JP5143982B2 - Biocide lock - Google Patents

Description

〔ここで、Ｒ¹は水素またはアルキルであり、そしてＲ²は水素、アルキルまたは式（ＩＩ）
【化３２】

の基である〕
の少なくとも１種の化合物
および
（Ｂ）生物学的に受容し得る酸および生物学的に受容し得るそれらの塩から成る群から選択された少なくとも１種の化合物
を含む組成物中において用いられる。
【００８７】
式Ｉの化合物の代表的例の製造は、英国特許第１，１２４，２８５号に記載されている。基本的には、これらの化合物は、タウリンアミドとホルムアルデヒドの縮合生成物であり、そしてそれ故ここにおいて「タウリンアミド誘導体」と称する。それらは、グラム陽性およびグラム陰性菌の両方に対してのみならず、これらの生物体により生成される外毒素および内毒素に対しても活性である。
【００８８】
Ｒ¹および／またはＲ²がアルキルである場合、それらは、直鎖または分岐鎖のいずれかのアルキルであり得、そして好ましくは、１から８個の炭素原子を有するアルキル、すなわち、メチル、エチル、プロピル、ブチル、ペンチル、ヘキシル、ヘプチル、オクチルおよびそれらの異性体から独立に選択される。一層好ましくは、Ｒ¹および／またはＲ²がアルキルである場合、それらは、１から６個の炭素原子を有するアルキル、すなわち、メチル、エチル、プロピル、ブチル、ペンチル、ヘキシルおよびそれらの異性体から独立に選択される。最も好ましくは、アルキル基は、１から４個の炭素原子を有し、すなわち、メチル、エチル、プロピル、ブチルおよびそれらの異性体である。しかしながら、Ｒ¹が水素でありそしてＲ²が水素または式ＩＩの基であることが最も好ましい。
【００８９】
本発明において、式Ｉの化合物のうち、化合物タウロリジン（Ｒ¹＝Ｈ、Ｒ²＝式ＩＩ）およびタウルルタム（Ｒ¹＝Ｒ²＝Ｈ）が特に好ましい。タウロリジンは、ビス−（１，１−ジオキソ−ペルヒドロキシ−１，２，４−チアジアジン−４−イル）メタンである。
これらの化合物は、ホルムアルデヒド担体、すなわち、ホルムアルデヒドを結合して含有する非毒性誘導体である。
【００９０】
タウロリジンの作用態様は、上記の毒素上にまたは細菌細胞壁のムレイン上に存在するヒドロキシルまたはアミノ基へのメチロール基の転移を含むことが分かった。溶液中で、タウロリジンは、タウルルタムおよびＮ−メチロールタウルルタムとの平衡にて存在し、タウロリジンが非常に優勢である。タウルルタムは、それ自体メチロールタウリンアミドとの平衡にあり、その平衡はタウルルタムの大いなる優勢にある。上記のメチロール誘導体すなわちメチロールタウルルタムおよびメチロールタウリンアミドが毒素または細菌と接触する時、メチロール基は転移される。メチロールタウルルタムはそれによりタウルルタムに転化され、一方メチロールタウリンアミドはタウリンすなわち人体において極めて十分に許容される天然に存在するアミノスルホン酸に転化される。かくして、タウロリジンおよびタウルルタムは、本質的に同じ具合に作用しそして同じ最終生成物を生成する、ということが認識されよう。
【００９１】
グラム陰性生物体による細菌感染は、通常、内毒素血症、すなわち、生物体により遊離された内毒素に対する患者の反応が伴う。
内毒素は、Ｏ菌体抗原の錯体リポポリサッカリド構成成分であり、そしてグラム陰性菌の細胞壁にゆるく付着している。細菌源に関係なく、すべての内毒素が、広範囲の個々の効果を奏するグラム陽性菌の外毒素とは反対に、同様な毒性質を示す。ヒトにおいて、それは、多数のグラム陰性菌が溶解される場合、内毒素性ショック症候群を生じ得る。この症候群は、グラム陰性敗血症を有する患者の約３０％において遭遇される。タウリンアミド誘導体は内毒素を不活性化し得るということが知られている。
【００９２】
外毒素のような毒性タンパク質を同様に不活性化することができ、またメチロール転移性抗菌剤を、リポポリサッカリド毒素の不存在下で毒性タンパク質と闘うために投与し得る。かかわり得る毒素は、グラム陰性菌、たとえば、イー・コリ（Ｅ．ｃｏｌｉ）およびバクテロイデス・フラジリス（Ｂａｃｔｅｒｏｉｄｅｓ ｆｒａｇｉｌｉｓ）の外毒素を含む。滅菌５％ポリビニルピロリドン中のタウロリジンの２０％溶液の０．２ｍＬのマウスへの静脈内投与は、イー・コリ（Ｅ．ｃｏｌｉ）およびビー・フラジリス（Ｂ．ｆｒａｇｉｌｉｓ）の両方の病原性菌株の腹腔内投与についての死亡率を非常に有意的に低減し得るということが知られている。
【００９３】
他の毒性タンパク質は、タウロリジンにより実質的に解毒されることが示されている、動物毒液、たとえば、メリチン並びに真菌毒素、たとえば、アマニチンおよびα−ブンガロトキシンを含む。
タウロリジンの格別な利点は、その非常に低い毒性である。すなわち、それはマウスにおいて非催奇性であり、そして腹腔内ＬＤ₅₀は１．５ｇ／ｋｇ程度であるということが示された。上記のように、これらの化合物は、体内において天然に存在しかつ特に無毒であるタウリンの生成をもたらすことになるメチロール転移活性を示す。タウロリジンの更なる利点は、水溶液におけるその安定性であり、該溶液を予備包装し、そして比較的長期間にわたって保管することを可能にする。
【００９４】
これらのタウリンアミド誘導体は、通常、本発明の内部補てつ装置中への注入により、水溶液として投与される。かかる溶液は、所与のタウリンアミド誘導体に加えて、タウリンアミド誘導体を溶液に維持するのを助けるためにおよび該溶液の等張性に寄与するために、可溶化剤、たとえば、ポリビニルピロリドン（ＰＶＰ）を含有し得る。かかる溶液中のタウリンアミド誘導体の濃度は、ゼロより大から約２ｗｔ％の範囲にあり得、約０．０１〜約１．５ｗｔ％の範囲の濃度が好ましく、そして約１ｗｔ％の濃度が最も好ましい。これらより高い濃度は有用であるが、しかし溶解性が問題になる。
【００９５】
ＰＶＰを該溶液中に組み込む場合、それは、通常、低い水溶解性を有するタウリンアミド誘導体、特にタウロリジンの比較的高い濃度を達成するために、４〜７重量％の範囲の濃度にて用いる。ＰＶＰの分子量は、約３０，０００より大きくあるべきではなく、そして好ましくは１０，０００未満であり、たとえば約２００〜約３５００の間にある。ＢＡＳＦにより販売されているＫｏｌｌｉｄｏｎｅ（登録商標）は、特に適合する。かかるＰＶＰは、かなり速く吸収されそして腎臓を通じて排泄される。
【００９６】
内部補てつ装置中に注入されるタウリンアミド誘導体の溶液の量は、通常、それを満たすのに十分である。かかるシステムは、典型的には、約０．１ｍＬ〜約１０ｍＬの範囲の内容積を有する。かかる量は、無論、とりわけ個々の患者のサイズの関数であり得るところの、該装置と共に用いられるチューブの長さおよび直径と共に変動する。
【００９７】
かかる溶液中のタウリンアミド誘導体の濃度は、好ましくは、該化合物の溶解性に最も依存して、約０．４〜５重量％の範囲にある。約０．４〜約２．０重量％のタウロリジン、すなわち、１リットル当たり約４〜約２０グラムの溶液が特に好ましい。
【００９８】
タウロリジンの原液の製造を記載する例は、いくつかの特許たとえば米国特許第４，３３７，２５１号に載っている。
すなわち、１５リットルの２回蒸留された発熱物質不含水を、撹拌機および強力還流装置を備えた２５リットルガラス容器中に装填し、そして撹拌しながら５０℃に加熱する。タウロリジン（４００ｇ）を添加し、次いでＰＶＰ（Ｋｏｌｌｉｄｏｎｅ １７、１０００ｇ）を添加する。溶解後、この溶液を冷却し、そしてｐＨを数滴の０．１Ｎ塩酸で６．０に調整する。この溶液を次いで吸着フィルターに通して微生物および発熱物質を除去し、そして滅菌用Ｍｉｌｌｉｐｏｒｅフィルターに通した後に１００ｍＬバイアル中に満たし、しかして最終的に加圧滅菌される。
【００９９】
所望されるなら、ＰＶＰのいくらかまたは全部を、非経口的に受容し得るポリオールにより置換し得る。ポリオールについてのこの使用は、米国特許第５，２１０，０８３号に開示されており、しかしてその開示はそのままそっくり参照により本書に組み込まれる。そこには、これは、タウロリジンのより高い濃度において、溶液を使用できなくし得る結晶化が起こり得るために有利であるということが指摘されている。
【０１００】
細菌およびそれらの内および外毒素の場合、上記のようなメチロール転移後、脱水を伴う更なる不可逆工程があるということが分かった。かくして、リポポリサッカリドである細菌内毒素の場合、該内毒素がその致死的効果を奏するのを妨害する不可逆架橋反応が起こるということが分かった。同様に、タンパク質またはポリペプチドでありかつ内毒素において見出される種類のリポポリサッカリド物質を含有しない細菌外毒素の場合、解毒反応は、不可逆的であることが分かった。しかしながら、米国特許第５，２１０，０８３号において、上述のメカニズムによるメチロール基の転移は多くのヒドロキシルまたはアミノ化合物の場合可逆的であり、従ってタウロリジンの利用能を有意には妨害しない平衡を確立し得るということが開示されている。かくして、ポリオール、たとえば、糖および糖アルコールも、水溶液中のタウロリジンおよび／またはタウルルタムの比較的高い濃度をそれらの抗菌および抗毒素活性に有意には影響を及ぼすことなく維持するために用い得る。好ましいポリオールは、炭水化物、たとえば、ヘキソース、たとえば、グルコース、フルクトースおよびそれらの混合物；ペントース、たとえば、キシロース；ポリサッカリド、たとえば、デキストランまたは加水分解デンプン；グリセロール；並びに糖アルコール、たとえば、ソルビット、マンニットおよびキシリットを含む。グルコースが、最も好ましい。
【０１０１】
ポリオールの濃度は、典型的には、約３〜約４０重量％の範囲にある。グルコースの場合、濃度は、好ましくは約１０〜約３０重量％の範囲、一層好ましくは約２０％である。
かかるポリオールが用いられる場合、溶液中のタウロリジンの濃度は、好ましくは約０．５〜約５重量％の範囲に、一層好ましくは約２〜３重量％の範囲にある。タウルルタムの濃度は、好ましくは約１〜約７．５重量％、一層好ましくは約３〜約５重量％の範囲にある。
【０１０２】
グラム陰性生物体がしばしば存在するのでおよびタウリンアミド誘導体の静菌活性は多くの抗生物質のそれより低いので、広域抗生物質、一層特にグラム陽性およびグラム陰性病原体の両方に対して強活性の、好ましくは抵抗性を全くまたは遅延的にしか誘発しない物質、たとえば、β−ラクタム抗生物質、たとえば、ペニシリン、アンピシリンまたはセファロスポリン；テトラサイクリン抗生物質；マクロライド抗生物質、たとえば、エリスロマイシン；ポリペプチド抗生物質、たとえば、バシトラシンまたはノボビオシン；または一層好ましくはアミノグリコシド抗生物質、たとえば、アミカシン、ブチロシン、ホルチマイシン、ストレプトマイシン、ネオマイシン、リンコマイシン（たとえば、クリンダマイシンおよびリンコマイシン）、カナマイシン、ジデオキシカナマイシンＢ（ＤＫＰ）、リビドマイシン、ネチルマイシン、リボスタマイシン、サガマイシン、セルドマイシンおよびそれらのエピマー、シソマイシン、ソルビスチン、トブラマイシン、バンコマイシン、ゲンタマイシンおよびリファマイシン（たとえば、リファンピシンおよびリファマイシン）；等と共に、本発明の実施において用いられる組成物を投与することが有利であり得る。これらのうち、ゲンタマイシンが好ましい。
【０１０３】
しかしながら、抗生物質は、耐性菌株を生み出すそれらの傾向の故に、外科的処置における使用についてしばしば禁忌され、そして普通でない場合においてを除いて、タウリンアミド誘導体を抗細菌作用について専ら頼りにすることが、かかる誘導体は耐性菌株を生み出さないので好ましい。
本発明の実施において用いられる組成物は、好ましくは、薬理学的に受容し得る担体溶液、たとえば、水、リンガー液または食塩水も含有する。加えて、本発明の組成物はまた、それらの物理的および生化学的性質に好影響を及ぼし得る他の溶解添加剤、たとえば、アミノ酸、砂糖、食塩、脂肪、脂質、等を含有し得る。
【０１０４】
抗微生物性タウリンアミド誘導体を本発明の実施において用いる場合、それらは、生物学的に受容し得る酸または生物学的に受容し得るその塩と組み合わせて用いられる。酸はカルボン酸であることが好ましく、そしてそれは抗凝固剤でもあることが一層好ましい。米国特許第５，０７７，２８１号は、タウロリン化合物は独力で顕著な凝固阻止作用を示し、そして透析を必要とする医学的症状においておよび脈管補てつ装置用に単独でまたは他の抗凝固剤、たとえば、クマリンもしくはヘパリンと組み合わせてのいずれかで用いるために特に適合するということを教示する。該特許に指摘されているように、このことは、タウロリンは血液凝固に影響を及ぼさずそして消炎作用を示さないことを明記するところの、Ｗ．Ｌ．ＢｒｕｃｋｎｅｒおよびＲ．Ｗ．Ｐｆｉｒｒｍａｎｎ、「Ｖｅｒｌａｇ Ｕｒｂａｎ ｕｎｄ Ｓｃｈｗａｒｚｅｎｂｅｒｇ」、ミュンヘン、１９８５により出版された「Ｔａｕｒｏｌｉｎ」の教示と反対である。本発明の実施において用いられるタウリンアミド誘導体は、より良好な公知の抗凝固剤、たとえば、ヘパリンで見られるより小さい程度であるけれども、ある程度の抗凝固活性を示すということを本発明者は確信している。従って、タウリンアミド誘導体を抗凝固剤好ましくは生物学的に受容し得る酸またはその塩であるものと組み合わせて用いることが有益である。
【０１０５】
本発明に従って、抗微生物性タウリンアミド誘導体が、７より高くない、好ましくは約３．５〜約６．５の範囲に、一層好ましくは約４．５〜約６．５の範囲にある最終組成物についてのｐＨを生じるように、生物学的に受容し得る酸または生物学的に受容し得るその塩と組み合わせられる場合、有益な結果が達成される。かかる酸の例示的なものは、酢酸、ジヒドロ酢酸、安息香酸、クエン酸、ソルビン酸、プロピオン酸、コハク酸、リンゴ酸、フマル酸、マレイン酸、塩酸、リンゴ酸、リン酸、亜硫酸、バニリン酸、酒石酸、アスコルビン酸、ホウ酸、乳酸、エチレンジアミン四酢酸（ＥＤＴＡ）、エチレングリコール−ビス−｛β−アミノエチルエーテル｝−Ｎ，Ｎ，Ｎ′，Ｎ′−四酢酸およびジエチレントリアミン五酢酸、等、並びに、前記のものの生物学的に受容し得る塩、たとえば、リン酸アンモニウム、クエン酸カリウム、メタリン酸カリウム、酢酸ナトリウム、クエン酸ナトリウム、乳酸ナトリウム、リン酸ナトリウム、等である。血液抗凝固量の、クエン酸、リン酸、エチレンジアミン四酢酸（ＥＤＴＡ）、エチレングリコール−ビス−｛β−アミノエチルエーテル｝−Ｎ，Ｎ，Ｎ′，Ｎ′−四酢酸およびジエチレントリアミン五酢酸から成る群から選択された酸および生物学的に受容し得るそれらの塩が好ましい。本発明の実施において用いられる酸は、有機酸、特に少なくとも１個のカルボキシル基を有するもの、特にクエン酸またはＥＤＴＡであることが好ましい。酸はクエン酸であることが一層好ましく、そしてそれがクエン酸塩、たとえば、クエン酸ナトリウムと組み合わせて用いることが最も好ましい。
【０１０６】
Ｍｅｒｍｅｌ，Ｌ．Ａ．等は、Ｉｎｔｅｒｓｃｉｅｎｃｅ Ｃｏｎｆｅｒｅｎｃｅ ｏｎ Ａｎｔｉｍｉｃｒｏｂｉａｌ Ａｇｅｎｔｓ ａｎｄ Ｃｈｅｍｏｔｈｅｒａｐｙ（１９９８）にて発表された「バンコマイシン介在感受性スタフィロコッカス・アウレウス（ＶＩＳＡ）およびメチシリン耐性スタフィロコッカス・アウレウス（ＭＲＳＡ）に対するタウロリジン活性（Ｔａｕｒｏｌｉｄｉｎｅ Ａｃｔｉｖｉｔｙ Ａｇａｉｎｓｔ Ｖａｎｃｏｍｙｃｉｎ−Ｉｎｔｅｒｍｅｄｉａｔｅ Ｓｕｓｃｅｐｔｉｂｉｌｉｔｙ ＳｔａｐｈｙｌｏｃｏｃｃｕｓＡｕｒｅｕｓ （ＶＩＳＡ） ａｎｄ Ｍｅｔｈｉｃｉｌｌｉｎ−Ｒｅｓｉｓｔａｎｔ Ｓｔａｐｈｙｌｏｃｏｃｃｕｓ Ａｕｒｅｕｓ （ＭＲＳＡ））」という題目の講演において、タウロリジン活性はｐＨ７．０〜ｐＨ５．０の範囲においてｐＨを低減すると共に増大することを開示した。
【０１０７】
ＥＤＴＡは、採血チューブにおいて用いられる公知の抗凝固剤である。それはまた、カルシウムとキレートを形成するべき能力を有すると知られている。カルシウムは血液凝固において役割を有することが知られている一つの因子であるので、抗凝固活性におけるＥＤＴＡの効能の少なくとも一部はこの手段によりもたらされることがあり得ると信じられる。クエン酸ナトリウムもまた、不溶性クエン酸カルシウムを発生するべきその能力により抗凝固性質を有すると信じられる。
【０１０８】
前記の酸抗凝固剤は、遊離酸状態にて単独で用い得るが、しかし一層しばしばそれらのカルボン酸基のいくらかもしくは全部が適切な塩基で中和されて用いられまたは同様な塩と組み合わされる。一般に、水溶液中に可溶である塩を形成するカチオン、たとえば、アルカリ金属イオン、たとえばナトリウムまたはカリウムを用いることが望ましい。クエン酸亜鉛も用い得る。ナトリウムまたはカリウム塩、特にナトリウムが通常好ましく、そしてＥＤＴＡの二ナトリウム塩およびクエン酸ナトリウムが最も好ましい。
【０１０９】
