JP7532763B2 - Dialysis fluid solid preparations - Google Patents

Description

The present invention relates to a solid preparation for dialysis, in particular to a so-called agent A for preparing a sodium bicarbonate-containing dialysis solution.

When hemodialysis is performed on a patient with impaired renal function, the patient's blood is purified in an artificial kidney. Dialysis fluid is perfused inside this artificial kidney, and waste products in the blood are generally transferred to the dialysis fluid through a dialysis membrane. In recent years, in order to reduce the burden on patients, sodium bicarbonate-containing dialysis fluid, which uses less acetic acid, has been widely used as the dialysis fluid, instead of the conventional acetic acid dialysis fluid.

Dialysis fluids containing sodium bicarbonate are not suitable for use as a single agent because insoluble compounds are usually produced by the reaction between the electrolyte components and bicarbonate ions. Therefore, two-component solid preparations for dialysis fluids are usually used, consisting of a preparation (hereinafter referred to as "Agent A") containing electrolyte components (e.g., sodium chloride, potassium chloride, calcium chloride, magnesium chloride) and a pH adjuster (e.g., acetic acid) and a preparation (hereinafter referred to as "Agent B") containing sodium bicarbonate. When glucose is used, it is either added to Agent A, or a three-component solid preparation for dialysis fluid in which glucose powder is packaged separately is also used.

These solid preparations for dialysis fluid use acetic acid as a pH adjuster, but because acetic acid is flammable and volatile, adding it to the granulation equipment during granulation can cause fires or emit a pungent odor. For these reasons, preparations have been developed that use solid organic acids such as citric acid as the pH adjuster and further reduce the acetic acid content. However, when an organic acid other than acetic acid, such as citric acid, is used as the pH adjuster, there are problems such as the citric acid not dissolving sufficiently, causing precipitation when preparing a concentrated solution of Agent A, and insufficient compatibility with existing equipment.

Meanwhile, Patent Document 1 discloses dialysis agent A, which uses acetic acid as a pH adjuster and specifies the total acetate ion concentration in the dialysis fluid to be 2 mEq/L or more and less than 6 mEq/L, and by setting the molar ratio of acetic acid:acetate to 1:0.5-2.0, the agent has excellent storage stability, can reduce the acetic acid odor, and can suppress corrosion of the dialysis fluid preparation device and dialysis device.

Patent No. 5376480

In addition, the total acetate ion concentration in the dialysis fluid is preferably around 6 mEq/L, for example 5.0 to 7.0 mEq/L, because (a) it is necessary to ensure the amount of acetic acid used as a pH adjuster, (b) it is necessary to ensure the amount of sodium acetate used, which contributes to granulation, and (c) it is desirable to reduce the total acetate ion concentration as much as possible from the current mainstream of 8 to 10 mEq/L for bicarbonate-type hemodialysis fluid preparations, due to concerns about the effect on circulatory conductors, such as the inhibitory effect on cardiac function and vasoconstriction, known as acetic acid intolerance. However, with this total acetate ion concentration, the invention described in Patent Document 1 does not sufficiently reduce odor, and there are problems such as delamination of the packaging material (floating and peeling between layers), and further improvement is required.

Therefore, the present invention aims to provide a solid preparation for dialysis fluid that does not undergo delamination of the packaging during storage and that reduces the problematic acetic acid odor during use.

As a result of intensive research into solving the above problems, the present inventors discovered that the above problems can be solved by setting the molar ratio of acetic acid:sodium acetate to 1:2.10-3.66 in a solid preparation for dialysis in which the total acetate ion concentration is 5.0-7.0 mEq/L and the acetate ion concentration derived from acetic acid is 1.5-2.0 mEq/L when used as a dialysis solution, and thus completed the present invention.

