoxin, find to take place irreversible cross-linking reaction, this reaction prevents that endotoxin from bringing into play its lethal effect.Similarly, be under the situation of albumen or polypeptide and the bacterial exotoxin that is not contained in the lipopolysaccharide substance classes of finding in the endotoxin at extracellular toxin, found that the detoxification reaction is irreversible.Yet, at United States Patent (USP) 5,210, disclosing under the situation of multiple hydroxyl or amino-compound in 083, it is reversible that the methylol that is undertaken by above-mentioned mechanism shifts, therefore can equilibrium establishment, this balance is also disturbed the effectiveness of taurolidine indistinctively.Therefore also can be with polyhydric alcohol as sugar and sugar alcohol in order to relative high taurolidine and/or tauroflex concentration in the maintenance aqueous solution, and their antibiotic and antitoxin activity of not appreciable impact.Preferred polyhydric alcohols comprises carbohydrate, and hexose for example is as glucose, fructose and their mixture; Pentose is as xylose; Polysaccharide is as glucosan or hydrolyzed starch; Glycerol; And sugar alcohol, as Sorbitol, mannitol and xylitol.It most preferably is glucose.
The concentration of polyhydric alcohol usually about 3 to the scope of about 40% (weight).Under the situation of glucose, this concentration is preferably about 10 to the scope of about 30% (weight), more preferably about 20% (weight).
If use this polyhydric alcohol, in the solution concentration of taurolidine preferably about 0.5 to the scope of about 5% (weight), more preferably about 2 to the scope of about 3% (weight).The concentration of tauroflex is preferably about 1 to the scope of about 7.5% (weight), more preferably about 3 to the scope of about 5% (weight).
Yet nearest test shows that for increasing the dissolubility of taurolidine in aqueous solution, PVP or polyhydric alcohol are all optional.In fact, these tests prove that adding citric acid increases the dissolubility of taurolidine in water fully, and PVP be not effectively real aspect the increase dissolubility.In these trials, researcher has prepared a series of solution with the citric acid assist in dissolving of about 2.6% (weight), obtains the taurolidine solution of 1.5,2.0,3.0,4.0% (weight), and does not use PVP or polyhydric alcohol.Researcher thinks that the citric acid that adds easily is elevated to 5% with the dissolubility of taurolidine, and does not use PVP or polyhydric alcohol.In fact, these researcheres find to add PVP basically to not influence of dissolubility.By with sodium hydroxide with pH regulator to 5.2 to 5.3, with the pH regulator of afore-mentioned test solution to the acceptable pH scope of biologic applications.This method has produced the citric acid/sodium citrate buffer system.
In addition, known citric acid is an antioxidant.The formed buffer system of pH is also resisted because the pH that the oxidation of formaldehyde formic acid causes changes by regulating with sodium hydroxide.Therefore this being used in combination of citric acid and sodium citrate increased the stability of taurolidine in solution, and the product that prevents or significantly slow down and be settled out the solid taurolidine and often see in the taurolidine solution with the PVP preparation.Long-term stable experiment has confirmed this result.
Because gram-negative bacteria often exists, and because the bacteriostatic activity of tauryl amine derivative is lower than the antibiotic bacteriostatic activity of many routines, so can advantageously the compositions that adopts in practice of the present invention be given with the broad ectrum antibiotic material, more particularly, described broad ectrum antibiotic material is that Gram-positive and Gram-negative pathogen are all had strong active material, the drug resistance that it does not preferably cause or only causes postponing, for example, beta-Lactam antibiotic is as penicillin, ampicillin or cephalosporin; Tetracycline antibiotic; Macrolide antibiotic is as erythromycin; Peptide antibiotics is as bacitracin or novobiocin; Or more preferably, be aminoglycoside antibiotics, as amikacin, butirosin, astromicin, streptomycin, neomycin, lincomycin class (linkomycins), as clindamycin, lincomycin, kanamycin, Dibekacin (DKP), lividomycin, netilmicin, ribostamycin, micronomicin, seldomycin and their epimer, sisomicin, sorbistin, tobramycin, vancomycin, gentamycin and rifomycins such as rifampicin and rifamycin; Or the like.In these antibiotic, gentamycin is preferred.
Yet because antibiotic produces the tendency of Resistant strain, unless in extraordinary circumstances, antibiosis usually is used for surgical intervention by taboo, preferably only depends on the antibacterial action of tauryl amine derivative, because this derivant does not produce Resistant strain.
The compositions that adopts in the practice of the present invention preferably also contains pharmacology's acceptable carrier solution, as water, Ringer's solution or saline.In addition, compositions of the present invention can also contain other dissolved additive that can advantageously influence its physics and biochemical property, for example aminoacid, sugar, Sal, fat and lipid etc.
