Stable acetylcysteine injection and preparation method thereof

Abstract

The invention provides a stable acetylcysteine injection and a preparation method thereof. The acetylcysteine injection provided by the invention only contains a small amount of metal ion chelating agent, and can still improve the content of related substances in the preparation and obviously reduce the content of hydrogen sulfide in the preparation by using a novel package and performing terminal high-temperature sterilization under the condition of a pre-cleaning process. More importantly, in the long-term storage process of the acetylcysteine injection provided by the invention, the content of hydrogen sulfide presents a trend of continuously reducing.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a stable acetylcysteine ​​injection and a preparation method thereof. Background Art

[0002] Acetylcysteine ​​injection is an amino acid drug. Its main function is to be used for the early treatment of patients with liver failure on the basis of comprehensive treatment. It can reduce bilirubin and increase prothrombin activity. However, acetylcysteine ​​injection has poor stability and is prone to oxidative degradation to produce a variety of related substances. In addition, hydrogen sulfide will continue to be produced and accumulated after terminal sterilization and during long-term storage. Hydrogen sulfide is a colorless gas that is irritating and asphyxiating and has strong neurotoxic effects.

[0003] In order to solve the problem of high content of related substances and hydrogen sulfide caused by the degradation of acetylcysteine ​​during high temperature and long-term storage, the following three methods are currently used:

[0004] The first method is to use a non-terminal sterilization process. For example, patent CN113318075B uses a filtration sterilization process, and at the same time uses methods such as lowering pH and controlling residual oxygen in the headspace to reduce the content of related substances and hydrogen sulfide in the acetylcysteine ​​solution. However, this sterilization method cannot guarantee a high level of sterility and cannot meet the current review and approval requirements of the State Food and Drug Administration for injection products.

[0005] The second method is to add high concentrations of metal ion chelators, such as the original research company adding 1 mg / mL of edetate disodium to acetylcysteine ​​injection. However, high concentrations of edetate disodium react with metal ions in the blood, resulting in a side effect of a significant decrease in blood magnesium and blood calcium concentrations.

[0006] The third method is to optimize the injection production equipment. For example, patent application CN116350581A reduces the content of related substances and improves product quality by lining the preparation tank with inert polymer material polytetrafluoroethylene. However, the lining preparation tank requires a larger area of ​​polytetrafluoroethylene, and polytetrafluoroethylene is usually expensive, which leads to a significant increase in production equipment costs.

[0007] Therefore, there is still a need to provide a simple, easy, safe and effective means to solve the problem of acetylcysteine ​​injection being easily oxidized and degraded, especially the continuous increase in hydrogen sulfide content after terminal sterilization and during long-term storage, while ensuring a high level of sterility. Summary of the invention

[0008] In view of the defects in the prior art, the present invention provides a stable acetylcysteine ​​injection and a preparation method thereof.

[0009] In a first aspect, the present invention provides the following technical solutions: a stable acetylcysteine ​​injection, comprising a high-barrier packaging bag, a plastic ampoule and a drug solution, wherein the drug solution comprises acetylcysteine, disodium edetate, sodium hydroxide and water for injection, the drug solution is filled in a plastic ampoule, and the plastic ampoule is packaged in a high-barrier packaging bag.

[0010] In some embodiments, the content of disodium edetate is 0.1 mg / mL. Before preparing the acetylcysteine ​​injection, the disodium edetate solution is used to clean the liquid preparation system and the filling system. The mass concentration of the disodium edetate solution can be selected to be 0.01% to 0.05%.

[0011] In some embodiments, the space between the plastic ampoule and the high-barrier packaging bag is in a vacuum compression state, and the high-barrier packaging bag has an oxygen absorber built in. More specifically, the oxygen absorber is placed between the plastic ampoule and the high-barrier packaging bag.

[0012] In some embodiments, the plastic ampoule is selected from one of polypropylene plastic ampoule, cyclic polyolefin plastic ampoule and polyethylene plastic ampoule, preferably polypropylene plastic ampoule, and the high barrier packaging bag is a high barrier composite film bag.

[0013] In some embodiments, the high barrier composite film bag is a multi-layer structure selected from two layers, three layers, four layers or five layers.

