Replacement liquid matched with nafamostat mesylate for injection and preparation method thereof

Abstract

The invention relates to the technical field of preparation of medical drugs, and discloses a preparation method of a replacement liquid matched with nafamostat mesylate for injection, which comprises the following steps: adding fresh water for injection into a preparation container, adding anhydrous dextrose in a prescription amount, stirring for dissolving, supplementing the fresh water for injection, and fixing the volume to a preparation amount to prepare a liquid A; regulating the pH value of the solution A to a proper pH value by using an acidic pH regulator; adding fresh water for injection into another preparation container, adding calcium chloride and magnesium chloride according to the prescription amount, stirring and dissolving, supplementing the fresh water for injection, and fixing the volume to the preparation amount to prepare a solution B; taking a preparation container, adding sodium bicarbonate, sodium chloride and potassium chloride according to the prescription dosage into the preparation container, stirring and dissolving, supplementing fresh water for injection to a constant volume to the preparation amount to prepare a solution C, regulating the solution C to a proper pH value by using a pH regulator, performing pre-filtration and terminal filtration on the solution A, the solution B and the solution C, respectively filling the solutions into each chamber of a three-chamber infusion bag according to the proportion of 2: 3: 95, and filling the three chambers of the three-chamber infusion bag into the three-chamber infusion bag. And plugging and sealing, and sterilizing in a water bath.

Description

Technical Field

[0001] The present invention relates to the technical field of medical drug preparation, and specifically relates to a replacement solution adapted to nafamostat mesilate for injection and a preparation method thereof. Background Art

[0002] Acute kidney injury (AKI), formerly known as acute renal failure (ARF), is a clinical syndrome characterized by a rapid decline in renal function caused by various etiologies. It can occur in patients without previous 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 2012 clinical guidelines for AKI issued by the Kidney Disease Improving Global Outcome (KDIGO), when patients present with life-threatening volume, electrolyte, and acid-base balance disorders, renal replacement therapy should be initiated emergently.

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

[0004] When nafamostat mesilate for injection is used for anticoagulation of the extracorporeal circulation circuit, based on its solubility characteristics, it first needs to be dissolved in 5% glucose injection solution. Before the start of extracorporeal circulation, 20 mg of dissolved nafamostat mesilate is injected into 500 ml of 0.9% sodium chloride injection solution to prime the extracorporeal circulation circuit for blood. After the start of extracorporeal circulation, the dissolved nafamostat mesilate is continuously injected at a rate of 20 - 50 mg per hour through the anticoagulant injection tube. In CRRT, on the one hand, to better dissolve nafamostat mesilate, 5% glucose injection solution needs to be used alone for dissolution. On the other hand, after the start of circulation, in addition to pumping in the traditional replacement solution, nafamostat mesilate also needs to be continuously pumped in through the anticoagulant injection tube. Therefore, when using the traditional replacement solution, with nafamostat mesilate as the anticoagulant, the cumbersome dilution steps and usage steps bring great trouble to clinical use. In view of the above problems and deficiencies, it is necessary to develop a new replacement solution adapted to nafamostat mesilate and a preparation method for this replacement solution. Summary of the Invention

[0005] In view of the deficiencies in the prior art, the present invention is solved by the following technical solutions: A method for preparing a replacement solution adapted to nafamostat mesilate for injection. S1. Add fresh injection water to a preparation container, add the prescribed amount of anhydrous glucose, stir to dissolve, and then make up with fresh injection water to the prescribed volume to prepare Solution A. Then adjust the pH value of Solution A to an appropriate value with an acidic pH regulator; S2. Add fresh injection water to another preparation container, add the prescribed amounts of calcium chloride and magnesium chloride, stir to dissolve, and then make up with fresh injection water to the prescribed volume to prepare Solution B; S3. Take another preparation container, add the prescribed amounts of sodium bicarbonate, sodium chloride, and potassium chloride, stir to dissolve, and then make up with fresh injection water to the prescribed volume to prepare Solution C. Then adjust the pH value of Solution C to an appropriate value with a pH regulator. S4. After pre-filtering and terminal filtering the said Solution A, Solution B, and Solution C, fill them into each chamber of a three-chamber infusion bag at a ratio of 2:3:95 respectively, stopper and seal, and sterilize in a water bath to obtain a three-chamber sodium bicarbonate hemofiltration replacement solution.

