CN115998677A - Meta-hydroxylamine bitartrate injection and preparation method thereof - Google Patents
Meta-hydroxylamine bitartrate injection and preparation method thereof Download PDFInfo
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- CN115998677A CN115998677A CN202310157562.6A CN202310157562A CN115998677A CN 115998677 A CN115998677 A CN 115998677A CN 202310157562 A CN202310157562 A CN 202310157562A CN 115998677 A CN115998677 A CN 115998677A
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Abstract
An m-hydroxylamine bitartrate injection and a preparation method thereof, wherein each 1ml injection comprises the following components: 18.05mg to 19.95mg of metahydroxylamine bitartrate, 8.075mg to 8.925mg of osmotic pressure regulator and the balance of water for injection, and the metahydroxylamine bitartrate injection does not contain an antioxidant. The m-hydroxylamine bitartrate injection disclosed by the embodiment of the application does not contain an antioxidant, so that the side effect of the antioxidant can be avoided, and the stability of the m-hydroxylamine bitartrate is better.
Description
Technical Field
The present application relates to the field of pharmaceutical preparations, and more particularly, to an m-hydroxylamine bitartrate injection and a preparation method thereof.
Background
Meta-hydroxylamine bitartrate, CAS number 33402-03-8, has the following structural formula:
according to the forced degradation experimental result of the meta-hydroxylamine bitartrate, the meta-hydroxylamine bitartrate is suspected to be sensitive to oxygen and easy to oxidize (3% hydrogen peroxide, after 7 days of treatment, 0.26% of degradation impurities are detected by a related substance method, and 1.6% of degradation impurities are detected by a content method).
M-hydroxylamine bitartrate injection with the specification of 1ml to 10mg is an alpha adrenergic receptor agonist, and the indications are: preventing and treating acute hypotension caused by internal resistance of vertebral canal during anesthesia; can be used for treating hypotension caused by hemorrhage, drug allergy, surgical complications or brain trauma or brain tumor complicated with shock, and can be used for adjuvant symptomatic treatment; can also be used for treating hypotension caused by cardiogenic shock or septicemia.
The original company of metahydroxylamine bitartrate was Phebra Pty Ltd, approved for sale in Australia on month 1 and 16 of 2018 under the trade name of
Prescription composition [1] The following are provided:
sulfites are chemicals that are added to certain pharmaceutical products to inhibit oxidation of the active pharmaceutical ingredient. Oxidation of the active pharmaceutical ingredient may lead to drug instability and loss of potency. Sulfites used to inhibit such oxidation processes include sodium bisulfite, sodium metabisulfite, sodium sulfite, potassium bisulfite, potassium metabisulfite, and the like. Recent studies have shown that sulphites may cause allergic reactions in certain susceptible people, especially in asthmatic patients [2]-[3] . Therefore, the addition of sulfite should be careful.
Meta-hydroxylamine bitartrate injection original grinding
The sodium metabisulfite as an antioxidant is added in the prescription, so that allergic reaction can be caused. />
Chinese patent application CN107157925a discloses a meta-hydroxylamine bitartrate injection and a preparation method thereof, wherein each 10000mL of meta-hydroxylamine bitartrate injection comprises: 190g of meta-hydroxylamine bitartrate, 90-110 g of sodium chloride, 10-20 g of sodium bisulphite, 0.05-0.2 g of calcium sodium edetate, 0.01-0.1 g of lipoic acid and the balance of water. The preparation method of the meta-hydroxylamine bitartrate injection comprises the following steps: step one, concentration: taking water for injection, introducing nitrogen, dissolving sodium bisulphite and sodium chloride, sequentially adding lipoic acid, calcium sodium edetate and meta-hydroxylamine bitartrate, introducing nitrogen to saturation, and filtering; step two, diluting: under the condition of continuously introducing nitrogen, adding water for injection to the preparation amount, and circularly filtering to be clear to obtain a semi-finished product; and thirdly, filtering the semi-finished product, filling nitrogen, filling and sealing, sterilizing the semi-finished product for 15 minutes at the temperature of 100 ℃ by using circulating steam, detecting leakage, and cooling to obtain the m-hydroxylamine bitartrate injection. The preparation process has simple and effective utilization method and substances, low cost and various indexes meeting the relevant regulations of the national food and drug administration. However, the formula of the meta-hydroxylamine bitartrate injection of the patent application contains the antioxidant sodium bisulphite, and can cause allergic reaction.
