Sugammadex sodium injection and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a sugammadex sodium injection and a preparation method thereof. The sugammadex sodium, the pH buffer pair and the water for injection are included; the content of the sugammadex sodium is 50 mg / mL to 200 mg / mL; the pH value of the injection is 7.9-8.2, and in the preparation process, a chelating agent solution is used for pretreatment so as to reduce the concentration of metal ions; the sugammadex sodium injection is stable in pH value, the problem that API is separated out after being dissolved is solved, the concentration of metal ions in the sugammadex sodium injection is reduced, generation of insoluble substances and visible foreign matter are reduced, the product stability is good, and the sugammadex sodium injection is suitable for large-scale industrial production.

Description

Technical Field

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

[0002] Sugammadex sodium, molecular formula: C 72 H 104 O 48 S8Na8, molecular weight: 2178.01, CAS number: 343306-71-8. Sugammadex sodium is a specific binding neuromuscular blocking antagonist. It is a γ-cyclodextrin derivative with a cyclic molecular structure composed of 8 adjacent glucose molecules and a lipophilic inner cavity. Sugammadex sodium injection is mainly used to reverse the neuromuscular blocking effect caused by rocuronium or vecuronium. Sugammadex sodium does not cause cholinergic stimulation of the nervous system and does not require simultaneous administration of antimuscarinic drugs. Therefore, it has good safety. Compared with the cholinesterase inhibitor neostigmine, it has a faster onset, faster reversal, and fewer side effects. Sugammadex sodium injection has been approved for the rapid reversal of neuromuscular blockade in adults and children and adolescents aged 2-17 years. The recommended dose for adults is 2mg / kg, 4mg / kg, or 16mg / kg (calculated by body weight). When sugammadex sodium injection is used for routine antagonism of rocuronium-induced blockade in children and adolescents aged 2 to 17 years, the recommended dose is 2 mg / kg body weight. In order to improve the accuracy of medication for pediatric patients, the marketed product (2 mL: 0.2 g or 5 mL: 0.5 g of sugammadex sodium injection) needs to be diluted with 0.9% sodium chloride injection to a concentration of 10 mg / mL before use. The method of administration is a single dose of intravenous rapid injection, which needs to be injected into the existing intravenous access within 10 seconds.

[0003] Sugammadex sodium is used in emergency situations during clinical surgery, but there are the following problems:

[0004] (1) Sugammadex sodium contains sulfur and multiple hydrogen donor and hydrogen acceptor groups in its structure, which is prone to produce degradation impurities under strong acid, strong alkali, oxidation, light and high temperature conditions.

[0005] (2) The entire production process of Sugammadex Sodium Injection is nitrogen-filled, and nitrogen is also filled after canning. The main purpose is to prevent oxidative degradation of Sugammadex Sodium. The low dissolved oxygen environment in the original packaging is destroyed during the dilution process of the injection. The diluted injection is very easy to oxidize at room temperature and has poor chemical stability. Therefore, the instructions for Bridon (Chinese trade name: Bu Ruiting) Sugammadex Sodium Injection launched by the original research company Merck clearly stipulates that after the first opening of the bottle and dilution, the physical and chemical properties can be maintained at 2-25°C for 48 hours. Under non-sterile conditions, the diluent of Sugammadex Sodium Injection should not be stored at 2-8°C for more than 24 hours.

[0006] Patent application CN112933040A discloses a sodium sugammadex injection, in which the concentration of sodium sugammadex is 100 mg / mL. In order to control the effect of the preparation process on degradation impurities, protective agents phosphate inositol esters and their derivatives are added to control the growth of degradation products. The protective agent is finally removed by a reverse osmosis membrane, and the pH value is adjusted to a range of 7.0 to 8.0 using hydrochloric acid or sodium hydroxide solution. The use of the protective agent will cause sodium sugammadex to react with it to produce impurity proteins, which is difficult to produce and apply industrially.

[0007] Patent applications CN118319854A and CN116172953A disclose low-concentration (5 mg / mL-50 mg / mL) sugammadex sodium injections. Low-concentration sugammadex sodium has worse chemical stability.