Antimicrobial tauryl amine derivative that adopts in the practice of the present invention and acceptable acid biology or its biology acceptable salt be used in combination.Preferred this acid is carboxylic acid, is more preferably anticoagulant.United States Patent (USP) 5,077,281 instruction Taurolidine chemical compounds itself show the significant consolidations that suppress, its suitable especially independent or with other anticoagulant, share in medical symptom that requires to dialyse and blood vessel reparation as coumarin or heparin group.As pointed in this patent, and this is by W.L.Bruckner and R.W.Pfirrmann, Verlag Urbanund Schwarzenberg, Munich, the instruction of 1985 " Taurolin " that publish is opposite, and it clearly explains Taurolidine does not influence hemopexis and do not show antiinflammation.Inventor of the present invention believes that the tauryl amine derivative that adopts in the practice of the present invention shows anticoagulating active to a certain degree really, although compare with more famous anticoagulant such as heparin, its anticoagulant degree is lower.Therefore, with tauryl amine derivative and anticoagulant, it is useful being preferably that acceptable acid biology or its salt is used in combination.
According to the present invention; be not higher than 7 when antimicrobial tauryl amine derivative and acceptable acid biology or its biology of acceptable salt combination so that for the final composition generation; preferably about 3.5 to about 6.5 scope; more preferably when about 4.5 pH to about 6.5 scope, realize favourable result.The example of this acid is an acetic acid, dihydrokainic acid, benzoic acid, citric acid, sorbic acid, propanoic acid, oxalic acid, fumaric acid, maleic acid, hydrochloric acid, malic acid, phosphoric acid, sulphuric acid, vanillic acid, tartaric acid, ascorbic acid, boric acid, lactic acid, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-two-{ beta-amino ether }-N, N, N ', the ester of N '-tetraacethyl and diethylene-triamine pentaacetic acid and P-hydroxybenzoic acid (p-Hydroxybenzoate) etc., and aforesaid biology acceptable salt, as ammonium phosphate, potassium citrate, potassium metaphosphate, sodium acetate, sodium citrate, sodium lactate and sodium phosphate etc.The anticoagulant blood volume be selected from citric acid, phosphoric acid, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-two-{ beta-amino ether }-N, N, N ', the acid of N '-tetraacethyl and diethylene-triamine pentaacetic acid and biology thereof, acceptable salt was preferred.The acid of adopting in the preferred practice of the present invention is organic acid, particularly has the organic acid of at least one carboxyl, especially citric acid or EDTA.More preferably this acid is citric acid, and most preferably be itself and citrate for example sodium citrate be used in combination, this is because except it reduces pH and anticoagulant ability, also known it under 3% content, be antiseptic.
Mermel; L.A. wait antimicrobial and chemotherapeutical cross discipline meeting (Interscience Conference on AntimicrobialAgent and Chemotherapy) in 1998 and go up in the speech of doing that is entitled as " taurolidine is to the activity (Taurolidine Activity AgainstVancomycin-Intermediate SusceptibilityStaphylococcus Aureus (VISA) and Methicillin-Resistant Staphylococcus Aureus (MRSA)) of vancomycin intermediate sensitivity staphylococcus aureus (VISA) and anti-methicillin BRL-1241 staphylococcus aureus (MRSA) "; disclose with pH and reduced in the scope of pH 7.0 to pH 5.0, taurolidine is active to be increased.
EDTA is the known anticoagulant that uses in blood collection tube.Also known it have the ability that forms chelate with calcium.Because known calcium is a kind of factor that works in blood coagulation, therefore believe might be in anticoagulating active to produce by this kind mode to small part EDTA effect.Produce the ability of insoluble calcium citrate according to sodium citrate, believe that sodium citrate also has anticoagulant character.
Ethylene glycol-two-{ beta-amino ether }-N, N, N ', N '-tetraacethyl (EGTA) and diethylene-triamine pentaacetic acid (DTPA) and their salt are other known chelating agen, they can be used to substitute EDTA or citric acid/citrate, or use with EDTA or citric acid/citrate.
Aforementioned anticoagulant can use separately with the state of free acid, but uses or be used in combination with similar salt with the state with suitable their some or all carboxyls of alkali neutralization usually.Usually, use the cation that is formed on soluble salt in the aqueous solution, as alkali metal ion, for example sodium, potassium or lithium conform with expectation.Also can use zinc citrate.Usually be preferably sodium salt or potassium salt, particularly sodium salt, and most preferably be sodium salt and disodium salt and the sodium citrate of EDTA.
