CN111067864A - Ropivacaine hydrochloride sodium chloride injection and preparation method thereof - Google Patents
Ropivacaine hydrochloride sodium chloride injection and preparation method thereof Download PDFInfo
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- CN111067864A CN111067864A CN202010071429.5A CN202010071429A CN111067864A CN 111067864 A CN111067864 A CN 111067864A CN 202010071429 A CN202010071429 A CN 202010071429A CN 111067864 A CN111067864 A CN 111067864A
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- injection
- sodium chloride
- ropivacaine hydrochloride
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
- A61P23/02—Local anaesthetics
Abstract
The invention relates to the field of medicines, and in particular relates to ropivacaine hydrochloride sodium chloride injection and a preparation method thereof. The ropivacaine hydrochloride sodium chloride injection comprises: ropivacaine hydrochloride, sodium chloride and water for injection. The invention has the advantages of mature preparation process, stable product quality and high use safety. The influence of the activated carbon on the element impurities of the injection, the influence of the activated carbon on insoluble particles of the injection and the influence of the activated carbon on the content of the main drug of the injection are avoided, meanwhile, the medication safety of patients is greatly reduced, and various risks caused by the process of using the activated carbon are avoided.
Description
Technical Field
The invention relates to the field of medicines, and in particular relates to ropivacaine hydrochloride sodium chloride injection and a preparation method thereof.
Background
Ropivacaine is the first new long-acting amide local anesthetic synthesized as a pure isomer, and has the pharmacological characteristics of low cardiotoxicity, more obvious sensory block separation and vasoconstriction effect. The ropivacaine has the dual effects of anesthesia and analgesia, and can effectively block sensory nerve transmission to generate the analgesia effect at a lower concentration, so that the ropivacaine has small influence on motor nerves.
In the prior art, the ropivacaine hydrochloride and sodium chloride injection liquid uses activated carbon to remove bacterial endotoxin. However, the use of activated carbon has the following problems:
1. influence of activated carbon on injection element impurities: the activated carbon has various sources of raw materials and production processes, so that it may contain various elemental impurities, some of which have toxicity including neurotoxicity and nephrotoxicity, such as: long-term exposure to lead can lead to mental retardation in children. In addition to the risks posed by the elemental impurities themselves, there may also be an impact on the product quality of the injection, e.g. Fe3+、Zn2+The like is easy to promote the oxidative discoloration of the injection of vitamin C, phenolic hydroxyl medicaments and the like, and Fe3+May be precipitated by binding to glucose, which is formed during glucose sterilization, as a salt.
2. The active carbon can adsorb impurities in the liquid medicine, but has the risk of introducing the impurities, and in the use process, the active carbon is carefully selected by comprehensively considering the risk-benefit ratio in combination with the drug property.
3. Effect of activated carbon on insoluble microparticles of injections: the insoluble particles in the injection are particles which are generated by various routes in the process of production or use or generated or mixed by various routes in the process of use, have the particle size of 1-50 mu m, are invisible to naked eyes, but can flow along with blood but cannot be metabolized, so that the insoluble particles can cause difficult discovery and potential serious harm to human bodies. Common sources of insoluble particulates are activated carbon, talc, oak dust, glass dust, and iodine compounds. Activated carbon has received attention as a potential source of risk for insoluble particles in injections. The particle size of the activated carbon is not specified in pharmacopoeia of various countries, and when the particle size of the activated carbon is smaller, the risk of introducing insoluble particles is increased. Therefore, while the product quality is ensured, the use of the activated carbon is reduced as much as possible, and the harm caused by insoluble particles is reduced to the greatest extent.
4. Influence of the active carbon on the content of the main drug of the injection: the active carbon has a certain adsorption effect on the medicine, and particularly has a large influence on the content of the medicine with low dosage. The current general method is that for the preparation with low content of main drug or easy absorption of the main drug by active carbon, the main drug absorbed is compensated mainly by adopting a mode of excessive feeding. The method has certain requirements on the consumption and the source of the active carbon, the product batch and the like, and has certain risks in production.
Disclosure of Invention
Therefore, the present invention has been made in view of the above problems, and it is an object of the present invention to provide a ropivacaine hydrochloride sodium chloride injection that does not contain activated carbon.
The embodiment of the application provides a ropivacaine hydrochloride sodium chloride injection, which comprises: ropivacaine hydrochloride, sodium chloride and water for injection; in the case of 1L injection, the prescription contains 1.0-3.0g of ropivacaine hydrochloride and 7.0-10.0g of sodium chloride.
