JP2018079319A - Replenishment liquid for blood filtration - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a replenisher for blood filtration having good long-term stability suitable for use in a replenisher or a dialysate in CRRT. SOLUTION: This is a time-mixed blood filtration replenisher consisting of solution A containing sodium chloride, potassium chloride and sodium hydrogen carbonate, and solution B containing sodium chloride, potassium chloride, calcium chloride, magnesium chloride and glucose. Solution A and solution B are blood filtration supplements containing phosphate ion in either solution A or solution B and not containing acetate ion in the same volume as solution A and solution B, and solution A and B. Supplement for blood filtration in which the sodium ion concentration, potassium ion concentration, calcium ion concentration, magnesium ion concentration, chloride ion concentration, inorganic phosphorus concentration, hydrogen carbonate ion concentration, and glucose concentration are predetermined concentrations in the mixed solution. liquid. [Selection diagram] None

Description

  The present invention relates to a hemofiltration replenisher, particularly a replenisher or dialysate with excellent long-term stability for use in continuous renal replacement therapy (CRRT).

  Continuous renal replacement therapy is a blood purification method for the purpose of renal support, and it involves removing excess water in the blood (water removal) and removing unnecessary metabolites (waste products) continuously. The one set at the start. Specifically, acute kidney injury, severe acute pancreatitis, fulminant hepatitis, postoperative liver failure, other severe acute hepatitis, etc. may cause abnormal blood biochemistry, abnormal electrolyte / acid-base balance, abnormal fluid balance, etc. When homeostasis is remarkably impaired, CRRT is performed because it is required to urgently purify blood and body fluid to maintain the homeostasis of the living body and improve the pathological condition.

  Continuous renal replacement therapy is mainly used in intensive care units and emergency departments to treat critically ill patients and emergency patients. Examples of its implementation include continuous hemofiltration (CHF), continuous hemodialysis (CHD) and continuous hemofiltration dialysis (CHDF), and the most practiced clinical practice is CHDF. In order to improve the removal efficiency in a short time, high flow continuous hemodiafiltration (HFVCHDF) and high flow continuous hemofiltration (HVCHF) are also performed. These CRRTs may require a replenisher or dialysate, depending on the mode of implementation, but currently there are no CRRT-specific replenishers or dialysates available on the market. doing.

  However, conventional blood filtration replenishers are designed for intermittent and short-term treatment for patients with chronic renal failure. Therefore, when used for CRRT, (1) potassium concentration is lower than physiological concentration and serum K + concentration is decreased, (2) serum phosphorus concentration is decreased because it does not contain phosphorus, (3) calcium Concentration and bicarbonate concentration is higher than physiological concentration, so dosage adjustment is necessary. (4) Since the subject is a serious patient and slowly and continuously treated for a long time, waste products, There is a problem that an existing replenisher cannot secure a sufficient dose for removing excess product, moisture and correcting the concentration.

  In other words, at present, in order to solve the above problem, mixing operation for concentration correction and replenishment for addition of additional components are performed at the time of use. There is a problem in chemical stability after mixing (contamination, contamination, misoperation, needle stick accident) and mixing.

  On the other hand, in order to solve such problems, Patent Document 1 increases the potassium ion concentration of a conventional replenisher, and develops a dialysate / replenisher for use in acute blood purification therapy containing phosphate ions. However, it is not something that can be solved by simply adjusting the concentration of the components, but it is difficult to add phosphate ions due to the formation of insoluble precipitates of phosphate by reacting with calcium ions and magnesium ions. After showing the difficulty of specific formulation development, such as the stability when magnesium ions coexist for a long time, the problem of insoluble fine particles such as calcium carbonate and magnesium carbonate and the occurrence of precipitation, etc. Disclosure.

International Publication No. 2009/044919

  However, Patent Document 1 points out the above-mentioned difficulty, but shows only two types of specific preparation examples. In addition, since CRRT is an emergency treatment, it may not be frequently performed in one facility, and long-term stability in the storage form is desired, but the long-term stability of the preparation is mentioned. There is room for consideration.

