A kind of norepinephrine bitartrate injection and its preparation process

Abstract

The present application relates to the technical field of pharmaceutical products, and specifically discloses a norepinephrine bitartrate injection and its preparation process. Every 10kg of the injection contains 25-45g norepinephrine bitartrate, 70-90g sodium chloride, 280-300g injection-grade soybean oil, 10-20g antioxidant microcapsules, and the remaining components are all base liquid, the base liquid is an aqueous solution treated with deoxygenation, and the antioxidant microcapsules include capsule core and capsule wall, the components of the capsule core include sodium pyrosulfite, and the components of the capsule wall include hydroxyethyl starch. The present application stores sodium pyrosulfite through antioxidant microcapsules, and sodium pyrosulfite can consume oxygen that enters the capsule core through the capsule wall. The capsule wall also isolates sodium pyrosulfite from norepinephrine bitartrate, reducing the possibility that norepinephrine bitartrate fails due to sulfonation reaction, which helps to improve the efficacy of norepinephrine bitartrate injection.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical products, and more specifically, to a norepinephrine bitartrate injection and a preparation process thereof. Background Art

[0002] Norepinephrine is a substance produced by removing the N-methyl group from adrenaline. Currently, norepinephrine bitartrate is commonly used in medicine to prepare injections, which can be used to constrict blood vessels and increase blood pressure.

[0003] In the related art, there is a norepinephrine bitartrate injection, each 10000mL of the injection contains the following components: 22g of norepinephrine bitartrate, 10g of sodium metabisulfite, 88g of sodium chloride, and the remaining part is supplemented to 10000mL by injection water.

[0004] With respect to the above-mentioned related technologies, the inventor believes that although sodium pyrosulfite has an antioxidant effect, sodium pyrosulfite will undergo a sulfonation reaction with norepinephrine bitartrate, and the resulting sulfonated product has no pharmaceutical activity. The sulfonation reaction causes the efficacy of part of norepinephrine bitartrate to disappear, affecting the efficacy of norepinephrine bitartrate injection. Summary of the invention

[0005] In the related art, sodium pyrosulfite will undergo sulfonation reaction with norepinephrine bitartrate, resulting in the disappearance of the efficacy of part of norepinephrine bitartrate, affecting the efficacy of norepinephrine bitartrate injection. In order to improve this defect, the present application provides a norepinephrine bitartrate injection and its preparation process.

[0006] In the first aspect, the present application provides a norepinephrine bitartrate injection, which adopts the following technical scheme: a norepinephrine bitartrate injection, wherein each 10 kg of the injection contains 25-45 g of norepinephrine bitartrate, 70-90 g of sodium chloride, 280-300 g of injection-grade soybean oil, and 10-20 g of antioxidant microcapsules, and the remaining components are all base liquid, which is a deoxygenated aqueous solution, and the antioxidant microcapsules include a capsule core and a capsule wall, the component of the capsule core includes sodium metabisulfite, and the component of the capsule wall includes hydroxyethyl starch.

[0007] By adopting the above technical solution, the present application uses antioxidant microcapsules to store sodium pyrosulfite, hydroxyethyl starch makes the capsule wall have a certain air permeability, and the sodium pyrosulfite in the capsule core can react with oxygen that passes through the capsule wall. The capsule wall isolates the sodium pyrosulfite from the norepinephrine bitartrate, reducing the possibility of sulfonation reaction of the norepinephrine bitartrate, which helps to improve the efficacy of the norepinephrine bitartrate injection.

[0008] Although the coating of the capsule wall limits the absorption of oxygen by sodium pyrosulfite to a certain extent, the injection of the present application is prepared from a base liquid, which has been deoxygenated to reduce the dissolved oxygen content, and the injection-grade soybean oil can also absorb a portion of the dissolved oxygen. The norepinephrine bitartrate of the present application is not prone to oxidation loss, which helps to improve the efficacy of the norepinephrine bitartrate injection.

