A muscle relaxant antagonist composition and its preparation method

Abstract

The present invention discloses a muscle relaxant antagonist composition, according to mass volume ratio, including 0.5mg / ml active ingredient, 8mg / ml-10mg / ml isotonic agent, 2mg / ml-4mg / ml sulfobutyl ether-β-cyclodextrin, appropriate pH adjusting agent, the remaining water for injection, and the composition pH value are 3.5-4.5. Especially when pH is 3.7-4.0, impurity A content can be controlled at less than 0.1%;In addition, the inventors also unexpectedly found that when pH is about 3.8, impurity A can be controlled at less than 0.05%. In short, the present invention has the advantages of high product quality, good stability, simple preparation method, etc.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical drugs, and in particular relates to a muscle relaxant antagonist composition and a preparation method thereof. Background Art

[0002] Neostigmine methylsulfate is a nonspecific, nondepolarizing muscle relaxant antagonist that primarily exerts its cholinergic effects by inhibiting cholinesterase activity. This muscle relaxant antagonist combination was first developed by Kyowa Pharmaceutical Industry Co., Ltd. in Japan and first marketed in 1936 under the trade name Vagostigmin. Available in 1ml: 0.5mg and 4ml: 2mg, the "original product" (hereinafter referred to as the "original product") is indicated for myasthenia gravis, prolonged respiratory depression caused by curare (tubocurarine), postoperative and postpartum intestinal paralysis and gastrointestinal dysfunction, and dysuria after surgery and childbirth; it also antagonizes the effects of nondepolarizing muscle relaxants.

[0003] Neostigmine methylsulfate chemical name N,N,N-trimethyl-3-[(dimethylamino)formyloxy]anilinium methylsulfate, molecular formula C 13 H 22 N₂O₂S, with a molecular weight of 334.39 and a structural formula as shown in Formula (I), primarily degrades the impurity 3-hydroxytrimethylaniline methylsulfate (Impurity A). Impurity A itself is non-toxic, but because its structural formula contains a phenolic hydroxyl group, phenolic compounds are susceptible to further oxidation, which, after oxidation, can contain benzoquinone compounds, which are potentially genotoxic impurities. Therefore, to reduce product safety risks, it is essential to minimize the content of Impurity A to avoid the production of toxic substances.

[0004]

[0005] There are numerous existing documents on the control of impurity A. For example, patent CN113230206A mentions in its specification that the degradation pathway of impurity A is hydrolysis, which is highly dependent on the pH environment. It was found that a pH range of 2.5 to 3.5 can effectively slow the hydrolysis reaction and reduce the content of impurity A. Patent CN116650412A reduces the content of impurity A by controlling the oxygen content during the solution preparation process.

[0006] In summary, the only way to reduce the risk of impurity A oxidizing into a potential genotoxic impurity is to control the growth of impurity A at the source. In-depth research on existing neostigmine methylsulfate injections (CN113230206A and CN116650412A) revealed that the content of impurity A in both solutions can only be controlled at 0.1-0.2%, and cannot be controlled below 0.1%.

[0007] In order to further reduce the content of impurity A, the present inventors ultimately discovered through extensive research that by adding sulfobutyl ether-β-cyclodextrin and controlling the pH at 3.5-4.5 (preferably 3.7-4.0), the level of impurity A in the muscle relaxant antagonist composition can be significantly controlled, thereby obtaining a new muscle relaxant antagonist composition that can effectively control the growth of impurity A. Summary of the Invention

[0008] The purpose of the present invention is to overcome the problems existing in the prior art and provide a new muscle relaxant antagonist composition and a preparation method thereof, which can effectively reduce the generation of impurity A in the muscle relaxant antagonist composition and ensure stable product quality.

[0009] The technical solution of the present invention is:

[0010] A muscle relaxant antagonist composition comprises, by mass-to-volume ratio, 0.5 mg / ml neostigmine methylsulfate, 8 mg / ml-10 mg / ml sodium chloride, 2 mg / ml-4 mg / ml sulfobutyl ether-β-cyclodextrin, an appropriate amount of a pH adjuster, and the balance water for injection. The pH value of the composition is 3.5-4.5, preferably 3.7-4.0.

[0011] Furthermore, the pH adjuster is an acetic acid-sodium acetate buffer pair, or a citric acid-sodium citrate buffer pair.

[0012] The present invention also provides a method for preparing a muscle relaxant antagonist composition, comprising the following steps:

[0013] (1) Weighing: weigh the raw materials and auxiliary materials according to the prescribed amount;

[0014] (2) Preparation of solution: Take 80% of water for injection, add the prescribed amount of sodium chloride, sulfobutyl ether-β-cyclodextrin, and pH adjuster, stir until completely dissolved, adjust the pH to 3.7-4.0, then add the prescribed amount of neostigmine methylsulfate and stir until completely dissolved, finally make up to the full volume with water for injection, stir for 10 minutes to mix evenly; wherein, the water temperature of the water for injection is not higher than 30°C.

