A Sugammadex Injection and Its Preparation Method

Abstract

The present invention belongs to the field of pharmaceutical preparations, and particularly relates to a sugammadex sodium injection and a preparation method thereof; the sugammadex sodium, a pH buffer pair and water for injection; the content of sugammadex sodium is 50 mg / mL to 200 mg / mL; the pH value of the injection is 7.9 to 8.2, and a chelating agent solution is used for pretreatment during the preparation process to reduce the metal ion concentration; the pH value of the sugammadex sodium injection is stable, the problem of precipitation after API dissolution is solved, the metal ion concentration in the sugammadex sodium injection is reduced, the generation of insoluble substances and visible foreign matters is reduced, the product has good stability and is suitable for large-scale industrial production.

Description

Technical Field

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

[0002] Sugammadex, molecular formula: C 72 H 104 O 48 S8Na8, molecular weight: 2178.01, CAS No.: 343306-71-8. Sugammadex is a specific binding neuromuscular blockade antagonist drug, a γ-cyclodextrin derivative, composed of 8 adjacent glucose molecules to form a cyclic molecular structure, with a lipophilic inner cavity. The sugammadex injection is mainly applicable to reverse the neuromuscular blockade caused by rocuronium or vecuronium, and sugammadex will not cause cholinergic stimulation of the nervous system and does not require concomitant administration of antimuscarinic drugs. Therefore, it has good safety. Compared with the cholinesterase inhibitor neostigmine, it has a faster onset, more rapid reversal, and fewer side effects. The sugammadex 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 2 mg / kg or 4 mg / kg or 16 mg / kg (calculated by body weight). When the sugammadex injection is used for routine antagonism of rocuronium-induced blockade in pediatric patients aged 2-17 years, the recommended dose is 2 mg / kg body weight. In order to improve the medication accuracy of pediatric patients, the marketed product (2 mL: 0.2 g or 5 mL: 0.5 g sugammadex injection) needs to be diluted with 0.9% sodium chloride injection to a concentration of 10 mg / mL before use. The administration method is single-dose intravenous rapid injection, and it needs to be injected into the existing intravenous access within 10 seconds.

[0003] When sugammadex is used in emergency situations during clinical surgery, the following problems exist:

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

[0005] (2) The production process of the sugammadex injection is filled with nitrogen throughout, and nitrogen is also filled after canning. The main purpose is to avoid oxidative degradation of sugammadex. However, the dilution process of the injection destroys the low dissolved oxygen environment in the original package, and the diluted injection is extremely easy to oxidize when placed at room temperature, and its chemical stability is poor. Therefore, the instruction manual of the sugammadex injection Bridon (Chinese trade name: Bruitin) marketed by the original research company Merck Sharp & Dohme clearly stipulates that after the first opening and dilution, the physical and chemical properties can be maintained stable for 48 hours at 2-25°C. Under non-sterile conditions, the diluted sugammadex injection should not be stored at 2-8°C for more than 24 hours.

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

[0007] Patent applications CN118319854A and CN116172953A disclose sugammadex injections with low concentrations (5 mg / mL - 50 mg / mL). The chemical stability of low-concentration sugammadex is worse.

[0008] The prescription disclosed in patent application CN118105339A adds Lc-NKlysin-1a peptide, increasing the production cost and the risk of allergic reactions. Summary of the Invention

[0009] The present invention provides a sugammadex injection with stable pH value and its preparation method, ensuring the stable pH value of the liquid medicine, solving the problem of precipitation after API dissolution, reducing the metal ion concentration in the sugammadex injection, reducing the generation of insoluble substances and visible foreign matters, improving the product stability, and being suitable for large-scale industrial production.

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

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

[0012] In this application, the content of sugammadex in the injection is calculated as the sum of the sugammadex active entity (C 72 H 112 O 48 S8) and the single-hydroxy sugammadex active entity (C 69 H 108 O 47 S7); wherein, the single-hydroxy sugammadex 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, and is preferably sodium dihydrogen phosphate - disodium hydrogen phosphate.

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

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

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

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

[0019] 100 mg of sugammadex;

[0020] 0.04 mg of sodium dihydrogen phosphate;

[0021] 1.36 mg of disodium hydrogen phosphate;

[0022] The balance of water for injection;

[0023] The pH of the injection is 7.9 - 8.2.

