N-acetylcysteine xylitol injection and preparation method thereof

Abstract

The invention discloses an N-acetylcysteine xylitol injection and a preparation method thereof. The N-acetylcysteine xylitol injection is prepared from the following raw materials in mass volume ratio: 0.020 to 0.035 g / mL of N-acetylcysteine, 0.015 to 0.030 g / mL of xylitol, 0.005 to 0.010 g / mL of pH (Potential of Hydrogen) regulator and the balance of water for injection. According to the method disclosed by the invention, by controlling the dissolution concentration, temperature and headspace residual oxygen range of the acetylcysteine and selecting the pH regulator with proper concentration to control the pH value of the liquid medicine and control the preparation time, the oxidation and degradation of the acetylcysteine in the liquid medicine preparation process can be reduced, so that the stability of the product quality is improved, and the generation of related substances is controlled. The quality stability of the acetylcysteine xylitol injection is remarkably improved, the medication safety of a patient is guaranteed, and the acetylcysteine xylitol injection has wide application prospects and value.

Description

Technical Field

[0001] The present invention relates to a high-stability N-acetylcysteine ​​xylitol injection and a preparation method thereof. Background Art

[0002] N-acetylcysteine ​​(NAC) is the acetylated form of the endogenous semi-essential amino acid cysteine, which has multiple effects in the body.

[0003] First, the most obvious effect of NAC in the body is its antioxidant effect. It has reducing properties and can remove reactive oxygen species (ROS) in the body. At the same time, it can significantly increase the level of glutathione (GSH) in the body. The chemical structure of NAC contains a free sulfhydryl group that can interact with electrophilic oxidizing groups. Many free radicals are produced during the metabolism of the human body, such as O·, ONOO - , OH•, etc. These free radicals can damage the body's normal metabolism and lead to various diseases. As a free radical scavenger, the active sulfhydryl groups in NAC molecules can combat tissue oxidative damage caused by various factors and exert an antioxidant effect.

[0004] Secondly, NAC has significant anti-inflammatory effects in vivo. During the onset and progression of inflammation in the liver, lungs, and other organs, many effector cells accumulate in the target tissues via the bloodstream. Simultaneously, the expression of numerous adhesion molecules, such as ELAM-1, VCAM-1, ICAM-1, LFA-1, and VLA-4, increases significantly, participating in the entire inflammatory process. Studies have shown that NAC can exert significant anti-inflammatory effects by inhibiting the expression of these adhesion molecules on central venous and portal vascular endothelial cells in patients with hepatitis, such as by suppressing ICAM-1 expression, reducing NF-kB levels, inhibiting the release of proinflammatory mediators from activated monocytes and macrophages, and preventing the release of chemokines (such as p38 and MAPK).

[0005] Thirdly, NAC has immunomodulatory function, which can enhance the host's defense function and prevent or alleviate the deterioration of some chronic diseases such as liver disease, kidney disease, bronchial and lung diseases. Studies have shown that NAC can not only regulate lymphocyte activity and reduce T ‐ Cellular IL-4 synthesis and B ‐ The production of IgE and IgG4 cells can also inhibit T ‐ It can induce cell apoptosis, reverse the downregulation of IL-2 mRNA and IL-2, and exert its immunomodulatory function.

[0006] Finally, NAC also has a powerful and specific detoxification effect. Under normal conditions, acetaminophen is metabolized by the cytochrome P450 enzyme system to produce a toxic metabolite, acetaminophen isoquinolinimide (NAPQI). This metabolite is bound to GSH in liver cells and excreted, preventing liver damage. When acetaminophen is consumed excessively, GSH in liver cells is depleted, and NAPQI binds to liver cell proteins, leading to liver cell necrosis. At this time, NAC can specifically bind to NAPQI to form a non-toxic compound that is excreted from the body. It can also exert its detoxification function by increasing GSH levels in the body.

[0007] Currently, acetylcysteine ​​is available in injections, tablets, capsules, effervescent tablets, and solutions. Tablets, capsules, effervescent tablets, and solutions are primarily used to treat pulmonary diseases such as acute or chronic bronchitis and chronic obstructive pulmonary disease, including expectoration. Acetylcysteine ​​injection was first marketed in the United States in 2004, primarily as an antidote for liver failure caused by acetaminophen (APAP) overdose. It is recommended as the preferred treatment based on Level I evidence-based medicine by the three leading international guidelines (EASL / AASLD / CMA) in Europe, the United States, and China. It is also the only drug approved by the US FDA for emergency treatment of liver failure and detoxification of drug-induced liver injury. Acetylcysteine-related products marketed in Canada and Germany are primarily used for pulmonary diseases such as acute and chronic bronchopneumonia. The European Union has also granted orphan drug designation to related products for the treatment of pseudomyxoma peritonei. In my country, acetylcysteine ​​injection was first launched on the market in 2005. It is a drug recommended for use in authoritative guidelines such as the Chinese Medical Association's "Guidelines for the Diagnosis and Treatment of Drug-Induced Liver Injury", "Clinical Pathway for Drug-Induced Liver Injury" and "Guidelines for the Diagnosis and Treatment of Liver Failure".

