TWI566790B - Transdermal venous access locking solutions - Google Patents

Transdermal venous access locking solutions Download PDF

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TWI566790B
TWI566790B TW101131649A TW101131649A TWI566790B TW I566790 B TWI566790 B TW I566790B TW 101131649 A TW101131649 A TW 101131649A TW 101131649 A TW101131649 A TW 101131649A TW I566790 B TWI566790 B TW I566790B
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catheter
solution
growth inhibiting
microbial growth
chelating agent
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TW101131649A
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TW201323024A (en
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史坦利 米爾斯
賈桂琳 米爾斯
羅伯特 莫若
蓋瑞 雷賁
馬文 寇泉斯
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有機醫療事業公司
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皮膚穿透靜脈接觸鎖定溶液 Skin penetrating vein contact locking solution

本發明關於皮膚穿透留置醫學裝置(諸如導管)之領域,以及用於沖洗、鎖定及包覆該等醫學裝置之微生物生長抑制溶液之領域。更特別地,本發明之領域關於微生物生長抑制溶液。本發明亦關於可用於維持導管暢通及預防感染之微生物生長抑制溶液。本發明之揭示內容亦關於使用本發明之微生物生長抑制溶液以處理及維持皮膚穿透血管接觸導管之方法。 The present invention relates to the field of skin penetration indwelling medical devices, such as catheters, and to the field of microbial growth inhibiting solutions for rinsing, locking and coating such medical devices. More particularly, the field of the invention relates to microbial growth inhibiting solutions. The present invention also relates to a microbial growth inhibiting solution that can be used to maintain a smooth catheter and prevent infection. The present disclosure also relates to a method of using the microbial growth inhibiting solution of the present invention to treat and maintain a skin penetrating vascular contact catheter.

皮膚穿透醫學裝置(包括血管導管)已成為處理住院或慢性病患者之必要裝置。不幸的是,血管導管是醫院獲得性敗毒症之主要來源。因此,源自皮膚穿透醫學裝置諸如血管導管之益處通常被感染性併發症抵銷。中央靜脈導管(“CVC”)之管腔的栓塞性阻塞係另一種併發症,該併發症通常將導致導管移除。 Skin penetration medical devices, including vascular catheters, have become a necessary device for treating hospitalized or chronically ill patients. Unfortunately, vascular catheters are a major source of hospital acquired sepsis. Thus, the benefits derived from skin penetration medical devices such as vascular catheters are often offset by infectious complications. An embolic obstruction of the lumen of a central venous catheter ("CVC") is another complication that typically results in catheter removal.

為了減少血栓形成導致之問題,現在的做法通常是在連續使用之間「鎖定」血管內接觸導管。鎖定通常涉及先以鹽水沖洗導管以移除血液、藥物、細胞殘渣及該導管管腔中之其他物質。在沖洗該導管之後,接著注射鎖定溶液(通常是肝素)以取代鹽水並充滿管腔。該肝素鎖定溶液排出管腔中之血液,同時主動抑制該管腔內之凝血及血栓形成。為了防止感染,多種抗微生物物質被用於與該鎖定 溶液組合以在抑制血栓形成之同時抑制感染。然而,抗微生物物質目前所面臨及持續出現之抗藥性的問題以及抗微生物劑之過度使用(因此增加抗藥性發生之風險)皆日益令人擔憂。 In order to reduce the problems caused by thrombosis, it is now common to "lock" the intravascular contact catheter between successive uses. Locking typically involves first flushing the catheter with saline to remove blood, drugs, cell debris, and other substances in the lumen of the catheter. After rinsing the catheter, a locking solution (usually heparin) is then injected to replace the saline and fill the lumen. The heparin lock solution discharges blood from the lumen while actively inhibiting coagulation and thrombosis in the lumen. In order to prevent infection, a variety of antimicrobial substances are used to lock with The solutions are combined to inhibit infection while inhibiting thrombosis. However, the current resistance problems that antimicrobial substances face and continue to emerge, as well as the excessive use of antimicrobial agents (and therefore the risk of developing drug resistance), are increasingly worrying.

表皮葡萄球菌(Staphylococcus epidermidis)及金黃葡萄球菌(S.aureus)造成75%之CVC相關性感染。假絲酵母屬(Candida)造成另外10%至15%之該等感染。研究發現使用抗葡萄球菌抗生素以預防該等感染減少CVC相關性細菌感染,但卻帶來較高之真菌(假絲酵母屬)感染之發生率。由葡萄球菌及假絲酵母屬產生之纖維性醣外被物質有助於該等微生物附著及黏附至導管表面。該等微生物性生物膜層係由主成分為多醣之纖維性醣外被物質構成。由感染部位之醣外被所提供之保護性外殼有效防止該等感染被清除及處理。因此,需要能有效減少或清除通常與導管(微生物)定殖及感染有關之感染性微生物的醣外被之微生物生長抑制溶液。 Staphylococcus epidermidis and S. aureus cause 75% of CVC-associated infections. Candida causes an additional 10% to 15% of these infections. Studies have found that the use of anti-staphylococcal antibiotics to prevent such infections reduces CVC-associated bacterial infections, but results in a higher incidence of fungal (Candida) infections. Fibrous sugar coatings produced by Staphylococcus and Candida contribute to the attachment and adhesion of such microorganisms to the surface of the catheter. These microbial biofilm layers are composed of a fibrous sugar exogenous substance whose main component is a polysaccharide. The protective outer shell provided by the sugar outside of the infected site is effective in preventing the infection from being removed and disposed of. Therefore, there is a need for a microbial growth inhibiting solution which is effective in reducing or eliminating the glucoside of an infectious microorganism which is usually associated with catheter (microbial) colonization and infection.

皮膚穿透血管導管會被纖維蛋白鞘包覆,該纖維蛋白鞘接著覆蓋導管之內部及外部表面。此纖維蛋白鞘提供葡萄球菌及假絲酵母屬這些微生物增加之附著至導管表面之能力。和這些特定微生物不同的是,革蘭氏陰性桿菌並不黏附至纖維蛋白及纖維粘連蛋白。因此阻止纖維蛋白形成之組成物將特別被用於防止葡萄球菌、假絲酵母屬及該類似微生物於皮膚穿透導管部位之定殖。 The skin penetrating vascular catheter is covered by a fibrin sheath which then covers the inner and outer surfaces of the catheter. This fibrin sheath provides the ability of these microorganisms, Staphylococcus and Candida, to attach to the surface of the catheter. Unlike these specific microorganisms, Gram-negative bacilli do not adhere to fibrin and fibronectin. The composition that prevents fibrin formation will therefore be particularly useful for preventing the colonization of staphylococcal, Candida and similar microorganisms at the site of penetration of the skin through the catheter.

乙二胺四乙酸(“EDTA”)係用於採血管中之抗凝血 劑。其亦被認為是一種鈣螯合劑。EDTA亦被認為具有抗細菌及抗葡萄球菌作用(單獨或組合)(Harper & Epis(1987)Microbios.51:107;Said et al.(1987)J.Med.Microbiol.24:267;Root et al.(1988)Antimicrob.Agents Chemother.32:1627)。雖然該些研究人員發現EDTA具有殺菌效應,但沒有人提出針對消除裝置相關性感染之微生物醣外被的療法或建議。 Ethylenediaminetetraacetic acid ("EDTA") is used as an anticoagulant in blood collection tubes. It is also considered to be a calcium chelating agent. EDTA is also considered to have antibacterial and anti-staphylocal effects (alone or in combination) (Harper & Epis (1987) Microbios. 51 :107; Said et al. (1987) J. Med. Microbiol. 24 :267; Root et al (1988) Antimicrob. Agents Chemother. 32 :1627). Although these researchers have found that EDTA has a bactericidal effect, no one has proposed a therapy or suggestion for a microbial sugar rinsing that eliminates device-associated infections.

乙二醇四乙酸(“EGTA”)係另一種公認之螯合劑。此劑不曾被描述為作為抗微生物劑。三乙烯四胺二鹽酸鹽(三乙撐四胺2HCl)(“TTH”)係公認之螯合劑,其與銅螯合。TTH及其他螯合劑(包括二伸乙三胺五乙酸(“DTPA”))同樣不被認為具有抗微生物作用。 Ethylene glycol tetraacetic acid ("EGTA") is another recognized chelating agent. This agent has not been described as an antimicrobial agent. Triethylenetetramine dihydrochloride (triethylenetetramine 2HCl) ("TTH") is a recognized chelating agent that chelate with copper. TTH and other chelating agents, including diamethylenetriaminepentaacetic acid ("DTPA"), are also not considered to have antimicrobial effects.

雖然糖肽抗生素(萬古黴素及壁黴素(teicoplanin))於試管內及組織中能有效抑制葡萄球菌,但它們無法有效對抗包埋於生物膜層(像是醣外被)中附著之葡萄球菌。利用該等劑沖洗雖然可快速殺死該等微生物,但是在經治療之病患體內快速出現耐受性及抗藥性菌株之風險使其無法應用於大部分之病例。 Although glycopeptide antibiotics (vancomycin and teicoplanin) are effective in inhibiting staphylococci in vitro and in tissues, they are not effective against grapes that are embedded in biofilm layers (like sugar quilts). Cocci. Flushing with such agents can quickly kill such microorganisms, but the risk of rapid emergence of tolerant and drug resistant strains in treated patients makes them unsuitable for most cases.

美國專利第5,362,754號(發明人Raad)(此案簡稱為“Raad I”)描述用於導管之組成物,該組成物包括四環素抗生素(諸如二甲胺四環素(minocycline))及EDTA。Raad I揭示使用10-100 mg/ml之EDTA與0.001-100 mg/ml之二甲胺四環素之組合,更佳之組合為20-60 mg/ml之EDTA與2-9 mg/ml之二甲胺四環素。美國專利 第5,688,516號(發明人亦為Raad)(簡稱為“Raad II”)中之實施例10揭示二甲胺四環素與EDTA之組成物(其包含低於3 mg/ml EDTA)無法控制所有微生物生長。Raad II另揭示:「這些試驗亦顯示,當使用10:1比例之二甲胺四環素與EDTA(10% EDTA)時,其顯著增進抗白色念珠菌(Candida albicans)之抑制性活性。」 U.S. Patent No. 5,362,754 (Inventor Raad) (referred to herein as "Raad I") describes a composition for a catheter comprising a tetracycline antibiotic (such as minocycline) and EDTA. Raad I discloses the use of 10-100 mg/ml EDTA in combination with 0.001-100 mg/ml minocycline, more preferably 20-60 mg/ml EDTA and 2-9 mg/ml dimethylamine. tetracycline. US patent Example 10, No. 5,688,516 (also known as Raad II) (abbreviated as "Raad II") discloses that the composition of minocycline and EDTA (which contains less than 3 mg/ml EDTA) does not control the growth of all microorganisms. Raad II also revealed: "These trials have also shown that when using a 10:1 ratio of minocycline and EDTA (10% EDTA), it significantly enhances the inhibitory activity against Candida albicans."

美國專利第4,343,788及4,479,795號(發明人R.V.Mustacich)描述用於併入導管內之包含羧酸酯抗微生物劑之聚合物組成物。美國專利第4,392,848號(發明人D.S.Lucas)說明用於併入導管內之聚合物組成物,該導管可被羧酸酯抗微生物劑穿透。美國專利第4,489,097號(發明人R.L.Stone)(簡稱為“Stone”)說明靜脈溶液,其包含羧酸酯抗微生物劑,較佳地正己酸及正辛酸及彼等之醫藥上可接受之水溶性鹽。Stone揭示使用該等羧酸酯抗微生物劑以滅菌靜脈溶液並維持該等靜脈溶液在操作期間之無菌性。如所述之投予Stone溶液至靜脈導管以「鎖定」該導管於靜止(無流動)狀態將導致該通路快速阻塞,因為血液回流進入該裝置內且該所述之組成物缺乏抗凝血性質。 U.S. Patent Nos. 4,343,788 and 4,479,795 (inventor R.V. Mustacich) describe a polymer composition comprising a carboxylate antimicrobial agent for incorporation into a catheter. U.S. Patent No. 4,392,848 (Inventor D.S. Lucas) describes a polymer composition for incorporation into a catheter which can be penetrated by a carboxylate antimicrobial agent. U.S. Patent No. 4,489,097 (Inventor RLStone) (hereinafter referred to as "Stone") describes an intravenous solution comprising a carboxylate antimicrobial agent, preferably n-hexanoic acid and n-octanoic acid, and their pharmaceutically acceptable water solubility. salt. Stone discloses the use of such carboxylate antimicrobial agents to sterilize intravenous solutions and maintain the sterility of such intravenous solutions during operation. Administration of the Stone solution to the venous catheter as described to "lock" the catheter in a resting (no flow) state will result in rapid obstruction of the passage as blood flows back into the device and the composition lacks anticoagulant properties .

