A prefilled sugammadex sodium and sodium chloride injection

Abstract

The present invention discloses a prefilled sugammadex sodium and sodium chloride injection and a preparation method thereof, the injection comprising a prefilled syringe and a liquid medicine in the syringe, the liquid medicine comprising sugammadex sodium, sodium chloride, a pH regulator, and water for injection, wherein the concentration of sugammadex sodium is 5 mg / mL to 50 mg / mL; the inner wall of the prefilled syringe sleeve and the piston are coated with a silicone-free organic lubricating film. The injection has better chemical stability and higher safety than the prior art, does not require secondary dilution during clinical use, and the dosage is easy to accurately control, thereby improving the safety of medication for patients and the convenience of emergency medication for doctors during surgery, and reducing the incidence of safety accidents in clinical emergencies.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a prefilled sugammadex sodium and sodium chloride injection and a preparation method thereof. Background Art

[0002] Sugammadex sodium is the world's first neuromuscular blocking antagonist drug developed by Merck. It forms a complex with the neuromuscular blocking drugs rocuronium or vecuronium through intermolecular interactions, thereby reducing the amount of neuromuscular blocking drugs that bind to nicotinic receptors at the neuromuscular junction with rocuronium or vecuronium, thereby achieving an antagonistic effect.

[0003] Sugammadex sodium (Merck code: Org25969) is available in the form of injection. It was first approved for marketing in the European Union in July 2008 under the trade name Bridion. The specification is 100 mg / mL and the packaging specifications are 2mL: 0.2g and 5mL: 0.5g. Currently, Sugammadex sodium injection has been approved for marketing in at least 79 countries around the world. The chemical structure of Sugammadex sodium is shown in Formula 1:

[0004] Formula 1 Sugammadex Sodium (C 72 H 104 Na8O 48 S8, 2178.01)

[0005] However, sugammadex sodium injection also contains another reaction byproduct, monohydroxysugammadex sodium (Merck code: Org48302), which has a safety profile similar to that of sugammadex sodium, but has a 50% lower affinity for rocuronium or vecuronium. According to Merck's research results, sugammadex sodium injection containing no more than 20% monohydroxysugammadex sodium has no difference in the reversal results of rocuronium and vecuronium. Therefore, Org48302 is also one of the active ingredients of sugammadex sodium injection, and a clear upper control limit (not to exceed 6.0%) has been established in the quality standards. Its chemical structure is shown in Formula 2:

[0006]

[0007] Formula 2 Monohydroxysugammadex sodium (C 69 H 101 Na7O 47 S7, 2067.90)

[0008] The launch of Sugammadex Sodium Injection is a major breakthrough in the field of anesthesia and has caused a sensation in emergency rooms and anesthesia rooms in major hospitals around the world. Although the only indication approved in the instructions for use of Buritin is to reverse neuromuscular blockade caused by rocuronium or vecuronium during surgery, the drug will almost certainly be used in emergency departments, operating rooms, and potential pre-hospital rescue scenarios off-label for different situations. In actual applications, the factors that anesthesiology departments, emergency rooms, and operating rooms are most concerned about are:

[0009] Rapid reversal of paralysis. For patients with traumatic brain injury, intracranial hemorrhage, ongoing seizures, burns, or spinal cord injury, the most promising use of sugammadex is the immediate rescue reversal (IRR) of paralysis after rapid sequence intubation (RSI). In this case, due to the short duration of action of succinylcholine, it is clinically avoided or used with caution. Sugammadex sodium injection can recover relatively quickly and conduct neurological assessments or allow other key tests to be carried out. However, in real-world clinical scenarios, the turnaround time from the doctor's decision to use sugammadex sodium injection to the reversal of paralysis is unclear. The results of a real-world scenario simulation exercise conducted by the Amsterdam Medical Center in the Netherlands showed that when the immediate reversal rescue of paralysis after rapid sequence intubation (RSI) was performed, it took an average of 6.7 minutes ± 1.5 minutes from the decision to use sugammadex sodium injection to the completion of the administration of sugammadex sodium injection, and the longest time should not exceed 8.9 minutes (to achieve a TOF ratio of 0.9). The results showed that only 22% of the anesthesia teams gave the patients the correct dose, 56% of the anesthesia teams gave doses lower than the clinically recommended dose, and 22% of the anesthesia teams gave doses higher than the recommended dose, which means that 78% of the anesthesia teams gave the wrong dose. According to this study, if sugammadex sodium is used in a real clinical setting, it will only take 9 minutes from the decision to administer the drug to the reversal of paralysis. If a prefilled sugammadex sodium injection is used, the time can be reduced by at least half, and there will be no such alarming dose error incidents.