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

[0025] 100 mg of sugammadex;

[0026] 0.04 mg of sodium dihydrogen phosphate;

[0027] Disodium hydrogen phosphate 1.36 mg;

[0028] The balance is water for injection;

[0029] The pH of the injection is 8.0.

[0030] On the other hand, the present invention provides a method for preparing the above-mentioned sugammadex sodium injection, comprising:

[0031] Pretreating the ampoules, liquid preparation tanks and pipelines for encapsulating the sugammadex sodium injection with a chelating agent solution;

[0032] Mixing the sugammadex sodium, the pH buffer pair and water for injection.

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

[0034] Soaking the ampoules with a chelating agent solution, and rinsing the liquid preparation tanks and pipelines with a chelating agent solution;

[0035] Mixing the sugammadex sodium, the pH buffer pair and water for injection.

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

[0037] Soaking the ampoules with a chelating agent solution for 30 min, rinsing the liquid preparation containers and pipelines with a chelating agent solution for 20 min, rinsing with purified water for 5-6 times, and then rinsing with water for injection for 3-4 times;

[0038] Mixing the sugammadex sodium, the pH buffer pair and water for injection.

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

[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% - 0.002 w / w%.

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

[0043] In some embodiments of the present invention, the preparation method further comprises: pre-treating the water for injection 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, and the sterilization conditions of the sterilization step are sterilization at 121 °C for 25-35 min.

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

[0046] (1) The ampoules are soaked in pentetic acid solution for 30 min, and the dispensing tank and pipelines are rinsed with pentetic acid solution for 20 min in sequence, rinsed with purified water for 5 - 6 times, and then rinsed with injection water for 3 - 4 times;

[0047] (2) Sugammadex is wetted with injection water to obtain the wetted active ingredient; the buffer pair is dissolved with injection water to obtain the buffer solution;

[0048] (3) The wetted active ingredient is added to a dispensing tank containing injection water, stirred until the active ingredient is completely dissolved, the buffer solution is added to adjust the pH value to 7.9 - 8.2, and after stirring evenly, injection water is added to the full volume;

[0049] (4) Nitrogen is filled, filtered, and the ampoules are filled and sealed;

[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 filtration conditions for the filtration in step (4) are filtering with 0.45 μm, 0.22 μm, and 0.22 μm filter elements in sequence.

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

[0054] Advantages of the present invention:

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

[0056]

[0057] Preparation method:

[0058] Weigh the raw material drug sugammadex according to the prescription, add 5 L of injection water and stir to wet it, transfer it to a dispensing tank containing about 80% injection water, stir until the raw material drug is completely dissolved, adjust the pH to 8.0 with 3.7% hydrochloric acid, add injection water to the full volume, fill with nitrogen, and filter with 0.45 μm, 0.22 μm, and 0.22 μm filter elements in sequence. After the pH, visible foreign matters, and content are qualified, fill 2 ml into ampoules and seal them, and sterilize at 121 °C for 25 - 35 min.

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

[0060] The inventors used pretreated (nitrogen-filled) water for injection in the product preparation process, and the dissolved oxygen in the water did not exceed 1.0 mg / L.

[0061] After the inventors measured the pH value, visible foreign matters, related substances, and content of different batches of samples, they found that the pH value of sugammadex injection produced in different batches fluctuated greatly. In some individual batches, there were phenomena such as precipitation after the dissolution of the raw material drug or problems with unqualified visible foreign matters.

[0062] For injections, trace metal ions in the production process usually act as catalysts for the oxidation reaction of compounds, which will significantly shorten the induction period of drug oxidation, accelerate the generation rate of free radicals, and thus lead to rapid drug degradation. Generally, a chelating agent can be added to form a stable complex with metal ions, thereby slowing down the drug degradation rate and improving the product stability.

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

[0064] (1) The present invention adds a suitable buffer pair to stably control the pH value of the liquid medicine within a certain range (pH value 7.9 - 8.2). Because if the pH is too low, the API is not completely dissolved, and if the pH is too high, there is a risk of erosion to the ampoule bottle, resulting in an increase in the leaching of internal metal ions, which will affect the stability of the injection. Moreover, trivalent ions such as Fe 3+ and Al 3+ may also complex with the API, leading to problems such as the generation of insoluble substances and unqualified visible foreign matters. The present invention preferably uses the sodium dihydrogen phosphate - disodium hydrogen phosphate buffer pair, and the prepared liquid medicine has a stable pH value, solving problems such as precipitation after the dissolution of the API, unqualified clarity and visible foreign matters of the liquid medicine, and improving the 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 ampoules, liquid preparation tanks and pipelines for encapsulating sugammadex injection are pretreated with a chelating agent solution in the present invention. Pentetic acid is preferably used as the chelating agent, and the ampoules are soaked with a pentetic acid solution, and the liquid preparation tanks and pipelines are rinsed, which can effectively remove various metal ions in the ampoules, liquid preparation tanks and pipelines, avoid increasing the metal ion concentration in the injection, improve the product stability, and are suitable for large-scale industrial production.

