JP4284737B2 - Neutral peritoneal dialysis solution - Google Patents
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- JP4284737B2 JP4284737B2 JP05110099A JP5110099A JP4284737B2 JP 4284737 B2 JP4284737 B2 JP 4284737B2 JP 05110099 A JP05110099 A JP 05110099A JP 5110099 A JP5110099 A JP 5110099A JP 4284737 B2 JP4284737 B2 JP 4284737B2
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D81/00—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents
- B65D81/32—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents for packaging two or more different materials which must be maintained separate prior to use in admixture
- B65D81/3261—Flexible containers having several compartments
- B65D81/3266—Flexible containers having several compartments separated by a common rupturable seal, a clip or other removable fastening device
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
- A61M1/28—Peritoneal dialysis ; Other peritoneal treatment, e.g. oxygenation
- A61M1/287—Dialysates therefor
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Description
【０００１】
【発明の属する技術分野】
本発明は腹膜透析液に関するものであり、特に生体適合性に優れた中性腹膜透析液に関する。
【０００２】
【従来の技術】
腎不全の患者に対する治療法として、従来より血液透析療法や腹膜透析療法等が行われてきた。腹膜透析療法は、適性でない処置による腹膜炎の発生や長期間継続による腹膜機能の低下等のデメリットはあるが、通院の必要が無い、患者が時間的に拘束されない、瀕回の体外血液循環や血管穿刺による問題が無い、有害物質の分子量による除去効率の問題が少ない、治療費が高価でない等のメリットが多く、今後も伸びてゆく治療法と考えられる。
【０００３】
近年の報告によると、酸性の腹膜透析液は、腹膜機能低下の原因の１つに挙げられている。また、酸性の腹膜透析液によって、腹膜機能の低下だけでなく、腹腔内リンパ球の免疫能が低下し、腹膜炎が発生し易くなるという説もある。このように、酸性の腹膜透析液は生体にとって好ましくないと考えられているにも関わらず、浸透圧調整剤のブドウ糖を中性域で滅菌・保存すると、分解してしまうため、酸性側領域に調整しているという事情があった。
【０００４】
しかし、生体適合性や上記弊害改善の点から、中性腹膜透析液が注目されており、調製方法や薬液組成を工夫することによって、上記ブドウ糖の分解を抑制する研究も広く行われている。それは、ブドウ糖やカルシウム、マグネシウムや乳酸塩を含有する酸性濃縮液と、重炭酸塩を含有するアルカリ側濃縮液の２液に分けて収容保存し、使用時に混合するというものである。それによって、ブドウ糖の分解を防止し、且つカルシウムやマグネシウムの不溶塩の生成を防止できる。このような調製方法や薬液組成を開示したものとして、特開平９−８７１８２号がある。或いは、乳酸塩を含まない酸性濃縮液と、重炭酸塩を含むアルカリ側濃縮液の２液を混合する方法が特許第２７８１４４７号に開示されている。また、ブドウ糖やカルシウム、マグネシウムを含有する酸性濃縮液と乳酸塩を含有する液を混合する方法を開示したものとしては、特開平８−１３１５４２号がある。さらに、特開平８−１６４１９９号に記載されているように、１剤によって中性腹膜透析液を調製しているものもある。
【０００５】
【発明が解決しようとする課題】
