CN115444816A - Calcium gluconate and sodium chloride injection and preparation method thereof - Google Patents

Calcium gluconate and sodium chloride injection and preparation method thereof Download PDF

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Publication number
CN115444816A
CN115444816A CN202211249554.6A CN202211249554A CN115444816A CN 115444816 A CN115444816 A CN 115444816A CN 202211249554 A CN202211249554 A CN 202211249554A CN 115444816 A CN115444816 A CN 115444816A
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China
Prior art keywords
sodium chloride
calcium gluconate
injection
calcium
chloride injection
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CN202211249554.6A
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Chinese (zh)
Inventor
卢德浩
方加林
陈彬
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Huaihai Pharmaceutical Factory Of Anhui Fengyuan Pharmaceutical Co ltd
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Huaihai Pharmaceutical Factory Of Anhui Fengyuan Pharmaceutical Co ltd
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Publication of CN115444816A publication Critical patent/CN115444816A/en
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/08Solutions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/191Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02Inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12Carboxylic acids; Salts or anhydrides thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Abstract

The invention discloses a calcium gluconate and sodium chloride injection and a preparation method thereof, and relates to the technical field of chemical pharmaceutical preparations. The injection prepared by the invention contains the following components: calcium gluconate, sodium chloride and calcium glucarate. The preparation method provided by the invention fundamentally overcomes the defects of high limit of related substances in the calcium gluconate and sodium chloride injection and adverse reaction caused by easy crystallization in the prior art.