酸および／または塩は、所望の抗凝固効果をもたらすのにおよび同時に生物学的使用にとって適切なｐＨをもたらすまたはもたらすのを助けるのに有効な濃度にて用いられる。典型的には、本発明の組み合わされた殺生物剤および抗凝固剤の組成物は、約３．０〜約７好ましくは約３．５〜約６．５、一層好ましくは約４．５〜約６．５の範囲のｐＨを有する。組成物は、通常、生理学的ｐＨにある。必要なら、ｐＨは、追加の酸または塩基、たとえば、鉱酸、たとえば、塩酸、または、好ましくはアシドーシスを引き起こさないもの（たとえば、酢酸、リンゴ酸、グルタミン酸、アスパラギン酸または乳酸）により調整し得る。当業者に精通されているところのｐＨを調整するための他の方法もまた用い得る。好ましいところのクエン酸三ナトリウムおよびクエン酸が本発明の実施において用いられる場合、クエン酸三ナトリウムは、典型的には、１リットル当たり約５〜約５０グラムの濃度範囲にて用いられる。クエン酸が、次いで、ｐＨを所望のレベルをもたらすのに十分な量で添加される。
【０１１０】
本発明の方法は、主として、すでに適所にある内部補てつ装置中への殺生物剤／抗凝固剤組成物を導入することに関するけれども、当業者は、体の外部の人工表面をこれらの組成物と接触させることはその埋没後かかる表面における血液凝塊の付着を防止しおよび細菌増殖にとっての部位の排除を助成し得ることを理解するであろう。かくして、内部補てつ装置は、細菌増殖にとっての好都合な部位を呈する血液凝塊に因る閉塞を予防しそしてそれにより後続し得る感染を予防するために、本発明の実施において用いられる組成物により内面にておよび／または外面にて予備処理し得る。かかる外面処理は、典型的には、組成物を装置の外面上の適所に一時的に保持しそして次いでゆっくりそれらの放出を可能にする手段、たとえば、適合に応じて、多孔性材料、半透膜、カチオンまたはアニオン種、等を用いる。装置の内面は、初めに組成物でそして次いで挿入後上記に参照されるような反復的な周期的フラッシングで処理し得る。
【０１１１】
更に、本発明は、主としておよび好ましくは、埋没血液透析カテーテルの開存性および無菌性を維持することに向けられているけれども、有益な効果はまた、他の同様な内部補てつ装置へのその適用により得ることができ、しかしてかかる装置は、排液管、腹膜透析用カテーテル、中心静脈カテーテル、末梢静脈内カテーテル、動脈カテーテル、スワン−ガンツカテーテル、臍カテーテル、経皮非トンネル状シリコーンカテーテル、カフ付きトンネル状中心静脈カテーテル並びに皮下中心静脈ポートを含むが、しかしこれらに限定されない。
【０１１２】
本発明の様々な特徴および観点は、更に以下の例において説明される。これらの例は本発明の範囲内における実施の仕方を当業者に示すために呈示されているけれども、それらは、本発明の範囲における限定として供するようには決して意図されていない。
【０１１３】
例１
リンガー−乳酸塩溶液（独国ビベラッハのＴｈｏｍａｅ）中のタウロリジンの０．５％溶液を、３０ｍＬ容積を有する４本のポリエチレンボトルの各々中に導入した。充填容量は、５、１０および１５ｍＬであった。一つのボトルには、５ｍＬの該タウロリジン溶液および２ｍＬのＡＣＤ−Ａ（独国バッドホンブルグのＦｒｅｓｅｎｉｕｓ）を満たした。ＡＣＤ−Ａ溶液は、全血の保存のために用いられ、そして１リットル当たり２２．０グラムのクエン酸ナトリウム二水和物、７．３グラムのクエン酸および３４．５グラムのグルコース一水和物を含有する。
【０１１４】
血液を屠殺場にて雌ブタから屠殺創傷から直接的に該容器中に採集し、しかして該容器をその際３０ｍＬのレベルまで満たした。これらの容器に蓋をし、そして穏やかに動かして血液を該溶液と混合した。これらの容器を、３０分後検査した。タウロリジンのみを含有する容器中の血液は凝固したが、しかしタウロリジンとＡＣＤ−Ａの混合物を含有する容器中の血液は凝固しなかった。かくして、タウロリジンと組み合わせてのクエン酸ナトリウムおよびクエン酸抗凝固剤の使用は、実質的に高められた抗凝固性を全血にもたらすということが結論される。
【０１１５】
例２
本発明の実施において用いられかつ米国特許第５，９５４，６９１号に記載されているタイプの皮下に埋没可能なチタン製ポートシステム（以後、ＤＩＡＬＯＣＫ（登録商標）ポート）が、この例において用いられる。それは、先端が右心房中に導入される２つの１２フレンチシラスチック製カテーテルと連結される。ポートの弁は、上記のような２本の特殊針により開放されて、約３００ｍＬ／分の血流を許容する。
【０１１６】
ポートは、平均年齢が６８．９歳である１０人の女性および６人の男性の患者に彼等のインフォームドコンセント後、熟練腎臓病学者により埋没された。１６人の患者のうち９人は、糖尿病患者であった。この調査についての患者の包含基準は、血液透析のために利用し得る腕において血液アクセス部位をもたらさない管疲はいであった。１６人のうち８人は重いうっ血性心不全を患っており、そしてすべてが高い共存症を有していた。患者のうち９人は埋没直後に血液透析を開始し、そしてその他の者は長期の血液透析中でありそしてカテーテルからポートシステムに切り替えた（４人の患者は、誘導ワイヤによる交換）。周術期の合併症は起こらなかった。
【０１１７】
好ましい管は右内頸静脈であったが、しかし外頸および鎖骨下静脈もまた用いられた。装置は、今までのところ、１１．０年の患者年数の総継続期間用いられてきた。ポートは、すべての計画ＩＩＤセッション（ｎ＝１２００）について用いられた。
【０１１８】
装置の内腔内汚染を避けるために、抗微生物剤ロックがセッション間に適用されそして次の処置の前に除去された。この水性抗微生物性殺生物剤ロックは１３．３グラム／リットルのタウロリジン、１リットル当たり６．７グラムのクエン酸三ナトリウムおよび１リットル当たりおおよそ３．３グラムのクエン酸を含んでいた。該クエン酸は、ｐＨ範囲を４．７５〜５．２５に調整するために添加された。これらのクエン酸およびクエン酸ナトリウムにより、カテーテルの凝固は防止されそしてヘパリンの適用は不必要であった。
調査の期間中、菌血症（エス・アウレウス（Ｓ．ａｕｒｅｕｓ））の２つの症状出現が観察され、そして装置の損失なしに首尾よく処置された（１０００日当たり０．５感染）。
【０１１９】
例３
この例において、例２に記載された皮下に埋没可能なＤＩＡＬＯＣＫポートが用いられた。
管疲はいが、血液透析患者における増大する問題である。１９９８年６月から開始する有望な複中心パイロット試用において、３１個のポートが、１９人の女性および１２人の男性の患者（平均年齢６６歳，最低３０歳，最高８１歳）に埋没された。新規装置の受容に加えて、この調査の目標は、いかなる病原微生物に対しても、多抵抗性を有するものに対してさえ、優秀な効能でもって、完全に無毒の殺生物性混合物（抗感染物質としてのタウロリジンおよび凝固阻止用のクエン酸／クエン酸ナトリウムを含有するヘパリン不含殺生物剤ロック）により支持される感染の回避であった。
【０１２０】
１０個の関与センターにおいて、ポートは、調査の開始以来損失されなかった（３，８４７日の埋没）。高い共存症にもかかわらず、２人の患者しか、血流関連感染（エス・アウレウス（Ｓ．ａｕｒｅｕｓ））を経験しなかった。総観察感染は、１０００日当たり０．５であった。全身性抗生処置は、成功であった。先在的カテーテル関連敗血症は、５／３１の患者に起こった。再発は、皮下に埋没可能なＤＩＡＬＯＣＫ（登録商標）ポートを用いる患者に起こらなかった。
【０１２１】
入院は短期であり、そしてアクセスは埋没直後に用いられた。受容は、カテーテルからポートに切り替えた患者（１２／３１）においてさえ高かった。６／３１の患者において、誘導ワイヤによる交換が可能であった。通常の設置技法は、３人の腎臓病学者により適用されたセルディンガーであった。好ましい管は、右内頸静脈（１８／３１）であったが、しかしすべての他の中心静脈が用いられた。
この調査の結果は、表１に示されている。
カテーテルの不利に比べて、ＤＩＡＬＯＣＫ（登録商標）ポートシステムは、入浴を許容し、また非常に安全である。本発明の殺生物剤ロックと結び付いて、感染の危険は低く、また移植と同様な穿刺技法を許容する。装置の寿命は、これから確立されねばならない。
【０１２２】
例４
比較例
４つの別々の設備において、例３において上述されたものと同様な、米国における２つおよびヨーロッパにおける２つすなわちＡ、Ｂ、ＣおよびＤの調査が行われたが、但し、用いられたロック溶液は、１ｍＬ当たり２，０００から１０，０００国際単位の範囲の濃度におけるヘパリンまたはヘパリン化食塩水であった。米国における調査、すなわち、ＡおよびＢにおいて、ベンジルアルコールもまた、標準保存剤として存在した。これらの比較調査の結果は、表１に示されている。
【０１２３】
【表１】

【０１２４】
例５
実験は、人血と接触している時に十分に機能するところの最小タウロリジン／クエン酸塩殺生物剤ロック酸性度を決定するために行われた。様々な殺生物剤ロック酸濃度が、新鮮なヒト全血と重量により５０／５０にて混合された。ｐＨは、実験的にｐＨ３．０〜ｐＨ７．０まで変動された。４．０以下の殺生物剤ロック酸性度において、生じた血液混合物は、殺生物剤ロックとの１時間の接触後固くなり凝固物状になる。この固化は、凝塊が色において非常に暗くそして特質において乾いて見えるので（色または物理的性質において正常でない）、明らかに、殺生物剤ロックの酸レベルおよび正常な血液凝固に因った。殺生物剤ロックの酸性度がｐＨ５．０より高く維持された場合、血液凝固は起こらずそして血液の色は健康な赤色のままであった。かくして、タウロリジン殺生物剤ロックの酸性度についての最も好ましい下限は約５．０である。
【０１２５】
例６
敗血症の危険は、埋没静脈カテーテルのアキレス腱である。抗生物質でのロック技法は、普及しておらず、また真菌感染を避け得ない。本発明に従って、抗感染性殺生物剤ロックが、ＤＩＡＬＯＣＫポートシステムと一緒になされる適用のために開発された。皮下埋没ＤＩＡＬＯＣＫポートは、先端が右心房中に導入される２つの１２フレンチシラスチック製カテーテルと連結される。ポートの弁は、２本の特殊針により開放されて、３００ｍＬ／分までの血流を許容する。
【０１２６】
充填溶液は、タウロリジン、すなわち真菌および多耐性病原微生物に対して効能を有する抗敗血症物質を含む。クエン酸およびクエン酸ナトリウムと組み合わせにより、カテーテルの凝固は阻止され、またヘパリンの適用は不必要である。該混合物は、絶対的に無毒であり、そしていかなる害も伴うことなく静脈内に注入し得る。装置およびカテーテルの内腔内汚染を避けるために、抗感染性ロックがセッション間に適用されそして次の処置の前に吸引により除去される。
【０１２７】
１９９８年６月に開始する複中心パイロット試用において、２８個のポートが、１８人の女性および１０人の男性の患者（平均年齢６８±９歳）にインフォームドコンセント後、３人の熟練腎臓病学者により１９９９年１月まで埋没された。
【０１２８】
８つの透析センターが、この調査に関与した。包含基準は、管疲はいであった。８／２８の患者は重いうっ血性心不全を患っており、そしてすべてが高い共存症を有していた。埋没直後の血液透析（ＨＤ）の開始は１３人の患者であり、その他の患者は長期のＨＤ中であり、そして５人の患者はカテーテルからポートに切り替えた（誘導ワイヤによる交換）。好ましい管は、右内頸静脈（ＩＪＶ，ｎ＝１６）であり、その他のものは、左ＩＪＶ（ｎ＝４）、両鎖骨下静脈（ｎ＝８）および１人の患者における外頸静脈であった。装置の総継続期間は、９人の患者において６ヶ月より多い３，０６８日であった。ポートの穿刺は、アルコールでの皮膚消毒後いかなる特殊な手法を用いることなくなされた。
【０１２９】
４人の患者は埋没の直前または時間中にカテーテル感染の故に敗血症の症状出現を有した事実にもかかわらず、装置の感染は、更なる経過中起こらなかった。エス・アウレウス（Ｓ．ａｕｒｅｕｓ）での血流関連感染の２つの症状出現が、調査期間中観察され、そして装置の損失なしに首尾よく処置された（０．６５感染／１０００日）。一方の患者は、調査の開始の４ヶ月前に脊椎炎を発現しそして埋没カテーテルを有し、そして積極的血液培養を持った他方の患者はエム・クローン（Ｍ．Ｃｒｏｈｎ）に因る免疫抑制治療を受けた。
【０１３０】
例７
コアグラーゼ陰性ブドウ球菌、カンジダ・アルビカンス（Ｃａｎｄｉｄａ ａｌｂｉｃａｎｓ）、スタフィロコッカス・アウレウス（Ｓｔａｐｈｙｌｏｃｏｃｃｕｓ ａｕｒｅｕｓ）、エンテロコッカス（Ｅｎｔｅｒｏｃｏｃｃｕｓ）およびシュードモナス・エルジノーサ（Ｐｓｅｕｄｏｍｏｎａｓ ａｅｒｕｇｉｎｏｓａ）の臨床血液分離菌を、トリプチカーゼダイズブイヨン中に接種し、そして培養物が可視的に濁るようになるまで３７℃にてインキュベートした。段階希釈を行って、エス・アウレウス（Ｓ．ａｕｒｅｕｓ）、エンテロコッカス（Ｅｎｔｅｒｏｃｏｃｃｕｓ）およびシュードモナス・エルジノーサ（Ｐｓｅｕｄｏｍｏｎａｓ ａｅｒｕｇｉｎｏｓａ）について１０コロニー形成単位（ｃｆｕ）／０．１ｍＬ、カンジダ（Ｃａｎｄｉｄａ）について５ｃｆｕ／０．１ｍＬ、コアグラーゼ陰性ブドウ球菌およびエンテロバクター（Ｅｎｔｅｒｏｂａｃｔｅｒ）について１００ｃｆｕ／０．１ｍＬの最終細胞密度が得られた。最終希釈液から、０．１ｍＬをＤＩＡＬＯＣＫポートチューブの各遠位端中に滴注し、そしてＤＩＡＬＯＣＫポートを室温にて一晩インキュベートした。
【０１３１】
インキュベーション後、普通のシリコン製カテーテルを、各ＤＩＡＬＯＣＫポートの両側の遠位端に置いた。５０００Ｕ／ｍＬのヘパリン（保存剤と共に）の溶液または２％クエン酸化タウロリジンの溶液を該ＤＩＡＬＯＣＫポートの近位端を通じて滴注して、ＤＩＡＬＯＣＫポートおよびカテーテルを満たした。該カテーテルをクランプ固定し、そして該ＤＩＡＬＯＣＫポート／カテーテルを３７℃にて７２時間インキュベートした。
【０１３２】
このインキュベーション後、両方のカテーテルを各ＤＩＡＬＯＣＫポートから取り外し、そして各々を０．１ｍＬの栄養ブイヨンでフラッシングした。各フラッシング物の０．１ｍＬアリコートを血液寒天平板上で培養して、残存生物体の数を決定した。それらの結果は、表２に示されている。
【０１３３】
【表２】

【０１３４】
^*寒天平板上でカンジダ・アルビカンス（Ｃａｎｄｉｄａ ａｌｂｉｃａｎｓ）の増殖なし。しかしながら、おそらくカテーテル外面からの、汚染物（コアグラーゼ陰性ブドウ球菌およびコリネバクテリウム）の数個のコロニーがあった。^**寒天平板上でピー・エロジノーサ（Ｐ．ａｅｒｏｇｉｎｏｓａ）の増殖なし。
しかしながら、おそらくカテーテル外面からの、汚染物の２個のコロニーがあった。
【０１３５】
本発明の根底にある原理から逸脱することなくなし得る多くの変更および改変にかんがみて、本発明に与えられる保護の範囲の理解のために、請求の範囲が参照されるべきである。
【図面の簡単な説明】
【図１】図１は、本発明の埋没アクセス装置の横断面図である。
【図２】図２は、本発明の装置の第２態様の横断面図である。
【図３】図３は、本発明の装置の第３態様の横断面図である。
【図４】図４は、針が挿入されている図３に示された態様の横断面図である。
【図５】図５は、図３に示された態様の弁の横断面図である。
【図６】図６は、図３に示された態様のロッキングマウントの横断面図である。
【図７】図７は、図３に示された態様の弁受座マウントの横断面図である。
【図８】図８は、図３に示された態様の遠位ハウジングの横断面図である。
【図９】図９は、滑動性シール−一体摩擦ロックを有する本発明の装置の第４態様の横断面図である。
【図１０】図１０は、縦方向滑動性シールを有する本発明の装置の第５態様の横断面図である。
【図１１】図１１は、トランペット型弁を有する本発明の装置の第６態様の横断面図である。
【図１２】図１２は、針が挿入された図１１に示された態様の横断面図である。
【図１３】図１３は、膨張可能なシールを有する本発明の装置の第５態様の横断面図である。
【図１４】図１４は、好ましい針および閉塞具の組立体の横断面図である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to prosthetic devices for internal use in patients (hereinafter “internal prosthetic devices”), in particular catheters and ports, and compositions for their flushing and coating to prevent infection and blood clotting. Things and methods. In accordance with the present invention, a biocide / anticoagulant composition is provided for use in flushing and coating internal prosthetic devices, particularly ports and catheters.
