JP2021155338A - Acute blood purification drug solution - Google Patents
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- 229940079593 drug Drugs 0.000 title claims abstract description 40
- 239000003814 drug Substances 0.000 title claims abstract description 40
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- 238000000502 dialysis Methods 0.000 claims abstract description 41
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Abstract
Description
本発明は、急性血液浄化用薬液、とりわけ急性腎障害と認められるものを対象とする持続的腎代替療法（ＣＲＲＴ）において使用するための補充液または透析液に関する。 The present invention relates to a drug solution for acute blood purification, particularly a replacement solution or dialysate for use in continuous renal replacement therapy (CRRT) for those recognized as acute kidney injury.
持続的腎代替療法とは、腎補助を目的とした血液浄化法であり、血液中の過剰な水分の除去（除水）および不要な代謝産物（老廃物）の除去を持続的に行うことを開始時に設定したものをいう。具体的には、急性腎障害、重症急性膵炎、劇症肝炎、術後肝不全、その他重症な急性肝炎などにより、血液生化学異常、電解質・酸塩基平衡異常、体液バランス異常などが生じ体液の恒常性が著しく損なわれた場合に、緊急に血液・体液を浄化して生体の恒常性を保ち、病態を改善することが求められるため、ＣＲＲＴが実施されている。 Sustained renal replacement therapy is a blood purification method aimed at assisting the kidneys, which means that excess water in the blood is removed (water removal) and unnecessary metabolites (waste products) are continuously removed. The one set at the start. Specifically, acute renal injury, severe acute pancreatitis, fulminant hepatitis, postoperative liver failure, and other severe acute hepatitis cause blood biochemical abnormalities, electrolyte / acid-base imbalances, and body fluid imbalances, resulting in body fluids. When homeostasis is significantly impaired, CRRT is performed because it is urgently required to purify blood and body fluids to maintain homeostasis of the living body and improve the pathological condition.
ＣＲＲＴは、主に集中治療部や救急部で重症患者、救急患者の治療として実施されている。その実施形式には、持続的血液濾過（ＣＨＦ）、持続的血液透析（ＣＨＤ）および持続的血液濾過透析（ＣＨＤＦ）などがあり、臨床上最も多く施行されているのは、ＣＨＤＦである。短時間で除去効率を向上させるため高流量持続的血液透析濾過（ＨＦＶＣＨＤＦ）、高流量持続的血液濾過（ＨＶＣＨＦ）も施行されている。これらのＣＲＲＴには、その実施形式により、補充液や透析液が必要となるが、現在のところ、ＣＲＲＴ専用の補充液や透析液は市販されておらず、従来の血液ろ過用補充液で代用している（非特許文献１）。しかし、従来の血液ろ過用補充液は、慢性腎不全患者を対象とした間歇的、短時間の治療を目的に処方設計されている。一方、ＣＨＤＦは数日間連続して行われることが多く、さらには、ＣＨＤＦ等のＣＲＲＴの施行を必要とする重症病態、例えば急性腎障害は背景疾患がさまざまであり、高度の高カリウム血症で緊急透析が必要な場合などもある。従来の血液濾過用補充液をＣＲＲＴに使用する場合、通常カリウムイオン濃度が生理的濃度に対して低く、長時間ＣＲＲＴを行うことにより血清カリウムイオン濃度が低下するといった問題があり、カリウムイオンを混注したり、カリウム製剤を別途投与する必要がある。 CRRT is mainly carried out in the intensive care unit and the emergency department as a treatment for critically ill patients and emergency patients. The embodiments include continuous hemodiafiltration (CHF), continuous hemodialysis (CHD) and continuous hemodiafiltration (CHDF), with CHDF being the most clinically practiced. High-flow continuous hemodiafiltration (HFVCHDF) and high-flow continuous hemofiltration (HVCHF) are also performed to improve the removal efficiency in a short time. Depending on the embodiment, these CRRTs require a replenisher or dialysate, but at present, no replenisher or dialysate dedicated to CRRT is commercially available, and a conventional replenisher for blood filtration is used instead. (Non-Patent Document 1). However, conventional replacement fluids for blood filtration are formulated and designed for the purpose of intermittent and short-term treatment for patients with chronic renal failure. On the other hand, CHDF is often performed continuously for several days, and moreover, severe pathological conditions such as CHDF that require CRRT, such as acute kidney injury, have various background diseases and are severely hyperkalemia. In some cases, emergency dialysis may be required. When a conventional hemofiltration replacement solution is used for CRRT, there is a problem that the potassium ion concentration is usually lower than the physiological concentration, and the serum potassium ion concentration decreases by performing CRRT for a long time. Therefore, potassium ions are mixedly injected. Or, it is necessary to administer a potassium preparation separately.
このため、現状では、使用の際に濃度補正のための混合操作や追加成分の添加のための補給が行われているが、この混合操作や補給操作は、医療安全性（汚染、異物混入、誤操作、針刺し事故）や混合後の薬液安定性に問題がある。そこで、特許文献１は、このような問題を解決するため、従来の補充液のカリウムイオン濃度を高め、リン酸イオンを配合した急性血液浄化療法に使用するため、特定のイオン組成や沈殿の発生の防止のために具体的な処方開発を行った特定の処方を開示している。
For this reason, at present, a mixing operation for concentration correction and replenishment for addition of additional components are performed at the time of use, but this mixing operation and replenishment operation are medical safety (contamination, contamination with foreign substances, etc.). There is a problem with erroneous operation, needle stick accident) and chemical stability after mixing. Therefore, in order to solve such a problem,
しかしながら、ＣＲＲＴは、緊急時の処置であるため、一施設において頻繁に行われない可能性もあり、ＣＲＲＴ用に特別に製剤化された製剤ではなく、従来の血液ろ過用補充液を利用することが望まれており、付加的な補給をなるべく減らして用いることができる可能性を見出すことが望まれている。 However, since CRRT is an emergency procedure, it may not be performed frequently in one facility, and a conventional blood filtration replacement solution should be used instead of a formulation specially formulated for CRRT. Is desired, and it is desired to find the possibility that the additional supply can be reduced as much as possible.