[0014] In some embodiments, the material of each layer of the high barrier composite film bag is selected from one of polyester, polyamide, cast polypropylene, polyethylene and aluminum foil.

[0015] In some embodiments, the polyester is brown coated polyester or vacuum aluminized polyester.

[0016] In some embodiments, the high barrier composite film bag is a brown coated polyester / polyamide / cast polypropylene high barrier composite film bag. In some embodiments, the high barrier composite film bag is a polyester / polyamide / aluminum foil / polyethylene high barrier composite film bag. In some embodiments, the high barrier composite film bag is a polyester / vacuum aluminized polyester / polyamide / polyethylene high barrier composite film bag.

[0017] In some embodiments, the drug solution includes 300 mg of acetylcysteine, 0.3 mg of disodium edetate, sodium hydroxide for adjusting the pH value of the drug solution to 6.0-7.5, and water for injection fixed to 3.0-3.3 mL;

[0018] The liquid medicine is filled in a polypropylene plastic ampoule, and the polypropylene plastic ampoule is packaged in a brown coated polyester / polyamide / cast polypropylene high barrier composite film bag. The polypropylene plastic ampoule and the brown coated polyester / polyamide / cast polypropylene high barrier composite film bag are in a vacuum compression state, and the brown coated polyester / polyamide / cast polypropylene high barrier composite film bag is equipped with an oxygen absorber.

[0019] In some embodiments, the drug solution includes 300 mg of acetylcysteine, 0.3 mg of disodium edetate, sodium hydroxide for adjusting the pH value of the drug solution to 6.0-7.5, and water for injection fixed to 3.0-3.3 mL;

[0020] The drug solution is filled in a polypropylene plastic ampoule, and the polypropylene plastic ampoule is packaged in a polyester / aluminum foil / cast polypropylene high-barrier composite film bag. The polypropylene plastic ampoule and the polyester / aluminum foil / cast polypropylene high-barrier composite film bag are in a vacuum compression state, and the polyester / aluminum foil / cast polypropylene high-barrier composite film bag is equipped with an oxygen absorbent.

[0021] In some embodiments, the drug solution includes 600 mg of acetylcysteine, 0.3 mg of disodium edetate, sodium hydroxide for adjusting the pH value of the drug solution to 6.0-7.5, and water for injection fixed to 3.0-3.3 mL;

[0022] The drug solution is filled in a polypropylene plastic ampoule, and the polypropylene plastic ampoule is packaged in a polyester / vacuum aluminum-plated polyester / polyamide / polyethylene high-barrier composite film bag. The polypropylene plastic ampoule and the polyester / vacuum aluminum-plated polyester / polyamide / polyethylene high-barrier composite film bag are in a vacuum compression state, and the polyester / vacuum aluminum-plated polyester / polyamide / polyethylene high-barrier composite film bag is equipped with an oxygen absorber.

[0023] In a second aspect, the present invention further provides a method for preparing the stable acetylcysteine ​​injection solution appearing in any of the above, comprising the following steps:

[0024] (1) Pre-cleaning: Use edetate disodium solution to clean the dispensing system and filling system, then use injection water to clean, remove the residual edetate disodium solution, and blow dry;

[0025] (2) Liquid preparation: Add water for injection, disodium edetate and acetylcysteine ​​into the liquid preparation tank, fill with nitrogen to control the dissolved oxygen content to ≤0.5 ppm, adjust the pH value to 6.0-7.5, add water for injection to make up the volume, and obtain the drug solution;

[0026] (3) Filling: filling the drug solution into a plastic ampoule, and packaging the plastic ampoule in a high-barrier packaging bag;

[0027] (4) Sterilization: Moist heat sterilization, sterilization temperature is 121°C, standard sterilization time is: F0 value>12;

[0028] Wherein, steps (1) and (3) are both carried out under nitrogen protection conditions, and the residual oxygen content is controlled to be ≤3%.

[0029] In some embodiments, in step (2), the pH value of the drug solution is adjusted to 6.7-7.5.

[0030] In some embodiments, the mass concentration of the disodium edetate solution in step (1) is 0.01% to 0.05%.

