A norepinephrine bitartrate injection and its preparation process

Abstract

The present application aims to provide a kind of norepinephrine bitartrate injection capable of effectively controlling norepinephrine sulfonate and product color and its preparation method, the present application is by norepinephrine bitartrate as active ingredient and edetate disodium, L-cysteine, sodium chloride, hydrochloric acid and water as excipients, and its preparation method, a kind of norepinephrine bitartrate injection specifically includes the following ingredients: 20g norepinephrine bitartrate, 80g sodium chloride, 2.5-3.0g edetate disodium, 4.0-5.0g L-cysteine per 10000ml, the scheme of the present application can effectively control norepinephrine sulfonate impurity and other oxidative impurities and product color.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically, to a norepinephrine bitartrate injection and its formulation process. Background Technology

[0002] Norepinephrine bitartrate, chemically named (R)-4-(2-amino-1-hydroxyethyl)-1,2-benzenediol bitartrate monohydrate, formerly known as "norepinephrine," is mainly used for blood pressure control in certain acute hypotensive states (such as pheochromocytrectomy, sympathectomy, poliomyelitis, myocardial infarction, sepsis, blood transfusion, and drug reactions). Research on the formulation process of norepinephrine bitartrate injection has great economic and social value.

[0003] There are many reports in the existing literature on the synthetic route of norepinephrine bitartrate. Most of them use catechol as raw material, and obtain it by chloroacetylation, amination, palladium carbon-catalyzed hydrogenation, and L-tartaric acid resolution to salt (see, for example, non-patent literature 1 ((—)-Norepinephrine bitartrate synthesis study, Liang Dawei and Wang Yueqiu, Chemical Technology and Development, No. 8, 2014).

[0004] The production process used is an over-sterilization method of terminal sterilization. The Chinese Pharmacopoeia clearly states that this product is easily deteriorated when exposed to air and oxidized into impurities such as norepinephrine and quinone. Currently, the marketed products and reference preparations all use the antioxidant sodium metabisulfite added to the prescription or use nitrogen protection during production to prevent oxidation. However, such prescriptions and processes will produce norepinephrine sulfonate impurities and other impurities. Summary of the Invention

[0005] The purpose of this invention is to provide a norepinephrine bitartrate injection and its formulation process, so as to achieve the technical effect of reducing sulfonated impurities and other impurities in the norepinephrine bitartrate injection.

[0006] This invention is achieved through the following technical solution:

[0007] A norepinephrine bitartrate injection contains the following components: 20g norepinephrine bitartrate, 80g sodium chloride, 2.5-3.0g disodium edetate, and 4.0-5.0g L-cysteine ​​per 10,000ml.

[0008] By adding 20g of norepinephrine bitartrate, 80g of sodium chloride, 2.5-3.0g of disodium edetate, and 4.0-5.0g of L-cysteine ​​to every 10,000ml, a pharmaceutical composition is formed by norepinephrine bitartrate as the active ingredient and disodium edetate, L-cysteine, sodium chloride, hydrochloric acid, and water as excipients. This composition can effectively control norepinephrine sulfonate impurities, other oxidative impurities, and product color.

[0009] To better realize the present invention, the pH value of the injection solution is further adjusted to 2-4 using hydrochloric acid.

[0010] A formulation process for a norepinephrine bitartrate injection includes the following steps:

[0011] (1) Add 90% of the total amount of water for injection to the preparation container;

[0012] (2) Disodium edetate, sodium chloride, L-cysteine ​​and norepinephrine bitartrate were respectively added to the water for injection obtained in step (1), and stirred to dissolve completely. The pH value was adjusted to 2-4 with hydrochloric acid, and water for injection was added to the total volume to obtain norepinephrine bitartrate solution.

[0013] (3) Filter the medicine obtained in step (2) through a filter cartridge;

[0014] (4) Fill the liquid obtained in step (3) according to the filling procedure and sterilize it at 121°C for 15 minutes.