また、高度の高カリウム血症で緊急透析をする場合には、カリウムイオンを含まない処方が望まれており、そのような場合は、カリウムイオンが含まれている処方を用いると、ＣＲＲＴを開始しても高い血清カリウムイオン濃度を抑えることができず、あるいは血清カリウムイオン濃度が急激に上昇するという問題もある。 In addition, in the case of emergency dialysis for severe hyperkalemia, a prescription that does not contain potassium ions is desired, and in such cases, if a prescription that contains potassium ions is used, CRRT is started. However, there is also a problem that the high serum potassium ion concentration cannot be suppressed, or the serum potassium ion concentration rises sharply.
そこで、本発明は、従来のカリウムイオン濃度の低い血液ろ過用補充液、透析液を安全性に優れた急性血液浄化用薬液として提供することを課題とする。 Therefore, an object of the present invention is to provide a conventional replenisher for blood filtration and dialysate having a low potassium ion concentration as a highly safe drug solution for acute blood purification.
本発明者は、カリウムイオンを含み、カリウムイオン濃度が３ｍＥｑ／Ｌ未満の補充液／透析液用薬液を、補充液および／または透析液として所定の血液浄化量で処置を行うことにより、腎機能が急激に低下した急性腎障害と認められる対象において血清カリウムイオン濃度を適切に維持できることを見出し、本発明を完成した。 The present inventor treats a replacement solution / dialysate drug solution containing potassium ions and having a potassium ion concentration of less than 3 mEq / L as a replacement solution and / or a dialysate with a predetermined blood purification amount, thereby performing renal function. The present invention has been completed by finding that the serum potassium ion concentration can be appropriately maintained in a subject having a sharply decreased acute renal injury.
すなわち、本発明は、
［１］カリウムイオンを含み、カリウムイオン濃度が１．５ｍＥｑ／Ｌ以上かつ３．０ｍＥｑ／Ｌ未満の急性血液浄化用薬液であって、急性腎障害と認められる対象に、少なくとも透析開始時から透析開始後１２時間の間の血液浄化量を１０ｍＬ／ｋｇ／ｈｒ以上かつ１００ｍＬ／ｋｇ／ｈｒ未満として行う急性血液浄化法において、透析液および／または補充液として使用する急性血液浄化用薬液、
［２］少なくとも透析開始時から透析開始後１２時間の間の血液浄化量が１０ｍＬ／ｋｇ／ｈｒ以上かつ５０ｍＬ／ｋｇ／ｈｒ以下である上記［１］記載の急性血液浄化用薬液、
［３］少なくとも透析開始時から透析開始後１２時間の間の血液浄化量が１０ｍＬ／ｋｇ／ｈｒ以上かつ２５ｍＬ／ｋｇ／ｈｒ以下である上記［１］または［２］記載の急性血液浄化用薬液、
［４］カリウムイオン濃度が２．０〜２．５ｍＥｑ／Ｌ、好ましくは２ｍＥｑ／Ｌである上記［１］〜［３］のいずれかに記載の急性血液浄化用薬液、
［５］ナトリウムイオン濃度が１３２〜１４３ｍＥｑ／Ｌ、好ましくは１４０ｍＥｑ／Ｌ、カリウムイオン濃度が２．０〜２．５ｍＥｑ／Ｌ、好ましくは２ｍＥｑ／Ｌ、カルシウムイオン濃度が２．５〜３．６ｍＥｑ／Ｌ、好ましくは３．５ｍＥｑ／Ｌ、マグネシウムイオン濃度が０．９〜１．５ｍＥｑ／Ｌ、好ましくは１．０〜１．１ｍＥｑ／Ｌ、塩素イオン濃度が１０４〜１１５ｍＥｑ／Ｌ、好ましくは１１１〜１１３ｍＥｑ／Ｌ、酢酸イオン濃度が０〜３．５ｍＥｑ／Ｌ、好ましくは０〜０．５ｍＥｑ／Ｌ、炭酸水素イオン濃度が２８〜３６ｍＥｑ／Ｌ、好ましくは３０〜３５ｍＥｑ／Ｌ、ブドウ糖濃度が５０〜２００ｍｇ／ｄＬ、好ましくは１００〜１５０ｍｇ／ｄＬである上記［１］〜［４］のいずれかに記載の急性血液浄化用薬液、
［６］塩化ナトリウム、塩化カリウムおよび炭酸水素ナトリウムを含む水溶液（Ａ液）、ならびに塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム、無水酢酸ナトリウムおよびブドウ糖を含む水溶液（Ｂ液）からなる用時混合型製剤である上記［１］〜［５］のいずれかに記載の急性血液浄化用薬液、
［７］Ａ液が、塩化ナトリウム４．８６ｇ／Ｌ、塩化カリウム１４９．０ｍｇ／Ｌおよび炭酸水素ナトリウム５．９４ｇ／Ｌを含有する水溶液であり、
Ｂ液が、塩化ナトリウム７．３３ｇ／Ｌ、塩化カリウム１４８．０ｍｇ／Ｌ、塩化カルシウム二水和物５０９．６ｍｇ／Ｌ、塩化マグネシウム六水和物２０１．４ｍｇ／Ｌ、無水酢酸ナトリウム８１．２ｍｇおよびブドウ糖１．９８ｇ／Ｌを含有する水溶液である
上記［６］記載の急性血液浄化用薬液、
［８］連通可能な隔離手段で区画された少なくとも２室を有する複室容器製剤であって、上記［６］または［７］記載の急性血液浄化用薬液を構成するＡ液およびＢ液をそれぞれ第１室および第２室に収容してなる複室容器製剤、
［９］複室容器がプラスチック製ダブルバッグである上記［８］記載の複室容器製剤、
［１０］複室容器を脱酸素剤と共にガスバリア性フィルムによりさらに包装した上記［８］または［９］記載の複室容器製剤、および
［１１］さらに複室容器外側かつガスバリア性フィルム内側に酸素検知剤を含む上記［１０］記載の複室容器製剤
に関する。
That is, the present invention
[1] A drug solution for acute blood purification containing potassium ions and having a potassium ion concentration of 1.5 mEq / L or more and less than 3.0 mEq / L, and dialysis is performed on a subject recognized as having acute renal injury at least from the start of dialysis. Acute blood purification drug solution used as a dialysate and / or a replacement solution in an acute blood purification method in which the blood purification amount for 12 hours after the start is 10 mL / kg / hr or more and less than 100 mL / kg / hr.
[2] The drug solution for acute blood purification according to the above [1], wherein the blood purification amount is at least 10 mL / kg / hr or more and 50 mL / kg / hr or less from the start of dialysis to 12 hours after the start of dialysis.