[0031] In some embodiments, step (3) further includes the steps of placing an oxygen absorber into the high barrier packaging bag and evacuating the high barrier packaging bag.

[0032] It has been verified that the acetylcysteine ​​injection and the preparation method thereof provided by the present invention have any one or both of the following beneficial effects:

[0033] 1. The applicant unexpectedly discovered that under the condition of using a terminal high temperature sterilization process to ensure the sterilization level, by filling the acetylcysteine ​​injection into a plastic ampoule and packaging the plastic ampoule in a high barrier packaging bag, the hydrogen sulfide content in the obtained product is less than 100ppm, and under long-term storage conditions, the hydrogen sulfide content in the acetylcysteine ​​injection shows a continuous downward trend. Compared with the prior art, the present invention not only ensures that the sterilization method meets the review and approval requirements of the injection product, but also reduces the requirements for production equipment and has lower production costs.

[0034] 2. The present invention reduces the content of metal ion chelating agents through a pre-cleaning process, thereby achieving the effects of controlling the content of related substances and reducing the side effects of high metal ion chelating agents, such as a significant decrease in blood magnesium and blood calcium concentrations. DETAILED DESCRIPTION

[0035] In order to more clearly illustrate the technical solution of the present invention, the technical solution of the present invention will be described using embodiments below. It should be understood that the description of the embodiments is only for the convenience of understanding the technical solution, rather than limiting the present invention to the specific embodiments shown. The titles in the present invention are provided only for convenience and should not be interpreted as limiting the present invention in any way. The embodiments shown under any title can be combined with the embodiments shown under any other title. For those of ordinary skill in the art, various modifications, improvements and amendments can also be made to these embodiments without paying creative work. So such modifications, improvements and amendments still belong to the spirit and scope of the exemplary embodiments of this specification.

[0036] The term "high barrier packaging bag" used in this specification is defined as a packaging bag that has a strong ability to prevent small molecules such as oxygen, moisture, water vapor, liquid, etc. from passing through the film. The barrier capacity is manifested in that the oxygen permeation rate should not exceed 1.0 cm 3 / (m 2 24h 0.1MPa) or 1.0cm 3 / (m 2 ·24h) and water vapor transmission rate shall not exceed 5.5g / (m 2 ·24h).

[0037] The term "high barrier composite film" used in this specification is defined as a multilayer film made by simultaneously extruding a material with strong gas barrier properties and a polyolefin with strong heat-sealing and moisture barrier properties. The strong gas barrier property means that the oxygen permeability does not exceed 1.0 cm 3 / (m 2 24h 0.1MPa) or 1.0cm 3 / (m 2 ·24h), the moisture barrier is very strong, which means that the water vapor transmission rate should not exceed 5.5g / (m 2 ·24h).

[0038] The high-barrier composite film bag used in the present invention has a multi-layer structure, and the layers are separated by the symbol " / ". For example, "brown coated polyester / polyamide / cast polypropylene high-barrier composite film bag" means that the high-barrier composite film bag has a three-layer structure, and the materials of each layer are brown coated polyester, polyamide, and cast polypropylene, respectively.

[0039] The contents of related substances and hydrogen sulfide in acetylcysteine ​​injection were determined according to the following method.

[0040] (1) Related substance detection methods

[0041] Determined according to high performance liquid chromatography (General Rules 0512 of Part IV of the Chinese Pharmacopoeia 2020 Edition).

[0042] Blank excipient solution Take 0.5 mL of blank excipient and place it in a 25 mL volumetric flask. Add 1.25 mL of 0.1 mol / L hydrochloric acid solution, dilute to the scale with mobile phase, and shake well.

[0043] Test solution Take 0.5 mL of this product and place it in a 25 mL volumetric flask, add 1.25 mL of 0.1 mol / L hydrochloric acid solution, dilute to the mark with mobile phase, and shake well. Prepare fresh before use.

[0044] Reference solution: Take appropriate amount of acetylcysteine, impurity A, impurity B, impurity C, impurity D and impurity E reference substances, weigh accurately, add mobile phase to dissolve and dilute to make a solution containing approximately 5 μg of acetylcysteine, 10 μg of impurity A, 40 μg of impurity B, 40 μg of impurity C, 25 μg of impurity D and 10 μg of impurity E per 1 mL.