[0002]
[Prior art]
Hemodialysis access systems for accessing the vascular system of a human or animal patient for the exchange of blood between the vascular system and an external processing device are well known in the art. One method involves a catheter placed in a patient, with one end extending into the central venous system and the other end being placed in the patient's body, commonly referred to as a “port”. Attached to one of the possible devices. Herein, a “tube” is defined as a conduit that carries fluid within a patient's body. These devices generally include a chamber having an access opening sealed by a septum and having an outlet from a second location leading to a catheter disposed within the fluid space or tube. The septum allows a needle to pass through the chamber, but then closes when the needle is removed, thereby preventing leakage from within the space or tube and also anything entering or exiting the chamber. To prevent. These devices are usually buried under the skin to prevent infection, other contamination and mishandling.
[0003]
Recently, improved devices of this class have been developed and described in US Pat. No. 5,954,691 and US patent application Ser. No. 09 / 083,078 filed May 21, 1998. These inventions provide hemodialysis for access to the vascular system of a human or animal patient for high fluid flow exchange of blood between the vascular system and an external processing device at a volumetric flow rate exceeding 250 mL / min. An access system,
(A) a needle set that includes a lumen defined by an inner surface and is configured and arranged to pierce the patient's skin and to carry and pass blood at a flow rate consistent with the high blood flow requirements of the blood exchange process Solid,
(B) a subcutaneously implantable access device that allows fluid connection to a tube or space in the patient's body, the device comprising:
(I) providing a flow path having a linear or gently changing flow direction and having a distal end and a proximal end with respect to the inner surface and the patient's skin puncture site and insertion of a needle through the proximal end of the channel; A channel structure constructed and arranged to remove the needle therefrom;
(Ii) a seal disposed within the channel and movable between a first and second position, wherein the fluid passes through the seal with the needle not inserted into the seal in the first position. And allows fluid to pass through the needle and emerge substantially at the distal end of the channel with the needle inserted into the seal in the second position and when the sealing means is in the second position. The above-mentioned seal wherein the blood flow transition between the inner surface and the channel inner surface is substantially continuous and smooth
And the apparatus further includes a structure for joining the distal end of the channel to the catheter extending to the inner tube of the patient's body, the joint being continuous and continuous along the inner surface of the channel and the inner surface of the catheter. Access device that is smooth
Is directed to the above hemodialysis access system.
[0004]
As with any invasive procedure, prevention of infection has been a problem, especially with devices that must remain in place for an extended period of time. Coagulation of blood in and around the catheter and / or port has also been found to be troublesome and to prevent occlusion of the catheter (which can reduce or destroy its usefulness), particularly for its prevention. Is needed. A considerable amount of research has been devoted to alleviating these problems.
[0005]
It is standard practice to flush the catheter and / or port with an anticoagulant such as heparin. However, heparin is not antibacterial and in addition, if not carefully controlled, it can transmit the anti-aggregation process too far, thereby presenting a risk of bleeding. The use of antibiotics with anticoagulants is also known in the art, but when this is done, hybrid microorganisms that are immune to the applied antibiotic, as is usual with antibiotics, are used. Increased chance of being made. For this reason, it is desirable in medical technology to minimize the amount of antibiotic used to maintain efficacy over a long period of time.
[0006]
U.S. Pat. No. 4,107,305 discloses a method of combating endotoxemia by administering an effective amount of a tauroline composition.
U.S. Pat. No. 4,445,889 is a method for preventing infection in a patient introduced through an indwelling catheter, the patient being connected to the catheter, the catheter being connected to a fluid receiving container, Place a biocide dispensing device and release the biocide into the fluid in the container for prevention of the growth of infectious bacteria in the container and concomitant introduction into the catheter and the patient The above method is disclosed.
[0007]
US Pat. No. 4,587,268 is a composition for the treatment of wounds in which one or more water soluble drugs (preferably antibiotics or methylol transfer antibacterials) are dissolved or dispersed. Disclosed is the above composition comprising a resorbable aqueous gel.
U.S. Pat. No. 4,626,536 discloses the use of taurolin compounds to combat toxic proteins or peptides, such as venoms, fungal toxins and bacterial exotoxins, in the bloodstream of humans or warm-blooded animals.
[0008]
U.S. Pat. No. 4,797,282 is a drug depot that can be embedded in the body for the controlled delayed release of a cytostatic agent, comprising a polyacrylate containing the cytostatic agent and at least one amino acid, and Disclosed above is a drug depot comprising a synthetic material based on polymethacrylate.
US Pat. No. 4,853,225 is an implantable drug depot useful for combating infection, comprising a physiologically acceptable excipient and at least one delayed release active compound (gyrase inhibition) The drug depot is disclosed comprising a drug type chemotherapeutic agent).
[0009]
U.S. Pat. No. 4,960,415 is a device for insertion into wounds and wound holes, comprising a container containing a pharmaceutically active substance, the wall of the container containing the active substance Disclosed is a device as described above consisting at least in part of a membrane, preferably a semi-permeable membrane, that escapes into the wound area. The container is more preferably a dialysis tube. In order to drain wound secretions, the container containing a pharmaceutically active substance, in particular taurolidine, is conveniently connected to a drainage tube. Preferably, a drain tube is used in which the end leading into the wound is torn into filaments.
[0010]
US Pat. No. 5,077,281 discloses the use of tauroline compounds as blood clotting inhibitors and as non-bacterial inflammation inhibitors. According to this patent, tauroline has a significant anticoagulant effect and is particularly suitable for use in medical situations requiring dialysis and for vascular prosthetic devices. It is also disclosed that these compounds can be used in conjunction with other anticoagulants such as coumarin or peppertin.
[0011]
US Pat. No. 5,093,117 discloses pharmaceutical compositions that are said to be useful for the treatment or prevention of Gram-negative bacteremia or septic shock. These compositions contain a bactericidal effective amount of polyclonal immunoglobulins against Gram negative bacteria and a clot lysis effective amount of protein C. The composition may further contain one or more protein C cofactors and monoclonal antibodies against gram negative bacterial endotoxin. Methods for the treatment or prevention of gram-negative bacteremia or septic shock include either a polyclonal immunoglobulin against a sterilizing effective amount of gram-negative bacteria and a clot lysis effective amount of protein C, either together or separately. Administration. The method can optionally include administering a monoclonal antibody against one or more protein C cofactors and gram negative endotoxin.
[0012]
U.S. Pat. No. 5,210,083 discloses an aqueous solution containing an effective concentration of taurolidine and / or taurultam, together with a parenterally acceptable polyol, in bacteria. The aqueous solution is said to be particularly suitable for parenteral administration.
US Pat. No. 5,362,754 discloses a pharmaceutical composition of a mixture of minocycline and EDTA (M-EDTA) and methods of using the composition in maintaining the efficacy of a catheter port. A method of blocking the formation of polysaccharide-enriched glycocalyx (eg, glycocalyx of staphylococcal organisms) is also provided using M-EDTA solutions. M-EDTA solutions can also be used to pre-treat medical devices to prevent the attachment of infectious organisms such as S. epidermis and S. aureus. The composition destroys and prevents the formation of polysaccharide-enriched glycocalyx.
[0013]
US Pat. No. 5,545,213 has a graft polymer with an effective ionic charge attached to the surface of a polymer support to provide an improved method for administering a bioactive agent having an effective ionic charge. Disclose the article. The article is said to be particularly useful as a thrombus resistant and / or antimicrobial medical device.
US Pat. No. 5,593,665 describes tumor necrosis factor and taurolidine as a simultaneous, separate or sequential use combination formulation for the treatment of patients suffering from medical conditions mediated by tumor necrosis factor. Disclosed are products containing / and taurultam.
[0014]
US Pat. No. 5,688,516 discloses compositions and methods of using the compositions in flushing and coating medical devices. The composition comprises a selected combination of a chelating agent, anticoagulant or antithrombotic agent and a non-glycopeptide antimicrobial agent, such as a tetracycline antibiotic. Methods for using these compositions to coat medical devices and to prevent catheter infections are also disclosed. Certain combinations include minocycline or other non-glycopeptide antimicrobial agents in combination with EDTA, EGTA, DTPA, TTH, heparin and / or hirudin in a pharmaceutically acceptable diluent.
[0015]
US Pat. No. 5,718,899 contains a high concentration of the full range of immunoglobulins used to combat infection from microorganisms and viruses in wounds, surgery or burn sites, or normal tissues at the time of risk of infection A composition is disclosed. The composition can be attached to biological or bacterial attachments or biofilms so that pathogen attachment is blocked and the pathogen closest to the wound or burn site is pre-opsonized for phagocytic lethality prior to toxin release. Prior to formation, it is applied directly to the wound or burn site as an ointment, cream, fluid, spray, etc. The immunoglobulin in the composition may be immobilized on biocompatible materials such as collagen, fibrin, hyaluronan, biodegradable polymers and fragments thereof that are placed in situ at the site of the wound, surgery or burn. In addition, the immunoglobulin in the composition can be coated on the body contacting surface of an implantable device such as a catheter, contact lens or total joint. The composition is said to have particular use in preventing infection.
[0016]
US Pat. No. 5,752,941 discloses central venous polyurethane catheters with a thin hydrophilic coating to which ramoplanin antibiotics or mixtures thereof have been added, and their use in preventing catheter-related infections. To do. These catheters are said to be useful to prevent bacterial adherence and colonization and thus reduce the risk of vascular infection in patients who have been catheterized. The method for producing the catheter of the invention consists in incubating a polyurethane catheter coated with a hydrophilic thin film in an aqueous solution of a selected antibiotic.
[0017]
US Pat. No. 5,783,570 discloses an organic solvent soluble mucopolysaccharide comprising an ionic complex of at least one mucopolysaccharide (preferably heparin or a heparin derivative) and a quaternary phosphonium, the organic solvent soluble mucopolysaccharide and Disclosed is an antibacterial and antithrombogenic composition comprising an antibacterial agent (preferably an inorganic antibacterial agent such as silver zeolite), as well as a medical material comprising the organic solvent soluble mucopolysaccharide. The organic solvent soluble mucopolysaccharides, and antibacterial and antithrombogenic compositions and medical materials containing the same, easily impart antithrombogenic and antibacterial properties to polymers that are to be substrates, and these Properties are said to be maintained not only immediately after the manufacture of this material, but also after long-term elution.
[0018]
US Pat. No. 5,788,979 coats a biomaterial to be placed in contact with a patient's bloodstream to prevent blood clotting from adhering to the biomaterial that would otherwise result from such contact A method is disclosed. A liquid biodegradable material that is compatible with human blood and tissue is produced and an anticoagulant drug is incorporated into the liquid state of the biodegradable material to form a liquid coating material. The liquid coating material is a surface of the biomaterial in a substantially continuous overlapping layer having a formulation, pattern and thickness selected according to the period during which the coating material is to perform its anticoagulant action. Is applied adhesively. The coating material is then dried to a layer thickness of less than about 100 microns for continuous disintegration as a function of time when the layer is in contact with blood.
[0019]
Gorman et al., “J. Clin. Pharm. Ther.” 12: 393-399 (1987) reported the investigation of three antimicrobial agents, namely taurolidine, chlorhexidine and povidone-iodine, for microbial anti-adhesive activity. Two attachment systems were examined: Candida albicans oral isolates on human buccal epithelial cells and E. coli urine isolates on human urethral epithelial cells. Each of the three drugs showed significant anti-adhesion activity and the activity was concentration dependent.
[0020]
Root et al., “Antimicrobial Agents and Chemotherapy” 32 (11): 1627-1631 (1988) suggests that patients with granulocytopenia with an intravascular catheter are at increased risk for infection with S. epidermis. I reported that. It is common practice to maintain patency of the catheter lumen with a solution containing heparin during periods when the catheter is not used for infusion. The authors have shown that heparin does not prevent the growth of S. epidermis isolated from the catheters of infected patients. A 20 mg / mL solution of disodium EDTA, a chelating agent that effectively anticoagulates blood at this concentration, is 10 per mL. ^Three An initial inoculum of CFU staphylococci was shown to be bactericidal at 24 hours. Vancomycin, an antibiotic often used to treat staphylococcal infections, is also available at a dose of 6.7 μg / mL, a drug concentration in the therapeutic range. ^Three The initial inoculum of CFU / mL was found to be bactericidal. In light of the low cost, anticoagulant efficacy and bactericidal activity of EDTA, the authors recommended that EDTA be studied as an alternative to heparin solution for intravenous catheter maintenance in patients with granulocytopenia.
