Preparation method of moxifloxacin hydrochloride sodium chloride injection

Abstract

The invention discloses a preparation method of a moxifloxacin hydrochloride sodium chloride injection, the injection contains 0.16% by weight / volume of moxifloxacin hydrochloride and 0.8% by weight / volume of sodium chloride, the preparation method comprises the following steps: taking 20% by weight of water for injection, adding sodium chloride at 0-5 DEG C for dissolving, filtering by a filter membrane, then adding 50-70% by weight of water for injection, filtering by a filter membrane at 0-5 DEG C, filtering by a filter membrane at 0-5 DEG C, adding 10-30% by weight of water for injection, and finally adding 10-30% by weight of water for injection. Adding moxifloxacin hydrochloride, stirring and dissolving, filtering with a 0.2 mu m filter membrane, adding the balance of water for injection, stirring for at least 0.5 hour, filling nitrogen, filtering with a membrane, filling and sterilizing to obtain the moxifloxacin hydrochloride injection. The method can effectively control the generation and stability of foreign particles in the injection and ensure the medicine quality.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a method for preparing moxifloxacin hydrochloride and sodium chloride injection. Background Art

[0002] Moxifloxacin hydrochloride is a new broad-spectrum and highly effective fourth-generation quinolone antibacterial drug developed by Bayer, Germany. It was first launched in Germany in September 1999 under the trade name "Avelox". In November 2001, moxifloxacin hydrochloride sodium chloride injection was approved by the US FDA for marketing. It was launched in China in 2005 under the trade name "Baifule". Moxifloxacin hydrochloride is a DNA topoisomerase inhibitor, mainly used to treat respiratory tract, skin and soft tissue infections caused by Gram-positive bacteria, Gram-negative bacteria, anaerobic bacteria, acid-fast bacteria and atypical microorganisms such as mycoplasma, chlamydia and Legionella. At present, the dosage forms launched at home and abroad include film-coated tablets, injections, eye drops, and the literature reports gels, ear drops and suppositories. Oral administration may cause adverse reactions to the digestive system.

[0003] Bayer's Chinese patent ZL00811427.7 discloses that when moxifloxacin hydrochloride injection coexists with iron ions, sugars or sugar alcohols, sub-visible particles may be produced during storage. Chinese patent ZL00811427.7 also discloses that the moxifloxacin hydrochloride preparation is insensitive to iron ions when adjusted to isotonicity with sodium chloride, but according to the specific embodiments of the invention, the samples prepared by the invention still have an increasing trend of insoluble particles greater than or equal to 25 μm after long-term storage, and it is not disclosed whether particles greater than 50 μm (visible foreign matter) are produced. However, the inventors found in the experimental process that the moxifloxacin hydrochloride sodium chloride injection prepared strictly in accordance with the technical scheme of patent ZL00811427.7 may still produce visible foreign matter greater than 50 μm when stored for more than 6 months at its recommended storage temperature of 15-30°C.

[0004] Visible foreign matter in injections can cause vascular thrombosis, phlebitis, granulomas, allergic reactions, and even systemic infections when they enter the body, directly endangering the safety of patients' medication. Visible foreign matter inspection failures in injections at home and abroad and the resulting drug recalls are frequent. Among the 344 drug recalls released by the US FDA from May 2017 to May 2022 in the past five years, 30 involved visible foreign matter failures, accounting for 9.0%, second only to microbial contamination (50 cases).

[0005] In order to solve the problem of stability of moxifloxacin hydrochloride injection, the technical solution adopted in Chinese patent CN101732246 A is to add substances that improve stability, such as sodium salt of lactic acid, sodium salt of citric acid, sodium salt of carbonate, sodium salt of phosphoric acid, etc., in a relatively high dosage. However, the additional addition of these salt substances in a relatively high dosage may bring new quality risks to the product. However, the inventors have found through comprehensive process research that the stability of moxifloxacin hydrochloride sodium chloride injection is affected by multiple factors, such as temperature, feeding order, stirring rate, whether nitrogen is filled, etc.

[0006] Therefore, it is necessary to develop a moxifloxacin hydrochloride injection with simple prescription and stable quality. Summary of the invention

[0007] The object of the present invention is to provide a method for preparing moxifloxacin hydrochloride and sodium chloride injection, which achieves long-term stability of moxifloxacin hydrochloride and sodium chloride injection by controlling process parameters and processes, avoids the generation of visible foreign particles, and ensures the quality of the product.

