A displacement solution matched with nafamostat mesilate for injection and a preparation method thereof

Abstract

The application relates to the technical field of medical medicine preparation, and discloses a preparation method of a replacement solution matched with nafamostat mesilate for injection, wherein fresh water for injection is added into a preparation container, a prescription amount of anhydrous glucose is added, fresh water for injection is supplemented after stirring and dissolving, and the preparation container is filled with fresh water for injection to a preparation amount to prepare A liquid, the A liquid is adjusted to a suitable pH value by using an acidic pH adjuster; fresh water for injection is added into another preparation container, a prescription amount of calcium chloride and magnesium chloride is added, fresh water for injection is supplemented after stirring and dissolving, and the preparation container is filled with fresh water for injection to a preparation amount to prepare B liquid; another preparation container is taken, a prescription amount of sodium bicarbonate, sodium chloride and potassium chloride is added into the preparation container, fresh water for injection is supplemented after stirring and dissolving, and the preparation container is filled with fresh water for injection to a preparation amount to prepare C liquid, the C liquid is adjusted to a suitable pH value by using a pH adjuster, the A liquid, the B liquid and the C liquid are pre-filtered and finally filtered, the A liquid, the B liquid and the C liquid are respectively filled into cavities of a three-chamber infusion bag at a proportion of 2:3:95, stoppers are sealed, and water bath sterilization is carried out.

Description

TECHNICAL FIELD

[0001] The application relates to the technical field of medical medicine preparation, in particular to a replacement solution matched with nafamostat mesilate for injection and a preparation method thereof. BACKGROUND

[0002] Acute kidney injury (AKI), formerly known as acute renal failure (ARF), is a clinical syndrome caused by rapid decline in renal function due to various causes. It can occur in people without kidney disease, or on the basis of pre-existing chronic kidney disease. In the intensive care unit, the incidence of AKI is as high as 30%. According to the AKI clinical guidelines released by the Kidney Disease Improving Global Outcome (KDIGO) in 2012, when patients have life-threatening volume, electrolyte, and acid-base balance disorders, emergency renal replacement therapy should be started.

[0003] In continuous renal replacement therapy (CRRT), replacement fluid plays a key role in balancing volume and regulating solutes. During treatment, complications such as bleeding or thrombosis may occur. To prevent the occurrence of this complication, doctors need to use anticoagulants reasonably. Nafamostat mesilate is an anticoagulant with the advantages of strong anticoagulant activity, short half-life, and fewer bleeding complications.

[0004] When nafamostat mesilate for injection is used for anticoagulation in extracorporeal circulation, based on its solubility characteristics, 5% glucose injection is first used for dissolution. Before the start of extracorporeal circulation, 20 mg of dissolved nafamostat mesilate is injected into 500 ml of 0.9% sodium chloride injection to pre-charge the blood extracorporeal circulation loop. After the start of extracorporeal circulation, the dissolved nafamostat mesilate is continuously injected through the anticoagulant injection tube at a rate of 20-50 mg per hour. In CRRT, on the one hand, 5% glucose injection is needed to dissolve nafamostat mesilate separately, and on the other hand, in addition to the traditional replacement fluid, nafamostat mesilate needs to be continuously pumped through the anticoagulant injection tube. Therefore, when using the traditional replacement fluid, nafamostat mesilate as an anticoagulant, the complicated dilution and use steps cause great inconvenience to clinical use. In view of the above problems and deficiencies, a new type of replacement fluid matched with nafamostat mesilate and a preparation method of the replacement fluid need to be developed. SUMMARY

[0005] The present application is directed to the deficiencies in the prior art, the present application is solved by the following technical scheme: a preparation method of a replacement fluid matched with nafamostat mesylate for injection, S1, fresh water for injection is added to a preparation container, a prescription amount of anhydrous glucose is added, after stirring and dissolving, fresh water for injection is supplemented to constant volume to prepare A liquid, and the A liquid is adjusted to a suitable pH value by using an acidic pH adjuster; S2, fresh water for injection is added to another preparation container, a prescription amount of calcium chloride and magnesium chloride is added, after stirring and dissolving, fresh water for injection is supplemented to constant volume to prepare B liquid; S3, another preparation container is taken, a prescription amount of sodium bicarbonate, sodium chloride and potassium chloride is added, after stirring and dissolving, fresh water for injection is supplemented to constant volume to prepare C liquid, and the C liquid is adjusted to a suitable pH value by using a pH adjuster, S4, after the A liquid, the B liquid and the C liquid are pre-filtered and finally filtered, they are respectively filled into the cavities of a three-chamber infusion bag at a ratio of 2:3:95, stoppers are sealed, and water bath sterilization is carried out, so as to obtain a three-chamber sodium bicarbonate hemofiltration replacement fluid.