[0021]
Jones et al., “J. Appl. Bacteriol.” 71: 218-227 (1991) are the clinical strains E. coli, S. saprophyticus, S. epidermidis (S. The effects of three non-antibiotic antimicrobial agents, namely taurolidine, chlorhexidine acetate and povidone-iodine, on the surface hydrophobicity of epidermidis and C. albicans were investigated. All three drugs were found to alter cell surface hydrophobicity at concentrations reported to interfere with microbial-epithelial cell attachment. However, these effects did not show a uniform relationship. In general, taurolidine and povidone-iodine treatment reduced the hydrophobicity of the investigated strains, whereas the effect of chlorhexidine acetate was dependent on the treated microorganism.
[0022]
Traub et al., “Chemotherapie” 39: 322-330 (1993) against a representative number of multi-antibiotic resistant bacterial isolates in broth and in the presence of bovine and human serum and fresh defibrinated human blood. Taurolidine was investigated for bactericidal activity. The author recommends that this antimicrobial substance be produced by a glycopeptide resistant strain of E. faecium, S. aureus (GRMRSA) or enterobacteriaceae that produces a broad spectrum of β-lactamases. Suggested that it can be used for local treatment of patients colonized or superficially infected.
[0023]
Willatts et al., “Crit. Care Med.” 23 (6): 1033-1039 (1995), Taurolidine is a clinical bacteriological outcome, progression of endotoxemia, resolution of organ failure and 28 days as endpoint. Using mortality, we reported that there was no beneficial therapeutic effect on the outcomes of patients placed in the intensive care unit of a university hospital with sepsis syndrome.
[0024]
Darrouche et al., Nutrition 13 (4) (augmentation): 26S-29S (1997), prevention of vascular catheter-related infections is mostly focused on preventing attachment of microorganisms from either the skin or catheter hub to the catheter Reported. They have described two general approaches that can be used non-dedicated for the successful prevention of vascular catheter-related infections. The first approach does not use antimicrobial agents and involves strategies such as vascular catheter placement and maintenance by skilled infusion therapy teams and the use of a maximum sterility barrier. The second approach is to use antimicrobial agents and apply topical antiseptics such as chlorhexidine, use of silver-impregnated subcutaneous cuffs (for short-term central venous catheters), and combinations of antimicrobial and antithrombotic agents. Catheter flushing and coating of the catheter with either preservatives (chlorhexidine and silver sulfadiazine) or antimicrobial agents (minocycline and rifampin).
[0025]
In a lecture presented at the 30th Annual Meeting of the American Society of Nephrology on November 2-5, 1997 in San Antonio, Texas, Sodemann et al. A 4-year trial of a gentamicin / sodium citrate mixture as an antibiotic lock technique was reported. They concluded that replacement of the catheter due to infection could be avoided by routine application of concentrated gentamicin / citrate mixture, as well as even relieving an intraluminal contamination catheter.
The disclosures of the foregoing are hereby incorporated by reference in their entirety.
[0026]
[Problems to be solved by the invention]
Despite the above contributions to the art, there is a need for safe and effective methods for the prevention of infection and blood clotting in patients whose illness requires the implantation of internal prosthetic devices such as catheters and ports. It continues.
[0027]
[Means for Solving the Problems]
In accordance with the present invention, a biocide / anticoagulant composition is provided for use in flushing and coating internal prosthetic devices, particularly catheters and ports.
The present invention is an internal prosthetic device,
(A) means for providing a continuous flow path across the patient's skin between the external site for the patient and the internal site for the patient;
(B) means for blocking the flow path; and
(C) a biocide lock,
(I) an anticoagulant and
(Ii) non-antibiotic biocides
Including biocide lock
Directed to an internal prosthetic device including
[0028]
More particularly, the present invention is an internal prosthetic device access system comprising:
(A) means for providing a continuous flow path across the patient's skin between the external site for the patient and the internal site for the patient;
(B) means for blocking the flow path at a location under the patient's skin;
(C) means for removing a flow path portion across the patient's skin; and
(D) a biocide lock,
(I) an anticoagulant and
(Ii) non-antibiotic biocides
Including biocide lock
Directed to an internal prosthetic device access system.
[0029]
In a particularly preferred embodiment, the present invention is a hemodialysis access system comprising:
(A) means for providing a continuous flow path across the patient's skin between the external dialysis site and the patient's internal blood vessel to the patient, the means having a gentle direction change only And the inner surface of the flow conduit is smooth and does not have a sudden change in the basin and defines a flow path that is sized for the hemodialysis flow rate, and is free of obstruction and resulting in low flow resistance and The above means to avoid any stagnation point,
(B) means for blocking the flow path at a location under the patient's skin;
(C) means for removing a flow path portion across the patient's skin; and
(D) a biocide lock,
(I) an anticoagulant and
(Ii) non-antibiotic biocides
Including biocide lock
Directed to a hemodialysis access system including:
[0030]
In another preferred embodiment, the present invention provides a human or animal patient's vasculature for high fluid flow exchange of blood between the vasculature and an external processing device at a volumetric flow rate greater than 100 mL / min. A hemodialysis access system for access to the body and with a reduced tendency to cause infection and blood clotting,
(A) a needle configured and arranged to pierce the patient's skin and to carry and pass blood at a flow rate consistent with the high blood flow requirements of the blood exchange process, including a lumen defined by the inner surface Assembly,
(B) a subcutaneously implantable access device that allows fluid connection to a tube or space in the patient's body, the device comprising:
(I) providing a flow path having a linear or gently changing flow direction and having a distal end and a proximal end with respect to the inner surface and the patient's skin puncture site and insertion of a needle through the proximal end of the channel; A channel structure constructed and arranged to remove the needle therefrom;
(Ii) a seal disposed within the channel and movable between a first and second position, wherein the fluid passes through the seal with the needle not inserted into the seal in the first position. And allows fluid to pass through the needle and emerge substantially at the distal end of the channel with the needle inserted into the seal in the second position and when the sealing means is in the second position. The above-mentioned seal wherein the blood flow transition between the inner surface and the channel inner surface is substantially continuous and smooth
And the apparatus further includes a structure for joining the distal end of the channel to the catheter extending to the inner tube of the patient's body, the joint being continuous and continuous along the inner surface of the channel and the inner surface of the catheter. The access device being smooth, and
(C) a biocide lock,
(I) an anticoagulant and
(Ii) non-antibiotic biocides
Including biocide lock
Directed toward the hemodialysis access system.
[0031]
In a particularly preferred embodiment, the access system comprises a device constructed and arranged to be implanted between the device at the proximal catheter end and the patient's blood vessel at or into the distal catheter end, and the surrounding patient. Further comprising means for attaching to the tissue.
[0032]
Preferred embodiment
As stated above, in a preferred aspect, the present invention is an internal prosthetic device access system comprising:
(A) means for providing a continuous flow path across the patient's skin between the external site for the patient and the internal site for the patient;
(B) means for blocking the flow path at a location under the patient's skin;
(C) means for removing a flow path portion across the patient's skin; and
(D) a biocide lock,
(I) an anticoagulant and
(Ii) non-antibiotic biocides
Including biocide lock
Directed to an internal prosthetic device access system.
Preferably, the present invention is for access to the vascular system of a human or animal patient for high fluid flow exchange of blood between the vascular system and an external processing device at a volumetric flow rate greater than 100 mL / min. And a hemodialysis access system with a reduced tendency to cause infection and blood clotting,
(A) a needle set that includes a lumen defined by an inner surface and is configured and arranged to pierce the patient's skin and to carry and pass blood at a flow rate consistent with the high blood flow requirements of the blood exchange process Solid,
(B) a subcutaneously implantable access device that allows fluid connection to a tube or space in the patient's body, the device comprising:
(I) providing a flow path having a linear or gently changing flow direction and having a distal end and a proximal end with respect to the inner surface and the patient's skin puncture site and insertion of a needle through the proximal end of the channel; A channel structure constructed and arranged to remove the needle therefrom;
(Ii) a seal disposed within the channel and movable between a first and second position, wherein the fluid passes through the seal with the needle not inserted into the seal in the first position. And allows fluid to pass through the needle and emerge substantially at the distal end of the channel with the needle inserted into the seal in the second position and when the sealing means is in the second position. The above-mentioned seal wherein the blood flow transition between the inner surface and the channel inner surface is substantially continuous and smooth
And the apparatus further includes a structure for joining the distal end of the channel to the catheter extending to the inner tube of the patient's body, wherein such joining is continuous and smooth along the inner surface of the channel and the catheter. The access device, and
(C) a biocide lock,
(I) an anticoagulant and
(Ii) non-antibiotic biocides
Including biocide lock
Directed toward the hemodialysis access system.
[0033]
A “biocide lock solution” as used herein replaces body fluids such as blood from an internal prosthetic device, such as a catheter lumen, making the lumen space unsuitable for microorganisms and the device. It is a solution of biocide lock that prevents coagulation of residual blood in it.
[0034]
A preferred subcutaneously implantable device of the present invention comprises (a) an access guide having a penetration channel and (b) a catheter having a penetration channel and including an access portion, a sealing portion and a distal portion. A resilient sealing means is disposed within the sealed portion of the catheter. The elastic sealing means usually prevents fluid from passing through the seal. However, when the mechanical device is inserted percutaneously and guided to the access portion of the catheter by the access guide means, the mechanical device penetrates the access portion of the catheter, engages the sealing means and pushes it. Open. This provides access to the lumen of the catheter as it extends into the lumen and ultimately to the distal portion of the catheter and ultimately from the access guidance means. The catheter is attached to the surrounding tissue that supports the catheter.
[0035]
The sealing means, in a preferred embodiment, includes a tube made of an elastic material that embodies the features of the valve mechanism within the tube lumen. The tube is disposed axially along the inner wall of the channel. A spring clamp is provided adjacent to and external to the tube and serves to compress the tube so that the inner lumen of the tube is closed, thereby preventing fluid from passing through.
[0036]
The spring clamp is arranged and configured to close the lumen of the tube so that the longitudinal transition cross-section from the open position to the closed position forms a special shape. The shape of the valve allows the tip of the needle obturator to open or push away the rubber valve slit with a pushing action as the needle is pushed through the seal. The pushing force of the needle overcomes the biasing force of the spring and the internal stress of the seal as the needle enters the seal zone without cutting the rubber. Since no cutting occurs, the rubber particles as seen for the partition at the port are not generated. Furthermore, the number of penetration cycles for failure is very high since negligible damage occurs during penetration.
[0037]
The flow transition between the needle, tube lumen and catheter has a maximum smoothness, continuous flow without sudden changes in flow diameter and only gentle flow, preferably no flow direction change. Arranged and configured to include a path. Any narrowing and spreading of the flow path is gentle and at an angle of 25 degrees or less. Any change in the direction of flow is gentle, i.e., preferably less than about 20 degrees, and in any case less than 30 degrees and at the same time a bend radius (if any) greater than about twice the diameter of the channel. Have
[0038]
The device of the present invention also includes a hollow needle device that fits matingly with the penetration channel of the access device, and an obturator that is inserted into and fills the lumen of the needle. This needle / obturator combination comprises a needle assembly having a tip and an outer surface having a smooth transition that is configured to easily puncture tissue and open the valve without damage. provide.
[0039]
The access device of the present invention is compatible with both single needle and standard hemodialysis, plasma export and fluid exchange therapy (such as peritoneal dialysis) applications. For standard applications requiring two flow paths, the housing can be arranged and configured to engage two needle assemblies as described above and can include a dual lumen penetrating channel. If two needles are used, a bar can be provided that engages each needle, thereby locking both needles together and eliminating accidental disconnection of only one needle, thereby ensuring patient safety To increase.
[0040]
The implantable subcutaneous access device of the present invention requires a flow rate of 100 mL / min or more, preferably 200 mL / min or more, with a low pressure drop along a streamline channel having substantially no stagnation point. It is important to note that it is suitable for the application. The low pressure drop and substantial elimination of the stagnation point is due to having a smooth transition point (eg, channel-catheter interface) where different elements of the device meet, and any change in lumen diameter is gradual. And having a straight or nearly straight flow path (ie, having at most a gradual change in flow direction) with no dead volume and no steep curves or protrusions in the flow path Is achieved.
[0041]
Because such large flow rates are desired with low resistance, it is necessary to use the maximum needle outer diameter that the patient will accept. Therefore, the rigidity of the puncture needle is desirable. The hard needle allows a larger bore inner diameter (ie thinner wall) per member outer diameter than the flexible tube. This is important because it allows the needle to be as small as possible, thereby reducing trauma at the patient's puncture site while still handling large flow rates. Flexible tubes have a much higher outer diameter to inner diameter aspect ratio. Thus, if a flexible material rather than a hard material is used to accommodate normal blood flow during hemodialysis, a much larger outer diameter will be required. The hard needle also allows a greater force to be transmitted to the seal to overcome the resistance force generated by the spring. Thus, greater resistance can be used to provide a stronger, more reliable and fault tolerant seal.
[0042]
Furthermore, the absence of sharp angles or bends in the flow path is much less likely to damage fragile blood cells. Since the flow path from the needle to the catheter (or vice versa) is only a gentle flow direction change (if any) and is linear or substantially linear, turbulence is minimized and shear stress Will be reduced, leading to reduced red blood cell damage and a tendency to activate platelets.
[0043]
In its simplest form, as shown in FIG. 1, the device of the present invention comprises an improved catheter 2 (skin line) having an access segment 4, a distal segment 6 and an integral valve segment 8 disposed therebetween. 1 can be placed under the skin). The improved catheter 2 has a standard inner diameter 10 and a standard outer diameter 12 almost throughout its length. However, there are some distinct deviations from these values to achieve the functional objectives of the present invention.
[0044]
At the end of the access segment 4 is a raised identification ring 14 that allows the operator to locate the subcutaneous access device inlet 16. The access segment 4 has an inwardly conical access guide portion 18 and an access alignment portion 20. The access guide portion 18 has a starting inner diameter 22 that is larger than the standard valve inner diameter 10 that tapers inwardly until the standard valve inner diameter 10 is achieved. Thus, upon insertion, the conical access guide portion 18 guides the percutaneous mating needle 40 into the access alignment portion 20 where the needle 40 having the needle end 48 is aligned with the valve slit 28. Needle 40 has a barrel outer diameter 50 that is compatible with standard valve inner diameter 10 and a barrel inner diameter 54. Needle 40 includes an obturator 42 having a conical tip for percutaneously inserting needle 40 into the device without allowing tissue to remain in the lumen of needle 40.
[0045]
The integral valve segment 8 includes a tapered valve access portion 24 and a valve portal 26 to further align the needle 40 with the valve slit 28. It is important to note that the integral valve segment 8 is most preferably molded with a solid valve sealing portion 30 where the valve slit 28 is subsequently formed. This configuration will result in a more complete seal and will require less sealing force than the flat tube.
[0046]
The integral valve segment 8 further includes an opposing tapered distal portion 32, and a valve sealing means seat 34 is formed in its outer surface in radial alignment with the valve sealing portion 30 so that the valve sealing means seat 34 is A circumferential recess in the outer surface of the segment such that the outer diameter of the catheter through the valve sealing means seat 34 is smaller than the standard outer diameter 12 but larger than the standard inner diameter 10. The valve sealing means seat 34 houses the valve sealing means 36 so that the valve sealing means 36 provides a radial biasing force sufficient to close the valve sealing portion 30 and when the device is not in use. Leave closed. In another aspect, the valve sealing means 36 may have one or more attachment tabs 38 formed therefrom or attached thereto. During implantation, one or more attachment tabs 38 are attached to the surrounding tissue so that the catheter 2 is secured throughout the integral valve segment 8 but allows lateral movement of the access segment 4 under the skin.
[0047]
The outflow segment 6 is buried such that the end is placed in a tube or space where access is desired. To begin the procedure, the operator first locates the access segment 4 through the skin using the raised identification ring 14 as a guide. The operator punctures the skin with an obturator 42 disposed within the needle 40 so that the needle-obturator assembly enters the access guide portion 18 and is aligned by the access alignment portion 20. As it continues to be inserted into the device, the needle-obturator assembly encounters the valve access portion 24 and the valve portal 26. As the tip of the obturator 42 enters the valve portal 26, the tapered leading edge of the obturator 42 presses the valve access portion 24 to overcome the radial bias force exerted by the valve sealing means 36 and thereby the needle 40. The valve slit 28 is opened so that can pass through the valve sealing portion 30. This is achieved without damage to the valve sealing portion 30. This is because needle 40 is already axially aligned with valve slit 28 by access alignment portion 20. This process is much smoother and causes less discomfort to the patient if the needle is given a medically acceptable aqueous lubricant prior to insertion.
