Calcium gluconate injection and preparation method thereof

Abstract

The present invention provides a calcium gluconate injection and a preparation method thereof, and relates to the technical field of drug preparation. The calcium gluconate injection is composed of calcium gluconate, calcium gluconate diacid, calcium hydroxide, lactic acid, sodium chloride, sodium benzoate and water for injection, and the calcium gluconate injection is mainly prepared by adding calcium gluconate to boiled water for injection and dissolving it, then mixing calcium hydroxide, sodium chloride and sodium benzoate, adding activated carbon, performing pressurized low-temperature treatment, and then boiling at high temperature and filtering. The present invention overcomes the shortcomings of the prior art, and by optimizing the composition of the injection and adjusting the production process, the storage stability and low-temperature stability of the calcium gluconate injection are effectively improved, thereby ensuring the safety of the drug.

Description

Technical Field

[0001] The invention relates to the technical field of drug preparation, and in particular to a calcium gluconate injection and a preparation method thereof. Background Art

[0002] Calcium gluconate is a calcium supplement that is often used to treat calcium deficiency. It can also be used for anti-allergic treatment and the rescue of magnesium poisoning and fluoride poisoning. It is usually used in the form of injection. Compared with other calcium supplements, calcium gluconate injection is less irritating to human tissues and is safer to inject.

[0003] The solubility of calcium gluconate raw material in water is about 3.33%, while the "Chinese Pharmacopoeia" stipulates that the content of calcium gluconate injection is 10%, which is a supersaturated solution. Therefore, certain solubilizing ingredients need to be added during the preparation of calcium gluconate injection. However, during the actual production and storage process, calcium gluconate injection will still produce a certain amount of crystallization, causing the solution to be turbid, which will reduce the overall quality of calcium gluconate injection. More seriously, it will reduce the safety of drug use. To address this problem, it is crucial to improve the stability of calcium gluconate injection by adjusting the composition of the injection and optimizing the preparation process. Summary of the invention

[0004] In view of the shortcomings of the prior art, the present invention provides a calcium gluconate injection and a preparation method thereof, which effectively improves the storage stability and low-temperature stability of the calcium gluconate injection by optimizing the composition of the injection and adjusting the production process, thereby ensuring the safety of the drug.

[0005] To achieve the above objectives, the technical solution of the present invention is implemented through the following technical solutions:

[0006] Calcium gluconate, calcium gluconate, calcium hydroxide, lactic acid, sodium chloride, sodium benzoate and water for injection, wherein the total content of calcium gluconate in the injection is 90-110 g / L, the total content of calcium gluconate in the injection is 2.5-4.5 g / L, the mass ratio of sodium chloride to sodium benzoate is 2:1, and the total addition amount of sodium chloride and sodium benzoate is 2%-5% of the addition amount of calcium gluconate, the addition amount of calcium hydroxide is 0.5%-2.5% of the addition amount of calcium gluconate, and the lactic acid is used to adjust the pH value of the whole system to 4.5-7.5.

[0007] Preferably, the preparation method of the calcium gluconate injection comprises the following steps:

[0008] S1. Add some water for injection into the liquid preparation tank and heat it to boiling, then add the prescribed amount of calcium gluconate and calcium glucarate, stir and dissolve, and obtain a preliminary solution for use;

[0009] S2, the above preliminary solution is kept warm at 70-80°C, and then calcium hydroxide, sodium chloride and sodium benzoate in the prescribed amount are added and stirred to dissolve, and a mixed solution is obtained for standby use;

[0010] S3, cooling the mixed solution to 40-50°C, heating the remaining water for injection to 70-80°C and injecting it into the liquid preparation tank under high pressure to mix with the mixed solution, adding lactic acid to adjust the pH to 4.5-7.5, and then stirring at high speed to obtain a pretreated injection for standby use;

[0011] S4, adding activated carbon to the above-mentioned pre-treated injection, stirring and evacuating, then filling with nitrogen to adjust the pressure to 4-6MPa, cooling and freezing to obtain a preliminary frozen liquid;

[0012] S5. Heat the above preliminary frozen liquid to 50-60°C and keep it warm and under pressure for 1-2h, then return to normal pressure and heat to boiling and keep it warm for 20-30min, then filter, make up the filtrate and adjust the pH to 4.5-5.2, then fill and sterilize to obtain calcium gluconate injection.