[0009] Preferably, every 10 kg of the injection contains 30-40 g of norepinephrine bitartrate, 75-85 g of sodium chloride, 285-295 g of injection-grade soybean oil, 13-17 g of antioxidant microcapsules, and the remaining components are all base liquid.

[0010] By adopting the above technical scheme, the raw material ratio of norepinephrine bitartrate injection is optimized, and the therapeutic effect of norepinephrine bitartrate injection is improved under the premise of considering the cost.

[0011] Preferably, the antioxidant microcapsules are prepared according to the following method:

[0012] (1) mixing a saturated aqueous solution of sodium pyrosulfite, xanthan gum, porous starch, and hydroxyethyl starch under anaerobic conditions, and stirring to obtain a capsule stock solution;

[0013] (2) adding an emulsifier, a thickener and water to the capsule stock solution, then heating the capsule stock solution to 70-80° C., and stirring the capsule stock solution to obtain an emulsion;

[0014] (3) The emulsion is cooled and then spray-dried to obtain antioxidant microcapsules.

[0015] By adopting the above technical scheme, the present application first prepares the capsule stock solution and the emulsion in sequence, and the porous starch in the emulsion adsorbs and stores the sodium pyrosulfite to obtain the capsule core. After cooling, the xanthan gum fills the pore structure of the porous starch, and the hydroxyethyl starch and the xanthan gum form the capsule wall together, and then the antioxidant microcapsules are obtained after spray drying.

[0016] Preferably, the emulsifier comprises linoleic acid.

[0017] By adopting the above technical scheme, linoleic acid has amphiphilicity, which can improve the uniformity of the emulsion, and the double bonds of linoleic acid can also play an antioxidant role, making norepinephrine bitartrate less likely to be oxidatively lost, which helps to improve the efficacy of norepinephrine bitartrate injection.

[0018] Preferably, the base liquid contains glucose.

[0019] By adopting the above technical solution, the aldehyde group in glucose has an antioxidant effect, and glucose can also be used to supplement blood sugar for hypoglycemic patients, thereby improving the therapeutic effect of norepinephrine bitartrate injection.

[0020] Preferably, the base liquid also contains gluconate.

[0021] By adopting the above technical solution, gluconate can increase the salt concentration of the base liquid, reduce the solubility of oxygen in the base liquid, and make norepinephrine bitartrate less likely to be oxidized and lost.

[0022] Preferably, the base solution is prepared as follows:

[0023] (1) Mixing water for injection, glucose, a reducing agent and an enzyme carrier, and then standing at 25-35° C. for 30-40 minutes to obtain an enzymatic solution; the enzyme carrier used in this step contains glucose oxidase;

[0024] (2) Filter the enzymatic hydrolyzate, and then mix the obtained filtrate with sodium bicarbonate to obtain a base solution.

[0025] By adopting the above technical scheme, the present application first prepares an enzymolysis solution, and controls the enzymolysis time and temperature, so that part of the glucose reacts with oxygen to produce gluconic acid and hydrogen peroxide under the catalytic action of glucose oxidase. Hydrogen peroxide is consumed by a reducing agent, and gluconic acid reacts with sodium bicarbonate to produce carbon dioxide and sodium gluconate. A portion of the generated carbon dioxide dissolves in the enzymolysis solution, improves the exclusion effect of oxygen, helps to reduce the oxidation loss of norepinephrine bitartrate, and improves the efficacy of norepinephrine bitartrate injection.

[0026] Preferably, the enzyme carrier is prepared according to the following method:

[0027] (1) Glucose oxidase, diatomaceous earth, sodium alginate and water are mixed and stirred to obtain liquid A; calcium chloride is mixed with water to obtain liquid B;

[0028] (2) Liquid A is added dropwise to liquid B, and then allowed to stand at 3-6°C for 1-2 hours. After the standing period, the liquid is filtered and washed, and then dried to obtain the enzyme carrier.

