JP6958265B2 - Replenisher for blood filtration - Google Patents

Description

The present invention relates to a replacement fluid for blood filtration, particularly a replacement fluid or dialysate having excellent long-term stability for use in continuous renal replacement therapy (CRRT).

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.

Continuous renal replacement therapy is mainly used in the intensive care unit and the emergency department to treat 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. doing.

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. Therefore, when used for CRRT, (1) the potassium concentration is lower than the physiological concentration and the serum K + concentration decreases, (2) the serum phosphorus concentration decreases because it does not contain phosphorus, and (3) calcium. Since the concentration and bicarbonate concentration are higher than the physiological concentration, it is necessary to adjust the dose. There is a problem that an existing replenisher cannot secure a sufficient dose for removing overproduced substances and water and correcting the concentration.

That is, at present, in order to solve the above problem, a mixing operation for concentration correction and a replenishment for adding additional components are performed at the time of use, but this mixing operation and replenishment operation are medical safety. There are problems with (contamination, foreign matter contamination, erroneous operation, needle stick accident) and chemical stability after mixing.

On the other hand, Patent Document 1 deals with the development of dialysate / replacement solution for use in acute blood purification therapy containing phosphate ions by increasing the calcium ion concentration of the conventional replacement solution in order to solve such a problem. It is not something that can be solved simply by adjusting the component concentration, but it is difficult to add phosphate ions due to the reaction with calcium ions and magnesium ions to form an insoluble precipitate of phosphate. After showing the difficulty of developing a specific formulation, such as the stability when coexisting with magnesium ions for a long time, the problem of insoluble fine particles such as calcium carbonate and magnesium carbonate, and the generation of precipitation, a specific formulation is made. It is disclosed.

International Publication No. 2009/044919

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

Therefore, it is an object of the present invention to provide a replenisher for blood filtration, which has good long-term stability and is suitable for use in a replenisher for CRRT and a dialysate.

The present inventors divide each component into solutions A and B to prepare a mixed preparation at the time of use of a specific formulation, thereby providing good long-term stability suitable for use as a replacement solution or dialysate in CRRT. The present invention has been completed by finding that a replenisher for blood filtration can be obtained.

That is, the present invention
[1] A solution for mixing blood filtration, which comprises 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. A replenisher for blood filtration in which either solution A or solution B contains phosphate ions and neither solution contains acetate ions, and solutions A and B have the same volume.
In a mixture of solutions A and 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, and the magnesium ion concentration is 1.1 mEq / L. A replenisher for blood filtration having a chlorine ion concentration of 115 to 120 mEq / L, an inorganic phosphorus concentration of 3.7 mg / dL, a hydrogen carbonate ion concentration of 30 mEq / L, and a glucose concentration of 110 to 180 mg / dL, preferably 150 mg / dL. ,
[2] Solution A contains 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 dihydrate. It is an aqueous solution
Solution B is 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 the above [1], 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 hydrogen carbonate.
Solution B is 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 dihydrogen. The replenisher for blood filtration according to the above [1], which is an aqueous solution containing 374.4 mg / L of hydrate and 2.20 to 3.60 g / L of glucose, preferably 3.00 g / L.
[4] The replenisher for blood filtration 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 a communicable isolation means, which is the liquid A and the liquid B of the blood filtration supplement according to any one of the above [1] to [4]. A multi-chamber container formulation, which is contained in the first and second chambers, respectively.
[6] The multi-chamber container formulation according to [5] above, wherein the multi-chamber container is a plastic double bag.
[7] The multi-chamber container formulation according to the above [5] or [6], in which the multi-chamber container is further packaged with a gas barrier film together with an oxygen scavenger, and [8] 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 [7], which contains an agent.

According to the present invention, blood filtration having good long-term stability suitable for CRRT replacement solution and dialysate is obtained by distributing each component to solution A and solution B to prepare a time-mixed preparation having a specific formulation. A replenisher for dialysis can be obtained.