用於導管維護之預防劑應同時抑制/消除富含多醣之醣外被的形成並消滅葡萄球菌及真菌。鑒於上述情況,需要經改良之組成物、套組及方法以用於沖洗、鎖定及消毒導管。該等組成物應具有對抗廣譜性微生物之抗微生物活性,較佳地包括真菌、革蘭氏陽性細菌及革蘭氏陰性細 菌,且較佳地有效對抗浮游性(自由懸浮)微生物及包埋於生物膜中之黏附性微生物。該等組成物應不利抗藥性微生物之出現、相對不貴、無毒性、相容於導管材料、若不小心注入全身系統仍安全、易於實施、需要極少或不需溶液且可用於大部分或所有類型之植入導管,包括血液透析及血液過濾導管、靜脈導管、腹膜透析導管、導尿管、化學治療導管及該類似物。稍後所述之本發明之實施態樣至少符合某些該等目標。 Prophylactic agents for catheter maintenance should simultaneously inhibit/eliminate the formation of polysaccharide-rich sugar vesicles and eliminate staphylococci and fungi. In view of the foregoing, improved compositions, kits, and methods are needed for rinsing, locking, and disinfecting catheters. Such compositions should have antimicrobial activity against a broad spectrum of microorganisms, preferably including fungi, Gram-positive bacteria, and Gram-negative Bacteria, and preferably effective against planktonic (free-suspended) microorganisms and adherent microorganisms embedded in biofilms. Such compositions should be resistant to the emergence of adversely resistant microorganisms, relatively inexpensive, non-toxic, compatible with catheter materials, safe to handle if inadvertently injected into the systemic system, require little or no solution, and can be used for most or all Types of implantable catheters include hemodialysis and blood filtration catheters, intravenous catheters, peritoneal dialysis catheters, catheters, chemotherapeutic catheters, and the like. Embodiments of the invention described later meet at least some of these objectives.

本發明之實施態樣提供獨特且有效之微生物生長抑制溶液(例如鎖定溶液),其包含有效量之羧酸酯抗微生物劑(諸如C4-C9羧酸酯抗微生物劑或抗真菌劑)及螯合劑。在一較佳之實施態樣中,該螯合劑係EDTA且該C4-C9羧酸酯抗微生物劑係正辛酸。在其他實施態樣中,該微生物生長抑制溶液包含C4-C9羧酸酯抗微生物劑及除了EDTA以外之螯合劑。較佳之組合包括C4-C9羧酸酯抗微生物劑及鈣螯合劑諸如EGTA。可與本發明組合使用之螯合劑包括但不限於EDTA、EGTA、DTPA、二巰基琥珀酸(“DMSA”)、去鐵胺、二巰基丙醇、三伸乙基四胺二鹽酸鹽、檸檬酸鋅、鉍與檸檬酸鹽之組合、青黴胺、羥乙磷酸鹽及彼等之醫藥上可接受之鹽。較佳之螯合劑包括該些與二價金屬陽離子諸如鈣、鎂、錳、鐵及鋅螯合者。 State of the sample embodiment of the present invention provides a unique and effective solution of the microbial growth inhibition (e.g. lock solution), comprising an effective amount of a carboxylate antimicrobial agent (such as C 4 -C 9 carboxylate antimicrobial or antifungal agent) And a chelating agent. In a preferred embodiment, the chelating agent is EDTA and the C 4 -C 9 carboxylate antimicrobial agent is n-octanoic acid. In other aspects of the embodiment, the microorganism growth inhibiting antimicrobial agent and the chelating agent solution comprises C 4 -C 9 carboxylic acid ester in addition to the EDTA. Preferred combinations include C 4 -C 9 carboxylate antimicrobial agents and calcium chelating agents such as EGTA. Chelating agents which may be used in combination with the present invention include, but are not limited to, EDTA, EGTA, DTPA, dimercaptosuccinic acid ("DMSA"), deferoxamine, dimercaptopropanol, tri-ethyltetramine dihydrochloride, lemon Zinc acid, a combination of hydrazine and citrate, penicillamine, hydroxyethyl phosphate and their pharmaceutically acceptable salts. Preferred chelating agents include those which are chelating with divalent metal cations such as calcium, magnesium, manganese, iron and zinc.

本發明意外發現C4-C9羧酸酯抗微生物劑與以大約2 mg/mL、1 mg/mL或更低之量存在之螯合劑組合可有效抑制導管中之微生物或真菌生長。在此處所述之任何實施態樣中,該微生物生長抑制溶液可包括螯合劑與C4-C9羧酸酯抗微生物劑之組合,其中該螯合劑之濃度係以自約0.01至約2 mg/mL之量存在於該溶液中,且該抗微生物劑之濃度係以自約0.05 mg/ml至約5 mg/ml之量存在於該溶液中。在較佳之實施態樣中,該組合包括大約0.5 mg/ml之螯合劑及大約1.15 mg/ml之C4-C9羧酸酯抗微生物劑。 The present invention unexpectedly found that C 4 -C 9 carboxylate antimicrobial agent at about 2 mg / mL, 1 mg / mL or less of the amount of chelating agent present compositions effective to inhibit microbial or fungal growth of the catheter. In any of the embodiments described herein, the microbial growth inhibiting solution can comprise a combination of a chelating agent and a C 4 -C 9 carboxylate antimicrobial agent, wherein the concentration of the chelating agent is from about 0.01 to about 2 An amount of mg/mL is present in the solution, and the concentration of the antimicrobial agent is present in the solution in an amount from about 0.05 mg/ml to about 5 mg/ml. In a preferred embodiment, the combination comprises about 0.5 mg/ml of a chelating agent and about 1.15 mg/ml of a C 4 -C 9 carboxylate antimicrobial agent.

當正辛酸係首選之抗微生物劑時,其可自正辛酸之小瓶被重構至適當濃度,然後以此處所述之方式組合以提供具有如微生物生長抑制溶液之領域中的一般技藝人士所熟知之方法所欲之正辛酸濃度之溶液。該載劑溶液(舉例來說)可包含pH調整至5.2或更低之鹽水、磷酸鹽緩衝鹽水、葡萄糖液、林格氏(Ringer’s)液或水。 When n-octanoic acid is the preferred antimicrobial agent, it can be reconstituted from a vial of n-octanoic acid to a suitable concentration and then combined in the manner described herein to provide a person of ordinary skill in the art having, for example, a microbial growth inhibiting solution. A well-known method of solution of the desired concentration of octanoic acid. The carrier solution, for example, may comprise saline, phosphate buffered saline, dextrose, Ringer's, or water adjusted to a pH of 5.2 or lower.

在一實施態樣中,該微生物生長抑制溶液包括醫藥上可接受之載劑溶液,諸如pH調整至5.2或更低之水、林格氏液或鹽水。該微生物生長抑制溶液可具有約6.0或低於6.0之作用pH,通常介於約3.5至約5.8,或最佳地介於約3.5至約5.2之pH範圍。在此酸性pH範圍之內,適當濃度之呈游離酸形式之羧酸酯化合物快速且有效地殺滅多種細菌及真菌。 In one embodiment, the microbial growth inhibiting solution comprises a pharmaceutically acceptable carrier solution, such as water adjusted to a pH of 5.2 or lower, Ringer's solution or saline. The microbial growth inhibiting solution can have an effecting pH of about 6.0 or less, typically between about 3.5 and about 5.8, or optimally between about 3.5 and about 5.2. Within this acidic pH range, a suitable concentration of the carboxylic acid ester compound in free acid form rapidly and effectively kills a variety of bacteria and fungi.

在一實施態樣中,該螯合劑提供有效之醣外被抑制活性。此外,該等組成物之C4-C9羧酸酯抗微生物劑(諸如高濃度之正辛酸)較佳地具有殺真菌效應及穿透富含多醣 之醣外被生物膜層之獨特能力。該C4-C9羧酸酯抗微生物劑與螯合劑之組合可有益地提供抗凝血劑、醣外被抑制、抗細菌及抗真菌劑以預防血栓形成、微生物附著及裝置相關性感染。正辛酸與EDTA之組合係優先適用於套組之該組合中之一例。除了EDTA以外,所欲之螯合劑包括EGTA及DTPA。 In one embodiment, the chelating agent provides effective extra-sugar inhibition activity. In addition, the C 4 -C 9 carboxylate antimicrobial agents of such compositions (such as high concentrations of n-octanoic acid) preferably have a fungicidal effect and a unique ability to penetrate the biofilm layer of the polysaccharide-rich sugar. The C 4 -C 9 carboxylic acid ester of the antimicrobial agent in combination with a chelating agent can advantageously provide anticoagulant, an outer sugar is suppressed, antibacterial and antifungal agents to prevent thrombosis, microbial adhesion and device-related infections. The combination of n-octanoic acid and EDTA is preferred for one of the combinations of the kits. In addition to EDTA, the desired chelating agents include EGTA and DTPA.

在另一實施態樣中,本發明提供在各種治療應用中使用包含螯合劑與C4-C9羧酸酯抗微生物劑之微生物生長抑制溶液之方法。其中一種治療應用係用於預防導管感染。將被用於實施該等方法之組成物實例包含正辛酸與螯合劑。EDTA係被考慮用於該等方法中之螯合劑實例,然而其他螯合劑亦被認為有用。 In another aspect of the embodiment, the present invention provides an antimicrobial agent of microbial growth inhibiting method using a solution of 4 -C 9 carboxylate chelating agent comprising C in various therapeutic applications. One of the therapeutic applications is for the prevention of catheter infections. Examples of compositions that will be used to carry out such methods include n-octanoic acid and a chelating agent. EDTA is contemplated for use as an example of a chelating agent in such methods, although other chelating agents are also considered useful.

在維持導管暢通性之用途方面,該微生物生長抑制溶液有效地與醫學裝置諸如中央靜脈導管、週邊靜脈導管、動脈導管、許旺蓋茲(Swant-Ganz)導管、血液透析導管、臍帶導管、經皮非隧道矽導管、袖口隧道中央靜脈導管以及皮下中央靜脈埠一起使用。 The microbial growth inhibiting solution is effective in conjunction with medical devices such as central venous catheters, peripheral venous catheters, arterial catheters, Swant-Ganz catheters, hemodialysis catheters, umbilical catheters, and meridians for the maintenance of catheter patency. A non-tunnel tunnel catheter, a cuff tunnel central venous catheter, and a subcutaneous central venous fistula are used together.

本發明之實施態樣亦提供經任何前述之微生物生長抑制溶液包覆之醫學裝置(諸如導管)。在一較佳之實施態樣中,該微生物生長抑制溶液包含EDTA及正辛酸。當該螯合劑不是EDTA時,在一實施例中之微生物生長抑制溶液包括EGTA與抗微生物劑諸如正辛酸之組合。可利用本發明之溶液製備及包覆之特定示範性醫學裝置係提供於上列。 Embodiments of the invention also provide a medical device (such as a catheter) coated with any of the aforementioned microbial growth inhibiting solutions. In a preferred embodiment, the microbial growth inhibiting solution comprises EDTA and n-octanoic acid. When the chelating agent is not EDTA, the microbial growth inhibiting solution in one embodiment comprises a combination of EGTA and an antimicrobial agent such as n-octanoic acid. Specific exemplary medical devices that can be prepared and coated with the solutions of the present invention are provided above.

本發明之實施態樣亦提供用於製備經此處所述之組成物包覆之醫學裝置之方法。在一實施態樣中,方法包含使該醫學裝置暴露於包括螯合劑與C4-C9羧酸酯抗微生物劑之組合之微生物生長抑制溶液足夠量之時間,以提供包覆於該裝置之經暴露之表面上。當該微生物生長抑制溶液係呈液體形式時,可允許其在該裝置表面上乾燥以形成膜。 Embodiments of the invention also provide methods for preparing a medical device coated with the compositions described herein. In one embodiment, the method comprises exposing the medical device to a microbial growth inhibiting solution comprising a combination of a chelating agent and a C 4 -C 9 carboxylate antimicrobial agent for a sufficient amount of time to provide a coating on the device On the exposed surface. When the microbial growth inhibiting solution is in a liquid form, it may be allowed to dry on the surface of the device to form a film.

在上述方法之較佳實施態樣中,該裝置首先係經界面活性劑處理,然後才使該裝置暴露於該微生物生長抑制溶液。該等界面活性劑舉例來說包括三月桂基甲基氯化銨及氯化烷基二甲基苄基銨。 In a preferred embodiment of the above method, the device is first treated with a surfactant prior to exposing the device to the microbial growth inhibiting solution. Such surfactants include, for example, trilaurylmethylammonium chloride and alkyldimethylbenzylammonium chloride.