ところが、上記の方法や薬液組成はブドウ糖分解やｐＨ調整の容易性の点で満足できるものではなかった。例えば、特開平９−８７１８２号に示されるように、酸性濃縮液に乳酸塩を含有するものは、滅菌時にブドウ糖分解を促進し、また酸性濃縮液を所望のｐＨ領域にするために多量の酸を添加する必要がある。重炭酸を配合しない緩衝剤として、乳酸イオンのみを含有する液では、混合後の液を望みの中性領域に調整することが困難であった。また、特許第２７８１４４７号のように、アルカリ性濃縮液に２５〜４０ｍＥｑの重炭酸塩を含有する方法では、混合後の透析液を所望の中性領域にするために、酸性濃縮液をより酸性にするか、或いはアルカリ性濃縮液を酸でｐＨ調整する必要があった。この場合、酸性濃縮液を酸性にし過ぎると、ブドウ糖の分解が加速される問題を生じ、さらにアルカリ性濃縮液に酸を添加すると、調整したｐＨを維持するために、製造時（調剤および高圧蒸気滅菌時）や保存時に、発生する炭酸ガスの放出を防止する対策が必要であった。上記の事は使用する容器の選択を限定し、また液を調製する際に少なからぬ負担となっていた。
【０００６】
従って、本発明の目的は使用前のブドウ糖の分解を防止でき、混合後の透析液が生理的なｐＨ範囲の腹膜透析液を提供することである。そして、製造時にｐＨ調整の容易な、また保存後も安定した中性腹膜透析液を提供することである。さらに、上記腹膜透析液を収容した透析容器や透析セットを提供することにある。
【０００７】
【課題を解決するための手段】
本発明者らは、創意工夫の末、混合する前の腹膜透析液を酸性側濃縮液（以下、酸性濃縮液ともいう）とアルカリ側濃縮液（以下、アルカリ性濃縮液ともいう）の２液に分離して収容し、前記酸性濃縮液にブドウ糖や、アルカリ性領域で沈殿を生成し易い無機塩を含有させ、前記アルカリ性濃縮液に血液アルカリ化剤（本願では、患者の腹膜を介して患者血液の酸・塩基平衡調節を行うものをいう）と微量のｐＨ調整剤を含有させることによって、ブドウ糖の分解が抑制でき、且つ薬液調製の容易な中性腹膜透析液が得られることを見出した。
【０００８】
本発明は酸性濃縮液とアルカリ性濃縮液の２液に分離して収容された腹膜透析液であって、前記酸性側濃縮液にブドウ糖や、アルカリ性領域で沈殿を生成し易いカルシウム塩、マグネシウム塩等の複数の種類の無機塩を含有し、前記アルカリ性濃縮液に血液アルカリ化剤である乳酸ナトリウムと微量のｐＨ調整剤を含有することを特徴とする。即ち、酸性濃縮液とアルカリ性濃縮液の２液に分離して収容された腹膜透析液であって、前記酸性濃縮液にブドウ糖やアルカリ性領域で沈殿を生成し易い複数の種類の無機塩を含有し、前記アルカリ性濃縮液に血液アルカリ化剤と微量のｐＨ調整剤を含有し、前記血液アルカリ化剤は乳酸ナトリウムであり、前記ｐＨ調整剤は１〜３ｍＭ濃度の炭酸水素ナトリウムであることを特徴とする腹膜透析液である。なお、前記アルカリ性濃縮液に、溶液のｐＨをアルカリ側にした場合でも沈殿を生成しない無機塩（例えば塩化ナトリウム等）を含有させるのは任意である。また、酸性濃縮液とアルカリ性濃縮液の混合液が、ナトリウムイオン１００〜１５０ｍＥｑ／Ｌ、カルシウムイオン１〜５ｍＥｑ／Ｌ、マグネシウムイオン０〜３ｍＥｑ／Ｌ、塩素イオン８０〜１２０ｍＥｑ／Ｌを含有するように無機塩を配合するのが、好ましい。微量のｐＨ調整剤としては、炭酸水素ナトリウム以外に、クエン酸ナトリウム、水酸化ナトリウムと炭酸ガス、或いは水酸化ナトリウムと塩酸および炭酸ガスの組合せが使用できる。さらに、上記水酸化ナトリウムに代えて、グリシンナトリウムを使用することもできる。
【０００９】
本発明は、上記構成によって以下の優れた効果を得ることが出来る。即ち、前記アルカリ性濃縮液に含有されるｐＨ調整剤として、１〜３ｍＭの炭酸水素ナトリウムを使用することによって、混合後の腹膜透析液のｐＨ値を容易且つ安定に中性領域（ｐＨ＝６．５〜７．５）にすることが可能であった。また、アルカリ性濃縮液のｐＨが７．６〜８．４となるよう、アルカリ性濃縮液にｐＨ調整剤として炭酸水素ナトリウムを加えることによっても、混合後の腹膜透析液のｐＨ値を容易且つ安定に中性領域にすることが可能であった。該濃縮液のｐＨを上記のようにすると、アルカリ性濃縮液の二酸化炭素分圧（ＣＯ ２ ）が低いために炭酸ガスの拡散が少なく、大気下でもｐＨが安定となる。この為、製造及び保存時に炭酸ガスの透過を防止する特別な手段が不要で製造が容易となるという利点がある。
【００１０】