[0006] Preferably, the pH value of the A liquid is 2.3-3.3, the pH value of the C liquid is 7.0-7.4, and the pH value of the three-chamber mixed liquid is 7.0-7.5.

[0007] Preferably, the acidic pH value adjuster added in the raw material of the A liquid is one or a mixture of hydrochloric acid, lactic acid and phosphoric acid, and the pH adjuster added in the raw material of the C liquid is one or a mixture of hydrochloric acid, sodium hydroxide and carbon dioxide.

[0008] Preferably, the anhydrous glucose in the raw material of the A liquid is 50g, the magnesium chloride in the raw material of the B liquid is 3.39g, and the sodium bicarbonate, sodium chloride and potassium chloride in the raw material of the C liquid are 3.09g, 6.46g and 0.157g respectively.

[0009] Preferably, the anhydrous glucose in the raw material of the A liquid is 50g, the calcium chloride and the magnesium chloride in the raw material of the B liquid are 6.13g and 5.08g respectively, and the sodium bicarbonate, sodium chloride and potassium chloride in the raw material of the C liquid are 3.09g, 6.46g and 0.314g respectively.

[0010] Preferably, the anhydrous glucose in the raw material of the A liquid is 50g, the calcium chloride and the magnesium chloride in the raw material of the B liquid are 6.13g and 5.08g respectively, and the sodium bicarbonate, sodium chloride and potassium chloride in the raw material of the C liquid are 3.09g, 6.46g and 0.314g respectively.

[0011] Preferably, the anhydrous glucose in the raw material of the A liquid is 50g, the magnesium chloride in the raw material of the B liquid is 4.07g, and the sodium bicarbonate, sodium chloride and potassium chloride in the raw material of the C liquid are 3.09g, 6.46g and 0.314g respectively.

[0012] Preferably, the A liquid raw material is 50g of anhydrous glucose, the B liquid raw material is 8.58g of calcium chloride, 3.39g of magnesium chloride, and the C liquid raw material is 3.09g of sodium bicarbonate, 6.46g of sodium chloride, and 0.157g of potassium chloride.

[0013] Preferably, the water bath sterilization condition is a temperature range of 118-126℃ and a time of 8-20min.

[0014] The replacement fluid prepared by the preparation method and suitable for nafamostat mesylate for injection comprises an A liquid, the A liquid comprising 50g of anhydrous glucose, an acid pH value regulator, and injection water, a B liquid, the B liquid comprising 0-8.58g of calcium chloride dihydrate, 3.39-5.08g of magnesium chloride hexahydrate, and injection water, and a C liquid, the C liquid comprising 3.09g of sodium bicarbonate, 6.46g of sodium chloride, 0-0.314g of potassium chloride, a pH value regulator, and injection water.

[0015] Compared with the prior art, the replacement fluid prepared by the method contains 5% glucose in a separate chamber, can be directly extracted to a certain volume and used to dilute nafamostat mesylate, and does not need to use 5% glucose injection additionally; the replacement fluid is stored in chambers respectively, and the quality is stable; the replacement fluid has good compatibility with nafamostat mesylate, the chambers are mixed uniformly after the joint between the chambers is opened, nafamostat mesylate is directly injected into the mixed replacement fluid for extracorporeal circulation, and there is no need to continuously pump in through an anticoagulant injection tube, which provides great convenience for clinical use, saves time for rescue of critical patients, and improves rescue efficiency. BRIEF DESCRIPTION OF DRAWINGS

[0016] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the drawings needed to be used in the embodiments or prior art description will be described below. Obviously, the technical solutions described in the description in combination with the drawings are only some embodiments of the present application, and other embodiments and drawings thereof can be obtained by those skilled in the art without creative effort.

[0017] Figure 1 is a structural schematic diagram of a three-chamber infusion bag used in the present application.

[0018] In the figure, 1 is a solution chamber A, 2 is a solution chamber B, 3 is a solution chamber C, 4 is a medicine adding port, and 5 is a medicine infusion port. DETAILED DESCRIPTION

[0019] The technical solutions of the embodiments of the present application will be clearly and completely described below with reference to the drawings. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments described in the present application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of the present application.