Description

Calcium gluconate and sodium chloride injection and preparation method thereof
Technical Field
The invention relates to the technical field of chemical pharmaceutical preparations, and in particular relates to a calcium gluconate and sodium chloride injection and a preparation method thereof.
Background
Calcium gluconate sodium chloride injection mainly comprises calcium gluconate (C) 12 H 22 CaO 14 ·H 2 O), sodium chloride (NaC 1), calcium gluconate with the content of 95.0-105.0 percent and sodium chloride with the content of 95.0-105.0 percent.
The formula of the calcium gluconate and sodium chloride injection in the Chinese pharmacopoeia is as follows: 1g of calcium gluconate, 0.9g of sodium chloride and a proper amount of injection water are prepared into 100ml of injection.
The calcium gluconate and sodium chloride injection prepared by adopting the prescription of the pharmacopoeia can generate degradation related substances, so that the qualification rate of finished products is gradually reduced, and the observation shows that the generation reason is the raw material calcium gluconate, and the method specifically comprises the following steps:
when the raw material calcium gluconate is D-calcium gluconate salt-hydrate, the pH regulator and the preparation or sterilization temperature thereof can generate degradation related substances and visible foreign matters during production. The related substances comprise: 5-hydroxymethylfurfural, glucono-delta-lactone, and glucono-gamma-lactone. All of which are degradation related substances.
Calcium gluconate and calcium chloride injection are added into the formula as a stabilizer, and the preparation and canning temperatures are controlled at the same time, so that the occurrence of related substances generated by an aqueous solution of the calcium gluconate and sodium chloride injection and the occurrence of crystallization or precipitation is reduced. Solves the defects of high limit of related substances in the calcium gluconate and sodium chloride injection and adverse reaction caused by easy crystallization in the prior art.
Disclosure of Invention
The invention aims to provide a calcium gluconate and sodium chloride injection and a preparation method thereof, so as to solve the problem that the calcium gluconate and sodium chloride injection in the prior art is easy to crystallize.
The purpose of the invention can be realized by the following technical scheme:
a calcium gluconate sodium chloride injection comprises the following components: calcium gluconate, calcium glucarate, sodium chloride and water for injection.
As the invention proceeds the one-step scheme comprises the following steps: the calcium gluconate and sodium chloride injection comprises the following components in percentage by weight: 1.96 percent of calcium gluconate, 0.68 percent of calcium glucarate, 0.09001 to 0.09401 percent of sodium chloride and the balance of water for injection.
As a further scheme of the invention: the calcium gluconate and sodium chloride injection comprises the following components in percentage by weight: 1.96 percent of calcium gluconate, 0.68 percent of calcium glucarate, 0.09151 to 0.09250 percent of sodium chloride and the balance of water for injection.
As a further scheme of the invention: the calcium gluconate and sodium chloride injection comprises the following components in percentage by weight: 1.96 percent of calcium gluconate, 0.68 percent of calcium glucarate, 0.09024 percent of sodium chloride and the balance of water for injection.
The preparation method of the calcium gluconate and sodium chloride injection comprises the following steps: dissolving calcium gluconate in water for injection under stirring, stirring for 10min, ultrafiltering, adding calcium gluconate and sodium chloride, dissolving, stirring for 15min, fine filtering, cooling, and sterilizing.
As a further scheme of the invention: the specific steps of ultrafiltration are as follows: ultrafiltering with 0.45 μm and 0.22 μm ultrafiltering membranes.
As a further scheme of the invention: the cooling method comprises the following specific steps: cooling the liquid medicine to 40-60 ℃.
As a further scheme of the invention: the specific sterilization conditions are as follows: the temperature is 121 ℃ for 15min.
The invention has the beneficial effects that:
(1) According to the application, calcium glucarate is added into raw material components as a stabilizer, so that the problem of crystallization generated during storage is well controlled, and the problem that crystallization is easily generated when a finished product is placed for a long time due to the fact that related substances in the raw material medicine are decomposed into superfine particles in the prior art is solved; and with the addition of calcium glucarate, the problems of easily generated related substances, visible foreign matters, crystallization, content reduction and the like in production are changed, and the problems that in the prior art, factors such as transfusion, film treatment unclean and the like cause unsmooth glass chips, fibers or bottle walls mixed in a liquid medicine, so that crystal nuclei are generated in the liquid medicine, and rapid deposition on the surface of the liquid medicine is gradually increased to generate white spots are solved.
(2) In the preparation process, calcium gluconate is dissolved by water for injection, and then is ultrafiltered to prepare stock solution for use, and calcium gluconate and sodium chloride are continuously added, stirred for 10 minutes and cooled to 40-60 ℃. Controlling the generation of related substances. According to the invention, through analysis of stability investigation data of influencing factors, acceleration and long-term tests to 12 months, all detection indexes are in a qualified range, the limit of related substances is lower when the calcium gluconate sodium chloride injection is stored for 3 months at the temperature of-6 ℃, and no crystallization appears in liquid medicine, so that the calcium gluconate sodium chloride injection prepared by the method has good stability.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the embodiments of the present invention, and it should be apparent that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Calcium gluconate sodium chloride injection
1. Comprises the following components: 19.76g of calcium gluconate, 0.9g of calcium gluconate and 6.75g of sodium chloride, and the total volume of the solution is made up to 1000ml by using water for injection.
2. The preparation method comprises the following steps:
(1) Opening the injection water valve of the concentration tank, and adding injection water with the preparation amount of 60 percent and 70-90 ℃ into the concentration tank. Weighing the calcium gluconate with the prescription amount, adding the calcium gluconate into a concentration tank, stirring for 10min for dissolving, and performing ultrafiltration.
(2) Weighing the calcium glucarate and the sodium chloride according to the prescription amount, and adding into a concentration tank. Stirring is continued for 15min after dissolution. The solution is then transferred to a dilution tank. The injection water with the total preparation amount of 30% is adopted to clean the concentrated preparation tank, and the cleaning liquid is transferred to the diluted preparation tank together.
(3) Adding water for injection into the diluting preparation tank to the total amount of the preparation, and stirring for 10min. Then cooling the liquid medicine to below 60 ℃.
(4) Measuring pH (6.0-8.0) of the medicinal liquid in the diluting preparation tank; if necessary, adjusting pH of the solution to 7.0-8.2 with 0.1mol/L hydrochloric acid solution or 2% sodium hydroxide solution, and stirring for 5min.
