A hemodialysis concentrate and preparation method thereof

Abstract

The present invention provides a hemodialysis concentrate and a preparation method thereof, belonging to the technical field of pharmaceutical preparations, the hemodialysis concentrate includes liquid A and liquid B; liquid A includes sodium chloride, potassium chloride, magnesium chloride, calcium chloride and citric acid; liquid B includes sodium bicarbonate; the method for preparing liquid A is: sodium chloride, potassium chloride, calcium chloride and magnesium chloride are added to dialysis water, and the feed is fed once, stirred evenly and then filtered in a circulation manner; after the quality inspection is qualified, citric acid is added for secondary feeding, pH=1.5~1.7 is controlled, stirred and circulated, and liquid A is obtained after the citric acid is tested and qualified; the method for preparing liquid B is: sodium bicarbonate is added to dialysis water, stirred evenly and then filtered in a circulation manner, and liquid B is obtained after the quality inspection is qualified. The present invention uses citric acid as the acid solution of liquid A, adopts secondary feeding when preparing liquid A, adjusts the addition order of the liquid preparation raw materials, and controls the temperature and pH value, so as to prepare a hemodialysis concentrate with high stability and strong quality and safety.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a hemodialysis concentrate and a preparation method thereof. Background Art

[0002] Hemodialysis concentrate is clinically used for hemodialysis treatment to correct electrolyte and acid-base imbalances in patients, remove some uremic toxins in the blood, and is suitable for the treatment of acute renal failure, chronic renal failure, etc. Hemodialysis concentrate consists of liquid A and liquid B. The traditional liquid A consists of sodium chloride, calcium chloride, potassium chloride, magnesium chloride and acetic acid; liquid B consists of sodium bicarbonate and / or sodium chloride. Since acetic acid can easily cause calcium and magnesium deposition in hemodialysis concentrate, existing research focuses on improving the acidic substances in liquid A.

[0003] Citric acid is a physiological acid that normally exists in the human body. It participates in the tricarboxylic acid cycle and can be rapidly metabolized in the body. Citrate ions can chelate with free calcium ions in the blood to form a soluble complex that is difficult to dissociate, thereby reducing the calcium ion concentration in the blood and blocking the coagulation cascade reaction, thereby achieving the effect of in vitro anticoagulation. Therefore, acetic acid in liquid A is replaced with citric acid. Compared with traditional hemodialysis concentrates, hemodialysis concentrates of citrate + bicarbonate have good anticoagulant properties, stable hemodynamic characteristics and biocompatibility.

[0004] Conventional hemodialysis concentrate A is prepared by directly mixing chloride salt and acidic substances at one time. Since citric acid is easily dissociated in water and then easily combines with calcium, magnesium and iron to form salts, the hemodialysis concentrate prepared by the conventional preparation method has defects such as poor stability and low quality and safety. Summary of the invention

[0005] In view of this, an object of the present invention is to provide a hemodialysis concentrate and a preparation method thereof, aiming to solve at least one technical problem in the background technology.

[0006] The present invention is achieved in that:

[0007] The first aspect of the present invention provides a method for preparing a hemodialysis concentrate, wherein the hemodialysis concentrate comprises a solution A and a solution B; the solution A comprises the following components in mass concentrations: sodium chloride 205.5 g / L to 215.9 g / L, potassium chloride 5.0 g / L to 5.5 g / L, magnesium chloride 3.4 g / L to 3.7 g / L, calcium chloride 7.3 g / L to 8.1 g / L, and citric acid 7.0 g / L to 7.7 g / L;

[0008] The B solution includes sodium bicarbonate, and its mass concentration is 79.8g / L~88.2g / L;

[0009] The preparation method of the liquid A is specifically as follows: sodium chloride, potassium chloride, calcium chloride and magnesium chloride are added to the dialysis water for a first feeding, stirred evenly and then circulated and filtered; after the quality inspection is qualified, citric acid is added for a second feeding, the pH is controlled to be 1.5-1.7, stirred and circulated, and the liquid A is obtained after the citric acid inspection is qualified;

[0010] The preparation method of the B solution is specifically as follows: sodium bicarbonate is added to dialysis water, the mixture is stirred evenly, and then circulated and filtered, and the B solution is obtained after the quality inspection is passed.