[0067] (4) Since the raw material drug sugammadex is easy to oxidize, the water for injection used in the production process needs to be pretreated (filled with nitrogen) so that the dissolved oxygen in the water does not exceed 1.0 mg / L, and nitrogen filling protection should also be carried out during the liquid preparation and filling processes.

[0068] (5) The present invention adopts the sterilization condition of "sterilizing at 121 °C for 25 - 35 min", avoiding too short sterilization time to ensure the aseptic level of the product, and too long sterilization time will significantly increase the related substances of the product. The present invention selects appropriate sterilization conditions to ensure the safety and effectiveness of clinical medication. Detailed implementation manners

[0069] The following further describes the present invention in detail with reference to embodiments, but it is not a limitation to the present invention. Any equivalent substitution in the art made in accordance with the disclosed content of the present invention belongs to the protection scope of the present invention.

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

[0071] In this application, the terms "comprising", "including" and "containing" and their equivalents should be understood in an open, non-exclusive sense, that is, "including but not limited to", meaning that in addition to the listed elements, components and steps, other unspecified elements, components and steps can also be covered. In this article, unless otherwise clearly specified in the context, singular terms cover plural referents and vice versa.

[0072] In this application, drug excipients or reagents involved can all be from commercial sources.

[0073] In this application, unless otherwise specified, "%" in the embodiments of this application refers to mass percentage. Without special instructions in the embodiments, the reaction temperature is 20 - 30 °C.

[0074] Table 1

[0075]

[0076]

[0077] Examples 1 to 10

[0078] 1. Prescription: The prescriptions of 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 100g Hydrochloric acid Appropriate amount Purified water Make up to 1000 ml

[0083] 2. Preparation processes of Examples 1-10 and Comparative Example 1 are as follows:

[0084] A. Weigh the raw material drug sugammadex sodium according to the prescription amount, dissolve it with 80% injection water (which belongs to the conventional preparation method of small-volume injection) to obtain Solution A;

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

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

[0087] D. Fill with nitrogen, filter (filter with a 0.22 μm filter membrane), and seal the ampoules;

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

[0089] Among them, the injection water is pre-treated by nitrogen filling to make the dissolved oxygen content not exceed 1.0 mg / L.

[0090] Examples 11 - 15

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

[0092] 1. Prescription: The prescriptions of Examples 11-16, Comparative Example 2, the types and concentrations of chelating agents are shown in Tables 4-6.

[0093] Table 4

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

[0095] Investigate the types and concentrations of chelating agents according to the above prescription:

[0096] Table 5

[0097] Name Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 Ethylenediaminetetraacetic acid 0.0005％ Not added Not added Not added Not added Not added Pentetic acid Not added 0.0005％ Not added Not added 0.002％ 0.01％ Disodium edetate Not added Not added 0.0005％ Not added Not added Not added Calcium disodium edetate Not added Not added Not added 0.0005％ Not added Not added

[0098] Table 6

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

[0100] 2. The preparation processes of Examples 11 - 15 are as follows:

[0101] A. The ampoules are soaked in the chelating agent solution for 30 min, the liquid preparation tank and pipelines are rinsed with the chelating agent solution for 20 min, then rinsed with purified water for 5 - 6 times, and then rinsed with injection water for 3 - 4 times;

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

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

[0104] D. Transfer the moistened raw material drug into a liquid preparation tank containing about 80% injection water, stir until the raw material drug is completely dissolved, add the buffer pair solution, adjust the pH value to 7.9 - 8.2, and add water to the full volume after stirring evenly;

[0105] E. Fill with nitrogen, filter (successively filter with 0.45μm, 0.22μm, and 0.22μm filters using a sterile filter), and fill and seal the ampoules;

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

[0107] Among them, the injection water is pre - treated by filling with nitrogen until the dissolved oxygen content does not exceed 1.0 mg / L.