また、ｐＨ調整剤として上記炭酸水素ナトリウムの他に、水酸化ナトリウムと適量の炭酸ガスを組合せて使用することでも同様の効果を得た。例えば１〜３ｍＭの水酸化ナトリウムと適量の炭酸ガスとをアルカリ性濃縮液に混入するものである。適量の炭酸ガスとは、アルカリ性濃縮液の調製時にバブリング（ｂｕｂｂｌｉｎｇ）が観察される程度以上の量をいい、通気量はスケールによって異なるので規定し難いが、アルカリ性濃縮液５０００〜１０，０００ｍｌに対し、およそ３０ｍｌ／ｍｉｎ以上であり、好ましくは２００〜５００ｍｌ／ｍｉｎで数十秒のバブリングである。ｐＨ調整剤として、上記のものに塩酸を加えても良い。即ち、アルカリ性濃縮液が、水酸化ナトリウムと塩酸及びｐＨを微調整するための炭酸ガスを含有するものでも良い。或いは、上記で水酸化ナトリウムの代りにグリシンナトリウムを使用することもできる。即ち、ｐＨ調整剤として、１〜３ｍＭのグリシンナトリウムと適量の炭酸ガスを組合せて使用するものである。さらにｐＨ調整剤としては、６〜１３ｍＭ濃度のクエン酸ナトリウムを使用することもできる。
【００１１】
また、本発明は以下のような実施様態によって、優れた効果を得ることができる。第１に、前記酸性濃縮液のｐＨが３〜４の範囲にある前記の腹膜透析液である。乳酸塩を含有しない酸性濃縮液のｐＨを上記範囲とすることによって、酸性濃縮液の高圧蒸気滅菌時や保存の際にブドウ糖の分解や着色を抑制することができた。これについて、方法と結果を実験１で後述する。
【００１２】
第２に、アルカリ性濃縮液のｐＨが７．６〜８．４の範囲にある前記腹膜透析液である。上記構成によって、混合後の腹膜透析液のｐＨ調整が容易で且つ安定なものとすることが可能であった。アルカリ性濃縮液が上記ｐＨ範囲内にあれば、該濃縮液の二酸化炭素分圧（ＰＣＯ２）が低いため、炭酸ガスの拡散が少なく、大気下でもｐＨが安定である。このため、製造及び保存時に炭酸ガスの透過を防止する特別な手段が不要で製造が容易となる。
【００１３】
第３に、前記酸性濃縮液と前記アルカリ性濃縮液を混合した後の腹膜透析液のｐＨが６．５〜７．５であるような前記の腹膜透析液は、生体の腹腔に貯留した際に中皮細胞やマクロファージに与える影響が少なく、生体適合性の点でより好ましい。
【００１４】
第４に、混合する前の２液、即ち酸性濃縮液とアルカリ性濃縮液との液量比が１：１．５〜１：２．０である前記の腹膜透析液である。上記の液量比を検討する場合、以下の点から酸性濃縮液の液量をなるべく少なくするのが望ましい。すなわち、酸性濃縮液は酸を添加して液のｐＨを酸性に調整しているため、酸性濃縮液の液量を少なくすると、酸の添加量が少量に抑えられ、その結果アルカリ性濃縮液に配合するｐＨ調整剤の量を少なくすることができる。また、酸性濃縮液またはアルカリ性濃縮液のうち、いずれかの液量を減らすことによって、酸性濃縮液とアルカリ性濃縮液が収納された２つの容器の連通路を開放し、２つの濃縮液を混合する際に、２液の混合が容易且つ迅速になり、容器構造の選択の幅を拡げることができる。
【００１５】
しかし、分離された２液に対する（高圧蒸気滅菌時の）熱感応性に差をつけないでおくためには、２つの液量を同等にするのが好ましい。すなわち、分離された２液に対して高圧蒸気滅菌を行うことによって、以下のような問題があることが確認された。アルカリ性濃縮液に比較して酸性濃縮液を極端に少量（濃縮）にした場合、液量に対する収納容器の表面積の比が異なるため、加熱滅菌時に２液の昇温状態に違いが生じ（少量の液側は直ぐに加温する）、酸性濃縮液に過度の熱負荷がかかることが判明した。酸性濃縮液にはブドウ糖が含有されており、この液への過度の熱負荷はブドウ糖分解に影響を与え、好ましくない。
【００１６】
酸性濃縮液とアルカリ性濃縮液の２液の液量比を決定するために、後述の実験を行った結果、酸性濃縮液とアルカリ性濃縮液の２液の液量比を１（酸側）：１．５〜２．０（アルカリ側）とすることによって、効果的に上記利点（アルカリ性濃縮液へのｐＨ調整剤の添加量を少量に抑え、しかも酸性濃縮液にかかる過度の熱負荷を防止できる。）を得ることが確認された。後記の実験２に方法と結果を示した。
【００１７】
さらに本発明としては、前記記載の腹膜透析液を包装した後、加熱滅菌した腹膜透析用セットも実施態様に含まれる。
【００１８】
【発明の実施の形態】
本発明の腹膜透析液の収容状態を図によって、説明する。図１は、本発明の腹膜透析液を２つの別々の容器に分離して収容した状態を示した概略図である。腹膜透析液容器１は、酸性濃縮液収容部２とアルカリ性濃縮液収容部３の２つの隔室からなり、これらの隔室は使用前は遮断されているが、使用前に連通路４を開放することによって、連通し液が混合される。
【００１９】
【実施例】
［実施例１］
以下に、本発明の腹膜透析液の調製例の１つを示す。酸性濃縮液の液組成として、以下のものを使用した。
（酸性濃縮液）
１．ブドウ糖（グルコース） ： ２３９．２ｍｍｏｌ／ｌ
２．塩化カルシウム ： ５．５６ｍｍｏｌ／ｌ
３．塩化マグネシウム ： １．４１ｍｍｏｌ／ｌ
４．３．５％塩酸 ： ０．３ｍｌ／ｌ
上記濃度になるように、各成分を蒸留水に溶解した。この時の酸性濃縮液のｐＨは３．５５であった。