在另一態樣中,本發明提供導管沖洗溶液。最佳地,該導管沖洗溶液包含醣外被抑制濃度之螯合劑及有效量之C4-C9羧酸酯抗微生物劑於醫藥上可接受之載劑溶液(例如pH經調整至5.2或更低之鹽水)中。 In another aspect, the invention provides a catheter irrigation solution. Most preferably, the catheter rinsing solution comprises a chelating agent at an inhibitory concentration of saccharide and an effective amount of a C 4 -C 9 carboxylic acid ester antimicrobial agent in a pharmaceutically acceptable carrier solution (eg, pH adjusted to 5.2 or greater) Low in salt water).

在該溶液之一較佳實施態樣中,該螯合劑係EGTA且該C4-C9羧酸酯抗微生物劑係正辛酸。該導管沖洗溶液之另一實施態樣包括約0.5 mg/mL之EDTA及約1.15 mg/ml之正辛酸。舉例來說,載劑溶液係pH調整至5.2或更低之鹽水、水或林格氏(Ringer’s)液。該導管沖洗溶液可有益地被用於抑制富含多醣之醣外被之形成。因此,特徵為該形成之感染可被有效消除。 In one preferred aspect the solution in the embodiment, the chelating agent EGTA and the line C 4 -C 9 carboxylic acid ester-based n-octanoic acid antimicrobial agent. Another embodiment of the catheter rinsing solution comprises about 0.5 mg/mL EDTA and about 1.15 mg/ml n-octanoic acid. For example, the carrier solution is saline, water or Ringer's solution adjusted to a pH of 5.2 or lower. The catheter irrigation solution can advantageously be used to inhibit the formation of polysaccharide-rich sugars. Therefore, the infection characterized by the formation can be effectively eliminated.

本發明之另一態樣提供製備抗生物膜醫學裝置之方法。在一實施態樣中,該方法包含使裝置暴露於此處所述之微生物生長抑制溶液。任何不同種類之導管可根據採用 該領域之一般技藝人士所熟知之包覆技術所述之方法處理或包覆。 Another aspect of the invention provides a method of making an anti-biofilm medical device. In one embodiment, the method comprises exposing the device to a microbial growth inhibiting solution as described herein. Any different type of catheter can be used It is processed or coated by methods known in the art of coating techniques well known to those skilled in the art.

雖然該方法可被用於包覆希望抑制該處之醣外被形成之幾乎任何表面,本發明特別設想使用該方法以製備抗微生物生物膜之導管裝置。舉例來說,可根據本發明之實施態樣製備及處理之導管包括中央靜脈導管及三腔導管。可預期的是,該方法將提供抗富含多醣之醣外被形成(諸如葡萄球菌之典型特徵)之裝置。 While this method can be used to coat almost any surface where it is desired to inhibit the formation of sugar outside, the present invention specifically contemplates the use of this method to prepare a catheter device for an antimicrobial biofilm. For example, catheters that can be prepared and treated in accordance with embodiments of the present invention include a central venous catheter and a three lumen catheter. It is contemplated that the method will provide a device that is resistant to the formation of polysaccharide-rich sugars, such as the typical characteristics of staphylococci.

在該所述方法之較佳態樣中,抗生物膜醫學裝置係利用螯合劑與C4-C9羧酸酯抗微生物劑之微生物生長抑制溶液製備。該溶液之實例包含正辛酸與EDTA之組合或除了EDTA以外之螯合劑與C4-C9羧酸酯抗微生物劑之組合。上述之C4-C9羧酸酯抗微生物劑與螯合劑之各種濃度範圍亦被考慮為可用於包覆醫學裝置之組成物中。 In the preferred aspect of the method, a medical device based anti-biofilm use of chelating agents with C 4 -C 9 carboxylate antimicrobial agent of microbial growth inhibition prepare a solution. Examples of the solution include a combination of n-octanoic acid and EDTA or a combination of a chelating agent other than EDTA and a C 4 -C 9 carboxylate antimicrobial agent. The above-mentioned C 4 -C 9 carboxylate antimicrobial agent concentration ranges with various chelating agents were also considered to be of a composition for the coating of a medical device.

在一態樣中,該方法包含於生物相容性附著包覆載劑溶液中製備該所欲組合之微生物生長抑制溶液。接著使受到關注之醫學裝置之表面暴露於該微生物生長抑制溶液一段足夠時間以允許該溶液在該裝置之表面上形成膜或包覆。此可藉由例如使該裝置浸泡於該溶液中完成。最佳地,將被包覆之裝置係導管。該處理提供抗生物膜之導管。 In one aspect, the method comprises preparing the desired microbial growth inhibiting solution in a biocompatible attachment coating vehicle solution. The surface of the medical device of interest is then exposed to the microbial growth inhibiting solution for a period of time sufficient to allow the solution to form a film or coating on the surface of the device. This can be accomplished, for example, by immersing the device in the solution. Most preferably, the device to be coated is a catheter. This treatment provides a catheter that is resistant to biofilm.

本發明之實施態樣亦提供抑制導管埠形成富含糖蛋白之醣外被之方法。在一實施態樣中之方法包含定期用微生物生長抑制溶液沖洗導管,該溶液包含醣外被抑制濃度之 螯合劑及C4-C9羧酸酯抗微生物劑於醫藥上可接受之載劑溶液。 Embodiments of the present invention also provide methods of inhibiting the formation of a glycoprotein-rich sugar coating by a catheter. In one embodiment of the method aspect of the microbial growth inhibition comprises periodically rinsing solution duct, the solution comprises an outer sugar-inhibitory concentration of chelating agent, and C 4 -C 9 carboxylate antimicrobial agent in a pharmaceutically acceptable carrier solution .

該所述方法可被用於抑制幾乎任何隧道或非隧道導管之感染。以導管維持配方之部分而言,該導管最佳地係經包含C4-C9羧酸酯抗微生物劑及螯合劑於醫藥上可接受之載劑溶液中之組成物沖洗。該所述之配方係重複一周一次、每4天一次、每2天一次、每天一次(約每24小時)、每天二次、每4小時或根據病患需求視需要重複。 The method can be used to inhibit infection by almost any tunnel or non-tunnel catheter. In terms of maintaining catheter portion of the formulation, the best lines through the conduit comprising C 4 -C 9 carboxylate antimicrobial agent, a chelating agent in a pharmaceutically acceptable carrier solution of the composition flushing. The formulation is repeated once a week, once every 4 days, once every 2 days, once a day (about every 24 hours), twice a day, every 4 hours or as needed according to the needs of the patient.

在又一態樣中,本發明之實施態樣提供用於消除微生物醣外被形成之方法,特別是導管腔中富含多醣(葡萄球菌)之醣外被形成。該方法在一實施態樣中包含製備微生物生長抑制溶液以提供沖洗組成物,及用有效抑制微生物生長之該沖洗組成物之量沖洗該導管,該微生物生長抑制溶液包含螯合劑(例如EDTA、EGTA或二者)與C4-C9羧酸酯抗微生物劑(例如正丁酸、正戊酸、正己酸、正庚酸、正辛酸或正壬酸及/或彼等之醫藥上可接受之鹽)之組合於載劑溶液。 In yet another aspect, embodiments of the present invention provide methods for eliminating the formation of microbial sugars, particularly sugar-rich (staphylococcus)-rich sugars in the lumen of the catheter. In one embodiment, the method comprises preparing a microbial growth inhibiting solution to provide a rinse composition, and rinsing the catheter with an amount of the rinse composition effective to inhibit microbial growth, the microbial growth inhibiting solution comprising a chelating agent (eg, EDTA, EGTA) Or both) and a C 4 -C 9 carboxylate antimicrobial agent (eg, n-butyric acid, n-pentanoic acid, n-hexanoic acid, n-heptanoic acid, n-octanoic acid or n-decanoic acid and/or their pharmaceutically acceptable The salt is combined with the carrier solution.

最佳地,該導管將利用大約3 mL體積之該所述正丁酸及EDTA溶液沖洗,該溶液包含大約0.5 mg/mL之EDTA及大約1.15 mg/ml之正丁酸。該導管可利用大約2至3 mL之該正丁酸及EDTA溶液定期沖洗,例如每周一次、每4天一次、每2天一次、每天一次、每天二次、每4小時一次或視病患需要時沖洗。該導管沖洗配方可於每次要使用或更換該導管時再沖洗一次。在該方法之較佳態 樣中,該導管係利用此處所述之溶液每4小時沖洗一次。 Most preferably, the catheter will be rinsed with about 3 mL of the volume of the n-butyric acid and EDTA solution containing about 0.5 mg/mL EDTA and about 1.15 mg/ml n-butyric acid. The catheter can be flushed periodically with about 2 to 3 mL of the n-butyric acid and EDTA solution, such as once a week, once every 4 days, once every 2 days, once a day, twice a day, every 4 hours, or depending on the patient. Rinse as needed. The catheter rinse formulation can be rinsed again each time the catheter is to be used or replaced. In the preferred state of the method In this case, the catheter was rinsed every 4 hours using the solution described herein.

此處所述之組成物較佳地在儲存於冷藏溫度之後仍維持作為導管沖洗劑之治療有效性。然而,在使用於動物或病患之前應使該正辛酸及EDTA溶液回復至室溫。 The compositions described herein preferably maintain therapeutic effectiveness as a catheter irrigant after storage at refrigerated temperatures. However, the n-octanoic acid and EDTA solution should be returned to room temperature before use in animals or patients.

本發明之其他態樣提供套組。在一實施態樣中,該套組包含盛裝一體積之該前述溶液之一者之容器(諸如針筒)及接受該溶液之植入式導管管腔,該前述溶液之一者包含C4-C9羧酸酯抗微生物劑及螯合劑。該套組可另包含盛裝該容器之包裝,像是盒、盤、管、套、袋或該類似物。在該容器中之溶液體積通常介於1 mL至20 mL,較佳地自2 mL至10 mL,通常大約2 mL至4 mL。可任意選擇地,該容器通常包含針筒,或能直接將該溶液導入該留置導管之裝置。 Other aspects of the invention provide kits. In one embodiment, the kit comprises a container (such as a syringe) containing one volume of the solution, and an implantable catheter lumen receiving the solution, one of the solutions comprising C 4 - C 9 carboxylate antimicrobial agent and chelating agent. The kit may additionally comprise a package containing the container, such as a box, tray, tube, sleeve, bag or the like. The volume of the solution in the vessel is typically between 1 mL and 20 mL, preferably from 2 mL to 10 mL, typically from about 2 mL to 4 mL. Optionally, the container typically comprises a syringe or means for direct introduction of the solution into the indwelling catheter.

在另一實施態樣中,該套組包含容器(諸如分區針筒),該容器包含多個區室。舉例來說,該容器可具有三個區室,其中一個區室包含C4-C9羧酸酯抗微生物劑像是正辛酸,該第二區室包含螯合劑像是EDTA,且該第三區室包含稀釋劑像是pH調整至5.2或更低之鹽水、林格氏液或水。包括經調整以接受至少二個區室之載具之套組構成該套組之又一實施態樣。在這些實施態樣中,該螯合劑將與該C4-C9羧酸酯抗微生物劑一起被包括於該容器之一區室內。該第二區室將包含稀釋劑,諸如該些於上描述者。在一實施態樣中,該螯合劑及抗微生物劑一起以乾燥粉末形式被包括於該裝置之第一區室。該乾燥成份將較佳 地與該第二區室之稀釋劑組合以提供適合使用之溶液。 In another embodiment, the kit includes a container (such as a zoned syringe) that contains a plurality of compartments. For example, the container can have three compartments, one of which contains a C 4 -C 9 carboxylate antimicrobial agent like n-octanoic acid, the second compartment contains a chelating agent like EDTA, and the third zone The chamber contains a diluent such as saline, Ringer's solution or water adjusted to a pH of 5.2 or lower. A kit comprising a carrier that is adapted to accept at least two compartments constitutes another embodiment of the kit. In these embodiments, the chelating agent will be included in a compartment of the container together with the C 4 -C 9 carboxylate antimicrobial agent. The second compartment will contain a diluent, such as those described above. In one embodiment, the chelating agent and antimicrobial agent are included together in a dry powder form in the first compartment of the device. The dry ingredients will preferably be combined with the diluent of the second compartment to provide a solution suitable for use.

在這些不同的實施態樣中,該套組較佳地包括螯合劑。在特定實施態樣中,該螯合劑係EDTA且該C4-C9羧酸酯抗微生物劑係舉例來說正辛酸。 In these various embodiments, the kit preferably includes a chelating agent. In a particular aspect of the embodiment, the chelating agent EDTA and the line C 4 -C 9 carboxylic acid ester-based anti-microbial agent for example, n-octanoic acid.

