CN112842992A - Dopamine hydrochloride injection serving as reference preparation and preparation method thereof - Google Patents
Dopamine hydrochloride injection serving as reference preparation and preparation method thereof Download PDFInfo
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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
- A61K9/08—Solutions
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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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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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
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
Abstract
The invention provides dopamine hydrochloride injection serving as a reference preparation and a preparation method thereof, belonging to the field of pharmacy. The dopamine hydrochloride injection comprises: dopamine hydrochloride, osmotic pressure regulator auxiliary materials, pH regulators and water, wherein the osmotic pressure regulator auxiliary materials are sodium chloride or glucose, and the pH regulators are hydrochloric acid. The preparation method provided by the embodiment of the invention is carried out in a closed environment filled with asphyxia gas from the initial liquid preparation to the split charging, so that oxygen can be well isolated, meanwhile, the preparation method does not adopt an antioxidant sodium metabisulfite, so that the problem of adverse reaction caused by the antioxidant can be solved, and the allergic reaction to sulfite antioxidants in asthma patients can be avoided, so that the dopamine hydrochloride injection prepared by the method has higher safety.
Description
Technical Field
The invention relates to the field of pharmacy, and in particular relates to a preparation method of dopamine hydrochloride injection serving as a reference preparation.
Background
The chemical name of dopamine hydrochloride is 4- (2-aminoethyl) -1, 2-benzenediol hydrochloride. Dopamine hydrochloride has a beta receptor agonism effect and a certain alpha receptor agonism effect, so that the dopamine hydrochloride can enhance myocardial contractility, increase cardiac output and accelerate heart rate slightly, has a slight contractility effect on peripheral blood vessels and raises arterial pressure; the blood flow is increased by expanding the blood vessels of the internal organs, so that the blood flow of the kidney and the filtration rate of the renal glomerulus are increased, the urine volume and the sodium excretion are increased, the peripheral circulation can be improved, the urine volume is obviously increased, and the heart rate is not obviously influenced.
The reference preparation refers to a reference medicine for evaluating the consistency of the quality and the curative effect of the imitation drugs. At present, in a dopamine hydrochloride injection liquid injection which is commonly used as a reference preparation, 5mL of the reference preparation contains 200mg of dopamine hydrochloride, 45mg of sodium metabisulfite, 50mg of anhydrous citric acid, 25mg of citric acid dihydrate and a proper amount of pH regulator, wherein the pH regulator can be anhydrous citric acid or sodium citrate. The components show that the content of antioxidant sodium metabisulfite in the reference preparation is high, and after the sodium metabisulfite is injected into a human body, serious lethal adverse reactions can be caused, wherein the adverse reactions generally comprise high-sensitivity reactions including bronchospasm and allergy. Although adverse reactions may occur in patients with no history of asthma, allergic reactions to sulfite antioxidants occur in about 5-10% of asthmatics. Therefore, the dopamine hydrochloride injection liquid injection of the current commonly used reference preparation has lower safety.
Disclosure of Invention
In order to solve the technical problems, the invention provides a preparation method of dopamine hydrochloride injection serving as a reference preparation, and the dopamine hydrochloride injection has high safety.
In one aspect, the embodiment of the present invention provides a preparation method of dopamine hydrochloride injection as a reference preparation, including: dopamine hydrochloride, osmotic pressure regulator auxiliary materials, pH regulators and water, wherein the osmotic pressure regulator auxiliary materials are sodium chloride or glucose, and the pH regulators are hydrochloric acid.
Specifically, the mass ratio of dopamine hydrochloride to sodium chloride to water is 40: 9: 1000.
specifically, the mass ratio of dopamine hydrochloride to glucose to water is 4: 5: 100.
specifically, the pH value of the dopamine hydrochloride injection serving as the reference preparation is 3.0-5.0.