[0015] (3) Filtration: The liquid obtained in step (2) was filtered using a two-stage filter element, with the first stage filtration using a 0.45 μm PES filter element and the second stage filtration using a 0.22 μm PES filter element;

[0016] (4) Filling: Fill the liquid obtained by filtration in step (3) into sterile vials or ampoules in a C / A clean area under nitrogen filling;

[0017] (5) Sterilization: The sterile vials or ampoules containing the drug solution in step (4) are terminally sterilized at 121° C. for 15 min.

[0018] The present invention introduces sulfobutyl ether-β-cyclodextrin into a muscle relaxant antagonist composition and controls the pH of the composition within a selected range suitable therefor, so that the prepared new muscle relaxant antagonist composition has the advantages of greatly reduced impurity A level, significantly improved product stability, simple preparation method, simpler production, and lower cost, thereby solving the technical problem that needs to be solved urgently, namely, the difficulty in controlling the impurity A level in the muscle relaxant antagonist composition and the unstable product quality. DETAILED DESCRIPTION

[0019] The present application is further illustrated below by means of specific examples. It should be understood that the examples of the present application are merely used to illustrate the present application, and are not intended to limit the present application. The experimental methods for which specific conditions are not specified in the following examples are generally carried out under conventional conditions or under conditions recommended by the manufacturer. The raw and auxiliary materials for which specific sources are not specified in the following examples are generally conventional products available on the market. Technical solutions obtained by simple improvements to the present application or by equivalent replacement of conventional means or components based on the technical solutions of the present application fall within the scope of protection of the present application.

[0020] Example 1

[0021] Prescription: Each 1000mL of muscle relaxant antagonist composition contains 0.5g of neostigmine methylsulfate, 8.5g of sodium chloride, 2g of sulfobutyl ether-β-cyclodextrin, 0.5g of sodium acetate, and an appropriate amount of acetic acid. The amount is made up to the full amount with water for injection. The pH value of the injection is 3.78.

[0022] The method for preparing neostigmine methylsulfate is:

[0023] (1) Weighing: Weigh 0.5 g of neostigmine methylsulfate, 8.5 g of sodium chloride, 2 g of sulfobutyl ether-β-cyclodextrin, and 0.5 g of sodium acetate.

[0024] (2) Solution preparation: Take 800 ml of water for injection (water temperature 25°C), add 8.5 g of sodium chloride, 2 g of sulfobutyl ether-β-cyclodextrin, and 0.5 g of sodium acetate, and stir until completely dissolved. Adjust the solution pH to 3.78 with appropriate amount of acetic acid. Then add 0.5 g of neostigmine methylsulfate and stir until completely dissolved. Finally, dilute to 1000 ml with water for injection and stir for 10 minutes to mix evenly.

[0025] (3) Filtration: The liquid medicine obtained in step (2) was filtered using a two-stage filter element, with the first stage filtration being a 0.45 μm PES filter element and the second stage filtration being a 0.22 μm PES filter element.

[0026] (4) Filling: The liquid medicine obtained by filtration in step (3) is filled into sterile vials or ampoules in a C / A clean area under nitrogen.

[0027] (5) Sterilization: The sterile vials or ampoules containing the drug solution in step (4) are terminally sterilized at a temperature of 121° C. for 15 min.

[0028] Example 2

[0029] Prescription: Each 1000mL of muscle relaxant antagonist composition contains 0.5g neostigmine methylsulfate, 9g sodium chloride, 3g sulfobutyl ether-β-cyclodextrin, 0.5g sodium acetate, and an appropriate amount of acetic acid. The injection volume is made up with water for injection. The pH value of the injection is 3.78.

[0030] The method for preparing neostigmine methylsulfate is:

[0031] (1) Weighing: Weigh 0.5 g of neostigmine methylsulfate, 9 g of sodium chloride, 3 g of sulfobutyl ether-β-cyclodextrin, and 0.5 g of sodium acetate.

[0032] (2) Solution preparation: Take 800 ml of water for injection (water temperature 25°C), add 9 g of sodium chloride, 5 g of sulfobutyl ether-β-cyclodextrin, and 0.5 g of sodium acetate, stir until completely dissolved, and adjust the solution pH to 3.83 with appropriate amount of acetic acid; then add 0.5 g of neostigmine methylsulfate and stir until completely dissolved, finally dilute to 1000 ml with water for injection, stir for 10 minutes and mix evenly.