在本發明之另一態樣中,本發明提供消毒經植入之導管之方法,該方法包括導入包含C4-C9羧酸酯抗微生物劑及螯合劑於醫藥上可接受之載劑溶液之溶液至導管管腔,其中該導管之至少一部分係具有足夠孔洞性以允許該溶液自管腔向外擴散至該導管之外部表面且進入該導管周圍之組織或血流以抑制感染。該經植入之導管可為皮下或經皮留置導管。 In another aspect of the present invention, the present invention provides a method of disinfecting a catheter implanted, the method comprising introducing the C 4 -C 9 comprising a carboxylate antimicrobial agent and a chelating agent in a pharmaceutically acceptable carrier solution The solution is to the catheter lumen, wherein at least a portion of the catheter is sufficiently porous to allow the solution to diffuse outwardly from the lumen to the exterior surface of the catheter and into the tissue or blood flow surrounding the catheter to inhibit infection. The implanted catheter can be a subcutaneous or percutaneous indwelling catheter.

抑制或預防該經植入之導管之感染的能力可被增進,藉由使用其中至少一部分之導管本體係具有足夠孔洞性以允許該抗微生物鎖定溶液穿透該導管本體且較佳地向外通過(即滲透、滲出、滲漏、擴散)至該導管周圍之組織區域的導管。雖然使用該等多孔性或部分多孔性導管體可受益於許多抗微生物鎖定溶液,像是該些於美國專利第4,186,745、4,767,400、4,968,306、5,077,281、5,913,856、6,949,087及7,004,923號及美國專利公開號2006/0074388及2006/0253101所揭示者,其特別受益於本發明之酸。將了解的是,C4-C9羧酸酯抗微生物劑具有使彼等能輕易穿透經過許多多孔性材料之分子量及其他性質。用於建構該導管本體之示範性多孔性材料包括矽膠、膨脹PTFE(例如GORE-TEX®、醫學膜)、TEFLON® 膜、天然、再生或半合成之纖維素材料諸如醋酸纖維素、二醋酸纖維素、銅銨薄膜及該類似物。該等材料可被製成管狀導管本體或作為分開之成份被納入該導管本體。 The ability to inhibit or prevent infection of the implanted catheter can be enhanced by using at least a portion of the catheter system having sufficient porosity to allow the antimicrobial locking solution to penetrate the catheter body and preferably pass outwardly (ie, seeping, seeping, leaking, spreading) a conduit to the tissue area surrounding the catheter. Although the use of such porous or partially porous conduit bodies can benefit from a number of antimicrobial locking solutions, such as those in U.S. Patent Nos. 4,186,745, 4,767,400, 4,968,306, 5,077,281, 5,913,856, 6,949,087, and 7,004,923, and U.S. Patent Publication No. 2006/ The one disclosed in 0074388 and 2006/0253101, which particularly benefits from the acid of the present invention. It will be appreciated that, C 4 -C 9 carboxylate their antimicrobial agent has a molecular weight can easily penetrate through many porous materials, and other properties. Exemplary Construction of a porous material of the catheter body comprising silicone, expanded PTFE (e.g. GORE-TEX ®, medical membranes), TEFLON ® films, natural, semisynthetic or regeneration of cellulosic material such as cellulose acetate, cellulose diacetate, , copper ammonium film and the like. The materials can be formed into a tubular catheter body or incorporated into the catheter body as separate components.

此處描述之微生物生長抑制溶液被預期可有效預防金黃葡萄球菌、表皮葡萄球菌及真菌黏附及定殖於導管表面,且能同時有效地治療及消除該等感染性有機體已經形成之醣外被形成。 The microbial growth inhibiting solution described herein is expected to be effective in preventing adhesion and colonization of Staphylococcus aureus, Staphylococcus epidermidis and fungi to the surface of the catheter, and at the same time effectively treating and eliminating the formation of sugar formed by the infectious organism. .

可考慮在只要適當時,本發明之任何實施態樣可與本發明之一或多個其他實施態樣組合,即使該等實施態樣係於本發明之不同態樣或實施態樣下描述。其他特徵及優點係說明於此,且將可自以下之詳細說明及圖式中顯見。 It is contemplated that any embodiment of the invention may be combined with one or more other embodiments of the invention, as appropriate, even if the embodiments are described in various aspects or embodiments of the invention. Other features and advantages will be apparent from the following detailed description and drawings.

〔本發明之詳細說明〕 [Detailed Description of the Invention]

本發明之一或多個實施態樣之細節係於以下隨附之說明中闡述。雖然任何與此處所描述之方法及材料類似或相等者均可被用於實施或測試本發明,該等方法及材料係於此描述。本發明之其他特徵、目的及優點將可自詳細說明中顯見。在本說明書中,單數形式亦包括多數形式,除非上下文中另外清楚地指示。除非另行定義,此處所使用之所有技術及科學用語具有本發明所屬領域之一般技藝人士所通常瞭解之相同意義。若有不同意義,以本說明書為主。 The details of one or more embodiments of the invention are set forth in the accompanying description below. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the methods and materials are described herein. Other features, objects, and advantages of the invention will be apparent from the description. In the present specification, the singular forms also include the plural forms unless the context clearly indicates otherwise. All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, unless otherwise defined. If there are different meanings, this manual is the main one.

定義 definition

以下用語具有下列意義除非另行說明。 The following terms have the following meanings unless otherwise stated.

此處所使用之用語「生物膜」係指富含多醣之醣外被,其通常伴隨微生物表面定殖。 The term "biofilm" as used herein refers to a polysaccharide-rich sugar rins, which is usually associated with microbial surface colonization.

此處所使用之「抗生物膜」裝置或表面係指一種將防止該產生富含多醣之醣外被材料之有機體黏附或生長之表面或裝置。該等有機體包括但不限於金黃葡萄球菌及表皮葡萄球菌。 As used herein, an "anti-biofilm" device or surface refers to a surface or device that will prevent the organism that produces the polysaccharide-rich sugar coating material from adhering or growing. Such organisms include, but are not limited to, Staphylococcus aureus and Staphylococcus epidermidis.

此處所使用之用語「醣外被抑制濃度」係指有效降解、溶解或以其他方式抑制富含多醣之醣外被之濃度。舉例來說,該富含多醣之醣外被係金黃葡萄球菌及表皮葡萄球菌之已建立之葡萄球菌感染之特徵。 As used herein, the term "exosaccharide inhibited concentration" refers to a concentration that effectively degrades, dissolves, or otherwise inhibits the polysaccharide-rich sugar. For example, the polysaccharide-rich sugar is characterized by an established staphylococcal infection of Staphylococcus aureus and Staphylococcus epidermidis.

此處所使用之用語「經植入」、「真皮下」、「皮下」及「留置」係用於同義地表示放置醫學裝置(例如導管)。該等經植入之導管通常將具有至少部分開放於身體體腔之末端。最常見地,該等導管將為靜脈導管,其中該末端係經植入或連接於血管--通常為靜脈,但有時為動脈。示範性血管內導管包括血液透析及血液過濾導管以及靜脈導管。靜脈導管可被用於廣泛目的,包括流體輸注及藥物遞送。連接於血管以外之導管包括開放於腹腔之腹膜透析導管,及開放於膀胱之導尿管。 The terms "implanted", "subdermal", "subcutaneous" and "retained" are used synonymously to mean the placement of a medical device (eg, a catheter). The implanted catheter will typically have an end that is at least partially open to the body cavity. Most commonly, the catheters will be venous catheters, wherein the ends are implanted or attached to blood vessels - usually veins, but sometimes arteries. Exemplary intravascular catheters include hemodialysis and blood filtration catheters as well as intravenous catheters. Intravenous catheters can be used for a wide range of purposes, including fluid infusion and drug delivery. Catheters connected to the blood vessels include a peritoneal dialysis catheter that is open to the abdominal cavity, and a catheter that is open to the bladder.

該等於此處描述之醫學裝置(諸如導管)可為經皮植入或皮下植入。所謂「經皮植入」係指該導管之末端係連接或植入於目標身體體腔,且該導管之近端係位於該病患體外。該導管之中間部分因此將通過或穿過該病患之皮膚, 且該導管之近側端通常將具有接頭,以允許輸注管、針頭、溶液袋及該類似物之選擇性連接。最常見地,該近側連接接頭將具有luer接頭。所謂「皮下植入」係指該整個導管被埋入皮膚層以下,沒有穿過皮膚層之導管部分。該等皮下植入之導管通常在彼等之近端與完全植入之接頭連接。該接頭允許經由針頭或其他穿刺元件經皮接觸。 The medical device (such as a catheter) equivalent to that described herein can be percutaneously implanted or subcutaneously implanted. By "percutaneously implanted" is meant that the end of the catheter is attached or implanted in a body cavity of a target, and the proximal end of the catheter is external to the patient. The middle portion of the catheter will therefore pass or pass through the skin of the patient, And the proximal end of the catheter will typically have a connector to allow selective attachment of the infusion tube, needle, solution bag, and the like. Most commonly, the proximal connector will have a luer connector. By "subcutaneous implantation" is meant that the entire catheter is buried below the skin layer without the portion of the catheter that passes through the skin layer. These subcutaneously implanted catheters are typically connected at their proximal ends to fully implanted joints. The joint allows for transdermal contact via a needle or other piercing element.

本發明之實施態樣提供C4-C9羧酸酯抗微生物劑與螯合劑之組合的微生物生長抑制溶液。該等微生物生長抑制溶液被預期可特別有用地預防該「生物膜」或富含多醣之醣外被之形成,其通常伴隨微生物表面定殖。特別是,該微生物生長抑制溶液被預期可最有效地分解葡萄球菌醣外被及抑制彼之形成。此特色使得本發明之微生物生長抑制溶液特別可用於治療其中富含多醣之醣外被已經形成或可能形成之葡萄球菌感染,亦可用於預防及治療葡萄球菌屬及假絲酵母屬之感染。 Embodiments of the present invention provide a microbial growth inhibiting solution in combination with a C 4 -C 9 carboxylate antimicrobial agent and a chelating agent. Such microbial growth inhibiting solutions are expected to be particularly useful in preventing the formation of the "biofilm" or polysaccharide-rich sugar, which is usually accompanied by microbial surface colonization. In particular, the microbial growth inhibiting solution is expected to most efficiently decompose staphylococcal sugar excipients and inhibit the formation of them. This feature makes the microbial growth inhibiting solution of the present invention particularly useful for treating staphylococcal infections in which polysaccharide-rich sugars have been formed or may be formed, and also for preventing and treating infections of Staphylococcus and Candida.

本發明之實施態樣亦提供預防葡萄球菌或真菌定殖之經處理或包覆之醫學裝置(諸如導管)。提供於該等裝置上之包覆或膜包含C4-C9羧酸酯抗微生物劑(諸如正辛酸)及螯合劑。該等微生物生長抑制溶液之特別較佳之成分組合包括正辛酸及EDTA。其他較佳之組合包含醣外被抑制濃度或量之C4-C9羧酸酯抗微生物劑及除了EDTA以外之螯合劑。包覆該等劑之組合的裝置亦被認為有用。 Embodiments of the invention also provide a treated or coated medical device (such as a catheter) that prevents staphylococcal or fungal colonization. The coating or film provided on such devices comprises a C 4 -C 9 carboxylate antimicrobial agent (such as n-octanoic acid) and a chelating agent. A particularly preferred combination of ingredients for such microbial growth inhibiting solutions includes n-octanoic acid and EDTA. Other preferred combinations comprise a C 4 -C 9 carboxylate antimicrobial agent in an inhibitory concentration or amount of extrasaccharide and a chelating agent other than EDTA. Devices that coat combinations of such agents are also considered useful.

抗微生物劑 Antimicrobial agent

使用於此處所述之任何微生物生長抑制溶液及方法中之C4-C9羧酸酯抗微生物劑可包括非芳香性水溶性C4-C9烷基、烯基或炔基有機酸或彼等之混合物,或任何彼等之水溶性醫藥上可接受之鹽。該等鹽包括例如鈉鹽、鉀鹽及銨鹽。鈉鹽及鉀鹽係較佳。 The C 4 -C 9 carboxylate antimicrobial agent used in any of the microbial growth inhibiting solutions and methods described herein may comprise a non-aromatic water-soluble C 4 -C 9 alkyl, alkenyl or alkynyl organic acid or A mixture of them, or any of their water-soluble pharmaceutically acceptable salts. Such salts include, for example, sodium, potassium and ammonium salts. Sodium salts and potassium salts are preferred.