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

[0007] Preferably, the acidic pH regulator added to the raw materials of Solution A is one or a mixture of hydrochloric acid, lactic acid, and phosphoric acid, and the pH regulator added to the raw materials of Solution C is one or a mixture of hydrochloric acid, sodium hydroxide, and carbon dioxide.

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

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

[0010] Preferably, in the raw materials of Solution A, there is 50 g of anhydrous glucose, in the raw materials of Solution B, there are 6.13 g of calcium chloride and 5.08 g of magnesium chloride, and in the raw materials of Solution C, there are 3.09 g of sodium bicarbonate and 6.46 g of sodium chloride.

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

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

[0013] Preferably, the conditions for water bath sterilization are a temperature range of 118 °C to 126 °C and a time of 8 min to 20 min.

[0014] The replacement solution adapted to nafamostat mesilate for injection prepared according to the above preparation method includes solution A, where solution A includes 50 g of anhydrous glucose, an acidic pH regulator, and water for injection; solution B, where solution B includes 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; and solution C, where solution C includes 3.09 g of sodium bicarbonate, 6.46 g of sodium chloride, 0 g to 0.314 g of potassium chloride, a pH regulator, and water for injection.

[0015] Compared with the prior art, the beneficial effects of the present invention are as follows: The replacement solution prepared by this method contains 5% glucose in a separate chamber, and a certain volume can be directly drawn to dilute nafamostat mesilate without the need to additionally use a 5% glucose injection solution; the replacement solution is stored separately in chambers, and the quality is stable; the replacement solution has good compatibility with nafamostat mesilate. After the seams between the chambers are opened, the three-chamber liquid medicines are mixed evenly. The dissolved nafamostat mesilate is directly injected into the mixed replacement solution and then extracorporeal circulation is carried out, without the need to continuously pump it in through an anticoagulant injection tube. This provides great convenience for clinical use, wins time for the rescue of critically ill patients, and improves the rescue efficiency. Description of the Drawings

[0016] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will discuss the drawings required for the description of the embodiments or the prior art. Obviously, the technical solutions described in combination with the drawings are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other embodiments and their drawings can be obtained based on the embodiments shown in these drawings.

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

[0018] In the figure: 1 - solution chamber A, 2 - solution chamber B, 3 - solution chamber C, 4 - medicine adding port, 5 - medicine delivery port. Detailed Embodiments

[0019] The technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all embodiments. Based on the embodiments described in the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts fall within the scope of protection of the present invention.

[0020] In the embodiment of the present invention, for Example 1, add fresh injection water to a preparation container, add 50 g of anhydrous glucose, stir to dissolve, and then make up fresh injection water to a constant volume of 1000 ml to prepare Solution A. Then adjust the pH of Solution A to 2.3 with an appropriate amount of hydrochloric acid; add fresh injection water to another preparation container, add 3.39 g of magnesium chloride, stir to dissolve, and then make up fresh injection water to the preparation volume to prepare Solution B; take another preparation container, add 3.09 g of sodium bicarbonate, 6.46 g of sodium chloride and 0.157 g of potassium chloride thereto, stir to dissolve, and then make up fresh injection water to the preparation volume to prepare Solution C, and then adjust the pH of Solution C to 7.0 with dilute hydrochloric acid. After sequentially filtering Solution A, Solution B and Solution C through 0.45 μm and 0.22 μm microporous filters, they are respectively corresponding to Solution Chamber A1, Solution Chamber B2 and Solution Chamber C3 of a three-chamber infusion bag in a ratio of 2:3:95, and are filled into the corresponding chambers through the medicine adding port 4, such as Figure 1 , stopper and seal, and sterilize in a water bath at 118 °C to 126 °C for 8 to 20 minutes to obtain a three-chamber sodium bicarbonate hemofiltration replacement solution, the pH of the mixed solution of which is 7.1. Example 2