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

[0109] A. The liquid preparation tank and pipelines are rinsed with purified water for 5 - 6 times, and then rinsed with injection water for 3 - 4 times;

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

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

[0112] D. Transfer the moistened raw material drug into a liquid preparation tank containing about 80% injection water, stir until the raw material drug is completely dissolved, add the buffer pair solution, adjust the pH value to 7.9 - 8.2, and add water to the full volume after stirring evenly;

[0113] E. Fill with nitrogen, filter (successively filter with 0.45μm, 0.22μm, and 0.22μm filters using a sterile filter), and fill and seal the ampoules;

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

[0115] Among them, the injection water is pre - treated by filling with nitrogen until the dissolved oxygen content does not exceed 1.0 mg / L.

[0116] Effect Example 1: Investigate the influence of different buffer salts on product quality under stress conditions.

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

[0118] The results of the influence factors such as appearance, pH, content, clarity of solution, visible foreign matters, and related substances on the reference preparation product are shown in Table 7 - 19.

[0119] Table 7 Results of the influence factor investigation for Example 1

[0120]

[0121]

[0122] Note: " / " indicates not detected or the detection level is lower than the neglect limit.

[0123] Table 8 Results of the influence factor investigation for Example 2

[0124]

[0125] Note: " / " indicates not detected or the detection level is lower than the neglect limit.

[0126] Table 9 Results of the influence factor investigation for Example 3

[0127]

[0128] Note: " / " indicates not detected or the detection level is lower than the neglect limit.

[0129] Table 10 Results of the influence factor investigation for Example 4

[0130]

[0131]

[0132] Note: " / " indicates not detected or the detection level is lower than the neglect limit.

[0133] Table 11 Results of the influence factor investigation for Example 5

[0134]

[0135] Note: " / " indicates not detected or the detection level is lower than the neglect limit.

[0136] Table 12 Results of the influence factor investigation for Example 6

[0137]

[0138]

[0139] Note: " / " indicates not detected or the detected level is lower than the ignore limit.

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

[0141]

[0142] Note: " / " indicates not detected or the detected level is lower than the ignore limit.

[0143] Table 14 Results of the investigation on influencing factors in Example 8

[0144]

[0145]

[0146] Note: " / " indicates not detected or the detected level is lower than the ignore limit.

[0147] Table 15 Results of the investigation on influencing factors in Example 9

[0148]

[0149] Note: " / " indicates not detected or the detected level is lower than the ignore limit.

[0150] Table 16 Results of the investigation on influencing factors in Example 10

[0151]

[0152]

[0153] Note: " / " indicates not detected or the detected level is lower than the ignore limit.

[0154] Table 17 Results of the investigation on influencing factors in Comparative Example 1

[0155]

[0156] Note: " / " indicates not detected or the detected level is lower than the ignore limit.

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

[0158]

[0159]

[0160] Note: " / " indicates not detected or the detected level is lower than the ignore limit.

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

[0162] It can be seen 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) that the pH value of the buffer pair is preferably 7.9 - 8.2.

[0163] It can be seen from Examples 3 and 6 - 8 that the buffer pair is preferably sodium dihydrogen phosphate - disodium hydrogen phosphate.

[0164] It can be seen from Examples 2 - 4 and 9 - 10 that the content of sodium dihydrogen phosphate in the buffer pair can be 0.01 - 0.04 mg / mL, and the content of disodium hydrogen phosphate can be 0.34 g - 1.36 mg / mL. As the concentration of the buffer pair increases, the product stability shows an increasing trend, and all meet the product quality requirements. Among them, Example 10 has the best effect, and 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 Influence Factor Investigation Test

[0166] Samples (Examples 11 - 15, Comparative Example 2) were inspected at 60 °C under high temperature and 4500 ± 500 lx under light for 5 days, 10 days, and 30 days.

[0167] The results of the influence factors of the appearance, pH, content, and related substances on the reference preparation product are shown in Tables 19 - 24.

[0168] Table 19 Results of Influence Factors of Example 11

[0169]

[0170]

[0171] Note: " / " indicates not detected or the detection level is lower than the neglect limit.

[0172] Table 20 Results of Influence Factors of Example 12

[0173]

[0174] Note: " / " indicates not detected or the detection level is lower than the neglect limit.

[0175] Table 21 Results of Influence Factors of Example 13

[0176]

[0177]

[0178] Note: " / " indicates non-detection or the detected level is lower than the neglect limit.