  Then, this invention makes it a subject to provide the further replenisher for blood filtration which has the favorable long-term stability suitable for the use to the replenisher in CRRT, and a dialysate.

  The present inventors assign each component to liquid A and liquid B to obtain a long-term stability suitable for use as a replenisher or dialysate in CRRT by making a mixed preparation at the time of use of a specific formulation. The present inventors have found that a blood filtration replenisher can be obtained.

That is, the present invention
[1] A replenisher for mixed-use blood filtration comprising a liquid A containing sodium chloride, potassium chloride and sodium bicarbonate, and a liquid B containing sodium chloride, potassium chloride, calcium chloride, magnesium chloride and glucose, A replenisher for blood filtration that contains phosphate ions in either one of the liquid or the B liquid and does not contain any acetate ions, and the A liquid and the B liquid have the same volume,
In a mixed liquid obtained by mixing liquid A and liquid B, the sodium ion concentration is 140 mEq / L, the potassium ion concentration is 3.7 mEq / L, the calcium ion concentration is 2.6 mEq / L, the magnesium ion concentration is 1.1 mEq / L, Blood filter replenisher having a chloride ion concentration of 115 to 120 mEq / L, an inorganic phosphorus concentration of 3.7 mg / dL, a bicarbonate ion concentration of 30 mEq / L, and a glucose concentration of 110 to 180 mg / dL, preferably 150 mg / dL ,
[2] Solution A contains sodium chloride 4.98 g / L, potassium chloride 275.8 mg / L, sodium hydrogen carbonate 5.04 g / L and disodium hydrogen phosphate dodecahydrate 859.6 mg / L An aqueous solution,
Liquid B was sodium chloride 7.60 g / L, potassium chloride 275.8 mg / L, calcium chloride dihydrate 382.2 mg / L, magnesium chloride hexahydrate 223.6 mg / L and glucose 2.20-3 A replenisher for blood filtration as described in [1] above, which is an aqueous solution containing .60 g / L, preferably 3.00 g / L;
[3] Solution A is an aqueous solution containing 5.26 g / L of sodium chloride, 283.3 mg / L of potassium chloride and 5.04 g / L of sodium bicarbonate,
Solution B was sodium chloride 7.46 g / L, potassium chloride 268.4 mg / L, calcium chloride dihydrate 382.2 mg / L, magnesium chloride hexahydrate 223.6 mg / L, sodium dihydrogen phosphate The replenisher for blood filtration according to the above [1], which is an aqueous solution containing a hydrate 374.4 mg / L and glucose 2.20 to 3.60 g / L, preferably 3.00 g / L,
[4] The blood filtration replenisher according to any one of the above [1] to [3], wherein the volumes of the liquid A and the liquid B are both 1000 mL,
[5] A multi-chamber container preparation having at least two chambers partitioned by an isolating means capable of communication, wherein the A and B solutions of the blood filtration replenisher according to any one of the above [1] to [4] A multi-chamber container preparation containing each in the first chamber and the second chamber,
[6] The multi-chamber container preparation according to the above [5], wherein the multi-chamber container is a plastic double bag,
[7] The multi-chamber container preparation according to the above [5] or [6], wherein the multi-chamber container is further packaged with a gas barrier film together with an oxygen scavenger, and [8] oxygen detection further outside the multi-chamber container and inside the gas barrier film. It relates to the multi-chamber container preparation described in [7] above containing an agent.

  According to the present invention, blood components having good long-term stability suitable for CRRT replenisher and dialysis fluid are obtained by assigning each component to liquid A and liquid B to obtain a mixed preparation at the time of use of a specific prescription. A replenishing solution can be obtained.

  The blood filtration replenisher of the present invention has (1) a higher potassium concentration, (2) phosphorus, (3) a lower calcium concentration and bicarbonate concentration than the conventional blood filtration replenisher, and ( 4) It is characterized by being a blood filtration replenisher more suitable for use in CRRT, in which glucose is set in a concentration range tailored to critically ill patients. This makes it possible to provide a replenisher or dialysis solution that does not require any special correction for hypokalemia or hypophosphatemia and is free from the risk of hypercalcemia or alkalosis when used in CRRT. Moreover, since it does not contain an acetate ion, it can be used in acetic acid intolerance.