【００２０】
アルカリ性濃縮液として、以下のものを使用した。
（アルカリ性濃縮液）
１．乳酸ナトリウム ： ５４．９ｍｍｏｌ／ｌ
２．塩化ナトリウム ： １５１．６ｍｍｏｌ／ｌ
３．重炭酸ナトリウム ： ２．０ｍｍｏｌ／ｌ
上記濃度になるように、各成分を蒸留水に溶解した。この時のアルカリ性濃縮液のｐＨは８．１であった。
【００２１】
上記処方によって得た、酸性濃縮液７２０ｍｌとアルカリ性濃縮液１２８０ｍｌを腹膜透析液容器の２つの隔室に各々収容した後、１１５℃で３０分間高圧蒸気滅菌した。その後、腹膜透析容器の隔室を連通して、上記の２液を混合した。混合後の腹膜透析液のｐＨは７．１〜７．３を示し、生理的な中性領域の範囲にあることが確認された。ブドウ糖分解副産物の指標となる２８４ｎｍの吸光度は、０．０９と僅かであり、また溶液の着色も無かったことから、ブドウ糖の分解の程度が低く抑制されていることが示された。
【００２２】
また、高圧蒸気滅菌後に隔室を連通せずに、酸性濃縮液とアルカリ性濃縮液を別々の容器に収容したまま、湿度７５±５％、温度４０±１℃で２ヶ月保存した後に、２液を混合して得られた液のｐＨを測定した。その結果、混合液のｐＨは７．０〜７．２の好ましい中性領域にあることが示された。
【００２３】
［実施例２］
実施例１と同じようにして酸性濃縮液を調製した。また、アルカリ性濃縮液を下記の濃度になるように調製した。
（アルカリ性濃縮液）
１．乳酸ナトリウム ： ５４．９ｍｍｏｌ／ｌ
２．塩化ナトリウム ： １５１．６ｍｍｏｌ／ｌ
３．水酸化ナトリウム ： ２．０ｍｍｏｌ／ｌ
４．二酸化炭素 ： 適量
乳酸ナトリウム、塩化ナトリウムを蒸留水に溶解後、二酸化炭素ガスを５００〜６００ｍｌ／ｍｉｎで数十秒バブリングした。その後、水酸化ナトリウムを添加し攪拌した。この時のｐＨは８．２０であった。
次に酸性濃縮液とアルカリ性濃縮液を混合してｐＨを測定した。混合液のｐＨは生理的な中性領域の７．２２であり、実施例１と同じように腹膜透析液のｐＨ調整が容易であった。
【００２４】
［実験１］
酸性濃縮液の安定性に関する実験
表１に示す電解質イオン、グルコース濃度、ｐＨになるように、グルコース、塩化ナトリウム、塩化カルシウム（２水塩）、塩化マグネシウム（６水塩）、乳酸ナトリウムを注射用蒸留水に溶解し、１規定の塩酸でｐＨ調整して比較例、試験例１〜４の酸性濃縮液を調製した。この液を塩化ビニル樹脂製バッグに充填し、さらに包材で前記バッグを真空包装した後に、高圧蒸気滅菌を行った。各酸性濃縮液は、滅菌直後（表中の製造直後）、加速条件（４０℃、７５％ＲＨ）で４週間保存後、紫外部分光分析でブドウ糖分解物濃度の指標となるＵＶ284nm、ＵＶ228nmでの吸光度、着色の指標となる色差、ｐＨを測定した。各液の測定結果を表１に示す。
【００２５】
【表１】
その結果、酸性濃縮液に乳酸イオンを含む比較例は着色を認めたが、乳酸イオンを含まない試験例１〜４では着色が僅かであった。また、ブドウ糖分解物の指標となる紫外部吸収について試験例１〜４を比較すると、ＵＶ284nmの吸光度は試験例１に比べ試験例２〜４が低く、ＵＶ228nmの吸光度は試験例４に比べて試験例１〜３が低値を示した。以上の結果により、酸性濃縮液の製造（滅菌）時および保存時におけるブドウ糖の安定性には乳酸イオンの存在が影響し、さらに液のｐＨは３〜４が好ましいことが確認された。
【００２７】
［実験２］
実施例１の酸性濃縮液とアルカリ性濃縮液を使用して、容量や液量比が表２になるように塩化ビニル樹脂製バッグに各液を収容し、高圧蒸気滅菌を行った。その際に各液が所定温度になるまでにかかる時間を測定した。表２に示されるように液量比が１：５のものに比べて、液量比が１：２のものは所定の温度になるまでに要する時間に差が無いことが確認された。
【００２８】
【表２】
【発明の効果】
本発明の腹膜透析液、或いは上記のように分離して収容された前記透析液は高圧蒸気滅菌時および保存時におけるブドウ糖の分解や液の着色が防止でき、また混合後の腹膜透析液のｐＨを、容易に生体に対して好ましい中性領域に調整することができた。
【図面の簡単な説明】
【図１】本発明の腹膜透析液を分離して収容した状態を示す概略図である。
【符号の説明】
１．腹膜透析液容器
２．酸性濃縮液収容部
３．アルカリ性濃縮液収容部
４．連通路[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a peritoneal dialysis solution, and more particularly to a neutral peritoneal dialysis solution excellent in biocompatibility.