[0013] Preferably, the stirring speed of the stirring and dissolving in step S1 is 120-160 r / min, and the stirring time is 5-10 min.

[0014] Preferably, the stirring speed in step S2 is 120-160 r / min, and the temperature is kept at 70-80° C. during the stirring process, and the stirring time is 20-30 min.

[0015] Preferably, in step S3, the pressure at which the remaining water for injection is injected into the liquid preparation tank under high pressure is 1.2-1.5 MPa, and the injection process is sealed.

[0016] Preferably, the rotation speed of the high-speed stirring in step S3 is 600-800 r / min, and the stirring time is 10-15 min.

[0017] Preferably, the amount of activated carbon added in step S4 is 0.05-0.1% of the mass of the pretreated injection.

[0018] Preferably, the cooling and freezing temperature in step S4 is -2°C to -5°C, and the freezing time is 2-4h.

[0019] Preferably, in step S5, firstly filter with a 0.45 μm polyethersulfone filter element, and then filter with a 0.22 μm polyethersulfone filter element for 3-5 times.

[0020] Preferably, the sterilization method in step S5 is high temperature sterilization at 105° C. for 40 minutes.

[0021] The present invention provides a calcium gluconate injection and a preparation method thereof, which has the following advantages over the prior art:

[0022] The invention adjusts the auxiliary material components and the addition amount of the calcium gluconate injection, further adjusts the stability of the injection by adding calcium hydroxide, lactic acid, sodium chloride and sodium benzoate, and can further improve the stability of the calcium gluconate injection by high-temperature dissolution, high-pressure and low-temperature mixing of activated carbon and high-temperature treatment and subsequent filtration in a subsequent configuration process, effectively preventing the calcium gluconate injection from deteriorating at low temperature during storage, and improving the quality of the calcium gluconate injection. DETAILED DESCRIPTION

[0023] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention is clearly and completely described below in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0024] The raw materials used in the following examples and comparative examples are as follows:

[0025] Calcium gluconate (C 12 H 22 CaO 14 ·H2O): Hebei Tiancheng Pharmaceutical Co., Ltd.;

[0026] Calcium glucarate (C6H8CaO8·4H2O): Hebei Tiancheng Pharmaceutical Co., Ltd.;

[0027] Sodium hydroxide: Hunan Erkang Pharmaceutical Co., Ltd.

[0028] Sodium chloride: Hunan Erkang Pharmaceutical Co., Ltd.;

[0029] Sodium benzoate: Hunan Erkang Pharmaceutical Co., Ltd.

[0030] Lactic acid: Nanjing Chemical Reagent Co., Ltd.;

[0031] Activated carbon: Nanjing Chemical Reagent Co., Ltd.

[0032] Embodiment 1:

[0033] Preparation of calcium gluconate injection:

[0034] (1) Prepare materials: 1.02 kg of calcium gluconate, 35 g of calcium glucarate, 15.03 g of calcium hydroxide, 23.38 g of sodium chloride, 11.69 g of sodium benzoate, water for injection, lactic acid, and activated carbon;

[0035] (2) Add 50 L of water for injection into a liquid preparation tank and heat to boiling, then add calcium gluconate and calcium glucarate, and stir at a speed of 140 r / min for 8 min to fully dissolve to obtain a preliminary solution;

[0036] (3) cooling the preliminary solution to 75° C. and then keeping it warm, adding calcium hydroxide, sodium chloride, and sodium benzoate, and stirring at a stirring speed of 140 r / min for 25 min to obtain a mixed solution for use;

[0037] (4) Cooling the mixed solution to 45° C., taking another 35 L of water for injection and heating it to 75° C., injecting the heated water for injection into the mixed solution at a pressure of 1.3 MPa in a sealed environment, adding lactic acid to adjust the pH to 4.8 after the mixture is completely mixed, and then adjusting the speed to 700 r / min and stirring for 12 min to obtain a pretreated injection;

[0038] (5) Add 0.08% activated carbon by weight of the pretreated injection into the pretreated injection, stir at a speed of 80 r / min for 2 min, seal and evacuate, then fill with nitrogen to adjust the pressure to 5 MPa, and then cool to -3°C for freezing for 3 h to obtain a low-temperature frozen liquid for use;