That is, the present invention provides
[1] A solid preparation for dialysis containing sodium acetate and acetic acid, the molar ratio of acetic acid:sodium acetate being 1:2.10-3.66, preferably 1:2.10-3.60, more preferably 1:2.10-3.50, and the concentration of total acetate ions in the dialysis solution being 5.0-7.0 mEq/L, preferably 5.1-6.9 mEq/L, more preferably 5.1-6.5 mEq/L, and the concentration of acetate ions derived from acetic acid being 1.5-2.0 mEq/L, preferably 1.6-2.0 mEq/L, more preferably 1.7-2.0 mEq/L;
[2] The solid preparation for dialysis according to the above-mentioned [1], which contains one or more electrolytes selected from the group consisting of sodium chloride, calcium chloride, magnesium chloride and potassium chloride, and glucose.
[3] A dialysis solution containing sodium chloride, calcium chloride, magnesium chloride and potassium chloride as electrolytes, the concentrations of the components being as follows: Na ⁺ : 130-147 mEq/L, preferably 133-145 mEq/L, more preferably 135-143 mEq/L; K ⁺ : 1.80-2.50 mEq/L, preferably 1.85-2.30 mEq/L, more preferably 1.90-2.20 mEq/L; Ca ²⁺ : 2.0-3.0 mEq/L, preferably 2.5-2.9 mEq/L, more preferably 2.7-2.8 mEq/L; Mg ²⁺ : 1.0-1.5 mEq/L, preferably 1.1-1.4 mEq/L, more preferably 1.2-1.3 mEq/L; Cl ^- and [4] a sodium bicarbonate solid preparation for dialysis comprising a combination of the solid preparation for dialysis according to any one of the above [1] to [3] and agent B containing sodium bicarbonate.

The present invention provides a solid preparation for dialysis fluid that does not undergo delamination of the packaging material during storage and reduces the problematic acetic acid odor during use.

The solid preparation for dialysis of the present invention is the so-called "agent A" and is used as a dialysis solution by diluting it with "agent B" containing sodium bicarbonate to appropriate concentrations and then mixing and diluting the mixture.

For packaging solid preparations for dialysis such as those of the present invention, a multi-layered packaging material containing a gas barrier deposition layer of aluminum, silicon, or the like in the middle layer is usually used. Examples of such packaging materials include packaging bags made of a multi-layered material having a biaxially oriented polypropylene (OPP) layer in the outer layer, a polyethylene terephthalate (PET) layer having a gas barrier deposition layer in the middle layer, and a polyethylene (PE) layer, preferably a multi-layered polyethylene layer, in the inner layer. Such multi-layered materials tend to cause delamination (floating and peeling between layers) due to strong volatile acid components. Specifically, it is thought that the acid components penetrate the inner PE layer, erode the adhesive layer between the deposition layer and the PE layer, and reach the deposition layer, causing the floating. It is thought that when it further reaches the PET layer, clear peeling occurs between the layers.

The solid preparation for dialysis of the present invention is a solid preparation for dialysis that contains sodium acetate and acetic acid, and is characterized in that the molar ratio of acetic acid:sodium acetate is 1:2.10-3.66, and when used as a dialysis solution, the total acetate ion concentration is 5.0-7.0 mEq/L, and the acetate ion concentration derived from acetic acid is 1.5-2.0 mEq/L.

The acetic acid is not particularly limited, but glacial acetic acid is preferably used. The sodium acetate is preferably anhydrous sodium acetate, sodium acetate trihydrate, etc.

The contents of acetic acid and sodium acetate are determined so that, when used as a dialysis fluid, the concentration of acetate ions derived from acetic acid is 1.5 to 2.0 mEq/L, the concentration of total acetate ions, which is the sum of acetate ions derived from acetic acid and acetate ions derived from sodium acetate, is 5.0 to 7.0 mEq/L, and the molar ratio of acetic acid to sodium acetate is 1:2.10 to 3.66.

When used as a dialysis fluid, the concentration of acetate ions derived from acetic acid is 1.5 mEq/L or more, preferably 1.6 mEq/L or more, and more preferably 1.7 mEq/L or more. If the acetate ion concentration derived from acetic acid is less than 1.5 mEq/L, the pH of the dialysis fluid will be outside the optimal range (pH higher than 7.4), and the dialysis fluid will not function as a pH adjuster. In addition, the acetate ion concentration derived from acetic acid is 2.0 mEq/L or less, and if it exceeds 2.0 mEq/L, the pH of the dialysis fluid will be outside the optimal range (pH lower than 7.2), and the dialysis fluid will tend not to function as a pH adjuster.