[0010] In addition, Sugammadex Sodium Injection has been approved for rapid reversal of neuromuscular blockade in adults and children and adolescents aged 2-17 years. The recommended dose for adults is 2 mg / kg, 4 mg / kg or 16 mg / 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 (2mL: 0.2g or 5mL: 0.5g 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 intravenous rapid injection, which needs to be injected into the existing intravenous access within 10 seconds. According to the weight range of children and adolescents aged 2-17 years published by the Beijing Institute of Children's Research, the dosage of sugammadex sodium as a muscle relaxant reversal agent is 22-158 mg. Directly using the 100 mg / mL marketed preparation cannot accurately control the dosage, and the remaining medicine after opening the bottle can only be thrown away, resulting in unnecessary waste. When sugammadex sodium is used in emergency situations during clinical surgery, there are the following problems:

[0011] (1) The drug must be diluted in advance. Otherwise, dilution during emergency use cannot meet the needs of actual clinical use scenarios. The above IRR for adult RSI patients does not take into account the error rate caused by dilution before use. The probability of error in dosage alone is as high as 78%.

[0012] (2) When used for children and adolescents, dilution before use can easily cause bacterial contamination.

[0013] (3) Nitrogen is filled throughout the production process of Sugammadex Sodium Injection, and it is also filled with nitrogen 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 kept stable 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.

[0014] (4) During the dilution process, a certain amount of 100 mg / ml sugammadex sodium injection and 0.9% sodium chloride injection must be mixed. The dilution process is prone to volume measurement deviation or volume calculation error, resulting in inaccurate dosage.

[0015] (5) The dilution process is performed manually, which may lead to incorrect dilution concentration, thereby increasing the risk of incorrect dosage, and in severe cases, may lead to the death of the patient.

[0016] (6) For adult patients with lower body weight, directly using the marketed sugammadex sodium injection may lead to inaccurate dosage due to the lower dosage and smaller volume of medication.

[0017] (7) The cost of this drug is relatively high. The existing large-scale injection is used for children, adolescents and patients with lighter weight. Once the bottle is opened, the remaining can no longer be used. Developing a pediatric sugammadex sodium injection for this group of people is of great significance in clinical applications.

[0018] Sugammadex sodium and monohydroxysugammadex sodium contain sulfur in their structures, and are prone to produce degradation impurities as shown in Table 1 below under strong acid, strong alkali, oxidation, light, and high temperature conditions:

[0019] Table 1 Degradation impurities

[0020]

[0021] Patent application CN112933040A, in the process of preparing sugammadex sodium injection, in order to control the influence of the preparation process on degradation impurities, in addition to nitrogen filling, protective agents inositol phosphates and their derivatives are added to control the growth of degradation products. Finally, the protective agent is removed by reverse osmosis membrane, and after filling, it is sterilized at 121°C for 15 minutes to obtain a 100 mg / mL injection.

[0022] Compared with high-concentration sugammadex sodium injection, low-concentration sugammadex sodium has worse chemical stability.

[0023] In order to solve the problem of chemical stability of low-concentration sugammadex sodium injection, CN116172953A discloses a low-concentration sugammadex sodium injection, in which the concentration of sugammadex sodium is 1 mg / mL to 50 mg / mL, avoiding a series of problems caused by dilution of high-concentration sugammadex sodium injection. However, the product is still packaged in vials or ampoules, and when used, the drug solution still needs to be drawn up with a syringe and then injected into the patient, and there is still a risk of contamination and error during the transfer of the drug solution.