[0029] By adopting the above technical solution, the present application uses calcium alginate and diatomaceous earth as enzyme carriers, and the enzyme carriers fix glucose oxidase. Since the diatomaceous earth can be filtered out, the difficulty of recovering the enzyme carrier is reduced, and the enzyme carrier can be reused.

[0030] Preferably, the reducing agent comprises vitamin C.

[0031] By adopting the above technical scheme, vitamin C can play an antioxidant role. At the same time, vitamin C is also acidic. Vitamin C reacts with sodium bicarbonate to produce carbon dioxide, which improves the oxygen elimination effect, helps to reduce the oxidative loss of norepinephrine bitartrate, and improves the efficacy of norepinephrine bitartrate injection.

[0032] In a second aspect, the present application provides a preparation process of norepinephrine bitartrate injection, which adopts the following technical solution.

[0033] A preparation process of norepinephrine bitartrate injection comprises the following steps:

[0034] (1) adding sodium chloride, antioxidant microcapsules and norepinephrine bitartrate into a base solution to obtain a suspension;

[0035] (2) Add injection-grade soybean oil dropwise onto the surface of the suspension, and heat and sterilize to obtain norepinephrine bitartrate injection.

[0036] By adopting the above technical scheme, the present application first prepares a suspension, and then drips injection-grade soybean oil on the surface of the suspension to obtain norepinephrine bitartrate injection. The unsaturated bonds in the injection-grade soybean oil can play an antioxidant role and hinder the diffusion of oxygen, so that the norepinephrine bitartrate injection is not easily oxidized even when exposed to the air, which helps to improve the efficacy of the norepinephrine bitartrate injection.

[0037] In summary, this application has the following beneficial effects:

[0038] 1. The present application stores sodium pyrosulfite through antioxidant microcapsules. Sodium pyrosulfite can consume oxygen that passes through the capsule wall. The capsule wall also isolates sodium pyrosulfite from norepinephrine bitartrate, reducing the possibility of norepinephrine bitartrate becoming ineffective due to sulfonation reaction, which helps to improve the efficacy of norepinephrine bitartrate injection.

[0039] 2. In the present application, under the catalytic action of glucose oxidase, part of glucose reacts with oxygen to produce gluconic acid, and gluconic acid reacts with sodium bicarbonate to produce carbon dioxide and sodium gluconate. A part of the generated carbon dioxide dissolves in the enzymolysis solution, which improves the effect of oxygen removal, helps to reduce the oxidation loss of norepinephrine bitartrate, and improves the efficacy of norepinephrine bitartrate injection.

[0040] 3. The method of the present application first prepares a suspension, and then drips injection-grade soybean oil on the surface of the suspension to obtain a norepinephrine bitartrate injection. The injection-grade soybean oil in the injection hinders the diffusion of oxygen, which helps to improve the efficacy of the norepinephrine bitartrate injection. DETAILED DESCRIPTION

[0041] The present application is further described in detail below in conjunction with embodiments, preparation examples and comparative examples. The raw materials involved in the present application can all be obtained commercially.

[0042] Preparation example of antioxidant microcapsules

[0043] The following is an explanation using Preparation Example 1.

[0044] Preparation Example 1

[0045] In this preparation example, antioxidant microcapsules were prepared according to the following method:

[0046] (1) Under anaerobic conditions, a saturated aqueous solution of sodium metabisulfite, xanthan gum, porous starch, and hydroxyethyl starch are mixed in a weight ratio of 5:2:1:1, and stirred to obtain a capsule stock solution; the operating temperature of this step is 20° C.;

[0047] (2) adding an emulsifier, a thickener and water to the capsule stock solution, then heating the capsule stock solution to 75° C. and stirring to obtain an emulsion; in this step, the emulsifier is Span 85, and the amount used is 2% of the total weight of the capsule stock solution; the thickener is polyethylene glycol 600, and the amount used is 0.5% of the total weight of the capsule stock solution; the amount of water added is 20% of the total volume of the base solution;

[0048] (3) Cooling the emulsion at 4°C, and then vacuum drying the emulsion after the temperature drops to 4°C, and obtaining antioxidant microcapsules after drying.