[0008] The addition of Lc-NKlysin-1a peptide to the prescription disclosed in patent application CN118105339A increases production costs and the risk of allergic reactions. Summary of the invention

[0009] The present invention provides a sugammadex sodium injection with a stable pH value and a preparation method thereof, which ensures the stability of the pH value of the drug solution, solves the problem of precipitation after API is dissolved, reduces the concentration of metal ions in the sugammadex sodium injection, reduces the generation of insoluble matter and visible foreign matter, improves product stability, and is suitable for large-scale industrial production.

[0010] On one hand, the present invention provides a sugammadex sodium injection, comprising: sugammadex sodium, a pH buffer and water for injection; the content of the sugammadex sodium is 50 mg / mL to 200 mg / mL; and the pH value of the injection is 7.9 to 8.2.

[0011] In some embodiments of the present invention, the content of sugammadex sodium in the injection is 95.0 mg / ml to 105.0 mg / ml, preferably 100 mg / mL.

[0012] In the present application, the content of sugammadex sodium in the injection is calculated according to the active entity of sugammadex sodium (C 72 H 112 O 48 S8 and mono-hydroxysugammadex sodium active entity (C 69 H 108 O 47 S7) and the sum of; wherein, the mono-hydroxylated sodium glucose active entity (C 69 H 108 O 47 S7)≤3.0%.

[0013] In some embodiments of the present invention, the buffer pair is selected from any one of boric acid-borax, hydrochloric acid-borax, sodium acetate-disodium hydrogen phosphate and sodium dihydrogen phosphate-disodium hydrogen phosphate, preferably sodium dihydrogen phosphate-disodium hydrogen phosphate.

[0014] In some embodiments of the present invention, the content of the sodium dihydrogen phosphate is 0.01-0.04 mg / mL, and the content of the sodium dihydrogen phosphate is 0.34-1.36 mg / mL.

[0015] In some embodiments of the present invention, the content of sodium dihydrogen phosphate is 0.04 mg / mL, and the content of sodium dihydrogen phosphate is 1.36 mg / mL.

[0016] In some embodiments of the present invention, the amount of the buffer pair is used to adjust the pH value of the injection solution to 7.9-8.2, for example: 7.9, 8.0, 8.2.

[0017] In some embodiments of the present invention, the sugammadex sodium injection consists of the active ingredient, a pH buffer pair and the balance water for injection. In some preferred embodiments of the present invention, the sugammadex sodium injection consists of the sugammadex sodium, a sodium dihydrogen phosphate-disodium hydrogen phosphate buffer pair and the balance water for injection. In some more preferred embodiments of the present invention, the sugammadex sodium injection consists of the sugammadex sodium, a sodium dihydrogen phosphate-disodium hydrogen phosphate buffer pair and the balance water for injection; the pH value of the injection is 7.9 to 8.2; the injection contains 95.0 mg / mL to 105.0 mg / mL of the sugammadex sodium, 0.01 to 0.04 mg / mL sodium dihydrogen phosphate, and 0.34 to 1.36 mg / mL sodium dihydrogen phosphate.

[0018] In some specific embodiments of the present invention, each milliliter of the injection solution consists of the following components:

[0019] Sugammadex sodium 100 mg;

[0020] Sodium dihydrogen phosphate 0.04 mg;

[0021] Disodium hydrogen phosphate 1.36 mg;

[0022] The remaining amount of water for injection;

[0023] The injection solution has a pH value of 7.9 to 8.2.

[0024] In some specific embodiments of the present invention, each milliliter of the injection solution consists of the following components:

[0025] Sugammadex sodium 100 mg;

[0026] Sodium dihydrogen phosphate 0.04 mg;

[0027] Disodium hydrogen phosphate 1.36 mg;

[0028] The remaining amount of water for injection;

[0029] The injection solution has a pH of 8.0.

[0030] Another aspect of the present invention provides a method for preparing the above-mentioned sugammadex sodium injection, comprising:

[0031] Pretreating the ampoule, the dispensing tank and the pipeline encapsulating the sugammadex sodium injection with a chelating agent solution;

[0032] The sugammadex sodium, the pH buffer pair and water for injection are mixed.

[0033] In some embodiments of the present invention, the preparation method specifically comprises:

[0034] The ampoule is soaked with a chelating agent solution, and the liquid preparation tank and pipeline are rinsed with the chelating agent solution;

[0035] The sugammadex sodium, the pH buffer pair and water for injection are mixed.