[0024] With the advantages of accurate dosing, high utilization rate of liquid medicine, and convenient use by medical staff, prefilled syringes have been used in many injection products in recent years. In order to ensure that the rubber piston on the push rod of the prefilled syringe assembly can slide freely in the needle tube, the inner wall of the needle tube and the piston must be sprayed with silicone oil for lubrication during the production process of the prefilled syringe assembly. The national pharmaceutical packaging material standard YBB 00112004-2015 Prefilled Syringe Assembly (with Injection Needle) stipulates clear control limits for the amount of silicone oil contained in prefilled syringes:

[0025] Table 2 YBB 00112004-2015 Prefilled syringe assembly (with injection needle) silicone oil limit

[0026]

[0027] However, the production process of prefilled injections is complex, and how to prepare products with good stability is also a challenge.

[0028] In summary, there is an urgent need for a prefilled sugammadex sodium and sodium chloride injection with high safety, good chemical stability, convenient clinical application, compliance with the actual clinical environment, and accurate dosage. Summary of the invention

[0029] The inventors unexpectedly solved the above problems through extensive and in-depth experimental research and developed a prefilled sugammadex sodium injection.

[0030] Specifically, the present invention provides the following technical solutions:

[0031] On the one hand, the present invention provides a prefilled sugammadex sodium and sodium chloride injection, characterized in that the injection comprises a prefilled syringe and a medicinal solution in the syringe, wherein the medicinal solution comprises sugammadex sodium, sodium chloride, a pH adjuster, and water for injection, wherein the concentration of sugammadex sodium is 5 mg / mL-50 mg / mL; the inner wall of the sleeve and / or the piston of the prefilled syringe is coated with an organic lubricating film that does not contain silicone oil.

[0032] In some embodiments, for children and adolescents, the concentration of sugammadex sodium is 5 mg / mL, 10 mg / mL or 20 mg / mL; for adults, the concentration of sugammadex sodium is 10 mg / ml, 20 mg / mL, 25 mg / mL or 50 mg / mL.

[0033] In some embodiments, the capacity of the prefilled syringe is 2-25 mL, preferably 2 mL, 5 mL, 8 mL, 10 mL, 15 mL, 20 mL and 25 mL.

[0034] In some embodiments, the concentration of sodium chloride is 4.5 mg / ml-9 mg / mL.

[0035] In some embodiments, the pH adjuster is selected from one or more of hydrochloric acid, acetic acid, citric acid, tartaric acid, malic acid, lactic acid, ascorbic acid, phosphoric acid, sodium hydroxide, sodium citrate, potassium citrate, monosodium citrate, sodium lactate, calcium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, tromethamine, meglumine, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium acetate, and potassium acetate.

[0036] In some embodiments, the pH of the drug solution is 6.5-8.5.

[0037] In some embodiments, the organic lubricating film free of silicone oil is a fluorinated organic lubricating film, such as a perfluoropolyether derivative.

[0038] The prefilled syringe barrel is made of glass or high molecular polymer material, the glass is preferably medium borosilicate glass, and the high molecular polymer is preferably cycloolefin polymer or polypropylene.

[0039] The prefilled syringe piston is selected from a chlorinated butyl rubber piston covered with an ethylene-tetrafluoroethylene copolymer film, a brominated butyl rubber piston covered with a polyethylene tetrafluoroethylene film, a chlorinated butyl rubber piston covered with a polytetrafluoroethylene film, and a brominated butyl rubber piston covered with a polytetrafluoroethylene film.

[0040] In some embodiments, the starting force is ≤25 N and the sustained force is ≤10 N when the piston is pushed at a forward speed of 100 mm / min±5 mm / min.