[0033] (3) Filtration: The liquid obtained in step (2) was filtered using a two-stage filter element, with the first stage filtration using a 0.45 μm PES filter element and the second stage filtration using a 0.22 μm PES filter element;

[0034] (4) Filling: Fill the liquid obtained by filtration in step (3) into sterile vials or ampoules in a C / A clean area under nitrogen filling;

[0035] (5) Sterilization: The sterile vials or ampoules containing the drug solution in step (4) are terminally sterilized at a temperature of 121° C. for 15 min.

[0036] Example 3

[0037] Prescription: Each 1000mL of muscle relaxant antagonist composition contains 0.5g neostigmine methylsulfate, 10g sodium chloride, 4g sulfobutyl ether-β-cyclodextrin, 0.5g sodium citrate, and an appropriate amount of citric acid. Water for injection is used to make up the full amount. The pH value of the injection solution is 3.89.

[0038] The method for preparing neostigmine methylsulfate is:

[0039] (1) Weighing: Weigh 0.5 g of neostigmine methylsulfate, 10 g of sodium chloride, 4 g of sulfobutyl ether-β-cyclodextrin, and 0.5 g of sodium citrate.

[0040] (2) Solution preparation: Take 800 ml of water for injection (water temperature 25°C), add 10 g of sodium chloride, 4 g of sulfobutyl ether-β-cyclodextrin, and 0.5 g of sodium citrate, stir until completely dissolved, and adjust the pH of the solution to 3.89 with appropriate amount of citric acid; then add 0.5 g of neostigmine methylsulfate and stir until completely dissolved, finally dilute to 1000 ml with water for injection, stir for 10 minutes and mix evenly.

[0041] (3) Filtration: The liquid obtained in step (2) was filtered using a two-stage filter element, with the first stage filtration using a 0.45 μm PES filter element and the second stage filtration using a 0.22 μm PES filter element;

[0042] (4) Filling: Fill the liquid obtained by filtration in step (3) into sterile vials or ampoules in a C / A clean area under nitrogen filling;

[0043] (5) Sterilization: The sterile vials or ampoules containing the drug solution in step (4) are terminally sterilized at a temperature of 121° C. for 15 min.

[0044] Long-term and accelerated product stability testing

[0045] In this test, Examples 1-3 were used as experimental groups, the original research product (trade name Vagostigmin, specification: 1 ml: 0.5 mg, licensed by Kyowa Pharmaceutical Co., Ltd.) was used as comparative example 1, CN113230206A (Example 1) was used as comparative example 2, and CN116650412A (Example 1) was used as comparative example 3. Product quality tests were performed on these products, and the results are shown in Table 1:

[0046] Table 1 Long-term and accelerated test results of different products

[0047]

[0048]

[0049] As can be seen from the data in Table 3, the muscle relaxant antagonist compositions prepared in Examples 1-3 of the present invention have a product pH in the range of 3.7-4.0. After accelerated stability studies for 3 months (40±2°C) and long-term stability studies for 3 months (25±2°C), the levels of impurity A and total impurities increase slowly, while the levels of impurity A and total impurities in the muscle relaxant antagonist compositions of Comparative Examples 1-3 increase relatively rapidly.

[0050] In order to determine the optimal formulation of the present invention, the inventors conducted various attempts and screenings, with the aim of exploring a formulation of a muscle relaxant antagonist composition that can effectively control the growth of impurity A. The research results are shown below:

[0051] Test Example 1: Effects of different excipients on product quality

[0052] In order to reduce the content of impurity A, the present inventors set up three excipients as a formula combination and screened their different contents (see Prescriptions 1 to 9). The three excipients were sulfobutyl ether-β-cyclodextrin (SBECD), sodium sulfite, and calcium sodium edetate. Prescriptions 1 to 9 and their test results are shown in Table 2.

[0053] The preparation method of prescription 1 to prescription 9 comprises the following steps:

[0054] (1) Weighing: Weigh the raw materials and excipients according to the prescription amounts of prescriptions 1 to 9 in Table 2;

[0055] (2) Preparation: Take 800 ml of water for injection (water temperature 25°C), add the prescribed amount of sodium chloride, sodium acetate, sulfobutyl ether-β-cyclodextrin or sodium sulfite or sodium calcium edetate, stir until completely dissolved, adjust the pH to 4.0 with appropriate amount of acetic acid, then add the prescribed amount of neostilbene methylsulfate and stir until completely dissolved, finally make up to 1000 ml with water for injection, stir for 10 min to mix evenly;

[0056] (3) Filtration: The liquid obtained in step (2) was filtered using a two-stage filter element, with the first stage filtration using a 0.45 μm PES filter element and the second stage filtration using a 0.22 μm PES filter element;

[0057] (4) Filling: Fill the liquid obtained by filtration in step (3) into sterile vials or ampoules in a C / A clean area under nitrogen filling;

[0058] (5) Sterilization: The sterile vials or ampoules containing the drug solution in step (4) are terminally sterilized at 121° C. for 15 min.