[0015] To better realize the present invention, further, in step (1), the temperature of the water for injection in the preparation container is 30-50℃.

[0016] To better realize the present invention, further, in step (2), the rotation speed of the stirring is 150-160 rpm, and the stirring time is 10-20 minutes.

[0017] To better realize the present invention, further, in step (3), the filter element is a 0.45μm or 0.22μm filter element.

[0018] The beneficial effects of this invention are: by controlling the selection of excipients and the process, this invention can stably control the growth of norepinephrine sulfonate impurities and other impurities in the product, solving the problem of product color change. Under sterilization conditions of 121℃ for 15 minutes, this formula can still effectively control norepinephrine sulfonate impurities and other oxidized impurities and product color. During the accelerated 6-month stability period, norepinephrine sulfonate impurities were detected, and the product color was colorless. Detailed Implementation

[0019] The present invention will be described in detail below with reference to the embodiments. The embodiments are intended to explain rather than limit the technical solutions of the present invention.

[0020] A norepinephrine bitartrate injection contains the following components: 20g norepinephrine bitartrate, 80g sodium chloride, 2.5-3.0g disodium edetate, 4.0-5.0g L-cysteine ​​per 10000ml, and hydrochloric acid to adjust the pH to 2-4, with a preferred pH of 3.5.

[0021] Example 1

[0022] A norepinephrine bitartrate injection contains the following components: 20g norepinephrine bitartrate, 80g sodium chloride, 2.5g disodium edetate, and 4.0g L-cysteine ​​per 10,000ml.

[0023] The preparation process of norepinephrine bitartrate injection includes the following steps: (1) Add 90% of the total amount of water for injection to the preparation container at a temperature of 30°C;

[0024] (2) Disodium edetate, sodium chloride, L-cysteine ​​and norepinephrine bitartrate were respectively added to the water for injection obtained in step (1), stirred at 150 rpm for 10 minutes to completely dissolve, the pH value was adjusted to 2 with hydrochloric acid, and water for injection was added to the total volume to obtain norepinephrine bitartrate solution.

[0025] (3) Filter the drug solution obtained in step (2) through a 0.45μm filter once and a 0.22μm filter twice;

[0026] (4) Fill the liquid obtained in step (3) according to the filling procedure and sterilize it at 121°C for 15 minutes.

[0027] Example 2

[0028] A norepinephrine bitartrate injection contains the following components: 20g norepinephrine bitartrate, 80g sodium chloride, 3g disodium edetate, and 4.0g L-cysteine ​​per 10,000ml.

[0029] The preparation process of norepinephrine bitartrate injection includes the following steps: (1) Add 90% of the total amount of water for injection to the preparation container at a temperature of 50°C;

[0030] (2) Disodium edetate, sodium chloride, L-cysteine ​​and norepinephrine bitartrate were respectively added to the water for injection obtained in step (1), stirred at 160 rpm for 20 minutes to completely dissolve, the pH value was adjusted to 4 with hydrochloric acid, and water for injection was added to the total volume to obtain norepinephrine bitartrate solution.

[0031] (3) Filter the drug solution obtained in step (2) through a 0.45μm filter once and a 0.22μm filter twice;

[0032] (4) Fill the liquid obtained in step (3) according to the filling procedure and sterilize it at 121°C for 15 minutes.

[0033] Example 3

[0034] A norepinephrine bitartrate injection contains the following components: 20g norepinephrine bitartrate, 80g sodium chloride, 3g disodium edetate, and 5g L-cysteine ​​per 10000ml.

[0035] The preparation process of norepinephrine bitartrate injection includes the following steps: (1) Add 90% of the total amount of water for injection to the preparation container at a temperature of 40°C;

[0036] (2) Disodium edetate, sodium chloride, L-cysteine ​​and norepinephrine bitartrate were respectively added to the water for injection obtained in step (1), stirred at 140 rpm for 15 minutes to completely dissolve, the pH value was adjusted to 3.5 with hydrochloric acid, and water for injection was added to the total volume to obtain norepinephrine bitartrate solution.