[0036] In some embodiments of the present invention, the preparation method specifically comprises:

[0037] The ampoule is soaked in the chelating agent solution for 30 minutes, the container and pipeline for liquid preparation are rinsed with the chelating agent solution for 20 minutes, rinsed with purified water for 5 to 6 times, and then rinsed with water for injection for 3 to 4 times;

[0038] The sugammadex sodium, the pH buffer pair and water for injection are mixed.

[0039] In some embodiments of the present invention, the chelating agent is selected from one or more of pentetic acid, edetic acid and edetate disodium.

[0040] In some embodiments of the present invention, the chelating agent is pentetic acid.

[0041] In some embodiments of the present invention, the concentration of the chelating agent solution is 0.0005 w / w% to 0.002 w / w%.

[0042] In some embodiments of the present invention, the chelating agent solution is a 0.0005 w / w% to 0.002 w / w% pentetic acid solution.

[0043] In some embodiments of the present invention, the preparation method further comprises: pre-filling the injection water with nitrogen until the dissolved oxygen content does not exceed 1.0 mg / L.

[0044] In some embodiments of the present invention, the preparation method further comprises: a sterilization step, wherein the sterilization condition of the sterilization step is sterilization at 121° C. for 25-35 min.

[0045] In some embodiments of the present invention, the preparation method specifically comprises:

[0046] (1) The ampoule is soaked in the pentetic acid solution for 30 minutes, the liquid preparation tank and the pipeline are rinsed with the pentetic acid solution for 20 minutes, rinsed with purified water for 5 to 6 times, and then rinsed with water for injection for 3 to 4 times;

[0047] (2) Wetting the sugammadex sodium with water for injection to obtain a wetted active ingredient; dissolving the buffer with water for injection to obtain a buffer solution;

[0048] (3) Add the wetted active ingredient to a liquid preparation tank containing water for injection, stir until the active ingredient is completely dissolved, add the buffer solution to adjust the pH value to 7.9 to 8.2, stir evenly, and then add water for injection to the full amount;

[0049] (4) Nitrogen filling, filtering, ampoule filling and sealing;

[0050] (5) Sterilize at 121°C for 25-35 min.

[0051] In some embodiments of the present invention, the filtration in step (4) is performed using a sterilizing filter.

[0052] In some embodiments of the present invention, the filtering conditions in step (4) are filtering with 0.45 μm, 0.22 μm, and 0.22 μm filter elements in sequence.

[0053] This aspect also covers solutions obtained by any combination, deletion or replacement of the above-mentioned embodiments and preferred embodiments.

[0054] Beneficial effects of the present invention:

[0055] The inventors designed the following prescription according to the prescription information published by Bridon, the reference preparation product of sugammadex sodium injection:

[0056]

[0057] Preparation method:

[0058] Weigh the raw material sugammadex sodium according to the prescription, add 5L of water for injection, stir and moisten, transfer to a preparation tank with about 80% water for injection, stir until the raw material is completely dissolved, adjust the pH to 8.0 with 3.7% hydrochloric acid, add water for injection to the full amount, fill with nitrogen, and filter with 0.45μm, 0.22μm, and 0.22μm filter elements in turn. After measuring the pH, visible foreign matter and content, fill with 2ml ampoule, seal it, and sterilize it at 121℃ for 25-35min.

[0059] The bulk drug sugammadex sodium contains no more than 3.0% mono-hydroxysugammadex sodium, and the prescription amount is based on the active entity of sugammadex sodium (C 72 H 112 O 48 S8 and mono-hydroxysugammadex sodium active entity (C 69 H 108 O 47 S7) and calculation.

[0060] The water for injection used by the inventors in the product preparation process is pretreated (filled with nitrogen) until the dissolved oxygen content in the water does not exceed 1.0 mg / L.

[0061] After measuring the pH value, visible foreign matter, related substances and content of samples from different batches, the inventors found that the pH value of sugammadex sodium injection produced in different batches fluctuated greatly. Some batches also had problems such as precipitation of the raw materials after dissolution or visible foreign matter that was unqualified.

[0062] For injections, trace metal ions in the production process usually act as catalysts for compound oxidation reactions, which significantly shorten the induction period of drug oxidation and accelerate the generation of free radicals, leading to rapid drug degradation. Generally, chelating agents can be added to form stable complexes with metal ions, thereby slowing down drug degradation and improving product stability.