[0049] Preparation Example 2

[0050] The difference between this preparation example and preparation example 1 is that the emulsifier is a mixture of linoleic acid and Span 85, and the amount of linoleic acid and Span 85 used is 1% of the total weight of the capsule stock solution.

[0051] Example of preparation of base solution

[0052] Preparation Example 3

[0053] In this preparation example, the base solution was prepared according to the following method:

[0054] At 20°C, carbon dioxide was introduced into water for injection until saturated to obtain a base solution.

[0055] Preparation Example 4

[0056] The difference between this preparation example and preparation example 3 is that the base solution is prepared according to the following method: glucose is added to water for injection at 20° C. until the mass fraction of glucose is 5%, and then carbon dioxide is introduced into the water for injection until saturation to obtain the base solution.

[0057] Preparation Example 5

[0058] The difference between this preparation example and preparation example 3 is that when glucose is added to the water for injection, sodium gluconate is also added simultaneously, and the weight of sodium gluconate is 30% of the glucose.

[0059] Preparation Example 6

[0060] In this preparation example, the base solution was prepared according to the following method:

[0061] (1) Mixing water for injection, glucose, a reducing agent and an enzyme carrier, and then standing at 30° C. for 35 minutes to obtain an enzymatic solution; the enzyme carrier used in this step contains glucose oxidase, and the reducing agent is vitamin C; in this step, the weight ratio of glucose to water for injection is 1:9, the weight ratio of the enzyme carrier to glucose is 1:5, the reducing agent is vitamin C, and the weight ratio of the reducing agent to glucose is 1:15;

[0062] (2) Filter the enzymatic hydrolyzate, and then mix the obtained filtrate with sodium bicarbonate in a weight ratio of 20:1 to obtain a base solution.

[0063] The enzyme carrier in this preparation example was prepared as follows:

[0064] (1) Glucose oxidase, diatomaceous earth, sodium alginate and water are mixed in a weight ratio of 5:10:3:100, and stirred to obtain liquid A; calcium chloride and water are mixed in a weight ratio of 1:19 to obtain liquid B;

[0065] (2) Liquid A was added dropwise to liquid B, and then allowed to stand at 4°C for 1.5 h. After the standing period, the liquid was filtered and washed, and then vacuum dried to obtain the enzyme carrier.

[0066] Preparation Example 7

[0067] This Preparation Example is different from Preparation Example 6 in that vitamin C sodium is used instead of vitamin C.

[0068] Example

[0069] Examples 1-5

[0070] The following description is given by taking Example 1 as an example.

[0071] Example 1

[0072] In this embodiment, norepinephrine bitartrate injection is prepared according to the following steps:

[0073] (1) adding 70 g of sodium chloride, 10 g of the antioxidant microcapsules of Preparation Example 1 and 25 g of norepinephrine bitartrate to 9615 g of the base solution of Preparation Example 3 to obtain a suspension;

[0074] (2) 280 g of injection-grade soybean oil was added dropwise to the surface of the suspension, and the suspension was sterilized by heating at 100° C. for 30 min to obtain norepinephrine bitartrate injection.

[0075] As shown in Table 1, the difference between Examples 1-5 is mainly that the raw material ratios of norepinephrine bitartrate injection are different.

[0076] Table 1

[0077]

[0078] Example 6

[0079] The difference between this embodiment and embodiment 5 is that the antioxidant microcapsules are the antioxidant microcapsules of preparation example 2.

[0080] Example 7

[0081] The difference between this embodiment and embodiment 6 is that the base liquid is the base liquid of preparation example 4.

[0082] Example 8

[0083] The difference between this embodiment and embodiment 7 is that the base liquid is the base liquid of preparation example 5.