On the other hand, the embodiment of the invention provides a preparation method of the dopamine hydrochloride injection, and the preparation method comprises the following steps:
adding the dopamine hydrochloride and the osmotic pressure regulator auxiliary material into the water in an oxygen-free environment, and uniformly stirring to obtain a mixed solution;
adjusting the pH value of the mixed solution to 3.0-5.0 by using the pH regulator to obtain the dopamine hydrochloride injection;
filling a first asphyxiant gas into the dopamine hydrochloride injection;
and filtering the dopamine hydrochloride injection to obtain the pure dopamine hydrochloride injection.
Specifically, the first asphyxiating gas is nitrogen, argon or carbon dioxide, and the gas flow of the first asphyxiating gas is 3-5 m3And/h, the charging time is 1-2 h.
Specifically, the method further comprises: and filling a second asphyxiating gas into the oxygen-free closed container, and adding the dopamine hydrochloride and the osmotic pressure regulator auxiliary material into the water and uniformly stirring in the asphyxiating gas environment.
Further, the second asphyxiating gas is nitrogen, argon or carbon dioxide, and the gas flow of the second asphyxiating gas is 3-5 m3And h, the charging time is 3-4 h.
Further, the method further comprises: and (3) subpackaging and sterilizing the pure dopamine hydrochloride injection in the environment of the asphyxiant gas.
Furthermore, the headspace oxygen and the dissolved oxygen of the dopamine hydrochloride injection after subpackaging are respectively 0.0-0.5% and 0-100 ppb.
The preparation method provided by the embodiment of the invention is carried out in a closed environment filled with asphyxia gas from the initial liquid preparation to the split charging, so that oxygen can be well isolated, meanwhile, the preparation method does not adopt an antioxidant sodium metabisulfite, so that the problem of adverse reaction caused by the antioxidant can be solved, and the allergic reaction to sulfite antioxidants in asthma patients can be avoided, so that the dopamine hydrochloride injection prepared by the method has higher safety.
Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention without any inventive step, are within the scope of protection of the invention.
The embodiment of the invention provides a preparation method of dopamine hydrochloride injection serving as a reference preparation, which comprises the following steps: dopamine hydrochloride, osmotic pressure regulator auxiliary materials, pH regulators and water, wherein the osmotic pressure regulator auxiliary materials are sodium chloride or glucose, and the pH regulators are hydrochloric acid aqueous solutions with the concentration of 0.2%. The water may be water for injection.
Specifically, the mass ratio of dopamine hydrochloride, sodium chloride and water is 40: 9: 1000.
specifically, the mass ratio of dopamine hydrochloride, glucose and water is 4: 9: 100.
specifically, the pH value of the dopamine hydrochloride injection serving as a reference preparation is 3.0-5.0.
The following briefly introduces a preparation method of dopamine hydrochloride injection provided by the embodiment of the invention, and the preparation method comprises the following steps:
filling a second asphyxiant gas into the oxygen-free closed container, and adding dopamine hydrochloride and osmotic pressure regulator auxiliary materials into water in the environment of the asphyxiant gas and uniformly stirring to obtain a mixed solution;
adjusting the pH value of the mixed solution to 3.0-5.0 by using a pH regulator to obtain dopamine hydrochloride injection; the dopamine hydrochloride injection after pH adjustment has stable properties.
Filling a first asphyxiant gas into the dopamine hydrochloride injection;
filtering the dopamine hydrochloride injection serving as the reference preparation to obtain the pure dopamine hydrochloride injection serving as the reference preparation.
Specifically, the first asphyxiating gas is nitrogen, argon or carbon dioxide, and the gas flow of the first asphyxiating gas is 3-5 m3And/h, the charging time is 1-2 h.
Further, the second asphyxiating gas is nitrogen, argon or carbon dioxide, and the gas flow of the second asphyxiating gas is 3-5 m3And h, the charging time is 3-4 h.
Further, the method further comprises: the dopamine hydrochloride injection serving as a reference preparation is packaged and sterilized in a pure environment of asphyxiant gas.
Furthermore, the packaged dopamine hydrochloride injection has 0.0-0.5% of headspace oxygen and 0-100 ppb of dissolved oxygen.