[0041] On the other hand, the present invention provides a method for preparing a prefilled sugammadex sodium and sodium chloride injection, comprising the following steps:

[0042] 1) Preparation: Weigh the prescribed amount of sugammadex sodium and sodium chloride, add to water for injection that has been cooled to below 50°C, and stir until completely dissolved; add pH adjuster to adjust pH to 6.5-8.5, add water for injection to the full amount, and fill the liquid with inert gas until the residual oxygen content is ≤2ppm;

[0043] 2) Filtration sterilization: sterilization by filter membrane, the filter membrane is 0.45μm and 0.22μm filter membrane;

[0044] 3) Filling and sealing: first evacuate the pre-filled syringe, fill it with liquid medicine, and at the same time, fill it with inert gas, seal it, add a stopper, and assemble other accessories such as the push rod;

[0045] 4) Sterilization.

[0046] In some embodiments, the step 3) is performed by vacuuming and then filling with inert gas, or the vacuuming-filling with inert gas is repeated 2 times or more; and the stoppering is preferably vacuum stoppering.

[0047] In some embodiments, the inert gas is nitrogen.

[0048] In some embodiments, the sterilization in step 4) is a steam / air mixed sterilization method, with an F0 value ≥ 8, preferably F0 ≥ 12.

[0049] On the other hand, the present invention provides the use of the prefilled sugammadex sodium chloride injection as described above in the preparation of a drug for antagonizing neuromuscular blockade induced by rocuronium and vecuronium, characterized in that the drug is suitable for adolescents, children, infants and adults aged 17 and below.

[0050] Starting force and sustained force: According to the piston activity performance item in the national pharmaceutical packaging material standard YBB00112004-2015 prefilled syringe assembly (with injection needle), push the push rod at a speed of 100mm / min±5mm / min to test the starting force and sustained force of piston sliding.

[0051] F0 value: standard sterilization time, is a comparative parameter to verify the reliability of moist heat sterilization during the sterilization process. When the F0 value is greater than 8, it can be confirmed that a reliable sterilization effect has been achieved. DETAILED DESCRIPTION

[0052] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments.

[0053] The materials and reagents used in the examples are all common commercially available products.

[0054] The prefilled syringes used in the examples are as follows:

[0055] Prefilled syringes: If not otherwise specified, the barrel of the prefilled syringe is made of medium borosilicate glass with a perfluoropolyether coating, and the piston is a polytetrafluoroethylene-filmed brominated butyl rubber piston.

[0056] Ordinary pre-filled syringe containing silicone oil: the sleeve is made of medium borosilicate glass, the piston is a bromobutyl rubber piston, and it is sprayed with silicone oil for lubrication.

[0057] Comparative Example 1: The sample was prepared according to the recipe and process of Example 2 of CN116172953A.

[0058] Comparative Example 2: Reference preparation BRIDION® Sugammadex Sodium Injection.

[0059] Table 3 Prescription composition

[0060]

[0061] Preparation process:

[0062] Example 1: Weigh the prescribed amount of sugammadex sodium and sodium chloride, add an appropriate amount of water for injection that has been cooled to below 50°C, and stir until completely dissolved; add a pH adjuster to adjust the pH to 7.5, add water for injection to the full amount of the prescription, fill with nitrogen, control the residual oxygen content to not more than 2ppm, and filter with 0.45μm and 0.22μm filter membranes.

[0063] First, the prefilled syringe is vacuumed, filled with nitrogen, filled with liquid medicine, filled with inert gas, sealed and plugged, and other accessories are assembled. Sterilize by steam / air mixed sterilization method at 121℃ for 15 minutes.

[0064] Comparative Example 1: Fill high-purity nitrogen (purity ≥ 99.999%) into water for injection until the dissolved oxygen content is less than 2ppm; then weigh the prescribed amount of sodium sugammadex and sodium chloride, stir until completely dissolved; adjust the pH of the solution to a predetermined value with a pH regulator; then add nitrogen-filled water for injection to the full amount of the prescription; filter with 0.45μm and 0.22μm polyethersulfone filter membranes, fill the liquid into a vial, press the plug and roll the cap after nitrogen is filled on the liquid surface; sterilize the filled liquid at 121℃ for 15 minutes to obtain the solution. The concentration is 10mg / mL.