  In the present specification, “blood filtration replenisher” means a chemical that can be used as a replenisher or as a dialysate. Accordingly, the hemofiltration replenisher of the present invention includes, for example, continuous hemofiltration (CHF) replenisher, continuous hemodialysis (CHD) dialysate, and continuous hemofiltration dialysis (CHDF) replenisher and dialysis. It can be used for liquids.

  The replenisher for blood filtration according to the present invention is a mixed blood at the time of use consisting of a solution A containing sodium chloride, potassium chloride and sodium bicarbonate and a solution B containing sodium chloride, potassium chloride, calcium chloride, magnesium chloride and glucose. Filtration replenisher. Either one of the A liquid or the B liquid contains phosphate ions, and neither acetate ions are contained.

  In the production of the replenisher for blood filtration of the present invention, components such as sodium chloride, potassium chloride, sodium hydrogen carbonate, calcium chloride, magnesium chloride may be used in the form of hydrates as well as anhydrides. it can. In addition, when containing phosphate ions, sodium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate and the like can be used, and various hydrates, For example, disodium hydrogen phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate, and the like can be used.

  The replenisher for blood filtration of the present invention is a mixed solution obtained by mixing solution A and solution B. The sodium ion concentration is 140 mEq / L, the potassium ion concentration is 3.7 mEq / L, the calcium ion concentration is 2.6 mEq / L, The magnesium ion concentration is 1.1 mEq / L, the chlorine ion concentration is 115 to 120 mEq / L, the inorganic phosphorus concentration is 3.7 mg / dL, the bicarbonate ion concentration is 30 mEq / L, and the glucose concentration is 110 to 180 mg / dL. The glucose concentration is more preferably 150 mg / dL.

  In one embodiment, the replenisher for blood filtration according to the present invention comprises a solution A comprising sodium chloride 4.98 g / L, potassium chloride 275.8 mg / L, sodium hydrogen carbonate 5.04 g / L, and disodium hydrogen phosphate An aqueous solution containing 859.6 mg / L of dihydrate, and B solution is 7.60 g / L of sodium chloride, 275.8 mg / L of potassium chloride, 382.2 mg / L of calcium chloride dihydrate, magnesium chloride It is an aqueous solution containing 223.6 mg / L of hexahydrate and 2.20 to 3.60 g / L of glucose. As for glucose, it is more preferred to contain 3.00 g / L. Specifically, the solution A was prepared by adding each component, sodium chloride 4.98 g, potassium chloride 275.8 mg, sodium hydrogen carbonate 5.04 g and disodium hydrogen phosphate dodecahydrate 859.6 mg to water for injection, It can be obtained by mixing and dissolving, and adding and mixing water for injection until the total amount becomes 1000 mL. Similarly, solution B was prepared by adding each component, 7.60 g of sodium chloride, 275.8 mg of potassium chloride, 382.2 mg of calcium chloride dihydrate, 223.6 mg of magnesium chloride hexahydrate, and 2.20 to 3 glucose. .60 g is added, mixed and dissolved, and water for injection is added and mixed until the total amount becomes 1000 mL.

  In the present embodiment, the pH of the liquid A is preferably 7.5 to 8.5, more preferably 7.7 to 8.5, and the pH of the liquid B is preferably 2.0 to 2.4. If the pH is not within this range, it is adjusted with a pH adjuster such as hydrochloric acid or sodium hydroxide.