Chinese patent application CN106389312a discloses a pharmaceutical composition of m-hydroxylamine bitartrate injection, which comprises m-hydroxylamine bitartrate, sodium chloride, sodium metabisulfite, edetate and water, wherein each 10000ml of the composition comprises 185-195g of m-hydroxylamine bitartrate, 80-90g of sodium chloride, 10-21g of sodium metabisulfite, the edetate is disodium edetate or calcium sodium edetate, the content is 0.1-0.5g, and the balance is water. However, the formulation of the meta-hydroxylamine bitartrate injection of the patent application contains sodium metabisulfite as an antioxidant, and can cause allergic reaction.
Chinese patent application CN103371969a discloses a meta-hydroxylamine bitartrate injection and a preparation process thereof, wherein the meta-hydroxylamine bitartrate injection comprises the following components: every 10000ml of injection contains 189g of meta-hydroxylamine bitartrate, 68 g-102 g of sodium chloride, 16 g-24 g of sodium metabisulfite and 10000ml of injection water. The quality of the meta-hydroxylamine bitartrate injection meets the relevant regulations of the national food and drug administration. However, the formulation of the meta-hydroxylamine bitartrate injection of the patent application contains sodium metabisulfite as an antioxidant, and can cause allergic reaction.
Chinese patent application CN112245387A discloses a composition and a preparation method of a meta-hydroxylamine bitartrate injection, wherein the prescription of the meta-hydroxylamine bitartrate injection consists of meta-hydroxylamine bitartrate, sodium chloride, L-carnosine and water for injection, wherein the dosage of the L-carnosine is 2-8mg/ml. The meta-hydroxylamine bitartrate injection has the advantages of simple composition, stable quality, simple and efficient preparation process, no need of special equipment and filling of inert gas, low impurity level of finished products prepared after terminal sterilization (F0 is more than or equal to 12), and good safety. However, the formula of the meta-hydroxylamine bitartrate injection of the patent application contains the antioxidant L-carnosine, and the L-carnosine is usually used in oral food additives or cosmetics, lacks safety data (FDA Inactive Ingredient (IIG) database is not loaded) for injection administration, cannot be added in the formula of the injection at will, and otherwise unpredictable side effects can be caused.
Therefore, there is a need for an m-hydroxylamine bitartrate injection and a preparation method thereof, which can avoid oxidation of m-hydroxylamine bitartrate and can not bring other side effects.
Disclosure of Invention
The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the application.
The application provides the meta-hydroxylamine bitartrate injection and the preparation method thereof, wherein the meta-hydroxylamine bitartrate injection does not contain an antioxidant, can avoid side effects of antioxidants such as sulfite, L-carnosine and the like, and has good stability.
The application provides a meta-hydroxylamine bitartrate injection, which comprises the following components in each 1ml of injection:
m-hydroxylamine bitartrate 18.05mg to 19.95mg
Osmotic pressure regulator 8.075mg to 8.925mg
The water for injection is the balance;
and the meta-hydroxylamine bitartrate injection does not contain an antioxidant.
In embodiments of the present application, each 1ml of injectate may comprise:
meta-hydroxylamine bitartrate 19mg
Osmotic pressure regulator 8.5mg
The balance of water for injection;
and the meta-hydroxylamine bitartrate injection does not contain an antioxidant.
In embodiments of the present application, the osmolality adjusting agent may be selected from any one or more of sodium chloride, glucose, phosphate, and citrate.
In embodiments of the present application, the osmolality adjusting agent may be sodium chloride.
The embodiment of the application also provides a preparation method of the meta-hydroxylamine bitartrate injection, which comprises the following steps:
weighing: the meta-hydroxylamine bitartrate, the osmotic pressure regulator and the water for injection are weighed according to the proportion;
preparing: adding a part of water for injection into a preparation tank, sequentially adding an osmotic pressure regulator and meta-hydroxylamine bitartrate under a stirring state, stirring until the osmotic pressure regulator and the meta-hydroxylamine bitartrate are dissolved, supplementing water for injection to a full amount, and uniformly stirring to obtain a liquid medicine;
and (3) filtering: filtering the liquid medicine;
and (3) filling and sealing: filling the filtered liquid medicine into a medicament container, and sealing;
and (5) sterilizing.