[0045] The chromatographic conditions are as follows: octadecylsilane bonded silica gel as filler (C18, 4.6 mm × 200 mm, 5 μm or chromatographic column with equivalent performance); 10 mmol / L sodium pentane sulfonate and 0.5% ammonium sulfate buffer solution (the pH value is adjusted to 2.0 with 2 mol / L hydrochloric acid solution)-methanol (80:20) as mobile phase; flow rate is 1.0 mL per minute; detection wavelength is 205 nm; column temperature is 30°C; injection volume is 10 μL; injector temperature is 5°C.

[0046] System suitability requires that in the chromatogram of the reference solution, impurity A, impurity B, impurity E, acetylcysteine, impurity C, and impurity D appear in sequence, and the separation between the peaks should meet the requirements.

[0047] Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram to 5 times the retention time of the main peak.

[0048] The solvent peak and excipient peak are deducted from the chromatogram of the limit test solution. If there are impurity peaks, the impurity B and impurity C shall not exceed 1.5% of the labeled amount, the impurity D shall not exceed 1.0% of the labeled amount, and the impurity A and impurity E shall not exceed 0.5% of the labeled amount; other single impurities shall not exceed 0.2% of the labeled amount calculated by the peak area of ​​the main component external standard method; the total amount of impurities shall not exceed 4.5% of the labeled amount; peaks less than 0.1 times (0.02%) of the peak area of ​​acetylcysteine ​​in the reference solution are ignored.

[0049] Among the relevant substances, impurity A is L-cystine, impurity B is L-cysteine, impurity E is (S)-2-acetylamino-3-(((S)-2-acetylamino-2-carboxyethyl)thio)propionic acid, impurity C is N,N'-diacetyl-L-cystine, and impurity D is N,S-diacetyl-L-cysteine.

[0050] (2) Determination of sulfide content

[0051] Take an appropriate amount of this product (equivalent to 0.6g of acetylcysteine) and place it in a round-bottom three-necked flask, add 40mL of water, and the flask is equipped with a gas inlet tube almost reaching the bottom of the flask, a dropping funnel containing hydrochloric acid, and an outlet tube leading to a 100mL volumetric flask containing a mixture of 1mL 5mol / L sodium hydroxide and 50mL water. Pass a steady stream of nitrogen through the flask and add 10mL of hydrochloric acid from the dropping funnel. Maintain the nitrogen flow for 30 minutes, then disconnect the absorption flask. Take 45mL of hydrochloric acid and 55mL of water decolorized with activated carbon and mix them evenly. Add 0.1g of N,N-dimethyl-p-phenylenediamine dihydrochloride and dissolve it in the mixed solution. Add 10mL of this solution to a flask. If necessary, add 5mL of 5% w / v iron (III) chloride hexahydrate solution prepared with 1mol / L hydrochloric acid and let it stand in the dark for 20 minutes. Add water to 100mL and measure the absorbance of the solution (Appendix II B) at 665nm using a 4cm optical path absorption cell, and use a blank solution prepared in the same way without the injection solution in the reference cell.

[0052] Prepare a 0.4% w / v sodium sulfide solution. Standardize as follows: Take 25 mL of 0.05 mol / L iodine titrant, add 8 mL of hydrochloric acid and 25 mL of sodium sulfide solution. Titrate with 0.1 mol / L sodium thiosulfate solution and add starch indicator near the end point. Repeat the operation without sodium sulfide solution. The difference between the blank and sample titer volumes is calculated to obtain the concentration of sodium sulfide (ppm), and then multiply by 68.16 to obtain the hydrogen sulfide content (ppm). Dilute the sodium sulfide solution appropriately with water to prepare a solution containing the equivalent of 20 ppm hydrogen sulfide.

[0053] 2 mL of 20 ppm hydrogen sulfide solution was used to replace the injection solution to be tested, and the operation on the injection solution was repeated. The absorbance of the injection solution was not greater than 5 times the absorbance of the standard solution (relative to 100 ppm of acetylcysteine).

[0054] Original preparation: The original preparation batch 28006078 was purchased from Zambon Svizzera SA of Germany, with a specification of 3mL:300mg, a content of edetate disodium of 1mg / mL, and was packaged in brown glass ampoules.

