An N-acetylcysteine xylitol injection and its preparation method

Abstract

The present invention discloses an N-acetylcysteine xylitol injection and its preparation method, which comprises raw materials with the following mass-volume ratios: 0.020 - 0.035 g / mL of N-acetylcysteine, 0.015 - 0.030 g / mL of xylitol, 0.005 - 0.010 g / mL of pH regulator, and the balance being injection water. The method of the present invention can reduce the oxidation and degradation of N-acetylcysteine during the preparation of the medicinal solution by controlling the dissolution concentration, temperature and range of the residual headspace oxygen amount of N-acetylcysteine, and selecting a pH regulator with an appropriate concentration to control the pH value of the medicinal solution and controlling the preparation time, thereby improving the stability of the product quality and controlling the generation of related substances. The present invention significantly improves the quality stability of the N-acetylcysteine xylitol injection, ensures the safety of patients' medication, and makes the product have broad application prospects and value.

Description

Technical Field

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

[0002] N-acetylcysteine (NAC) is an acetylated product of the endogenous semi-essential amino acid cysteine, and it has various effects in the body.

[0003] First of all, the most obvious effect of NAC in the body is its antioxidant effect. It itself has reducibility, can scavenge reactive oxygen species (ROS) in the body, and 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 oxidation groups. During the metabolic process in the human body, many free radicals are generated, such as O•, ONOO - , OH•, etc. These free radicals will damage the normal metabolism of the body and lead to the occurrence of different diseases. As a free radical scavenger, the active sulfhydryl group in the NAC molecule can play an antioxidant role against tissue oxidative damage caused by different reasons.

[0004] Secondly, NAC has a significant anti-inflammatory effect in the body. During the occurrence and continuous progression of inflammation in the liver, lungs, etc., many effector cells gather in the target tissue through the bloodstream. At the same time, the expression of many adhesion molecules such as ELAM-1, VCAM-1, ICAM-1, LFA-1, VLA-4 is significantly increased and participates in the whole inflammatory process. Research shows that NAC can play a significant anti-inflammatory role by inhibiting the expression of these adhesion molecules on the central vein and portal vascular endothelial cells of patients with hepatitis, etc., such as inhibiting the expression of ICAM-1, reducing the level of NF-kB, inhibiting the release of proinflammatory mediators by activated monocytes and macrophages, and preventing the release of chemokines (such as p38 and MAPK).

[0005] Thirdly, NAC has an immune regulatory function. It can enhance the host's defense function and prevent or reduce the deterioration of some chronic diseases such as liver diseases, kidney diseases, bronchial and lung diseases. Research shows that NAC can not only regulate lymphocyte activity, reduce the synthesis of interleukin-4 (IL-4) in T ‐ cells and the production of immunoglobulin E (IgE) and immunoglobulin G4 (IgG4) in B ‐ cells, but also play an immune regulatory function by inhibiting the apoptosis of T ‐ cells and reversing the down-regulation of IL-2 mRNA and IL-2.

[0006] Finally, NAC can also play a powerful and specific detoxifying role. Under normal conditions, acetaminophen is metabolized by the cytochrome P450 enzyme system to produce a toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI), which is then conjugated with glutathione (GSH) in hepatocytes and excreted to prevent liver injury. When acetaminophen is ingested in excess, GSH in hepatocytes is depleted, and NAPQI binds to hepatocyte proteins, leading to hepatocyte necrosis. At this time, NAC can specifically bind to NAPQI to form a non-toxic substance and be excreted from the body, or it can also play a detoxifying function by increasing the level of GSH in the body.