[0063] Due to the particularity of injection, the types of excipients need to be as few as possible, and it is best to add less or no excipients on the basis of meeting the preparation requirements. Based on the above situation, the inventors want to improve the existing formulation process, ensure the stability of the pH value of the drug solution, reduce metal ions, and improve product stability.

[0064] (1) The present invention adds a suitable buffer pair to stably control the pH value of the drug solution within a certain range (pH 7.9-8.2). If the pH is too low, the API will not be completely dissolved. If the pH is too high, there is a risk of corrosion to the ampoule, resulting in increased leaching of metal ions inside it, which affects the stability of the injection solution. 3+ 、Al 3+ The trivalent ions may also complex with the API, resulting in the generation of insoluble matter and unqualified visible foreign matter. The present invention preferably uses a sodium dihydrogen phosphate-disodium hydrogen phosphate buffer pair, and the pH value of the prepared drug solution is stable, which solves the problems of precipitation after API dissolution, clarity of the drug solution and unqualified visible foreign matter, and improves product stability.

[0065] (2) The preparation method of the present invention meets the standards of safety, stability and controllability of injection preparations.

[0066] (3) The present invention uses a chelating agent solution to pretreat the ampoule, dispensing tank and pipeline encapsulating the sugammadex sodium injection. Preferably, pentetic acid is used as the chelating agent, and the ampoule is soaked, the dispensing tank and the pipeline are rinsed with a pentetic acid solution, which can effectively remove various metal ions in the ampoule, the dispensing tank and the pipeline, avoid increasing the metal ion concentration in the injection, improve the product stability, and is suitable for large-scale industrial production.

[0067] (4) Since the raw material sugammadex sodium is easily oxidized, the water for injection used in the production process must be pretreated (filled with nitrogen) until the dissolved oxygen content in the water does not exceed 1.0 mg / L. Nitrogen filling protection must also be carried out during the preparation and filling process of the drug solution.

[0068] (5) The present invention adopts the sterilization condition of "sterilization at 121°C for 25-35min" to avoid the situation where the sterilization time is too short and the sterility level of the product cannot be guaranteed, and the sterilization time is too long and the related substances of the product increase significantly. The present invention selects appropriate sterilization conditions to ensure the safety and effectiveness of clinical medication. DETAILED DESCRIPTION

[0069] The present invention is further described in detail below in conjunction with the embodiments, but the present invention is not limited thereto. Any equivalent substitutions in the art made according to the disclosure of the present invention shall fall within the protection scope of the present invention.

[0070] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0071] In this application, the terms "include", "comprises", "contains" and their equivalents should be understood as open, non-exclusive meanings, i.e., "including but not limited to", meaning that in addition to the listed elements, components and steps, other unspecified elements, components and steps may also be included. In this document, unless the context clearly dictates otherwise, singular terms encompass plural referents and vice versa.

[0072] In this application, all pharmaceutical excipients or reagents mentioned may be from commercial sources.

[0073] In this application, unless otherwise specified, "%" in the examples of this application refers to mass percentage. Unless otherwise specified in the examples, the reaction temperature is 20-30°C.

[0074] Table 1

[0075]

[0076]

[0077] Example 1 to Example 10

[0078] 1. Prescription: Prescriptions for Examples 1-10 and Comparative Example 1 are shown in Tables 2 and 3

[0079] Table 2

[0080]

[0081] Table 3

[0082] name Comparative Example 1 Sugammadex Sodium 100g hydrochloric acid Moderate Purified water Add to 1000m1

[0083] 2. The preparation process of Examples 1 to 10 and Comparative Example 1 is as follows:

[0084] A. Weigh the raw material sugammadex sodium according to the prescription amount and dissolve it in 80% water for injection (a conventional preparation method for small-volume injections) to obtain solution A;

[0085] B. Weigh the buffer pair according to the prescription amount and dissolve it in 10% injection water to obtain a buffer solution; or measure 1mL of hydrochloric acid and add injection water to 10mL to prepare a 3.7% hydrochloric acid solution;

[0086] C. Add the buffer prepared in step B (or an appropriate amount of 3.7% hydrochloric acid solution) to solution A to adjust the pH value to 7.5-8.5, stir evenly and add water for injection to the full amount;

[0087] D. Nitrogen filling, filtration (using 0.22 μm filter membrane), ampoule filling and sealing;

[0088] E. Sterilize at 121℃ for 25-35min;

[0089] Wherein, the injection water is pre-filled with nitrogen to a dissolved oxygen content not exceeding 1.0 mg / L.