[0048]
Because the integral valve segment 8 is formed in a closed manner and the valve slit 28 is later opened, and also because of the sealing nature of the material from which the catheter 2 is made, the valve of the present invention is applied by the valve sealing means 36. It is important to note that complete sealing is achieved with the required minimum bias force. Thus, the force that must be applied by the needle / obturator combination to overcome this bias force to allow entry of the needle / obturator combination into the valve is an essentially flat tube and If a substantially greater biasing force is not used, it is substantially less than required to close a known valve that never achieves a complete seal. This reduction in force will result in a smaller impact on the device during needle insertion and removal, thereby greatly enhancing patient comfort.
[0049]
In the second embodiment, it is contemplated that the distal segment 6 is attached to a standard medical catheter 44 by insertion of an adapter 56 therebetween, as shown in FIG. The adapter 56 has a first end disposed within the distal segment 6 and a second end disposed within the catheter 44 and is tapered such that the streamline flow path is minimally disturbed. In addition, the adapter 56 is formed in its first end with a needle seating area 58 having an inner diameter 50 ′ that matches the barrel outer diameter 50 of the needle 40. The needle seat 58a extends radially inward such that its inner diameter 54 ′ matches the barrel inner diameter 54 of the needle 40. In this embodiment, when the needle-obturator assembly is inserted into the device and axially through the seal, the needle 40 is positioned so that the streamline flow path is minimally disturbed (if any). 58a (see FIG. 1, not shown in FIG. 2).
[0050]
In the third aspect, as shown in FIGS. 3 to 8, the buried access device 100 rests under the skin line 1. Access device 100 includes guide housing 102, locking mount 104, valve 106, valve seat mount 108, valve sealing means 120, adapter 220, catheter 240 and distal housing 110 (all disposed about axis AA ′). Includes assembly. The flow path through the device, shown as axis AA ′, can accept gentle flow direction changes. A gentle flow direction change (if present) never includes a bend angle of more than about 30 degrees within a bend radius less than about twice the standard inner diameter 10, and preferably no more than 20 degrees. More preferably, no such gentle flow direction change is greater than about 20 degrees within a bend radius of at least about 4 times the standard inner diameter 10. The standard inner diameter 10 is typically between about 0.060 and about 0.105 inches.
[0051]
The guide housing 102 is an improved hollow cylinder with a partially closed first end formed in an inwardly conical needle guide surface 122, which can be used for hemodialysis, plasma removal and fluid exchange. An axial access lumen 123 is defined that is sized to receive a needle suitable for use in therapy. The guide housing 102 has an open second end with a chamfered leading edge 124.
[0052]
The locking mount 104 defines a lumen 143 formed therethrough that can accommodate a needle suitable for use in hemodialysis, plasma removal and fluid exchange therapy. The locking mount 104 is formed with a locking or actuating portion 140 having a locking surface 144 formed with a locking lumen 145 such that the locking lumen 145 communicates with the lumen 143, and a valve seat 146 having a cross-sectional diameter 146 ′. Valve mounting portion 142. The locking portion 140 is attached to the locking bias means 152 such that the locking bias means 152 movably covers the lock lumen 145. The locking means 150 is disposed within the lock lumen 145 and is biased toward the lumen 143 by the lock bias means 152. When the needle 40 is inserted into the lumen 143, the conical tip of the obturator 42 overcomes the biasing force applied to the locking means 150 by the locking bias means 152, thereby locking the means 150 as the needle 40 is inserted. Withdraw. When the needle 40 is fully inserted into the needle seat 148, the semicircular locking groove 44 is aligned with the locking means 150. The rotation of the needle 40 causes the lock biasing means 152 to push the locking means 150 into the semicircular locking groove 44A, thereby locking the needle 40 into the access device 100. To withdraw the needle 40 from the access device 100, the needle 40 is rotated again so that the locking means 150 is retracted again and the needle 40 is free to be removed.
[0053]
The valve 106 has an access segment 160, a distal segment 164, and an integral valve segment 162 disposed therebetween. Access segment 160 is disposed at its distal end with a raised seat ring 166 having a cross-sectional outer diameter 166 ′ and defining a valve inlet 163. The integral valve segment 162 includes a tapered valve access portion 170 and optionally a valve portal 172 to further align the needle 40 with the valve slit 178. The integral valve segment 162 further includes an opposing tapered distal portion 174. It is important to note that the integral valve segment 162 is most preferably molded with a solid valve sealing portion 176 where a valve slit 178 is subsequently formed. This configuration will result in a more complete seal and will require less sealing force than the flat tube.
[0054]
The valve seat mount 108 is a disk-shaped member having a cross-sectional outer diameter 108 ′, a first side directed toward the valve access segment 160 and a second side directed toward the valve distal segment 164. The valve seat mount 108 defines a seat mount lumen 183 having a cross-sectional diameter 183 ′ that can accommodate the valve 106. The first side of the seat mount 108 has a circumferential groove 186 disposed just in the axial direction of the outer peripheral edge thereof. A raised valve seat spacer 182 is also formed on the first side of the seat mount 108. The valve seat spacer 182 has a cross-sectional outer diameter 182 'that is substantially similar to the valve seat ring cross-sectional diameter 166'. Thus, when the valve 106 is inserted into the seat mount lumen 183, the valve seat spacer 182 and the valve access ring 166 have substantially the same cross-sectional diameter and a recessed valve seat in the locking mount 104. 146 fits. This configuration further prevents undesirable lateral movement of the seat mount 108 with respect to the locking mount 104, thereby increasing the stability of the access device 100 and minimizing patient discomfort. The second side of the seat mount 108 is disposed around its outer periphery with a raised valve seal means spacer 184 of sufficient axial thickness to optimally position the valve seal means 120 with respect to the valve seal portion 176.
[0055]
The valve sealing means 120 may be any conventional or suitable sealing means capable of applying a radial sealing force sufficient to seal a valve slit 178 similar to the valve slit 28 of FIG.
[0056]
Adapter 220 has a first end disposed within distal segment 164 and a second end disposed within catheter 240 and is tapered such that the streamline flow path is minimally disrupted. In addition, the adapter 220 is formed in its first end with a needle seating area 226 having an inner diameter 50 ′ that matches the barrel outer diameter 50 of the needle 40. The needle seat 228 extends radially inward so that its inner diameter 54 ′ matches the barrel inner diameter 54 of the needle 40. In this embodiment, when the needle-obturator assembly is inserted into the device and axially through the seal, the needle 40 is positioned so that the streamline flow path is minimally disturbed (if any). Lock to 228.
[0057]
Catheter 240 may be of the type typical of those used in hemodialysis, plasma removal and fluid exchange therapy.
Distal housing 110 has a first end having a cross-sectional inner diameter 110 ′ sufficient to accommodate a valve seat mount 108 having a cross-sectional outer diameter 108 ′. In addition, the first end of the distal housing 110 is formed with a valve seal retainer 112 that can optimally position the valve seal 120 with respect to the valve seal portion 176. The distal housing 110 further has a second end formed therethrough through a lumen 113 that can accommodate the catheter 240.
[0058]
The cross section of the needle 40 includes a locking groove 44. Upon insertion of the needle 40 into the device 100, the locking means 150 extends into the locking groove 44 to lock the needle 40 in place. The force applied by the locking biasing means 152 to the locking means 150 is designed to allow a firm pull to disengage the locking groove 44 from the locking means 150. In another preferred embodiment, the locking groove 44 is discontinuous in the needle circumference, and removing the locking means 150 from the locking groove 44 rotates the needle 40 for deactivation and then causes the needle 40 to move. This is achieved by sampling.
[0059]
For hemodialysis, plasma removal and other fluid exchange therapy operations where flow rates of 200-500 mL / min are possible, the needle 40 can be 15-17 gauge. In such operation, the pressure drop through the needle 40 should not exceed 200 mmHg. Under these conditions, the needle 40 is made of stainless steel and may have a wall thickness of approximately 0.1 mm, thereby providing sufficient strength with a high safety factor. In contrast, the use of a flexible material would require a needle wall thickness that is 3 to 5 times greater to prevent buckling and collapse during insertion.
[0060]
In the assembly access device 100, the valve 106 is positioned within the lumen 183 of the valve seat mount 108, so that the combination is locked to the locking mount 104 as described above, and the combination is then guided to the guide housing 102. It is arranged in the whole. The chamfered front edge 124 of the guide housing 102 fits in a circumferential groove 186 disposed just in the axial direction on the outer peripheral edge of the valve seat mount 108. The guide housing 102 is attached to the valve seat mount 108 by known means to create a fluid tight seal. The valve sealing means 120 is optimally positioned by the valve sealing means spacer 184 and the valve sealing means retainer 112 to seal the valve sealing portion 176. The adapter 220 is partially disposed within the valve distal segment 144 and partially within the catheter 240 as described above. The adapter 220 has a needle seating area 226 that fits within the needle 40, thereby creating a smooth flow path from the lumen of the needle 40 to the catheter 240. Valve 106, valve seat mount 108, valve sealing means 120, adapter 220 and catheter 240 are all disposed within distal housing 110. Catheter 240 emerges from distal housing 110 through an axial lumen 113 formed therethrough.
[0061]
FIG. 4 shows the assembly access device 100 with the needle 40 inserted and the obturator 42 removed from the needle 40. Needle end 48 is in contact with needle seat 228 of adapter 220 so that the transition from the inner lumen of needle 40 to the inner lumen of adapter 220 is smooth. The assembly is designed and configured such that all flow diameter changes are gradual and continuous. The angle of these transitions is less than 25 degrees and is preferably less than 10 degrees. Here, the flow diameter is defined as the diameter of the conduit in which the fluid is flowing, measured perpendicular to the flow. The cross section of the needle 40 includes a raised locking groove 44. The locking groove 44 is discontinuous in the needle circumference and removal of the locking means 150 from the locking groove 44 is accomplished by rotating the needle 40 and then withdrawing the needle 40 from the device 100. In another contemplated aspect, the locking groove 44 is continuous at the needle circumference. The force applied to the locking means 150 by the locking bias means 152 allows the needle 40 to be withdrawn from the device 100 with a firm pull that should remove the locking groove 44 from the locking means 150.
[0062]
In any aspect, the catheter 240 is formed from or attached to one or more tabs 246 having through holes 248. These tabs 246 are used to secure the catheter 240 to the surrounding tissue by tying or sewing when the device 100 is implanted. The device 100 itself is not secured to the surrounding tissue. With this arrangement, the device 100 can move sufficiently under the skin to align with the needle 40 penetrating the skin without allowing the needle 40 to move laterally relative to the skin. Attachment from the tissue to the device 100 is lost by treating the housing surface with hyaluronic acid.
[0063]
FIG. 9 illustrates another contemplated aspect 300, where there is an integral friction lock that secures the needle 40 within the access device 300. FIG. A sealing plug 304 is disposed within the housing assembly 302/310 between its access lumen 303 and the biasing force transmission flange 309 of the piston 308. When the device is not in use, the spring 306 biases the piston 308 and presses against the sealing plug 304, pressing the sealing plug 304 against the tapered sealing surface 344, thereby preventing fluid from flowing into the device.
[0064]
In use, the needle 40 is guided to the access lumen 303 by the conical needle guide surface 322 of the guide housing 302 where the needle 40 contacts the sealing plug 304. As the needle 40 is further pushed into the device, the axial force applied by the needle 40 to the sealing plug 304 overcomes the sealing plug bias force applied by the spring 306 to the biasing force transmission flange 309 of the piston 308, causing the sealing plug 304 to Moving away from the sealing surface 344 and removing the radial compressive force normally applied to the sealing plug 304, it is sufficient to allow the needle 40 to pierce the sealing plug 304. Unlike the septum known in the art, where the needle randomly punctures and ultimately results in fragmentation of the septum, due to the guidance of the needle 40 by the conical needle guide surface 322 of the guide housing 302, the sealing plug It is important to note that 304 is punctured consistently at the same location and orientation. This feature effectively eliminates fragmentation of the sealing plug.
[0065]
When the needle 40 punctures the sealing plug 304, the needle 40 contacts the needle seat 318 of the piston 308, whereupon the needle tip 48 contacts the needle seat 318 and moves smoothly between the needle 40 and the piston 308 ( transition). When needle 40 is inserted, sealing plug 304 provides sufficient residual pressure on needle 40 to effectively lock needle 40 into device 300. Axial tension on the needle 40 tends to pull the sealing plug 304 against the sealing surface 344 to increase the radial force applied to the needle 40, thereby holding the needle 40 even more firmly. However, a mere twist of the needle 40 introduces dynamic friction and allows the needle 40 to be removed from the device. O-rings 312 and 314 seal needle 40 from piston 308 and piston 308 from sealed housing 310, respectively. When the device is not in use, spring 306 is formed by insertion of needle 40, biasing piston 308 toward skin line 1 and compressing sealing plug 304 such that sealing plug 304 seals itself. Close the aisle. It is noted that because the piston 308 slides with respect to the catheter 340 and the sealed housing 310, movement from the piston 308 and the inner wall of the catheter 340 and / or from the inner wall of the sealed housing 310 remains smooth.
[0066]
FIG. 10 is yet another contemplated valve mechanism for the present invention. In this embodiment, the needle 40 contacts the slidable spring-loaded poppet 404. As the needle 40 is pushed into the device 400 using the conical needle guide surface 422, the valve structure 408 is biased away from the guide housing 402 (as shown). An O-ring 416 leaves the housing wall 405 to allow fluid to pass through the valve. Spring 406 returns poppet 404 and O-ring 416 to contact with housing wall 405 when needle 40 is withdrawn from the device. The poppet 404 does not extend over the entire valve circumference because it obstructs fluid flow. Instead, the poppet 404 has a plurality of rod-like extensions 418, which provide an open area for fluid to pass through the valve when the needle 40 is inserted. O-ring 406 provides a seal and prevents leakage around needle 40. Since the piston 408 (valve structure) slides relative to the catheter 440 and the sealing housing 410, movement from the piston 408 and the inner wall of the catheter 440 and / or from the inner wall of the sealing housing 410 remains smooth.
[0067]
FIGS. 11 and 12 show another contemplated embodiment 500, where the valve sealing means is a trumpet type valve 504. Prior to each treatment session, a fine needle 509 is percutaneously introduced into the lumen 530 and penetrates the septum 512 to provide sufficient fluid in the reservoir 520 to overcome the bias force exerted by the spring 508. The valve 504 is opened by the injection. The needle 40 can then be introduced into the device 500 in a manner similar to that described above with respect to 300 (FIG. 9) and 400 (FIG. 10), and a guide housing 502 having a conical needle guide surface 522 is provided for the needle. Guide 40. When the treatment session is completed, the needle 40 is removed from the device and the trumpet valve 504 is closed by withdrawing fluid from the reservoir 520 via the fine needle 509, so that the fine needle 509 is then removed from the device. Removed. As shown, there is a sealed housing 510 that cooperates with the guide housing 502 and a seal 504 that seals the passage 503.
[0068]
FIG. 13 is another contemplated aspect 600 in which an inflatable seal 604 seals the passageway 603. The needle 40 guided by the conical needle guide surface 622 of the guide housing 602 pushes away the inflatable seal 604 when inserted. The needle 40 then strikes a stop 608 provided in the sealed housing 610. When the needle 40 is withdrawn, the seal 604 expands and closes the passage 603. A fine needle 609 is percutaneously introduced into the lumen 630 and penetrates the septum 612 into the reservoir 620 in fluid communication with the lumen of the seal 604, as may be required from time to time. Thus, the seal 604 can be re-expanded. As in other aspects, the flow path transition from the sealed housing 610 to the catheter 640 is smooth.
[0069]
FIG. 14 shows a preferred corresponding needle assembly constructed and arranged to mate with the previously described buried access housing. The needle barrel 40 is made of a thin metal material. The thinner material actually maximizes the flow diameter, and this is a general goal for any hemodialysis. Discomfort to the patient is reduced by a smaller diameter needle, but such a needle restricts flow or results in a large pressure drop when high flow is forced through a small needle. Low flow rates require excessive treatment time for hemodialysis, and high flow rates through fine needles damage the blood. There is an offset trade and the thin needle wall contributes to the maximized flow diameter for a given needle outer diameter. An obturator 42 is provided in the needle 40 to provide a smooth movement 43 between the outer surface of the needle 40 and the obturator 42 at the needle tip 48. The barrel of the needle 40 has a semicircular locking groove 44A. The obturator 42 is fixed to the housing 68 via a screw thread 62. The obturator 42 is necessary because the needle 40 is hollow and cannot be used to penetrate the skin (since its large diameter lumen becomes occluded). The obturator 42 has a tip 45 that just fills the hollow surface presented to the skin and is suitable for penetrating the skin. Housing 68 provides channel 69 with a threaded fitting 64 for connection to a hemodialysis machine. When the obturator 42 is removed, there is a slit disk valve 66 that closes the opening used by the obturator 42 to allow hemodialysis to proceed.