[0037] (3) Filter the drug solution obtained in step (2) through a 0.45μm filter once and a 0.22μm filter twice;

[0038] (4) Fill the liquid obtained in step (3) according to the filling procedure and sterilize it at 121°C for 15 minutes.

[0039] Comparative Example

[0040] (1) Add 90% of the total amount of water for injection to the preparation container, and purge with CO2 for 15 minutes to saturate it;

[0041] (2) Add sodium chloride, sodium metabisulfite and norepinephrine bitartrate to the water for injection obtained in step (1) and stir to dissolve.

[0042] (3) The pH value of the solution obtained in step (2) should be 2.3 to 4.3. Add water for injection to the total volume.

[0043] (4) Filter the solution obtained in step (3) through 0.45μm and 0.22μm filter membranes;

[0044] (5) Fill the ampoule with N2 during filling and sterilize at 121°C for 12 minutes.

[0045] The group distribution of Norepinephrine Tartrate Injection in Examples 1-3 is shown in the table below:

[0046]

[0047] Sample quality analysis results:

[0048] Following the preparation methods of Examples 1-3, two samples were prepared for each example, designated as Samples 1-3. The effects of high temperature (60°C) for 30 days and accelerated testing (40°C) for 6 months were investigated for each sample. A reference preparation published by the National Medical Products Administration was selected as a comparison. The norepinephrine sulfonate impurities in Samples 1-3 and the comparison samples were tested by HPLC, and the results are shown in the table below:

[0049]

[0050]

[0051] The data in the table above clearly show that the norepinephrine bitartrate injection of the present invention, after sterilization at 121°C for 15 minutes, can greatly reduce the content of norepinephrine sulfonate impurities in the solution, and at the same time solve the problem of product color change. The product quality is superior to the comparative sample.

[0052] Using the injection and formulation processes in the comparative example, the addition of sodium metabisulfite can appropriately control other oxidative impurities. However, this process will generate approximately 4% norepinephrine sulfonate impurities, which some manufacturers have observed increasing by more than 10% during stability studies. Additionally, the sample color turns yellow, exceeding the limits set by the Chinese Pharmacopoeia. If sodium metabisulfite is not added and nitrogen protection is used, sulfonate impurities can be controlled to some extent. However, other oxidative impurities are difficult to control, the process is complex, and microbial contamination is easily introduced. Furthermore, industrial-scale production in the workshop poses safety hazards.

[0053] In summary, this invention achieves the goal of reducing norepinephrine sulfonate impurities and other oxidizing impurities and controlling product color by controlling excipients and formulation processes. Under sterilization conditions of 121°C for 15 minutes, this formulation can still effectively control norepinephrine sulfonate impurities and other oxidizing impurities and product color. During the accelerated 6-month stability period, norepinephrine sulfonate impurities were detected, and the product color was colorless.

[0054] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A norepinephrine bitartrate injection, characterized in that, It contains the following ingredients: 20g of norepinephrine bitartrate, 80g of sodium chloride, 2.5-3.0g of disodium edetate, and 4.0-5.0g of L-cysteine ​​per 10,000ml. The pH of the injection solution is adjusted to 2-4 with hydrochloric acid. The formulation process of the norepinephrine bitartrate injection includes the following steps: (1) Add 90% of the total amount of water for injection to the preparation container. The temperature of the water for injection should be 30-50℃. (2) Add disodium edetate, sodium chloride, L-cysteine ​​and norepinephrine bitartrate to the water for injection obtained in step (1), and stir to dissolve completely. The stirring speed is 150-160 rpm and the stirring time is 10-20 minutes. Adjust the pH value to 2-4 with hydrochloric acid, and add water for injection to the total volume to obtain norepinephrine bitartrate solution. (3) Filter the drug solution obtained in step (2) through a filter cartridge. The filter cartridges are 0.45μm and 0.22μm filter cartridges. (4) Fill the liquid obtained in step (3) according to the filling procedure and sterilize at 121°C for 15 minutes.

Images