[0002]
[Prior art]
Conventionally, hemodialysis therapy, peritoneal dialysis therapy, and the like have been performed as treatments for patients with renal failure. Peritoneal dialysis has disadvantages such as the occurrence of peritonitis due to inadequate treatment and the decrease in peritoneal function due to long-term continuation, but there is no need to go to the hospital, the patient is not time-constrained, repeated extracorporeal blood circulation and blood vessels There are many merits such as no problem due to puncture, few problems of removal efficiency due to molecular weight of harmful substances, and low treatment costs, and it is considered to be a therapeutic method that will continue to grow in the future.
[0003]
According to recent reports, acidic peritoneal dialysis fluid has been cited as one of the causes of peritoneal hypofunction. There is also a theory that an acidic peritoneal dialysis solution not only lowers peritoneal function but also reduces the immunity of intraperitoneal lymphocytes, making peritonitis easy to occur. Thus, although acidic peritoneal dialysis fluid is considered to be unfavorable for the living body, sterilization and storage of glucose, an osmotic pressure regulator, in the neutral range will result in decomposition, so that There was a situation that it was adjusting.
[0004]
However, neutral peritoneal dialysis fluid has attracted attention from the viewpoint of biocompatibility and the above-mentioned adverse effects, and extensive studies have been conducted to suppress the degradation of glucose by devising the preparation method and the chemical composition. It is stored and stored separately in two liquids, an acidic concentrate containing glucose, calcium, magnesium and lactate, and an alkaline concentrate containing bicarbonate, and mixed at the time of use. Thereby, it is possible to prevent the decomposition of glucose and the formation of insoluble salts of calcium and magnesium. JP-A-9-87182 discloses such a preparation method and chemical composition. Alternatively, Japanese Patent No. 2781447 discloses a method of mixing two liquids, an acidic concentrated liquid not containing lactate and an alkaline concentrated liquid containing bicarbonate. Japanese Patent Laid-Open No. 8-131542 discloses a method of mixing an acidic concentrate containing glucose, calcium and magnesium and a liquid containing lactate. In addition, as described in JP-A-8-164199, there is also one in which a neutral peritoneal dialysis solution is prepared with one agent.
[0005]
[Problems to be solved by the invention]
However, the above methods and chemical composition are not satisfactory in terms of glucose decomposition and ease of pH adjustment. For example, as disclosed in JP-A-9-87182, an acid concentrate containing lactate accelerates glucose degradation during sterilization, and a large amount of acid in order to bring the acid concentrate to a desired pH range. Need to be added. In a liquid containing only lactate ions as a buffering agent not containing bicarbonate, it is difficult to adjust the mixed liquid to a desired neutral region. Moreover, in the method of containing 25-40 mEq of bicarbonate in the alkaline concentrate as in Japanese Patent No. 2781447, the acidic concentrate is made more acidic in order to bring the mixed dialysate into the desired neutral region. Or it was necessary to adjust the pH of the alkaline concentrate with an acid. In this case, if the acidic concentrate is made too acidic, it causes a problem of accelerated glucose degradation, and when an acid is added to the alkaline concentrate, it maintains the adjusted pH at the time of manufacture (preparation and high-pressure steam sterilization). And measures to prevent the release of carbon dioxide generated during storage. The above has limited the selection of the container to be used, and has caused a considerable burden when preparing the liquid.
[0006]
Accordingly, an object of the present invention is to provide a peritoneal dialysis solution in which glucose degradation before use can be prevented and the dialysis solution after mixing has a physiological pH range. And it is providing the neutral peritoneal dialysate which is easy to adjust pH at the time of manufacture, and was stable after storage. Furthermore, it is providing the dialysis container and dialysis set which accommodated the said peritoneal dialysate.
[0007]
[Means for Solving the Problems]
As a result of ingenuity, the present inventors changed the peritoneal dialysate before mixing into two liquids, an acidic side concentrated liquid (hereinafter also referred to as acidic concentrated liquid) and an alkaline side concentrated liquid (hereinafter also referred to as alkaline concentrated liquid). Separated and stored, the acidic concentrate contains glucose or an inorganic salt that easily produces precipitates in the alkaline region, and the alkaline concentrate contains a blood alkalizing agent (in this application, the blood of the patient's blood via the patient's peritoneum). It was found that a neutral peritoneal dialysis solution that can suppress the degradation of glucose and can be easily prepared is obtained by adding a trace amount of a pH adjusting agent).