[0008] To achieve the object of the present invention, the following embodiments are provided.

[0009] In one embodiment, a method for preparing moxifloxacin hydrochloride and sodium chloride injection of the present invention comprises the following steps:

[0010] (1) Take 20% of the prepared water for injection in a non-stainless steel container, cool it to 0-5°C, add sodium chloride, stir at a stirring speed of 5-15 rpm until the sodium chloride is completely dissolved, and filter through a 0.2 μm filter membrane;

[0011] (2) adding 50-70% injection water at 25-30° C. to the filtrate obtained in step (1), adding moxifloxacin hydrochloride, stirring at a stirring speed of 5-15 rpm until the moxifloxacin hydrochloride is completely dissolved, and filtering through a 0.2 μm filter membrane;

[0012] (3) adding the remaining amount of water for injection at 5-25° C. to the filtrate obtained in step (2) to 6 L, cooling to 5-8° C., stirring at a stirring speed of 5-15 rpm for not less than 0.5 hour, and filtering with a 0.2 μm filter membrane;

[0013] (4) introducing nitrogen into the filtrate obtained in step (3);

[0014] (5) The filtered solution of step (4) is filled into 250 ml glass bottles, 250 ml per bottle, the headspace is filled with nitrogen, stoppered, capped, and sterilized at 121° C. for 15 min.

[0015] In some embodiments, preferably, the stirring speed in step (1) is 5 to 8 rpm.

[0016] In some embodiments, preferably, the amount of water for injection added in step (2) is 50-55% of the prepared amount.

[0017] In some embodiments, preferably, the stirring speed in step (2) is 5 to 8 rpm.

[0018] In some embodiments, preferably, the temperature of the water for injection added in step (3) is 5 to 15°C.

[0019] In some embodiments, preferably, the stirring speed in step (3) is 5 to 8 rpm.

[0020] In some embodiments, the preparation method of the present invention, the moxifloxacin hydrochloride and sodium chloride injection contains 0.16% g / ml of moxifloxacin hydrochloride and 0.8% g / ml of sodium chloride based on moxifloxacin.

[0021] The inventors conducted a comprehensive study on the process and process parameters of moxifloxacin hydrochloride and sodium chloride injection through a large number of experiments, and combined technologies, and finally found process conditions that can effectively reduce the generation of visible foreign particles in moxifloxacin hydrochloride and sodium chloride injection, and achieved unexpected results. The inventors also unexpectedly found that although the stability of moxifloxacin hydrochloride is less affected by oxygen, in the process of preparing the moxifloxacin hydrochloride and sodium chloride injection preparation, nitrogen gas is introduced into the liquid and the headspace is filled with nitrogen before rolling the cap, which can further improve the stability of the preparation. DETAILED DESCRIPTION

[0022] The following examples are typical and are used to further understand the spirit of the present invention, but are not intended to limit the scope of the present invention in any way.

[0023] Example 1 Preparation of Moxifloxacin Hydrochloride and Sodium Chloride Injection

[0024] (1) Take 1.2 L of water for injection in a non-stainless steel container, cool it to 0-5°C, add 48.0 g of sodium chloride, stir at 15 rpm until the sodium chloride is completely dissolved, and filter through a 0.2 μm filter membrane.

[0025] (2) Add 4.2 L of 25° C. water for injection to the filtrate obtained in step (1), add 9.6 g of moxifloxacin hydrochloride (calculated as moxifloxacin), stir at a stirring speed of 15 rpm until the moxifloxacin hydrochloride is completely dissolved, and filter through a 0.2 μm filter membrane.

[0026] (3) Add 5°C water for injection to 6 L of the filtrate obtained in step (2), cool to 5-8°C, stir at 10 rpm for 0.5 h, and filter through a 0.2 μm filter membrane.

[0027] (4) Nitrogen is introduced into the filtrate obtained in step (3).

[0028] (5) The solution obtained in step (4) is filled into 250 ml glass bottles, 250 ml per bottle, the headspace is filled with nitrogen, stoppers are added, caps are rolled, and sterilized at 121° C. for 15 min.