[0070]
When not in use, the internal prosthetic device of the present invention, such as the device described above, is filled with an anti-biocide lock that includes an anticoagulant and a non-antibiotic biocide. The term “anticoagulant” as used herein, either directly or indirectly, is any that has the ability to prevent blood clotting or to dissolve clots or other coagulation species once formed. The composition is also intended to mean. Any compound known to have this ability can be used.
[0071]
Examples of such compounds are diammonium hydrogen citrate, diammonium tartrate, citric acid, disodium citrate, monopotassium citrate, monosodium citrate, tripotassium citrate, trisodium citrate, ethylenediamine Tetraacetic acid (EDTA), EDTA diammonium salt, EDTA dipotassium salt, EDTA disodium salt, EDTA tetrasodium salt, ethylenebis (oxyethylenenitrilo) tetraacetic acid (EGTA), EDTA trisodium salt, EDTA tripotassium salt, ethylene Glycol-O, O'-bis (2-aminoethyl) -N, N, N ', N'-tetraacetic acid, N- (2-hydroxyethyl) ethylenediamine-N, N', N'-trisodium triacetate Salt, nitrilotriacetic acid, sodium potassium tartrate, potassium potassium tartrate , L-tartaric acid dipotassium salt, L-tartaric acid disodium salt, L-tartaric acid monosodium salt, heparin, warfarin, acetylsalicylic acid, ibuprofen, indomethacin, prostaglandin, sulfinpyrazone, streptokinase, urokinase, tissue plasminogen Activators (TPA), coumarin, protamine sulfate, antithrombin III, coumadin, protein C / protein S, nikumarone, fenprocmon, hirudin, hirulog, etc. may be listed. Mixtures of the foregoing can be used. A preferred anticoagulant system for use in the present practice of the invention is a combination of citric acid and its salts, preferably trisodium citrate. This is discussed in more detail below.
[0072]
The term “biocide” as used herein refers to an agent that destroys, prevents, prevents, etc. the propagation, growth, multiplication, etc. of an unwanted organism. The term organism refers to microorganisms, bacteria, wavy bacteria, spirochetes, spores, sporulating organisms, gram negative organisms, gram positive organisms, yeast, fungi, filamentous fungi, viruses, aerobic organisms, anaerobic organisms , Mycobacteria, etc.
[0073]
The biocide used in the practice of this invention is one that is a “non-antibiotic”, ie it is not an antibiotic. For the purposes of the present invention, the term “antibiotic” is a chemical produced either synthetically or by a microorganism and has the ability to inhibit or kill the growth of other microorganisms in dilute solution. Defined as the chemical. Although it is an object of the present invention to minimize the probability of producing microorganisms that are genetically immune to these antibiotics, they may, if desired, be the biocides of the present invention. It can be present in addition to the agent. Preferably, the non-antibiotic biocide of the present invention is a chemotherapeutic agent.
[0074]
Biocides are used in dialysis machines to kill, clean, prevent and / or delay the presence or propagation of harmful or unwanted microorganisms. Microorganisms include the fungi Aspergillus niger, Aspergillus flavus, Rhizopus nigricans, Cladosporum herbium, Cladosporum herbium -Including Mentagrophytes, Histoplasma capsultatum, etc.
[0075]
The terms microorganisms are also referred to as Pseudomonas aeruginosa, Escherichia coli, Proteus vulgaris, Staphylococcus aureus, Staphylococcus aureus -Streptococcus faecalis, Klebsiella, Enterobacter aerogenes, Proteus mirabilis, other Gram-negative and other Gram-positive bacteria, Mi Contains antibacterial activity against kobactin, etc. The term also includes yeasts such as Saccharomyces cerevisiae, Candida albicans, and the like. In addition, microbial spores, viruses, etc. are within the spirit of the invention.
[0076]
Biocides used in the apparatus are, among others, phenol, quaternary ammonium, surfactant, chlorine-containing, quinoline, quinaldinium, lactone, dye, thiosemicarbazone, quinone, sulfa, carbamate, urea, salicylamide, carbanilide , Amides, guanides, amidines, chelates and imidazoline biocides.
[0077]
Among the non-antibiotic biocides that can be used in the practice of the present invention are, for example, acetic acid, benzoic acid, sorbic acid, propionic acid, boric acid, dehydroacetic acid, sulfurous acid, vanillic acid, esters of p-hydroxybenzoic acid, ethanol , Isopropanol, propylene glycol, benzyl alcohol, chlorobutanol, phenylethyl alcohol, 2-bromo-2-nitropropane-1,3-diol, formaldehyde, glutaraldehyde, calcium hypochlorite, potassium hypochlorite, hypochlorous acid Sodium chlorate, iodine (in various solvents), povidone-iodine, hexamethylenetetramine, noxythioline, 1- (3-chloroallyl) -3,5,7-triazo-1-azoniaadamantan chloride, taurolidine, taurultam, EDTA , N- (5- Tro-2-furfurylidene) -1-amino-hydantoin, 5-nitro-2-furaldehyde semicarbazone, 3,4,4'-trichlorocarbanilide, 3,4 ', 5-tribromosalicylanilide, salicyl Anilide, 3-trifluoromethyl-4,4'-dichlorocarbanilide, 8-hydroxyquinoline, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl)- 3-quinolinecarboxylic acid, 1,4-dihydro-1-ethyl-6-fluoro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid, hydrogen peroxide, peracetic acid, phenol, sodium oxychloro Sen, parachlorometaxylenol, 2,4,4'-trichloro-2'-hydroxydiphenol, thymol, chlorhex Emissions, benzalkonium chloride, cetylpyridinium chloride, there is silver sulfadiazine and silver nitrate.
[0078]
Exemplary biocidal dyes include acridine, acriflavine, aminacrine hydrochloride, proflavine hemisulfate, triphenylmethane, magenta, crystal violet, scarlet red, pararosaniline and rosaniline.
[0079]
Exemplary chlorine-releasing biocides are sodium hypochlorite, oxychlorocene, chloramine, dichlorodimethylhydantoin, harazone, dichloroamine, chloracin, succinchlorimide, trichloroisocyanuric acid, dichloroisocyanurate, trichloromelamine, dichloroglycol Including uril, halogenated dialkylhydantoins and halans. Exemplary biocidal quinaldinium and quinoline biocides are dequalinium, laurolinium, hydroxyquinoline, lioquinol, chlorquinaldol and halquinol.
[0080]
Exemplary quaternary ammonium biocides include pyridinium biocides, benzalkonium chloride, cetrimide, benzethonium chloride, cetylpyridinium chloride, chlorphenocium amsonate, dequalinium acetate, dequalinium chloride, domifen bromide, laurolith Including nitroacetate, methylbenzethonium chloride, myristyl-gamma-picolinium chloride, alterofonium chloride and triclovisonium chloride.
[0081]
Exemplary furans include griseofulvin, nitrofurfural, nitrofurazone, nitrofurantoin, furazolidone and furaltadone. Exemplary phenol biocides are chlorinated phenol, cresol phenol, thymol, chlorocresol, chloroxylenol, hexachlorophene, bisphenol, amylmetacresol, bithionol, chlorothymol, dichloroxylenol, chlorophene, p-chlorophenol, p- Including phenylphenol, trinitrophenol, dichlorobisphenol and bromochlorobisphenol.
[0082]
Exemplary lactones include propiolactone.
Exemplary urea biocides include noxythioline, polynoxylene and triclocarbon.
Examples of other biocides useful for the purposes of the present invention are chlorhexidine gluconate, chlorhexidine, chlorhexidine acetate, chlorhexidine hydrochloride, dibromopropamidine, diphenylalkanes halogenated, dibromosaran, metabromosaran, tribromosaran, Carbanilide, salicylanilide, tetrachlorosalicylanilide, trichlorocarbanilide, propamidine isethionate, pentamidine, picroxidine, mendaramine, acid addition and quaternary, methenamine mandelate, polyoxymethylene diester, for example, polyoxymethylene diester , Polyoxymethylene diacetate and the like and mixtures thereof.
[0083]
Preservatives that can be used as biocides used in the present invention include guanidines such as alexidine, ambazone, chlorhexidine and picroxidine; halogens and halogen compounds such as bornyl chloride, calcium iodate, chlorocarbon, flurosalan, iodic acid , Iodine, oxychlorocene, povidone-iodine, sodium hypochlorite, sodium iodate, synchrocene, thymol iodide, triclocarbon, triclosan and trocrocene potassium; mercury compounds such as hydragafen, melarein sodium, melbromine, Ammonia, sodium p-phenolsulfonate mercuric mercury, succinimide mercuric mercury, mercuric sulfide, red, mercurophene, mercuric acetate, mercuric chloride, Mercuric hydride, nitromersol, sodium thimeronate and thimerosal; nitrofurans such as furazolidone, 2- (methoxymethyl) -5-nitrofuran, nidroxyzone, nifuroxime, nifluzide and nitrofurazone; phenols such as aceto Meloctol, bithionol, carvacrol, chloroxylenol, chlorophene, cresol, p-cresol, fenclone, hexachlorophene, 1-naphthylsalicylate, 2-naphthylsalicylate, 2,4,6-tribromo-m Cresol and 3 ', 4', 5-trichlorosalicylanilide; quinoline, such as aminoquinuride, benzoxyquin, broxyquinoline, chloroxin, chlorquinaldol, cloxyquine, ethyl hydrox In, euprosin, halquinol, hydrastine, 8-hydroxyquinoline, 8-hydroxyquinoline sulfate and iodochlorhydroxyquine; others such as aluminum acetate solution, basic aluminum acetate solution, aluminum sulfate, 3-amino-4-hydroxy Contains butyric acid, boric acid, chlorhexidine, chloroazodine, m-cresyl acetate, cupric sulfate, dibromopropamidine, ictamol, negatol, noxythioline, ornidazole, β-propiolactone and α-terpineol.
[0084]
Biocides used in the practice of the present invention also include the polymer paraformaldehyde. Paraformaldehyde used as a biocide has the general formula (CH ₂ O) _n A cyclic tripolymer of the formula (where n is 3) and the general formula HO (CH ₂ O) _m Selected from the group consisting of linear polymers of H (where m is from 3 to 125). These polymers are white crystalline solids and undergo depolymerization in the presence of moisture, resulting in water soluble biocides and disinfectants formaldehyde. John Wiley & Sons, Inc., NY Published by Encyclopedia of Chemical Technology, Kirk-Othmer, Vol. 10, page 81, 1966. During operation, paraformaldehyde is water activated by the surrounding fluid and depolymerized to formaldehyde. Formaldehyde acts as a biocide or disinfectant to control the presence of microorganisms. In general, in the presence of moisture or in the presence of moisture and acid catalyst, cyclic and linear polymers are converted to 99% formaldehyde and released over a long period of time.
[0085]
The amount of biocide in the formulations used in the devices of the invention is generally from about 0.001 mg / mL to about 1000 mg / mL, with a more preferred amount being about 1 to about 200 mg / mL, and most A preferred amount is from about 2 mg / mL to about 100 mg / mL. Biocides can be found in Block “Disinfection, Sterilization and Preservation” published in 1977 by Lea & Febiger, Philadelphia, Pennsylvania, and Hugo ’s “Inhibitbion and Inhibition and Prejudice” published in 1971 by Academic Press, New York. Cells ", and in" Martindale, The Extra Pharmacopoeia "edited by Blacklaw published by The London Pharmaceutical Press, London.
[0086]
In a particularly preferred embodiment of the invention, the biocide and anticoagulant comprise a therapeutically effective amount of
(A) Formula (I)
Embedded image

[Where R ¹ Is hydrogen or alkyl and R ² Is hydrogen, alkyl or formula (II)
Embedded image

Is the basis of
At least one compound of
and
(B) at least one compound selected from the group consisting of biologically acceptable acids and biologically acceptable salts thereof.
In a composition comprising
[0087]
The preparation of a representative example of a compound of formula I is described in British Patent 1,124,285. Basically, these compounds are the condensation products of taurinamide and formaldehyde and are therefore referred to herein as “taurinamide derivatives”. They are active not only against both gram positive and gram negative bacteria, but also against exotoxins and endotoxins produced by these organisms.
[0088]
R ¹ And / or R ² When are alkyl, they can be either straight or branched alkyl and preferably have 1 to 8 carbon atoms, ie methyl, ethyl, propyl, butyl, pentyl, Independently selected from hexyl, heptyl, octyl and isomers thereof. More preferably, R ¹ And / or R ² When are alkyl, they are independently selected from alkyl having 1 to 6 carbon atoms, ie methyl, ethyl, propyl, butyl, pentyl, hexyl and isomers thereof. Most preferably, the alkyl group has 1 to 4 carbon atoms, ie, methyl, ethyl, propyl, butyl and isomers thereof. However, R ¹ Is hydrogen and R ² Is most preferably hydrogen or a group of formula II.
[0089]
In the present invention, among the compounds of formula I, the compound taurolidine (R ¹ = H, R ² = Formula II) and taurultam (R ¹ = R ² = H) is particularly preferred. Taurolidine is bis- (1,1-dioxo-perhydroxy-1,2,4-thiadiazin-4-yl) methane.
These compounds are formaldehyde carriers, i.e., non-toxic derivatives containing bound formaldehyde.
[0090]
It has been found that the mode of action of taurolidine involves the transfer of a methylol group to a hydroxyl or amino group present on the toxins described above or on the murein of the bacterial cell wall. In solution, taurolidine exists in equilibrium with taurultam and N-methylol taurultam, and taurolidine is very prevalent. Taurultam is itself in equilibrium with methylol taurinamide, and that equilibrium is a major advantage of taurultam. When the above methylol derivatives, i.e. methylol taurultam and methylol tauramide, come into contact with toxins or bacteria, the methylol group is transferred. Methylol taurultam is thereby converted to taurultam, while methylol tauramide is converted to taurine, a naturally occurring aminosulfonic acid that is very well tolerated in the human body. Thus, it will be appreciated that taurolidine and taurultam act essentially the same and produce the same end product.
[0091]
Bacterial infection by gram-negative organisms is usually accompanied by endotoxemia, ie the patient's response to endotoxins released by the organism.
Endotoxin is a complex lipopolysaccharide component of the O cell antigen and is loosely attached to the cell wall of Gram-negative bacteria. Regardless of the bacterial source, all endotoxins exhibit similar toxicities as opposed to Gram-positive bacterial exotoxins that have a wide range of individual effects. In humans, it can cause endotoxic shock syndrome when a large number of gram-negative bacteria are lysed. This syndrome is encountered in about 30% of patients with gram-negative sepsis. It is known that taurinamide derivatives can inactivate endotoxins.
[0092]
Toxic proteins such as exotoxins can be inactivated as well, and methylol transfer antibacterial agents can be administered to combat toxic proteins in the absence of lipopolysaccharide toxin. Toxins that may be involved include exotoxins of gram-negative bacteria such as E. coli and Bacteroides fragilis. Intravenous administration of 0.2% mice with a 20% solution of taurolidine in sterile 5% polyvinylpyrrolidone was administered to the peritoneal cavity of both E. coli and B. fragilis pathogenic strains. It is known that the mortality rate for internal administration can be reduced significantly.
[0093]
Other toxic proteins include animal venoms such as melittin and fungal toxins such as amanitin and α-bungarotoxin that have been shown to be substantially detoxified by taurolidine.
A particular advantage of taurolidine is its very low toxicity. That is, it is non-teratogenic in mice and intraperitoneal LD ₅₀ Was about 1.5 g / kg. As noted above, these compounds exhibit methylol transfer activity that results in the production of taurine that is naturally occurring in the body and is particularly non-toxic. A further advantage of taurolidine is its stability in aqueous solution, which allows the solution to be prepackaged and stored for a relatively long period of time.
[0094]
These taurinamide derivatives are usually administered as an aqueous solution by injection into the internal prosthetic device of the present invention. Such a solution, in addition to a given tauramide derivative, to help maintain the tauramide derivative in solution and to contribute to the isotonicity of the solution, eg, a solubilizer such as polyvinylpyrrolidone (PVP ). The concentration of the taurinamide derivative in such a solution can range from greater than zero to about 2 wt%, with a concentration in the range of about 0.01 to about 1.5 wt% being preferred, and a concentration of about 1 wt% being most preferred. . Higher concentrations are useful, but solubility is a problem.