雖然不同的羧酸酯化合物展現不同程度之抗微生物活性(每莫耳),具有式R-COOH(其中R=C3-C8正烷基)之水溶性劑及彼等之醫藥上可接受之鹽或彼等之組合展現優異之抗微生物活性。正己酸及正辛酸及彼等之醫藥上可接受之水溶性鹽係較佳,其中以正辛酸更為優異。該等物質在彼等之游離酸形式時在酸性pH範圍中以低溶液濃度快速殺滅實質上所有重要革蘭氏陽性、革蘭氏陰性病原體及假絲酵母屬。 Although different carboxylate compounds exhibit varying degrees of antimicrobial activity (per mole), water soluble agents having the formula R-COOH (wherein R = C 3 -C 8 n-alkyl) and their pharmaceutically acceptable The salts or combinations thereof exhibit excellent antimicrobial activity. It is preferred that n-hexanoic acid and n-octanoic acid and their pharmaceutically acceptable water-soluble salts are more excellent in n-octanoic acid. These materials rapidly kill virtually all important Gram-positive, Gram-negative pathogens and Candida in a low pH concentration in the acidic pH range in their free acid form.

該C4-C9羧酸酯抗微生物劑之殺微生物活性係直接與溶液中存在彼等之個別游離酸相關。溶液中之游離羧酸濃度與羧酸酯鹽(陰離子)形式不同,其隨著該溶液pH變化。可使用羧酸鹽,只要該溶液pH允許游離酸以最小致死濃度(“MLC”)存在。因此,所使用之酸或酸鹽之量在某種程度上將隨該使用pH而異。將於給定pH提供MLC之給定酸鹽或酸之量將視該酸之pKa而定。當然,知道該特定酸之pKa及MLC和該使用pH,即可自下式輕易計算出應使用之任何C4-C9酸或酸鹽之量:pKa=pH+log([HCx]/[Cx-]) The microbicidal activity of the C 4 -C 9 carboxylate antimicrobial agent is directly related to the presence of individual free acids in the solution. The free carboxylic acid concentration in the solution is different from the carboxylate salt (anion) form, which varies with the pH of the solution. Carboxylates can be used as long as the pH of the solution allows the free acid to be present at a minimum lethal concentration ("MLC"). Thus, the amount of acid or acid salt used will vary to some extent with the pH of the use. The amount of a given acid salt or acid that will provide MLC at a given pH will depend on the pK a of the acid. Of course, knowing the pK a and MLC of the particular acid and the pH of use, the amount of any C 4 -C 9 acid or acid salt that should be used can be easily calculated from: pK a =pH+log([HC x ]/[C x- ])

其中[HCx]係鏈長x之游離酸之濃度且[Cx-]係彼之陰 離子之濃度。 Wherein [HC x ] is the concentration of the free acid of the chain length x and [C x- ] is the concentration of the anion.

在一實施態樣中,該抗微生物劑係以介於該微生物生長抑制溶液中約0.05 mg/ml至約5 mg/ml之量存在。更特別地,該抗微生物劑之量可為約0.05 mg/mL、0.1 mg/mL、0.25 mg/mL、0.5 mg/mL、0.75 mg/mL、1 mg/mL、1.25 mg/mL、1.5 mg/mL、1.25 mg/mL、2 mg/mL、2.25 mg/mL、2.5 mg/mL、2.75 mg/mL、3 mg/mL、3.25 mg/mL、3.5 mg/mL、3.75 mg/mL、4 mg/mL、4.25 mg/mL、4.5 mg/mL、4.75 mg/mL、5 mg/mL及該類似量。應了解的是,此處列舉之抗微生物劑之任兩個量可另外代表該抗微生物劑之治療性較佳範圍之終點。舉例來說,0.5 mg/mL及1.5 mg/mL之量可代表該抗微生物劑之個別量及該抗微生物劑於溶液中自約0.5 mg/mL至約1.5 mg/mL之較佳範圍。 In one embodiment, the antimicrobial agent is present in an amount from about 0.05 mg/ml to about 5 mg/ml in the microbial growth inhibiting solution. More particularly, the amount of the antimicrobial agent can be about 0.05 mg/mL, 0.1 mg/mL, 0.25 mg/mL, 0.5 mg/mL, 0.75 mg/mL, 1 mg/mL, 1.25 mg/mL, 1.5 mg. /mL, 1.25 mg/mL, 2 mg/mL, 2.25 mg/mL, 2.5 mg/mL, 2.75 mg/mL, 3 mg/mL, 3.25 mg/mL, 3.5 mg/mL, 3.75 mg/mL, 4 mg /mL, 4.25 mg/mL, 4.5 mg/mL, 4.75 mg/mL, 5 mg/mL and the like. It will be appreciated that any two amounts of the antimicrobial agents listed herein may additionally represent the end of the therapeutically preferred range of the antimicrobial agent. For example, an amount of 0.5 mg/mL and 1.5 mg/mL may represent an individual amount of the antimicrobial agent and a preferred range of the antimicrobial agent from about 0.5 mg/mL to about 1.5 mg/mL in solution.

螯合劑及緩衝液 Chelating agent and buffer

除了C4-C9羧酸酯抗微生物劑以外,此處所述之微生物生長抑制溶液及方法亦包括一或多種螯合劑。此處所述之任何微生物生長抑制溶液及方法亦可包括一或多種適當緩衝液。可被用於本發明之各種實施態樣之適當螯合劑及緩衝液之非限制性實例可分別選自表1及2。表1所列之任何螯合劑之醫藥上可接受之鹽類(例如乙二胺四乙酸鈣二鈉鹽)亦可被使用。 In addition to the C 4 -C 9 carboxylate antimicrobial agent, the microbial growth inhibiting solutions and methods described herein also include one or more chelating agents. Any of the microbial growth inhibiting solutions and methods described herein may also include one or more suitable buffers. Non-limiting examples of suitable chelating agents and buffers that can be used in various embodiments of the invention can be selected from Tables 1 and 2, respectively. Pharmaceutically acceptable salts of any of the chelating agents listed in Table 1, such as calcium disodium ethylenediaminetetraacetate, may also be employed.

在某些較佳之實施態樣中,該C4-C9羧酸酯抗微生物劑係與EDTA組合。可用之EDTA包括乙二胺四乙酸二鈉鈣及乙二胺四乙酸鈉調製劑。較佳之形式係EDTA鈉。 In certain preferred embodiments, the C 4 -C 9 carboxylate antimicrobial agent is combined with EDTA. Useful EDTAs include calcium disodium edetate and sodium edetate modulators. A preferred form is sodium EDTA.

在選擇性實施態樣中,該C4-C9羧酸酯抗微生物劑係與除EDTA以外之螯合劑組合。由於投予過多鎖定溶液或投予該鎖定溶液過快將產生鈣錯合而導致可能造成心室性心律不整及猝死之低鈣血症,使用高濃度之該螯合劑將非為所欲。 In an alternative embodiment, the C 4 -C 9 carboxylate antimicrobial agent is combined with a chelating agent other than EDTA. The use of high concentrations of the chelating agent will be undesirable because administration of too much locking solution or administration of the locking solution will result in calcium mismatch resulting in hypocalcemia that may cause ventricular arrhythmia and sudden death.

該領域之技藝人士將了解前述表列僅用來作為示例之 用。其他螯合劑及緩衝劑亦被預期可有效地與C4-C9羧酸酯抗微生物劑組合使用。該等經調製為包覆劑之組合將較佳地另外包括像是陽離子界面活性劑之物質(例如三十二烷基甲基氯化銨或氯化烷基二甲基苄基銨),該物質將促進該溶液之附著或膜形成特性。作為沖洗液或其他醫學用途之溶液時,該等成分將被懸浮於pH調整至5.2或更低之載劑溶液中,像是無菌鹽水、磷酸鹽緩衝鹽水、葡萄糖液、林格氏液、蒸餾水或任何其他生理上可接受之溶液。 Those skilled in the art will appreciate that the foregoing list is for illustrative purposes only. Other chelating agents and buffers were also expected to be effective in the C 4 -C 9 carboxylate antimicrobials used in combination. The combination prepared as a coating agent will preferably additionally comprise a substance such as a cationic surfactant (for example, tridodecylmethylammonium chloride or alkyldimethylbenzylammonium chloride), The substance will promote the attachment or film forming properties of the solution. As a rinse solution or other medical use solution, the ingredients will be suspended in a carrier solution adjusted to pH 5.2 or lower, such as sterile saline, phosphate buffered saline, glucose solution, Ringer's solution, distilled water. Or any other physiologically acceptable solution.

在一實施態樣中,該螯合劑係以介於該微生物生長抑制溶液中約0.01 mg/mL至約2 mg/mL之量存在。更特別地,該螯合劑之量可為約0.01 mg/mL、0.05 mg/mL、0.1 mg/mL、0.15 mg/mL、0.2 mg/mL、0.25 mg/mL、0.3 mg/mL、0.35 mg/mL、0.4 mg/mL、0.45 mg/mL、0.5 mg/mL、0.55 mg/mL、0.6 mg/mL、0.65 mg/mL、0.7 mg/mL、0.75 mg/mL、0.8 mg/mL、0.85 mg/mL、0.9 mg/mL、0.95 mg/mL、1 mg/mL、1.05 mg/mL、1.1 mg/mL、1.15 mg/mL、1.2 mg/mL、1.25 mg/mL、1.3 mg/mL、1.35 mg/mL、1.4 mg/mL、1.45 mg/mL、1.5 mg/mL、1.55 mg/mL、1.6 mg/mL、1.65 mg/mL、1.7 mg/mL、1.75 mg/mL、1.8 mg/mL、1.85 mg/mL、1.9 mg/mL、1.95 mg/mL、2 mg/mL及該類似量。應了解的是,此處列舉之螯合劑之任兩個量可另外代表該螯合劑之治療性較佳範圍之終點。舉例來說,0.2 mg/mL及0.5 mg/mL之量可代表該螯合劑之個別量及該螯合劑於溶液中 自約0.2 mg/mL至約0.5 mg/mL之較佳範圍。 In one embodiment, the chelating agent is present in an amount from about 0.01 mg/mL to about 2 mg/mL in the microbial growth inhibiting solution. More particularly, the amount of the chelating agent can be about 0.01 mg/mL, 0.05 mg/mL, 0.1 mg/mL, 0.15 mg/mL, 0.2 mg/mL, 0.25 mg/mL, 0.3 mg/mL, 0.35 mg/ mL, 0.4 mg/mL, 0.45 mg/mL, 0.5 mg/mL, 0.55 mg/mL, 0.6 mg/mL, 0.65 mg/mL, 0.7 mg/mL, 0.75 mg/mL, 0.8 mg/mL, 0.85 mg/ mL, 0.9 mg/mL, 0.95 mg/mL, 1 mg/mL, 1.05 mg/mL, 1.1 mg/mL, 1.15 mg/mL, 1.2 mg/mL, 1.25 mg/mL, 1.3 mg/mL, 1.35 mg/ mL, 1.4 mg/mL, 1.45 mg/mL, 1.5 mg/mL, 1.55 mg/mL, 1.6 mg/mL, 1.65 mg/mL, 1.7 mg/mL, 1.75 mg/mL, 1.8 mg/mL, 1.85 mg/ mL, 1.9 mg/mL, 1.95 mg/mL, 2 mg/mL and the like. It will be appreciated that any two amounts of the chelating agents recited herein may additionally represent the end of the therapeutically preferred range of the chelating agent. For example, an amount of 0.2 mg/mL and 0.5 mg/mL may represent an individual amount of the chelating agent and the chelating agent is in solution A preferred range is from about 0.2 mg/mL to about 0.5 mg/mL.