The embodiment of the application provides ropivacaine hydrochloride sodium chloride injection as described in the first embodiment, and the preparation method comprises the following steps:
(1) pretreatment: washing the preparation tank and the pipeline by using a sodium hydroxide solution to remove bacterial endotoxin, and then washing the preparation tank and the pipeline by using injection water;
(2) preparing liquid: adding water for injection into a preparation tank, weighing a prescription amount of sodium chloride, adding the sodium chloride into the preparation tank, and starting a stirrer to completely dissolve the sodium chloride;
(3) weighing ropivacaine hydrochloride in a prescription amount, adding into a preparation tank, starting a stirrer to completely dissolve, measuring the pH value, adding hydrochloric acid solution as a pH regulator if necessary, adding water for injection to constant volume to full volume, and stirring uniformly;
(4) sampling and detecting the pH value and the content of the intermediate;
(5) the qualified liquid medicine is roughly filtered, finely filtered and filled in a three-layer co-extrusion transfusion bag;
(6) and (3) sterilization: sterilizing by adopting a mode of F0 being more than or equal to 8;
(7) and (6) lamp inspection, plastic packaging, packaging and warehousing.
In one embodiment, the concentration of the sodium hydroxide solution used in step (1) is set to 1mol/L to 5 mol/L.
In one embodiment, further, the concentration of the sodium hydroxide solution used in the step (1) is controlled to be 3 mol/L.
In one embodiment, the pH of the solution in step (3) is adjusted to 4.0-6.0.
In one embodiment, the proportion of the water for injection is controlled to be 70-90%.
In one embodiment, the coarse filtration in the step (5) is carried out by adopting a microporous filter element with a primary pore size of 0.45 μm; and in the fine filtration process, a filter membrane made of polyethersulfone, polyvinylidene fluoride and polytetrafluoroethylene with the primary pore diameter of 0.22 mu m is adopted for filtration.
In one embodiment, the filling amount in the step (5) is 100ml, 200ml and 500 ml.
In one embodiment, the autoclaving at 121 ℃ is used for 15 minutes in step (6).
The invention has the beneficial effects that:
the invention has the advantages of mature preparation process, stable product quality and high use safety. The influence of the activated carbon on the element impurities of the injection, the influence of the activated carbon on insoluble particles of the injection and the influence of the activated carbon on the content of the main drug of the injection are avoided, meanwhile, the medication safety of patients is greatly reduced, and various risks caused by the process of using the activated carbon are avoided.
Drawings
FIG. 1 is a flow chart of the present invention.
FIG. 2 is a table showing the results of the sodium hydroxide concentration test of the present invention.
FIG. 3 is a table of the results of the sterilization test of the present invention.
FIG. 4 is a table of the influence factors test results of the ropivacaine hydrochloride sodium chloride injection of the present invention.
FIG. 5 is a table of accelerated test results for ropivacaine hydrochloride sodium chloride injection of the present invention.
FIG. 6 is a table of the long-term test results of the ropivacaine hydrochloride sodium chloride injection of the present invention.
Detailed Description
Preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings, so that those embodiments can be easily implemented by those having ordinary skill in the art to which the present invention pertains. However, the present invention may be embodied in many different forms and is not limited to the embodiments described below. In addition, in order to more clearly describe the present invention, components not connected to the present invention will be omitted from the drawings.
The embodiment of the application provides a ropivacaine hydrochloride sodium chloride injection, which comprises: ropivacaine hydrochloride, sodium chloride and water for injection; in the case of 1L injection, the prescription contains 1.0-3.0g of ropivacaine hydrochloride and 7.0-10.0g of sodium chloride.
The embodiment of the application provides ropivacaine hydrochloride sodium chloride injection as described in the first embodiment, and the preparation method comprises the following steps:
(1) pretreatment: washing the preparation tank and the pipeline by using a sodium hydroxide solution to remove bacterial endotoxin, and then washing the preparation tank and the pipeline by using injection water;
(2) preparing liquid: adding water for injection into a preparation tank, weighing a prescription amount of sodium chloride, adding the sodium chloride into the preparation tank, and starting a stirrer to completely dissolve the sodium chloride;
(3) weighing ropivacaine hydrochloride in a prescription amount, adding into a preparation tank, starting a stirrer to completely dissolve, measuring the pH value, adding hydrochloric acid solution as a pH regulator if necessary, adding water for injection to constant volume to full volume, and stirring uniformly;
(4) sampling and detecting the pH value and the content of the intermediate;
(5) the qualified liquid medicine is roughly filtered, finely filtered and filled in a three-layer co-extrusion transfusion bag;
(6) and (3) sterilization: sterilizing by adopting a mode of F0 being more than or equal to 8;
(7) and (6) lamp inspection, plastic packaging, packaging and warehousing.