[0021] Add fresh injection water to a preparation container, add 50 g of anhydrous glucose, stir to dissolve, and then make up fresh injection water to a constant volume of 1000 ml to prepare Solution A. Then adjust the pH of Solution A to 2.3 with an appropriate amount of hydrochloric acid; add fresh injection water to another preparation container, add 6.13 g of calcium chloride and 5.08 g of magnesium chloride, stir to dissolve, and then make up fresh injection water to the preparation volume to prepare Solution B; take another preparation container, add 3.09 g of sodium bicarbonate, 6.46 g of sodium chloride and 0.314 g of potassium chloride thereto, stir to dissolve, and then make up fresh injection water to the preparation volume to prepare Solution C, and then adjust the pH of Solution C to 7.0 with dilute hydrochloric acid. After sequentially filtering Solution A, Solution B and Solution C through 0.45 μm and 0.22 μm microporous filters, they are respectively corresponding to Solution Chamber A1, Solution Chamber B2 and Solution Chamber C3 of a three-chamber infusion bag in a ratio of 2:3:95, and are filled into the corresponding chambers through the medicine adding port 4, stopper and seal, and sterilize in a water bath at 118 °C to 126 °C for 8 to 20 minutes to obtain a three-chamber sodium bicarbonate hemofiltration replacement solution, the pH of the mixed solution of which is 7.1. Example 3

[0022] Add fresh water for injection into a preparation container, add 50 g of anhydrous glucose, stir to dissolve, then make up with fresh water for injection to a volume of 1000 ml to prepare Solution A. Then adjust the pH of Solution A to 3.3 with an appropriate amount of hydrochloric acid. Add fresh water for injection into another preparation container, add 6.13 g of calcium chloride and 5.08 g of magnesium chloride, stir to dissolve, and then make up with fresh water for injection to the preparation volume to prepare Solution B. Take another preparation container, add 3.09 g of sodium bicarbonate and 6.46 g of sodium chloride, stir to dissolve, and then make up with fresh water for injection to the preparation volume to prepare Solution C. Then adjust the pH of Solution C to 7.0 with dilute hydrochloric acid. Filter Solution A, Solution B, and Solution C successively through 0.45 μm and 0.22 μm microporous filters, and then fill them into the solution chambers A1, B2, and C3 of the three-chamber infusion bag at a ratio of 2:3:95 respectively through the medicine adding port 4, add stoppers and seal. Sterilize in a water bath at 118 °C - 126 °C for 8 - 20 min to obtain a three-chamber sodium bicarbonate hemofiltration replacement solution with a mixed solution pH of 7.2. Example 4

[0023] Add fresh water for injection into a preparation container, add 50 g of anhydrous glucose, stir to dissolve, then make up with fresh water for injection to a volume of 1000 ml to prepare Solution A. Then adjust the pH of Solution A to 2.3 with an appropriate amount of hydrochloric acid. Add fresh water for injection into another preparation container, add 4.07 g of magnesium chloride, stir to dissolve, and then make up with fresh water for injection to the preparation volume to prepare Solution B. Take another preparation container, add 3.09 g of sodium bicarbonate, 6.46 g of sodium chloride and 0.314 g of potassium chloride, stir to dissolve, and then make up with fresh water for injection to the preparation volume to prepare Solution C. Then adjust the pH of Solution C to 7.4 with carbon dioxide. Filter Solution A, Solution B, and Solution C successively through 0.45 μm and 0.22 μm microporous filters, and then fill them into the solution chambers A1, B2, and C3 of the three-chamber infusion bag at a ratio of 2:3:95 respectively through the medicine adding port 4, add stoppers and seal. Sterilize in a water bath at 118 °C - 126 °C for 8 - 20 min to obtain a three-chamber sodium bicarbonate hemofiltration replacement solution with a mixed solution pH of 7.4. Example 5

[0024] Add fresh water for injection into a preparation container, add 55 g of anhydrous glucose, stir to dissolve, and then make up with fresh water for injection to a volume of 1000 ml to prepare Solution A. Then adjust the pH of Solution A to 3.3 with an appropriate amount of hydrochloric acid; add fresh water for injection into another preparation container, add 8.58 g of calcium chloride and 3.39 g of magnesium chloride, stir to dissolve, and then make up with fresh water for injection to the preparation volume to prepare Solution B; take another preparation container, add 3.09 g of sodium bicarbonate, 6.46 g of sodium chloride and 0.157 g of potassium chloride, stir to dissolve, and then make up with fresh water for injection to the preparation volume to prepare Solution C. Then adjust the pH of Solution C to 7.4 with carbon dioxide. Filter Solution A, Solution B and Solution C successively through 0.45 μm and 0.22 μm microporous filters, and then respectively correspond to Solution Chamber A1, Solution Chamber B2 and Solution Chamber C3 of a three-chamber infusion bag in a ratio of 2:3:95, and fill them into the corresponding chambers through the medicine adding port 4, stopper and seal, and sterilize in a water bath at 118 °C - 126 °C for 8 - 20 min to obtain a three-chamber sodium bicarbonate hemofiltration replacement solution, and the pH of the mixed solution is 7.4.