[0008] However, currently, some patients experience adverse reactions such as nausea, vomiting, rash, itching, bronchospasm, dizziness, headache, fever, and allergic reactions when using NAC injection. Occasionally, patients may experience facial flushing, angioedema, tachycardia, hypotension and hypertension, erythropenia and leukocytopenia, pharyngitis, rhinorrhoea, and tinnitus. Studies have found that, in addition to adverse reactions caused by the inherent pharmacological effects of the drug itself, the content and type of related substances are also associated with some adverse reactions.

[0009] The chemical structure of organic impurities in drugs is generally similar to or related to the active ingredient, so they are often referred to as related substances. Different preparation processes may produce different types and quantities of related substances. In the study of drug-related substances, the requirements of the "Technical Guidelines for the Study of Impurities in Chemical Drugs" must be followed to control the limits of each known impurity, unknown impurity, and total impurities. Products containing NAC are generally single-ingredient drugs. NAC itself has reducing properties and is easily oxidized and destroyed during the production process. Therefore, the stability of NAC and the control of its related substances in various dosage forms of NAC products, especially large-volume injectable products, are major technical difficulties and a key quality control focus in their production process, significantly affecting product stability and the incidence of adverse reactions.

[0010] Therefore, it is a major technical challenge in this field to prepare NAC-related products with low content of related substances and good product stability through reasonable formulation, packaging materials and production process design optimization.

[0011] In the field, according to the production processes reported in existing patents, NAC injections are generally stabilized by adding special protective agents, such as metal ion complexing agents like edetate disodium (CN 114681397 A, CN 116350581 A, CN101664384 A) or stabilizers like tromethamine (CN 101239037A). Although these special protective agents are inert, while increasing the stability of the injection, they may also introduce new impurities, potentially triggering a range of adverse drug reactions. Therefore, during actual formulation research, the selection of the appropriate protective agent requires extreme caution. Furthermore, during drug use, the appropriate use and incompatibilities of injections containing protective agents must be rigorously examined.

[0012] In addition, the limitations of the existing NAC injection preparation process will cause a certain degree of oxidative degradation of the acetylcysteine ​​raw material during the preparation process, making it difficult to control the relevant substances in the prepared acetylcysteine ​​injection, especially large-volume injection.

[0013] Therefore, developing a preparation process for NAC injection with low content of related substances and high product stability is of great significance to improving patients' medication safety and compliance. Summary of the Invention

[0014] The problem to be solved by the present invention is to provide an N-acetylcysteine ​​xylitol injection, which has a low content of related substances and good stability and safety.

[0015] Another object of the present invention is to provide a preparation process for the N-acetylcysteine ​​xylitol injection, which is scientific and reasonable, and the obtained product has stable quality, low content of related substances, and good product safety.

[0016] The technical solution adopted in the present invention is as follows: An N-acetylcysteine ​​xylitol injection comprises the following raw materials in a mass-to-volume ratio: 0.020-0.035 g / mL of N-acetylcysteine, 0.015-0.030 g / mL of xylitol, 0.005-0.010 g / mL of a pH regulator, and the remainder being water for injection.

[0017] Furthermore, the N-acetylcysteine ​​xylitol injection is preferably composed of the following raw materials in a mass-to-volume ratio: N-acetylcysteine ​​0.023-0.033 g / mL, xylitol 0.020-0.028 g / mL, pH adjuster 0.0065-0.009 g / mL, and the rest is water for injection.

[0018] Furthermore, the N-acetylcysteine ​​xylitol injection is more preferably composed of the following raw materials in the following mass-to-volume ratio: N-acetylcysteine ​​0.025-0.032 g / mL, xylitol 0.022-0.027 g / mL, pH adjuster 0.0070-0.0085 g / mL, and the rest is water for injection.

[0019] The N-acetylcysteine ​​xylitol injection of the present invention has an osmotic pressure of 450-650 mOsm / L and a pH of 6.5-7.5.