[0007] Currently, the pharmaceutical dosage forms of acetylcysteine mainly include injections, tablets, capsules, effervescent tablets, and solutions. Among them, tablets, capsules, effervescent tablets, and solutions are mainly used for expectoration in the treatment of pulmonary diseases such as acute or chronic bronchitis and chronic obstructive pulmonary disease. The injection of acetylcysteine was first marketed in the United States in 2004 and is mainly used as an antidote for liver failure caused by overdose of acetaminophen (APAP). It is the first-choice therapeutic drug recommended by the three major international authoritative guidelines in Europe, America, and China, namely EASL / AASLD / CMA, based on level I evidence-based medicine evidence. It is also the only drug approved by the US FDA for the rescue of liver failure and the detoxification of drug-induced liver injury. The related products of acetylcysteine marketed in Canada and Germany are mainly used for pulmonary diseases such as acute and chronic bronchopneumonia. The European Union has also granted orphan drug designation for the treatment of peritoneal pseudomyxoma to related products. In China, the injection of acetylcysteine was first marketed in 2005 and is a drug recommended in authoritative guidelines such as the "Diagnosis and Treatment Guidelines for Drug-induced Liver Injury", the "Clinical Pathway for Drug-induced Liver Injury", and the "Diagnosis and Treatment Guidelines for Liver Failure" of the Chinese Medical Association.

[0008] However, currently, when NAC injection is used clinically, some patients may experience adverse reactions such as nausea, vomiting, rash, itching, bronchospasm, dizziness, headache, fever, and allergic reactions. Occasionally, flushing, angioedema, tachycardia, hypotension and hypertension, reduction of red blood cells and white blood cells, pharyngitis, rhinorrhea, and tinnitus may also occur. Studies have found that in addition to the adverse reactions caused by the inherent pharmacological effects of the drug itself, the content and types of related substances are related to some adverse reactions.

[0009] The chemical structures of organic impurities in drugs are generally similar to or have an origin relationship with the active ingredient, so they are usually also called related substances. Different preparation processes may produce different types and amounts of related substances. In the study of drug related substances, it is necessary to control the limits of each known impurity, unknown impurity and total impurity in accordance with the requirements of the "Technical Guidelines for the Study of Impurities in Chemical Drugs". Related products containing NAC generally belong to single-component drugs, and NAC itself has reducibility and is easily oxidized and damaged during production and other processes. Therefore, the stability of NAC in various dosage forms of products, especially in large-volume injection products, and the control of its related substances are a major technical difficulty and a key point in quality control in its production process, and have an important impact on the stability of the product and the incidence of adverse reactions.

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

[0011] In this field, according to the production processes reported in existing patents, generally special protective agents such as metal ion complexing agents such as disodium edetate (CN 114681397 A, CN 116350581 A, CN101664384 A) or stabilizers such as tromethamine etc. (CN 101239037A) are added to improve the stability of NAC injection. Although these special protective agents are inert substances, while increasing the stability of the injection, they may also introduce new impurities, thus triggering a series of potential drug adverse reactions. Therefore, in the actual prescription research process, it is necessary to be very cautious when determining the protective agent to be added. At the same time, during the drug use process, it is also necessary to strictly investigate the rational drug use and compatibility taboos of the injection containing the protective agent.

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

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

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

[0015] Another object of the present invention is to provide a preparation process for the N-acetylcysteine xylitol injection. The process 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 by the present invention is as follows:

[0017] An N-acetylcysteine xylitol injection, comprising raw materials in the following mass-to-volume ratio: N-acetylcysteine 0.020 - 0.035 g / mL, xylitol 0.015 - 0.030 g / mL, pH regulator 0.005 - 0.010 g / mL, and the balance being water for injection.

[0018] Further, the N-acetylcysteine xylitol injection preferably consists of raw materials in the following mass-to-volume ratio: N-acetylcysteine 0.023 - 0.033 g / mL, xylitol 0.020 - 0.028 g / mL, pH regulator 0.0065 - 0.009 g / mL, and the balance being water for injection.

[0019] Still further, the N-acetylcysteine xylitol injection more preferably consists of 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 regulator 0.0070 - 0.0085 g / mL, and the balance being water for injection.

[0020] 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.

[0021] In the N-acetylcysteine xylitol injection, the content of N-acetylcysteine should be 90.0% - 110.0% of the labeled amount.

[0022] The impurity content in the N-acetylcysteine xylitol injection is ≤ 3%, calculated as the percentage of N-acetylcysteine contained in the injection.

[0023] The pH regulator is selected from sodium hydroxide, potassium hydroxide or sodium bicarbonate, and preferably sodium hydroxide.