[0055] Example 1

[0056] Acetylcysteine ​​injection prescription:

[0057]

[0058] The preparation method comprises the following steps:

[0059] (1) Pre-production treatment: After the injection water cleaning and production system sterilization, the stainless steel liquid preparation system and filling system are cleaned with disodium edetate solution. The mass concentration of disodium edetate solution is 0.01% to 0.05%, the temperature is 60°C, and the cleaning time is 30 minutes; then use injection water for cleaning again to remove the residual disodium edetate solution, and blow dry the residual pipes of the stainless steel liquid preparation system and filling system; fill the liquid preparation tank and its pipe system with nitrogen to control the residual oxygen content to ≤3%;

[0060] (2) Liquid preparation: Add about 80% of water for injection into the liquid preparation tank, and continue to fill with nitrogen so that the dissolved oxygen content of the water for injection is ≤0.5ppm; after cooling to 15-40°C, add disodium edetate and stir to dissolve, then add the prescribed amount of acetylcysteine ​​and stir to dissolve; adjust the pH value to 6.7-7.5 with an appropriate amount of sodium hydroxide, and then dilute to the total amount with an appropriate amount of water for injection;

[0061] (3) Filling: Under nitrogen conditions, filter the drug solution and fill it into polypropylene plastic ampoules at a filling volume of 3.0 to 3.3 mL / vial using a blow-fill-seal integrated machine, and control the headspace residual oxygen content of the plastic ampoule to be ≤3% after filling; package the polypropylene plastic ampoule in a brown coated polyester / polyamide / cast polypropylene high barrier composite film bag, with the polypropylene plastic ampoule and the brown coated polyester / polyamide / cast polypropylene high barrier composite film bag being in a vacuum compression state, and the brown coated polyester / polyamide / cast polypropylene high barrier composite film bag having an oxygen absorber built in;

[0062] (4) Sterilization: Moist heat sterilization, sterilization temperature is 121°C, standard sterilization time is: F0 value>12;

[0063] Example 2

[0064] The prescription for acetylcysteine ​​injection is as follows:

[0065]

[0066] The preparation method comprises the following steps:

[0067] (1) Pre-production treatment: After the injection water cleaning and production system sterilization, the stainless steel liquid preparation system and filling system are cleaned with disodium edetate solution. The mass concentration of disodium edetate solution is 0.01% to 0.05%, the temperature is 60°C, and the cleaning time is 30 minutes; then use injection water for cleaning again to remove the residual disodium edetate solution, and blow dry the residual pipes of the stainless steel liquid preparation system and filling system; then fill the liquid preparation tank and its pipe system with nitrogen to control the residual oxygen content to ≤3%;

[0068] (2) Liquid preparation: Add about 80% of water for injection into the liquid preparation tank, and continue to fill with nitrogen so that the dissolved oxygen content of the water for injection is ≤0.5ppm; after cooling to 15-40°C, add disodium edetate and stir to dissolve, then add the prescribed amount of acetylcysteine ​​and stir to dissolve; adjust the pH value to 6.7-7.5 with an appropriate amount of sodium hydroxide, and then dilute to the total amount with an appropriate amount of water for injection;

[0069] (3) Filling: Under nitrogen flow, filter the drug solution and fill it into a polypropylene plastic ampoule at a filling volume of 3.0-3.3 mL / vial using a blow-fill-seal integrated machine, and control the residual oxygen content in the headspace of the plastic ampoule after filling to be ≤3%; package the polypropylene plastic ampoule in a polyester / aluminum foil / cast polypropylene high barrier composite film bag, and the space between the polypropylene plastic ampoule and the polyester / aluminum foil / cast polypropylene high barrier composite film bag is in a vacuum compression state, and the polyester / aluminum foil / cast polypropylene high barrier composite film bag is built with an oxygen absorber;

[0070] (4) Sterilization: Moist heat sterilization, sterilization temperature is 121°C, standard sterilization time is: F0 value>12;

[0071] Example 3

[0072] The prescription for acetylcysteine ​​injection is as follows:

[0073]