[0008]
The present invention is a peritoneal dialysis solution separated and accommodated in two liquids, an acidic concentrated solution and an alkaline concentrated solution, wherein glucose, calcium salt, magnesium salt, etc. that easily generate precipitates in the alkaline region, etc. A plurality of types of inorganic salts, and the alkaline concentrate contains sodium lactate as a blood alkalizing agent and a trace amount of a pH adjusting agent. That is, a peritoneal dialysis solution separated into two liquids , an acidic concentrate and an alkaline concentrate, containing a plurality of types of inorganic salts that easily form precipitates in glucose or an alkaline region. The alkaline concentrate contains a blood alkalizing agent and a trace amount of a pH adjusting agent, the blood alkalizing agent is sodium lactate, and the pH adjusting agent is 1 to 3 mM sodium bicarbonate. Peritoneal dialysis solution . In addition, it is arbitrary to contain the inorganic salt (for example, sodium chloride etc.) which does not produce | generate precipitation even when the pH of a solution is made into the alkali side in the said alkaline concentrated liquid. Moreover, so that the liquid mixture of an acidic concentrate and an alkaline concentrate contains sodium ion 100-150 mEq / L, calcium ion 1-5 mEq / L, magnesium ion 0-3 mEq / L, chlorine ion 80-120 mEq / L. It is preferable to add an inorganic salt. As a slight amount of pH adjuster, sodium citrate, sodium hydroxide and carbon dioxide, or a combination of sodium hydroxide, hydrochloric acid and carbon dioxide can be used in addition to sodium hydrogen carbonate. Furthermore, glycine sodium can be used in place of the sodium hydroxide.
[0009]
The present invention can obtain the following excellent effects by the above configuration . That is, by using 1 to 3 mM sodium bicarbonate as a pH adjuster contained in the alkaline concentrate, the pH value of the peritoneal dialysis solution after mixing can be easily and stably neutral (pH = 6. 5 to 7.5). Moreover, the pH value of the peritoneal dialysate after mixing can be easily and stably added by adding sodium hydrogen carbonate as a pH adjuster to the alkaline concentrate so that the pH of the alkaline concentrate is 7.6 to 8.4. It was possible to make it neutral. When the pH of the concentrate is as described above, the carbon dioxide partial pressure (CO 2 ) of the alkaline concentrate is low, so that the diffusion of carbon dioxide gas is small and the pH is stable even in the atmosphere. For this reason, there is an advantage that manufacture is easy because a special means for preventing the permeation of carbon dioxide gas is unnecessary during manufacture and storage.
[0010]
Further, the same effect was obtained by using a combination of sodium hydroxide and an appropriate amount of carbon dioxide gas as a pH adjuster in addition to the above sodium hydrogen carbonate. For example, 1 to 3 mM sodium hydroxide and an appropriate amount of carbon dioxide gas are mixed into the alkaline concentrate. The appropriate amount of carbon dioxide gas means an amount that exceeds the level at which bubbling is observed during the preparation of the alkaline concentrate, and the amount of aeration varies depending on the scale and is difficult to define, but with respect to the alkaline concentrate 5000 to 10,000 ml. The bubbling is several tens of seconds at 200 to 500 ml / min. Hydrochloric acid may be added to the above as a pH adjuster. That is, the alkaline concentrate may contain sodium hydroxide, hydrochloric acid, and carbon dioxide gas for fine adjustment of pH. Alternatively, sodium glycine can be used in place of sodium hydroxide as described above. That is, as a pH adjuster, 1 to 3 mM glycine sodium and an appropriate amount of carbon dioxide gas are used in combination. Furthermore, 6-13 mM sodium citrate can also be used as a pH adjuster.
[0011]
In addition, the present invention can obtain excellent effects by the following embodiments. 1stly, it is the said peritoneal dialysate in which the pH of the said acidic concentrate exists in the range of 3-4. By setting the pH of the acidic concentrate not containing lactate within the above range, it was possible to suppress the degradation and coloring of glucose during autoclaving and storage of the acidic concentrate. The method and result will be described later in Experiment 1.
[0012]
Second, the peritoneal dialysis solution has a pH of the alkaline concentrate in the range of 7.6 to 8.4. With the above configuration, it was possible to easily and stably adjust the pH of the peritoneal dialysis solution after mixing. If the alkaline concentrate is within the above pH range, the carbon dioxide partial pressure (PCO 2 ) of the concentrate is low, so that the diffusion of carbon dioxide gas is small and the pH is stable even in the atmosphere. For this reason, a special means for preventing the permeation of carbon dioxide during production and storage is unnecessary, and the production is facilitated.
[0013]
Third, when the peritoneal dialysate having a pH of 6.5 to 7.5 after mixing the acidic concentrate and the alkaline concentrate is stored in the abdominal cavity of a living body, It has less influence on mesothelial cells and macrophages, and is more preferable in terms of biocompatibility.
[0014]
Fourth, second liquid prior to mixing, i.e. liquid volume ratio of the acidic concentrate and an alkaline concentrate 1: 1.5 to 1: is the peritoneal dialysate is 2.0. When examining the liquid volume ratio, it is desirable to reduce the volume of the acidic concentrate as much as possible from the following points. In other words, since the acid concentrate adjusts the pH of the solution to acid by adding an acid, if the amount of the acid concentrate is reduced, the amount of acid added can be suppressed to a small amount. As a result, it is blended into the alkaline concentrate. The amount of the pH adjusting agent to be reduced can be reduced. Further, by reducing the amount of either the acidic concentrate or the alkaline concentrate, the communication path between the two containers containing the acidic concentrate and the alkaline concentrate is opened, and the two concentrates are mixed. At this time, the mixing of the two liquids becomes easy and quick, and the range of selection of the container structure can be expanded.