[3] The acute blood purification drug solution according to the above [1] or [2], wherein the blood purification amount is at least 10 mL / kg / hr or more and 25 mL / kg / hr or less from the start of dialysis to 12 hours after the start of dialysis. ,
[4] The drug solution for acute blood purification according to any one of the above [1] to [3], wherein the potassium ion concentration is 2.0 to 2.5 mEq / L, preferably 2 mEq / L.
[5] The sodium ion concentration is 132 to 143 mEq / L, preferably 140 mEq / L, the potassium ion concentration is 2.0 to 2.5 mEq / L, preferably 2 mEq / L, and the calcium ion concentration is 2.5 to 3.6 mEq. / L, preferably 3.5 mEq / L, magnesium ion concentration 0.9 to 1.5 mEq / L, preferably 1.0 to 1.1 mEq / L, chlorine ion concentration 104 to 115 mEq / L, preferably 111 ~ 113 mEq / L, acetate ion concentration 0-3.5 mEq / L, preferably 0-0.5 mEq / L, hydrogen carbonate ion concentration 28-36 mEq / L, preferably 30-35 mEq / L,
[6] Time-to-use mixing consisting of an aqueous solution (solution A) containing sodium chloride, potassium chloride and sodium hydrogen carbonate, and an aqueous solution (solution B) containing sodium chloride, potassium chloride, calcium chloride, magnesium chloride, anhydrous sodium acetate and glucose. The drug solution for acute blood purification according to any one of the above [1] to [5], which is a type preparation.
[7] Solution A is an aqueous solution containing 4.86 g / L of sodium chloride, 149.0 mg / L of potassium chloride and 5.94 g / L of sodium hydrogen carbonate.
Solution B is sodium chloride 7.33 g / L, potassium chloride 148.0 mg / L, calcium chloride dihydrate 509.6 mg / L, magnesium chloride hexahydrate 201.4 mg / L, anhydrous sodium acetate 81.2 mg. And the chemical solution for acute blood purification according to the above [6], which is an aqueous solution containing 1.98 g / L of glucose.
[8] A multi-chamber container preparation having at least two chambers partitioned by a communicable isolation means, and liquids A and B constituting the acute blood purification drug solution according to the above [6] or [7], respectively. Multi-chamber container formulation contained in the first and second chambers,
[9] The multi-chamber container formulation according to [8] above, wherein the multi-chamber container is a plastic double bag.
[10] The multi-chamber container formulation according to the above [8] or [9], in which the multi-chamber container is further packaged with a gas barrier film together with an oxygen scavenger, and [11] oxygen detection on the outside of the multi-chamber container and inside the gas barrier film. The present invention relates to the multi-chamber container preparation according to the above [10], which comprises an agent.
本発明によれば、カリウムイオンを含み、カリウムイオン濃度が１．５ｍＥｑ／Ｌ以上かつ３．０ｍＥｑ／Ｌ未満の急性血液浄化用薬液を、急性腎障害と認められる対象に、少なくとも透析開始時から透析開始後１２時間の間の血液浄化量を１０ｍＬ／ｋｇ／ｈｒ以上かつ１００ｍＬ／ｋｇ／ｈｒ未満として行う急性血液浄化法において、透析液および／または補充液として使用することにより、高い血清カリウムイオン濃度を抑え、あるいは透析開始後の血清中のカリウムイオンの急激な上昇を抑制することができ、かつ血清カリウムイオン濃度を望ましい領域に維持することができ、さらに急性腎障害と認められる対象の貧血を抑制することが可能な急性血液浄化用とした補充液、透析液を提供することができる。 According to the present invention, an acute blood purification drug solution containing potassium ions and having a potassium ion concentration of 1.5 mEq / L or more and less than 3.0 mEq / L is applied to a subject recognized as having an acute renal disorder at least from the start of dialysis. High serum potassium ion by using as a dialysate and / or a replacement solution in an acute blood purification method in which the blood purification amount for 12 hours after the start of dialysis is 10 mL / kg / hr or more and less than 100 mL / kg / hr. Anemia of subjects who can suppress the concentration or suppress the rapid rise of potassium ion in blood after the start of dialysis, maintain the serum potassium ion concentration in the desired range, and are recognized as having acute renal injury. It is possible to provide a replacement solution and a dialysate for acute blood purification that can suppress the above.
さらに本発明によれば、従来の血液濾過用補充液をそのまま使用することができ、使用の際に濃度補正のための混合操作や追加成分の添加のための補給が基本的に必要とされない。 Further, according to the present invention, the conventional hemofiltration replenisher can be used as it is, and basically no mixing operation for concentration correction or replenishment for addition of additional components is required at the time of use.
本発明の急性血液浄化用薬液は、カリウムイオンを含み、カリウムイオン濃度が１．５ｍＥｑ／Ｌ以上かつ３．０ｍＥｑ／Ｌ未満の従来から血液ろ過補充液や透析液として使用されてきているものである。そして、急性腎障害と認められる対象に対し、本発明の急性血液浄化用薬液を、少なくとも透析開始時から透析開始後１２時間の間の血液浄化量を１０ｍＬ／ｋｇ／ｈｒ以上かつ１００ｍＬ／ｋｇ／ｈｒ未満として行う急性血液浄化法において、透析液および／または補充液として用いることを特徴とする。 The drug solution for acute blood purification of the present invention contains potassium ions and has been conventionally used as a blood filtration replacement solution or dialysate having a potassium ion concentration of 1.5 mEq / L or more and less than 3.0 mEq / L. be. Then, for a subject recognized as having acute renal injury, the amount of blood purified by the drug solution for acute blood purification of the present invention at least from the start of dialysis to 12 hours after the start of dialysis is 10 mL / kg / hr or more and 100 mL / kg / kg /. It is characterized in that it is used as a dialysate and / or a replacement solution in an acute blood purification method performed at less than hr.
本明細書において、「急性血液浄化用薬液」とは、急性血液浄化法、例えばＣＲＲＴにおいて、補充液として使用することも透析液として使用することもできる薬液を意味する。したがって、本発明の血液ろ過用補充液は、例えば、持続的血液濾過（ＣＨＦ）の補充液、持続的血液透析（ＣＨＤ）の透析液、および持続的血液濾過透析（ＣＨＤＦ）の補充液および透析液などに使用することができる。 As used herein, the term "drug solution for acute blood purification" means a drug solution that can be used as a replacement solution or a dialysate in an acute blood purification method, for example, CRRT. Thus, the hemofiltration replacement fluids of the present invention are, for example, continuous hemofiltration (CHF) replacement fluids, continuous hemodialysis (CHD) dialysate, and continuous hemodiafiltration (CHDF) replacement fluids and dialysis. It can be used for liquids and the like.