[0074] The preparation method comprises the following steps:

[0075] (1) Pre-production treatment: After the injection water cleaning and production system sterilization, the stainless steel liquid preparation system and filling system are cleaned with disodium edetate solution. The mass concentration of disodium edetate solution is 0.01% to 0.05%, the temperature is 60°C, and the cleaning time is 30 minutes; then use injection water for cleaning again to remove the residual disodium edetate solution, and blow dry the residual pipes of the stainless steel liquid preparation system and filling system; then fill the liquid preparation tank and its pipe system with nitrogen to control the residual oxygen content to ≤3%;

[0076] (2) Liquid preparation: Add about 80% of water for injection into the liquid preparation tank, and continue to fill with nitrogen so that the dissolved oxygen content of the water for injection is ≤0.5ppm; after cooling to 15-40°C, add disodium edetate and stir to dissolve, then add the prescribed amount of acetylcysteine ​​and stir to dissolve; adjust the pH value to 6.7-7.5 with an appropriate amount of sodium hydroxide, and then dilute to the total amount with an appropriate amount of water for injection;

[0077] (3) Filling: Under nitrogen flow, filter the drug solution and fill it into polypropylene plastic ampoule at a filling volume of 3.0-3.3 mL / vial using a blow-fill-seal integrated machine, and control the residual oxygen content in the headspace of the plastic ampoule after filling to be ≤3%; package the polypropylene plastic ampoule in a polyester / vacuum-aluminum-plated polyester / polyamide / polyethylene high-barrier composite film bag, the polypropylene plastic ampoule and the polyester / vacuum-aluminum-plated polyester / polyamide / polyethylene high-barrier composite film bag are in a vacuum compression state, and the polyester / vacuum-aluminum-plated polyester / polyamide / polyethylene high-barrier composite film bag is built with an oxygen absorber;

[0078] (4) Sterilization: Moist heat sterilization, sterilization temperature is 121°C, standard sterilization time is: F0 value>12;

[0079] Comparative Example 1

[0080] The prescription for acetylcysteine ​​injection is as follows:

[0081]

[0082] The preparation method comprises the following steps:

[0083] (1) Pre-production treatment: Use disodium edetate solution to clean the stainless steel liquid preparation system and filling system. The concentration of disodium edetate solution is 0.01% to 0.05%, the temperature is 60°C, and the cleaning time is 30 minutes; then use injection water to clean once to remove the residual disodium edetate solution, and blow dry the residual pipes of the stainless steel liquid preparation system and filling system; fill the liquid preparation tank and its pipe system with nitrogen to control the residual oxygen content to ≤3%;

[0084] (2) Liquid preparation: Add about 80% of water for injection into the liquid preparation tank, fill with nitrogen so that the dissolved oxygen content of the water for injection is ≤0.5 ppm; after cooling to 15-40° C., add disodium edetate and stir to dissolve, then add the prescribed amount of acetylcysteine ​​and stir to dissolve; adjust the pH value to 6.7-7.5 with sodium hydroxide, and make up the volume of water for injection to the total amount of preparation;

[0085] (3) Filling: Under nitrogen conditions, filter the drug solution using a washing, filling and sealing machine and fill it into glass ampoules at a volume of 3.0 to 3.3 mL / vial, and control the residual oxygen content in the headspace of the glass ampoules after filling to ≤3%;

[0086] (4) Sterilization: Moist heat sterilization, sterilization temperature is 121°C, standard sterilization time is F0 value>12;

[0087] Samples were taken from Example 1, Comparative Example 1 and the original preparation at different inspection times, and the following indicators were tested. The inspection results are shown in Table 1.

[0088] Table 1 Test results of factors affecting different time periods

[0089]

[0090] The results in Table 1 show that compared with the original preparation (1 mg / mL edetate disodium), after reducing the edetate disodium content in the prescription (0.1 mg / mL), the products after terminal sterilization were treated with a pre-cleaning process. After 0 days, 1 month of accelerated inspection, and 6 months of long-term inspection, the levels of impurity B and total impurities in Example 1 and Comparative Example 1 were significantly lower than those in the original preparation.