The used acid and/or the concentration of salt are to bring the expectation anticoagulation, bring simultaneously or auxiliary band comes the valid density of the appropriate pH of biological applications.Usually, the pH of the antimicrobial of combination of the present invention and anticoagulant compositions is about 3.0 to about 7 scope, is preferably about 3.5 to about 6.5, and most preferably is about 4.5 to about 6.5.Compositions is usually under physiological pH.If desired, can be by adding acid or alkali, as mineral acid, for example hydrochloric acid, or preferred adding does not cause acidosic acid, for example acetic acid, malic acid or lactic acid and regulate pH.Other that can adopt also that those skilled in the art are familiar with regulated the method for pH.If preferably adopt trisodium citrate and citric acid in practice of the present invention, then the concentration range of used trisodium citrate is usually in about scope of 5 to about 50g/l.The citric acid that then adds capacity makes pH reach the level of expectation.
Although method of the present invention relates generally to antimicrobial/anticoagulant compositions is incorporated in the fixed conduit, but it will be appreciated by those skilled in the art that external artificial surface is contacted the deposition and the auxiliary site of eliminating bacterial growth that can prevent that it from implanting back clot on this surface with these compositionss.Therefore, can as the obstruction of surface to prevent from the favourable site of bacterial growth to be caused of hemodialysis catheter, thereby prevent the consequential infection of possibility with the compositions pretreatment medical treatment device that adopts in the practice of the present invention owing to existing on the clot.At first can then after implantation, repeat aforesaid periodicity flushing with this device of compositions-treated.
Although method of the present invention mainly and preferably relates to the opening of the hemodialysis catheter of keep implanting and aseptic, but this method is used for other similar device, as conduit between central venous catheter, peripheral vein (peripheral intervenous catheter), ductus arteriosus, Swan-Ganz conduit, umbilicus conduit, the non-tunnel type of percutaneous (nontunneled) silicone conduit, cover capsule (cuffed) tunnel type central venous catheter and subcutaneous central vein passage, also can obtain beneficial effect.
Following examples are further set forth various features of the present invention and aspect.Show within the scope of the present invention how to operate although list these embodiment to those skilled in the art, they do not play the restriction scope of the invention.
Embodiment 1
(0.5% taurolidine solution in the solution (Thomae, Biberach, Germany) of Ringer ' s-lactate) is introduced in the polyethylene bottle of four 30ml volumes with Lin Ge-lactate.Packing volume is 5,10 and 15ml.A bottle is filled with 5ml taurolidine and 2ml ACD-A (Fresenius, Bad Homburg, Germany) solution.ACD-A solution is used for whole blood to be preserved, and its every liter contains: 22.0g two hydration sodium citrates, 7.3g citric acid and 34.5g one glucose monohydrate.
In the slaughterhouse, collect blood, directly be collected into the container from butchering wound from sow, then with this vessel filling to the 30ml level.Covered container also moves gently blood is mixed with solution.Inspecting containers after 30 minutes.Only contain the blood clotting in the container of taurolidine, but the blood that contains in the container of taurolidine and ACD-A mixture there is not grumeleuse.Therefore, reach a conclusion, being used in combination of sodium citrate and citric acid anticoagulant and taurolidine provides enhanced considerably anticoagulant character in whole blood.
Embodiment 2
The type described in the U.S. Patent application 08/485,498 can subcutaneous implantation titanium channel system be used for this embodiment.It links to each other with two 12French silication rubber catheters that end is introduced right atrium.The valve of passage is opened by two special stylus printers, makes that blood flow is about 300ml/min.
After the patient agreed, by experienced nephrologist passage being implanted the mean age was 10 female patients and 6 male patients of 68 ± 9.Nine examples among the 16 routine patients are diabeticss.The patient's permit standard that is studied is the blood vessel depletion (vessel exhaustion) that causes not having on the arm carrying out the site of hemodialysis.Eight examples in 16 examples suffer from serious congestive heart failure, and all patients have high common sickness rate (comorbidity).The nine routine patients hemodialysis that will begin in a minute after implantation, other patient carries out chronic hemodialysis and is converted to channel system (four routine patients are by traveller (guidewire) exchange) from conduit.Periphery operation property complication does not take place.
Preferred blood vessel is a right internal jugular vein, but also uses external jugular vein and subclavian vein.So far, this device has used 11.0 ill year (patient years) altogether.Passage be used in planned IID phase (IID sessions) (n=1200).
Tube chamber internal contamination for fear of device gives the antimicrobial locking between the treatment phase, and removes before the treatment in next time.Antimicrobial locking aqueous solution comprises 13.3g/l taurolidine, 6.7g/l trisodium citrate and about 3.3g/l citric acid.Add citric acid with pH regulator between 4.75 to 5.25.Rely on citric acid and sodium citrate, prevented the conduit grumeleuse and needn't use heparin.
During studying, observe the outbreak of two kinds of antibacterial mass formed by blood stasis (bacteriaemia) (staphylococcus aureus (S.aureous)), and successfully treatment (0.5 infected/1000 days) under the situation of not losing device.This research the results are shown in Table 1.