[0020] In the embodiment of the present application, fresh water for injection is added into a preparation container, 50 g of anhydrous glucose is added, and after stirring and dissolving, fresh water for injection is added to make up to 1000 ml to prepare A liquid. The A liquid is adjusted to pH 2.3 by adding appropriate hydrochloric acid. Fresh water for injection is added into another preparation container, 3.39 g of magnesium chloride is added, and after stirring and dissolving, fresh water for injection is added to make up to the preparation volume to prepare B liquid. Another preparation container is taken, 3.09 g of sodium bicarbonate, 6.46 g of sodium chloride and 0.157 g of potassium chloride are added into the preparation container, and after stirring and dissolving, fresh water for injection is added to make up to the preparation volume to prepare C liquid. The C liquid is adjusted to pH 7.0 by adding dilute hydrochloric acid. The A liquid, the B liquid and the C liquid are filtered through 0.45 μm and 0.22 μm microporous filter cores in sequence, and are respectively added into solution chamber A1, solution chamber B2 and solution chamber C3 of a three-chamber infusion bag in a ratio of 2:3:95 through a medicine adding port 4, and are filled into the corresponding chambers. Figure 1 The preparation container is sealed with a plug, and is sterilized in a water bath at 118 ℃ to 126 ℃ for 8 to 20 min to obtain a three-chamber sodium bicarbonate hemofiltration replacement fluid, and the mixed liquid has a pH of 7.1. Example 2

[0021] In the embodiment of the present application, fresh water for injection is added into a preparation container, 50 g of anhydrous glucose is added, and after stirring and dissolving, fresh water for injection is added to make up to 1000 ml to prepare A liquid. The A liquid is adjusted to pH 2.3 by adding appropriate hydrochloric acid. Fresh water for injection is added into another preparation container, 3.39 g of magnesium chloride is added, and after stirring and dissolving, fresh water for injection is added to make up to the preparation volume to prepare B liquid. Another preparation container is taken, 3.09 g of sodium bicarbonate, 6.46 g of sodium chloride and 0.157 g of potassium chloride are added into the preparation container, and after stirring and dissolving, fresh water for injection is added to make up to the preparation volume to prepare C liquid. The C liquid is adjusted to pH 7.0 by adding dilute hydrochloric acid. The A liquid, the B liquid and the C liquid are filtered through 0.45 μm and 0.22 μm microporous filter cores in sequence, and are respectively added into solution chamber A1, solution chamber B2 and solution chamber C3 of a three-chamber infusion bag in a ratio of 2:3:95 through a medicine adding port 4, and are filled into the corresponding chambers. Example 3

[0022] Into a preparation container, add fresh water for injection, add 50 g of anhydrous glucose, after stirring and dissolving, add fresh water for injection to constant volume of 1000 ml to prepare A liquid, then adjust the A liquid to pH 3.3 with appropriate amount of hydrochloric acid; into another preparation container, add fresh water for injection, add calcium chloride 6.13 g, magnesium chloride 5.08 g, after stirring and dissolving, add fresh water for injection to constant volume to prepare B liquid; take another preparation container, add sodium bicarbonate 3.09 g, sodium chloride 6.46 g into it, after stirring and dissolving, add fresh water for injection to constant volume to prepare C liquid, then adjust the C liquid to pH 7.0 with dilute hydrochloric acid. After filtering A liquid, B liquid and C liquid through 0.45 μm, 0.22 μm microporous filter in turn, in the proportion of 2:3:95, respectively corresponding to the solution chamber A1, solution chamber B2, solution chamber C3 of three-chamber infusion bag, and filling into the corresponding chambers through the medicine inlet 4, plug sealing, water bath sterilization at 118℃-126℃ for 8-20 min, to obtain three-chamber sodium bicarbonate hemofiltration replacement fluid, and the mixed liquid pH is 7.2. Example 4

[0023] Into a preparation container, add fresh water for injection, add 50 g of anhydrous glucose, after stirring and dissolving, add fresh water for injection to constant volume of 1000 ml to prepare A liquid, then adjust the A liquid to pH 2.3 with appropriate amount of hydrochloric acid; into another preparation container, add fresh water for injection, add magnesium chloride 4.07 g, after stirring and dissolving, add fresh water for injection to constant volume to prepare B liquid; take another preparation container, add sodium bicarbonate 3.09 g, sodium chloride 6.46 g and potassium chloride 0.314 g into it, after stirring and dissolving, add fresh water for injection to constant volume to prepare C liquid, then adjust the C liquid to pH 7.4 with carbon dioxide. After filtering A liquid, B liquid and C liquid through 0.45 μm, 0.22 μm microporous filter in turn, in the proportion of 2:3:95, respectively corresponding to the solution chamber A1, solution chamber B2, solution chamber C3 of three-chamber infusion bag, and filling into the corresponding chambers through the medicine inlet 4, plug sealing, water bath sterilization at 118℃-126℃ for 8-20 min, to obtain three-chamber sodium bicarbonate hemofiltration replacement fluid, and the mixed liquid pH is 7.4. Example 5