[0011] Furthermore, the specific steps of the preparation method of the liquid A are:

[0012] Inject dialysis water into the liquid preparation tank, weigh the preset raw materials in liquid A, add sodium chloride, potassium chloride, calcium chloride and magnesium chloride into the liquid preparation tank at one time, and stir at a temperature of 20℃~35℃ for 35min~40min to fully dissolve the raw materials;

[0013] Start the circulation pump to perform secondary filtration with a circulation time of 70 to 85 minutes, and conduct quality inspection on the solution;

[0014] Weigh the preset amount of citric acid in liquid A, add the citric acid into the liquid preparation tank after the solution passes the quality inspection, control the solution pH=1.5~1.7, preferably pH=1.6, stir and circulate at a temperature of 20°C~35°C for 60min~70min, and obtain the liquid A after the citric acid passes the inspection.

[0015] Furthermore, the specific steps of the preparation method of the B solution are:

[0016] Weigh the sodium bicarbonate required by solution B, and stir the sodium bicarbonate and dialysis water at 20℃~35℃ for 45min~50min;

[0017] After the sodium bicarbonate is fully dissolved, the circulation pump is turned on to perform three-stage filtration; the circulation time is 50min~65min, and the B solution is obtained after passing the quality inspection.

[0018] Furthermore, the quality inspection during the preparation of the A solution and the B solution is performed using an electrolyte analyzer and a titration method.

[0019] Furthermore, during the preparation of the liquid A, citric acid is tested by liquid chromatography.

[0020] The second aspect of the present invention provides a hemodialysis concentrate obtained by the above-mentioned preparation method.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] 1. The present invention uses citric acid as the acidic substance of the hemodialysis concentrate. When preparing liquid A, a secondary feeding method is adopted to adjust the addition order of the liquid preparation raw materials, and the temperature and pH value are controlled to prepare a hemodialysis concentrate with high stability and strong quality safety.

[0023] 2. The control of pH in the preparation method of the present invention makes it difficult for citric acid to react with calcium and magnesium, reduces the risk of complex formation, and is beneficial to the stability of the hemodialysis concentrate.

[0024] 3. In the present invention, when preparing liquid A of hemodialysis concentrate, the raw materials are fed separately, so there is no need to use ion chromatography to check the concentration of each component of the solution during process inspection. Only an electrolyte analyzer and titration method are required for detection, thereby eliminating uncertainties in the detection process. In addition, the production process inspection is convenient and rapid, reducing the increase in detection costs and shortening the time consumption. Compared with the conventional method for preparing hemodialysis concentrate, the detection time of the present invention is shortened by about 80 minutes.

[0025] 4. The preparation method of the present invention reduces the contact time between citric acid and pipelines and equipment, so that the hemodialysis concentrate has high transparency and is not easy to turn yellow.

[0026] 5. The hemodialysis concentrate prepared by the present invention is suitable for hemodialysis treatment of patients with acute and chronic renal failure, can be rapidly metabolized in vivo, and has an in vitro anticoagulant effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The figures are the actual pictures of Liquid A prepared in Example 1 and Comparative Example 1 of the present invention. DETAILED DESCRIPTION

[0028] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific implementation cases described herein are only used to explain the present invention and are not used to limit the present invention.

[0029] A hemodialysis concentrate comprises liquid A and liquid B; the liquid A comprises the following components in mass concentrations: sodium chloride 205.5 g / L to 215.9 g / L, potassium chloride 5.0 g / L to 5.5 g / L, magnesium chloride 3.4 g / L to 3.7 g / L, calcium chloride 7.3 g / L to 8.1 g / L, and citric acid 7.0 g / L to 7.7 g / L; the liquid B comprises sodium bicarbonate, and its mass concentration is 79.8 g / L to 88.2 g / L;

[0030] In a specific implementation, the concentrations of liquid A and liquid B of the hemodialysis concentrate may be any data within the above parameter range, without specific limitation herein. The following embodiment uses 210.7 g / L sodium chloride, 5.25 g / L potassium chloride, 3.55 g / L magnesium chloride, 7.7 g / L calcium chloride, 7.35 g / L citric acid, and 84 g / L sodium bicarbonate as raw materials for illustration, but is not limited to the listed values, and other values ​​not listed within the parameter range are equally applicable.