Example one
The embodiment of the invention provides a preparation method of dopamine hydrochloride injection serving as a reference preparation, which comprises the following steps: dopamine hydrochloride, osmotic pressure regulator auxiliary materials, pH regulators and water, wherein the osmotic pressure regulator auxiliary materials are sodium chloride or glucose, and the pH regulators are hydrochloric acid. The water may be water for injection.
Specifically, the mass ratio of dopamine hydrochloride, sodium chloride and water is 40: 9: 1000. further, dopamine hydrochloride, sodium chloride and water were 40g, 9g and 1000mL, respectively.
Specifically, the pH of dopamine hydrochloride injection as a reference formulation is 3.0.
The following briefly introduces a preparation method of dopamine hydrochloride injection provided by the embodiment of the invention, and the preparation method comprises the following steps:
filling a second asphyxiating gas into the oxygen-free closed glass container, and adding dopamine hydrochloride and osmotic pressure regulator auxiliary materials into water in the environment of the asphyxiating gas and uniformly stirring to obtain a mixed solution;
regulating the pH value of the mixed solution to 3.0 by using a pH regulator to obtain dopamine hydrochloride injection;
filling a first asphyxiant gas into the dopamine hydrochloride injection;
filtering the dopamine hydrochloride injection serving as the reference preparation to obtain the pure dopamine hydrochloride injection serving as the reference preparation.
Specifically, the first asphyxiating gas was nitrogen gas having a purity of 99.999%, and the flow rate of the first asphyxiating gas was 3m3And/h, the charging time is 1 h.
Further, the second asphyxiating gas is nitrogen gas having a purity of 99.999%, and the flow rate of the second asphyxiating gas is 3m3And/h, the charging time is 3 h.
Further, the method further comprises: the dopamine hydrochloride injection serving as a reference preparation is packaged and sterilized in a pure environment of asphyxiant gas. Specifically, the sterilization is carried out by overkill (F)0Not less than 12), the sterilization temperature is 121 ℃, and the sterilization time is 15 min.
Furthermore, the headspace oxygen of the packaged dopamine hydrochloride injection is 0.0 percent, and the dissolved oxygen is 0 ppb.
Specifically, the pH adjuster is a 0.2% aqueous hydrochloric acid solution.
Specifically, the filtration method is PES 0.45um membrane filtration.
In the present embodiment, the above-mentioned preparation method is performed in a sealed glass container, and the raw materials are weighed, prepared and filled in the sealed glass container, and at the same time, the raw materials and the used instruments and equipment are required to be placed in the sealed glass container in advance, so as to avoid introducing oxygen during the operation.
Example two
The embodiment of the invention provides a preparation method of dopamine hydrochloride injection serving as a reference preparation, which comprises the following steps: dopamine hydrochloride, osmotic pressure regulator auxiliary materials, pH regulators and water, wherein the osmotic pressure regulator auxiliary materials are sodium chloride or glucose, and the pH regulators are hydrochloric acid.
Specifically, the mass ratio of dopamine hydrochloride, glucose and water is 4: 5: 100. further, dopamine hydrochloride, glucose and water were 40g, 50g and 1000mL, respectively.
Specifically, the pH of dopamine hydrochloride injection as a reference formulation is 4.0.
The following briefly introduces a preparation method of dopamine hydrochloride injection provided by the embodiment of the invention, and the preparation method comprises the following steps:
filling a second asphyxiating gas into the oxygen-free closed glass container, and adding dopamine hydrochloride and osmotic pressure regulator auxiliary materials into water in the environment of the asphyxiating gas and uniformly stirring to obtain a mixed solution;
regulating the pH value of the mixed solution to 3.0 by using a pH regulator to obtain dopamine hydrochloride injection;
filling a first asphyxiant gas into the dopamine hydrochloride injection;
filtering the dopamine hydrochloride injection serving as the reference preparation to obtain the pure dopamine hydrochloride injection serving as the reference preparation.
Specifically, the first asphyxiating gas was argon gas having a purity of 99.999%, and a gas flow rate of the first asphyxiating gas was 4m3The charging time is 1.5 h.