The blood filtration replenisher of the present invention has (1) a higher potassium concentration, (2) a phosphorus content, (3) a lower calcium concentration and a bicarbonate concentration, and ( 4) It is characterized by being a blood filtration replacement solution more suitable for use in CRRT, in which glucose is set in a concentration range suitable for critically ill patients. Thereby, it is possible to provide a replacement solution or dialysate without a risk of hypercalcemia or alkalosis without requiring special correction for hypokalemia or hypophosphatemia when used for CRRT. Moreover, since it does not contain acetate ions, it can also be used in acetic acid intolerance.

As used herein, the term "replenisher for blood filtration" means a drug solution that can be used as a replenisher or as a dialysate. 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.

The replenisher for blood filtration of the present invention is a time-mixed blood composed 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. It is a replenisher for filtration. Either the liquid A or the liquid B contains a phosphate ion, and neither of the liquids contains an acetate ion.

In the production of the replenisher for blood filtration of the present invention, not only anhydrous but also hydrated components such as sodium chloride, potassium chloride, sodium hydrogencarbonate, calcium chloride and magnesium chloride may be used. can. Further, when the phosphate ion is contained, sodium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, etc. can be used, and various hydrates, respectively, can be used. For example, disodium hydrogen phosphate dihydrate, sodium dihydrogen phosphate dihydrate and the like can also be used.

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

In one embodiment, the replenisher for blood filtration of the present invention contains solution A containing 4.98 g / L of sodium chloride, 275.8 mg / L of potassium chloride, 5.04 g / L of sodium hydrogen carbonate and disodium hydrogen phosphate. It is an aqueous solution containing 859.6 mg / L of dihydrate, and the solution B is sodium chloride 7.60 g / L, potassium chloride 275.8 mg / L, calcium chloride dihydrate 382.2 mg / L, magnesium chloride. It is an aqueous solution containing 223.6 mg / L of hexahydrate and 2.20 to 3.60 g / L of glucose. It is more preferable that glucose is contained at 3.00 g / L. Specifically, for solution A, each component, sodium chloride 4.98 g, potassium chloride 275.8 mg, sodium hydrogen carbonate 5.04 g, and disodium hydrogen phosphate dusohydrate 859.6 mg were added to water for injection. It can be obtained by mixing and dissolving, adding water for injection until the total volume becomes 1000 mL, and mixing. Similarly, solution B contains 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 of glucose in water for injection. It can be obtained by adding .60 g, mixing and dissolving, and adding water for injection until the total volume becomes 1000 mL and mixing.

In the present embodiment, the pH of the solution A is preferably 7.5 to 8.5, more preferably 7.7 to 8.5, and the pH of the solution B is preferably 2.0 to 2.4. If the pH is not within this range, adjust 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 hydrogen carbonate. 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, dihydrogen phosphate It is an aqueous solution containing 374.4 mg / L of sodium and 2.20 to 3.60 g / L of glucose. It is more preferable that glucose is contained at 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 hydrogen carbonate are added to water for injection, mixed and dissolved, and water for injection is added until the total volume becomes 1000 mL. Can be obtained by mixing. Similarly, solution B contains 7.46 g of sodium chloride, 268.4 mg of potassium chloride, 382.2 mg of calcium chloride dihydrate, 223.6 mg of magnesium chloride hexahydrate, and 374 sodium dihydrogen phosphate in water for injection. It can be obtained by adding 0.4 mg and 2.20 to 3.60 g of glucose, mixing and dissolving, and adding water for injection until the total volume becomes 1000 mL and mixing.

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

In the replenisher for blood filtration according to the present invention, the volumes of the A solution and the B solution are the same, and the volume is not particularly limited, but 1000 mL each is preferable from the viewpoint of ease of mixing the A solution and the B solution. ..

As described above, the replenisher for blood filtration of the present invention is a time-mixed type composed of two liquids, a liquid A and a liquid B, and is partitioned by a communicable isolation means, for example, as one embodiment of the present invention. 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. 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.

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.

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.

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.

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

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

Hereinafter, the present invention will be specifically described based on examples, but the present invention is not intended to be limited to these examples.

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

The obtained solutions A and B were filled in a polypropylene double bag (manufactured by Nipro Co., Ltd.) and sealed. After that, the double bag was sterilized by high pressure steam, and a gas barrier film packaging material (Toppan Printing Co., Ltd.) was used together with an oxygen scavenger (manufactured by Oe Chemical Industry Co., Ltd.) and an oxygen detector (ageless eye manufactured by Mitsubishi Gas Chemical Co., Ltd.). Wrapped in).