(5) Sampling and detecting an intermediate. And (3) controlling the quality of an intermediate: the character is colorless and clear liquid; the pH value is 7.0-8.2; calcium content of 0.179% (g/mL) to 0.193% (g/mL); the calcium gluconate content is 96.0-104.0%; the limit of the microorganism is not more than 10cfu/100ml.
(6) Other operations and parameters were performed with reference to conventional production varieties.
3. Filtration step
(1) And after the intermediate is qualified, performing ultrafiltration on the liquid medicine through a primary 0.45 mu m polyether sulfone filter core and a secondary 0.22 mu m polyether sulfone filter core.
(2) Other operations and parameters were performed with reference to conventional production varieties.
4. Washing and filling and sealing:
(1) Starting the filling machine, filtering the liquid medicine by a filter element with the diameter of 0.22 mu m, starting filling, setting the filling speed to be 160-250 bags/minute and the filling volume to be 100-110 ml, and simultaneously checking the visible foreign matters and the filling amount of the liquid medicine.
(2) Other operations and parameters were performed with reference to conventional production varieties.
5. A sterilization procedure:
(1) Vertically stacking the filled and sealed product on a sterilization tray through a large-infusion automatic bottle (bag) stacking machine; the sterilization temperature is set to be 121 ℃, and the sterilization time is set to be 15 ℃. Starting an automatic sterilization control program and entering sterilization operation.
(2) Other operations and parameters were performed with reference to conventional production varieties.
6. A lamp inspection process:
the operation and parameters were performed with reference to conventional production varieties.
7. A packaging procedure:
the operation and parameters were performed with reference to conventional production varieties.
Comparative example 1:
calcium gluconate sodium chloride injection
1. Consists of the following components: 10g of calcium gluconate, 9g of sodium chloride and 1000ml of water for injection.
2. The preparation method comprises the following steps:
the formula of the calcium gluconate and sodium chloride injection is taken as a basis, and the formula and the preparation method thereof are shown in example 1 of the patent.
Stability survey
Three batches of samples were prepared for stability studies using the method of example 1, as follows:
1. test content and method
(one) test of influence factors
Sampling detection is carried out at the initial (0 day) and 5 and 10 days of the test respectively under the conditions of 60 ℃ and the illumination of 5000 lx.
(II) accelerated test
According to the technical requirements of Chinese pharmacopoeia on the drug stability inspection, the stability of the calcium gluconate and sodium chloride injection is inspected under the accelerated condition (the temperature is 40 +/-2 ℃, and the relative humidity is 25% +/-5%).
Respectively taking calcium gluconate and sodium chloride injection samples, placing the calcium gluconate and sodium chloride injection samples in a constant temperature and constant humidity box with the temperature of 40 +/-2 ℃ and the relative humidity of 25 +/-5%, and respectively sampling and measuring at 0 month and 1, 2, 3 and 6 months of the initial test.
(III) Long term test
According to the technical requirements of Chinese pharmacopoeia on drug stability investigation, the stability of long-term sample retention of three batches of calcium gluconate and sodium chloride injection is investigated.
Respectively taking calcium gluconate and sodium chloride injection samples, placing the samples at 30 +/-2 ℃ and under the condition of relative humidity of 35 +/-5 percent, flatly placing the samples (fully contacting the liquid medicine with a combined cover), respectively sampling and measuring the samples at the initial 0 month and 3, 6, 9 and 12 months of the test, and sampling and detecting the samples when the samples are continuously examined to 18, 24, 36 and 48 months.
(IV) examination item
1. The bag appearance: visual method; it should be transparent, smooth and free of macroscopic foreign matter.
2. The characteristics are as follows: visual method; it should be a colorless, clear liquid.
3. pH value: measuring by an acidimeter; should be 5.5-8.2.
4. Visible foreign matter (general rule 0904): and should comply with regulations.
5. Heavy metals: the Chinese pharmacopoeia (the first method of the general guidelines 0821); not more than three million.
6. Insoluble microparticles: a photoresist method; should comply with the regulations.
7. Bacterial endotoxin (general rule 1143): a gel method; the amount of endotoxin should be less than 0.50EU per 1 ml. (investigation in accelerated test 6 months and Long term tests 6, 12, 24, 36, 48 months)
8. And (3) sterilization: chinese pharmacopoeia (general rules 1101); should comply with the regulations. (investigation in accelerated test 6 months and Long term tests 6, 12, 24, 36, 48 months)
9. The content is as follows: high performance liquid chromatography; calcium should be 0.177% -0.195% (g/ml); the calcium gluconate and sodium chloride should be 95.0-105.0% (g/ml).
10. Water loss rate: gravimetric method; not more than 5%.
2. Conclusion
The accelerated test result shows that the content of the calcium gluconate sodium chloride injection in the vertical double-valve polypropylene infusion bag is slightly increased within 6 months of acceleration, which is related to the fact that the package is a semi-permeable container and the water loss rate of the product, and other detection indexes all meet the requirements of quality standards.
Long-term test results show that various detection indexes of the calcium gluconate and sodium chloride injection of the vertical double-valve polypropylene infusion bag meet the requirements and have no obvious change, so that the vertical double-valve polypropylene infusion bag can be used as an inner package of a marketed drug.
Through acceleration and long-term stability tests, the stability of the calcium gluconate and sodium chloride injection packaged by the vertical double-valve polypropylene infusion bag is not different, and the water loss rate of the product is in a qualified range, so that the requirement on the limit of the water loss rate of a semi-permeable container in the ICH stability investigation guiding principle is met; in addition, according to the long-term stability investigation result of the product and the effective period of the original polypropylene blending infusion bag packaged product, the effective period of the product is temporarily set to be 24 months, and the product is stored in a sealed manner. The results are shown in tables 1 and 2
Table 1: investigation result of calcium gluconate sodium chloride injection influence factor test
Figure BDA0003886413400000061
Figure BDA0003886413400000071
Table 2: accelerated test and long-term sample retention investigation result of calcium gluconate and sodium chloride injection
Figure BDA0003886413400000072
Figure BDA0003886413400000081
Figure BDA0003886413400000091
Shown by tables 1-2: through analysis of stability investigation data of influencing factors, acceleration and long-term tests to 12 months, all detection indexes are in a qualified range, and no related substance limit rise or crystallization occurs after storage for 3 months at the temperature of-6 ℃, so that the calcium gluconate and sodium chloride solution provided by the invention is good in stability.
Although one embodiment of the present invention has been described in detail, the description is only for the purpose of illustrating the preferred embodiments of the present invention and should not be taken as limiting the scope of the invention. All equivalent changes and modifications made within the scope of the present invention shall fall within the scope of the present invention.