  In another embodiment, the replenisher for blood filtration of the present invention is an aqueous solution in which Solution A contains 5.26 g / L of sodium chloride, 283.3 mg / L of potassium chloride and 5.04 g / L of sodium bicarbonate. Yes, liquid B is 7.46 g / L of sodium chloride, 268.4 mg / L of potassium chloride, 382.2 mg / L of calcium chloride dihydrate, 223.6 mg / L of magnesium chloride hexahydrate, dihydrogen phosphate This is an aqueous solution containing sodium 374.4 mg / L and glucose 2.20 to 3.60 g / L. As for glucose, it is more preferred to contain 3.00 g / L. Specifically, for solution A, each component, 5.26 g of sodium chloride, 283.3 mg of potassium chloride, and 5.04 g of sodium bicarbonate were added to water for injection, mixed and dissolved, and water for injection was added until the total volume reached 1000 mL. Can be obtained by mixing. Similarly, solution B was prepared by adding each component, sodium chloride 7.46 g, potassium chloride 268.4 mg, calcium chloride dihydrate 382.2 mg, magnesium chloride hexahydrate 223.6 mg, sodium dihydrogen phosphate 374 to water for injection. .4 mg and 2.20 to 3.60 g of glucose are added, mixed and dissolved, and water for injection is added and mixed until the total amount becomes 1000 mL.

  In this embodiment, the pH of the A liquid is preferably 7.5 to 8.5, more preferably 7.7 to 8.5, and the pH of the B liquid is preferably 2.2 to 2.6. If the pH is not within this range, it is adjusted with a pH adjuster such as hydrochloric acid or sodium hydroxide.

  In the blood filtration replenisher according to the present invention, the volume of the A liquid and the B liquid is the same volume, and is not particularly limited, but is preferably 1000 mL each from the viewpoint of easy mixing of the A liquid and the B liquid. .

  As described above, the blood filtration replenisher of the present invention is a mixed-use type consisting of two liquids, liquid A and liquid B. For example, as one embodiment of the present invention, the blood filtration replenisher is partitioned by a separating means that can communicate with each other. It is preferable to prepare a multi-chamber container preparation in which the liquid A and the liquid B are accommodated in the first chamber and the second chamber, respectively, in a multi-chamber container having at least two chambers. As such a multi-chamber container, for example, a plastic double bag type container such as polypropylene is preferable, and those used in conventional replenishers for blood filtration can be used. The same applies to the above.

  For example, in the multi-chamber container preparation of the present invention, the multi-chamber container is filled with liquid A and liquid B, and then the inlet is sealed. Then, according to the index | standard of the final sterilization method of the Japanese Pharmacopoeia, it can be set as a final product by performing the high pressure steam sterilization process for 20 minutes at the temperature of 121 degreeC according to a conventional method.

  After sterilization, the multi-chamber container is preferably packaged with a gas barrier packaging material in order to stabilize the chemical solution. The exterior may be hermetically housed in a packaging container made of a gas barrier packaging material, and may be hermetically sealed when the packaging material is a film. Gas barrier packaging materials include, for example, packaging materials composed of ethylene vinyl alcohol copolymer (EVOH), polyethylene terephthalate (PET), polyvinylidene chloride (PVDC), nylon, etc., and these materials include silica and alumina. The packaging material which vapor-deposited gas barrier substances, such as these, the packaging material produced from the multilayer film which combined these raw materials, etc. are used.

  In addition, when packaging a multi-chamber container, for the purpose of detecting pinholes in the exterior, it is also possible to store an oxygen scavenger or replace it with nitrogen gas, carbon dioxide gas, etc. In addition, oxygen detectors and the like can be stored together. As the oxygen scavenger and oxygen detector, commercially available products can be used.

  The replenisher for blood filtration of the present invention is about 0.6 to 1.5 L / hr continuously in an intensive care unit (ICU), for example, continuously for 24 hours (10 to 10 kg with an adult standard weight of 60 kg). 25 mL / kg / hr), but generally, for example, about 0.6-1 L / hr continuously for 24 hours (10-17 mL / kg / hr with 60 kg adult standard weight) ) Can be used. The continuous use period is not particularly limited, and can be shortened and extended as necessary. As a special use, in order to improve the removal efficiency in a short period of time, for example, about 1.5 to 1.8 L / hr continuously for 24 hours (25 to 30 mL / kg with 60 kg as the standard weight of an adult). / Hr).