沖洗、鎖定及消毒導管之方法 Method of rinsing, locking and disinfecting a catheter

參照圖1A及1B,現在將說明用於鎖定經植入之靜脈導管10之本發明之實施態樣之方法。該靜脈導管10將經由病患之皮膚S被植入至靜脈V以用於該病患之輸液。當欲使該病患與該輸液源斷開連接時,必須將該導管鎖定以抑制凝血造成之堵塞及血垢,且較佳地進一步抑制或消除感染之風險。如圖1A所示,包含IV溶液之管12正常將與該導管10之近端接頭14連接。該IV管線12將被斷開,並以沖洗溶液沖洗該導管10。在沖洗完成後,C4-C9羧酸酯抗微生物劑與螯合劑之鎖定溶液被導入以充滿該導管10之內腔,如圖1B所示。通常,足夠體積之鎖定溶液將被導入以完全充滿該經植入之導管10之腔,僅極少之多餘溶液自該導管之末端16流出。然而,損失多餘溶液至血管或大部份之其他體腔通常不會有問題。該溶液之「柱」接著將佔據內腔,該近端接頭將被封閉,以幫助保留該溶液於原地。C4-C9羧酸酯抗微生物劑與螯合劑之鎖定溶液將有效地抑制該末端16處之凝結凝血,同時抑制或消除該導管各處之感染。當欲重新連接該病患至該IV源時,該溶液將被移除並沖洗該導管腔。 Referring to Figures 1A and 1B, a method of locking an embodiment of the present invention for implanting an intravenous catheter 10 will now be described. The venous catheter 10 will be implanted into the vein V via the patient's skin S for infusion of the patient. When the patient is to be disconnected from the infusion source, the catheter must be locked to inhibit clogging caused by blood clotting and blood staining, and preferably further inhibit or eliminate the risk of infection. As shown in FIG. 1A, the tube 12 containing the IV solution will normally be coupled to the proximal end fitting 14 of the catheter 10. The IV line 12 will be disconnected and the catheter 10 flushed with a rinsing solution. After the rinsing is completed, a locking solution of the C 4 -C 9 carboxylate antimicrobial agent and the chelating agent is introduced to fill the lumen of the catheter 10 as shown in FIG. 1B. Typically, a sufficient volume of locking solution will be introduced to completely fill the lumen of the implanted catheter 10 with very little excess solution flowing from the end 16 of the catheter. However, losing excess solution to a blood vessel or most other body cavity is usually not a problem. The "column" of the solution will then occupy the lumen, which will be closed to help retain the solution in place. C 4 -C 9 carboxylate antimicrobial agent is a chelating agent of the lock solution will effectively inhibit clotting of the blood coagulation end 16, while suppressing or eliminating the infection throughout the catheter. When the patient is to be reattached to the IV source, the solution will be removed and the catheter lumen rinsed.

現在參照圖2A至2C,將說明沖洗及鎖定用於血液透析通路之經皮下植入之導管20。該導管20係經植入於標的血管BV(通常是靜脈)與植入埠22之間。在血液透析 期間,血液被抽取通過導管20、埠22及在體外通過用於經皮接觸該埠22之針頭N及連接管線23(圖2A)。選擇性地,該埠及導管可被用於返回該經處理之血液至該病患。 Referring now to Figures 2A through 2C, a catheter 20 for rinsing and locking a subcutaneous implant for a hemodialysis access will be described. The catheter 20 is implanted between the target blood vessel BV (usually a vein) and the implant fistula 22. Hemodialysis During this time, blood is drawn through the catheter 20, the fistula 22, and externally through the needle N for the percutaneous contact with the fistula 22 and the connecting line 23 (Fig. 2A). Optionally, the fistula and catheter can be used to return the treated blood to the patient.

當欲停止血液透析(或血液過濾)治療時,C4-C9羧酸酯抗微生物劑與螯合劑之沖洗溶液(「FS」)將經由該針頭N(通常自與該連接管線23相連之針筒)導入以沖洗管腔,如圖2B所示。在沖洗完成後,鎖定溶液係自容器諸如針筒26注入該管線23/埠22並進入導管20之管腔以取代該沖洗溶液及鎖定該導管(圖2C)。該鎖定溶液將維持鎖定於該導管20內。選擇性或額外地,該鎖定溶液可為C4-C9羧酸酯抗微生物劑與螯合劑之溶液。 To stop when hemodialysis (or hemofiltration) treatment time, C 4 -C 9 carboxylate antimicrobial agent is a chelating agent with the rinse solution ( "FS") through which the needle N (typically from the connecting line 23 is connected to the The syringe is introduced to flush the lumen as shown in Figure 2B. After the flushing is complete, the locking solution is injected from the container, such as syringe 26, into the line 23/埠22 and into the lumen of the catheter 20 to replace the irrigation solution and lock the catheter (Fig. 2C). The locking solution will remain locked within the catheter 20. Selectively or additionally, the antimicrobial solution may lock the solution of the chelating agent is a C 4 -C 9 carboxylic acid ester.

本發明之方法亦可被用於沖洗及鎖定非血管導管,像是腹膜透析導管30,如圖3A至3C所示。在腹膜透析治療之後,該用過之透析液係自該導管30抽出,如圖3A所示。在移除足量之透析液後,該透析導管30係以C4-C9羧酸酯抗微生物劑與螯合劑之沖洗溶液FS沖洗,如圖3B所示。在沖洗後,鎖定溶液被導入該腹膜透析導管30(如圖3C所示)以充滿該導管之管腔,如前述之血管導管。選擇性或額外地,該鎖定溶液可為C4-C9羧酸酯抗微生物劑與螯合劑之溶液。 The method of the present invention can also be used to flush and lock non-vascular catheters, such as peritoneal dialysis catheter 30, as shown in Figures 3A through 3C. After the peritoneal dialysis treatment, the used dialysate is withdrawn from the catheter 30 as shown in Fig. 3A. After removal of a sufficient amount of the dialysate line 30 to the dialysis catheter C 4 -C 9 carboxylate chelating agent and an antimicrobial rinse the rinsing solution FS, shown in Figure 3B. After rinsing, the locking solution is introduced into the peritoneal dialysis catheter 30 (shown in Figure 3C) to fill the lumen of the catheter, such as the vascular catheter described above. Selectively or additionally, the antimicrobial solution may lock the solution of the chelating agent is a C 4 -C 9 carboxylic acid ester.

現參照圖4,藉由使用至少部分係自多孔性材料形成之經植入之導管,可增進包含C4-C9羧酸酯抗微生物劑與螯合劑之鎖定溶液之用途。當該多孔性導管本體42之管 腔40係充滿包含C4-C9羧酸酯抗微生物劑與螯合劑之溶液時,該溶液將能緩慢地穿透(即滲透)進入該導管本體及向外通過至該導管周圍之組織T,如圖4之箭頭所示。因此,該鎖定溶液之抗微生物性質將不完全侷限於該導管之內腔,但亦將有效地作用於該導管之表面及緊鄰該導管本體周圍之組織區域。特別適合用於該導管本體之材料及多孔性質已於上描述。 Referring now to Figure 4, by using at least a portion of the system from the porous material is formed by implantation of catheters, can promote the use of a solution comprising a C 4 -C 9 carboxylate antimicrobial agent is a chelating agent of the lock. When the lumen 40 of the porous catheter body 42 is filled with a solution comprising a C 4 -C 9 carboxylate antimicrobial agent and a chelating agent, the solution will slowly penetrate (ie, penetrate) into the catheter body and Externally passed to the tissue T around the catheter, as indicated by the arrows in FIG. Thus, the antimicrobial properties of the locking solution will not be completely limited to the lumen of the catheter, but will also effectively act on the surface of the catheter and adjacent to the tissue region surrounding the catheter body. Materials and porous properties that are particularly suitable for use with the catheter body have been described above.

現參照圖5,本發明之套組將包括至少容器60(諸如針筒)以盛裝一體積之C4-C9羧酸酯抗微生物劑與螯合劑之鎖定溶液,及可植入之導管腔以接受該溶液。該體積將通常介於此處前述之範圍內。該套組可另包含包裝62以盛裝該容器60。該包裝可為任何傳統之醫學裝置包裝,包括盒、管、套、盤及袋。此外,該套組可包含使用說明(“IFU”),其解釋用於鎖定及/或消毒經植入之導管之方法,該方法係在連續使用該導管之間自該容器導入溶液至該經植入之導管之管腔之中。 Referring now to Figure 5, the kit of the present invention will include at least a container 60 (such as a syringe) for holding a volume of a locking solution of a C 4 -C 9 carboxylate antimicrobial agent and a chelating agent, and an implantable catheter The chamber receives the solution. This volume will typically be within the ranges previously described herein. The kit may additionally include a package 62 for holding the container 60. The package can be any conventional medical device package including boxes, tubes, sleeves, trays and bags. In addition, the kit can include instructions for use ("IFU") that explain a method for locking and/or disinfecting an implanted catheter by introducing a solution from the container to the passage between successive use of the catheter. In the lumen of the implanted catheter.

本發明另由以下實施例說明。應了解的是這些實施例雖然代表本發明之較佳實施態樣,但僅用於示範說明。由上述討論及這些實施例當中,該領域之技藝人士可確知本發明之重要特徵,且在不違背本發明之精神及範圍下可對本發明進行各種改變及修飾以使其適用於各種用途及狀況。 The invention is further illustrated by the following examples. It should be understood that these embodiments, while representative of the preferred embodiments of the invention, are intended to be illustrative only. From the above discussion and the embodiments, those skilled in the art can clarify the important features of the present invention, and various changes and modifications can be made to the various uses and conditions without departing from the spirit and scope of the invention. .

實施例1 評估微生物生長抑制溶液 Example 1 Evaluation of Microbial Growth Inhibition Solution

下列實驗提供對本發明之經調製之微生物生長抑制溶液之抗微生物/抗真菌測試。 The following experiments provide an antimicrobial/antifungal test of the modulated microbial growth inhibiting solution of the present invention.

二甲苯青黴素抗藥性金黃葡萄球菌(Staphylococcus Aureus)(“MRSA”) Xylene penicillin-resistant Staphylococcus Aureus ("MRSA")

金黃葡萄球菌之培養原液在使用前以冷凍培養原液儲存於-70℃。該細菌測試使用自人血液分離之金黃葡萄球菌。細胞懸浮液係自該冷凍培養原液製備,於大豆胰蛋白酶肉汁(“TSB”)中培養以產生每毫升大約1×108集落形成單位(“CFU”)之MRSA。該接種液之終濃度係利用培養皿計數證實。 The culture solution of Staphylococcus aureus was stored at -70 ° C in a frozen culture stock solution before use. The bacteria test uses Staphylococcus aureus isolated from human blood. Cell suspensions were prepared from the frozen culture stock and cultured in soybean trypsin gravy ("TSB") to produce approximately 1 x 10 8 colony forming units ("CFU") of MRSA per ml. The final concentration of the inoculum was confirmed by counting the dishes.

細菌測試-在此測試中,9.9 ml之各測試液係經100 ul之MRSA細胞懸浮液接種以產生大約1×106 CFU/ml之終細胞濃度。此代表該起始1×108 CFU/ml培養液之1:100稀釋液;該初始細胞濃度係根據該接種培養皿計數計算。各測試或對照溶液係經三次重複評估。樣本係於T=1小時收集。 Bacteria Test - In this test, 9.9 ml of each test solution based MRSA was inoculated with a suspension of 100 ul of the cell to produce about 1 × 10 6 CFU / ml of the final cell concentration. This represents a 1:100 dilution of the starting 1 x 10 8 CFU/ml broth; this initial cell concentration is calculated from the inoculum dish count. Each test or control solution was evaluated in triplicate. Samples were collected at T = 1 hour.

採樣經處理之有機體以供生長-各樣本係以PBS(pH 7.0)連續稀釋並接種二次於大豆胰蛋白酶洋菜膠(“TSA”)板上。所有板係倒置培養於37℃ 24小時。剩餘體積之該經處理之樣本:1)各樣本係經0.22 μm過濾膜過濾,2)各過濾膜係以15 ml之無菌水潤洗。將該過 濾膜直接放在TSA板上,於37℃不倒置培養24小時。 The treated organisms were sampled for growth - each sample was serially diluted in PBS (pH 7.0) and seeded twice on soybean tryptic gelatin ("TSA") plates. All plates were inverted and cultured at 37 ° C for 24 hours. The remaining volume of the treated sample: 1) each sample was filtered through a 0.22 μm filter membrane, and 2) each filter membrane was rinsed with 15 ml of sterile water. Will The filter was placed directly on the TSA plate and incubated at 37 ° C for 24 hours without inversion.

分析-各溶液之CFU/ml係經對數轉換(以10為底)。當板計數為零時,以0.5之值取代計數為零之值。此經取代之值係根據該接種之稀釋倍數或過濾體積按比例計算。將三個實驗之結果平均以決定該平均對數密度並計算該相關之標準差。藉由將時間零之平均對數密度減去24小時之平均對數密度,計算經鎖定溶液處理之培養物的對數減少。 Analysis - CFU/ml of each solution was log-transformed (base 10). When the board count is zero, the value of zero is replaced by a value of 0.5. This substituted value is calculated based on the dilution factor or filtration volume of the inoculum. The results of the three experiments were averaged to determine the average log density and the standard deviation of the correlation was calculated. The log reduction of the culture treated with the lock solution was calculated by subtracting the average log density of time zero from the average log density of 24 hours.