When used as a dialysis solution, the total acetate ion concentration, which is the sum of acetate ions derived from acetic acid and acetate ions derived from sodium acetate, is 5.0 mEq/L or more, but preferably 5.1 mEq/L or more. If the total acetate ion concentration is less than 5.0 mEq/L, the acetate ion derived from sodium acetate will be 3.5 mEq/L or less due to the above conditions regarding acetate ions derived from acetic acid, and the powdered dialysis agent will tend to deliquesce during storage. In addition, the total acetate ion concentration is 7.0 mEq/L or less, but preferably 6.9 mEq/L or less, and more preferably 6.5 mEq/L or less. If the total acetate ion concentration exceeds 7.0 mEq/L, there is a concern that it may cause acetic acid intolerance in clinical use.

The molar ratio of acetic acid to sodium acetate is 1:2.10 or more from the viewpoint of reducing the acetic acid odor and preventing delamination of the packaging material, and 1:3.66 or less from the viewpoint of the suitable content of acetic acid. If the molar ratio exceeds 1:3.66, the acetate ion content derived from acetic acid will be less than 1.5 mEq/L, and the pH of the dialysis solution described above will be outside the optimal range, which is not preferable. In addition, the molar ratio of acetic acid to sodium acetate is preferably 1:2.10 to 3.60, and more preferably 1:2.10 to 3.50.

The solid preparation for dialysis of the present invention preferably contains, in addition to acetic acid and sodium acetate, one or more electrolytes selected from the group consisting of sodium chloride, calcium chloride, magnesium chloride and potassium chloride, and glucose.

The electrolytes include one or more selected from the group consisting of sodium chloride, calcium chloride, magnesium chloride, and potassium chloride, but it is preferable that the dialysis fluid contains all of these electrolytes because it is used for the purpose of correcting the electrolyte balance in the blood of patients with renal failure.

Sodium chloride is preferably in a solid, crystalline state. Calcium chloride dihydrate, calcium chloride monohydrate, calcium chloride anhydrous, etc. are used. Magnesium chloride hexahydrate, etc. are preferably used.

The method for producing the solid preparation for dialysis solution of the present invention is not particularly limited, and the solid preparation may be prepared by simply mixing the components, but it may also be obtained by granulation using, for example, centrifugal fluidized bed granulation, fluidized bed granulation, rolling agitation fluidized bed granulation, etc., and preferably, rolling agitation fluidized bed granulation is used. For this rolling agitation fluidized bed granulation, a rolling agitation fluidized bed granulator is preferably used. The rolling agitation fluidized bed granulator is a device that causes core particles to tumble and flow by the fluidizing action of air flow from the vicinity of the bed wall and the rolling action caused by the rotation of the rotor at the bottom of the device, and sprays and coats the components in the aqueous solution. The air flow rate is preferably 0.2 to 300 m ³ /min, more preferably 0.5 to 200 m ³ /min. If the air flow rate is less than 0.2 m ³ /min, the core particles are likely to aggregate with each other. If the flow rate is more than 300 m ³ /min, the components in the aqueous solution are more likely to undergo the spray-dry phenomenon, and the impact on each particle is greater, which makes it easier for fine powder to form. The inlet air temperature is preferably 70 to 110°C, more preferably 85 to 105°C. If the inlet air temperature is less than 70°C, the fluidity tends to deteriorate and the granulated material tends to adhere to the inside of the granulator, and if it exceeds 110°C, the spray components dry out immediately and do not adhere to the core particles, so that granulation tends not to proceed. The rotor rotation speed is preferably 20 to 1,000 rpm, more preferably 50 to 500 rpm. If the rotor rotation speed is lower than 20 rpm, the thickness of the coating layer becomes non-uniform, and if it is higher than 1,000 rpm, the coating layer may be scraped off due to collision between the coated particles or friction with the inner wall of the device. Drying is preferably performed at an exhaust temperature of 25 to 70°C, more preferably 30 to 50°C, and is performed continuously during spraying.

The solid preparation for dialysis of the present invention preferably contains glucose.