Claims (8)

1. The calcium gluconate and sodium chloride injection is characterized by comprising the following components: calcium gluconate, calcium glucarate, sodium chloride and water for injection.
2. The calcium gluconate and sodium chloride injection according to claim 1, wherein the calcium gluconate and sodium chloride injection comprises the following components in percentage by weight: 1.96 percent of calcium gluconate, 0.68 percent of calcium glucarate, 0.09001 to 0.09401 percent of sodium chloride and the balance of water for injection.
3. The calcium gluconate and sodium chloride injection as claimed in claim 1, wherein the calcium gluconate and sodium chloride injection comprises the following components in percentage by weight: 1.96 percent of calcium gluconate, 0.68 percent of calcium glucarate, 0.09151 to 0.09250 percent of sodium chloride and the balance of water for injection.
4. The calcium gluconate and sodium chloride injection as claimed in claim 1, wherein the calcium gluconate and sodium chloride injection comprises the following components in percentage by weight: 1.96 percent of calcium gluconate, 0.68 percent of calcium glucarate, 0.09024 percent of sodium chloride and the balance of water for injection.
5. The preparation method of the calcium gluconate and sodium chloride injection as claimed in any one of claims 1 to 4, comprising the steps of: dissolving calcium gluconate in water for injection under stirring, stirring for 10min, ultrafiltering, adding calcium gluconate and sodium chloride, dissolving, stirring for 15min, fine filtering, cooling, and sterilizing.
6. The preparation method of the calcium gluconate and sodium chloride injection as claimed in claim 5, wherein the ultrafiltration comprises the following steps: ultrafiltering with 0.45 μm and 0.22 μm ultrafiltering membranes.
7. The preparation method of the calcium gluconate and sodium chloride injection as claimed in claim 5, wherein the cooling comprises the following steps: cooling the liquid medicine to 40-60 ℃.
8. The preparation method of the calcium gluconate and sodium chloride injection as claimed in claim 5, wherein the specific sterilization conditions are as follows: the temperature was 121 ℃ for 15min.
CN202211249554.6A 2022-10-12 2022-10-12 Calcium gluconate and sodium chloride injection and preparation method thereof Pending CN115444816A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111888327A (en) * 2020-08-13 2020-11-06 扬州中宝药业股份有限公司 Calcium gluconate injection and preparation method thereof
CN113041218A (en) * 2021-03-23 2021-06-29 回音必集团江西东亚制药有限公司 Calcium gluconate and sodium chloride injection and preparation method thereof
CN113230207A (en) * 2021-04-16 2021-08-10 江苏意诺飞生物科技有限公司 Preparation process of calcium gluconate and sodium chloride injection

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111888327A (en) * 2020-08-13 2020-11-06 扬州中宝药业股份有限公司 Calcium gluconate injection and preparation method thereof
CN113041218A (en) * 2021-03-23 2021-06-29 回音必集团江西东亚制药有限公司 Calcium gluconate and sodium chloride injection and preparation method thereof
CN113230207A (en) * 2021-04-16 2021-08-10 江苏意诺飞生物科技有限公司 Preparation process of calcium gluconate and sodium chloride injection

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