[0024] Into a preparation container, add fresh water for injection, add 55 g of anhydrous glucose, after stirring and dissolving, supplement with fresh water for injection to make up to 1000 ml to prepare A liquid, and then adjust the A liquid to pH 3.3 with appropriate amount of hydrochloric acid; into another preparation container, add fresh water for injection, add calcium chloride 8.58 g, magnesium chloride 3.39 g, stir and dissolve, then supplement with fresh water for injection to make up to the preparation amount to prepare B liquid; take another preparation container, add sodium bicarbonate 3.09 g, sodium chloride 6.46 g and potassium chloride 0.157 g, stir and dissolve, then supplement with fresh water for injection to make up to the preparation amount to prepare C liquid, and then adjust the C liquid to pH 7.4 with carbon dioxide. Filter A liquid, B liquid and C liquid through 0.45 μm and 0.22 μm microporous filter cartridges in sequence, and then add into the solution chamber A1, solution chamber B2 and solution chamber C3 of the three-chamber infusion bag in the proportion of 2:3:95 respectively through the medicine inlet 4, and then seal with plugs, and then sterilize in water bath at 118 ℃-126 ℃ for 8-20 min to obtain a three-chamber sodium bicarbonate hemofiltration replacement fluid, and the pH of the mixed liquid is 7.4.

[0025]

[0026] Performance test

[0027] By comparing the pH value and the content of 5-hydroxymethyl furfural of the sodium bicarbonate hemofiltration replacement fluid prepared in Examples 1-5 and the commercially available CRRT product, whether the content of the glucose degradation product 5-hydroxymethyl furfural of the hemofiltration replacement fluid prepared in the application is reduced is evaluated.

[0028] According to the clinical dosage of the nafamostat mesylate for injection and the clinical dosage of the CRRT product, the commercially available nafamostat mesylate for injection is dissolved in the A liquid (5% glucose) of the three-chamber sodium bicarbonate hemofiltration replacement fluid prepared in Examples 1-5, and then added into the sodium bicarbonate hemofiltration replacement fluid (mixed liquid) prepared in each example in the proportion of 17 mg / 500 ml, and then placed at 37 ℃ for 4 h, and then the changes of the solution properties, insoluble particles and the like are monitored, and the compatibility of the self-prepared sodium bicarbonate hemofiltration replacement fluid with nafamostat mesylate during use is preliminarily evaluated. The specific results are shown in Table 1.

[0029] Table 1 Changes of properties, pH value and insoluble particles before and after adding nafamostat mesylate in each of Examples 1-5

[0030]

[0031] From the results of Table 1, compared with the sodium bicarbonate hemofiltration replacement fluid prepared in Examples 1-5, the pH value and the content of 5-hydroxymethyl furfural of the commercially available CRRT product are relatively large. The three-chambered hemofiltration replacement fluid prepared in Examples 1-5 has a relatively reduced degradation product because the glucose is in a separate chamber, separated from the inorganic salts such as calcium chloride, magnesium chloride, sodium chloride, and the pH value is adjusted to a relatively stable pH value by adding a pH value adjusting agent. The three-chambered hemofiltration replacement fluid prepared in Examples 1-5 is mixed and then the nafamostat mesylate is added after being dissolved. Before and after the addition, the properties, pH value and insoluble particles of the mixed solution do not change significantly. The mixed solution containing nafamostat mesylate is kept at 37°C for 4h, and the properties and insoluble particles of the mixed solution do not change significantly, which can preliminarily evaluate that the self-prepared sodium bicarbonate hemofiltration replacement fluid has good compatibility with nafamostat mesylate during use.

[0032] Therefore, the dissolved nafamostat mesylate can be directly injected into the mixed replacement fluid for extracorporeal circulation, without the need for additional continuous pumping through the anticoagulant injection tube, which can provide great convenience for clinical use, and the drug can be more conveniently output through the drug output port 5 of the three-chambered infusion bag, which can win valuable time for the rescue of critically ill patients.

[0033] It will be obvious to a person skilled in the art that, without departing from the spirit or essential characteristics of the application, the present application can be implemented in other specific forms. The present examples are therefore to be considered in all respects as illustrative and not restrictive, the scope of the application being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalents are intended to be embraced therein. Any reference signs in the claims should not be construed as limiting the scope of the claims.

[0034] In addition, it should be understood that, although the present specification is described in terms of embodiments, not every embodiment contains only one independent technical solution, and the description of the specification is only for the sake of clarity, and those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can be appropriately combined to form other embodiments that those skilled in the art can understand.