[0024] The N-acetylcysteine xylitol injection is prepared by the following method:

[0025] Step a: Xylitol is completely dissolved in water for injection, activated carbon is added, and the mixture is fully mixed and heated to 75 - 80 °C, maintained for 10 - 20 min and then cooled to 60 - 65 °C, and filtered to remove carbon to obtain solution A; the concentration of xylitol in solution A is preferably 0.2 - 0.3 g / mL;

[0026] 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 liquid 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 liquid is adjusted to 4.0-7.5 with a pH regulator of 1-4 mol / L to obtain liquid B;

[0027] 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.

[0028] The present invention also provides a method for preparing N-acetylcysteine ​​xylitol injection, which comprises the following steps:

[0029] 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;

[0030] 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. with 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;

[0031] 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 (preferably 30-50°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.

[0032] In the step a, the concentration of activated carbon added is 0.00005-0.0005 g / mL, preferably 0.0001-0.0005 g / mL.

[0033] Preferably, before step a, pre-treatment is performed on the equipment. The pre-treatment refers to: preparing an aqueous solution of disodium edetate with a concentration range of 0.001 - 0.003 g / mL using water for injection, using the aqueous solution of disodium edetate to rinse the liquid preparation and filling system, and then rinsing with water for injection.

[0034] In step b, the dissolution N The temperature of the water for injection for dissolving L-acetylcysteine is preferably 30 - 50°C.

[0035] Preferably, in step b, the concentration range of the prepared NAC solution is 0.15 - 0.95 g / mL.

[0036] Preferably, in steps b and c, the temperature control range of the water for injection and the liquid medicine is ≤ 60°C. The general temperature of the water for injection is 70 - 90°C, so the water for injection needs to be cooled before use. More preferably, the temperature control range is 20 - 50°C.

[0037] Preferably, in steps b and c, the concentration of the pH regulator is 1 - 3.5 mol / L.

[0038] Preferably, in step b, the pH value range of liquid B is 4.5 - 7.0.

[0039] Preferably, in step c, after mixing liquid A and liquid B evenly, the pH value of the liquid medicine is adjusted to the range of 6.8 - 7.2.

[0040] In step c, the filtration time is more than 10 min, preferably 10 - 20 min. The filtration time should not be too long.

[0041] Furthermore, in step c, for the filling requirement, the residual oxygen content in the empty bottle before filling is ≤ 5%, and the headspace residual oxygen content of the intermediate product after filling and before stoppering is ≤ 2%. Preferably, the range of the headspace residual oxygen content in the empty bottle before filling is ≤ 4%, and the range of the headspace residual oxygen content of the filling high-level tank, the intermediate product of filling and stoppering is ≤ 2%.

[0042] In step c, for the sterilization requirement, from the start of liquid preparation in step a to the completion of sterilization, the total duration is ≤ 13 hours, the sterilization temperature is ≥ 110°C, and the F0 value > 8.

[0043] Preferably, in step c, the terminal sterilization method is adopted for sterilization, the sterilization temperature is ≥ 112°C, and the standard sterilization time is F0 value > 8.

[0044] More preferably, it is required that from the start of liquid preparation to the completion of sterilization, the total duration is ≤ 8 hours.

[0045] In the present invention, the inert gas can be nitrogen, helium, argon, etc., with a purity of ≥99.9%, and the gas source form can be clean compressed inert gas or medical liquefied inert gas.

[0046] In the method of the present invention, air displacement can be carried out in the liquid medicine preparation process, filling process and stopper adding process, using clean inert gas or its liquefied gas, and adopting a direct filling displacement or an air displacement method combined with a vacuum pumping process.

[0047] Further, in step c, after sterilization, lamp inspection, packaging and sampling inspection can be carried out to be qualified.

[0048] 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, multi-layer co-extruded infusion film or bag.

[0049] Preferably, the packaging container material of the N-acetylcysteine xylitol injection of this product is one of soda-lime glass, medium borosilicate glass, five-layer co-extruded infusion film or bag.