The present invention also provides a sodium bicarbonate solid preparation for dialysis, which is a combination of the above-mentioned solid preparation for dialysis "Agent A" and "Agent B" containing sodium bicarbonate.

The agent B in the present invention is a preparation containing sodium bicarbonate. In addition to sodium bicarbonate, the agent B may contain one or more electrolytes selected from the group consisting of sodium chloride and potassium chloride . The agent B may also contain glucose. Furthermore, sugar components other than glucose, such as maltose, xylitol, trehalose, etc., may be added as necessary.

The method for preparing the sodium bicarbonate dialysis solid preparation of the present invention as a dialysis solution is not particularly limited, and may be, for example, (1) a method in which agents A and B are mixed in a predetermined ratio, and then dissolved in deionized water to prepare a dialysis solution; (2) a method in which agents A and B are each dissolved in deionized water to prepare two aqueous solutions, and then the two are mixed and, if necessary, further deionized water is added to prepare a dialysis solution; or (3) a method in which agent A or agent B is dissolved in deionized water to prepare an aqueous solution, and then the remaining preparation is dissolved to prepare a dialysis solution.

The obtained dialysis solution preferably has a composition shown in Table 1 below, more preferably has a composition shown in Table 2, and even more preferably has a composition shown in Table 3. In Tables 1 to 3, "AcO ^- " represents the total acetate ion concentration, and the range of acetate ion concentration derived from acetic acid ("derived from acetic acid") and the range of acetate ion concentration derived from sodium acetate ("derived from sodium acetate") are shown in the lower row as details, but the actual acetate ion concentration derived from sodium acetate is determined within the ranges shown in each table, taking into consideration the range of total acetate ion concentration, the range of acetate ion concentration derived from acetic acid, and the molar ratio of acetic acid to sodium acetate, which are specified in the invention. In addition, "alkali" in each table means the total concentration of bicarbonate ions and acetate ions derived from sodium acetate.

The present invention will be described in detail below with reference to examples, but the present invention is not intended to be limited to these examples.

Examples 1 to 5 and Comparative Example 1
According to the composition shown in Table 4, potassium chloride, calcium chloride, magnesium chloride and anhydrous sodium acetate were dissolved in 623.7 g of deionized water to prepare a spray liquid. Sodium chloride was charged as core particles into a tumbling stirring fluidized bed granulator (Multiplex MP-01, manufactured by Powrex Corporation), and the spray liquid was sprayed and dried at the same time under conditions of an intake air temperature of 47°C, a rotor rotation speed of 300 rpm and an intake air volume of 0.7 ^m3 /sec. After the entire amount of the spray liquid was sprayed, the granules were dried in the device. The obtained granules were mixed with glacial acetic acid and glucose, and the mixture was filled into a packaging material to obtain a solid preparation for dialysis fluid.

The obtained solid preparation for dialysis was placed in a bag of multi-layer packaging material ((outer) biaxially oriented polypropylene (OPP) layer/silica-deposited GL-PET layer/(inner) multi-layer PE sealant layer) and sealed.

Test Example 1: Odor Sensory Test Each component was mixed according to the composition in Table 4 and sealed in a polyethylene bag. After shaking and mixing the bag, it was opened and the opening was placed at a certain distance from the nose to smell. The odor was evaluated according to the following criteria. The results are shown in Table 4 as the average of the evaluations of nine people.

Odor evaluation criteria: 0 points: no acetic acid odor at all; 1 point: almost no acetic acid odor or slight acetic acid odor; 2 points: acetic acid odor; 3 points: strong acetic acid odor; 4 points: acetic acid odor accompanied by pain or discomfort

Test Example 2: Acetic acid concentration in the gas phase For the packaged solid preparations for dialysis obtained in Examples 1 to 5 and Comparative Example 1, a microsyringe (volume: 250 μL) was inserted into the packaging material, and a test sample (100 μL) was extracted from the gas phase. In order to replace the inside of the syringe with the gas phase, the operation of sucking up the gas phase to about 150 μL and pushing it back was repeated 15 to 20 times. The acetic acid concentration of the extracted sample was measured under the following conditions using a gas chromatograph mass spectrometer (JMS-Q1050GC, manufactured by JEOL Ltd.). Cellotape (registered trademark) was attached to the place where the syringe was inserted once. The results are shown in Table 4.