[0031] The preparation method of the liquid A is specifically as follows: injecting dialysis water into a liquid preparation tank, weighing raw materials of preset requirements for liquid A, adding sodium chloride, potassium chloride, calcium chloride and magnesium chloride into the liquid preparation tank at one time, stirring at a temperature of 20°C to 35°C for 35min to 40min to fully dissolve the raw materials; starting a circulation pump to perform secondary filtration with a circulation time of 70min to 85min, taking samples for inspection after the circulation filtration, and using an electrolyte analyzer and titration method to obtain the test results; after passing the quality inspection, adding citric acid of preset requirements for secondary feeding, controlling the pH to 1.5 to 1.7, preferably 1.55 to 1.65, such as 1.64, 1.62, 1.60, 1.59, etc., most preferably 1.60, stirring and circulating at a temperature of 20°C to 35°C for 60min to 70min, and obtaining the liquid A after the citric acid inspection is passed.

[0032] The preparation method of the B liquid is specifically as follows: weigh the sodium bicarbonate required by the preset requirements of the B liquid, stir the sodium bicarbonate and dialysis water at a temperature of 20°C to 35°C for 45min to 50min; after the sodium bicarbonate is fully dissolved, start the circulation pump to perform three-stage filtration; the circulation time is 50min to 65min, and after the circulation filtration, take samples for inspection, and use an electrolyte analyzer and titration method to obtain the test results; after passing the quality inspection, the B liquid is obtained.

[0033] When preparing liquid A and liquid B, qualified quality inspection means that the test results of liquid A and liquid B meet the requirements of the pharmaceutical industry standard of the People's Republic of China YY 0598-2015 "Concentrates for hemodialysis and related treatments", in which citric acid replaces acetic acid, and qualified citric acid inspection means that its test results meet the relevant provisions of the Pharmacopoeia of the People's Republic of China (Part IV) (2020 edition) under citric acid. In view of the ionization equilibrium and certain reversible coordination equilibrium of citric acid in the solution, based on the standard formula, the present invention adjusts the order of adding the liquid preparation raw materials, controls the solution pH and reaction temperature, and provides a hemodialysis concentrate production process with safe quality, efficient and rapid detection, and good stability.

[0034] During the preparation of the A liquid and the B liquid, the secondary filtration or the tertiary filtration is carried out using a microporous filter membrane with different pore sizes, and the size of the microporous filter membrane can be adjusted according to actual needs, such as the secondary filtration of the A liquid using a microporous filter membrane with a pore size of 5 μm and 0.45 μm, and the tertiary filtration of the B liquid using a microporous filter membrane with a pore size of 5 μm, 0.45 μm and 0.22 μm; in practical applications, the size and combination of the microporous filter membrane can also be adjusted as needed, but is not limited to the listed values, and other unlisted values ​​and combinations are also applicable. In a specific implementation, the hemodialysis concentrate of the present invention can also be used as a basic formula, and together with other functional supplements such as glucose, iron, etc., it constitutes an improved hemodialysis concentrate.

[0035] Example 1

[0036] In this embodiment 1, a hemodialysis concentrate is prepared, which includes liquid A and liquid B;

[0037] Liquid A includes the following components in mass concentrations: 210.7 g / L sodium chloride, 5.25 g / L potassium chloride, 3.55 g / L magnesium chloride, 7.7 g / L calcium chloride, and 7.35 g / L citric acid; Liquid B includes 84 g / L sodium bicarbonate;

[0038] In a specific implementation, the preparation method of liquid A specifically includes the following steps:

[0039] S11, liquid preparation: inject a certain amount of dialysis water into the liquid preparation tank, weigh the sodium chloride, potassium chloride, calcium chloride, and magnesium chloride required by the preset liquid A, and add them into the liquid preparation tank;