[0065] Comparative Example 2: Bridion® Sugammadex Sodium Injection, concentration of 100 mg / mL, packaged in vials.

[0066] According to the quality requirements of injection products, the properties, solution color and clarity, pH, osmotic pressure and degradation products of Example 1 and Comparative Example 1 and Comparative Example 2 were checked respectively. The properties were checked by visual inspection, and the pH and osmotic pressure molar concentration were checked according to the general rules 0631 and 0632 of the fourth part of the 2020 edition of the Chinese Pharmacopoeia; and the degradation products were detected by high performance liquid chromatography.

[0067] The quantitative detection of degradation impurity acrylic acid was carried out by HPLC, C18 column (150 mm × 4.6 mm, 2.5 μm), mobile phase A was 0.05% phosphoric acid aqueous solution, mobile phase B was acetonitrile, gradient elution was 0-4 min (A88%), 4-6 min (A88%-10%), 6-10 min (A10%), 10-10.1 min (A10%-88%), 10.1-15 min (A88%), flow rate was 0.7 ml per minute, detection wavelength was 200 nm; column temperature was 40 ° C; injection volume was 20 μL. The content of acrylic acid was calculated by external standard method.

[0068] The structures of other degradation impurities are all cyclodextrin impurities, and their polarity and UV absorption are similar to those of sugammadex sodium and monohydroxysugammadex sodium. The content of each impurity is calculated using HPLC with the main component comparison method.

[0069] The chromatographic conditions for the detection method of degradation impurities B, C, D, E, and G are as follows:

[0070] C18 column (150mm×4.6mm, 2.5μm), mobile phase A was 25mM sodium dihydrogen phosphate solution (pH adjusted to 3.0 with phosphoric acid), mobile phase B was acetonitrile, gradient elution: 0-5min (A100%), 5-15min (A100%-98%), 15-22min (A98%-92%), 22-27min (A92%-75%), 27-32min (A75%-50%), 32-37min (A50%-30%), 37-42min (A30%), 42-42.1min (A30%-100%), 42.1-52min (A100%), flow rate was 0.5ml per minute, detection wavelength was 200nm; column temperature was 40℃; injection volume was 5μL.

[0071] The above samples were placed under high temperature of 60°C and light of 5000LX (barely placed) to investigate the influencing factors, focusing on the appearance of degradation impurities and solutions, and compared with the 0-day test results. The results are shown in the following table:

[0072] Table 4 10-day test results of influencing factors

[0073]

[0074] Conclusion: From the results of the 10-day investigation of the influencing factors of Example 1 and Comparative Example 1, it can be seen that when Example 1 was left naked under light conditions for 10 days, the growth rate of impurity B and total impurities was slightly lower than that of Comparative Example 1, but both did not exceed the control limits in the quality standards. Under high temperature conditions, the growth trends of each impurity in Example 1 and Comparative Example 1 were basically the same; Comparative Example 1 adopted nitrogen filling throughout the process and vial packaging, while Example 1 adopted a terminal nitrogen filling process and pre-filled syringe packaging, which has a simpler preparation process from a production perspective. When the samples of Example 1 and Comparative Example 1 were left naked under light conditions for 10 days, the growth rate of impurity B and impurities was much lower than that of Comparative Example 2, indicating that the chemical stability of Example 1 and Comparative Example 1 is better than that of Comparative Example 2.

[0075] According to the generation mechanism of impurity B, under strong light irradiation, the residual oxygen molecules in the sodium sugammadex solution will absorb energy and produce an excited oxygen molecule, which will further decompose into two oxygen free radicals, attacking the lone pair of electrons of the sulfur atom in the sodium sugammadex molecular structure to form impurity B.

[0076] The chemical stability of the samples of Example 1 and Comparative Example 1 is better than that of Comparative Example 2, which is also related to the presence of sodium chloride in the prescription or the reduction of the concentration of the main drug.