本発明の急性血液浄化用薬液を用いる対象としては、何らかの原因で短期間に腎機能が急速に低下した状態、すなわち急性腎障害（ＡＫＩ：Acute Kidney Injury）の状態の対象が挙げられ、心血管系疾患、敗血症、肝疾患、多臓器不全を併発している対象も含む。このような急性腎障害と認められる対象について、現在急性腎障害の診断基準としては、ＲＩＦＬＥ分類、ＡＫＩＮ分類、ＫＤＩＧＯ分類などがあり、（ａ）４８時間以内に血清クレアチニン値が０．３ｍｇ／ｄＬ以上増加した場合、（ｂ）血清クレアチニン値がそれ以前７日以内にわかっていたか、予想される基礎値よりも１．５倍以上の増加があった場合、（ｃ）尿量が６時間にわたって０．５ｍＬ／ｋｇ体重／時未満に減少した場合のいずれかを満たすと急性腎障害と診断され、本発明の急性血液浄化用薬液を用いる対象となる。また、本明細書において「対象」とは、哺乳動物、特にヒトを意味する。 The subject to which the drug solution for acute blood purification of the present invention is used includes a subject in which renal function rapidly declines in a short period of time for some reason, that is, a subject in a state of acute kidney injury (AKI: Acute Kidney Injury). Includes subjects with systemic disease, septicemia, liver disease, and multiple organ failure. Currently, there are RIFLE classification, AKIN classification, KDIGO classification, etc. as diagnostic criteria for acute kidney injury in subjects recognized as such acute kidney injury, and (a) serum creatinine level is 0.3 mg / dL within 48 hours. If the increase is more than (b) if the serum creatinine level was known within 7 days before, or if there was an increase of 1.5 times or more than the expected basal value, (c) the urine volume was increased over 6 hours. Acute kidney injury is diagnosed when any of the cases where the dose is reduced to less than 0.5 mL / kg body weight / hour is satisfied, and the drug solution for acute blood purification of the present invention is used. Further, as used herein, the term "subject" means a mammal, particularly a human.
本発明の急性血液浄化用薬液は、上述のとおり、少なくとも透析開始時から透析開始後１２時間の間の血液浄化量を１０ｍＬ／ｋｇ／ｈｒ以上かつ１００ｍＬ／ｋｇ／ｈｒ未満として血液浄化法を行うためのものであり、血液浄化量が１０ｍＬ／ｋｇ／ｈｒ未満では、透析効率が低下する傾向がある。また、少なくとも透析開始時から透析開始後１２時間の間の血液浄化量は、血圧の安定性または貧血の進行防止の観点から５０ｍＬ／ｋｇ／ｈｒ以下が好ましく、２５ｍＬ／ｋｇ／ｈｒ以下が好ましい。 As described above, the drug solution for acute blood purification of the present invention performs the blood purification method with the blood purification amount at least 10 mL / kg / hr or more and less than 100 mL / kg / hr from the start of dialysis to 12 hours after the start of dialysis. Therefore, if the blood purification amount is less than 10 mL / kg / hr, the dialysis efficiency tends to decrease. The amount of blood purified at least from the start of dialysis to 12 hours after the start of dialysis is preferably 50 mL / kg / hr or less, preferably 25 mL / kg / hr or less, from the viewpoint of blood pressure stability or prevention of progression of anemia.
また、本発明の急性血液浄化用薬液を適用する急性血液浄化法における血液浄化量は、透析開始からカリウムイオン濃度の上昇が落ち着くまで、少なくとも透析開始時から透析開始後１２時間の間、１０ｍＬ／ｋｇ／ｈｒ以上かつ１００ｍＬ／ｋｇ／ｈｒ未満とする限り、透析開始後１２時間を超えれば特に限定されるものではないが、カリウムイオン濃度の上昇が継続する場合には、透析開始後１２時間を超えても１０ｍＬ／ｋｇ／ｈｒ以上かつ１００ｍＬ／ｋｇ／ｈｒ未満の血液浄化量で継続することができる。 In addition, the amount of blood purified in the acute blood purification method to which the chemical solution for acute blood purification of the present invention is applied is 10 mL / 10 mL from the start of dialysis until the increase in potassium ion concentration subsides, at least from the start of dialysis to 12 hours after the start of dialysis. As long as it is at least kg / hr and less than 100 mL / kg / hr, it is not particularly limited as long as it exceeds 12 hours after the start of dialysis, but if the increase in potassium ion concentration continues, 12 hours after the start of dialysis is allowed. Even if it exceeds, it can be continued with a blood purification amount of 10 mL / kg / hr or more and less than 100 mL / kg / hr.
本明細書において、「血液浄化量」とは、透析液流量（Ｑｄ）とろ過流量（Ｑｆ）の和を意味する。 In the present specification, the "blood purification amount" means the sum of the dialysate flow rate (Qd) and the filtration flow rate (Qf).
本発明の急性血液浄化用薬液は、カリウムイオンを含み、カリウムイオン濃度が１．５ｍＥｑ／Ｌ以上かつ３．０ｍＥｑ／Ｌ未満のものであり、一般の慢性腎臓病の透析などに用いられている市販の透析液や補充液などを使用することができる。急性血液浄化用薬液におけるカリウムイオン濃度は、２．０ｍＥｑ／Ｌ以上が好ましく、２．５ｍＥｑ／Ｌ以下が好ましい。急性血液浄化用薬液は、カリウムイオンの他に、ナトリウムイオン、カルシウムイオン、マグネシウムイオン、塩素イオン、炭酸水素イオン、酢酸イオン、およびブドウ糖などを含むことができる。 The drug solution for acute blood purification of the present invention contains potassium ions and has a potassium ion concentration of 1.5 mEq / L or more and less than 3.0 mEq / L, and is used for dialysis of general chronic kidney disease and the like. Commercially available dialysate, replenisher, etc. can be used. The potassium ion concentration in the drug solution for acute blood purification is preferably 2.0 mEq / L or more, and preferably 2.5 mEq / L or less. The drug solution for acute blood purification can contain sodium ion, calcium ion, magnesium ion, chlorine ion, bicarbonate ion, acetate ion, glucose and the like in addition to potassium ion.