[0020] The content of N-acetylcysteine ​​in N-acetylcysteine ​​xylitol injection should be 90.0% ~110.0% of the labeled amount.

[0021] The impurity content in N-acetylcysteine ​​xylitol injection is ≤3%, calculated as the percentage of N-acetylcysteine ​​contained in the injection.

[0022] The pH regulator is selected from sodium hydroxide, potassium hydroxide or sodium bicarbonate, preferably sodium hydroxide.

[0023] The N-acetylcysteine ​​xylitol injection is prepared according to the following method: Step a: Xylitol is completely dissolved in water for injection, activated carbon is added, the mixture is thoroughly mixed, and the temperature is raised to 75-80°C, maintained for 10-20 minutes, and then cooled to 60-65°C. The mixture is filtered and decarbonized to obtain Solution A; the concentration of xylitol in Solution A is preferably 0.2-0.3 g / mL; Step b: N-Acetylcysteine ​​is added to water for injection at 20-65°C to adjust the NAC concentration to 0.12-1g / mL. The temperature of the solution is controlled to ≤65°C under inert gas protection and the residual oxygen content in the headspace is controlled to ≤2%. The pH value of the solution is adjusted to 4.0-7.5 with 1-4 mol / L pH regulator to obtain Solution B. Step c: Under inert gas protection, according to the ratio of N-acetylcysteine ​​to a final concentration of 0.020-0.035 g / mL and xylitol to a final concentration of 0.015-0.030 g / mL, solution A and solution B are mixed evenly in proportion, and the pH value is adjusted to 6.5-7.5 with a 1-4 mol / L pH regulator, and the headspace residual oxygen content is controlled to be ≤2%, and the liquid temperature is ≤65°C. Water for injection at a temperature of ≤65°C is added to the full amount, and the headspace residual oxygen content is controlled to be ≤2%, and the liquid temperature is ≤65°C. The mixture is mixed evenly, filtered, and after sampling and testing, the mixture is filled and sterilized to prepare the N-acetylcysteine ​​xylitol injection.

[0024] The present invention also provides a method for preparing N-acetylcysteine ​​xylitol injection, which comprises the following steps: Step a: Xylitol is completely dissolved in water for injection, activated carbon is added, the mixture is thoroughly mixed, and the temperature is raised to 75-80°C, maintained for 10-20 minutes, and then cooled to 60-65°C. The mixture is filtered and decarbonized to obtain Solution A; the concentration of xylitol in Solution A is preferably 0.2-0.3 g / mL; Step b: N-acetylcysteine ​​is added to water for injection at 20-65°C to adjust the NAC concentration to 0.12-1 g / mL. The temperature of the solution is controlled to ≤65°C and the residual oxygen content in the headspace to ≤2% under inert gas protection throughout the process. The pH value of the solution is adjusted to 4.0-7.5 with a 1-4 mol / L pH adjuster to obtain Solution B. Step c: Under inert gas protection, solution A and solution B are mixed in proportion so that the final concentration of N-acetylcysteine ​​is 0.020-0.035 g / mL and the final concentration of xylitol is 0.015-0.030 g / mL, and the pH value is adjusted to 6.5-7.5 with a 1-4 mol / L pH regulator, and the headspace residual oxygen content is controlled to be ≤2%, and the liquid temperature is ≤65°C. Water for injection at a temperature of ≤65°C (preferably 30-50°C) is added to the full amount, and the headspace residual oxygen content is controlled to be ≤2%, and the liquid temperature is ≤65°C. The mixture is mixed, filtered, and after sampling and testing, the mixture is filled and sterilized to prepare the N-acetylcysteine ​​xylitol injection.

[0025] In the step a, the concentration of activated carbon added is 0.00005-0.0005 g / mL, preferably 0.0001-0.0005 g / mL.

[0026] Preferably, the method comprises pre-treating the equipment before step a, wherein the pre-treatment comprises: preparing an aqueous solution of disodium edetate with water for injection in a concentration range of 0.001-0.003 g / mL, flushing the disodium edetate aqueous solution with the solution preparation and filling system, and then flushing with water for injection.

[0027] In the step b, dissolve N The temperature of the water for injection of acetylcysteine ​​is preferably 30 to 50°C.

[0028] Preferably, in step b, the concentration of the prepared NAC solution is in the range of 0.15-0.95 g / mL.