[0077] Example 2 Preparation of prefilled sugammadex sodium and sodium chloride injection and analysis of influencing factors

[0078] Table 5 Prescription composition

[0079]

[0080] Example 2-3: Weigh the prescribed amount of sugammadex sodium and sodium chloride, add an appropriate amount of water for injection cooled to below 50°C, stir until completely dissolved, add a pH adjuster to adjust the pH to 6.5 or 8.5, add water for injection to the full amount, fill the liquid with inert gas to the residual oxygen content ≤2ppm, and filter through 0.45μm and 0.22μm filter membranes.

[0081] First, the prefilled syringe is vacuumed, filled with nitrogen, filled with liquid medicine, and filled with inert gas at the same time, sealed and plugged, and other accessories are assembled. Sterilize by steam / air mixed sterilization method, sterilize at 121℃ for 15 minutes.

[0082] Example 4 and Comparative Example 3: Weigh the prescribed amount of sugammadex sodium and sodium chloride, add an appropriate amount of water for injection cooled to below 50°C, and stir until completely dissolved; add a pH adjuster to adjust the pH to 7.5, add water for injection to the full amount, fill the drug solution with inert gas to a residual oxygen content of ≤2ppm, and pass through 0.45μm and 0.22μm filter membranes.

[0083] Example 4: First, evacuate the prefilled syringe, fill it with nitrogen, evacuate it again, fill it with nitrogen, fill it with liquid medicine, fill it with inert gas at the same time, seal it, add a stopper, and assemble other accessories. Sterilize it with steam / air mixed sterilization method, sterilize it at 121℃ for 15 minutes.

[0084] Comparative Example 3: Filling with liquid medicine, sealing and plugging, assembling other accessories. Sterilization by steam / air mixed sterilization method, 121℃ for 15 minutes.

[0085] Example 5: High-purity nitrogen (purity ≥ 99.999%) is added to water for injection cooled to below 50°C until the dissolved oxygen content is less than 2 ppm, and the prescribed amount of sodium sugammadex and sodium chloride are added and stirred until completely dissolved; the pH of the solution is adjusted to 7.5 with a pH adjuster, and nitrogen-filled water for injection is added to the full amount; use 0.45μm and 0.22μm polyethersulfone filter membranes.

[0086] First, the prefilled syringe is vacuumed, filled with nitrogen, filled with liquid medicine, and filled with inert gas at the same time, sealed and plugged, and other accessories are assembled. Sterilize by steam / air mixed sterilization method, sterilize at 121℃ for 15 minutes.

[0087] The samples of Examples 2-5 and Comparative Example 3 were placed under high temperature of 60°C and light of 5000 Lx (placed with packaging) for 10 days to investigate the influencing factors. After the influencing factor test, the properties and degradation products were checked and compared with the test results on day 0. The results are shown in the following table:

[0088] Table 6 Test results of influencing factors of Examples 2-5 and Comparative Example 3

[0089]

[0090] The pH of the sodium dextrose and sodium chloride solution prepared in Example 1 is 7.5. Examples 2-3 have exactly the same prescription as Example 1, but the pH is controlled at pH 6.5 and pH 8.5, respectively. From the 10-day test results of the influencing factors, it can be seen that the growth rate and change trend of each degradation impurity and total impurity are basically the same. The pH of the sodium dextrose and sodium chloride pre-filling solution is controlled in the range of 6.5-8.5, and the chemical stability of the solution is good.

[0091] According to the 10-day test results of the influencing factors of Example 1 and Example 5, there is no significant difference in the effect of nitrogen filling during the entire sample preparation process or during the end filling on the chemical stability of the solution.