  The blood filtration replenisher of the present invention can be used for patients with AKI (Acute Kidney Injury) in continuous renal replacement therapy (CRRT). AKI patients include patients with cardiovascular disease, sepsis, liver disease, and multiple organ failure.

  EXAMPLES Hereinafter, although this invention is demonstrated concretely based on an Example, this invention is not intended to be limited to these Examples.

Examples 1 and 2
According to the composition of Table 1, the components of solution A were mixed and dissolved in water for injection, the pH was adjusted, and the total volume was made up to 1000 mL with water for injection. Similarly, according to the composition shown in Table 2, the active ingredient of solution B was dissolved in water for injection, the pH was adjusted, and the total volume was finally adjusted to 1000 mL with water for injection.

  The obtained liquid A and liquid B were filled in a polypropylene double bag (manufactured by Nipro Corporation) and sealed. After that, the double bag was autoclaved and gas barrier film packaging material (Toppan Printing Co., Ltd.) together with oxygen scavenger (Oe Chemical Co., Ltd.) and oxygen detector (Ageless Eye manufactured by Mitsubishi Gas Chemical Co., Ltd.). ).

  In this specification, the Japanese Pharmacopoeia represents the 17th revised Japanese Pharmacopoeia, the external regulations represent the Japanese Pharmacopoeia Standards 2002, and the supplementary regulations represent the Pharmaceutical Additives Standard 2003 and its supplements.

Test Example 1: Stability test after mixing The double bag (n = 2) obtained in Examples 1 and 2 was taken out from the outer bag of the film package, compressed so that the lower chamber was grasped with both hands, and the partition was opened. . The liquid A (lower chamber) side and the liquid B (upper chamber) side were pressed alternately to mix well, and then allowed to stand at room temperature. Stability is measured immediately after mixing at 4, 12, 24 and 36 hours, properties, pH, purity test (measurement of sugar degradation product 5-hydroxymethylfurfural (5-HMF)), insoluble foreign matter, insoluble It carried out about each item of fine particles. The test method for each item follows the test method prescribed by the Japanese Pharmacopoeia, and is shown in Table 3 together with the target standards.

  The results are shown in Table 4.

  In the mixed solutions of Examples 1 and 2, no crystal precipitation was observed until 36 hours after mixing. In addition, the pH was almost unchanged from 36 hours after mixing in any formulation, and was within the target specification range of 7.29 in Example 1 and 7.31 in Example 2. As for other evaluation items (property, purity test 5-HMF, insoluble foreign matter and insoluble fine particles), almost no change over time was observed in any of the examples. From the above results, it was confirmed that all examples were stable for 36 hours after storage at room temperature.

Test example 2: Storage stability test (acceleration test)
The double bag obtained in Examples 1 and 2 was further packaged in a paper box as a secondary packaging and stored at a temperature of 40 ° C. ± 1 ° C. and a humidity of 75% PH ± 5% RH. The storage stability was measured at the start of storage, 1, 2, 3 and 6 months from the start of storage, for the evaluation items shown in Table 5 for liquid A and liquid B (n = 3). The test method for each item follows the test method specified by the Japanese Pharmacopoeia, and is shown in Table 5 together with the target standards.

  The results of the liquid A and the liquid B are shown in Table 6 and Table 7, respectively.

  When stored for 6 months, the pH of solution A slightly increased after 1 month and then gradually decreased, and the pH after 6 months was 8.04 in Example 1 and Example 2. It was 8.06, and all the preparations were within the target specification range in any test period. Moreover, about the purity test (5-HMF) of B liquid, although the increase with time was recognized in both of Examples 1 and 2, even after 6 months, 0.1135 in Example 1 In Example 2, it was 0.0951, which was within the target standard range.

  As for other evaluation items (A liquid: property, insoluble foreign substance, insoluble fine particle and sodium bicarbonate quantitative, B liquid: property, pH, insoluble foreign substance, insoluble fine particle and glucose, calcium and magnesium quantitative) Almost no change in quality over time was observed. Thus, it was confirmed that both Examples 1 and 2 were stable for 6 months under the conditions of 40 ° C. and 75% RH.