[0091] The results in Table 1 show that Example 1 and Comparative Example 1 can not only avoid the clinical side effects caused by high-concentration metal ion chelators, but also effectively improve the levels of related substances, thereby ensuring product quality by using the pre-cleaning process with the dosage of disodium edetate reduced to 1 / 10.

[0092] Samples were taken from Example 1, Comparative Example 1 and the original preparation at different inspection times, and the following indicators were tested. The inspection results are shown in Table 2.

[0093] Table 2 Test results of factors affecting different time periods

[0094]

[0095]

[0096] The results in Table 2 show that the hydrogen sulfide content of the product of Comparative Example 1 (glass ampoule) after terminal high temperature sterilization is greater than 100ppm on day 0, and the hydrogen sulfide content increases significantly during the accelerated test, and under long-term storage conditions at 25°C, the hydrogen sulfide content still shows a slow increase trend, which is consistent with the change trend of the hydrogen sulfide content in the original preparation. Unlike Comparative Example 1 and the original preparation, Example 1 uses a plastic ampoule combined with a high-barrier composite film bag, and the hydrogen sulfide content of the product obtained after terminal high temperature sterilization is only 75ppm on day 0, which is significantly lower than that of Comparative Example 1 and the original preparation. Moreover, during the accelerated test, the rate of increase of the hydrogen sulfide content of the product of Example 1 is significantly slower than that of Comparative Example 1 and the original preparation. In addition, surprisingly, the hydrogen sulfide content of the product of Example 1 even shows a continuous downward trend under long-term storage conditions at 25°C, and the hydrogen sulfide content is reduced to 20ppm after 24 months of long-term storage.

[0097] Based on the above research results, the applicant of the present invention further took samples from Example 2 and Example 3 at different observation times to test the hydrogen sulfide content. The results showed that the hydrogen sulfide content of the products of Example 2 and Example 3 after terminal high-temperature sterilization on day 0 was less than 100 ppm, and the hydrogen sulfide content increased slowly during the accelerated test. At the same time, the hydrogen sulfide content of the products of Example 2 and Example 3 also showed a continuous downward trend under long-term storage conditions at 25°C.

[0098] The above test results all show that the hydrogen sulfide content in the acetylcysteine ​​injection obtained by filling the drug solution into a plastic ampoule and then packaging the plastic ampoule in a high-barrier composite film bag after terminal sterilization is significantly lower than the hydrogen sulfide content in the acetylcysteine ​​injection packaged in a glass ampoule, and in the long-term stability investigation test, the hydrogen sulfide content shows a continuous downward trend.

[0099] The use of any and all examples or exemplary language provided herein is intended merely to illustrate certain materials and methods and is not intended to limit the scope. No language in the specification should be construed as indicating any non-claimed element as essential to practice the disclosed materials and methods.

[0100] As shown in the present invention and claims, unless the context clearly indicates an exception, the words "a", "an", "an" and / or "the" do not specifically refer to the singular, but also include the plural. Generally speaking, the terms "include" and "comprise" only indicate the inclusion of the steps and elements that have been clearly identified, and these steps and elements do not constitute an exclusive list, and the method or composition may also include other steps or elements.

[0101] At the same time, this specification uses specific words to describe the embodiments of this specification. For example, "in some embodiments", "in various embodiments", "one embodiment", "an embodiment", and / or "some embodiments" refer to a certain feature, structure or characteristic related to at least one embodiment of this specification. Therefore, it should be emphasized and noted that "in some embodiments", "in various embodiments", "one embodiment", "an embodiment", and / or "some embodiments" mentioned twice or more in different positions in this specification do not necessarily refer to the same embodiment. In addition, some features, structures or characteristics in one or more embodiments of this specification can be appropriately combined.

[0102] Although the above disclosure discusses some of the invention embodiments currently considered useful through various examples, it should be understood that such details are only for illustrative purposes, and the appended claims are not limited to the disclosed embodiments. On the contrary, the claims are intended to cover all modifications and equivalent combinations that are consistent with the essence and scope of the embodiments of this specification.

[0103] Similarly, it should be noted that in order to simplify the description disclosed in this specification and thus help understand one or more embodiments of the invention, in the description of the embodiments of this specification, multiple features are sometimes combined into one embodiment. However, this disclosure method does not mean that the features required by the subject matter of this specification are more than the features mentioned in the claims.