綠膿桿菌(Pseudomonas aeruginosa) Pseudomonas aeruginosa

綠膿桿菌(代表性革蘭氏陰性細菌)係於培養中生長至經定義之對數生長期。該培養之代表性樣本係經各種載具(溶劑)或鎖定溶液培養/處理一段經定義之時間。該經處理之樣本等分係經接種於洋菜膠板,在足夠生長時間後實施菌落數計算以評估該鎖定溶液殺滅該受到關注之有機體之效力。 Pseudomonas aeruginosa (representative Gram-negative bacteria) is grown in culture to the defined logarithmic growth phase. Representative samples of this culture are cultured/treated with various vehicles (solvents) or locking solutions for a defined period of time. The treated sample aliquot was inoculated on a canola board and the colony count calculation was performed after sufficient growth time to assess the effectiveness of the lock solution in killing the organism of interest.

細菌菌株及培養溶液-欲接受測試之綠膿桿菌之培養原液在使用前係以冷凍培養原液保存於-70℃。該細菌測試使用自人血液分離之綠膿桿菌。細胞懸浮液係自該冷凍培養原液製備,於TSB中培養以產生每毫升大約1×108 CFU之綠膿桿菌。供參考而言,0.5麥氏(McFarland)比濁單位通常將反映此大約數量之有機體。該接種液之終濃度係利用培養皿計數證實。 Bacterial strain and culture solution - The culture stock solution of Pseudomonas aeruginosa to be tested was stored at -70 ° C in a frozen culture stock solution before use. This bacterium test uses Pseudomonas aeruginosa isolated from human blood. The cell suspension was prepared from the frozen culture stock and cultured in TSB to produce approximately 1 x 10 8 CFU of Pseudomonas aeruginosa per ml. For reference, a 0.5 McFarland turbidity unit will typically reflect this approximate number of organisms. The final concentration of the inoculum was confirmed by counting the dishes.

細菌測試-在此測試中,9.9 ml之各測試液係經100 ul之綠膿桿菌細胞懸浮液接種以產生大約1×106 CFU/ml之終細胞濃度。應注意此代表該起始1×108 CFU/ml培養之1:100稀釋。該初始細胞濃度係根據該接種培養皿計數計算。各測試或對照溶液係經三次重複評估。樣本係於T=1小時收集。各樣本係以PBS(pH 7.0)連續稀釋,並接種三次於TSA板上。所有板係倒置培養於37℃ 24小時。剩餘體積之該經處理之樣本:1)各樣本係經0.22 μm過濾膜過濾,2)各過濾膜係以15 ml之無菌水潤洗。將該過濾膜直接放在TSA板上,於37℃不倒置培養24小時。 Bacteria Test - In this test, 9.9 ml of each test liquid system of P. aeruginosa was inoculated with 100 ul of a suspension of cells to produce about 1 × 10 6 CFU / ml of the final cell concentration. It should be noted that this represents a 1:100 dilution of the initial 1 x 10 8 CFU/ml culture. The initial cell concentration was calculated based on the inoculum dish count. Each test or control solution was evaluated in triplicate. Samples were collected at T = 1 hour. Each sample was serially diluted in PBS (pH 7.0) and inoculated three times on TSA plates. All plates were inverted and cultured at 37 ° C for 24 hours. The remaining volume of the treated sample: 1) each sample was filtered through a 0.22 μm filter membrane, and 2) each filter membrane was rinsed with 15 ml of sterile water. The filter membrane was placed directly on the TSA plate and cultured at 37 ° C for 24 hours without inversion.

分析-各溶液之CFU/ml係經對數轉換(以10為底)。當板計數為零時,以0.5之值取代計數為零之值。此經取代之值係根據該接種之稀釋倍數或過濾體積按比例計算。將三個實驗之結果平均以決定該平均對數密度並計算該相關之標準差。藉由將時間零之平均對數密度減去24小時之平均對數密度,計算經鎖定溶液處理之培養物的對數減少。 Analysis - CFU/ml of each solution was log-transformed (base 10). When the board count is zero, the value of zero is replaced by a value of 0.5. This substituted value is calculated based on the dilution factor or filtration volume of the inoculum. The results of the three experiments were averaged to determine the average log density and the standard deviation of the correlation was calculated. The log reduction of the culture treated with the lock solution was calculated by subtracting the average log density of time zero from the average log density of 24 hours.

白色念珠菌(Candida albicans) Candida albicans

白色念珠菌(代表性真菌/酵母菌)係於培養中生長至經定義之對數生長期。該培養之代表性樣本係經各種載具(溶劑)或鎖定溶液培養/處理一段經定義之時間。該經處理之樣本等分係經接種於洋菜膠板,在足夠生長時間後實施菌落數計算以評估該鎖定溶液殺滅該受到關注之有 機體之效力。 Candida albicans (representative fungi/yeast) is grown in culture to the defined logarithmic growth phase. Representative samples of this culture are cultured/treated with various vehicles (solvents) or locking solutions for a defined period of time. The treated sample aliquot is inoculated into a canola board, and after a sufficient growth time, the colony number calculation is performed to evaluate that the locking solution kills the concern. The effectiveness of the body.

白色念珠菌ATCC之培養原液在使用前以冷凍培養原液儲存於-70℃。該細菌測試使用自人血液分離之白色念珠菌ATCC編號90028。細胞懸浮液係自該冷凍培養原液製備,於TSB中培養以產生每毫升大約1×108 CFU之白色念珠菌。供參考而言,0.5麥氏(McFarland)比濁單位通常將反映此大約數量之有機體。該接種液之終濃度係利用培養皿計數證實。 The culture stock solution of Candida albicans ATCC was stored at -70 ° C in a frozen culture stock solution before use. This bacterial test used Candida albicans ATCC No. 90028 isolated from human blood. The cell suspension was prepared from the frozen culture stock and cultured in TSB to produce approximately 1 x 10 8 CFU of Candida albicans per ml. For reference, a 0.5 McFarland turbidity unit will typically reflect this approximate number of organisms. The final concentration of the inoculum was confirmed by counting the dishes.

細菌測試-在此測試中,9.9 ml之各測試液係經100 ul之白色念珠菌細胞懸浮液接種以產生大約1×106 CFU/ml之終細胞濃度。應注意此代表該起始1×108 CFU/ml培養之1:100稀釋。該初始細胞濃度係根據該接種培養皿計數計算。各測試或對照溶液係經三次重複評估。樣本係於T=1小時收集。 Bacteria Test - In this test, each test solution via lines 100 ul of 9.9 ml of cell suspension was inoculated with C. albicans to produce approximately 1 × 10 6 CFU / ml of the final cell concentration. It should be noted that this represents a 1:100 dilution of the initial 1 x 10 8 CFU/ml culture. The initial cell concentration was calculated based on the inoculum dish count. Each test or control solution was evaluated in triplicate. Samples were collected at T = 1 hour.

採樣經處理之有機體以供生長-各樣本係以PBS(pH 7.0)連續稀釋並接種於TSA板上。所有板係接種二次並倒置培養於37℃ 24小時。剩餘體積之該經處理之樣本:1)各樣本係經0.22 μm過濾膜過濾,2)各過濾膜係以15 ml之無菌水潤洗。將該過濾膜直接放在TSA板上,於37℃不倒置培養24小時。 The treated organisms were sampled for growth - each sample was serially diluted in PBS (pH 7.0) and plated on TSA plates. All plates were inoculated twice and cultured in an inverted manner at 37 ° C for 24 hours. The remaining volume of the treated sample: 1) each sample was filtered through a 0.22 μm filter membrane, and 2) each filter membrane was rinsed with 15 ml of sterile water. The filter membrane was placed directly on the TSA plate and cultured at 37 ° C for 24 hours without inversion.

分析-各溶液之CFU/ml係經對數轉換(以10為底)。當板計數為零時,以0.5之值取代計數為零之值。此經取代之值係根據該接種之稀釋倍數或過濾體積按比例計算。將三個實驗之結果平均以決定該平均對數密度並計 算該相關之標準差。藉由將時間零之平均對數密度減去24小時之平均對數密度,計算經鎖定溶液處理之培養物的對數減少。表3顯示上述試驗1.0之結果摘要。 Analysis - CFU/ml of each solution was log-transformed (base 10). When the board count is zero, the value of zero is replaced by a value of 0.5. This substituted value is calculated based on the dilution factor or filtration volume of the inoculum. Average the results of the three experiments to determine the average log density Calculate the standard deviation of the correlation. The log reduction of the culture treated with the lock solution was calculated by subtracting the average log density of time zero from the average log density of 24 hours. Table 3 shows a summary of the results of the above test 1.0.

用於金黃葡萄球菌、表皮葡萄球菌、糞腸球菌VRE、大腸桿菌、克雷白氏肺炎桿菌及黏質沙雷氏菌之試驗方法係類似或相同,僅受測之微生物不同。由試驗1.0可清楚得知濃度0.575 mg/mL之辛酸鈉及濃度0.5 mg/mL之EDTA二鈉於pH調整至5.0之檸檬酸鹽緩衝液可有效減少7至8對數之主要醫學重要微生物。此外,濃度低至0.0625 mg/mL之辛酸鈉及EDTA二鈉可有效減少6至7對數之至少一種醫學重要微生物(例如綠膿桿菌)。整體來說,試驗1.0顯示該具有C4-C9羧酸酯抗微生物劑與螯合劑之微生物生長抑制溶液在螯合劑濃度為1 mg/mL或更低時有協同作用。 Test methods for Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis VRE, Escherichia coli, Klebsiella pneumoniae and Serratia marcescens are similar or identical and differ only in the microorganisms tested. It can be clearly seen from Test 1.0 that sodium octanoate at a concentration of 0.575 mg/mL and disodium EDTA at a concentration of 0.5 mg/mL at a pH adjusted to 5.0 citrate buffer can effectively reduce the main medically important microorganisms of 7 to 8 logs. In addition, sodium octanoate and disodium EDTA at concentrations as low as 0.0625 mg/mL can effectively reduce at least one medically important microorganism (eg, Pseudomonas aeruginosa) from 6 to 7 logs. Overall, Test 1.0 showed that the microbial growth inhibiting solution having a C 4 -C 9 carboxylate antimicrobial agent and a chelating agent had a synergistic effect at a chelating agent concentration of 1 mg/mL or less.

如表4及5(試驗2.0)所示,在檸檬酸鹽緩衝液中之報告濃度之EDTA二鈉導致2對數減少,但無法完全殺滅該受測之有機體。然而,添加1.15 mg/mL之辛酸鈉至 該基底EDTA二鈉檸檬酸鹽緩衝液導致該受測有機體之8對數減少。 As shown in Tables 4 and 5 (Test 2.0), the reported concentration of disodium EDTA in citrate buffer resulted in a 2-log reduction, but the tested organism could not be completely killed. However, add 1.15 mg/mL sodium octanoate to The base EDTA disodium citrate buffer resulted in an 8-log reduction in the organism being tested.

由試驗1.0及2.0可知,該經評估之螯合劑的有效濃度係遠低於先前報告之濃度,且該濃度可大幅減少與較高劑量有關之突發心臟病死亡之潛在風險。此外,該經評估之微生物生長抑制溶液能以圖6所示之組成物使靜脈導管維持於「鎖定」無流動之狀態。 As can be seen from tests 1.0 and 2.0, the effective concentration of the evaluated chelating agent is much lower than previously reported, and this concentration can substantially reduce the potential risk of sudden cardiac death associated with higher doses. In addition, the evaluated microbial growth inhibiting solution maintains the venous catheter in a "locked", no-flow state with the composition shown in FIG.

當微生物以預期可於留置靜脈接觸裝置中見到之濃度存在時,結論是該具有本發明之螯合劑濃度之微生物生長抑制溶液能維持該等裝置且有效減少或清除該微生物成為系統性感染之來源。 When the microorganism is present in a concentration expected to be found in the indwelling intravenous contact device, it is concluded that the microbial growth inhibiting solution having the concentration of the chelating agent of the present invention can maintain the device and effectively reduce or eliminate the microorganism into a systemic infection. source.

應了解的是此處所述之本發明之較佳實施態樣之各種改變及修飾將為該領域之技藝人士所顯見。該等改變及修飾可在不背離本發明之主題的精神及範圍下進行且不減少彼之預期優點。因此該等改變及修飾將包含於隨附之權利要求之內。 It will be appreciated that various changes and modifications of the preferred embodiments of the invention described herein will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the spirit and scope of the invention. Accordingly, such changes and modifications are intended to be included within the scope of the appended claims.