[0084] Example 9

[0085] The difference between this embodiment and embodiment 8 is that the base liquid is the base liquid of preparation example 6.

[0086] Example 10

[0087] The difference between this embodiment and embodiment 9 is that the base liquid is the base liquid of preparation example 7.

[0088] Comparative Example

[0089] Comparative Example 1

[0090] A norepinephrine bitartrate injection, each 10000 mL of the injection contains the following components: 22 g of norepinephrine bitartrate, 10 g of sodium pyrosulfite, 88 g of sodium chloride, and the remainder is made up to 10000 mL with injection water.

[0091] The norepinephrine bitartrate injection of this comparative example is prepared according to the following method:

[0092] Mix 22 g of norepinephrine bitartrate, 10 g of sodium pyrosulfite, 88 g of sodium chloride and 9000 g of water for injection, then add water for injection to 10000 mL, and heat sterilize at 100° C. for 30 min to obtain norepinephrine bitartrate injection.

[0093] Comparative Example 2

[0094] The difference between this comparative example and Example 3 is that commercially available water for injection is used instead of the base liquid.

[0095] Comparative Example 3

[0096] The difference between this comparative example and Example 3 is that the injection-grade soybean oil in the components of the injection solution is replaced with an equal weight of water for injection.

[0097] Performance testing methods

[0098] The weight percentage of the sulfonate in the injection before and after heating sterilization was determined by high performance liquid chromatography, and the difference in the weight percentage of the sulfonate before and after heating sterilization was calculated. The ratio of the difference obtained in each embodiment and comparative example to the difference obtained in comparative example 1 was calculated, and the ratio was recorded as the relative content of the sulfonate. The results were expressed as a percentage, as shown in Table 2.

[0099] The weight percentage of norepinephrine bitartrate in the injection solution before and after heat sterilization was determined by high performance liquid chromatography. The weight percentage of norepinephrine bitartrate after heat sterilization was divided by the weight percentage of norepinephrine bitartrate before heat sterilization. The result was recorded as the residual rate of the active ingredient. The result was expressed as a percentage, see Table 2.

[0100] Table 2

[0101]

[0102] Combining Examples 1-5 and Comparative Example 1 and Table 2, it can be seen that the relative contents of sulfonated products measured in Examples 1-5 are lower than those in Comparative Example 1, indicating that the capsule wall of the antioxidant microcapsule isolates sodium pyrosulfite from norepinephrine bitartrate, reduces the possibility of sulfonation of norepinephrine bitartrate, and reduces the failure of norepinephrine bitartrate.

[0103] Combining Example 3 and Comparative Examples 2-3 and Table 2, it can be seen that the residual rate of the effective ingredient measured in Example 3 is higher than that in Comparative Example 2, while the relative content of the sulfonated substance is close to that in Comparative Example 2, indicating that the dissolved oxygen content of the base liquid of Example 3 is reduced after deoxygenation treatment, and the injection-grade soybean oil can also absorb part of the dissolved oxygen. Therefore, the dissolved oxygen in the injection of Example 3 is less, which has the effect of reducing the oxidation loss of norepinephrine bitartrate.

[0104] Combining Example 3 and Example 6 with Table 2, it can be seen that the residual rate of effective ingredients measured in Example 6 is greater than that in Example 3, indicating that linoleic acid reduces the oxidative loss of norepinephrine bitartrate and helps to improve the therapeutic effect of norepinephrine bitartrate injection.

[0105] Combining Example 6, Example 7 and Table 2, it can be seen that the residual rate of effective ingredients measured in Example 7 is greater than that in Example 6, indicating that the antioxidant effect of glucose reduces the amount of dissolved oxygen in the base solution, reduces the oxidative loss of norepinephrine bitartrate, and helps to improve the efficacy of norepinephrine bitartrate injection.