[0015]
However, in order not to make a difference in heat sensitivity (at the time of high-pressure steam sterilization) with respect to the two separated liquids, it is preferable to make the two liquid amounts equal. That is, it was confirmed that the following problems were caused by high-pressure steam sterilization of the separated two liquids. When the acidic concentrate is made extremely small (concentrated) compared to the alkaline concentrate, the ratio of the surface area of the storage container to the liquid volume is different. The liquid side was warmed immediately), and it was found that an excessive heat load was applied to the acidic concentrate. Glucose is contained in the acidic concentrated liquid, and excessive heat load on this liquid affects glucose decomposition, which is not preferable.
[0016]
In order to determine the liquid volume ratio of the two liquids of the acidic concentrate and the alkaline concentrate, the following experiment was performed. As a result, the liquid volume ratio of the two liquids of the acidic concentrate and the alkaline concentrate was 1 (acid side): 1 0.5 to 2.0 (on the alkali side), the above-mentioned advantages (addition of the pH adjuster to the alkaline concentrate can be suppressed to a small amount, and an excessive heat load applied to the acidic concentrate can be prevented. .) Was obtained. The method and results are shown in
[0017]
Furthermore, the present invention includes a set for peritoneal dialysis that is packaged with the peritoneal dialysis solution described above and then sterilized by heating.
[0018]
DETAILED DESCRIPTION OF THE INVENTION
The accommodation state of the peritoneal dialysate of the present invention will be described with reference to the drawings. FIG. 1 is a schematic view showing a state in which the peritoneal dialysate of the present invention is separated and accommodated in two separate containers. The peritoneal dialysate container 1 is composed of two compartments, an
[0019]
【Example】
[Example 1]
One example of preparation of the peritoneal dialysis solution of the present invention is shown below. The following was used as the liquid composition of the acidic concentrate.
(Acid concentrate)
1. Glucose (glucose): 239.2 mmol / l
2. Calcium chloride: 5.56 mmol / l
3. Magnesium chloride: 1.41 mmol / l
4. 3.5% hydrochloric acid: 0.3 ml / l
Each component was dissolved in distilled water so as to have the above concentration. At this time, the pH of the acidic concentrate was 3.55.
[0020]
The following was used as the alkaline concentrate.
(Alkaline concentrate)
1. Sodium lactate: 54.9 mmol / l
2. Sodium chloride: 151.6 mmol / l
3. Sodium bicarbonate: 2.0 mmol / l
Each component was dissolved in distilled water so as to have the above concentration. The pH of the alkaline concentrate at this time was 8.1.
[0021]
720 ml of acidic concentrate and 1280 ml of alkaline concentrate obtained by the above formulation were placed in two compartments of the peritoneal dialysis fluid container and then autoclaved at 115 ° C. for 30 minutes. Thereafter, the two liquids were mixed by communicating with the compartment of the peritoneal dialysis container. The pH of the peritoneal dialysis solution after mixing was 7.1 to 7.3, which was confirmed to be in the physiological neutral range. The absorbance at 284 nm, which is an index of glucose degradation by-products, was as small as 0.09, and the solution was not colored, indicating that the degree of degradation of glucose was suppressed to a low level.
[0022]
In addition, after the autoclave sterilization, the two compartments are stored after storing for 2 months at 75 ± 5% humidity and 40 ± 1 ° C. with the acid concentrate and the alkaline concentrate kept in separate containers without communicating with the compartment. The pH of the liquid obtained by mixing was measured. As a result, it was shown that the pH of the mixed solution was in a preferable neutral region of 7.0 to 7.2.
[0023]
[Example 2]
An acidic concentrate was prepared in the same manner as in Example 1. Moreover, the alkaline concentrated liquid was prepared so that it might become the following density | concentration.
(Alkaline concentrate)
1. Sodium lactate: 54.9 mmol / l
2. Sodium chloride: 151.6 mmol / l
3. Sodium hydroxide: 2.0 mmol / l
4). Carbon dioxide: After dissolving appropriate amounts of sodium lactate and sodium chloride in distilled water, carbon dioxide gas was bubbled at 500 to 600 ml / min for several tens of seconds. Thereafter, sodium hydroxide was added and stirred. The pH at this time was 8.20.
Next, pH was measured by mixing an acidic concentrate and an alkaline concentrate. The pH of the mixed solution was 7.22 in the physiological neutral region, and the pH adjustment of the peritoneal dialysis solution was easy as in Example 1.