Preferably, as an embodiment, the concentration of the sodium hydroxide solution used in step (1) is set to 1mol/L to 5 mol/L. If the concentration of the sodium hydroxide solution is too small, the removal effect of bacterial endotoxin is poor; if the concentration of the sodium hydroxide solution is too high, the equipment is corroded, so that 1mol/L-5mol/L can be selected to well remove bacterial endotoxin, and the corrosion to the equipment can be avoided.
Preferably, as an implementation mode, further, the concentration of the sodium hydroxide solution used in the step (1) is controlled to be 3mol/L, and the sodium hydroxide solution is the optimal choice through experimental data.
Preferably, as an embodiment, the pH of the solution in step (3) is adjusted to 4.0 to 6.0, which can ensure the stability of the quality of the product and does not cause physical discomfort when a large volume of injection is administered to a patient.
Preferably, as an implementable mode, the proportion of the water for injection is controlled to be 70-90%, and the configuration effect is better.
Preferably, as an embodiment, the coarse filtration in the step (5) is performed by using a microporous filter element with a primary pore size of 0.45 μm; and in the fine filtration process, a filter membrane made of polyethersulfone, polyvinylidene fluoride and polytetrafluoroethylene with the primary pore diameter of 0.22 mu m is adopted for filtration.
Preferably, as an embodiment, the filling amount in the step (5) is 100ml, 200ml and 500 ml.
Preferably, as an implementation mode, the step (6) adopts autoclave sterilization at 121 ℃ for 15 minutes, and experiments prove that the sterilization effect is better under the conditions, and the quality of the obtained product is higher.
The embodiment of the present application further provides the following experimental results:
as shown in FIG. 2, the table shows the test results of the sodium hydroxide concentration, and it can be seen from the table that the bacterial endotoxin can be effectively removed by cleaning the preparation tank and the ropivacaine hydrochloride sodium chloride injection in the pipeline by using 1mol/L-5mol/L sodium hydroxide solution, the bacterial endotoxin levels of the equipment and the pipeline after cleaning meet the regulations, and the preparation tank and the pipeline are not corroded.
As shown in FIG. 3, the results of the sterilization test are shown in the table, and the product was packed as an infusion bag and sterilized at 115 ℃ for 40 minutes, 121 ℃ for 8 minutes, 121 ℃ for 12 minutes, and 121 ℃ for 15 minutes, respectively. As can be seen from the table, all detection indexes of the product have no obvious change under four sterilization conditions, the sterilization effect at 121 ℃ for 15 minutes is optimal, the actual sterilization effect and the production requirement are comprehensively considered, and the sterilization condition of the product is determined to be the moist heat sterilization at 121 ℃ for 15 minutes.
The ropivacaine hydrochloride sodium chloride injection prepared in the embodiment of the application is subjected to stability test according to the stability guiding principle and relevant regulations under the injection, and the indexes are examined as characters, pH values, dextroisomer, relevant substances, content, bacterial endotoxin and the like.
As shown in fig. 4, the table shows the influence factor test results of ropivacaine hydrochloride and sodium chloride injection. As can be seen from the table, the product is placed under illumination (5000lx) and high temperature of 60 ℃ for 10 days, and the measurement results of all indexes are in accordance with the self-simulation standard.
As shown in fig. 5, the table shows the accelerated test results of ropivacaine hydrochloride and sodium chloride injection. As can be seen from the table, when the ropivacaine hydrochloride sodium chloride injection prepared in the above examples is placed at 40 ℃ +/-2 ℃ for 6 months, and is sampled and measured at 1 month, 2 months, 3 months and 6 months, all indexes meet the self-simulation standard.
As shown in fig. 6, the table shows the long-term test results of ropivacaine hydrochloride and sodium chloride injection. As can be seen from the table, the ropivacaine hydrochloride sodium chloride injection prepared in the above examples is packaged according to the market, and is placed under the condition of 25 ℃ +/-2 ℃, and is sampled and measured at months 0, 3, 6, 9 and 12, and all indexes are in accordance with the self-matching standard.
Claims (9)
1. A ropivacaine hydrochloride sodium chloride injection, comprising: ropivacaine hydrochloride, sodium chloride and water for injection; in the case of 1L injection, the prescription contains 1.0-3.0g of ropivacaine hydrochloride and 7.0-10.0g of sodium chloride.