[0106] Combining Example 7 and Example 8 with Table 2, it can be seen that the residual rate of the effective ingredient measured in Example 8 is greater than that in Example 7, indicating that gluconate increases the salt concentration of the base solution, reduces the solubility of oxygen in the base solution, and makes norepinephrine bitartrate less prone to oxidation loss, which helps to improve the efficacy of norepinephrine bitartrate injection.

[0107] Combining Example 8 and Example 9 with Table 2, it can be seen that the residual rate of the effective ingredient measured in Example 9 is greater than that in Example 7, indicating that the base liquid used in Example 9 is more thoroughly deoxygenated, which helps to reduce the oxidation loss of norepinephrine bitartrate and improves the therapeutic effect of norepinephrine bitartrate injection.

[0108] Combining Example 9, Example 10 and Table 2, it can be seen that the residual rate of effective ingredients measured in Example 10 is lower than that in Example 9, indicating that sodium vitamin C cannot react with sodium bicarbonate to produce carbon dioxide, thereby reducing the deoxygenation effect of the base liquid and increasing the oxidation loss of norepinephrine bitartrate.

[0109] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make modifications to the present embodiment without any creative contribution as needed. However, as long as it is within the scope of the claims of the present application, it shall be protected by the patent law.

Claims

1. A norepinephrine bitartrate injection, characterized in that: Every 10kg of the injection contains 25-45g of norepinephrine bitartrate, 70-90g of sodium chloride, 280-300g of injection-grade soybean oil, and 10-20g of antioxidant microcapsules. The remaining components are all base liquid, which is a deoxygenated aqueous solution. The antioxidant microcapsules include a capsule core and a capsule wall. The components of the capsule core include sodium pyrosulfite, and the components of the capsule wall include hydroxyethyl starch. The base liquid contains glucose and gluconate. The base solution is prepared as follows: (1) Mix water for injection, glucose, a reducing agent and an enzyme carrier, and then let it stand at 25-35°C for 30-40 minutes to obtain an enzymatic solution; the enzyme carrier used in this step contains glucose oxidase; (2) filtering the enzymatic hydrolyzate, and then mixing the obtained filtrate with sodium bicarbonate to obtain a base solution; The enzyme carrier is prepared according to the following method: (1) Glucose oxidase, diatomaceous earth, sodium alginate and water are mixed and stirred to obtain liquid A; calcium chloride is mixed with water to obtain liquid B; (2) Add liquid A dropwise into liquid B, and then let it stand at 3-6°C for 1-2 hours. After the standing time, filter and wash, and then dry to obtain the enzyme carrier; The antioxidant microcapsules are prepared according to the following method: (1) Mixing a saturated aqueous solution of sodium metabisulfite, xanthan gum, porous starch, and hydroxyethyl starch under anaerobic conditions, and stirring to obtain a capsule stock solution; (2) adding an emulsifier, a thickener and water to a capsule stock solution, then heating the capsule stock solution to 70-80° C., and stirring the capsule stock solution to obtain an emulsion; the emulsifier comprises linoleic acid; (3) The emulsion is cooled and then spray-dried to obtain antioxidant microcapsules.

2. The norepinephrine bitartrate injection according to claim 1, characterized in that: Every 10 kg of the injection contains 30-40 g of norepinephrine bitartrate, 75-85 g of sodium chloride, 285-295 g of injection-grade soybean oil, 13-17 g of antioxidant microcapsules, and the remaining components are all base liquid.

3. The norepinephrine bitartrate injection according to claim 1, characterized in that: The reducing agent includes vitamin C.

4. The preparation process of the norepinephrine bitartrate injection according to any one of claims 1 to 3, characterized in that: The following steps are involved: (1) adding sodium chloride, antioxidant microcapsules and norepinephrine bitartrate into a base solution to obtain a suspension; (2) Add injection-grade soybean oil dropwise onto the surface of the suspension and sterilize by heating to obtain norepinephrine bitartrate injection.

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