急性血液浄化用薬液において、ナトリウムイオン濃度は、１３２〜１４３ｍＥｑ／Ｌが好ましく、１４０ｍＥｑ／Ｌがより好ましい。また、カルシウムイオン濃度は、２．５〜３．６ｍＥｑ／Ｌが好ましく、３．５ｍＥｑ／Ｌがより好ましい。マグネシウムイオン濃度は、０．９〜１．５ｍＥｑ／Ｌが好ましく、１．０〜１．１ｍＥｑ／Ｌがより好ましい。塩素イオン濃度は、１０４〜１１５ｍＥｑ／Ｌが好ましく、１１１〜１１３ｍＥｑ／Ｌがより好ましい。酢酸イオン濃度は、０〜３．５ｍＥｑ／Ｌが好ましく、０〜０．５ｍＥｑ／Ｌがより好ましい。炭酸水素イオン濃度は、２８〜３６ｍＥｑ／Ｌが好ましく、３０〜３５ｍＥｑ／Ｌがより好ましい。ブドウ糖濃度は、５０〜２００ｍｇ／ｄＬが好ましく、１００〜１５０ｍｇ／ｄＬがより好ましい。 In the drug solution for acute blood purification, the sodium ion concentration is preferably 132 to 143 mEq / L, more preferably 140 mEq / L. The calcium ion concentration is preferably 2.5 to 3.6 mEq / L, more preferably 3.5 mEq / L. The magnesium ion concentration is preferably 0.9 to 1.5 mEq / L, more preferably 1.0 to 1.1 mEq / L. The chlorine ion concentration is preferably 104 to 115 mEq / L, more preferably 111 to 113 mEq / L. The acetate ion concentration is preferably 0 to 3.5 mEq / L, more preferably 0 to 0.5 mEq / L. The hydrogen carbonate ion concentration is preferably 28 to 36 mEq / L, more preferably 30 to 35 mEq / L. The glucose concentration is preferably 50 to 200 mg / dL, more preferably 100 to 150 mg / dL.
一実施形態において、本発明の急性血液浄化用薬液は、ナトリウムイオン濃度が１４０ｍＥｑ／Ｌ、カリウムイオン濃度が２．０ｍＥｑ／Ｌ、カルシウムイオン濃度が３．５ｍＥｑ／Ｌ、マグネシウムイオン濃度が１．０ｍＥｑ／Ｌ、塩素イオン濃度が１１３ｍＥｑ／Ｌ、炭酸水素イオン濃度が３５ｍＥｑ／Ｌ、酢酸イオン濃度が０．５ｍＥｑ／Ｌ、ブドウ糖濃度が１００ｍｇ／ｄＬである。 In one embodiment, the drug solution for acute blood purification of the present invention has a sodium ion concentration of 140 mEq / L, a potassium ion concentration of 2.0 mEq / L, a calcium ion concentration of 3.5 mEq / L, and a magnesium ion concentration of 1.0 mEq. / L, chlorine ion concentration is 113 mEq / L, hydrogen carbonate ion concentration is 35 mEq / L, acetate ion concentration is 0.5 mEq / L, and glucose concentration is 100 mg / dL.
本発明の急性血液浄化用薬液は、塩化ナトリウム、塩化カリウムおよび炭酸水素ナトリウムを含むＡ液と、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム、酢酸ナトリウムおよびブドウ糖を含むＢ液とからなる用時混合型製剤とすることができる。 The drug solution for acute blood purification of the present invention comprises a solution A containing sodium chloride, potassium chloride and sodium hydrogen carbonate, and a solution B containing sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium acetate and glucose. It can be a mixed preparation.
本発明の急性血液浄化用薬液の製造においては、塩化ナトリウム、塩化カリウム、炭酸水素ナトリウム、塩化カルシウム、塩化マグネシウム、酢酸ナトリウムなどの成分について、無水物のみならず、水和物の形態のものを用いることもできる。 In the production of the chemical solution for acute blood purification of the present invention, not only anhydrous but also hydrated components such as sodium chloride, potassium chloride, sodium hydrogencarbonate, calcium chloride, magnesium chloride and sodium acetate are used. It can also be used.
一実施形態において、本発明の急性血液浄化用薬液は、Ａ液が、塩化ナトリウム４．８６ｇ／Ｌ、塩化カリウム１４９．０ｍｇ／Ｌおよび炭酸水素ナトリウム５．９４ｇ／Ｌを含有する水溶液であり、Ｂ液が、塩化ナトリウム７．３３ｇ／Ｌ、塩化カリウム１４８．０ｍｇ／Ｌ、塩化カルシウム二水和物５０９．６ｍｇ／Ｌ、塩化マグネシウム六水和物２０１．４ｍｇ／Ｌ、無水酢酸ナトリウム８１．２ｍｇおよびブドウ糖１．９８ｇ／Ｌを含有する水溶液である。具体的には、Ａ液は、注射用水に各成分、塩化ナトリウム４．８６ｇ、塩化カリウム１４９．０ｍｇおよび炭酸水素ナトリウム５．９４ｇを加え、混合溶解し、全量が１０００ｍＬとなるまで注射用水を加えて混合することにより得ることができる。同様にＢ液は、注射用水に各成分、塩化ナトリウム７．４８ｇ、塩化カリウム１５１．０ｍｇ、塩化カルシウム二水和物５１９．８ｍｇ、塩化マグネシウム六水和物２０５．４ｍｇ、無水酢酸ナトリウム８２．８ｍｇおよびブドウ糖２．０２ｇを加え、混合溶解し、全量が１０２０ｍＬとなるまで注射用水を加えて混合することにより得ることができる。 In one embodiment, the chemical solution for acute blood purification of the present invention is an aqueous solution in which solution A contains 4.86 g / L of sodium chloride, 149.0 mg / L of potassium chloride and 5.94 g / L of sodium hydrogen carbonate. Solution B is sodium chloride 7.33 g / L, potassium chloride 148.0 mg / L, calcium chloride dihydrate 509.6 mg / L, magnesium chloride hexahydrate 201.4 mg / L, anhydrous sodium acetate 81.2 mg. And an aqueous solution containing 1.98 g / L of glucose. Specifically, for solution A, each component, sodium chloride 4.86 g, potassium chloride 149.0 mg and sodium hydrogen carbonate 5.94 g were added to water for injection, mixed and dissolved, and water for injection was added until the total volume became 1000 mL. Can be obtained by mixing. Similarly, solution B contains 7.48 g of sodium chloride, 151.0 mg of potassium chloride, 519.8 mg of calcium chloride dihydrate, 205.4 mg of magnesium chloride hexahydrate, and 82.8 mg of anhydrous sodium acetate in water for injection. And 2.02 g of glucose are added, mixed and dissolved, and water for injection is added and mixed until the total volume becomes 1020 mL.