[0040] S12, feeding and stirring: stirring temperature is 20℃~25℃, time is 35min~40min;

[0041] S13, circulation filtration: after the raw materials are fully dissolved, the circulation pump is turned on, and secondary filtration is performed using 5μm and 0.45μm microporous filter membranes; the circulation time is 70min~85min;

[0042] S14, process inspection: after circulating filtration, take samples for inspection, and use electrolyte analyzer and titration method to test the calcium, sodium, potassium, magnesium and chlorine content. The electrolyte analyzer detects sodium, potassium and chlorine; the titration method detects calcium and magnesium. The two detection methods must be carried out at the same time, and the results can be obtained in 15 minutes;

[0043] S15, secondary feeding: after the process inspection is qualified, add the citric acid required by liquid A, the pH needs to be controlled at about 1.6, the stirring temperature is 20℃~25℃, and the stirring cycle time is 60min~70min;

[0044] S16. Semi-finished product inspection: Use liquid chromatography to test the citric acid content and the test results can be obtained;

[0045] S17, filling: After the semi-finished product is inspected and qualified, it is filled to obtain the A liquid of the hemodialysis concentrate. Figure 1 As shown, Figure 1 The left side is the liquid A obtained in this embodiment 1.

[0046] The preparation method of liquid B specifically comprises the following steps:

[0047] S21, liquid preparation: according to the sterile operation rules, a certain amount of dialysis water is injected into the liquid preparation tank, and sodium bicarbonate required by the preset B solution is weighed;

[0048] S22, feeding and stirring: adding sodium bicarbonate into the liquid preparation tank, stirring at a temperature of 20°C to 35°C for 45min to 50min;

[0049] S23, circulation filtration: after the raw materials are fully dissolved, the circulation pump is turned on, and three-stage filtration is performed using 5μm, 0.45μm and 0.22μm microporous membranes; the circulation time is 50min~65min;

[0050] S24, process inspection: After circulating filtration, take samples for inspection, and use electrolyte analyzer and titration method to get the test results. The electrolyte analyzer detects sodium, and the titration method detects bicarbonate. The two detection methods are carried out simultaneously, which can quickly and accurately detect the results;

[0051] S25, filling: After the semi-finished product has passed the inspection, it is filled to obtain the B liquid of the hemodialysis concentrate.

[0052] In actual application, mix liquid A and liquid B according to the required ratio, add dialysis water and mix evenly before use.

[0053] Example 2

[0054] On the basis of Example 1, in Example 2, the temperature during the preparation of liquid A is adjusted, and the stirring temperature after two feedings is adjusted to 25° C. to 30° C. The other preparation steps and parameters are the same as those in Example 1.

[0055] Example 3

[0056] On the basis of Example 1, the temperature of the A liquid during preparation was adjusted in Example 3, and the stirring temperature was adjusted to 30° C. to 35° C. after two additions. The other preparation steps and parameters were the same as those in Example 1.

[0057] Example 4

[0058] On the basis of Example 1, the pH value of Example 3 was adjusted to 1.5, and the other preparation steps and parameters were the same as those of Example 1.

[0059] Example 5

[0060] On the basis of Example 1, the pH value of Example 3 was adjusted to 1.7, and the other preparation steps and parameters were the same as those of Example 1.

[0061] Comparative Example 1

[0062] In this comparative example 1, a hemodialysis concentrate is prepared. The hemodialysis concentrate includes liquid A and liquid B. In this comparative example 1, the order of adding the raw materials for preparing liquid A is adjusted. The rest is the same as in Example 1.

[0063] The preparation process of liquid A includes:

[0064] (1) Liquid preparation: inject a certain amount of dialysis water into the liquid preparation tank, and weigh the preset required sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and citric acid;

[0065] (2) Adding and stirring: Add the liquid A weighed in step (1) into the liquid preparation tank at once and stir and mix at a temperature of 20°C to 25°C for 35 min to 40 min;

[0066] (3) Circulation filtration: After the raw materials are fully dissolved, start the circulation pump for secondary filtration; the circulation time is 70min~85min;

[0067] (4) Process inspection: After circulating filtration, samples are taken for inspection, and the solution is qualitatively and quantitatively analyzed using ion chromatography and liquid chromatography;

[0068] (5) Filling: After the process inspection is passed, filling is carried out to obtain the liquid A. Figure 1 As shown, Figure 1 The right side in the middle is Liquid A obtained in Comparative Example 1.