[0039] (6) The cryogenic liquid is heated to 55° C. and kept at this temperature for 1.5 h at a pressure of 5 MPa, then restored to normal pressure and heated to boiling and kept at this temperature for 25 min to obtain a pretreated liquid;

[0040] (7) The pre-treated liquid was first filtered through a 0.45 μm polyethersulfone filter element, and then filtered three times through a 0.22 μm polyethersulfone filter element. The filtrate was then fixed to 100 L, and the pH was adjusted to 4.8. The solution was then sterilized at 105° C. for 40 min to obtain calcium gluconate injection.

[0041] Comparative Example 1:

[0042] Preparation of calcium gluconate injection:

[0043] (1) Prepare materials: 1.02 kg of calcium gluconate, 35 g of calcium glucarate, 15.03 g of calcium hydroxide, water for injection, lactic acid, and activated carbon;

[0044] (2) Add 50 L of water for injection into a liquid preparation tank and heat to boiling, then add calcium gluconate and calcium glucarate, and stir at a speed of 140 r / min for 8 min to fully dissolve to obtain a preliminary solution;

[0045] (3) cooling the preliminary solution to 75° C. and then keeping it warm, adding calcium hydroxide, and stirring at a stirring speed of 140 r / min for 25 min to obtain a mixed solution for use;

[0046] (4) Cooling the mixed solution to 45° C., taking another 35 L of water for injection and heating it to 75° C., injecting the heated water for injection into the mixed solution at a pressure of 1.3 MPa in a sealed environment, adding lactic acid to adjust the pH to 4.8 after the mixture is completely mixed, and then adjusting the speed to 700 r / min and stirring for 12 min to obtain a pretreated injection;

[0047] (5) Add 0.08% activated carbon by weight of the pretreated injection into the pretreated injection, stir at a speed of 80 r / min for 2 min, seal and evacuate, then fill with nitrogen to adjust the pressure to 5 MPa, and then cool to -3°C for freezing for 3 h to obtain a low-temperature frozen liquid for use;

[0048] (6) The cryogenic liquid is heated to 55° C. and kept at this temperature for 1.5 h at a pressure of 5 MPa, then restored to normal pressure and heated to boiling and kept at this temperature for 25 min to obtain a pretreated liquid;

[0049] (7) The pre-treated liquid was first filtered through a 0.45 μm polyethersulfone filter element, and then filtered four times through a 0.22 μm polyethersulfone filter element. The filtrate was then fixed to 100 L, and the pH was adjusted to 4.8. The solution was then sterilized at 105° C. for 40 min to obtain calcium gluconate injection.

[0050] Comparative Example 2:

[0051] Preparation of calcium gluconate injection:

[0052] (1) Prepare materials: 1.02 kg of calcium gluconate, 35 g of calcium glucarate, 15.03 g of calcium hydroxide, 23.38 g of sodium chloride, 11.69 g of sodium benzoate, water for injection, lactic acid, and activated carbon;

[0053] (2) Add 50 L of water for injection into a liquid preparation tank and heat to boiling, then add calcium gluconate and calcium glucarate, and stir at a speed of 140 r / min for 8 min to fully dissolve to obtain a preliminary solution;

[0054] (3) cooling the preliminary solution to 75° C. and then keeping it warm, adding calcium hydroxide, sodium chloride, and sodium benzoate, and stirring at a stirring speed of 140 r / min for 25 min to obtain a mixed solution for use;

[0055] (4) Take 35L of water for injection and heat it to 75°C, add it to the above mixture and stir evenly, then add lactic acid to adjust the pH to 4.8, then adjust the speed to 700 r / min and stir for 12 minutes to obtain a pretreated injection;

[0056] (5) Add 0.08% activated carbon by weight of the pretreated injection into the pretreated injection, stir at a speed of 80 r / min for 2 min, seal and evacuate, then fill with nitrogen to adjust the pressure to 5 MPa, and then cool to -3°C for freezing for 3 h to obtain a low-temperature frozen liquid for use;

[0057] (6) The cryogenic liquid is heated to 55° C. and kept at this temperature for 1.5 h at a pressure of 5 MPa, then restored to normal pressure and heated to boiling and kept at this temperature for 25 min to obtain a pretreated liquid;

[0058] (7) The pre-treated liquid was first filtered through a 0.45 μm polyethersulfone filter element, and then filtered four times through a 0.22 μm polyethersulfone filter element. The filtrate was then fixed to 100 L, and the pH was adjusted to 4.8. The solution was then sterilized at 105° C. for 40 min to obtain calcium gluconate injection.