N‧‧‧針頭 N‧‧‧ needle

S‧‧‧皮膚 S‧‧‧ skin

V‧‧‧靜脈 V‧‧‧ vein

BV‧‧‧血管 BV‧‧‧Vascular

FS‧‧‧沖洗溶液 FS‧‧‧Washing solution

LS‧‧‧鎖定溶液 LS‧‧‧Locking solution

T‧‧‧組織 T‧‧‧ organization

IFU‧‧‧使用說明 IFU‧‧‧Instructions for use

10‧‧‧靜脈導管 10‧‧‧ intravenous catheter

12‧‧‧IV管線管 12‧‧‧IV line pipe

14‧‧‧近端接頭 14‧‧‧ proximal joint

16‧‧‧末端 End of 16‧‧‧

20‧‧‧經皮下植入之導管 20‧‧‧Subcutaneously implanted catheter

22‧‧‧植入埠 22‧‧‧ implants

23‧‧‧連接管線 23‧‧‧Connected pipeline

26‧‧‧針筒 26‧‧‧Syringe

30‧‧‧腹膜透析導管 30‧‧‧Peritoneal dialysis catheter

40‧‧‧管腔 40‧‧‧ lumen

42‧‧‧多孔性導管本體 42‧‧‧Porous catheter body

60‧‧‧容器 60‧‧‧ container

62‧‧‧包裝 62‧‧‧Packaging

圖1A及1B說明本發明之用於鎖定及消毒經皮導管之方法。 1A and 1B illustrate a method of the present invention for locking and disinfecting a percutaneous catheter.

圖2A至2C說明本發明之用於沖洗、鎖定及消毒皮下植入導管之方法。 2A through 2C illustrate a method of the present invention for rinsing, locking and disinfecting a subcutaneous implanted catheter.

圖3A至3C說明本發明之用於沖洗、鎖定及消毒腹膜透析導管之方法。 3A to 3C illustrate a method of the present invention for rinsing, locking and disinfecting a peritoneal dialysis catheter.

圖4說明本發明之實施態樣,其中抗微生物鎖定溶液滲透進入經植入之導管本體且較佳地進入該導管本體周圍之組織。 Figure 4 illustrates an embodiment of the invention wherein the antimicrobial lock solution penetrates into the implanted catheter body and preferably into the tissue surrounding the catheter body.

圖5說明根據本發明之原則建構之套組。 Figure 5 illustrates a kit constructed in accordance with the principles of the present invention.

圖6顯示辛酸鈉/EDTA及肝素之aPTT比較。 Figure 6 shows a comparison of aPTT of sodium octoate/EDTA and heparin.

S‧‧‧皮膚 S‧‧‧ skin

V‧‧‧靜脈 V‧‧‧ vein

10‧‧‧靜脈導管 10‧‧‧ intravenous catheter

12‧‧‧IV管線管 12‧‧‧IV line pipe

14‧‧‧近端接頭 14‧‧‧ proximal joint

16‧‧‧末端 End of 16‧‧‧

23‧‧‧連接管線 23‧‧‧Connected pipeline

LS‧‧‧鎖定溶液 LS‧‧‧Locking solution

Claims (24)

一種微生物生長抑制溶液,其包含作為抗微生物劑之辛酸或彼之醫藥上可接受之鹽、作為螯合劑之乙二胺四乙酸(EDTA)、及包含檸檬酸鹽之緩衝劑,其中該抗微生物劑係以自約0.071mg/mL至約1.15mg/mL之量存在,該螯合劑係以自約0.01mg/mL至約2mg/mL之量存在且該緩衝劑係以自約1.5mM至約24mM之量存在,且其中該微生物生長抑制溶液具有pH 5.2或低於pH 5.2。 A microbial growth inhibiting solution comprising octanoic acid or a pharmaceutically acceptable salt thereof as an antimicrobial agent, ethylenediaminetetraacetic acid (EDTA) as a chelating agent, and a buffer comprising citrate, wherein the antimicrobial agent The agent is present in an amount from about 0.071 mg/mL to about 1.15 mg/mL, the chelating agent being present in an amount from about 0.01 mg/mL to about 2 mg/mL and the buffer is from about 1.5 mM to about An amount of 24 mM is present, and wherein the microbial growth inhibiting solution has a pH of 5.2 or less than pH 5.2. 如申請專利範圍第1項之微生物生長抑制溶液,其中該螯合劑螯合鈣、鎂、錳、鐵或鋅。 A microbial growth inhibiting solution according to claim 1, wherein the chelating agent chelate calcium, magnesium, manganese, iron or zinc. 如申請專利範圍第1項之微生物生長抑制溶液,其中該螯合劑係以自約0.1mg/mL至約1mg/mL之量存在。 The microbial growth inhibiting solution of claim 1, wherein the chelating agent is present in an amount from about 0.1 mg/mL to about 1 mg/mL. 如申請專利範圍第1項之微生物生長抑制溶液,其中該螯合劑係以自約0.25mg/mL至約0.5mg/mL之量存在。 The microbial growth inhibiting solution of claim 1, wherein the chelating agent is present in an amount from about 0.25 mg/mL to about 0.5 mg/mL. 如申請專利範圍第1項之微生物生長抑制溶液,其另包含醫藥上可接受之載劑溶液。 A microbial growth inhibiting solution according to claim 1 further comprising a pharmaceutically acceptable carrier solution. 如申請專利範圍第5項之微生物生長抑制溶液,其中該醫藥上可接受之載劑溶液包含pH調整至5.2或更低之鹽水、林格氏(Ringer’s)液或水。 A microbial growth inhibiting solution according to claim 5, wherein the pharmaceutically acceptable carrier solution comprises saline, Ringer's solution or water having a pH adjusted to 5.2 or lower. 如申請專利範圍第1項之微生物生長抑制溶液,其中該螯合劑係以自約0.0625mg/mL至約1mg/mL之量存在。 The microbial growth inhibiting solution of claim 1, wherein the chelating agent is present in an amount from about 0.0625 mg/mL to about 1 mg/mL. 如申請專利範圍第1項之微生物生長抑制溶液,其中該抗微生物劑係辛酸鈉且該螯合劑係乙二胺四乙酸二鈉。 The microorganism growth inhibiting solution according to claim 1, wherein the antimicrobial agent is sodium octanoate and the chelating agent is disodium edetate. 一種消毒經植入之導管的細菌及真菌之方法,該方法包含:導入如申請專利範圍第1至8項中任一項之微生物生長抑制溶液至導管管腔。 A method of sterilizing bacteria and fungi of an implanted catheter, the method comprising: introducing a microorganism growth inhibiting solution according to any one of claims 1 to 8 to a catheter lumen. 如申請專利範圍第9項之方法,其中該導管之至少一部分係具有足夠孔洞性以允許該微生物生長抑制溶液自管腔向外擴散至該導管之外部表面且進入該導管周圍之組織或血流以抑制感染。 The method of claim 9, wherein at least a portion of the conduit has sufficient porosity to allow the microbial growth inhibiting solution to diffuse outwardly from the lumen to the outer surface of the catheter and into the tissue or blood flow surrounding the catheter. To suppress infection. 一種包覆醫學裝置之方法,該方法包含:暴露該醫學裝置於如申請專利範圍第1至8項中任一項之微生物生長抑制溶液足夠量之時間以提供在該裝置之經暴露之表面上之包覆。 A method of coating a medical device, the method comprising: exposing the medical device to a microbial growth inhibiting solution according to any one of claims 1 to 8 for a sufficient amount of time to provide on the exposed surface of the device Wrapped. 如申請專利範圍第11項之方法,其另包含在暴露該醫學裝置於該微生物生長抑制溶液之前以界面活性劑處理該醫學裝置。 The method of claim 11, further comprising treating the medical device with a surfactant prior to exposing the medical device to the microbial growth inhibiting solution. 如申請專利範圍第12項之方法,其中該界面活性劑係選自三月桂基甲基氯化銨、氯化烷基二甲基苄基銨及彼等之組合。 The method of claim 12, wherein the surfactant is selected from the group consisting of trilaurylmethylammonium chloride, alkyldimethylbenzylammonium chloride, and combinations thereof. 如申請專利範圍第11項之方法,其中該醫學裝置係選自中央靜脈導管、週邊靜脈導管、動脈導管、許旺蓋茲(Swant-Ganz)導管、血液透析導管、臍帶導管、經 皮非隧道矽導管、袖口隧道中央靜脈導管及皮下中央靜脈埠。 The method of claim 11, wherein the medical device is selected from the group consisting of a central venous catheter, a peripheral venous catheter, an arterial catheter, a Swant-Ganz catheter, a hemodialysis catheter, an umbilical catheter, and a Pediatric tunnel catheter, cuff tunnel central venous catheter and subcutaneous central venous fistula. 一種鎖定及/或沖洗經植入之導管之方法,該方法包含:用如申請專利範圍第1至8項中任一項之微生物生長抑制溶液充滿經植入之開口於體腔之導管的管腔。 A method of locking and/or rinsing an implanted catheter, the method comprising: filling a lumen of a catheter inserted into a body lumen with a microbial growth inhibiting solution according to any one of claims 1 to 8 . 一種鎖定及/或沖洗經植入之導管之套組,該套組包含:盛裝一體積之如申請專利範圍第1至8項中任一項之微生物生長抑制溶液之容器;及接受該微生物生長抑制溶液之植入式導管管腔。 A kit for locking and/or rinsing an implanted catheter, the kit comprising: a container containing a volume of a microbial growth inhibiting solution according to any one of claims 1 to 8; and receiving the growth of the microorganism The implanted catheter lumen that inhibits the solution. 如申請專利範圍第16項之套組,其中該容器包含針筒。 A kit of claim 16 wherein the container comprises a syringe. 一種鎖定及/或沖洗經植入之導管之套組,該套組包含:具有第一區室及第二區室之容器,該第一區室盛裝粉末形式之如申請專利範圍第1至8項中任一項之微生物生長抑制溶液,該第二區室盛裝醫藥上可接受之載劑溶液。 A kit for locking and/or rinsing an implanted catheter, the kit comprising: a container having a first compartment and a second compartment, the first compartment being in powder form as claimed in claims 1 to 8 A microbial growth inhibiting solution according to any one of the preceding claims, wherein the second compartment contains a pharmaceutically acceptable carrier solution. 如申請專利範圍第18項之套組,其中該容器包含植入式導管管腔。 A kit of claim 18, wherein the container comprises an implantable catheter lumen. 如申請專利範圍第18項之套組,其中該容器包含針筒。 A kit of claim 18, wherein the container comprises a syringe. 如申請專利範圍第18項之套組,其中當與該醫藥上可接受之載劑溶液混合時,該抗微生物劑係以自約 0.05mg/mL至約5mg/mL之量存在。 The kit of claim 18, wherein the antimicrobial agent is self-contained when mixed with the pharmaceutically acceptable carrier solution It is present in an amount from 0.05 mg/mL to about 5 mg/mL. 如申請專利範圍第18項之套組,其中當與該醫藥上可接受之載劑溶液混合時,該螯合劑係以自約0.1mg/mL至約1mg/mL之量存在。 The kit of claim 18, wherein the chelating agent is present in an amount from about 0.1 mg/mL to about 1 mg/mL when mixed with the pharmaceutically acceptable carrier solution. 如申請專利範圍第18項之套組,其中當與該醫藥上可接受之載劑溶液混合時,該螯合劑係以自約0.25mg/mL至約0.5mg/mL之量存在。 The kit of claim 18, wherein the chelating agent is present in an amount from about 0.25 mg/mL to about 0.5 mg/mL when mixed with the pharmaceutically acceptable carrier solution. 如申請專利範圍第18項之套組,其中該第一區室或該第二區室包含該緩衝劑,該緩衝劑包含檸檬酸鹽,其中當與該醫藥上可接受之載劑溶液混合時,該抗微生物劑係以自約0.071mg/mL至約1.15mg/mL之量存在且該螯合劑係以自約0.0625mg/mL至約1mg/mL之量存在。 The kit of claim 18, wherein the first compartment or the second compartment comprises the buffer, the buffer comprising citrate, wherein when mixed with the pharmaceutically acceptable carrier solution The antimicrobial agent is present in an amount from about 0.071 mg/mL to about 1.15 mg/mL and the chelating agent is present in an amount from about 0.0625 mg/mL to about 1 mg/mL.
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Publication number Priority date Publication date Assignee Title
US4489097A (en) * 1976-07-28 1984-12-18 The Procter & Gamble Company Intravenous solutions with antimicrobial agent
US5688516A (en) * 1992-11-12 1997-11-18 Board Of Regents, The University Of Texas System Non-glycopeptide antimicrobial agents in combination with an anticoagulant, an antithrombotic or a chelating agent, and their uses in, for example, the preparation of medical devices

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4489097A (en) * 1976-07-28 1984-12-18 The Procter & Gamble Company Intravenous solutions with antimicrobial agent
US5688516A (en) * 1992-11-12 1997-11-18 Board Of Regents, The University Of Texas System Non-glycopeptide antimicrobial agents in combination with an anticoagulant, an antithrombotic or a chelating agent, and their uses in, for example, the preparation of medical devices

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