[0050] Compared with the prior art, the preparation method of the N-acetylcysteine xylitol injection provided by the present invention can reduce the oxidation and degradation of N-acetylcysteine during the liquid medicine preparation process by controlling the dissolution concentration, temperature and headspace residual oxygen content range of N-acetylcysteine (step b), and by selecting a pH regulator with a suitable concentration to adjust and control the pH value of the liquid medicine (step b and step c), thereby improving the stability of the product quality and controlling the generation of related substances; by controlling the temperature of the injection water and the liquid medicine (step b and step c) and controlling the preparation time, the oxidation and degradation of N-acetylcysteine during the preparation process are further reduced, thereby greatly reducing the content of related substances and improving the safety of the product; the specific pH value of the liquid medicine (step b and step c) can reduce the degradation of N-acetylcysteine and lower the content of related substances; by protecting with inert gas throughout the process to control the liquid preparation process and the headspace residual oxygen content of the product, the oxidation and degradation of N-acetylcysteine can be effectively reduced, thereby improving the stability of the product, lowering the content of related substances, and enhancing the internal quality of the product, which is of great significance for improving the safety of medication.

[0051] The related substances of the acetylcysteine xylitol injection prepared by the present invention are significantly reduced. The change in the content of the related substances of NAC is generally controllable in the stability study test. Both the long-term test and the accelerated test of the stability study prove that the injection of the present invention has been 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 patients' medication and making the product have broad application prospects and value. Detailed implementation mode

[0052] In order to make the objectives, technical solutions and advantages of the present invention clearer, the following further describes the present invention in detail with reference to the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0053] Embodiment 1

[0054] This embodiment provides a prescription for an acetylcysteine xylitol injection, and the prescription dosage is as follows:

[0055] Acetylcysteine 20 g

[0056] Xylitol 25 g

[0057] Sodium hydroxide 5.5 g, and a 2 mol / L sodium hydroxide solution is prepared.

[0058] Water for injection 1000 mL

[0059] pH value 6.8

[0060] This embodiment also provides a preparation method for an acetylcysteine xylitol injection, and the specific steps are as follows:

[0061] Step a: Weigh 25 g of xylitol by weight, dissolve it in 100 mL of water for injection, add activated carbon with a concentration of 0.0002 g / mL, mix well and heat to 80 °C, keep it for 10 min and then cool to 65 °C, and decarbonize to obtain solution A;

[0062] Step b: Weigh 20 g of N-acetylcysteine, put it into 15 mL of water for injection at 40 °C, protect it with nitrogen throughout the process and control the temperature of the liquid medicine (the residual oxygen content in the headspace ≤ 1%, the temperature ≤ 60 °C), and adjust the pH value of the liquid medicine to 4.5 with 2 mol / L sodium hydroxide to obtain solution B;

[0063] Step c: Under nitrogen protection, combine Liquid A and Liquid B, mix them thoroughly, and adjust the pH value to 6.8 with 2 mol / L sodium hydroxide (control the residual oxygen content in the headspace ≤ 1%, the temperature of the liquid medicine ≤ 60°C, preferably 40 - 50°C); add water for injection (temperature ≤ 60°C, preferably 40 - 50°C) to the full volume (control the residual oxygen content in the headspace ≤ 1%, the temperature of the liquid medicine ≤ 60°C, preferably 40 - 50°C), mix, filter for 15 min, and take samples of the intermediate for inspection and pass the inspection; replace the filling process with high-purity nitrogen (control the residual oxygen content in the empty bottle ≤ 5% and control the residual oxygen content in the headspace of the intermediate during the filling and stoppering process ≤ 2%), cap, initially inspect and sterilize (the total time from the start of liquid preparation to the completion of sterilization ≤ 8 hours, sterilization temperature 115°C, 30 min), perform lamp inspection, and package to obtain the finished product, and take samples for inspection and pass the inspection, then it is obtained. The prepared N-acetylcysteine xylitol injection.