[0069] The preparation process of liquid B is consistent with that of Example 1.

[0070] Comparative Example 2

[0071] In this comparative example 2, a hemodialysis concentrate is prepared, which includes liquid A and liquid B, wherein the preparation process of liquid B is consistent with that of Example 1; the preparation process of liquid A differs from that of Example 1 only in the pH value during the secondary feeding, and in this comparative example 2, the pH value during the secondary feeding is 1.4.

[0072] Comparative Example 3

[0073] In this comparative example 3, a hemodialysis concentrate is prepared, which includes liquid A and liquid B, wherein the preparation process of liquid B is consistent with that of Example 1; the preparation process of liquid A differs from that of Example 1 only in the pH value during the secondary feeding, and in this comparative example 3, the pH value during the secondary feeding is 1.8.

[0074] Comparative Example 4

[0075] In this comparative example 4, a hemodialysis concentrate is prepared, which includes liquid A and liquid B, wherein the preparation process of liquid B is consistent with that of Example 1; the preparation process of liquid A differs from that of Example 1 only in the stirring temperature during feeding, and in this comparative example 4, the stirring temperature is adjusted to 15°C after two feedings.

[0076] Comparative Example 5

[0077] In this comparative example 5, a hemodialysis concentrate is prepared, which includes liquid A and liquid B, wherein the preparation process of liquid B is consistent with that of Example 1; the difference between the preparation process of liquid A and that of Example 1 lies in the stirring temperature during feeding, and in this comparative example 5, the stirring temperature is adjusted to 40°C after two feedings.

[0078] The chemical and biological indicators of the hemodialysis concentrates prepared in Examples 1 to 5 and Comparative Examples 1 to 5 are all qualified. In addition, the performance of each A liquid is analyzed, and the results are shown in Table 1.

[0079] Table 1

[0080]

[0081] In Example 1, when preparing Liquid A in the hemodialysis concentrate, citric acid and chloride salt are added separately. In Comparative Example 1, when preparing Liquid A, all of its raw materials, namely citric acid and chloride salt, are mixed and dissolved in dialysis water at one time. It can be seen from the data in Table 1 that the indicators of Liquid A prepared in Example 1 are better. Figure 1 It can be seen that the solution of Example 1 is more colorless and transparent than that of Comparative Example 1, and the solution A prepared in Comparative Example 1 is yellow; the iron ion content detected in Example 1 is less than that in Comparative Example 1.

[0082] The liquid A prepared in comparative example 2 contains calcium citrate because: citrate ions have a high degree of dissociation in water and are easily combined with calcium, magnesium and iron to form salts; citrate ions and calcium ions will generate calcium citrate when the pH value is low (pH is about <1.5), and this product has good solubility in hot water at about 60°C, but only a small amount is soluble in cold water; and thus, calcium citrate precipitates when preparing liquid A in comparative example 2, resulting in turbidity of the solution, and citric acid is consumed, so that its concentration does not meet the standard.

[0083] The liquid A prepared in comparative example 3 contains calcium carbonate because: when the reaction pH value is high (pH about > 1.7), calcium ions react with the hydroxyl and carboxyl groups of citrate ions to form calcium carbonate. Calcium carbonate is not only highly stable, but also has low solubility in fluid systems; thus, calcium carbonate precipitation is produced when preparing liquid A in comparative example 3, resulting in turbidity of the solution, and citric acid is consumed, so that its concentration does not meet the standard.

[0084] From the performance comparison of Example 1, Example 4 to Example 5, and Comparative Example 2 to Comparative Example 3 in Table 1, it can be seen that in the preparation process of liquid A, when the pH value is controlled to be 1.5-1.7, the color of the obtained liquid A is more colorless and transparent, the loss of citric acid is small, and the performance of liquid A is optimal in the range of pH=1.5-1.7, especially when pH=1.6. In comprehensive comparison, pH=1.6>pH=1.5>pH=1.7.