Measurement conditions:
Column: HP-5 (Agilent) (inner diameter: 0.32 mm × film thickness: 0.25 μm × length: 30 m)
Column temperature: 35°C (hold for 2.5 minutes) to 200°C
Inlet temperature: 200℃
Ion source temperature: 250°C
GCITF temperature: 240℃
Injection mode: Split 50:1
Detector voltage: 1050V
Carrier gas: He

Test Example 3: Evaluation of delamination of packaging material The packaged solid preparations for dialysis obtained in Examples 1, 2, 4 and Comparative Example 1 were stored for 2 months under accelerated test conditions (40°C, 75% RH) and then the packaging materials were observed. The presence or absence of delamination (floating or peeling between layers) of the multi-layered packaging material was observed. In Comparative Example 1, peeling was observed near the boundary between the surface part of the packaging material and the sealed part, but such floating or peeling between layers was not observed in Examples 1, 2 and 4. The results are shown in Table 4.

The results of Test Examples 1 and 2 show that in Examples 1 to 5, in which the molar ratio of acetic acid:sodium acetate is 1:2.10 or more, odor is significantly suppressed compared to Comparative Example 1, in which the molar ratio is 1:2.07.

Test Example 4: Concentration of each component in the dialysis solution According to the composition shown in Table 4, each component was added to deionized water, stirred at room temperature for 60 minutes to dissolve, and diluted with deionized water to 9 L to prepare a concentrated solution of A agent. In addition, 741.3 g of sodium bicarbonate was dissolved in deionized water to make 10.59 L to prepare a concentrated solution of B agent. The obtained concentrated solutions of A agent and B agent and deionized water were diluted and mixed in a ratio of 1:1.18:32.82 to prepare a dialysis solution. The composition of the obtained dialysis solution is shown in Table 5. In Table 5, "AcO ^- " represents the total acetate ion concentration, and the lower row shows the acetate ion concentration derived from acetic acid ("derived from acetic acid") and the acetate ion concentration derived from sodium acetate ("derived from sodium acetate") as a breakdown. In addition, "alkali" in Table 5 means the total concentration of bicarbonate ions and acetate ions derived from sodium acetate.

Claims (6)

A solid agent A for dialysis fluid, comprising sodium chloride, calcium chloride, magnesium chloride, potassium chloride, sodium acetate and acetic acid,
Sodium chloride, calcium chloride, magnesium chloride, potassium chloride and sodium acetate are included as granules containing sodium chloride, calcium chloride, magnesium chloride, potassium chloride and sodium acetate,
A solid agent A for dialysis fluid has a molar ratio of acetic acid:sodium acetate of 1:2.10-3.66, and when a dialysis fluid is prepared using a solid agent B for dialysis fluid containing sodium carbonate and deionized water to have a sodium ion concentration of 130-147 mEq/L and a bicarbonate ion concentration of 25-31 mEq/L, the total acetate ion concentration is 5.0-7.0 mEq/L and the acetate ion concentration derived from acetic acid is 1.5-2.0 mEq/L. The solid agent A for dialysis according to claim 1, which contains glucose . 3. The solid agent A for dialysis fluid according to claim 1 or 2, which contains sodium chloride, calcium chloride, magnesium chloride and potassium chloride as electrolytes, and when used as a dialysis fluid, the concentrations of the respective components are as follows: Na ⁺ : 133-145 mEq/L, K ⁺ : 1.80-2.50 mEq/L, Ca ²⁺ : 2.0-3.0 mEq/L, Mg ²⁺ : 1.0-1.5 mEq/L, Cl ^- : 105-115 mEq/L, and glucose: 100-150 mg/dL. A sodium bicarbonate solid preparation for dialysis comprising a combination of a solid agent A for dialysis fluid according to any one of claims 1 to 3 and a solid agent B for dialysis fluid containing sodium bicarbonate. A package in which the solid agent A for dialysis fluid according to any one of claims 1 to 3 is packaged in a packaging material having a multi-layer structure. The package according to claim 5, wherein the multi-layered packaging material includes a gas barrier layer as an intermediate layer.