[0092] According to the results of the influencing factors of Example 1, Example 4, and Comparative Example 3, the growth rate of the degradation products related to the residual oxygen content of impurities B and C in Comparative Example 3 for 10 days is slightly greater than the growth rate of B and C in Example 4 (the impurities B, C, D, and total impurities in Comparative Example 3 increased by 0.04%, 0.21%, 0.12%, and 0.32% respectively at high temperature for 10 days, and increased by 0.36%, 0.24%, 0.10%, and 0.68% respectively at 10 days of illumination; the impurities B, C, D, and total impurities in Example 4 increased by 0.01%, 0.06%, 0.05%, and 0.08% respectively at high temperature for 10 days, and increased by 0.04%, 0.07%, 0.10%, and 0.16% respectively at 10 days of illumination). During filling, repeatedly vacuuming and filling the syringe with nitrogen in advance can more fully remove oxygen in the container and improve the chemical stability of the product. If the syringe is not vacuumed and filled with nitrogen, the residual oxygen content in the container is higher and the chemical stability of the product is poor.

[0093] Example 3 Preparation of prefilled sugammadex sodium chloride injection and analysis of influencing factors

[0094] Table 7 Prescription composition

[0095]

[0096] Note: The sleeve of the pre-filled syringe without silicone oil is made of medium borosilicate glass, coated with perfluoropolyether, and the piston is a polytetrafluoroethylene-filmed brominated butyl rubber piston. Pre-filled syringe with silicone oil: The sleeve is made of medium borosilicate glass, the piston is a brominated butyl rubber piston, and is sprayed with silicone oil for lubrication.

[0097] Preparation process of Examples 6-8 and Comparative Example 4:

[0098] Weigh the prescribed amount of sugammadex sodium and sodium chloride, add to an appropriate amount of water for injection that has been cooled to below 50°C, and stir until completely dissolved; add a pH adjuster to adjust the pH to 7.5, add water for injection to the full amount, fill the liquid with inert gas to the residual oxygen content ≤2ppm, and pass through 0.45μm and 0.22μm filter membranes.

[0099] Example 6-8: Use a silicone oil-free pre-filled syringe. First, evacuate the pre-filled syringe, fill it with nitrogen, fill it with liquid medicine, and then fill it with inert gas, seal it, add a stopper, and assemble other accessories. Sterilize it using steam / air mixed sterilization method at 121℃ for 15 minutes.

[0100] Comparative Example 4: Using a common pre-filled syringe containing silicone oil, the pre-filled syringe was first vacuumed, filled with nitrogen, filled with liquid medicine, and filled with inert gas at the same time, sealed and plugged, and other accessories were assembled. Sterilization was performed by steam / air mixed sterilization method at 121°C for 15 minutes.

[0101] The above samples were subjected to stability inspection under accelerated conditions of 40℃ / RH75% and long-term conditions of 30℃ / RH65%. The results are shown in the table below and compared with the 0-day test results.

[0102] Table 8 Stability test results of Examples 6-8 and Comparative Examples 2 and 4 (I)

[0103]

[0104] Table 9 Stability test results of Examples 6-8 and Comparative Examples 2 and 4 (II)

[0105]

[0106] Note: *Y stands for yellow, Y+number, the larger the number, the darker the yellow.

[0107] According to Examples 6-8, the stability of sugammadex sodium injection at different concentrations is good.

[0108] According to the stability test results of Example 6 and Comparative Example 4, under the same test conditions, the change range of each degradation impurity in Example 6 and Comparative Example 4 is basically the same, and the changes in other properties, pH, content, solution clarity and color are also basically the same. However, the insoluble particles in Comparative Example 4 are significantly increased, which should be related to the silicone oil in the prefilled syringe.

[0109] According to YBB00112004-2015, the piston sliding performance was tested and the results are as follows:

[0110] Table 10 Sliding performance test results

[0111]

[0112] Silicone oil is a lubricant commonly used in prefilled syringes. The syringe is low in price and has good lubrication effect, so it is the first choice. However, according to the results in Table 10, the present invention shows that the samples prepared by using common prefilled syringes containing silicone oil will have silicone oil migrate into the liquid medicine, resulting in an increase in insoluble particles, a significant increase in the friction of the syringe, difficulty in pushing during injection, and the sliding performance of the piston exceeds the range specified in YBB00112004-2015 (starting force ≤ 25N, continuous force ≤ 10N).