In embodiments of the present application, the filtering may include filtering using a polyvinylidene fluoride filter cartridge having a diameter of 0.2 microns.
In embodiments of the present application, the temperature of the sterilization may be 121 ℃, and the time of the sterilization may be ≡12 minutes.
In embodiments of the present application, the sterilization time may be 12 minutes to 25 minutes.
According to the meta-hydroxylamine bitartrate injection and the preparation method thereof, the side effect caused by the antioxidant can be avoided by removing the antioxidant, the sensitivity of the preparation to oxygen is improved (strict oxygen control is not needed), and the production control cost is reduced; meanwhile, the level of related substances of the finished product can be effectively controlled and good product stability can be obtained under the condition that an antioxidant is not added.
Additional features and advantages of the application 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 application. Other advantages of the present application may be realized and attained by the instrumentalities and aspects depicted in the specification.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the present application more apparent, embodiments of the present application will be described in detail hereinafter. It should be noted that, in the case of no conflict, the embodiments and features in the embodiments may be arbitrarily combined with each other.
The application provides a meta-hydroxylamine bitartrate injection, which comprises the following components in each 1ml of injection:
m-hydroxylamine bitartrate 18.05mg to 19.95mg
Osmotic pressure regulator 8.075mg to 8.925mg
The balance of water for injection;
and the meta-hydroxylamine bitartrate injection does not contain an antioxidant.
In the examples of the present application, each 1ml of injection may consist of the following components:
m-hydroxylamine bitartrate 18.05mg to 19.95mg
Osmotic pressure regulator 8.075mg to 8.925mg
The balance of water for injection.
In embodiments of the present application, each 1ml of injectate may comprise:
meta-hydroxylamine bitartrate 19mg
Osmotic pressure regulator 8.5mg
The balance of water for injection;
and the meta-hydroxylamine bitartrate injection does not contain an antioxidant.
In the examples of the present application, each 1ml of injection may consist of the following components:
meta-hydroxylamine bitartrate 19mg
Osmotic pressure regulator 8.5mg
The balance of water for injection.
In embodiments of the present application, the osmolality adjusting agent may be selected from any one or more of sodium chloride, glucose, phosphate, and citrate.
In the embodiment of the application, other auxiliary materials such as EDTA, citric acid and other common auxiliary materials acceptable to human bodies or sugar sources such as sorbitol, xylitol and glucose can be added into the meta-hydroxylamine bitartrate injection.
In embodiments of the present application, the osmolality adjusting agent may be sodium chloride.
The embodiment of the application also provides a preparation method of the meta-hydroxylamine bitartrate injection, which comprises the following steps:
weighing: the meta-hydroxylamine bitartrate, the osmotic pressure regulator and the water for injection are weighed according to the proportion;
preparing: adding a part of water for injection into a preparation tank, sequentially adding an osmotic pressure regulator and meta-hydroxylamine bitartrate under a stirring state, stirring until the osmotic pressure regulator and the meta-hydroxylamine bitartrate are dissolved, supplementing water for injection to a full amount, and uniformly stirring to obtain a liquid medicine;
and (3) filtering: filtering the liquid medicine;
and (3) filling and sealing: filling the filtered liquid medicine into a medicament container, and sealing;
and (5) sterilizing.
In embodiments of the present application, the filtering may include filtering using a polyvinylidene fluoride filter cartridge having a diameter of 0.2 microns.
In embodiments of the present application, the temperature of the sterilization may be 121 ℃, and the time of the sterilization may be ≡12 minutes.
In embodiments of the present application, the sterilization time may be 12 minutes to 25 minutes.
In the embodiments of the present application, the medicament container may be a bottle, a dual-cavity bag, a multi-cavity bag package or a multi-layer co-extrusion infusion film (bag) which meets the requirements of medicine, and may be, for example, an infusion bottle, an infusion bag or the like.