[0024]
[Experiment 1]
Experiments on the stability of acidic concentrates For the injection of glucose, sodium chloride, calcium chloride (dihydrate), magnesium chloride (hexahydrate), and sodium lactate so that the electrolyte ions, glucose concentration, and pH shown in Table 1 are obtained. It melt | dissolved in distilled water and adjusted the pH with 1N hydrochloric acid, and prepared the acidic concentrated liquid of the comparative example and Test Examples 1-4. This solution was filled in a vinyl chloride resin bag, and the bag was vacuum-packed with a packaging material, followed by high-pressure steam sterilization. Each acidic concentrate was stored at UV284nm and UV228nm immediately after sterilization (immediately after production in the table), after storage for 4 weeks under accelerated conditions (40 ° C, 75% RH), and as an index of glucose degradation product concentration by ultraviolet partial light analysis. Absorbance, color difference serving as an index of coloring, and pH were measured. Table 1 shows the measurement results of each solution.
[0025]
[Table 1]
As a result, although the comparative example which contains a lactic acid ion in an acidic concentrated liquid recognized coloration, in Test Examples 1-4 which does not contain a lactic acid ion, coloring was slight. Moreover, when the test examples 1 to 4 are compared with respect to the ultraviolet absorption as an index of the glucose degradation product, the UV 284 nm absorbance is lower in the test examples 2 to 4 than the test example 1, and the UV 228 nm absorbance is compared to the test example 4. Examples 1 to 3 showed low values. From the above results, it was confirmed that the presence of lactic acid ions had an effect on the stability of glucose during the production (sterilization) and storage of the acidic concentrate, and that the pH of the solution was preferably 3-4.
[0027]
[Experiment 2]
Using the acidic concentrated solution and the alkaline concentrated solution of Example 1, each solution was placed in a bag made of vinyl chloride resin so that the volume and the liquid volume ratio were as shown in Table 2, and high-pressure steam sterilization was performed. At that time, the time required for each liquid to reach a predetermined temperature was measured. As shown in Table 2, it was confirmed that there was no difference in the time required for the liquid volume ratio of 1: 2 to reach the predetermined temperature compared to the liquid volume ratio of 1: 5.
[0028]
[Table 2]
【The invention's effect】
The peritoneal dialysate of the present invention, or the dialysate stored separately as described above, can prevent glucose degradation and coloration during high-pressure steam sterilization and storage, and the pH of the peritoneal dialysate after mixing Can be easily adjusted to a neutral region preferable for a living body.
[Brief description of the drawings]
FIG. 1 is a schematic view showing a state in which the peritoneal dialysis solution of the present invention is separated and accommodated.
[Explanation of symbols]
1. 1.
Claims (8)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP05110099A JP4284737B2 (en) | 1999-02-26 | 1999-02-26 | Neutral peritoneal dialysis solution |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP05110099A JP4284737B2 (en) | 1999-02-26 | 1999-02-26 | Neutral peritoneal dialysis solution |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2000245826A JP2000245826A (en) | 2000-09-12 |
| JP4284737B2 true JP4284737B2 (en) | 2009-06-24 |
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| JP05110099A Expired - Lifetime JP4284737B2 (en) | 1999-02-26 | 1999-02-26 | Neutral peritoneal dialysis solution |
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Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6770148B1 (en) | 1998-12-04 | 2004-08-03 | Baxter International Inc. | Peritoneal dialysis solution containing modified icodextrins |
| US7186420B2 (en) | 1999-04-26 | 2007-03-06 | Edwards Lifesciences Corporation | Multi-part substitution infusion fluids and matching anticoagulants |
| US6743191B1 (en) | 1999-04-26 | 2004-06-01 | Edwards Lifesciences Ag | Substitution infusion fluid and citrate anticoagulation |
| US8105258B2 (en) | 1999-04-26 | 2012-01-31 | Baxter International Inc. | Citrate anticoagulation system for extracorporeal blood treatments |
| JP2003019198A (en) * | 2001-07-06 | 2003-01-21 | Jms Co Ltd | Peritoneal dialysate |
| JP2003088582A (en) * | 2001-09-19 | 2003-03-25 | Jms Co Ltd | Peritoneal dialysate and storage vessel |
| DE10217356B4 (en) * | 2002-04-18 | 2012-03-29 | Fresenius Medical Care Deutschland Gmbh | Solution for peritoneal dialysis |
| US20040121982A1 (en) * | 2002-12-20 | 2004-06-24 | Leo Martis | Biocompatible dialysis fluids containing icodextrins |
| US7053059B2 (en) | 2003-07-25 | 2006-05-30 | Baxter International Inc. | Dialysis solutions with reduced levels of glucose degradation products |
| JP2006000482A (en) * | 2004-06-18 | 2006-01-05 | Jms Co Ltd | Biocompatible liquid preparation, method for its production and method for its preservation |
| CN102940622A (en) | 2005-05-30 | 2013-02-27 | 弗雷森纽斯医疗护理德国有限责任公司 | Peritoneal dialysis fluid |
| JP7032321B2 (en) * | 2016-05-06 | 2022-03-08 | ガンブロ・ルンディア・エービー | Distribution liquid system |
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