[0064] Example 2

[0065] This example provides an acetylcysteine xylitol injection, and the prescription dosage is as follows:

[0066] Acetylcysteine 30 g

[0067] Xylitol 15 g

[0068] Sodium hydroxide 7.5 g, prepare a 1 mol / L sodium hydroxide solution

[0069] Water for injection 1000 mL

[0070] PH value 7.0

[0071] This example also provides a preparation method for an acetylcysteine xylitol injection, and the specific steps are as follows:

[0072] Step a: Weigh 15 g of xylitol by weight, dissolve it in 110 mL of water for injection, add activated carbon with a concentration of 0.0004 g / mL, mix thoroughly and heat to 80°C, keep it for 10 min and then cool to 65°C, and remove carbon to obtain Liquid A;

[0073] Step b: Weigh 30 g of N-acetylcysteine, put it into 20 mL of water for injection at 50°C, protect it with nitrogen throughout the process and control the temperature of the liquid medicine (residual oxygen content in the headspace ≤ 1%, temperature ≤ 60°C), and adjust the pH value of the liquid medicine to 5.5 with 1 mol / L sodium hydroxide to obtain Liquid B;

[0074] Step c: Under nitrogen protection, combine Liquid A and Liquid B, mix them thoroughly, and adjust the pH value to 7.0 with 1 mol / L sodium hydroxide (control the residual oxygen in the headspace ≤ 1%, and the liquid temperature ≤ 60°C); add injection water (temperature ≤ 60°C) to the full volume (control the residual oxygen in the headspace ≤ 1%, and the liquid temperature ≤ 60°C), mix, filter for 15 min, and take samples of the intermediate for inspection and pass the test; use high-purity nitrogen to replace the filling process (control the residual oxygen in the empty bottle ≤ 5%, and control the residual oxygen in the headspace of the intermediate product during the filling and stoppering process ≤ 2%), crimp the cap, conduct primary inspection and sterilization (the time from liquid preparation to sterilization ≤ 10 hours, sterilization temperature 115°C, 30 min), conduct lamp inspection, and package to obtain the finished product, and take samples for inspection and pass the test, then it is obtained. The prepared N-acetylcysteine xylitol injection.

[0075] Example 3

[0076] This example provides an acetylcysteine xylitol injection, and the prescription dosage is as follows:

[0077] Acetylcysteine 32 g

[0078] Xylitol 28 g

[0079] Sodium hydroxide 9.5 g, prepare a 4 mol / L sodium hydroxide solution

[0080] Injection water 1000 mL

[0081] PH value 7.5

[0082] This example also provides a preparation method for an acetylcysteine xylitol injection, and the specific steps are as follows:

[0083] Step a: Weigh 28 g of xylitol by weight, dissolve it in 105 mL of injection water, add activated carbon with a concentration of 0.0001 g / mL, mix thoroughly and heat up to 80°C, keep it for 10 min and then cool it to 65°C, and remove carbon to obtain Liquid A;

[0084] Step b: Weigh 32 g of N-acetylcysteine, put it into 250 mL of injection water at 30°C, protect it with nitrogen throughout the process and control the liquid temperature (residual oxygen in the headspace ≤ 1%, temperature ≤ 60°C), and adjust the pH value of the liquid to 6.5 with 4 mol / L sodium hydroxide to obtain Liquid B;

[0085] Step c: Under nitrogen protection, combine liquid A and liquid B, mix them thoroughly, and adjust the pH to 7.5 with 4 mol / L sodium hydroxide (control the residual oxygen content in the headspace ≤ 1%, and the temperature of the liquid medicine ≤ 60°C); add injection water (temperature ≤ 60°C) to the full volume (control the residual oxygen content in the headspace ≤ 1%, and the temperature of the liquid medicine ≤ 60°C), mix, filter for 15 min, and take samples of the intermediate for inspection and pass the test; use high-purity inert gas to replace the filling process (control the residual oxygen content in the empty bottle ≤ 5%, and control the residual oxygen content in the headspace of the intermediate during the filling and stoppering process ≤ 1%), crimp the cap, conduct preliminary inspection and sterilization (the time from liquid preparation to sterilization ≤ 8 hours, sterilization temperature 115°C, 30 min), conduct lamp inspection, and package to obtain the finished product, and take samples for inspection and pass the test, then it is obtained. The prepared N-acetylcysteine xylitol injection.