The raw materials, chemicals, instruments and the like used in the following examples are commercially available products unless otherwise specified.
Example 1
The formulation of the meta-hydroxylamine bitartrate injection of this example was as follows:
the preparation method of the meta-hydroxylamine bitartrate injection in the embodiment comprises the following steps:
(1) Weighing: m-hydroxylamine bitartrate, sodium chloride and water for injection are weighed according to a prescription;
(2) Preparing: adding 80% of water for injection into a preparation tank, continuously introducing nitrogen into the preparation tank for bubbling, keeping the dissolved oxygen content of the solution in the preparation tank to be less than or equal to 500pp, sequentially adding sodium chloride and meta-hydroxylamine bitartrate in a stirring state, stirring until the sodium chloride and the meta-hydroxylamine bitartrate are completely dissolved, adding water for injection to a full volume, and uniformly stirring to obtain a liquid medicine;
(3) And (3) filtering: filtering the liquid medicine obtained in the step (2) through a polyvinylidene fluoride filter element with the diameter of 0.2 microns;
(4) And (3) filling and sealing: filling the filtered liquid medicine into a borosilicate glass ampoule bottle, filling nitrogen into the borosilicate glass ampoule bottle after filling is finished, so that the residual oxygen in the headspace of the borosilicate glass ampoule bottle is less than or equal to 5%, and sealing;
(5) And (3) sterilization: sterilizing at 121 ℃ for 12 minutes to prepare the meta-hydroxylamine bitartrate injection of the embodiment.
Example 2
The formulation composition of the meta-hydroxylamine bitartrate injection of this example was the same as that of example 1.
The preparation method of the meta-hydroxylamine bitartrate injection in the embodiment comprises the following steps:
(1) Weighing: m-hydroxylamine bitartrate, sodium chloride and water for injection are weighed according to a prescription;
(2) Preparing: adding 80% of water for injection into a preparation tank, sequentially adding sodium chloride and meta-hydroxylamine bitartrate under stirring, stirring until the sodium chloride and the meta-hydroxylamine bitartrate are completely dissolved, adding water for injection to a certain volume, and stirring uniformly to obtain a liquid medicine;
(3) And (3) filtering: filtering the liquid medicine obtained in the step (2) through a polyvinylidene fluoride filter element with the diameter of 0.2 microns;
(4) And (3) filling and sealing: filling the filtered liquid medicine into borosilicate glass ampoule bottles, and sealing;
(5) And (3) sterilization: sterilizing at 121 ℃ for 12 minutes to prepare the meta-hydroxylamine bitartrate injection of the embodiment.
Comparative example 1
The formulation of the meta-hydroxylamine bitartrate injection of the comparative example is as follows:
the preparation method of the meta-hydroxylamine bitartrate injection of the comparative example comprises the following steps:
with reference to the preparation method of example 1, sodium metabisulfite was added in step (2), and the other operations were the same as in example 1.
Comparative example 2
The formulation of the meta-hydroxylamine bitartrate injection of this comparative example was the same as that of comparative example 1.
With reference to the preparation method of example 2, sodium metabisulfite was added in step (2), and the other operations were the same as in example 2.
Stability evaluation
Reference formulation
Meta-hydroxylamine bitartrate injection prepared in examples 1-2 and comparative examples 1-2Stability was tested after a period of time and the properties, pH, content and related substances of the formulation were tested. The results are shown in Table 1.
TABLE 1 stability test results of meta-hydroxylamine bitartrate injection
Note that: the acceleration conditions were that the samples were placed in a stability test chamber at 40 ℃ at 75% rh.
From the above results, the properties, pH and content of the reference formulation and each of the examples and comparative examples were not significantly changed, and thus, attention was paid to the related substances.
Example 1 was run without antioxidant addition but with an oxygen scavenging process (formulation stage to control the dissolved oxygen content of the solution and potting nitrogen charge to control headspace residual oxygen) with lower levels of relevant material (better than the reference formulation and comparative) and no increase in relevant material levels with longer stability hold time. Example 2 was free of antioxidant addition and was not subjected to the deoxygenation (nitrogen protection) process, with lower levels of relevant substances (better than the reference formulation and comparative example) and no increase in relevant substance levels with prolonged stability standing time. The levels of relevant substances for comparative example 1 and the reference formulation were lower and did not increase with prolonged stability placement time, but were slightly higher than for examples 1 and 2. As the stability standing time was prolonged, the level of the relevant substances of comparative example 2 increased significantly to a final overrun.