[0029] Preferably, in steps b and c, the temperature of the water for injection and the drug solution is controlled within a range of ≤ 60°C. Water for injection generally has a temperature of 70-90°C, so it is necessary to cool the water for injection before use. More preferably, the temperature is controlled within a range of 20-50°C.

[0030] Preferably, in step b and step c, the concentration of the pH regulator is 1-3.5 mol / L.

[0031] Preferably, in step b, the pH value of the B solution is in the range of 4.5-7.0.

[0032] Preferably, in step c, after liquid A and liquid B are evenly mixed, the pH value of the liquid is adjusted to be in the range of 6.8-7.2.

[0033] In step c, the filtration time is at least 10 minutes, preferably 10 to 20 minutes. The filtration time should not be too long.

[0034] Furthermore, in step c, the filling requires that the residual oxygen content in the empty bottle before filling is ≤5%, and the residual oxygen content in the headspace of the product after filling and in the stoppering process is ≤2%. Preferably, the range of the residual oxygen content in the headspace of the empty bottle before filling is ≤4%, and the range of the residual oxygen content in the headspace of the product during filling the high-level tank and the filling and stoppering process is ≤2%.

[0035] In the step c, the sterilization is required to take a total time of ≤13 hours from the start of liquid preparation in step a to the completion of sterilization, the sterilization temperature is ≥110°C, and the F0 value is >8.

[0036] Preferably, in step c, the sterilization method adopts terminal sterilization, the sterilization temperature is ≥112°C, and the standard sterilization time is F0 value>8.

[0037] More preferably, the total time from the start of liquid preparation to the completion of sterilization is required to be ≤ 8 hours.

[0038] In the present invention, the inert gas can be nitrogen, helium, argon, etc., with a purity of ≥99.9%. The gas source can be clean compressed inert gas or medical liquefied inert gas.

[0039] In the method of the present invention, air replacement can be performed in the drug solution preparation process, the filling process and the stoppering process, using clean inert gas or its liquefied gas, and adopting a direct filling replacement or an air replacement method combined with a vacuum process.

[0040] Furthermore, in step c, after sterilization, light inspection, packaging, and sampling inspection can be carried out to ensure that the product is qualified.

[0041] In the present invention, the packaging container material of the N-acetylcysteine ​​xylitol injection can be one of soda-lime glass, medium borosilicate glass, high borosilicate glass, low-density polyethylene infusion bottle, polypropylene infusion bottle, three-layer co-extruded infusion film or bag, five-layer co-extruded infusion film or bag, and multi-layer co-extruded infusion film or bag.

[0042] Preferably, the packaging container of the N-acetylcysteine ​​xylitol injection described in this product is made of one of soda-lime glass, medium borosilicate glass, and a five-layer co-extruded infusion film or bag.

[0043] Compared with the prior art, the preparation method of N-acetylcysteine ​​xylitol injection provided by the present invention can reduce the oxidation and degradation of acetylcysteine ​​during the preparation of the medicinal solution by controlling the dissolution concentration, temperature, and headspace residual oxygen content range of acetylcysteine ​​(step b), and selecting a pH regulator of appropriate concentration to adjust and control the pH value of the medicinal solution (steps b and c). This can thereby improve the stability of product quality and control the generation of related substances. By controlling the temperature of the water for injection and the medicinal solution (steps b and c), and controlling the preparation time, the oxidation and degradation of acetylcysteine ​​during the preparation process can be further reduced, thereby greatly reducing the content of related substances and improving product safety. The specific pH value of the medicinal solution (steps b and c) can reduce the degradation of acetylcysteine ​​and reduce the content of related substances. By using inert gas protection throughout the preparation process to control the headspace residual oxygen content of the product, the oxidation and degradation of acetylcysteine ​​can be effectively reduced, thereby improving product stability, reducing the content of related substances, and improving the intrinsic quality of the product. This is of great significance for improving drug safety.

[0044] The acetylcysteine ​​xylitol injection prepared by the present invention has significantly reduced related substances. In the stability investigation test, the change in the content of NAC related substances is generally controllable. Both the long-term test and the accelerated test of the stability investigation show that the injection of the present invention is significantly improved compared with the comparative example with changed condition parameters and the examples of the prior art. Therefore, the present invention significantly improves the quality stability of the acetylcysteine ​​xylitol injection, thereby ensuring the safety of patient use of the drug, and making the product have broad application prospects and value. DETAILED DESCRIPTION