[0104] Finally, it should be understood that the embodiments described in this specification are only used to illustrate the principles of the embodiments of this specification. Other variations may also fall within the scope of this specification. Therefore, as an example and not a limitation, alternative compositions of the embodiments of this specification may be considered consistent with the teachings of this specification. Accordingly, the embodiments of this specification are not limited to the embodiments explicitly introduced and described in this specification.

Claims

1. A stable acetylcysteine ​​injection, comprising a high-barrier packaging bag, a plastic ampoule and a medicinal solution, wherein the medicinal solution comprises acetylcysteine, disodium edetate, sodium hydroxide and water for injection, the medicinal solution is filled in the plastic ampoule, and the plastic ampoule is packaged in the high-barrier packaging bag.

2. The acetylcysteine ​​injection according to claim 1, wherein the content of the edetate disodium in the medicinal liquid is 0.1 mg / mL. Before preparing the acetylcysteine ​​injection, the edetate disodium solution is used to clean the liquid preparation system and the filling system. The mass concentration of the edetate disodium solution can be selected to be 0.01% to 0.05%.

3. The acetylcysteine ​​injection according to claim 1, wherein the plastic ampoule and the high-barrier packaging bag are in a vacuum compression state, and the high-barrier packaging bag has an oxygen absorbent built in.

4. The acetylcysteine ​​injection according to claim 1, wherein the plastic ampoule is selected from one of a polypropylene plastic ampoule, a cyclic polyolefin plastic ampoule and a polyethylene plastic ampoule, preferably a polypropylene plastic ampoule, and the high-barrier packaging bag is a high-barrier composite film bag.

5. The acetylcysteine ​​injection according to claim 4, wherein the high-barrier composite film bag is a multilayer structure selected from two layers, three layers, four layers or five layers.

6. The acetylcysteine ​​injection according to claim 5, wherein the material of each layer of the high-barrier composite film bag is selected from one of polyester, polyamide, cast polypropylene, polyethylene and aluminum foil.

7. The acetylcysteine ​​injection according to claim 6, wherein the polyester is brown-coated polyester or vacuum-aluminum-plated polyester.

8. The acetylcysteine ​​injection according to any one of claims 1 to 7, wherein the liquid medicine comprises 300 mg or 600 mg of acetylcysteine, 0.3 mg of disodium edetate, sodium hydroxide for adjusting the pH value of the liquid medicine to 6.0 to 7.5, and water for injection fixed to 3.0 to 3.3 mL; The plastic ampoule is a polypropylene plastic ampoule, and the high-barrier packaging bag is a brown-coated polyester / polyamide / cast polypropylene high-barrier composite film bag, a polyester / aluminum foil / cast polypropylene high-barrier composite film bag, or a polyester / vacuum-aluminized polyester / polyamide / polyethylene high-barrier composite film bag; The plastic ampoule and the high-barrier packaging bag are in a vacuum compression state, and the high-barrier packaging bag is internally provided with an oxygen absorbent.

9. A method for preparing the stable acetylcysteine ​​injection according to any one of claims 1 to 8, comprising the following steps: (1) Pre-cleaning: Use edetate disodium solution to clean the dispensing system and filling system, then use injection water to clean, remove the residual edetate disodium solution, and blow dry; (2) Liquid preparation: Add water for injection, disodium edetate and acetylcysteine ​​into the liquid preparation tank, fill with nitrogen to control the dissolved oxygen content to ≤0.5 ppm, adjust the pH value to 6.0-7.5, add water for injection to make up the volume, and obtain the drug solution; (3) Filling: filling the drug solution into a plastic ampoule, and packaging the plastic ampoule in a high-barrier packaging bag; (4) Sterilization: Moist heat sterilization, sterilization temperature is 121°C, standard sterilization time is: F0 value>12; in, Steps (1) and (3) are both carried out under nitrogen protection conditions, and the residual oxygen content is controlled to be ≤3%.

10. The preparation method according to claim 9, step (3) further comprises the steps of placing an oxygen absorber into the high barrier packaging bag and evacuating the high barrier packaging bag.

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