[0059] Comparative Example 3:

[0060] Preparation of calcium gluconate injection:

[0061] (1) Prepare materials: 1.02 kg of calcium gluconate, 35 g of calcium glucarate, 15.03 g of calcium hydroxide, 23.38 g of sodium chloride, 11.69 g of sodium benzoate, water for injection, lactic acid, and activated carbon;

[0062] (2) Add 50 L of water for injection into a liquid preparation tank and heat to boiling, then add calcium gluconate and calcium glucarate, and stir at a speed of 140 r / min for 8 min to fully dissolve to obtain a preliminary solution;

[0063] (3) cooling the preliminary solution to 75° C. and then keeping it warm, adding calcium hydroxide, sodium chloride, and sodium benzoate, and stirring at a stirring speed of 140 r / min for 25 min to obtain a mixed solution for use;

[0064] (4) Cooling the mixed solution to 45° C., taking another 35 L of water for injection and heating it to 75° C., injecting the heated water for injection into the mixed solution at a pressure of 1.3 MPa in a sealed environment, adding lactic acid to adjust the pH to 4.8 after the mixture is completely mixed, and then adjusting the speed to 700 r / min and stirring for 12 min to obtain a pretreated injection;

[0065] (5) Add 0.08% activated carbon by weight of the pretreatment injection into the pretreatment injection, heat to boiling and keep warm for 25 minutes to obtain a pretreatment solution;

[0066] (6) The pre-treated liquid was first filtered through a 0.45 μm polyethersulfone filter element, and then filtered four times through a 0.22 μm polyethersulfone filter element. The filtrate was then fixed to 100 L, and the pH was adjusted to 4.8. The solution was then sterilized at 105° C. for 40 min to obtain calcium gluconate injection.

[0067] Comparative Example 4:

[0068] Preparation of calcium gluconate injection:

[0069] (1) Prepare materials: 1.02 kg of calcium gluconate, 35 g of calcium glucarate, 15.03 g of calcium hydroxide, 23.38 g of sodium chloride, 11.69 g of sodium benzoate, water for injection, lactic acid, and activated carbon;

[0070] (2) Add 50 L of water for injection into a liquid preparation tank and heat to boiling, then add calcium gluconate and calcium glucarate, and stir at a speed of 140 r / min for 8 min to fully dissolve to obtain a preliminary solution;

[0071] (3) cooling the preliminary solution to 75° C. and then keeping it warm, adding calcium hydroxide, sodium chloride, and sodium benzoate, and stirring at a stirring speed of 140 r / min for 25 min to obtain a mixed solution for use;

[0072] (4) Take 35L of water for injection and heat it to 75°C, add it to the above mixture and stir evenly, then add lactic acid to adjust the pH to 4.8, then adjust the speed to 700 r / min and stir for 12 minutes to obtain a pretreated injection;

[0073] (5) Add 0.08% activated carbon by weight of the pretreatment injection into the pretreatment injection, heat to boiling and keep warm for 25 minutes to obtain a pretreatment solution;

[0074] (7) The pre-treated liquid was first filtered through a 0.45 μm polyethersulfone filter element, and then filtered four times through a 0.22 μm polyethersulfone filter element. The filtrate was then fixed to 100 L, and the pH was adjusted to 4.8. The solution was then sterilized at 105° C. for 40 min to obtain calcium gluconate injection.