[0086] Comparative Example 1

[0087] This comparative example provides an acetylcysteine xylitol injection, whose formulation and preparation method are exactly the same as those of Example 1, except that the temperature of the liquid medicine in Steps b and c is controlled at 70°C, and other operations are the same as those of Example 1.

[0088] Comparative Example 2

[0089] This comparative example provides an acetylcysteine xylitol injection, whose formulation and preparation method are exactly the same as those of Example 1, except that the concentration of sodium hydroxide for adjusting the pH value in Steps b and c is 5 mol / L, and other operations are the same as those of Example 1.

[0090] Comparative Example 3

[0091] This comparative example provides an acetylcysteine xylitol injection, whose formulation and preparation method are exactly the same as those of Example 1, except that in Step b, the pH value of the liquid medicine is adjusted to 3.0 with 2 mol / L sodium hydroxide, and other operations are the same as those of Example 1.

[0092] Comparative Example 4

[0093] This comparative example provides an acetylcysteine xylitol injection, whose formulation and preparation method are exactly the same as those of Example 1, except that in Step c, the pH value is adjusted to 7.8 with 2 mol / L sodium hydroxide, and other operations are the same as those of Example 1.

[0094] Comparative Example 5

[0095] This comparative example provides an acetylcysteine xylitol injection, whose formulation and preparation method are exactly the same as those of Example 1, except that the total time from liquid preparation in Step a to the end of sterilization is controlled at 15 hours, and other operations are the same as those of Example 1.

[0096] Comparative Example 6

[0097] This comparative example provides an acetylcysteine xylitol injection, whose formulation and preparation method are exactly the same as those in Example 1 of Patent CN101664384 A (an acetylcysteine injection and its preparation method), and nitrogen protection was not carried out in this example.

[0098] The specific steps are as follows: Weigh 12 kg of 100-mesh xylitol fine powder and put it into 100 L of injection water, stir to dissolve; successively add 6 kg of sodium N-acetylcysteine and 30 g of disodium edetate, stir to dissolve; make up the volume to 250 L with injection water, then add 30 mL of sodium hydroxide with a concentration of 3 mol / L (pH regulator) to adjust the pH value of the solution to 7.0, stir evenly, and make 250 L of intravenous injection according to the conventional method.

[0099] Comparative Example 7

[0100] This comparative example provides an acetylcysteine injection, whose formulation and preparation method are exactly the same as those in Example 1 of Patent CN116350581 A (an acetylcysteine injection and its preparation method).

[0101] The prescription dosages are as follows:

[0102] Disodium edetate 1 g

[0103] Acetylcysteine 200 g

[0104] Injection water to 1000 mL

[0105] pH value 6.8

[0106] The specific steps are as follows:

[0107] Step a: Add 40% of the total preparation volume of injection water into a preparation tank with a polytetrafluoroethylene lining, fill with nitrogen to exhaust the air in the preparation tank, and add the prescription amount of disodium edetate at 40 °C, mix evenly to obtain a disodium edetate solution;

[0108] Step b: Add the prescription amount of acetylcysteine to the disodium edetate solution, stir to dissolve, then add sodium hydroxide to adjust the pH value to 6.8, and make up the volume to the total preparation amount with 40 °C injection water to obtain an acetylcysteine medicinal solution;

[0109] Step c: Filter the acetylcysteine solution through a polyethersulfone filter with a pore size of 0.45 μm and then through another with a pore size of 0.2 μm; Fill nitrogen into a 25 mL ampoule at a pressure of 0.1 MPa to expel the air inside, fill the acetylcysteine solution at a speed of 60 vials per minute, with the filling temperature being 20 °C. After filling, fill nitrogen at a pressure of 0.1 MPa until the residual oxygen content in the headspace is less than 3%, and then perform melt sealing; Use the terminal sterilization method, set the sterilization temperature at 121 °C, and perform sterilization with the standard sterilization time F0 value > 12; Control the illuminance at 1000 lx for lamp inspection; Set the voltage of the high-voltage discharge leak detector at 16 kV, with the threshold ≤ 5, for leak detection; After passing the leak detection, perform packaging to obtain the acetylcysteine injection.