本実施形態においては、Ａ液のｐＨは、７．５〜８．１が好ましく、Ｂ液のｐＨは、２．４〜２．７が好ましい。ｐＨがこの範囲内にない場合には、塩酸または水酸化ナトリウムなどのｐＨ調整剤により調整することができる。 In the present embodiment, the pH of the liquid A is preferably 7.5 to 8.1, and the pH of the liquid B is preferably 2.4 to 2.7. If the pH is not within this range, it can be adjusted with a pH adjuster such as hydrochloric acid or sodium hydroxide.
上述したように、本発明の急性血液浄化用薬液は、Ａ液とＢ液との二液からなる用時混合型製剤とすることができ、例えば本発明の一実施態様として、連通可能な隔離手段で区画された少なくとも２室を有する複室容器に、Ａ液およびＢ液をそれぞれ第１室および第２室に収容してなる複室容器製剤とすることが好ましい。このような複室容器としては、例えばポリプロピレン製などのプラスチック製のダブルバッグ型容器が好ましく、従来の血液ろ過用補充液に使用されているものなどを使用することができ、充填方法、使用方法などについても同様に適用することができる。 As described above, the drug solution for acute blood purification of the present invention can be a time-mixed preparation composed of two liquids, a liquid A and a liquid B. For example, as one embodiment of the present invention, a communicable isolation is possible. It is preferable to prepare a multi-chamber container formulation in which the liquid A and the liquid B are housed in the first chamber and the second chamber, respectively, in a multi-chamber container having at least two chambers partitioned by means. As such a multi-chamber container, for example, a plastic double bag type container such as polypropylene is preferable, and a container used in a conventional replenisher for blood filtration can be used, and a filling method and a method of use can be used. The same can be applied to such as.
例えば、本発明の複室容器製剤は、複室容器にＡ液およびＢ液を充填したのち、それぞれ注入口を密封する。その後、日本薬局方の最終滅菌法の指標に準じ、常法に従って、温度１２１℃で、２０分間の高圧蒸気滅菌処理を行うことにより最終製品とすることができる。 For example, in the multi-chamber container formulation of the present invention, the multi-chamber container is filled with the liquid A and the liquid B, and then the injection port is sealed. Then, according to the index of the final sterilization method of the Japanese Pharmacopoeia, the final product can be obtained by performing a high-pressure steam sterilization treatment at a temperature of 121 ° C. for 20 minutes according to a conventional method.
滅菌後、複室容器は、薬液安定化のため、ガスバリア性の包装材を用いて外装することが好ましい。外装は、ガスバリア性の包装材からなる包装容器に密封収納してもよく、また包装材がフィルムの場合には、密封包装してもよい。ガスバリア性の包装材としては、例えば、エチレンビニルアルコール共重合体（ＥＶＯＨ）、ポリエチレンテレフタレート（ＰＥＴ）、ポリ塩化ビニリデン（ＰＶＤＣ）、ナイロンなどから構成された包装材、そしてこれらの素材にシリカやアルミナなどのガスバリア性物質の蒸着処理を行った包装材、また、これらの素材を組み合わせた多層フィルムから作製された包装材などが用いられる。 After sterilization, the multi-chamber container is preferably exteriorized with a gas barrier packaging material for stabilizing the chemical solution. The exterior may be hermetically sealed and stored in a packaging container made of a gas barrier packaging material, or may be hermetically packaged when the packaging material is a film. Examples of the gas barrier packaging material include a packaging material composed of ethylene vinyl alcohol copolymer (EVOH), polyethylene terephthalate (PET), polyvinylidene chloride (PVDC), nylon and the like, and silica and alumina as these materials. Packaging materials that have been subjected to vapor deposition treatment of gas barrier substances such as, and packaging materials made from a multilayer film that combines these materials are used.
また、複室容器を外装する際には、外装のピンホールを検出する目的で、脱酸素剤を併せて収納したり、窒素ガスや炭酸ガスなどで置換して、外装内を無酸素状態として、酸素検知剤などを併せて収納することができる。脱酸素剤や酸素検知剤としては、一般に市販されているものを用いることができる。 In addition, when exteriorizing a multi-chamber container, for the purpose of detecting pinholes in the exterior, an oxygen scavenger is also stored or replaced with nitrogen gas or carbon dioxide gas to make the exterior anoxic. , Oxygen detector, etc. can be stored together. As the oxygen scavenger and the oxygen detector, commercially available ones can be used.
以下、本発明を実施例にもとづき具体的に説明するが、本発明はこれらの実施例に限定されることを意図するものではない。 Hereinafter, the present invention will be specifically described based on examples, but the present invention is not intended to be limited to these examples.
実施例１〜２および比較例１
（１）被験医療溶液の調製
本明細書において、日局とは第十七改正日本薬局方を、局外規とは日本薬局方外医薬品規格２００２を、薬添規とは医薬品添加物規格２００３および同追補を表す。
最終濃度が表１の組成となるよう、塩化ナトリウム（日局）、塩化カリウム（日局）、塩化カルシウム（日局）、塩化マグネシウム（局外規）、炭酸水素ナトリウム（日局）、無水酢酸ナトリウム（日局）、ブドウ糖（日局）に、ｐＨ調整剤として塩酸（日局）を用い、注射用水を用いて透析液または補充液を製造した。
Examples 1-2 and Comparative Example 1
(1) Preparation of test medical solution In this specification, the Japanese Pharmacopoeia is the 17th revised Japanese Pharmacopoeia, the Japanese Pharmacopoeia is the Japanese Pharmacopoeia Non-Pharmaceutical Standard 2002, and the drug supplement is the Pharmaceutical Additive Standard 2003 and Represents the same supplement.