Further, second asphyxiabilityThe gas is carbon dioxide with a purity of 99.999%, and the gas flow rate of the second asphyxiating gas is 4m3The charging time is 3.5 h.
Further, the method further comprises: the dopamine hydrochloride injection serving as a reference preparation is packaged and sterilized in a pure environment of asphyxiant gas. Specifically, the sterilization is carried out by overkill (F)0Not less than 12), the sterilization temperature is 121 ℃, and the sterilization time is 15 min.
Furthermore, the headspace oxygen of the packaged dopamine hydrochloride injection is 0.30 percent, and the dissolved oxygen is 50 ppb.
Specifically, the pH adjuster is a 0.2% aqueous hydrochloric acid solution.
Specifically, the filtration method is PES 0.45um membrane filtration.
In the present embodiment, the above-mentioned preparation method is performed in a sealed glass container, and the raw materials are weighed, prepared and filled in the sealed glass container, and at the same time, the raw materials and the used instruments and equipment are required to be placed in the sealed glass container in advance, so as to avoid introducing oxygen during the operation.
EXAMPLE III
The embodiment of the invention provides a preparation method of dopamine hydrochloride injection serving as a reference preparation, which comprises the following steps: dopamine hydrochloride, osmotic pressure regulator auxiliary materials, pH regulators and water, wherein the osmotic pressure regulator auxiliary materials are sodium chloride or glucose, and the pH regulators are hydrochloric acid.
Specifically, the mass ratio of dopamine hydrochloride, glucose and water is 4: 5: 100. further, dopamine hydrochloride, glucose and water were 40g, 50g and 1000mL, respectively.
Specifically, the pH of dopamine hydrochloride injection as a reference formulation is 5.0.
The following briefly introduces a preparation method of dopamine hydrochloride injection provided by the embodiment of the invention, and the preparation method comprises the following steps:
filling a second asphyxiating gas into the oxygen-free closed glass container, and adding dopamine hydrochloride and osmotic pressure regulator auxiliary materials into water in the environment of the asphyxiating gas and uniformly stirring to obtain a mixed solution;
regulating the pH value of the mixed solution to 3.0 by using a pH regulator to obtain dopamine hydrochloride injection;
filling a first asphyxiant gas into the dopamine hydrochloride injection;
filtering the dopamine hydrochloride injection serving as the reference preparation to obtain the pure dopamine hydrochloride injection serving as the reference preparation.
Specifically, the first asphyxiating gas is carbon dioxide having a purity of 99.999%, and the flow rate of the first asphyxiating gas is 5m3And/h, the charging time is 2 h.
Further, the second asphyxiating gas is carbon dioxide with a purity of 99.999%, and the gas flow rate of the second asphyxiating gas is 5m3And/h, the charging time is 4 h.
Further, the method further comprises: the dopamine hydrochloride injection serving as a reference preparation is packaged and sterilized in a pure environment of asphyxiant gas. Specifically, the sterilization is carried out by overkill (F)0Not less than 12), the sterilization temperature is 121 ℃, and the sterilization time is 15 min.
Furthermore, the headspace oxygen of the packaged dopamine hydrochloride injection is 0.50 percent, and the dissolved oxygen is 100 ppb.
Specifically, the pH adjuster is a 0.2% aqueous hydrochloric acid solution.
Specifically, the filtration method is PES 0.45um membrane filtration.
In the present embodiment, the above-mentioned preparation method is performed in a sealed glass container, and the raw materials are weighed, prepared and filled in the sealed glass container, and at the same time, the raw materials and the used instruments and equipment are required to be placed in the sealed glass container in advance, so as to avoid introducing oxygen during the operation.
Comparative example 1
The comparative example provides a dopamine hydrochloride injection, which comprises: dopamine hydrochloride raw materials, sodium metabisulfite, anhydrous citric acid, sodium citrate dihydrate, a pH regulator and water for injection, and specifically, the 1000mL dopamine hydrochloride injection comprises: 40g of dopamine hydrochloride raw material, 9g of sodium metabisulfite, 100g of anhydrous citric acid, 5g of sodium citrate dihydrate and a proper amount of pH regulator, and water for injection is added until the volume is 1000 mL. The pH adjusting agent was anhydrous citric acid or sodium citrate, and in this comparative example the pH adjusting agent was anhydrous citric acid.