[0059] Table 2 Prescriptions 1-9 and their test results

[0060]

[0061] As shown in Table 2, among sodium sulfite, formulation 5 is the best, but impurity A is still higher than 0.1%; among calcium sodium edetate, formulation 8 is the best, but impurity A is still higher than 0.1%; among sulfobutyl ether-β-cyclodextrin, formulations 2 and 3 both have impurity contents lower than 0.1%, but according to the principle of minimum dosage, formulation 2 is preferred.

[0062] Test Example 2: Effect of different pH on product quality

[0063] Based on prescription 2, the inventors set up prescriptions 10 (pH 3.0), 11 (pH 3.5), 12 (pH 3.8), and 13 (pH 4.5), and tested their product quality. Prescriptions 2, 10-12, and their test results are shown in Table 3. The preparation method of prescriptions 10-12 includes the following steps:

[0064] (1) Weighing: Weigh the raw materials and auxiliary materials according to the prescription amounts of prescriptions 10-12 in Table 3;

[0065] (2) Preparation: Take 800 ml of water for injection (water temperature 25°C), add the prescribed amount of sodium chloride, sodium acetate, and sulfobutyl ether-β-cyclodextrin, stir until completely dissolved, adjust the pH to the prescribed pH with appropriate amount of acetic acid, then add the prescribed amount of neostilbene methylsulfate and stir until completely dissolved, finally dilute to 1000 ml with water for injection, stir for 10 minutes to mix evenly;

[0066] (3) Filtration: The liquid obtained in step (2) was filtered using a two-stage filter element, with the first stage filtration using a 0.45 μm PES filter element and the second stage filtration using a 0.22 μm PES filter element;

[0067] (4) Filling: Fill the liquid obtained by filtration in step (3) into sterile vials or ampoules in a C / A clean area under nitrogen filling;

[0068] (5) Sterilization: The sterile vials or ampoules containing the drug solution in step (4) are terminally sterilized at 121° C. for 15 min.

[0069] Table 3 Prescription 2, prescription 10-12 and their test results

[0070]

[0071] The results in Table 3 show that, with the addition of sulfobutyl ether-β-cyclodextrin, the content of impurity A can be controlled below 0.1% when the pH is within the range of 3.5-4.0. Furthermore, the inventors unexpectedly discovered that the content of impurity A can be reduced to below 0.05% when the pH is 3.8.

[0072] The above specific implementation methods are only used to illustrate the technical solutions of the present application and are not intended to limit them. Although the present application has been described in detail with reference to examples, those skilled in the art should understand that the technical solutions of the present application can be modified or replaced by equivalents without departing from the scope of the technical solutions of the present application, and all of them should be included in the scope of the claims of the present application.

Claims

1. A muscle relaxant antagonist composition, characterized in that Each 1000 mL of the muscle relaxant antagonist composition contains 0.5 g of neostigmine methylsulfate, 8.5 g of sodium chloride, 2 g of sulfobutyl ether-β-cyclodextrin, 0.5 g of sodium acetate, and an appropriate amount of acetic acid. The amount is made up to the full amount with water for injection. The pH value of the composition is 3.

78. The preparation method of the muscle relaxant antagonist composition comprises the following steps: (1) Weighing: Weigh 0.5 g of neostigmine methylsulfate, 8.5 g of sodium chloride, 2 g of sulfobutyl ether-β-cyclodextrin, and 0.5 g of sodium acetate; (2) Solution preparation: Take 800 ml of water for injection at 25°C, add 8.5 g of sodium chloride, 2 g of sulfobutyl ether-β-cyclodextrin, and 0.5 g of sodium acetate, and stir until completely dissolved. Adjust the pH of the solution to 3.78 with an appropriate amount of acetic acid, then add 0.5 g of neostigmine methylsulfate and stir until completely dissolved. Finally, dilute to 1000 ml with water for injection and stir for 10 min to mix evenly. (3) Filtration: The liquid obtained in step (2) was filtered using a two-stage filter element, with the first stage filtration using a 0.45 μm PES filter element and the second stage filtration using a 0.22 μm PES filter element; (4) Filling: Fill the liquid obtained by filtration in step (3) into sterile vials or ampoules in a C / A clean area under nitrogen filling; (5) Sterilization: The sterile vial or ampoule containing the drug solution in step (4) is terminally sterilized at a temperature of 121° C. for 15 min.

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