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

[0180]

[0181] Note: " / " indicates non-detection or the detected level is lower than the neglect limit.

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

[0183]

[0184] Note: " / " indicates non-detection or the detected level is lower than the neglect limit.

[0185] Table 24 Results of influencing factors in Comparative Example 2

[0186]

[0187] Note: " / " indicates non-detection or the detected level is lower than the neglect limit.

[0188] No chelating agent residue was detected in Examples 11 - 15. Chelating agent residue was 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, resulting in chelating agent residue in the product.

[0189] It can be seen from Examples 11 - 15 and Comparative Example 2 that pre-soaking and rinsing ampoules, liquid preparation tanks, and pipelines with a chelating agent can significantly improve product stability. Among them, pentetic acid (Examples 12 and 15) has the most significant effect on improving product stability because it contains multiple coordination atoms and can form stable complexes with various metal ions, thereby reducing the metal ion residue on the surfaces of ampoules, liquid preparation tanks, and pipelines and improving the stability of the injection solution.

[0190] It can be seen from Example 12 and Example 15 that the preferred chelating agent concentration is 0.0005% - 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 purposes of description and disclosure, all patents, patent applications, and other publications are hereby expressly incorporated herein by reference. These publications are provided only because their disclosures predated the filing date of the present application. All statements as to the dates of these documents or as to the contents thereof are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or of the contents thereof. Moreover, any reference to these publications in this application does not constitute an admission that such publication is 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 embodiments and examples described above, but that various modifications, substitutions, 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 injection, comprising: Sugammadex sodium, pH buffer pair and water for injection; the content of sugammadex sodium is 50 mg / mL to 200 mg / mL; the pH value of the injection solution is 7.9 to 8.2; 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; The preparation method of the sugammadex sodium injection solution includes: pretreating the ampoules, liquid dispensing tanks and pipelines for encapsulating the sugammadex sodium injection solution with a chelating agent solution; Mixing the sugammadex sodium, the pH buffer pair and water for injection; The concentration of the chelating agent solution is 0.0005 w / w% to 0.002 w / w%.

2. The injection according to claim 1, characterized in that, The content of sugammadex sodium in the injection solution 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 sodium dihydrogen phosphate-disodium hydrogen phosphate.

4. The injection according to claim 3, wherein, The content of sodium dihydrogen phosphate is 0.01 to 0.04 mg / mL, and the content of disodium hydrogen phosphate is 0.34 to 1.36 mg / mL.

5. The injection according to claim 4, wherein, The content of sodium dihydrogen phosphate is 0.04 mg / mL, and the content of disodium hydrogen phosphate is 1.36 mg / mL.

6. The injection according to claim 1, wherein Each milliliter of the injection solution is composed of the following components: Each milliliter of the injection solution is composed of the following components: 100 mg of sugammadex sodium; 0.04 mg of sodium dihydrogen phosphate; 1.36 mg of disodium hydrogen phosphate; The balance of water for injection; The pH of the injection solution is 7.9 - 8.

2.

7. A method for preparing the injection according to any one of claims 1-6, characterized in that: Including: Pretreating the ampoules, liquid dispensing tanks and pipelines for encapsulating the sugammadex sodium injection solution with a chelating agent solution; Mixing the sugammadex sodium, the pH buffer pair and water for injection.

8. The preparation method of the injection according to claim 7, characterized in that, The chelating agent solution is a pentetic acid solution of 0.0005 w / w% to 0.002 w / w%.

9. The preparation method of the injection solution according to claim 7, characterized in that (1) The ampoules are soaked in the pentetic acid solution for 30 min, and the liquid dispensing tanks and pipelines are successively rinsed with the pentetic acid solution for 20 min, rinsed with purified water for 5 - 6 times, and then rinsed with water for injection for 3 - 4 times; (2) Wetting the sugammadex sodium with water for injection to obtain a wetted active ingredient; dissolving the buffer pair with water for injection to obtain a buffer solution; (3) Adding the wetted active ingredient to the liquid dispensing tank of water for injection, stirring until the active ingredient is completely dissolved, adding the buffer solution to make the pH value reach 7.9 - 8.2, stirring evenly and then adding water for injection to the full volume; (4) Filling with nitrogen, filtering, and filling and sealing the ampoules; (5) Sterilizing at 121 °C for 25 - 35 min.

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