The preparation method of dopamine hydrochloride injection provided by the first comparative example is briefly introduced as follows:
the preparation process is carried out in a closed glass cover, and dopamine hydrochloride raw materials, sodium metabisulfite, anhydrous citric acid, sodium citrate dihydrate, a pH regulator, water for injection and used instruments and equipment which are required by weighing are placed in the closed glass cover in advance;
introducing nitrogen into the sealed glass cover, wherein the flow rate of the nitrogen is 5m3The aeration time is 4 hours; weighing 40g of dopamine hydrochloride, 9g of sodium metabisulfite, 100g of anhydrous citric acid and 5g of sodium citrate dihydrate according to 1000mL of prescription, adding 700mL of water for injection, stirring and dissolving, adjusting the pH value to 3.0 by using a pH regulator, and adding the water for injection to reach the volume of 1000 mL; introducing nitrogen into the prepared solution, wherein the flow rate of the nitrogen is 5m3H, time 2 h; filtering the solution through a PES 0.45um filter membrane; subpackaging the prepared solution, pressing, and capping; and (3) sterilizing the solution at 121 ℃ for 15min to obtain the dopamine hydrochloride injection provided by the comparative example. The headspace oxygen was measured to be 0.25% and the dissolved oxygen was 75 ppb.
Comparative example No. two
The comparative example provides a dopamine hydrochloride injection, which comprises: dopamine hydrochloride raw material, sodium metabisulfite, hydrochloric acid with the concentration of 0.2 percent and water for injection. Specifically, 1000mL dopamine hydrochloride injection comprises: 40g of dopamine hydrochloride raw material, 9g of sodium metabisulfite and a proper amount of dilute hydrochloric acid, and water for injection is added until the volume is 1000 mL.
The preparation method of dopamine hydrochloride injection provided by the comparative example II is briefly introduced as follows:
the preparation process is carried out in a closed glass cover, and dopamine hydrochloride raw material, sodium pyrosulfite and 0.2% hydrochloric acid aqueous solution which are required by weighing are injectedInjecting water, weighing, preparing liquid, filling, and placing the used instruments and equipment in a closed glass cover in advance; filling nitrogen into the closed glass cover, wherein the flow rate of the nitrogen is 5m3H, the time is 4 h; weighing 40g of dopamine hydrochloride and 9g of sodium metabisulfite according to the prescription amount of 1000mL, adding 1000mL of water for injection, fully stirring, adjusting the pH value to 3.0 by using 0.2% hydrochloric acid, and adding the water for injection to 1000 mL; introducing nitrogen into the prepared solution, wherein the flow rate of the nitrogen is 5m3The charging time is 2 hours; filtering the solution through a PES 0.45um filter membrane; subpackaging the prepared solution, pressing, and capping; and (3) sterilizing the solution at 121 ℃ for 15min to obtain the dopamine hydrochloride injection provided by the comparative example II. Headspace oxygen of 0.36%, dissolved oxygen 72ppb
Comparative example No. three
The comparative example provides a dopamine hydrochloride injection, which comprises: dopamine hydrochloride raw material, anhydrous citric acid, sodium citrate dihydrate, 0.2% hydrochloric acid aqueous solution and water for injection. Specifically, 1000mL dopamine hydrochloride injection comprises: 40g of dopamine hydrochloride raw material, 100g of anhydrous citric acid, 5g of sodium citrate dihydrate and a proper amount of 0.2% hydrochloric acid aqueous solution, and water for injection is added to 1000 mL.