[0045] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0046] Example 1 This embodiment provides a prescription for acetylcysteine ​​xylitol injection, and the prescription dosage is as follows: Acetylcysteine ​​20g 25g xylitol 5.5g of sodium hydroxide was used to prepare a 2mol / L sodium hydroxide solution. Water for injection 1000mL pH 6.8 This embodiment also provides a method for preparing acetylcysteine ​​xylitol injection, the specific steps are as follows: Step a: Weigh 25 g of xylitol by weight and dissolve it in 100 mL of water for injection. Add activated carbon at a concentration of 0.0002 g / mL, mix thoroughly, and heat to 80°C. Hold for 10 minutes, then cool to 65°C for decarbonization to obtain Solution A. Step b: Weigh 20 g of N-acetylcysteine ​​and add it to 15 mL of 40°C water for injection. Maintain nitrogen atmosphere throughout the process and control the temperature of the solution (residual oxygen in the headspace ≤ 1%, temperature ≤ 60°C). Adjust the pH of the solution to 4.5 with 2 mol / L sodium hydroxide to obtain Solution B. Step c: Under nitrogen protection, combine solution A and solution B, mix thoroughly, and adjust the pH to 6.8 with 2 mol / L sodium hydroxide (control the headspace residual oxygen content ≤1%, and the liquid temperature ≤60°C, preferably 40-50°C). Add water for injection (temperature ≤60°C, preferably 40-50°C) to the full volume (control the headspace residual oxygen content ≤1%, and the liquid temperature ≤60°C, preferably 40-50°C), mix, filter for 15 minutes, and sample the intermediate for qualified testing. High-purity nitrogen replacement and filling steps are performed (control the residual oxygen content in the empty bottle ≤5%, and control the headspace residual oxygen content of the intermediate product in the filling and stoppering steps ≤2%), followed by capping, initial inspection and sterilization (total time from liquid preparation to completion of sterilization ≤8 hours, sterilization temperature 115°C, 30 minutes), lamp inspection, and packaging to obtain the finished product. Samples are then taken for qualified testing to obtain the prepared N-acetylcysteine ​​xylitol injection.

[0047] Example 2 This embodiment provides an acetylcysteine ​​xylitol injection, the prescription dosage is as follows: Acetylcysteine ​​30 g Xylitol 15 g 7.5 g of sodium hydroxide was used to prepare a 1 mol / L sodium hydroxide solution. Water for injection 1000 mL pH 7.0 This embodiment also provides a method for preparing acetylcysteine ​​xylitol injection, the specific steps are as follows: Step a: Weigh 15 g of xylitol by weight and dissolve it in 110 mL of water for injection. Add activated carbon at a concentration of 0.0004 g / mL, mix thoroughly, and heat to 80°C. Maintain for 10 minutes, then cool to 65°C for decarbonization to obtain Solution A. Step b: Weigh 30 g of N-acetylcysteine ​​and add it to 20 mL of 50°C water for injection. Maintain nitrogen protection throughout the process and control the temperature of the solution (headspace residual oxygen ≤ 1%, temperature ≤ 60°C). Adjust the pH of the solution to 5.5 with 1 mol / L sodium hydroxide to obtain Solution B. Step c: Under nitrogen protection, combine Solution A and Solution B, mix thoroughly, and adjust the pH to 7.0 with 1 mol / L sodium hydroxide (control the headspace residual oxygen content ≤1%, and the liquid temperature ≤60°C). Add water for injection (temperature ≤60°C) to the full volume (control the headspace residual oxygen content ≤1%, and the liquid temperature ≤60°C). Mix and filter for 15 minutes, and sample the intermediate for inspection. High-purity nitrogen displacement and filling are performed (control the residual oxygen content in the empty bottle ≤5%, and control the headspace residual oxygen content of the intermediate product in the filling and stoppering process ≤2%). Capping, initial inspection and sterilization (from preparation to sterilization time ≤10 hours, sterilization temperature 115°C, 30 minutes), lamp inspection, and packaging to obtain the finished product. Samples are then taken for inspection to obtain the finished product. The N-acetylcysteine ​​xylitol injection prepared as described above is obtained.