[0095]
When PVP is incorporated into the solution, it is usually used at a concentration in the range of 4-7% by weight to achieve a relatively high concentration of tauramide derivatives, particularly taurolidine, which have low water solubility. The molecular weight of PVP should not be greater than about 30,000 and is preferably less than 10,000, for example between about 200 and about 3500. Kollidone® sold by BASF is particularly suitable. Such PVP is absorbed fairly quickly and is excreted through the kidney.
[0096]
The amount of taurinamide derivative solution injected into the internal prosthetic device is usually sufficient to satisfy it. Such systems typically have an internal volume ranging from about 0.1 mL to about 10 mL. Such amounts will of course vary with the length and diameter of the tube used with the device, which may be a function of the size of the individual patient, among others.
[0097]
The concentration of taurinamide derivative in such a solution is preferably in the range of about 0.4 to 5% by weight, depending most on the solubility of the compound. Particularly preferred is about 0.4 to about 2.0 weight percent taurolidine, ie, about 4 to about 20 grams of solution per liter.
[0098]
Examples describing the production of taurolidine stock solutions are found in several patents such as US Pat. No. 4,337,251.
That is, 15 liters of twice distilled pyrogen-free water is loaded into a 25 liter glass vessel equipped with a stirrer and a strong reflux and heated to 50 ° C. with stirring. Taurolidine (400 g) is added, followed by PVP (Kollidone 17, 1000 g). After dissolution, the solution is cooled and the pH is adjusted to 6.0 with a few drops of 0.1N hydrochloric acid. This solution is then passed through an adsorption filter to remove microorganisms and pyrogens and passed through a sterilizing Millipore filter before filling into a 100 mL vial and finally autoclaved.
[0099]
If desired, some or all of the PVP can be replaced by a parenterally acceptable polyol. This use for polyols is disclosed in US Pat. No. 5,210,083, the disclosure of which is hereby incorporated by reference in its entirety. There it is pointed out that this is advantageous because at higher concentrations of taurolidine, crystallization can occur which can render the solution unusable.
[0100]
In the case of bacteria and their endotoxins and exotoxins, it has been found that there is an additional irreversible step with dehydration after methylol transfer as described above. Thus, it has been found that in the case of bacterial endotoxins that are lipopolysaccharides, an irreversible cross-linking reaction occurs that prevents the endotoxins from exerting their lethal effects. Similarly, in the case of bacterial exotoxins that are proteins or polypeptides and do not contain the type of lipopolysaccharide substance found in endotoxins, the detoxification reaction has been found to be irreversible. However, in US Pat. No. 5,210,083, the methylol group transfer by the mechanism described above is reversible for many hydroxyl or amino compounds, thus establishing an equilibrium that does not significantly interfere with the availability of taurolidine. It is disclosed to obtain. Thus, polyols such as sugars and sugar alcohols can also be used to maintain relatively high concentrations of taurolidine and / or taurultam in aqueous solutions without significantly affecting their antibacterial and antitoxin activities. Preferred polyols are carbohydrates such as hexoses such as glucose, fructose and mixtures thereof; pentoses such as xylose; polysaccharides such as dextran or hydrolyzed starch; glycerol; and sugar alcohols such as sorbit, mannitol and Includes xylit. Glucose is most preferred.
[0101]
The concentration of the polyol is typically in the range of about 3 to about 40% by weight. In the case of glucose, the concentration is preferably in the range of about 10 to about 30% by weight, more preferably about 20%.
When such a polyol is used, the concentration of taurolidine in the solution is preferably in the range of about 0.5 to about 5% by weight, more preferably in the range of about 2-3% by weight. The concentration of taurultam is preferably in the range of about 1 to about 7.5% by weight, more preferably about 3 to about 5% by weight.
[0102]
Because gram-negative organisms are often present and the bacteriostatic activity of taurinamide derivatives is lower than that of many antibiotics, they are preferably highly active against broad spectrum antibiotics, more particularly both gram-positive and gram-negative pathogens. Is a substance that induces resistance at all or only lately, for example β-lactam antibiotics such as penicillin, ampicillin or cephalosporin; tetracycline antibiotics; macrolide antibiotics such as erythromycin; polypeptide antibiotics, For example, bacitracin or novobiocin; or more preferably aminoglycoside antibiotics such as amikacin, butyrosine, fortimycin, streptomycin, neomycin, lincomycin (eg clindamycin and lincomycin) , Kanamycin, dideoxykanamycin B (DKP), ribidomycin, netilmycin, ribostamycin, sagamycin, cerdomycin and their epimers, sisomycin, sorbistin, tobramycin, vancomycin, gentamicin and rifamycin (eg, rifampicin and rifamycin); etc. In addition, it may be advantageous to administer the composition used in the practice of the present invention. Of these, gentamicin is preferred.
[0103]
However, antibiotics are often contraindicated for use in surgical procedures because of their propensity to produce resistant strains and, except in unusual cases, relying solely on taurinamide derivatives for antibacterial activity, Such derivatives are preferred because they do not produce resistant strains.
The composition used in the practice of the present invention preferably also contains a pharmacologically acceptable carrier solution such as water, Ringer's solution or saline. In addition, the compositions of the present invention may also contain other solubilizing additives such as amino acids, sugars, salt, fats, lipids, etc. that may positively affect their physical and biochemical properties.
[0104]
When antimicrobial taurinamide derivatives are used in the practice of the present invention, they are used in combination with a biologically acceptable acid or a biologically acceptable salt thereof. The acid is preferably a carboxylic acid, and more preferably it is also an anticoagulant. US Pat. No. 5,077,281 shows that tauroline compounds show significant anticoagulant activity by themselves and in medical conditions requiring dialysis and for vascular prosthetic devices alone or other anticoagulants. It is taught to be particularly suitable for use in combination with agents such as coumarin or heparin. As pointed out in the patent, this indicates that tauroline does not affect blood clotting and does not exhibit anti-inflammatory activity. L. Bruckner and R.M. W. Contrary to the teaching of “Taurolin” published by Pfilrmann, “Verlag Urban und Schwarzenberg”, Munich, 1985. The inventor believes that the taurinamide derivatives used in the practice of the present invention exhibit some anticoagulant activity, albeit to a lesser extent than that found with better known anticoagulants such as heparin. ing. Thus, it is beneficial to use a taurinamide derivative in combination with an anticoagulant, preferably one that is a biologically acceptable acid or salt thereof.
[0105]
In accordance with the present invention, the final composition wherein the antimicrobial tauramide derivative is not higher than 7, preferably in the range of about 3.5 to about 6.5, more preferably in the range of about 4.5 to about 6.5. Beneficial results are achieved when combined with a biologically acceptable acid or a biologically acceptable salt thereof to produce a pH for the object. Illustrative of such acids are acetic acid, dihydroacetic acid, benzoic acid, citric acid, sorbic acid, propionic acid, succinic acid, malic acid, fumaric acid, maleic acid, hydrochloric acid, malic acid, phosphoric acid, sulfurous acid, vanillic acid , Tartaric acid, ascorbic acid, boric acid, lactic acid, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis- {β-aminoethyl ether} -N, N, N ′, N′-tetraacetic acid and diethylenetriaminepentaacetic acid, etc. And biologically acceptable salts of the foregoing, such as ammonium phosphate, potassium citrate, potassium metaphosphate, sodium acetate, sodium citrate, sodium lactate, sodium phosphate, and the like. Blood anticoagulant amount consisting of citric acid, phosphoric acid, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis- {β-aminoethyl ether} -N, N, N ', N'-tetraacetic acid and diethylenetriaminepentaacetic acid Acids selected from the group and biologically acceptable salts thereof are preferred. The acid used in the practice of the present invention is preferably an organic acid, particularly one having at least one carboxyl group, especially citric acid or EDTA. More preferably, the acid is citric acid, and most preferably it is used in combination with a citrate salt such as sodium citrate.
[0106]
Mermel, L.M. A. Et al., Published in Interscience Conference on Antimicrobial Agents and Chemotherapy (1998), “Vancomycin-Mediated Sensitive Staphylococcus aureus (VISA) and Auridine against Tatyrcoin Aureus (MRSA). In the lecture entitled “Intermediate Susceptibility Staphylococcus Aureus (VISA) and Methicillin-Resistant Staphylococcus Aureus (MRSA))”, Taurolidine activity has a pH of 7.0 to pH 5.0. It disclosed that increases with reducing the pH in the circumference.
[0107]
EDTA is a known anticoagulant used in blood collection tubes. It is also known to have the ability to form chelates with calcium. Since calcium is one factor known to have a role in blood clotting, it is believed that at least part of the efficacy of EDTA in anticoagulant activity can be brought about by this means. Sodium citrate is also believed to have anticoagulant properties due to its ability to generate insoluble calcium citrate.
[0108]
The acid anticoagulants described above can be used alone in the free acid state, but more often some or all of their carboxylic acid groups are neutralized with a suitable base or are combined with similar salts. In general, it is desirable to use cations that form salts that are soluble in aqueous solutions, such as alkali metal ions such as sodium or potassium. Zinc citrate can also be used. Sodium or potassium salts, especially sodium, are usually preferred, and disodium EDTA and sodium citrate are most preferred.
[0109]
The acid and / or salt is used in a concentration effective to provide the desired anticoagulant effect and at the same time to provide or help provide an appropriate pH for biological use. Typically, the combined biocide and anticoagulant compositions of the present invention will have about 3.0 to about 7, preferably about 3.5 to about 6.5, more preferably about 4.5 to It has a pH in the range of about 6.5. The composition is usually at a physiological pH. If necessary, the pH can be adjusted with additional acids or bases, such as mineral acids, such as hydrochloric acid, or preferably those that do not cause acidosis (eg, acetic acid, malic acid, glutamic acid, aspartic acid or lactic acid). Other methods for adjusting the pH that are familiar to those skilled in the art may also be used. When preferred trisodium citrate and citric acid are used in the practice of the present invention, trisodium citrate is typically used in a concentration range of about 5 to about 50 grams per liter. Citric acid is then added in an amount sufficient to bring the pH to the desired level.
[0110]
Although the method of the present invention is primarily concerned with introducing biocide / anticoagulant compositions into the internal prosthetic device already in place, those skilled in the art will recognize the artificial surfaces external to the body as these compositions. It will be appreciated that contacting with an object may prevent adhesion of blood clots on such surfaces after its implantation and may assist in eliminating sites for bacterial growth. Thus, the internal prosthetic device is a composition used in the practice of the invention to prevent occlusion due to blood clots presenting a favorable site for bacterial growth and thereby prevent subsequent infection. Can be pretreated on the inner surface and / or on the outer surface. Such external treatment typically involves means to temporarily hold the compositions in place on the external surface of the device and then allow their release slowly, such as a porous material, semi-permeable, depending on the fit. Membrane, cation or anion species, etc. are used. The inner surface of the device can be treated with the composition first and then with repeated periodic flushing as referred to above after insertion.
[0111]
In addition, although the present invention is primarily and preferably directed to maintaining the patency and sterility of the implanted hemodialysis catheter, the beneficial effect is also directed to other similar internal prosthetic devices. It can be obtained by its application, and such devices include drainage tubes, peritoneal dialysis catheters, central venous catheters, peripheral venous catheters, arterial catheters, Swan-Ganz catheters, umbilical catheters, percutaneous non-tunneled silicone catheters , Including but not limited to cuffed tunnel-like central venous catheters as well as subcutaneous central venous ports.
[0112]
Various features and aspects of the present invention are illustrated further in the examples that follow. Although these examples are presented to show one skilled in the art how to practice within the scope of the invention, they are in no way intended to serve as a limitation on the scope of the invention.
[0113]
Example 1
A 0.5% solution of taurolidine in Ringer-lactate solution (Tomae, Biberach, Germany) was introduced into each of four polyethylene bottles having a volume of 30 mL. Filling volumes were 5, 10 and 15 mL. One bottle was filled with 5 mL of the taurolidine solution and 2 mL of ACD-A (Fresenius, Bad Homburg, Germany). The ACD-A solution is used for storage of whole blood and 22.0 grams of sodium citrate dihydrate, 7.3 grams of citric acid and 34.5 grams of glucose monohydrate per liter Contains products.
[0114]
Blood was collected in the container directly from the slaughter wound at the slaughterhouse, and the container was then filled to a level of 30 mL. The containers were capped and gently moved to mix the blood with the solution. These containers were inspected after 30 minutes. The blood in the container containing only taurolidine clotted, but the blood in the container containing a mixture of taurolidine and ACD-A did not clot. Thus, it is concluded that the use of sodium citrate and citrate anticoagulant in combination with taurolidine provides substantially enhanced anticoagulant properties to whole blood.
[0115]
Example 2
A subcutaneously implantable titanium port system (hereinafter DIALOCK® port) of the type used in the practice of the present invention and described in US Pat. No. 5,954,691 is used in this example. . It is connected with two 12 French silastic catheters whose tips are introduced into the right atrium. The port valve is opened by two special needles as described above to allow blood flow of about 300 mL / min.
[0116]
Port was buried by skilled nephrologists after their informed consent in 10 female and 6 male patients with an average age of 68.9 years. Nine of the 16 patients were diabetics. Patient inclusion criteria for this study were tube fatigue that did not result in blood access sites in the arm available for hemodialysis. Eight of the 16 had severe congestive heart failure and all had high comorbidities. Nine of the patients started hemodialysis immediately after implantation, and others were on long-term hemodialysis and switched from the catheter to the port system (four patients replaced with a guide wire). There were no perioperative complications.
[0117]
The preferred tube was the right internal jugular vein, but the external jugular and subclavian veins were also used. The device has so far been used for a total duration of 11.0 patient years. The port was used for all planned IID sessions (n = 1200).
[0118]
In order to avoid intraluminal contamination of the device, an antimicrobial lock was applied between sessions and removed before the next treatment. This aqueous antimicrobial biocide lock contained 13.3 grams / liter taurolidine, 6.7 grams trisodium citrate per liter, and approximately 3.3 grams citric acid per liter. The citric acid was added to adjust the pH range to 4.75-5.25. With these citric acid and sodium citrate, catheter coagulation was prevented and application of heparin was unnecessary.
During the study period, two manifestations of bacteremia (S. aureus) were observed and were successfully treated without device loss (0.5 infection per 1000 days).
[0119]
Example 3
In this example, the subcutaneously implantable DIALOCK port described in Example 2 was used.
Tube fatigue is an increasing problem in hemodialysis patients. In a promising multi-center pilot trial starting in June 1998, 31 ports were buried in 19 female and 12 male patients (mean age 66 years, minimum 30 years, maximum 81 years) . In addition to accepting new devices, the goal of this study is to achieve a completely non-toxic biocidal mixture (anti-infective) with excellent efficacy against any pathogenic microorganisms, even those that are multi-resistant. Heparin-free biocide lock containing taurolidine as a substance and citrate / sodium citrate to prevent coagulation) was avoided.
[0120]
In 10 participating centers, no ports were lost since the beginning of the investigation (3,847 burial). Despite the high comorbidity, only two patients experienced a bloodstream related infection (S. aureus). Total observed infection was 0.5 per 1000 days. Systemic antibiotic treatment was successful. Pre-existing catheter-related sepsis occurred in 5/31 patients. No recurrence occurred in patients using a DIALOCK® port that could be implanted subcutaneously.
[0121]
Hospitalization was short term and access was used immediately after burial. Receptivity was high even in patients who switched from catheter to port (12/31). In 6/31 patients, exchange with a guide wire was possible. The usual installation technique was Seldinger applied by three nephrologists. The preferred tube was the right internal jugular vein (18/31), but all other central veins were used.
The results of this investigation are shown in Table 1.
Compared to the disadvantages of catheters, the DIALOCK® port system allows bathing and is very safe. Coupled with the biocide lock of the present invention, the risk of infection is low and a puncture technique similar to transplantation is allowed. The lifetime of the device must now be established.
[0122]
Example 4
Comparative example
In four separate installations, two studies in the United States and two in Europe, namely A, B, C and D, were performed, similar to those described above in Example 3, except that the lock solution used was Was heparin or heparinized saline at concentrations ranging from 2,000 to 10,000 international units per mL. In a survey in the United States, ie A and B, benzyl alcohol was also present as a standard preservative. The results of these comparative studies are shown in Table 1.
[0123]
[Table 1]

[0124]
Example 5
Experiments were performed to determine the minimum taurolidine / citrate biocide lock acidity that worked well when in contact with human blood. Various biocide lock acid concentrations were mixed 50/50 by weight with fresh human whole blood. The pH was experimentally varied from pH 3.0 to pH 7.0. At biocide lock acidity below 4.0, the resulting blood mixture becomes hard and coagulated after 1 hour contact with the biocide lock. This solidification was apparently due to the biocide lock acid level and normal blood clotting, as the clot appears very dark in color and dry in character (not normal in color or physical properties). When the biocide lock acidity was maintained above pH 5.0, blood clotting did not occur and the color of the blood remained a healthy red color. Thus, the most preferred lower limit for the acidity of taurolidine biocide lock is about 5.0.