The preparation method of dopamine hydrochloride injection provided by the third comparative example is briefly introduced as follows:
the preparation process is carried out in a closed glass cover, dopamine hydrochloride raw material, anhydrous citric acid, sodium citrate dihydrate, 0.2% hydrochloric acid aqueous solution and water for injection which are required by weighing are placed in the closed glass cover in advance by instruments and equipment for weighing, preparing and filling; the glass cover is flushed with nitrogen with the flow rate of 5m3H, the time is 4 h; weighing 40g of dopamine hydrochloride, 100g of anhydrous citric acid and 5g of sodium citrate dihydrate according to 1000mL of prescription, adding 1000mL of water for injection, stirring and dissolving, adjusting the pH value to 3.0 by using 0.2% dilute hydrochloric acid, and adding the water for injection to 1000 mL; the prepared solution is filled with nitrogen with the flow rate of 5m3H, time 2 h; filtering the solution through a PES 0.45um filter membrane; subpackaging the prepared solution, pressing, and capping; sterilizing the solution, and sterilizingAnd the bacterium temperature is 121 ℃, and the sterilization time is 15min, so as to obtain the dopamine hydrochloride injection provided by the comparative example III. Headspace oxygen of 0.27%, dissolved oxygen 77ppb
Comparative example No. four
The embodiment of the invention provides a preparation method of dopamine hydrochloride injection serving as a reference preparation, which comprises the following steps: dopamine hydrochloride, osmotic pressure regulator auxiliary materials, pH regulators and water, wherein the osmotic pressure regulator auxiliary materials are sodium chloride or glucose, and the pH regulators are hydrochloric acid. The water may be water for injection.
Specifically, the mass ratio of dopamine hydrochloride, sodium chloride and water is 40: 9: 1000. further, dopamine hydrochloride, sodium chloride and water were 40g, 9g and 1000mL, respectively.
Specifically, the pH of dopamine hydrochloride injection as a reference formulation is 3.0.
The following briefly introduces a preparation method of dopamine hydrochloride injection provided by the embodiment of the invention, and the preparation method comprises the following steps:
adding dopamine hydrochloride and osmotic pressure regulator auxiliary materials into water, and uniformly stirring to obtain a mixed solution;
regulating the pH value of the mixed solution to 3.0 by using a pH regulator to obtain dopamine hydrochloride injection;
filtering the dopamine hydrochloride injection to obtain a pure dopamine hydrochloride injection serving as a reference preparation;
filling nitrogen into penicillin bottles, subpackaging immediately after filling nitrogen, pressing, and sterilizing after capping, wherein the sterilization adopts an overkill method (F)0Not less than 12), the sterilization temperature is 121 ℃, and the sterilization time is 15 min.
Furthermore, the headspace oxygen of the packaged dopamine hydrochloride injection is 0.27 percent, and the dissolved oxygen is 2225 ppb.
Specifically, the pH adjuster is a 0.2% aqueous hydrochloric acid solution.
Specifically, the filtration method is PES 0.45um membrane filtration.
The products obtained in the first example and the first to fourth comparative examples provided in the example of the present invention were tested, and the specific results are shown in table 1.
Table 1 shows the results of the measurements
Note: in Chinese pharmacopoeia standard, the maximum unknown single impurity of reference preparation is limited to be not more than 0.5%, the total impurity content is not more than 1.0%, and the content of dopamine hydrochloride injection is 93.0-107.0%. Therefore, the dopamine hydrochloride injection provided by the first embodiment of the invention meets the regulations of Chinese pharmacopoeia, and the maximum unknown impurity content, the total impurity content and the dopamine hydrochloride injection content in the first comparative example, the third comparative example and the reference preparation exceed the limit. The fourth comparative example is not carried out in a closed glass container filled with the asphyxiating gas, so that the headspace oxygen and the dissolved oxygen index of the dopamine hydrochloride injection are both higher, and the stability of the dopamine hydrochloride injection is seriously reduced.
The first example, the second example, the third example, the fourth comparative example and the purchased reference preparation (HOSPIRA) provided by the invention are respectively subjected to influence factor sample retention detection, the stability of each sample is examined, and the comparison result is shown in Table 2.