Claims

1. A method for the preparation of a displacement solution adapted to nafamostat mesylate for injection, characterized by: S1, adding fresh water for injection into a preparation container, adding the prescription amount of anhydrous glucose, dissolving after stirring, supplementing with fresh water for injection to constant volume to prepare A liquid, and adjusting the A liquid to a suitable pH value with an acidic pH adjuster; S2, adding fresh water for injection into another preparation container, adding 0g-8.58g of calcium chloride dihydrate and 3.39g-5.08g of magnesium chloride hexahydrate, dissolving after stirring, and supplementing with fresh water for injection to constant volume to prepare B liquid; S3, taking another preparation container, adding 3.09g of sodium bicarbonate, 6.46g of sodium chloride and 0g-0.314g of potassium chloride, dissolving after stirring, supplementing with fresh water for injection to constant volume to prepare C liquid, and adjusting the C liquid to a suitable pH value with a pH adjuster; S4, after pre-filtering and terminal filtering of the A liquid, the B liquid and the C liquid, filling them into the respective chambers of a three-chamber infusion bag in a ratio of 2:3:95, sealing with a plug, and obtaining a three-chamber sodium bicarbonate hemofiltration replacement fluid through water bath sterilization.

2. The method for preparing a displacement solution adapted to nafamostat mesylate for injection according to claim 1, characterized by: The pH value of the A liquid is 2.3-3.3, the pH value of the C liquid is 7.0-7.4, and the pH value of the three-chamber mixed liquid is 7.0-7.

5.

3. The method for preparing a displacement solution adapted to nafamostat mesylate for injection according to claim 1, characterized by: The acidic pH adjuster added in the A liquid raw material is one or a mixture of hydrochloric acid, lactic acid and phosphoric acid, and the pH adjuster added in the C liquid raw material is one or a mixture of hydrochloric acid, sodium hydroxide and carbon dioxide.

4. The method for preparing a displacement solution adapted to nafamostat mesylate for injection according to claim 1, characterized by: The A liquid raw material contains 50g of anhydrous glucose, the B liquid raw material contains 3.39g of magnesium chloride, and the C liquid raw material contains 3.09g of sodium bicarbonate, 6.46g of sodium chloride and 0.157g of potassium chloride.

5. The method for preparing a displacement solution adapted to nafamostat mesylate for injection according to claim 1, characterized by: The A liquid raw material contains 50g of anhydrous glucose, the B liquid raw material contains 6.13g of calcium chloride and 5.08g of magnesium chloride, and the C liquid raw material contains 3.09g of sodium bicarbonate, 6.46g of sodium chloride and 0.314g of potassium chloride.

6. The method for preparing a displacement solution adapted to nafamostat mesylate for injection according to claim 1, characterized by: The A liquid raw material contains 50g of anhydrous glucose, the B liquid raw material contains 6.13g of calcium chloride and 5.08g of magnesium chloride, and the C liquid raw material contains 3.09g of sodium bicarbonate, 6.46g of sodium chloride and 0g of potassium chloride.

7. The method for preparing a displacement solution adapted to nafamostat mesylate for injection according to claim 1, characterized by: The A liquid raw material contains 50g of anhydrous glucose, the B liquid raw material contains 4.07g of magnesium chloride, and the C liquid raw material contains 3.09g of sodium bicarbonate, 6.46g of sodium chloride and 0.314g of potassium chloride.

8. The method for preparing a displacement solution adapted to nafamostat mesylate for injection according to claim 1, characterized by: The A liquid raw material contains 50g of anhydrous glucose, the B liquid raw material contains 8.58g of calcium chloride and 3.39g of magnesium chloride, and the C liquid raw material contains 3.09g of sodium bicarbonate, 6.46g of sodium chloride and 0.157g of potassium chloride.

9. The method for preparing a displacement solution adapted to nafamostat mesylate for injection according to claim 1, characterized by: The water bath sterilization conditions are a temperature range of 118℃-126℃ and a time of 8min-20min.

10. The replacement fluid adapted to nafamostat mesylate for injection prepared according to the preparation method of any one of the above, characterized in that: A liquid comprising 50 g of anhydrous glucose, an acidic pH adjuster and water for injection, a B liquid comprising 0 g to 8.58 g of calcium chloride dihydrate, 3.39 g to 5.08 g of magnesium chloride hexahydrate and water for injection, a C liquid comprising 3.09 g of sodium bicarbonate, 6.46 g of sodium chloride, 0 g to 0.314 g of potassium chloride, a pH adjuster and water for injection.

Images