[0048] Example 3 This embodiment provides an acetylcysteine ​​xylitol injection, the prescription dosage is as follows: Acetylcysteine ​​32g 28g xylitol 9.5g of sodium hydroxide was used to prepare a 4 mol / L sodium hydroxide solution. Water for injection 1000mL pH 7.5 This embodiment also provides a method for preparing acetylcysteine ​​xylitol injection, the specific steps are as follows: Step a: Weigh 28 g of xylitol by weight and dissolve it in 105 mL of water for injection. Add activated carbon at a concentration of 0.0001 g / mL, mix thoroughly, and heat to 80°C. Maintain for 10 minutes, then cool to 65°C for decarbonization to obtain Solution A. Step b: Weigh 32 g of N-acetylcysteine ​​and add it to 250 mL of 30°C water for injection. Maintain nitrogen protection throughout the process and control the temperature of the solution (headspace residual oxygen ≤ 1%, temperature ≤ 60°C). Adjust the pH of the solution to 6.5 with 4 mol / L sodium hydroxide to obtain Solution B. Step c: Under nitrogen protection, combine Solution A and Solution B, mix thoroughly, and adjust the pH to 7.5 with 4 mol / L sodium hydroxide (control the headspace residual oxygen content ≤1%, and the liquid temperature ≤60°C). Add water for injection (temperature ≤60°C) to the full volume (control the headspace residual oxygen content ≤1%, and the liquid temperature ≤60°C). Mix and filter for 15 minutes, and sample the intermediate for qualified testing. High-purity inert gas displacement filling process is used (control the residual oxygen content in the empty bottle ≤5%, and control the headspace residual oxygen content of the intermediate product in the filling and stoppering process ≤1%). Capping, initial inspection and sterilization (from preparation to sterilization time ≤8 hours, sterilization temperature 115°C, 30 minutes), lamp inspection, and packaging to obtain the finished product. Samples are then taken for qualified testing to obtain the prepared N-acetylcysteine ​​xylitol injection.

[0049] Comparative Example 1 This comparative example provides an acetylcysteine ​​xylitol injection, the formula and preparation method of which are exactly the same as those in Example 1, except that the temperature of the drug solution in steps b and c is controlled at 70° C. Other operations are the same as those in Example 1.

[0050] Comparative Example 2 This comparative example provides an acetylcysteine ​​xylitol injection, the formula and preparation method of which are exactly the same as those in Example 1, except that the concentration of sodium hydroxide for adjusting the pH value in steps b and c is 5 mol / L, and the other operations are the same as those in Example 1.

[0051] Comparative Example 3 This comparative example provides an acetylcysteine ​​xylitol injection, the formula and preparation method of which are exactly the same as those in Example 1, except that 2 mol / L sodium hydroxide is used in step b to adjust the pH value of the solution to 3.0. Other operations are the same as those in Example 1.

[0052] Comparative Example 4 This comparative example provides an acetylcysteine ​​xylitol injection, the formula and preparation method of which are exactly the same as those in Example 1, except that in step c, 2 mol / L sodium hydroxide is used to adjust the pH value to 7.8. Other operations are the same as those in Example 1.

[0053] Comparative Example 5 This comparative example provides an acetylcysteine ​​xylitol injection, the formula and preparation method of which are exactly the same as those in Example 1, except that the total time from the start of liquid preparation in step a to the end of sterilization is controlled to 15 hours, and the other operations are the same as those in Example 1.

[0054] Comparative Example 6 This comparative example provides an acetylcysteine ​​xylitol injection, the formula and preparation method of which are exactly the same as those of Example 1 in patent CN101664384 A (an acetylcysteine ​​injection and its preparation method), and this example does not perform nitrogen protection.

[0055] The specific steps are as follows: weigh 12 kg of 100-mesh xylitol fine powder, add it to 100 L of water for injection, and stir to dissolve; add 6 kg of sodium N-acetylcysteine ​​and 30 g of disodium edetate in sequence, and stir to dissolve; dilute to 250 L with water for injection, then add 30 mL of 3 mol / L sodium hydroxide (pH regulator) to adjust the pH of the solution to 7.0, stir evenly, and prepare 250 L of intravenous injection solution according to the routine method.

[0056] Comparative Example 7 This comparative example provides an acetylcysteine ​​injection, the formula and preparation method of which are exactly the same as those of Example 1 in patent CN116350581 A (an acetylcysteine ​​injection and its preparation method).