[0029] Example 2 Preparation of Moxifloxacin Hydrochloride and Sodium Chloride Injection

[0030] (1) Take 1.2 L of water for injection in a non-stainless steel container, cool it to 0-5°C, add 48.0 g of sodium chloride, stir at 10 rpm until the sodium chloride is completely dissolved, and filter through a 0.2 μm filter membrane.

[0031] (2) Add 3.3 L of 28° C. water for injection to the filtrate obtained in step (1), add 9.6 g of moxifloxacin hydrochloride (calculated as moxifloxacin), stir at 8 rpm until the moxifloxacin hydrochloride is completely dissolved, and filter through a 0.2 μm filter membrane.

[0032] (3) Add 15°C water for injection to 6 L of the filtrate obtained in step (2), cool to 5-8°C, stir at 8 rpm for 2 hours, and filter through a 0.2 μm filter membrane.

[0033] (4) Nitrogen is introduced into the filtrate obtained in step (3).

[0034] (5) The solution obtained in step (4) is filled into 250 ml glass bottles, 250 ml per bottle, the headspace is filled with nitrogen, stoppers are added, caps are rolled, and sterilized at 121° C. for 15 min.

[0035] Example 3 Preparation of Moxifloxacin Hydrochloride and Sodium Chloride Injection

[0036] (1) Take 1.2 L of water for injection in a non-stainless steel container, cool it to 0-5°C, add 48.0 g of sodium chloride, stir at 5 rpm until the sodium chloride is completely dissolved, and filter through a 0.2 μm filter membrane.

[0037] (2) Add 3 L of 30° C. water for injection to the filtrate obtained in step (1), add 9.6 g of moxifloxacin hydrochloride (calculated as moxifloxacin), stir at a stirring speed of 5 rpm until the moxifloxacin hydrochloride is completely dissolved, and filter through a 0.2 μm filter membrane.

[0038] (3) Add 5°C water for injection to 6 L of the filtrate obtained in step (2), cool to 5-8°C, stir at 5 rpm for 1 hour, and filter through a 0.2 μm filter membrane.

[0039] (4) Nitrogen is introduced into the filtrate obtained in step (3).

[0040] (5) The solution obtained in step (4) is filled into 250 ml glass bottles, 250 ml per bottle, the headspace is filled with nitrogen, stoppers are added, caps are rolled, and sterilized at 121° C. for 15 min.

[0041] Comparative Example 1 Comparison of existing technologies

[0042] Prepared according to the technical solution disclosed in Patent ZL00811427.7.

[0043] Take 5.95L of water for injection into a glass container, add 9.6g of moxifloxacin hydrochloride (calculated as moxifloxacin) under stirring to dissolve it, add 48.0g of sodium chloride, stir to dissolve the sodium chloride, filter with a 0.2μm filter membrane, fill the filtrate into a glass bottle at an amount of 250ml / portion, stopper, roll cap, and sterilize at 121℃ for 20min.

[0044] Comparative Example 2 Method of Changing Process Conditions

[0045] Step (4) does not involve nitrogen filling.

[0046] (1) Take 1.2 L of water for injection in a non-stainless steel container, cool to 0-5°C, add 48.0 g of sodium chloride, stir at 5 rpm until the sodium chloride is completely dissolved, and filter through a 0.2 μm filter membrane;

[0047] (2) Add 3 L of 30° C. water for injection to the filtrate obtained in step (1), add 9.6 g of moxifloxacin hydrochloride (calculated as moxifloxacin), stir at a stirring speed of 5 rpm until the moxifloxacin hydrochloride is completely dissolved, and filter through a 0.2 μm filter membrane.

[0048] (3) Add 5°C water for injection to 6 L of the filtrate obtained in step (2), cool to 5-8°C, stir at 5 rpm for 1 hour, and filter through a 0.2 μm filter membrane.

[0049] (4) The filtrate obtained in step (3) is filled into 250 ml glass bottles, 250 ml per bottle, the headspace is filled with nitrogen, stoppered, capped, and sterilized at 121° C. for 15 min.

[0050] Comparative Example 3: Comparison of existing technologies

[0051] Prepared according to the method of comparative example 2-1 of patent CN115944586A.

[0052] (1) Add 2.7 g of sodium chloride to 270 ml of water, heat to 60°C and stir at 300 rpm using a magnetic stirrer until completely dissolved.