2. The ropivacaine hydrochloride sodium chloride injection of claim 1, which is prepared by the following steps:
(1) pretreatment: washing the preparation tank and the pipeline by using a sodium hydroxide solution to remove bacterial endotoxin, and then washing the preparation tank and the pipeline by using injection water;
(2) preparing liquid: adding water for injection into a preparation tank, weighing a prescription amount of sodium chloride, adding the sodium chloride into the preparation tank, and starting a stirrer to completely dissolve the sodium chloride;
(3) weighing ropivacaine hydrochloride in a prescription amount, adding into a preparation tank, starting a stirrer to completely dissolve, measuring the pH value, adding hydrochloric acid solution as a pH regulator if necessary, adding water for injection to constant volume to full volume, and stirring uniformly;
(4) sampling and detecting the pH value and the content of the intermediate;
(5) the qualified liquid medicine is roughly filtered, finely filtered and filled in a three-layer co-extrusion transfusion bag;
(6) and (3) sterilization: sterilizing by adopting a mode of F0 being more than or equal to 8;
(7) and (6) lamp inspection, plastic packaging, packaging and warehousing.
3. The method of claim 2, wherein: the concentration of the sodium hydroxide solution used in the step (1) is set to be 1mol/L-5 mol/L.
4. The production method according to claim 3, characterized in that: further, the concentration of the sodium hydroxide solution used in the step (1) is controlled to be 3 mol/L.
5. The method of claim 4, wherein: and (4) adjusting the pH value of the solution in the step (3) to 4.0-6.0.
6. The method of claim 5, wherein: the proportion of the water for injection is controlled to be 70-90%.
7. The method of claim 6, wherein: in the rough filtration process in the step (5), a primary microporous filter element with the aperture of 0.45 mu m is adopted for filtration; and in the fine filtration process, a filter membrane made of polyethersulfone, polyvinylidene fluoride and polytetrafluoroethylene with the primary pore diameter of 0.22 mu m is adopted for filtration.
8. The method of claim 7, wherein: the filling amount in the step (5) is 100ml, 200ml and 500 ml.
9. The method of claim 8, wherein: and (4) performing autoclave sterilization at 121 ℃ for 15 minutes in the step (6).
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| Application Number | Priority Date | Filing Date | Title |
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| CN202010071429.5A CN111067864A (en) | 2020-01-21 | 2020-01-21 | Ropivacaine hydrochloride sodium chloride injection and preparation method thereof |
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| CN202010071429.5A CN111067864A (en) | 2020-01-21 | 2020-01-21 | Ropivacaine hydrochloride sodium chloride injection and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112933041A (en) * | 2021-03-05 | 2021-06-11 | 遂成药业股份有限公司 | Preparation method of lidocaine hydrochloride injection |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102670489A (en) * | 2012-05-10 | 2012-09-19 | 山东洁晶药业有限公司 | Ropivacaine hydrochloride sodium chloride injection and preparation method thereof |
| CN103405473A (en) * | 2013-08-27 | 2013-11-27 | 山东齐都药业有限公司 | Mixed carbohydrate-electrolyte injection and preparation method thereof |
-
2020
- 2020-01-21 CN CN202010071429.5A patent/CN111067864A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102670489A (en) * | 2012-05-10 | 2012-09-19 | 山东洁晶药业有限公司 | Ropivacaine hydrochloride sodium chloride injection and preparation method thereof |
| CN103405473A (en) * | 2013-08-27 | 2013-11-27 | 山东齐都药业有限公司 | Mixed carbohydrate-electrolyte injection and preparation method thereof |
Non-Patent Citations (2)
| Title |
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| 于敏主编: "《药剂学学习指导》", 31 January 2009, 中国医药科技出版社 * |
| 刘元芬主编: "《药剂学》", 31 January 2018, 江苏凤凰科学技术出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112933041A (en) * | 2021-03-05 | 2021-06-11 | 遂成药业股份有限公司 | Preparation method of lidocaine hydrochloride injection |
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Effective date of registration: 20210202 Address after: Room 101, building a, NO.402, building 4, Luotian Road, Jinan City, Shandong Province Applicant after: JINAN KANGQIAO PHARMACEUTICAL R&D Co.,Ltd. Address before: Room 402, 4th floor, block a, building 1, 88 Tianluo Road, high tech Zone, Jinan City, Shandong Province Applicant before: SHANDONG MEITAI PHARM Co.,Ltd. |
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Application publication date: 20200428 |