[0075] Detection:

[0076] The calcium gluconate content of the calcium gluconate injections prepared in Example 1 and Comparative Examples 1-4 was tested respectively, as well as the stability when stored in different environments:

[0077] 1. Strong light stability:

[0078] Each group of calcium gluconate injection was placed in a transparent glass bottle and then placed under a light intensity of 4000 lx for 30 days. The content and stability of each group of calcium gluconate injection were detected and observed at different times. The specific results are shown in Table 1 below:

[0079] Table 1

[0080]

[0081]

[0082] 2. High temperature storage stability:

[0083] Each group of calcium gluconate injection was stored at 50°C for 3 months and 6 months, and the content and stability of each group of calcium gluconate injection were tested and observed. The specific results are shown in Table 2 below:

[0084] Table 2

[0085]

[0086] 3. Low temperature storage stability:

[0087] Each group of calcium gluconate injection was stored at 5°C for 3 months and 6 months, and the content and stability of each group of calcium gluconate injection were tested and observed. The specific results are shown in Table 3 below:

[0088] Table 3

[0089]

[0090] It can be seen from the above tests that the calcium gluconate injection prepared in Example 1 has high stability.

[0091] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A calcium gluconate injection, characterized in that: The calcium gluconate injection comprises the following raw materials: calcium gluconate, calcium glucarate, calcium hydroxide, lactic acid, sodium chloride, sodium benzoate and water for injection, wherein the total content of calcium gluconate in the injection is 90-110 g / L, the total content of calcium glucarate in the injection is 2.5-4.5 g / L, the mass ratio of sodium chloride to sodium benzoate is 2:1, and the total addition amount of sodium chloride and sodium benzoate is 2%-5% of the addition amount of calcium gluconate, the addition amount of calcium hydroxide is 0.5%-2.5% of the addition amount of calcium gluconate, and the lactic acid adjusts the pH of the whole system to 4.5-7.5; The preparation method of the calcium gluconate injection comprises the following steps: S1. Add some water for injection into the liquid preparation tank and heat it to boiling, then add the prescribed amount of calcium gluconate and calcium glucarate, stir and dissolve, and obtain a preliminary solution for use; S2, the above preliminary solution is kept warm at 70-80°C, and then calcium hydroxide, sodium chloride and sodium benzoate in the prescribed amount are added and stirred to dissolve, and a mixed solution is obtained for standby use; S3, cooling the mixed solution to 40-50°C, heating the remaining water for injection to 70-80°C and injecting it into the liquid preparation tank under high pressure to mix with the mixed solution, adding lactic acid to adjust the pH to 4.5-7.5, and then stirring at high speed to obtain a pretreated injection for standby use; S4, adding activated carbon to the above-mentioned pre-treated injection, stirring and evacuating, then filling with nitrogen to adjust the pressure to 4-6MPa, cooling and freezing to obtain a preliminary frozen liquid; S5. Heat the above preliminary frozen liquid to 50-60°C and keep it warm and under pressure for 1-2h, then return to normal pressure and heat to boiling and keep it warm for 20-30min, then filter, make up the filtrate and adjust the pH to 4.5-5.2, then fill and sterilize to obtain calcium gluconate injection.

2. A calcium gluconate injection according to claim 1, characterized in that: The stirring speed of the stirring and dissolving in step S1 is 120-160 r / min, and the stirring time is 5-10 min.

3. A calcium gluconate injection according to claim 1, characterized in that: The stirring speed in step S2 is 120-160 r / min, and the temperature is kept at 70-80° C. during the stirring process, and the stirring time is 20-30 min.

4. A calcium gluconate injection according to claim 1, characterized in that: In the step S3, the pressure of the remaining water for injection into the liquid preparation tank under high pressure is 1.2-1.5 MPa, and the injection process is sealed.

5. A calcium gluconate injection according to claim 1, characterized in that: The rotation speed of the high-speed stirring in step S3 is 600-800 r / min, and the stirring time is 10-15 min.

6. A calcium gluconate injection according to claim 1, characterized in that: The amount of activated carbon added in step S4 is 0.05-0.1% of the mass of the pretreated injection.

7. A calcium gluconate injection according to claim 1, characterized in that: The temperature of the cooling and freezing in step S4 is -2°C to -5°C, and the freezing time is 2-4h.

8. A calcium gluconate injection according to claim 1, characterized in that: In the step S5, the mixture is first filtered using a 0.45 μm polyethersulfone filter element, and then filtered 3-5 times using a 0.22 μm polyethersulfone filter element.

9. A calcium gluconate injection according to claim 1, characterized in that: The sterilization method in step S5 is high temperature sterilization at 105° C. for 40 minutes.

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