  From Test Examples 1 and 2, liquid A and liquid B in the circulation storage period of any of the blood filtration replenishers of Examples 1 and 2 are excellent in long-term stability in the multi-chamber container, and blood filtration after mixing in use The liquid was also shown to be stable at room temperature for 36 hours after mixing.

<Test conditions>
Through Test Examples 1 and 2, 5-HMF, sodium bicarbonate, glucose, calcium and magnesium were quantified under the following conditions.

(1) 5-HMF
Detector: UV-visible spectrophotometer (UV-2700 manufactured by Shimadzu Corporation, measurement wavelength: 284 nm)
(2) Sodium bicarbonate detector: automatic titrator (COM-1700S manufactured by Hiranuma Sangyo Co., Ltd.)
(3) Glucose detector: High-speed automatic polarimeter (SEPA-200 manufactured by Horiba, Ltd.)
(4) Calcium detector: High performance liquid chromatography (L-7000, Hitachi High-Technologies Corporation)
(5) Magnesium detector: high-performance liquid chromatography (L-7000, Hitachi High-Technologies Corporation)

Claims (8)

A replenisher for mixed blood filtration at the time of use consisting of sodium chloride, potassium chloride and sodium hydrogen carbonate A liquid, and sodium chloride, potassium chloride, calcium chloride, magnesium chloride and glucose B liquid, A liquid or B A replenishment solution for blood filtration containing phosphate ions in any one of the solutions and not containing acetate ions, and A solution and B solution have the same volume,
In a mixed liquid obtained by mixing liquid A and liquid B, the sodium ion concentration is 140 mEq / L, the potassium ion concentration is 3.7 mEq / L, the calcium ion concentration is 2.6 mEq / L, the magnesium ion concentration is 1.1 mEq / L, A blood filtration replenisher having a chloride ion concentration of 115 to 120 mEq / L, an inorganic phosphorus concentration of 3.7 mg / dL, a bicarbonate ion concentration of 30 mEq / L, and a glucose concentration of 110 to 180 mg / dL. Solution A is an aqueous solution containing 4.98 g / L of sodium chloride, 275.8 mg / L of potassium chloride, 5.04 g / L of sodium hydrogen carbonate and 859.6 mg / L of disodium hydrogen phosphate dodecahydrate. ,
Liquid B was sodium chloride 7.60 g / L, potassium chloride 275.8 mg / L, calcium chloride dihydrate 382.2 mg / L, magnesium chloride hexahydrate 223.6 mg / L and glucose 2.20-3 The replenisher for blood filtration according to claim 1, which is an aqueous solution containing .60 g / L. Solution A is an aqueous solution containing 5.26 g / L of sodium chloride, 283.3 mg / L of potassium chloride and 5.04 g / L of sodium bicarbonate,
Solution B was sodium chloride 7.46 g / L, potassium chloride 268.4 mg / L, calcium chloride dihydrate 382.2 mg / L, magnesium chloride hexahydrate 223.6 mg / L, sodium dihydrogen phosphate The replenisher for blood filtration according to claim 1, which is an aqueous solution containing hydrate 374.4 mg / L and glucose 2.20 to 3.60 g / L. The blood filtration replenisher according to any one of claims 1 to 3, wherein the volume of each of the liquid A and the liquid B is 1000 mL. A multi-chamber container preparation having at least two chambers partitioned by a separating means that can communicate with each other, wherein the A solution and the B solution of the blood filtration replenisher according to any one of claims 1 to 4 are respectively first. A multi-chamber container preparation housed in the chamber and the second chamber. The multi-chamber container preparation according to claim 5, wherein the multi-chamber container is a plastic double bag. The multi-chamber container preparation according to claim 5 or 6, wherein the multi-chamber container is further packaged with a gas barrier film together with an oxygen scavenger. The multi-chamber container preparation according to claim 7, further comprising an oxygen detecting agent outside the multi-chamber container and inside the gas barrier film.