[0057] The prescribed dosage is as follows: Edetate disodium 1g Acetylcysteine ​​200g Water for injection up to 1000mL pH 6.8 The specific steps are as follows: Step a, adding 40% of the total volume of water for injection into a preparation tank lined with polytetrafluoroethylene, filling with nitrogen to exhaust the air in the preparation tank, adding the prescribed amount of edetate disodium at 40°C, mixing evenly, to obtain edetate disodium solution; Step b, adding a prescribed amount of acetylcysteine ​​to the disodium edetate solution, stirring to dissolve, adding sodium hydroxide to adjust the pH to 6.8, and adding 40° C. water for injection to the total amount to obtain an acetylcysteine ​​solution; Step c, filtering the acetylcysteine ​​solution sequentially through a polyethersulfone filter element with a pore size of 0.45 μm and a pore size of 0.2 μm; filling a 25mL ampoule with nitrogen at a pressure of 0.1MPa to discharge the air therein, filling the acetylcysteine ​​solution at a rate of 60 ampoules / minute, the filling temperature being 20°C, and after filling, filling with nitrogen at a pressure of 0.1MPa until the residual oxygen content in the headspace is less than 3%, and sealing is performed; adopting a terminal sterilization method, setting the sterilization temperature to 121°C, and sterilizing with a standard sterilization time F0 value>12; controlling the illumination to 10001x for light inspection; setting the voltage of a high-voltage discharge leak detector to 16KV, a threshold value ≤5, and performing leak detection; packaging after leak detection is qualified to obtain acetylcysteine ​​injection.

[0058] HPLC detection conditions for NAC-related substances: Chromatographic conditions and system suitability test: Octadecylsilane bonded silica gel was used as the filler; ammonium sulfate buffer (4.5 g of ammonium sulfate and 3.64 g of sodium heptanesulfonate were diluted to 900 mL with water and the pH value was adjusted to 1.4 with 7 mol / L hydrochloric acid solution)-methanol solution (90:10) was used as the mobile phase, the detection wavelength was 205 nm, the flow rate was 1.0 mL / min, and the column temperature was 30°C.

[0059] Preparation of test solution: Accurately measure 1.8 mL of the product, dilute with water to a 50 mL volumetric flask, and shake well.

[0060] Preparation of reference solution: Accurately measure 1 mL of the test solution, dilute with water to a 100 mL volumetric flask, and shake well.

[0061] Assay: Accurately pipette 10 μL of each reference solution and test solution into a liquid chromatograph for detection. The peak elution time for cysteine ​​is 7-8 minutes, the peak time for N,N′-diacetylcysteine ​​is 12-13 minutes, and the peak time for N,S-diacetylcysteine ​​is 16-18 minutes.

[0062] Quality and stability inspection conditions and methods: Except for related substances (impurities), other test items were carried out in accordance with the "Chinese Pharmacopoeia" (2020 edition), and quality inspection and stability tests were carried out on the acetylcysteine ​​injection products prepared in Examples 1-3 and Comparative Examples 1-7.

[0063] The items of stability inspection are: properties, content, pH value, insoluble particles and sterility.

[0064] The duration of stability study (long-term test) is: 0, 3, 6, 9, and 12 months (temperature is 25°C).

[0065] The time for stability investigation (accelerated test) is: 10 days and 30 days (light 4500 lx), 10 days and 30 days (high temperature 60℃).

[0066] The results of stability investigation (long-term test) are shown in Table 1: Table 1 The results of the stability study (accelerated test) are shown in Table 2: Table 2 As can be seen from the data in Tables 1-2 above, in both the stability investigation (long-term test) and the stability investigation (accelerated test) experiments, Examples 1-3, prepared using inert gas protection, controlling the solution preparation temperature below 65°C, and controlling the sodium hydroxide concentration at 4 mol / L or less, achieved indicators such as hydrogen sulfide and related substances that met quality standards. Compared with Comparative Example 1 (the solution preparation temperature was too high), Comparative Example 2 (the sodium hydroxide solution concentration was too high), Comparative Examples 3 and 4 (the liquid pH value was outside the scope of the present invention), Comparative Example 5 (the time from solution preparation to sterilization was too long), Comparative Example 6 (no inert gas protection), and Comparative Examples 6 and 7 (different processes and the addition of disodium edetate), the N-acetylcysteine ​​xylitol injections prepared in Examples 1-3 of the present invention had lower levels of related substances, were less susceptible to oxidative decomposition of the active substance, and had higher product stability, thereby further improving safety in clinical applications.

[0067] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A N-acetylcysteine ​​xylitol injection, characterized in that The N-acetylcysteine ​​xylitol injection comprises the following raw materials in a mass-to-volume ratio: 0.020-0.035 g / mL of N-acetylcysteine, 0.015-0.030 g / mL of xylitol, 0.005-0.010 g / mL of a pH adjuster, and the rest being water for injection.

2. The N-acetylcysteine ​​xylitol injection as claimed in claim 1, characterized in that The osmotic pressure of the N-acetylcysteine ​​xylitol injection is 450-650mOsm / L, the pH is 6.5-7.5; the impurity content is ≤3%, calculated as the percentage of N-acetylcysteine ​​contained in the injection.