[0090] Example 11 to Example 15

[0091] Investigate the influence of chelating agents on product influencing factors

[0092] 1. Prescription: Examples 11-16, Comparative Example 2 Prescription, chelating agent type and concentration are shown in Tables 4-6.

[0093] Table 4

[0094] Sugammadex Sodium 6kg Sodium dihydrogen phosphate 81.6g Disodium hydrogen phosphate 2.4g Water for injection Add up to 60L Made 30,000

[0095] According to the above prescription, the types and concentrations of chelating agents are examined:

[0096] Table 5

[0097] name Embodiment 11 Example 12 Example 13 Embodiment 14 Embodiment 15 Example 16 Edetic acid 0.0005％ No No No No No Pentetic acid No 0.0005％ No No 0.002％ 0.01％ Edetate Disodium No No 0.0005％ No No No Edetate calcium sodium No No No 0.0005％ No No

[0098] Table 6

[0099] name Comparative Example 2 Sugammadex Sodium 6kg Sodium dihydrogen phosphate 81.6g Disodium hydrogen phosphate 2.4g Purified water Add up to 60L

[0100] 2. The preparation process of Examples 11-15 is as follows:

[0101] A. Soak the ampoule in the chelating agent solution for 30 minutes, rinse the dispensing tank and pipeline with the chelating agent solution for 20 minutes, then rinse with purified water for 5 to 6 times, and then rinse with water for injection for 3 to 4 times;

[0102] B. Weigh the raw material sugammadex sodium and buffer salt according to the prescription amount;

[0103] C. Moisten the raw material sugammadex sodium with a small amount of water for injection, and dissolve the buffer with a small amount of water for injection;

[0104] D. Transfer the wetted API into a dispensing tank filled with about 80% water for injection, stir until the API is completely dissolved, add buffer solution to adjust the pH value to 7.9-8.2, stir evenly and add water to the full amount;

[0105] E. Nitrogen filling, filtering (using sterilizing filter with 0.45μm, 0.22μm, 0.22μm filter element in sequence), ampoule filling and sealing;

[0106] F. Sterilize at 121℃ for 25-35min;

[0107] Wherein, the injection water is pre-filled with nitrogen to a dissolved oxygen content not exceeding 1.0 mg / L.

[0108] 3. The preparation process of Comparative Example 2 is as follows:

[0109] A. Rinse the dispensing tank and pipelines with purified water 5 to 6 times, and then rinse with injection water 3 to 4 times;

[0110] B. Weigh the raw material sugammadex sodium and buffer salt according to the prescription amount;

[0111] C. Moisten the raw material sugammadex sodium with a small amount of water for injection, and dissolve the buffer with a small amount of water for injection;

[0112] D. Transfer the wetted API into a dispensing tank filled with about 80% water for injection, stir until the API is completely dissolved, add buffer solution to adjust the pH value to 7.9-8.2, stir evenly and add water to the full amount;

[0113] E. Nitrogen filling, filtering (using sterilizing filter with 0.45μm, 0.22μm, 0.22μm filter element in sequence), ampoule filling and sealing;

[0114] F. Sterilize at 121℃ for 25-35min;

[0115] Wherein, the injection water is pre-filled with nitrogen to a dissolved oxygen content not exceeding 1.0 mg / L.

[0116] Effect Example 1 investigates the effects of different buffer salts on product quality under influencing factors.

[0117] The samples (Examples 1 to 10, Comparative Example 1, and reference preparation sugammadex sodium injection product (Bridion)) were inspected at 0 days, 10 days, and 30 days under high temperature of 60°C and light of 4500±500 lx.

[0118] The results of the influencing factors of properties, pH, content, solution clarity, visible foreign matter and related substances compared with the reference preparation are shown in Table 7-19.

[0119] Table 7 Investigation results of influencing factors of Example 1

[0120]

[0121]

[0122] Note: “ / ” indicates that the substance was not detected or the detection level was below the negligible limit.

[0123] Table 8 Investigation results of influencing factors of Example 2

[0124]

[0125] Note: “ / ” indicates that the substance was not detected or the detection level was below the negligible limit.

[0126] Table 9 Investigation results of influencing factors in Example 3

[0127]

[0128] Note: “ / ” indicates that the substance was not detected or the detection level was below the negligible limit.