In this specification, the Japanese Pharmacopoeia refers to the 17th revised Japanese Pharmacopoeia, the Japanese Pharmacopoeia refers to the Japanese Pharmacopoeia Non-Pharmacopeia Standard 2002, and the Pharmacopoeia refers to 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 packaging, compressed so that the lower chamber could be grasped with both hands, and the partition wall was opened. .. Liquid A (lower chamber) side and liquid B (upper chamber) side were pressed alternately to mix well, and then allowed to stand at room temperature. Stability was measured immediately after mixing at 4, 12, 24 and 36 hours by property, pH and purity tests (measurement of 5-hydroxymethylfurfural (5-HMF), which is a decomposition product of sugar), insoluble foreign matter, and insoluble. It was carried out for each item of fine particles. The test methods for each item follow the test methods specified in the Japanese Pharmacopoeia, and are shown in Table 3 together with the target standards.

The results are shown in Table 4.

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

Test Example 2: Storage stability test (accelerated test)
The double bags obtained in Examples 1 and 2 were further stored in a paper box as a secondary wrapping with the exterior as it was, 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 after the start of storage, and the evaluation items shown in Table 5 were carried out for each of the solutions A and B (n = 3). The test methods for each item follow the test methods specified in the Japanese Pharmacopoeia, and are shown in Table 5 together with the target standards.

The results of solutions A and B are shown in Tables 6 and 7, respectively.

When stored for 6 months, the pH of solution A increased slightly after 1 month in each formulation and then gradually decreased, and the pH after 6 months was 8.04 in Example 1 and Example 2 in Example 2. The pH was 8.06, which was within the target standard range for all test periods. Regarding the purity test (5-HMF) of Liquid B, an increase with time was observed in both Examples 1 and 2, but even after 6 months, 0.1135 in Example 1. It was 0.0951 in Example 2, which was within the target standard range.

For other evaluation items (Liquid A: Quantification of properties, insoluble foreign substances, insoluble fine particles and sodium hydrogen carbonate, Solution B: properties, pH, insoluble foreign substances, insoluble fine particles and quantification of glucose, calcium and magnesium), all the formulations are available. Almost no change in quality was observed over time. This 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, both solutions A and B during the flow and storage period of the blood filtration supplements of Examples 1 and 2 have excellent long-term stability in a multi-chamber container, and blood filtration after mixing during 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, the quantification of 5-HMF, sodium hydrogen carbonate, glucose, calcium and magnesium was carried out under the following conditions.

(1) 5-HMF
Detector: UV-2700 manufactured by Shimadzu Corporation, measurement wavelength: 284 nm)
(2) Sodium hydrogen carbonate 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)

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. A replenisher for blood filtration in which either one of the solutions contains phosphate ions and none of them contains acetate ions, and the solutions A and B have the same volume.
In a mixture of solutions A and 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, and the magnesium ion concentration is 1.1 mEq / L. A replenisher for blood filtration having a chlorine ion concentration of 115 to 120 mEq / L, an inorganic phosphorus concentration of 3.7 mg / dL, a hydrogen carbonate 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 dihydrate. ,
Solution B is 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 hydrogen carbonate.
Solution B is 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 dihydrogen. The replenisher for blood filtration according to claim 1, which is an aqueous solution containing 374.4 mg / L of hydrate and 2.20 to 3.60 g / L of glucose. The replenisher for blood filtration according to any one of claims 1 to 3, wherein the volumes of the liquid A and the liquid B are both 1000 mL. A multi-chamber container preparation having at least two chambers partitioned by a communicable isolation means, wherein the liquid A and the liquid B of the blood filtration replenisher according to any one of claims 1 to 4 are the first. A multi-chamber container formulation that is housed in a chamber and a second chamber. The multi-chamber container formulation according to claim 5, wherein the multi-chamber container is a plastic double bag. The multi-chamber container formulation 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 formulation according to claim 7, further comprising an oxygen detector on the outside of the multi-chamber container and inside the gas barrier film.