[0113] The specific embodiments described above further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above description is only a specific embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. Prefilled sugammadex sodium and sodium chloride injection, characterized in that: The injection comprises a prefilled syringe and a medicinal solution in the syringe, wherein the medicinal solution comprises sodium sugammadex, sodium chloride, a pH adjuster, and water for injection, wherein the concentration of sodium sugammadex is 5 mg / mL-50 mg / mL; the sleeve of the prefilled syringe is made of medium-borosilicate glass coated with a perfluoropolyether coating, and the piston is a brominated butyl rubber piston covered with a polytetrafluoroethylene film.

2. The prefilled sugammadex sodium and sodium chloride injection according to claim 1, characterized in that: For children and adolescents, the concentration of sugammadex sodium is 5 mg / mL, 10 mg / mL or 20 mg / mL; for adults, the concentration of sugammadex sodium is 10 mg / ml, 20 mg / mL, 25 mg / mL or 50 mg / mL.

3. The prefilled sugammadex sodium and sodium chloride injection according to claim 2, characterized in that: The capacity of the prefilled syringe is 2-25mL.

4. The prefilled sugammadex sodium and sodium chloride injection according to claim 2, characterized in that: The capacity of prefilled syringes is 2mL, 5mL, 8mL, 10mL, 15mL, 20mL or 25mL.

5. The prefilled sugammadex sodium and sodium chloride injection according to claim 1, characterized in that: The concentration of the sodium chloride is 4.5 mg / ml-9 mg / mL.

6. The prefilled sugammadex sodium and sodium chloride injection according to any one of claims 1 to 5, characterized in that: The pH regulator is selected from one or more of hydrochloric acid, acetic acid, citric acid, tartaric acid, malic acid, lactic acid, ascorbic acid, phosphoric acid, sodium hydroxide, sodium citrate, potassium citrate, monosodium citrate, sodium lactate, calcium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, tromethamine, meglumine, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium acetate, and potassium acetate.

7. The prefilled sugammadex sodium and sodium chloride injection according to any one of claims 1 to 5, characterized in that: The pH of the medicinal solution is 6.5-8.

5.

8. The prefilled sugammadex sodium and sodium chloride injection according to any one of claims 1 to 5, characterized in that: The starting force measured when pushing the piston at a forward speed of 100mm / min±5mm / min is ≤25N, and the continuous force is ≤10N.

9. A method for preparing the prefilled sugammadex sodium and sodium chloride injection according to any one of claims 1 to 8, characterized in that: The following steps are included: 1) Preparation: Weigh the prescribed amount of sugammadex sodium and sodium chloride, add to water for injection that has been cooled to below 50°C, and stir until completely dissolved; add pH adjuster to adjust pH to 6.5-8.5, add water for injection to the full amount, and fill the liquid with inert gas until the residual oxygen content is ≤2ppm; 2) Filtration sterilization: sterilization by filter membrane, the filter membrane is 0.45μm and 0.22μm filter membrane; 3) Filling and sealing: first evacuate the pre-filled syringe, fill it with liquid medicine, and at the same time, fill it with inert gas, seal it, add a stopper, and assemble other accessories; 4) Sterilization.

10. The method according to claim 9, characterized in that The other accessory is a push rod.

11. The method according to claim 9, characterized in that In the step 3), the inert gas is filled in after vacuuming, or the vacuuming-filling inert gas is repeated 2 times or more; the stoppering is vacuum stoppering.

12. The method according to claim 9 or 11, characterized in that: The inert gas is nitrogen.

13. The method according to claim 9, characterized in that The sterilization in step 4) is a steam / air mixed sterilization method, and the F0 value is ≥8.

14. The method according to claim 9, characterized in that The sterilization in step 4) is a steam / air mixed sterilization method, and F0≥12.

15. Use of the prefilled sugammadex sodium and sodium chloride injection according to any one of claims 1 to 8 in the preparation of a medicament for antagonizing neuromuscular blockade induced by rocuronium bromide and vecuronium bromide, characterized in that: The drug is suitable for adolescents, children, infants and adults aged 17 and below.

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