3. The N-acetylcysteine ​​xylitol injection as claimed in claim 1, characterized in that The pH regulator is selected from sodium hydroxide, potassium hydroxide or sodium bicarbonate.

4. The N-acetylcysteine ​​xylitol injection according to any one of claims 1 to 3, characterized in that The N-acetylcysteine ​​xylitol injection is prepared by the following method: Step a: xylitol is completely dissolved in water for injection, activated carbon is added, the mixture is fully mixed and the temperature is raised to 75-80°C, maintained for 10-20 minutes, then cooled to 60-65°C, filtered and decarbonized to obtain liquid A; the concentration of xylitol in the liquid A is 0.2-0.3 g / mL; Step b: N -Acetylcysteine ​​is added to water for injection at 20-65°C to make the concentration of NAC range from 0.12 to 1 g / mL. The temperature of the drug solution is controlled to be ≤65°C under inert gas protection and the residual oxygen content in the headspace is ≤2%. The pH value of the drug solution is adjusted to 4.0-7.5 with a pH regulator of 1-4 mol / L to obtain Solution B; Step c: under the protection of inert gas, according to the ratio of N-acetylcysteine ​​final concentration of 0.020-0.035 g / mL and xylitol final concentration of 0.015-0.030 g / mL, liquid A and liquid B are mixed evenly in proportion, and the pH value is adjusted to 6.5-7.5 with 1-4 mol / L pH regulator, the headspace residual oxygen content is controlled to be ≤2%, and the liquid temperature is ≤65°C, and water for injection with a temperature of ≤65°C is added to the full amount, the headspace residual oxygen content is controlled to be ≤2%, and the liquid temperature is ≤65°C, mixed evenly, filtered, sampled and tested, and then filled and sterilized to obtain the N-acetylcysteine ​​xylitol injection.

5. The method for preparing the N-acetylcysteine ​​xylitol injection according to any one of claims 1 to 3, characterized in that The method comprises the following steps: Step a: xylitol is completely dissolved in water for injection, activated carbon is added, the mixture is fully mixed and the temperature is raised to 75-80°C, maintained for 10-20 minutes, then cooled to 60-65°C, filtered and decarbonized to obtain liquid A; the concentration of xylitol in the liquid A is preferably 0.2-0.3 g / mL; Step b: N-acetylcysteine ​​is added to water for injection at 20-65°C to make the concentration of NAC range from 0.12 to 1 g / mL. The temperature of the drug solution is controlled to be ≤65°C under inert gas protection and the residual oxygen content in the headspace is ≤2%. The pH value of the drug solution is adjusted to 4.0-7.5 with a pH regulator of 1-4 mol / L to obtain solution B; Step c: under the protection of inert gas, according to the ratio of N-acetylcysteine ​​final concentration of 0.020-0.035 g / mL and xylitol final concentration of 0.015-0.030 g / mL, liquid A and liquid B are mixed evenly in proportion, and the pH value is adjusted to 6.5-7.5 with 1-4 mol / L pH regulator, the headspace residual oxygen content is controlled to be ≤2%, and the liquid temperature is ≤65°C, and water for injection with a temperature of ≤65°C is added to the full amount, the headspace residual oxygen content is controlled to be ≤2%, and the liquid temperature is ≤65°C, mixed evenly, filtered, sampled and tested, and then filled and sterilized to obtain the N-acetylcysteine ​​xylitol injection.

6. The method according to claim 5, characterized in that In the step a, the concentration of activated carbon added is 0.00005-0.0005 g / mL.

7. The method according to claim 5, characterized in that Before step a, the equipment is pre-treated, and the pre-treatment is: using water for injection to prepare a disodium edetate aqueous solution with a concentration range of 0.001-0.003 g / mL, using the disodium edetate aqueous solution to flush the liquid preparation and filling system, and then flushing with water for injection.

8. The method according to claim 5, characterized in that In the step c, after the A solution and the B solution are evenly mixed, the pH value of the solution is adjusted to a range of 6.8-7.

2.

9. The method according to claim 5, characterized in that In the step c, the filling requires that the residual oxygen content in the empty bottle before filling is ≤5%, and the residual oxygen content in the headspace of the product after filling and in the stoppering process is ≤2%.

10. The method according to claim 5, characterized in that In the step c, the sterilization is required to be carried out from the liquid preparation in step a to the completion of sterilization, with a total time of ≤13 hours, a sterilization temperature of ≥110°C, and an F0 value of >8.

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