[0129] Table 10 Investigation results of influencing factors in Example 4

[0130]

[0131]

[0132] Note: “ / ” indicates that the substance was not detected or the detection level was below the negligible limit.

[0133] Table 11 Investigation results of influencing factors in Example 5

[0134]

[0135] Note: “ / ” indicates that the substance was not detected or the detection level was below the negligible limit.

[0136] Table 12 Results of investigation on influencing factors of Example 6

[0137]

[0138]

[0139] Note: “ / ” indicates that the substance was not detected or the detection level was below the negligible limit.

[0140] Table 13 Results of investigation on influencing factors of Example 7

[0141]

[0142] Note: “ / ” indicates that the substance was not detected or the detection level was below the negligible limit.

[0143] Table 14 Investigation results of influencing factors in Example 8

[0144]

[0145]

[0146] Note: “ / ” indicates that the substance was not detected or the detection level was below the negligible limit.

[0147] Table 15 Investigation results of influencing factors of Example 9

[0148]

[0149] Note: “ / ” indicates that the substance was not detected or the detection level was below the negligible limit.

[0150] Table 16 Investigation results of influencing factors of Example 10

[0151]

[0152]

[0153] Note: “ / ” indicates that the substance was not detected or the detection level was below the negligible limit.

[0154] Table 17 Results of investigation on influencing factors of comparative example 1

[0155]

[0156] Note: “ / ” indicates that the substance was not detected or the detection level was below the negligible limit.

[0157] Table 18 Results of investigation on influencing factors of reference preparation (Bridion)

[0158]

[0159]

[0160] Note: “ / ” indicates that the substance was not detected or the detection level was below the negligible limit.

[0161] It can be seen from Examples 1 to 10 and Comparative Example 1 that adding a pH buffer to the prescription can effectively improve product stability.

[0162] From Example 1 (pH 7.5), Example 2 (pH 7.9), Example 3 (pH 8.0), Example 4 (pH 8.2), and Example 5 (pH 8.5), it can be seen that the pH value of the buffer pair is preferably 7.9 to 8.2.

[0163] From Examples 3, 6 to 8, it can be seen that the buffer pair is preferably sodium dihydrogen phosphate-disodium hydrogen phosphate.

[0164] From Examples 2 to 4, 9 to 10, it can be seen that the content of sodium dihydrogen phosphate in the buffer pair can be 0.01 to 0.04 mg / mL, and the content of disodium hydrogen phosphate can be 0.34 g to 1.36 mg / mL. As the concentration of the buffer pair increases, the product stability tends to increase, and all meet the product quality requirements; among them, Example 10 has the best effect, the content of sodium dihydrogen phosphate is preferably 0.04 mg / mL, and the content of disodium hydrogen phosphate is preferably 1.36 mg / ml.

[0165] Effect Example 2: Experiment on Influencing Factors

[0166] The samples (Examples 11 to 15, Comparative Example 2) were inspected at a high temperature of 60° C. and a light intensity of 4500±500 lx for 5 days, 10 days, and 30 days, respectively.

[0167] The results of the influencing factors of properties, pH, content and related substances compared with the reference preparation products are shown in Tables 19 to 24.

[0168] Table 19 Influencing factors results of Example 11

[0169]

[0170]

[0171] Note: “ / ” indicates that the substance was not detected or the detection level was below the negligible limit.

[0172] Table 20 Influencing factors results of Example 12

[0173]

[0174] Note: “ / ” indicates that the substance was not detected or the detection level was below the negligible limit.

[0175] Table 21 Results of influencing factors of Example 13

[0176]

[0177]

[0178] Note: “ / ” indicates that the substance was not detected or the detection level was below the negligible limit.

[0179] Table 22 Results of influencing factors of Example 14

[0180]

[0181] Note: “ / ” indicates that the substance was not detected or the detection level was below the negligible limit.

[0182] Table 23 Results of influencing factors of Example 15

[0183]

[0184] Note: “ / ” indicates that the substance was not detected or the detection level was below the negligible limit.

[0185] Table 24 Results of influencing factors of comparative example 2

[0186]

[0187] Note: “ / ” indicates that the substance was not detected or the detection level was below the negligible limit.