[0085] From the performance comparison of Examples 1 to 3 and Comparative Examples 4 to 5 in Table 1, it can be seen that during the preparation of Liquid A, when the preparation temperature is controlled at 20°C to 35°C, the prepared Liquid A has stable performance and is more colorless and transparent.

[0086] The stirring temperature of the liquid A prepared in comparative example 4 was low, and the raw materials were not completely dissolved. The reason is that the change in temperature can directly change the solubility of the solvent, thereby affecting whether the components can be fully dissolved. Therefore, if the temperature is too low, some raw materials may not be completely dissolved, and particles or suspended matter are easily formed, thereby reducing the quality of the product; and thus, when preparing liquid A in comparative example 4, the solution was turbid and the ion concentration did not meet the standard.

[0087] The higher stirring temperature of the feed material in the liquid A prepared in comparative example 5 accelerates the solution reaction. The reason is that: the higher stirring temperature accelerates the complexation reaction between citric acid and metal ions. Therefore, the concentration of the liquid A in comparative example 5 does not meet the standard when it is prepared, and the iron ion content is significantly increased.

[0088] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for preparing a hemodialysis concentrate, characterized in that: The hemodialysis concentrate includes liquid A and liquid B; the liquid A includes the following components in mass concentrations: sodium chloride 205.5 g / L to 215.9 g / L, potassium chloride 5.0 g / L to 5.5 g / L, magnesium chloride 3.4 g / L to 3.7 g / L, calcium chloride 7.3 g / L to 8.1 g / L, and citric acid 7.0 g / L to 7.7 g / L; The B solution includes sodium bicarbonate, and its mass concentration is 79.8g / L~88.2g / L; The preparation method of the liquid A is specifically as follows: sodium chloride, potassium chloride, calcium chloride and magnesium chloride are added to the dialysis water for a first feeding, stirred evenly and then circulated and filtered; after the quality inspection is qualified, citric acid is added for a second feeding, the pH is controlled to be 1.5-1.7, stirred and circulated, and the liquid A is obtained after the citric acid inspection is qualified; The preparation method of the B solution is specifically as follows: adding sodium bicarbonate to the dialysis water, stirring evenly and then filtering in a circulation manner, and obtaining the B solution after passing the quality inspection; The specific steps of the preparation method of the liquid A are: Inject dialysis water into the liquid preparation tank, weigh the preset raw materials in liquid A, add sodium chloride, potassium chloride, calcium chloride and magnesium chloride into the liquid preparation tank at one time, and stir at a temperature of 20℃~35℃ for 35min~40min to fully dissolve the raw materials; Start the circulation pump to perform secondary filtration with a circulation time of 70 to 85 minutes, and conduct quality inspection on the solution; Weigh the preset amount of citric acid in liquid A, add the citric acid into the liquid preparation tank after the solution passes the quality inspection, control the solution pH to 1.5-1.7, stir and circulate at a temperature of 20°C-35°C for 60min-70min, and obtain the liquid A after the citric acid passes the inspection.

2. The method for preparing a hemodialysis concentrate according to claim 1, characterized in that: The specific steps of the preparation method of the B solution are: Weigh the sodium bicarbonate required by solution B, and stir the sodium bicarbonate and dialysis water at 20℃~35℃ for 45min~50min; After the sodium bicarbonate is fully dissolved, the circulation pump is turned on to perform three-stage filtration; the circulation time is 50min~65min, and the B solution is obtained after passing the quality inspection.

3. The method for preparing a hemodialysis concentrate according to claim 1, characterized in that: When preparing the A solution, pH=1.

6.

4. The method for preparing a hemodialysis concentrate according to claim 2, characterized in that: The quality inspection during the preparation of the A solution and the B solution is performed using an electrolyte analyzer and a titration method.

5. The method for preparing a hemodialysis concentrate according to claim 1 or 4, characterized in that: During the preparation of the liquid A, the citric acid test was performed using liquid chromatography.

6. A hemodialysis concentrate obtained by the preparation method according to any one of claims 1 to 5.

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