Table 2 shows the stability results
As shown in the comparison in Table 2, the maximum unknown single impurity content, the total impurity content and the dopamine hydrochloride injection content of the first to third embodiments of the invention are all superior to those of the fourth embodiment, and therefore, sodium chloride and glucose serving as osmotic pressure regulators adopted in the invention can be well compatible with dopamine hydrochloride; the dopamine hydrochloride injection obtained by the preparation method provided by the invention has lower related impurity level and lower headspace oxygen and dissolved oxygen content, and can maintain good stability after 30-day influence factor tests.
The preparation method provided by the embodiment of the invention is carried out in a closed environment filled with asphyxia gas from the initial liquid preparation to the split charging, so that oxygen can be well isolated, meanwhile, the preparation method does not adopt an antioxidant sodium metabisulfite, so that the problem of adverse reaction caused by the antioxidant can be solved, and the allergic reaction to sulfite antioxidants in asthma patients can be avoided, so that the dopamine hydrochloride injection prepared by the method has higher safety. And the preparation method does not adopt anhydrous citric acid and sodium citrate, so that the problem of incompatibility of the anhydrous citric acid and the sodium citrate is solved.
Although the embodiments of the present invention have been described above, the above description is only for the convenience of understanding the present invention, and is not intended to limit the present invention. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (10)
1. Dopamine hydrochloride injection serving as a reference preparation is characterized by comprising the following components: dopamine hydrochloride, osmotic pressure regulator auxiliary materials, pH regulators and water, wherein the osmotic pressure regulator auxiliary materials are sodium chloride or glucose, and the pH regulators are hydrochloric acid.
2. Dopamine hydrochloride injection as reference preparation according to claim 1, characterized in that the mass ratio of dopamine hydrochloride, sodium chloride and water is 40: 9: 1000.
3. dopamine hydrochloride injection as reference formulation according to claim 1, characterized in that the mass ratio of dopamine hydrochloride, glucose and water is 4: 5: 100.
4. the dopamine hydrochloride injection as a reference preparation according to claim 1, wherein the dopamine hydrochloride injection as a reference preparation has a pH of 3.0-5.0.
5. The preparation method of the dopamine hydrochloride injection as claimed in any one of claims 1 to 4, wherein the preparation method comprises the following steps:
adding the dopamine hydrochloride and the osmotic pressure regulator auxiliary material into the water in an oxygen-free environment, and uniformly stirring to obtain a mixed solution;
adjusting the pH value of the mixed solution to 3.0-5.0 by using the pH regulator to obtain the dopamine hydrochloride injection;
filling a first asphyxiant gas into the dopamine hydrochloride injection;
and filtering the dopamine hydrochloride injection to obtain the pure dopamine hydrochloride injection.
6. The method according to claim 5, wherein the first asphyxiating gas is nitrogen, argon or carbon dioxide, and the flow rate of the first asphyxiating gas is 3 to 5m3And/h, the charging time is 1-2 h.
7. The method of manufacturing according to claim 5, further comprising: and filling a second asphyxiating gas into the oxygen-free closed container, and adding the dopamine hydrochloride and the osmotic pressure regulator auxiliary material into the water and uniformly stirring in the asphyxiating gas environment.
8. The method of claim 7, wherein the second step is performedThe asphyxiating gas is nitrogen, argon or carbon dioxide, and the gas flow of the second asphyxiating gas is 3-5 m3And h, the charging time is 3-4 h.
9. The method of manufacturing according to claim 7, further comprising: and (3) subpackaging and sterilizing the pure dopamine hydrochloride injection in the environment of the asphyxiant gas.
10. The preparation method according to claim 9, wherein the headspace oxygen and the dissolved oxygen of the dopamine hydrochloride injection after subpackaging are 0.0-0.5% and 0-100 ppb, respectively.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113876697A (en) * | 2021-09-26 | 2022-01-04 | 武汉久安药业有限公司 | Dopamine hydrochloride injection and preparation process thereof |
| CN114617844A (en) * | 2022-04-20 | 2022-06-14 | 江苏吴中医药集团有限公司 | Preparation method of dobutamine hydrochloride water injection |
| CN117180187A (en) * | 2023-08-18 | 2023-12-08 | 亚邦医药股份有限公司 | Preparation method of dopamine hydrochloride injection |
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