It can be seen from the above that: when the prescription contains an antioxidant (sodium metabisulfite), the oxygen content needs to be strictly controlled (for example, a nitrogen charging and deoxidizing process can be adopted) so as to ensure that related substances of the product are not obviously increased in the stability process; when the prescription does not contain an antioxidant (sodium metabisulfite), the oxygen content does not need to be controlled, and the related substances of the product can be ensured not to be obviously increased in the stability process.
Therefore, the prescription and the preparation method adopted in the embodiment 1 of the application can avoid side effects caused by the antioxidant by removing the antioxidant, improve the sensitivity of the preparation to oxygen (without strictly controlling oxygen), reduce the production control cost, effectively control the related substance level of the finished product and obtain good product stability.
Reference to the literature
[1]Meta-hydroxylamine bitartrate injection
Reference formulation instructions.
[2] U.S. Food and Drug Administration (FDA) CFR-2012-title-vol4-sec201.22.
[3] Xuelian, etc.; sulfite in the compound amino acid injection causes anaphylactic reaction and risk, and the journal of clinical medicine treatment, 16 th and 4 th phases, and 2018, 4 months.
Although the embodiments disclosed in the present application are described above, the embodiments are only used for facilitating understanding of the present application, and are not intended to limit the present application. Any person skilled in the art to which this application pertains will be able to make any modifications and variations in form and detail of implementation without departing from the spirit and scope of the disclosure, but the scope of the application is still subject to the scope of the claims that follow.
Claims (8)
1. An m-hydroxylamine bitartrate injection, characterized in that each 1ml of injection comprises:
m-hydroxylamine bitartrate 18.05mg to 19.95mg
Osmotic pressure regulator 8.075mg to 8.925mg
The water for injection is the balance;
and the meta-hydroxylamine bitartrate injection does not contain an antioxidant.
2. The meta-hydroxylamine bitartrate injection according to claim 1, wherein each 1ml of the injection comprises:
meta-hydroxylamine bitartrate 19mg
Osmotic pressure regulator 8.5mg
The water for injection is the balance;
and the meta-hydroxylamine bitartrate injection does not contain an antioxidant.
3. The meta-hydroxylamine bitartrate injection according to claim 1 or 2, wherein the osmotic pressure regulator is selected from any one or more of sodium chloride, glucose, phosphate and citrate.
4. A meta-hydroxylamine bitartrate injection as claimed in claim 3, wherein the osmotic pressure regulator is sodium chloride.
5. A method for preparing the meta-hydroxylamine bitartrate injection according to any one of claims 1 to 4, comprising:
weighing: the meta-hydroxylamine bitartrate, the osmotic pressure regulator and the water for injection are weighed according to the proportion;
preparing: adding a part of water for injection into a preparation tank, sequentially adding an osmotic pressure regulator and meta-hydroxylamine bitartrate under a stirring state, stirring until the osmotic pressure regulator and the meta-hydroxylamine bitartrate are dissolved, supplementing water for injection to a full amount, and uniformly stirring to obtain a liquid medicine;
and (3) filtering: filtering the liquid medicine;
and (3) filling and sealing: filling the filtered liquid medicine into a medicament container, and sealing;
and (5) sterilizing.
6. The method of making according to claim 5 or wherein the filtering comprises filtering with a polyvinylidene fluoride filter cartridge having a diameter of 0.2 microns.
7. The method according to claim 5 or 6, wherein the sterilization temperature is 121 ℃, and the sterilization time is not less than 12 minutes.
8. The method of claim 7, wherein the sterilization time is 12 minutes to 25 minutes.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202310157562.6A CN115998677A (en) | 2023-02-23 | 2023-02-23 | Meta-hydroxylamine bitartrate injection and preparation method thereof |
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| CN202310157562.6A CN115998677A (en) | 2023-02-23 | 2023-02-23 | Meta-hydroxylamine bitartrate injection and preparation method thereof |
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