[0188] No chelating agent residues were detected in Examples 11 to 15, but chelating agent residues were detected in Example 16, indicating that appropriately increasing the chelating agent concentration within a certain range has no significant effect on improving product stability. However, when the chelating agent concentration exceeds this range, the current cleaning procedure cannot meet the requirements and chelating agent residues will remain in the product.

[0189] It can be seen from Examples 11 to 15 and Comparative Example 2 that pre-immersion and flushing of ampoules, dispensing tanks and pipelines with chelating agents can significantly improve product stability, among which pentetic acid (Example 12, Example 15) has the most significant improvement on product stability because it contains multiple coordinating atoms and can form stable complexes with a variety of metal ions, thereby reducing the residual metal ions on the surface of ampoules, dispensing tanks and pipelines, and improving the stability of the injection solution.

[0190] It can be seen from Examples 12 and 15 that the concentration of the chelating agent is preferably 0.0005% to 0.002%.

[0191] In summary, the stability of the technical solution of the present invention is significantly better than that of the prior art, ensuring the safety and effectiveness of the product.

[0192] For the purpose of description and disclosure, all patents, patent applications and other publications are expressly incorporated herein by reference. These publications are provided only because they are disclosed prior to the filing date of the present application. All statements about the dates of these documents or the representations of the contents of these documents are based on the information available to the applicant and do not constitute any admission of the correctness of the dates of these documents or the contents of these documents. Moreover, any reference to these publications in this document does not constitute an admission that the publications are part of the common general knowledge in the art in any country.

[0193] Those skilled in the art will recognize that the scope of the present application is not limited to the various specific implementations and examples described above, but that various modifications, replacements, or recombinations can be made without departing from the spirit of the present application, which all fall within the scope of protection of the present application.

Claims

1. A sugammadex sodium injection, comprising: Sugammadex sodium, pH buffer and water for injection; the content of sugammadex sodium is 50mg / mL to 200mg / mL; the pH value of the injection is 7.9 to 8.

2.

2. The injection according to claim 1, characterized in that: The content of sugammadex sodium in the injection is 95.0 mg / mL to 105.0 mg / mL.

3. The injection according to claim 1, characterized in that: The pH buffer pair is selected from any one of boric acid-borax, hydrochloric acid-borax, sodium acetate-disodium hydrogen phosphate and sodium dihydrogen phosphate-disodium hydrogen phosphate.

4. The injection according to claim 3, characterized in that: The pH buffer pair is sodium dihydrogen phosphate-disodium hydrogen phosphate.

5. The injection according to claim 4, characterized in that: The content of the sodium dihydrogen phosphate is 0.01-0.04 mg / mL, and the content of the sodium dihydrogen phosphate is 0.34-1.36 mg / mL.

6. The injection according to claim 5, characterized in that: The content of the sodium dihydrogen phosphate is 0.04 mg / mL, and the content of the sodium dihydrogen phosphate is 1.36 mg / mL.

7. The injection according to claim 1, characterized in that: Each milliliter of the injection consists of the following components: Each milliliter of the injection consists of the following components: Sugammadex sodium 100 mg; Sodium dihydrogen phosphate 0.04 mg; Disodium hydrogen phosphate 1.36 mg; The remaining amount of water for injection; The injection solution has a pH of 7.9-8.

2.

8. The method for preparing the injection according to any one of claims 1 to 7, characterized in that: include: Pretreating the ampoule, the dispensing tank and the pipeline encapsulating the sugammadex sodium injection with a chelating agent solution; The sugammadex sodium, the pH buffer pair and water for injection are mixed.

9. The injection according to claim 8, characterized in that: The chelating agent solution is a 0.0005 w / w% to 0.002 w / w% pentetic acid solution.

10. The injection according to claim 8, characterized in that: (1) The ampoule is soaked in the pentetic acid solution for 30 minutes, the liquid preparation tank and pipeline are rinsed with the pentetic acid solution for 20 minutes, rinsed with purified water for 5 to 6 times, and then rinsed with water for injection for 3 to 4 times; (2) Wetting the sodium sugammadex with water for injection to obtain a wetted active ingredient; dissolving the buffer with water for injection to obtain a buffer solution; (3) Add the wetted active ingredient to the injection water preparation tank, stir until the active ingredient is completely dissolved, add the buffer solution to adjust the pH value to 7.9-8.2, stir evenly, and add injection water to the full amount; (4) Nitrogen filling, filtering, ampoule filling and sealing; (5) Sterilization at 121°C for 25-35 min.

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