[0110] High-performance liquid chromatography detection conditions for NAC related substances:

[0111] Chromatographic conditions and system suitability test: Use octadecylsilane chemically bonded silica as the filler; Use ammonium sulfate buffer solution (take 4.5 g of ammonium sulfate, 3.64 g of sodium heptanesulfonate, dilute with water to 900 mL, and adjust the pH value to 1.4 with 7 mol / L hydrochloric acid solution) - methanol solution (90:10) as the mobile phase, with the detection wavelength at 205 nm, the flow rate at 1.0 mL / minute, and the column temperature at 30 °C.

[0112] Preparation of the test solution: Precisely measure 1.8 mL of this product, dilute it with water and make up the volume to a 50 mL volumetric flask, shake well, and you will get it.

[0113] Preparation of the reference solution: Precisely measure 1 mL of the test solution, dilute it with water and make up the volume to a 100 mL volumetric flask, shake well, and you will get it.

[0114] Determination method: Precisely pipette 10 μL each of the reference solution and the test solution, inject them into the liquid chromatograph for detection. Among them, the peak emergence time of cysteine is 7 - 8 min, the peak emergence time of N,N′-diacetylcysteine is 12 - 13 min, and the peak emergence time of N,S-diacetylcysteine is 16 - 18 min.

[0115] Quality and stability investigation conditions and methods:

[0116] Except for related substances (impurities), for other detection items, according to the Chinese Pharmacopoeia (2020 Edition), conduct quality inspection and stability tests on the acetylcysteine injection products prepared in Examples 1 - 3 and Comparative Examples 1 - 7.

[0117] The items for stability investigation are: appearance, content, pH value, insoluble particles, and sterility.

[0118] The time for stability investigation (long-term test) is: 0, 3, 6, 9, 12 months (temperature is 25 °C).

[0119] The time for stability study (accelerated test) is respectively: 10 days and 30 days (under 4500 lx light), 10 days and 30 days (at 60 °C high temperature).

[0120] The results of stability study (long-term test) are shown in Table 1 as follows:

[0121] Table 1

[0122]

[0123] The results of stability study (accelerated test) are shown in Table 2 as follows:

[0124] Table 2

[0125]

[0126] It can be seen from the data in the above Tables 1-2 that in the stability study (long-term test) experiment and the stability study (accelerated test) experiment, for Examples 1-3 prepared by using inert gas protection, controlling the liquid preparation temperature below 65 °C, and controlling the sodium hydroxide concentration at 4 mol / L or below, the indicators such as hydrogen sulfide and related substances all meet the quality standard requirements. Compared with Comparative Example 1 (too high liquid preparation temperature), Comparative Example 2 (too high sodium hydroxide solution concentration), Comparative Examples 3 and 4 (the liquid pH value is not within the scope of the present invention), Comparative Example 5 (too long time from liquid preparation to sterilization), Comparative Example 6 (not using inert gas protection), and Comparative Examples 6 and 7 (different processes and adding disodium edetate), the content of related substances and the like in the N-acetylcysteine xylitol injection prepared in Examples 1-3 of the present invention is lower, the active substance is not easily oxidized and decomposed, and the product stability is higher, thus being more beneficial to improving the safety of clinical application.

[0127] The above are only the preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements or improvements made within the spirit and principle of the present invention shall be included in the protection scope 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-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 is water for injection; 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 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, and sampled and tested to be qualified before filling and sterilization to obtain the N-acetylcysteine ​​xylitol injection; the sterilization requires that the total time from the preparation of the solution in step a to the completion of sterilization is ≤13 hours, the sterilization temperature is ≥110°C, and the F0 value is greater than 8.

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 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 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, and sampled and tested to be qualified before filling and sterilization to obtain the N-acetylcysteine ​​xylitol injection; the sterilization requires that the total time from the preparation of the solution in step a to the completion of sterilization is ≤13 hours, the sterilization temperature is ≥110°C, and the F0 value is greater than 8.

5. The method according to claim 4, characterized in that In the step a, the concentration of activated carbon added is 0.00005-0.0005 g / mL.

6. The method according to claim 4, 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.

7. The method according to claim 4, 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.

8. The method according to claim 4, 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%.

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