[0125]
Example 6
The risk of sepsis is the Achilles tendon of the buried vein catheter. Antibiotic lock techniques are not widespread and unavoidable for fungal infections. In accordance with the present invention, an anti-infective biocide lock has been developed for applications made in conjunction with the DIALOCK port system. The subcutaneously implanted DIALOCK port is connected to two 12 French silastic catheters whose tips are introduced into the right atrium. The port valve is opened by two special needles to allow blood flow up to 300 mL / min.
[0126]
The filling solution contains taurolidine, an anti-septic substance that has efficacy against fungi and multi-resistant pathogenic microorganisms. In combination with citric acid and sodium citrate, catheter coagulation is prevented and heparin application is unnecessary. The mixture is absolutely non-toxic and can be injected intravenously without any harm. In order to avoid intraluminal contamination of the device and catheter, an anti-infectious lock is applied between sessions and removed by aspiration prior to the next procedure.
[0127]
In a multi-center pilot trial starting in June 1998, 28 ports were informed consent to 18 female and 10 male patients (mean age 68 ± 9 years), 3 skilled kidney diseases It was buried by a scholar until January 1999.
[0128]
Eight dialysis centers were involved in this study. Inclusion criteria were tube fatigue. 8/28 patients had severe congestive heart failure and all had high comorbidities. The start of hemodialysis (HD) immediately after implantation was 13 patients, the other patients were in long-term HD, and 5 patients switched from catheter to port (guide wire exchange). The preferred tube is the right internal jugular vein (IJV, n = 16), others are the left IJV (n = 4), both subclavian veins (n = 8) and the external jugular vein in one patient. there were. The total duration of the device was 3,068 days, more than 6 months in 9 patients. The port was punctured without any special technique after skin disinfection with alcohol.
[0129]
Despite the fact that four patients had septic episodes due to catheter infection just prior to or during implantation, device infection did not occur during the further course. Two manifestations of blood flow-related infection in S. aureus were observed during the study period and were successfully treated without loss of the device (0.65 infection / 1000 days). One patient developed spondylitis 4 months before the start of the study and had an implanted catheter, and the other patient with active blood culture was immunosuppressed due to M. Crohn Received treatment.
[0130]
Example 7
Coagulase-negative Staphylococcus, Candida albicans, Staphylococcus aureus, Enterococcus and Pseudomonas aeruginosa And incubated at 37 ° C. until the culture became visibly turbid. Serial dilutions were made to give 10 colony forming units (cfu) /0.1 mL for S. aureus, Enterococcus and Pseudomonas aeruginosa, 5 cfu / 0.1 mL for Candida A final cell density of 100 cfu / 0.1 mL was obtained for Coagulase negative staphylococci and Enterobacter. From the final dilution, 0.1 mL was dropped into each distal end of the DIALOCK port tube and the DIALOCK port was incubated overnight at room temperature.
[0131]
After incubation, a regular silicone catheter was placed at the distal end on each side of each DIALOCK port. A solution of 5000 U / mL heparin (with preservative) or 2% citrated taurolidine was instilled through the proximal end of the DIALOCK port to fill the DIALOCK port and catheter. The catheter was clamped and the DIALOCK port / catheter was incubated at 37 ° C. for 72 hours.
[0132]
After this incubation, both catheters were removed from each DIALOCK port and each was flushed with 0.1 mL of nutrient broth. A 0.1 mL aliquot of each flushed product was cultured on a blood agar plate to determine the number of remaining organisms. The results are shown in Table 2.
[0133]
[Table 2]

[0134]
^* No growth of Candida albicans on agar plates. However, there were several colonies of contaminants (coagulase negative staphylococci and corynebacteria), possibly from the outer surface of the catheter. ^** No growth of P. aeroginosa on agar plates.
However, there were two colonies of contaminants, possibly from the outer surface of the catheter.
[0135]
In view of the many changes and modifications that can be made without departing from the principles underlying the invention, reference should be made to the claims for an understanding of the scope of protection afforded the invention.
[Brief description of the drawings]
FIG. 1 is a cross-sectional view of a buried access device of the present invention.
FIG. 2 is a cross-sectional view of a second embodiment of the device of the present invention.
FIG. 3 is a cross-sectional view of a third embodiment of the apparatus of the present invention.
FIG. 4 is a cross-sectional view of the embodiment shown in FIG. 3 with a needle inserted.
FIG. 5 is a cross-sectional view of the valve of the embodiment shown in FIG.
FIG. 6 is a cross-sectional view of the locking mount of the embodiment shown in FIG.
FIG. 7 is a cross-sectional view of the valve seat mount of the embodiment shown in FIG.
FIG. 8 is a cross-sectional view of the distal housing of the embodiment shown in FIG.
FIG. 9 is a cross-sectional view of a fourth embodiment of the device of the present invention having a sliding seal-integral friction lock.
FIG. 10 is a cross-sectional view of a fifth embodiment of the device of the present invention having a longitudinal slidable seal.
FIG. 11 is a cross-sectional view of a sixth embodiment of the apparatus of the present invention having a trumpet type valve.
FIG. 12 is a cross-sectional view of the embodiment shown in FIG. 11 with a needle inserted.
FIG. 13 is a cross-sectional view of a fifth embodiment of the device of the present invention having an inflatable seal.
FIG. 14 is a cross-sectional view of a preferred needle and obturator assembly.

Claims (13)

A prosthetic device,
(A) means for providing a continuous flow path across the patient's skin between the external site for the patient and the internal site for the patient;
(B) means for blocking the flow path, and (c) a composition comprising:
(I) an anticoagulant, and (ii) a composition comprising a non-antibiotic biocide seen including,
Wherein the anticoagulant is a mixture of citric acid and trisodium citrate, and the biocide is a taurinamide derivative, phenol, a quaternary ammonium surfactant, a chlorine-containing product, quinoline, quinaldinium, A prosthetic device selected from the group consisting of lactones, dyes, thiosemicarbazones, quinones, sulfa, carbamates, ureas, salicylamides, carbanilides, amides, guanides, amidines, chelates and imidazoline biocides .   The device of claim 1, wherein the device is a catheter.   The apparatus of claim 1, wherein the apparatus is a port. Repeat to the patient's vasculature for hemodialysis repeat blood exchange therapy via a catheter having a distal end implanted subcutaneously in the patient and attached to the patient's blood vessel and a proximal end near the patient's skin A hemodialysis access system for access,
(A) a subcutaneously implantable access device having an inlet area, an outlet area and a passage between them provided for the introduction of a needle, whereby a gentle flow with each other and with the catheter Access as described above defining a continuous streamlined flow path that is constructed and arranged to have only a change of direction and is essentially free of stagnation points and blood flow through the flow path at a flow rate of at least 100 milliliters per minute apparatus,
(B) a needle that defines a continuous channel extension with respect to the catheter with the front of the obturator emerging from and removable from the cannula, a cannula configured and arranged as a passageway when the obturator is removed, and Means for communication from the distal end inside the cannula to an external patient site;
Puncture the skin (c) the patient, the passage of the reach and buried device at the entrance zone of the buried device through the subcutaneous tissue to a point for removal of the obturator of adjacent and needle means to the outlet zone of the device the moved, thereby being constructed and arranged to provide a blood exchange passage and the flushing passage establishes fluid communication between the external site and the catheter to the patient from outside the patient to the vascular system of a patient Needle ,
(D) is provided at a portion to be passed Ri by the needle inserted into the passageway of the apparatus, the cannula / obturator to seal the passage when not in passage and means can be opened when the exterior surface of the needle means is in contact, A seal configured and arranged such that the needle surface pushes the seal to push the seal to the open position and allows the needle to move through the device passageway without the needle tip contacting the sealing surface; A needle, the cannula sufficiently hard to keep the seal open when the obturator is withdrawn from the insertion cannula, and (e) a composition comprising:
(I) an anticoagulant, and (ii) a combination of composition comprising a non-antibiotic biocide seen including,
Wherein the anticoagulant is a mixture of citric acid and trisodium citrate, and the biocide is a taurinamide derivative, phenol, quaternary ammonium surfactant, chlorine-containing product, quinoline, quinaldinium, The hemodialysis access system selected from the group consisting of lactones, dyes, thiosemicarbazones, quinones, sulfa, carbamates, ureas, salicylamides, carbanilides, amides, guanides, amidines, chelates and imidazoline biocides . 5. The system of claim 4 , wherein the passage includes a zone adjacent to its outlet for stopping the front end of the cannula of the insertion needle and forming a smooth wall flow path transition therewith. Infection and blood clotting for access to the vasculature of human or animal patients for high fluid flow exchange of blood between the vasculature and external processing devices at volumetric flow rates in excess of 100 mL / min A hemodialysis access system with a reduced tendency to produce
(A) a needle configured and arranged to pierce the patient's skin and to carry and pass blood at a flow rate consistent with the high blood flow requirements of the blood exchange process, including a lumen defined by the inner surface Assembly,
(B) a subcutaneously implantable access device that allows fluid connection to a tube or space within the patient's body, the device comprising: (i) a flow path having a linear or gently changing flow direction; Provided and configured and arranged to have a distal end and a proximal end with respect to the flow channel inner surface and the patient's skin puncture site, and to insert and withdraw the needle through the proximal end of the channel Channel structure,
(Ii) a seal disposed within the channel and movable between a first and second position, wherein the fluid passes through the seal with the needle not inserted into the seal in the first position. And allows fluid to pass through the needle and emerge substantially at the distal end of the channel with the needle inserted into the seal in the second position and when the sealing means is in the second position. The blood flow transition between the inner surface and the channel inner surface includes the seal described above being substantially continuous and smooth, and the device is for joining the distal end of the channel to a catheter that extends to the inner tube of the patient's body. The access device is continuous and smooth along the inner surface of the channel and the inner surface of the catheter, and (c) a composition comprising:
(I) an anticoagulant, and (ii) a combination of composition comprising a non-antibiotic biocide seen including,
Wherein the anticoagulant is a mixture of citric acid and trisodium citrate, and the biocide is a taurinamide derivative, phenol, quaternary ammonium surfactant, chlorine-containing product, quinoline, quinaldinium, The hemodialysis access system selected from the group consisting of lactones, dyes, thiosemicarbazones, quinones, sulfa, carbamates, ureas, salicylamides, carbanilides, amides, guanides, amidines, chelates and imidazoline biocides . Further comprising a catheter configured and arranged to be implanted between the device at the proximal catheter end and the patient's blood vessel at or into the distal catheter end, and means for attaching the device to surrounding patient tissue. Item 6. The access system according to Item 6 . 7. The access system of claim 6 for high flow blood exchange between a human or animal patient by simultaneous inflow and outflow to and from the patient through separate passages, wherein An inlet, each proximal to and distal to the skin, for receiving one or more hollow needles that can be buried underneath and that are inserted percutaneously with an internal lumen At least one subcutaneously implantable access device having at least one passage with a transition between the internal lumen of the needle and the interior of the passage of the device with a gentle flow direction change and streamline flow path It has, thereby allowing the fluid connection to one or two blood vessels within a patient, the access system. 9. The access system of claim 8 , further comprising means for securing the needles to each other and locking means for securing the needles within the device. A hemodialysis access system for use in a blood exchange treatment system comprising an extracorporeal blood treatment device operating at a flow rate of at least 100 milliliters per minute and capable of allowing hundreds of blood exchange treatment cycles, The blood exchange treatment system includes a catheter that is implanted in the patient and connected at a distal end to the patient's blood vessel and having a proximal portion within the patient adjacent to the patient's skin, the access system comprising:
(A) means extending from the exterior of the patient to the catheter and forming a continuous streamline flow path essentially free of surface discontinuities and flow stagnation sites and substantial pressure drops, wherein the means comprises a gentle flow Including a channel structure that provides a flow path having only a change of direction, and the means has two means of smoothly connecting at the abutment , the changes in the abutment and all the flow cross sections a and, moreover said means, the
(I) a device that can be buried in a patient and has a passage therein;
(Ii) a needle that can be percutaneously inserted into the patient and into the device passage to establish a portion of the flow path and can be removed from the device and the patient; and (iii) when the needle is not inserted passage shut automatically and the needle lies outside of the fully passage when inserted, a said means, and (b) a composition comprising a flexible seal in the device,
A composition comprising (i) an anticoagulant, and (ii) a non-antibiotic biocide, whereby blood exchange therapy is highly resistant to blood clotting, infection, erythrocyte damage and platelet activation, and blood exchange therapy available der maintained at a low pressure drop along the matched flow path and flow requirements is,
Wherein the anticoagulant is a mixture of citric acid and trisodium citrate, and the biocide is a taurinamide derivative, phenol, quaternary ammonium surfactant, chlorine-containing product, quinoline, quinaldinium, The hemodialysis access system selected from the group consisting of lactones, dyes, thiosemicarbazones, quinones, sulfa, carbamates, ureas, salicylamides, carbanilides, amides, guanides, amidines, chelates and imidazoline biocides . Long-term fluid exchange between a patient's distal vasculature and a proximal blood treatment site via a catheter having a distal end and a proximal end implanted under the patient's skin and coupled to the patient's blood vessel A hemodialysis access system for repeated access to the distal vasculature of a patient under treatment comprising:
(A) an elongated thin-walled rigid cannula with a proximal end towards the blood treatment site and a distal end towards the vasculature, and inserted through the full length of the cannula and with a sharp distal end of the obturator A needle assembly comprising an obturator configured and arranged such that the distal end emerges from the distal end of the cannula and is removable from the cannula, wherein the cannula is adapted to receive blood flow when the obturator is removed. Configured and arranged to pass through the interior of the cannula at a high flow rate of at least 100 milliliters per minute so that the longitudinal flow of blood at such end can enter or exit the cannula at its distal end Said needle assembly comprising means for communicating from a rear end portion inside the cannula to an external blood treatment site,
(B) having an inlet zone and an outlet zone and a passage between them, the cannula enters the inlet end zone and occupies a substantial passage length with a smooth transition between the distal end of the cannula and the outlet zone of the device; A subcutaneously embeddable access device having an outlet region attached to the proximal catheter end and an inlet region connected to the needle assembly through the patient's skin, cannula interior and outlet region. Defines a continuous streamline flow path that can be placed subcutaneously so as to be accessible, thereby having only a flow direction that gently changes together and essentially free of stagnation points or abrupt transitions, and The access device configured and arranged to pass blood through the flow path defined by at a flow rate of at least 100 milliliters per minute;
(C) penetrates the patient's skin and subcutaneous tissue to reach the entry area of the device and the passage of the buried device to a point adjacent to the exit area of the device and to a point outside the patient's skin for removal of the obturator A needle configured and arranged to be moved so that an external blood treatment site can be placed in fluid communication with the cannula and catheter to establish a blood exchange path and a flushing path from outside the patient to the patient's vasculature Assembly,
(D) is placed in the path of the device to the site to be passed Ri by the insertion of the cannula / obturator, and when the cannula / obturator is actuated by the biasing force to produce a seal seat stress when not in passage A seal including means for closing the passageway and opening when the cannula / occlusion is contacted, wherein the means pushes the means against the outer surface of the cannula / occlusion to overcome the biasing force to the open position. The seal, obturator, configured and arranged to displace and allow the cannula / obturator to move through the device passageway without the obturator distal point in contact with the elastic seal is removed from the insertion needle. The cannula sufficiently hard to keep the seal open when withdrawn, and (e) the composition comprising:
(I) an anticoagulant, and (ii) a combination of composition comprising a non-antibiotic biocide seen including,
Wherein the anticoagulant is a mixture of citric acid and trisodium citrate, and the biocide is a taurinamide derivative, phenol, quaternary ammonium surfactant, chlorine-containing product, quinoline, quinaldinium, The hemodialysis access system selected from the group consisting of lactones, dyes, thiosemicarbazones, quinones, sulfa, carbamates, ureas, salicylamides, carbanilides, amides, guanides, amidines, chelates and imidazoline biocides . 12. The access system of claim 11 , wherein the passage includes an area proximate to its outlet for docking with and forming a smooth wall flow transition with the distal end of the insertion cannula. The biocide is the formula

Wherein R ¹ is hydrogen or alkyl and R ² is hydrogen, alkyl or formula

Is the basis of
12. The system of claim 4, 6, 10 or 11 which is a taurine amide derivative.

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