[0025]

[0026] Performance test By comparing the pH values and the contents of 5-hydroxymethylfurfural of the sodium bicarbonate hemofiltration replacement solutions prepared in Examples 1 - 5 and commercially available CRRT products, evaluate whether the glucose degradation product 5-hydroxymethylfurfural of the hemofiltration replacement solution prepared by the present invention is reduced.

[0027] Dissolve commercially available nafamostat mesilate for injection respectively with Solution A (5% glucose) in the three-chamber sodium bicarbonate hemofiltration replacement solutions prepared in Examples 1 - 5, and then add it to the sodium bicarbonate hemofiltration replacement solutions (mixed solutions) prepared in each example at a ratio of 17 mg / 500 ml according to the clinical dosage in its instruction manual and the clinical usage dosage of CRRT products. Place it at 37 °C for 4 h, and monitor the changes of solution properties, insoluble particles, etc., and preliminarily evaluate the compatibility between the self-made sodium bicarbonate hemofiltration replacement solution and nafamostat mesilate during use. The specific results are shown in Table 1.

[0028] Table 1 Changes in properties, pH values and insoluble particles before and after adding nafamostat mesilate in Examples 1 - 5

[0029] As can be seen from the results in Table 1, compared with the sodium bicarbonate hemofiltration replacement solution prepared in Examples 1-5, the pH value and the content of 5-hydroxymethylfurfural of the commercially available CRRT products are relatively large. Since the glucose is in a separate chamber in the three-chamber hemofiltration replacement solution prepared in Examples 1-5, separated from inorganic salts such as calcium chloride, magnesium chloride, and sodium chloride, and a pH regulator is added to adjust it to maintain a relatively stable pH value, the degradation products thereof are relatively reduced. After the three-chamber hemofiltration replacement solution prepared in Examples 1-5 was mixed and mesylate nafamostat after dissolution was added, there were no significant changes in the properties, pH value, and insoluble particles of the mixed solution before and after the addition; and the mixed solution containing mesylate nafamostat was kept at 37 °C for 4 h, and there were no obvious changes in the properties and insoluble particles of the mixed solution, which can preliminarily evaluate that there is good compatibility between the self-made sodium bicarbonate hemofiltration replacement solution and mesylate nafamostat during use.

[0030] Therefore, the dissolved mesylate nafamostat can be directly injected into the mixed replacement solution and then extracorporeal circulation can be carried out, without the need to continuously pump it in through an anticoagulant injection tube. It can provide great convenience for clinical use. It is more convenient to directly output through the medicine injection port 5 of the three-chamber infusion bag, winning precious time for the rescue of critically ill patients.

[0031] For those skilled in the art, it is obvious that the present invention is not limited to the details of the above exemplary embodiments, and the present invention can be implemented in other specific forms without departing from the spirit or basic characteristics of the present invention. Therefore, from any point of view, the embodiments should be regarded as exemplary and non-restrictive. The scope of the present invention is defined by the appended claims rather than the above description. Therefore, all changes falling within the meaning and scope of the equivalent elements of the claims are intended to be embraced within the present invention. Any reference signs in the claims should not be regarded as limiting the claims involved.