Embodiment 3
Comparative Examples
Four independent device, among A, B, C, the D, wherein two in the U.S., and two in Europe, except employed locking is a concentration 2000 heparin or the saline of heparinization to 10000 ius/ml scope, be similar to the research of the above embodiment 2.Research in the U.S. among A and the B, also exists benzyl alcohol as the standard antiseptic.These The comparative result see Table 1.
Table 1
Embodiment Patient's number Ill year of time There is reason to shift out (Explant for Cause) (#s) Infect Fibrin/thrombosis
Number Infected patient (%) The equispaced 1(week) Number The equispaced 2(week)
2 31 11.0 0 2 7 286 0 ＞500
3A 8 8.0 1 6 50 70 2 208
3B 4 4.2 2 1 0 75 22 4 54
3C 7 6.1 2 6 43 53 4 79
3D 4 3.4 0 0 0 ＞176 0 ＞176
Sum (embodiment 3) 23 21.7 4 2 2 44 51 10 113
1The equispaced that does not have infection;
2The equispaced that does not have grumeleuse.
Embodiment 4
In the present embodiment of the test of describing embodiment 2 in more detail, use the described peptide channel system that can subcutaneous implantation of embodiment 2.
In the expection multicenter pilot scale that begins in June, 1998,31 passages are implanted among 19 routine female patients and the 12 routine male patients (mean age 66, minimum 30, maximum 81).Except accepting new equipment; the purpose of research is to avoid the infection supported by the mixture of totally nontoxic (contain as the taurolidine of infection material and suppress to solidify the no heparin locking solution of the citric acid/sodium citrate of usefulness); this mixture has any microorganism of opposing, even the splendid effect of the microorganism of multidrug resistance.
In 10 participations,,, the research beginning do not lose (3847 days implantation) in the heart since just having passage.Although high common sickness rate is arranged, the only infection that two routine patient experiences are relevant with blood flow (staphylococcus aureus (S.aureus)).Total observed infection is 0.5/1000 day.The whole body antibiotic therapy is successful.The sepsis relevant with conduit that exists takes place in 5/31 routine patient in advance; In the patient who uses peptide channel system that can subcutaneous implantation, do not recur.
Be in hospital short and after implantation, use passage (access) just, even the acceptance in be converted to the patient (12/31) of passage by conduit also is high.In 6/31 routine patient, the conversion by traveller is possible.Common placement technique is the seldinger technique (Seldinger) that is used by three nephrologists.Preferred blood vessel is right internal jugular vein (18/31), but can use all other central vein.
Compare with the unfavorable of conduit, channel system is held fair dipping bath (bathing) and as safe as a house.With locking solution of the present invention combination, infection dangerous low and make puncture technique be similar to transplanting.The life-span of this device waits to determine.
Embodiment 5
Test to determine when contacting the minimum taurolidine of function well/citrate locking solution acidity with human blood.With various locking solution acid concentration by 50/50 ratio (weight) and Freshman whole blood bulk testing ground with pH in 3.0 to pH 7.0 changes of pH.In locking solution acidity level is 4.0 and when lower, with the blood mixture fluid hardening of gained after locking solution contacts a hour and solidify.This sclerosis obviously is because the acidity of locking solution and normal blood clotting, and very dark and its state is done because grumeleuse seems color, and color or physical property are undesired.When the acidity of locking solution was kept above pH 5.0, the redness that blood clotting and blood color are kept fit did not take place.Therefore, the lower limit of the acidity of taurolidine locking solution most preferably is about 5.0.
Consider under the prerequisite that does not deviate from essence of the present invention and can make many changes and modification, therefore should understand protection scope of the present invention with reference to claims.

Claims (2)

1. the method for taurolidine dissolubility in the increase aqueous solution, described method comprises the adding citric acid.
2. the method for claim 1, it comprises the pH that adds sodium hydrate regulator solution in addition and produces citric acid and the step of sodium citrate buffer system.
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GB1124285A (en) * 1964-10-06 1968-08-21 Geistlich Soehne Ag Novel perhydro-1,2,4-thiadiazine dioxides-(1,1), their preparation and compositionscontaining them
US6166007A (en) * 1998-07-02 2000-12-26 Sodemann; Klaus Antimicrobial locks comprising taurinamide derivatives and carboxylic acids and/or salts thereof

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Publication number Priority date Publication date Assignee Title
GB1124285A (en) * 1964-10-06 1968-08-21 Geistlich Soehne Ag Novel perhydro-1,2,4-thiadiazine dioxides-(1,1), their preparation and compositionscontaining them
US6166007A (en) * 1998-07-02 2000-12-26 Sodemann; Klaus Antimicrobial locks comprising taurinamide derivatives and carboxylic acids and/or salts thereof

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