Sodium chloride (Japanese Pharmacopoeia), Potassium Chloride (Japanese Pharmacopoeia), Calcium Chloride (Japanese Pharmacopoeia), Magnesium Chloride (External Regulations), Sodium Hydrogen Carbonate (Japanese Pharmacopoeia), Acetate Anhydrous so that the final concentration has the composition shown in Table 1. A dialysate or a replenisher was prepared using hydrochloric acid (Japanese Pharmacopoeia) as a pH adjuster for sodium (Japanese Pharmacopoeia) and glucose (Japanese Pharmacopoeia), and water for injection.
（２）腎障害モデルの作製
ミニブタ（Gottingen minipig系統、雄性、１４〜２０月齢、体重：２３〜４０ｋｇ、オリエンタル酵母工業（株））を用い、左腎臓虚血および右腎臓摘出により急性腎障害モデルを作出した。これらのブタは、急性腎障害の指標である、（ａ）４８時間以内に血清クレアチニン値が０．３ｍｇ／ｄＬ以上増加した場合、（ｂ）血清クレアチニン値がそれ以前７日以内にわかっていたか、予想される基礎値よりも１．５倍以上の増加があった場合、（ｃ）尿量が６時間にわたって０．５ｍＬ／ｋｇ体重／時未満に減少した場合のいずれも満足していた。
(2) Preparation of renal injury model Acute renal injury model by left kidney ischemia and right nephrectomy using a mini pig (Gottingen minipig strain, male, 14 to 20 months old, weight: 23 to 40 kg, Oriental Yeast Co., Ltd.) Was created. In these pigs, if (a) serum creatinine level increased by 0.3 mg / dL or more within 48 hours, (b) serum creatinine level was known within 7 days before, which is an index of acute renal injury. When there was an increase of 1.5 times or more from the expected basal value, (c) when the urine volume decreased to less than 0.5 mL / kg body weight / hour over 6 hours, both were satisfied.
（３）持続的腎代替療法（ＣＲＲＴ）
上記（１）で調製した薬液を用い、上記（２）で作出した急性腎障害モデルのミニブタを対象に、左腎臓虚血および右腎臓摘出を０日目とし、２日目（透析開始）から４８時間、ＣＲＲＴを、覚醒下、急性腎障害モデルのミニブタを測定ケージに入れて行なった。動物のブラッドアクセスカテーテルに血液回路および持続緩徐式血液濾過器を接続（図１参照）し、以下の条件で行った。ただし、条件については表２に示すように、適宜変更した。医療溶液は、透析液として使用する場合は、濾過器の濾液入口より流入させ、補充液として使用する場合は、血液回路静脈側から投与した。なお、ＣＲＲＴを行わない上記（２）で作出した急性腎障害モデルについても対照として以下の（５）〜（７）の採血および検査を行った。
(3) Continuous renal replacement therapy (CRRT)
Using the drug solution prepared in (1) above, left kidney ischemia and right nephrectomy were set as
血液浄化装置：ＡｃｕＦｉｌ Ｍｕｌｔｉ Ｘ−５５Ｘ−ＩＩ（日本ライフライン（株））
血液回路：多用途血液回路（７０５５８０００、日本ライフライン（株））
持続緩徐式血液濾過器：シュアフィルター（膜面積０．９ｍ2 ＰＵＴ−０９ ｅｃｏ、ニプロ（株））
血液流量（Ｑｂ）：１．６７ｍＬ／ｋｇ／ｍｉｎ
透析液流量（Ｑｄ）：５ｍＬ／ｋｇ／ｈｒ
補充液流量（Ｑｓ）：５ｍＬ／ｋｇ／ｈｒ
濾液流量（Ｑｆ）：５ｍＬ／ｋｇ／ｈｒ
施行時間：４８時間
抗凝固薬：透析直前にヘパリン加生理食塩液を１００単位／ｋｇ（投与液量：０．５ｍＬ／ｋｇ）ボーラス投与し、透析中はヘパリン加生理食塩液を１０００単位／５ｍＬ／ｈｒで投与した。
Blood circuit: Versatile blood circuit (70558000, Nippon Lifeline Co., Ltd.)
Continuous slow hemofiltration: Sure filter (membrane area 0.9m 2 PUT-09 eco, Nipro Co., Ltd.)
Blood flow rate (Qb): 1.67 mL / kg / min
Dialysate flow rate (Qd): 5 mL / kg / hr
Replenisher flow rate (Qs): 5 mL / kg / hr
Filtration flow rate (Qf): 5 mL / kg / hr
Duration: 48 hours Anticoagulant: Heparinized saline 100 units / kg (administration volume: 0.5 mL / kg) bolus immediately before dialysis, heparinized saline 1000 units / 5 mL during dialysis It was administered at / hr.
（４）採血方法
ＣＲＲＴ施行前は、ブラッドアクセスから、ＣＲＲＴ施行中は、血液回路のＡ（動脈側）の採血ポートから血液学的検査および血液生化学検査に用いる血液を採取した。また、血液ガス測定用に大腿動脈に挿入したカテーテルから注射筒を用いて血液を採取した。採血時期はＣＲＲＴ施行直前、施行直後、施行後６、１２、１８、２４、３０、３６、４２、４８時間とした。採血に対する許容範囲は±１０分とした。なお、左腎臓虚血および右腎臓摘出１２時間前にも採血を行った。
(4) Blood collection method Blood was collected from Blood Access before CRRT and from the blood collection port A (arterial side) of the blood circuit during CRRT for hematological and blood biochemical tests. In addition, blood was collected using a syringe from a catheter inserted into the femoral artery for blood gas measurement. Blood collection was performed immediately before CRRT, immediately after CRRT, and 6, 12, 18, 24, 30, 36, 42, and 48 hours after CRRT. The permissible range for blood collection was ± 10 minutes. Blood was also collected 12 hours before left kidney ischemia and right kidney removal.