[0032] In addition, it should be understood that although this specification is described according to embodiments, not each embodiment only contains an independent technical solution. This narrative way of the specification is only for clarity. Those skilled in the art should regard the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A preparation method of a replacement solution adapted to nafamostat mesilate for injection, characterized in that: S1. Add fresh injection water into a preparation container, add the prescribed amount of anhydrous glucose, stir to dissolve, then supplement with fresh injection water to make up to the preparation volume to prepare Solution A, and then adjust the pH value of Solution A to an appropriate value with an acidic pH regulator; S2. Add fresh injection water into another preparation container, add the prescribed amounts of calcium chloride and magnesium chloride, stir to dissolve, then supplement with fresh injection water to make up to the preparation volume to prepare Solution B; S3. Take another preparation container, add the prescribed amounts of sodium bicarbonate, sodium chloride and potassium chloride into it, stir to dissolve, then supplement with fresh injection water to make up to the preparation volume to prepare Solution C, and then adjust the pH value of Solution C to an appropriate value with a pH regulator, S4. After pre-filtering and terminal filtering the above-mentioned Solution A, Solution B and Solution C, fill them into each chamber of a three-chamber infusion bag at a ratio of 2:3:95 respectively, stopper and seal, and sterilize in a water bath to obtain a three-chamber sodium bicarbonate hemofiltration replacement solution.

2. The preparation method of the replacement fluid adapted to nafamostat mesilate for injection according to claim 1, characterized in that: The pH value of the said Solution A is 2.3 - 3.3, the pH value of the said Solution C is 7.0 - 7.4, and the pH value of the three-chamber mixed solution is 7.0 - 7.

5.

3. The preparation method of the replacement fluid adapted to nafamostat mesilate for injection according to claim 1, characterized in that: The acidic pH regulator added to the raw materials of Solution A is one or a mixture of hydrochloric acid, lactic acid, and phosphoric acid, and the pH regulator added to the raw materials of Solution C is one or a mixture of hydrochloric acid, sodium hydroxide, and carbon dioxide.

4. The preparation method of the replacement solution adapted to nafamostat mesilate for injection according to claim 1, characterized in that: In the raw materials of Solution A, there is 50 g of anhydrous glucose, in the raw materials of Solution B, there is 3.39 g of magnesium chloride, and in the raw materials of Solution C, there are 3.09 g of sodium bicarbonate, 6.46 g of sodium chloride, and 0.157 g of potassium chloride.

5. The preparation method of the replacement fluid adapted to nafamostat mesilate for injection according to claim 1, characterized in that: In the raw materials of Solution A, there is 50 g of anhydrous glucose, in the raw materials of Solution B, there are 6.13 g of calcium chloride and 5.08 g of magnesium chloride, and in the raw materials of Solution C, there are 3.09 g of sodium bicarbonate, 6.46 g of sodium chloride, and 0.314 g of potassium chloride.

6. The preparation method of the replacement fluid adapted to nafamostat mesilate for injection according to claim 1, characterized in that: In the raw materials of Solution A, there is 50 g of anhydrous glucose, in the raw materials of Solution B, there are 6.13 g of calcium chloride and 5.08 g of magnesium chloride, and in the raw materials of Solution C, there are 3.09 g of sodium bicarbonate and 6.46 g of sodium chloride.

7. The preparation method of the replacement fluid adapted to nafamostat mesilate for injection according to claim 1, characterized in that: In the raw materials of Solution A, there is 50 g of anhydrous glucose, in the raw materials of Solution B, there is 4.07 g of magnesium chloride, and in the raw materials of Solution C, there are 3.09 g of sodium bicarbonate, 6.46 g of sodium chloride, and 0.314 g of potassium chloride.

8. The preparation method of the replacement fluid adapted to nafamostat mesilate for injection according to claim 1, characterized in that: In the raw materials of Solution A, there is 50 g of anhydrous glucose, in the raw materials of Solution B, there are 8.58 g of calcium chloride and 3.39 g of magnesium chloride, and in the raw materials of Solution C, there are 3.09 g of sodium bicarbonate, 6.46 g of sodium chloride, and 0.157 g of potassium chloride.

9. The preparation method of the replacement fluid adapted to nafamostat mesilate for injection according to claim 1, wherein: The conditions for water bath sterilization are a temperature range of 118°C - 126°C and a time of 8 min - 20 min.

10. A replacement solution adapted to nafamostat mesilate for injection, prepared by the preparation method according to any one of the above, characterized in that: It includes Solution A, the said Solution A includes 50 g of anhydrous glucose, an acidic pH regulator and injection water, Solution B, the said Solution B includes 0 g - 8.58 g of calcium chloride dihydrate, 3.39 g - 5.08 g of magnesium chloride hexahydrate and injection water, Solution C, the said Solution C includes 3.09 g of sodium bicarbonate, 6.46 g of sodium chloride, 0 g - 0.314 g of potassium chloride, a pH regulator and injection water.

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