（５）血液学的検査
採取した血液１ｍＬをＥＤＴＡ−２Ｋ コーティングチューブ（ベノジェクト（登録商標）ＩＩ真空採血管、ＶＰ−ＤＫ０５２Ｋ０５、テルモ（株））に分取した血液を用いて、ヘモグロビン量（ＨＧＢ）およびヘマトクリット値（ＨＣＴ）を測定した。結果を図２および図３に示す。
(5)
（６）血液生化学的検査
血液３ｍＬをヘパリン処理真空採血管に採取し、遠心機（ＣＦ９ＲＸ、日立工機（株））を用いて遠心分離［４℃、３０００ｒｐｍ（２１５０×ｇ）、１５分間］して得た血漿は、測定用１ｍＬと保存用（残り）に分けて分取した。測定用の血漿は、測定時まで超低温フリーザー（ＣＬＮ−５１ＵＤ２、日本フリーザー（株））で凍結（管理温度：−９０〜−７０°Ｃ）保存し、測定後の残余血漿は廃棄した。検査内容は、ナトリウムイオン、カリウムイオン、塩素イオン、マグネシウムイオン、カルシウムイオン、無機リン、尿素窒素、クレアチニン（クレアチニナーゼ・ＨＭＭＰＳ法）、尿酸、アルブミン、ブドウ糖であり、カリウムイオン濃度についての結果を図４に示す。
(6) Blood biochemical test Collect 3 mL of blood in a heparin-treated vacuum blood collection tube and centrifuge using a centrifuge (CF9RX, Hitachi Koki Co., Ltd.) [4 ° C, 3000 rpm (2150 × g), 15 minutes. ], The plasma obtained was separated into 1 mL for measurement and (remaining) for storage. The plasma for measurement was stored frozen in an ultra-low temperature freezer (CLN-51UD2, Nippon Freezer Co., Ltd.) until the time of measurement (control temperature: -90 to -70 ° C), and the residual plasma after measurement was discarded. The test contents are sodium ion, potassium ion, chlorine ion, magnesium ion, calcium ion, inorganic phosphorus, urea nitrogen, creatinine (creatinase / HMMPS method), uric acid, albumin, glucose, and the results of potassium ion concentration are shown. It is shown in FIG.
（７）尿検査
尿検査用カテーテルより尿をそのまま採取した。尿は尿量を測定後、遠心機（ＣＦ９ＲＸ、日立工機（株））で遠心分離（室温、５４０×ｇ、５分間）し、その上清を約１ｍＬ採取し、測定時まで超低温フリーザー（ＣＬＮ−５１ＵＤ２、日本フリーザー（株））で凍結保存（管理温度：−９０〜−７０°Ｃ）し、測定後の残余尿は廃棄した。尿中クレアチニンをクレアチニナーゼ・ＨＭＭＰＳ法により測定し、施行後６、１２、１８、２４、３０、３６、４２および４８時間のクレアチニン・クリアランスを下記式により算出した。結果を図５に示す。
クレアチニン・クリアランス＝（尿中クレアチニン濃度（ｍｇ／ｄＬ）×６時間総尿量（ｍＬ／６ｈｒ））／（血中クレアチニン濃度（ｍｇ／ｄＬ））
(7) Urinalysis Urinalysis was collected as it was from a urinalysis catheter. After measuring the amount of urine, centrifuge (CF9RX, Hitachi Koki Co., Ltd.) centrifuge (room temperature, 540 xg, 5 minutes), collect about 1 mL of the supernatant, and use an ultra-low temperature freezer (ultra-low temperature freezer) until measurement. It was cryopreserved in CLN-51UD2, Nippon Freezer Co., Ltd. (control temperature: -90 to -70 ° C), and the residual urine after measurement was discarded. Urinary creatinine was measured by the creatinase-HMMPS method, and creatinine clearance at 6, 12, 18, 24, 30, 36, 42 and 48 hours after the procedure was calculated by the following formula. The results are shown in FIG.
Creatinine clearance = (urinary creatinine concentration (mg / dL) x 6-hour total urine volume (mL / 6hr)) / (blood creatinine concentration (mg / dL))
実施例１および実施例２では、透析開始後、血清中のカリウムイオン濃度は低下し、４８時間後まで４ｍＥｑ／Ｌ付近の適切な濃度を維持していた。一方、比較例１では、透析開始後、透析開始１２時間後まで血清中のカリウムイオン濃度が上昇することが確認された。また、比較例１では、透析開始の２４時間後には、ヘモグロビン量（ＨＧＢ）およびヘマトクリット値（ＨＣＴ）が、開始時から５０％以上低下した。また、クレアチニン・クリアランスについても、実施例１および実施例２では対照や比較例１に対して高い値を示した。
In Examples 1 and 2, the potassium ion concentration in the serum decreased after the start of dialysis, and maintained an appropriate concentration around 4 mEq / L until 48 hours later. On the other hand, in Comparative Example 1, it was confirmed that the potassium ion concentration in the serum increased from the start of dialysis to 12 hours after the start of dialysis. Further, in Comparative Example 1, the hemoglobin amount (HGB) and the hematocrit value (HCT) decreased by 50% or more from the
１ 血液濾過器
２ 透析液
３ 補充液
４ 抗凝固薬
Ｐ１ 血流ポンプ
Ｐ２ 濾過ポンプ
Ｐ３ 透析液ポンプ
Ｐ４ 補充液ポンプ
Ａ 動脈側
Ｖ 静脈側
1
Claims (11)
Ｂ液が、塩化ナトリウム７．３３ｇ／Ｌ、塩化カリウム１４８．０ｍｇ／Ｌ、塩化カルシウム二水和物５０９．６ｍｇ／Ｌ、塩化マグネシウム六水和物２０１．４ｍｇ／Ｌ、無水酢酸ナトリウム８１．２ｍｇおよびブドウ糖１．９８ｇ／Ｌを含有する水溶液である請求項６記載の急性血液浄化用薬液。 Solution A is an aqueous solution containing 4.86 g / L of sodium chloride, 149.0 mg / L of potassium chloride and 5.94 g / L of sodium hydrogen carbonate.
Solution B is sodium chloride 7.33 g / L, potassium chloride 148.0 mg / L, calcium chloride dihydrate 509.6 mg / L, magnesium chloride hexahydrate 201.4 mg / L, anhydrous sodium acetate 81.2 mg. The drug solution for acute blood purification according to claim 6, which is an aqueous solution containing 1.98 g / L of glucose and glucose.
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Non-Patent Citations (3)
| Title |
|---|
| ニプロ株式会社: "「サブパック 血液ろ過用補充液 -Bi」", 添付文書, JPN6023047014, 2017, ISSN: 0005200491 * |
| 扶桑薬品工業株式会社: "「サブラッド 血液ろ過用補充液 BSG」", 添付文書, JPN6023047013, 2017, ISSN: 0005200490 * |
| 根木 茂雄ほか, 日本透析会雑誌, vol. 51, no. 2, JPN6023047012, 2018, pages 141 - 148, ISSN: 0005200489 * |
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