[0053] (2) Add 12.0 g of moxifloxacin hydrochloride to the solution of step (1), and stir at 300 rpm at room temperature until dissolved.

[0054] (3) The solution obtained in step (2) was adjusted to pH 7.9-8.1 using 1 mol / L sodium hydroxide, stirred until dissolved, and fixed to 200 ml, then cooled to 25°C for later use.

[0055] (4) Filling and sterilization: The solution obtained in step (3) is filled into bottles at a rate of 10.8 ml per bottle, plugged and capped, and sterilized at 121° C. for 15 min to obtain a moxifloxacin hydrochloride preparation.

[0056] Comparative Example 4: Changing the process flow - changing the order of feeding

[0057] Moxifloxacin hydrochloride was added first, followed by sodium chloride.

[0058] (1) Take 1.2 L of water for injection in a non-stainless steel container, cool it to 0-5°C, add 9.6 g of moxifloxacin hydrochloride (calculated as moxifloxacin), stir at 5 rpm until the moxifloxacin hydrochloride is completely dissolved, and filter through a 0.2 μm filter membrane.

[0059] (2) Add 3 L of 30° C. water for injection to the filtrate obtained in step (1), add 48.0 g of sodium chloride, stir at 5 rpm until the sodium chloride is completely dissolved, and filter through a 0.2 μm filter membrane.

[0060] (3) Add 5°C water for injection to 6 L of the filtrate obtained in step (2), cool to 5-8°C, stir at 5 rpm for 1 hour, and filter through a 0.2 μm filter membrane.

[0061] (4) Nitrogen is introduced into the filtrate obtained in step (3).

[0062] (5) The solution obtained in step (4) is filled into 250 ml glass bottles, 250 ml per bottle, the headspace is filled with nitrogen, stoppers are added, caps are rolled, and sterilized at 121° C. for 15 min.

[0063] Comparative Example 5 Effect of increasing dissolution temperature on stability

[0064] A preparation process for dissolving sodium chloride and moxifloxacin hydrochloride at high temperature.

[0065] (1) Take 1.2 L of water for injection in a non-stainless steel container, cool it to 60°C, add 48.0 g of sodium chloride, stir at 5 rpm until the sodium chloride is completely dissolved, and filter through a 0.2 μm filter membrane.

[0066] (2) Add 3 L of 60° C. water for injection to the filtrate obtained in step (1), add 9.6 g of moxifloxacin hydrochloride (calculated as moxifloxacin), stir at a stirring speed of 5 rpm until the moxifloxacin hydrochloride is completely dissolved, and filter through a 0.2 μm filter membrane.

[0067] (3) Add 5°C water for injection to 6 L of the filtrate obtained in step (2), cool to 5-8°C, stir at 5 rpm for 1 hour, and filter through a 0.2 μm filter membrane.

[0068] (4) Nitrogen is introduced into the filtrate obtained in step (3).

[0069] (5) The solution obtained in step (4) is filled into 250 ml glass bottles, 250 ml per bottle, the headspace is filled with nitrogen, stoppers are added, caps are rolled, and sterilized at 121° C. for 15 min.

[0070] Comparative Example 6 Effect of stirring speed on stability

[0071] The preparation process at different stirring speeds was investigated.

[0072] (1) Take 1.2 L of water for injection in a non-stainless steel container, cool it to 0-5°C, add 48.0 g of sodium chloride, stir at 30 rpm until the sodium chloride is completely dissolved, and filter through a 0.2 μm filter membrane.

[0073] (2) Add 3 L of 30° C. water for injection to the filtrate obtained in step (1), add 9.6 g of moxifloxacin hydrochloride (calculated as moxifloxacin), stir at 30 rpm until the moxifloxacin hydrochloride is completely dissolved, and filter through a 0.2 μm filter membrane.

[0074] (3) Add 5°C injection water to the filtrate obtained in step (2) to make up to 6 L, cool to 5-8°C, stir at 30 rpm for 1 hour, and filter through a 0.2 μm filter membrane.

[0075] (4) Nitrogen is introduced into the filtrate obtained in step (3).

[0076] (5) The solution obtained in step (4) is filled into 250 ml glass bottles, 250 ml per bottle, the headspace is filled with nitrogen, stoppers are added, caps are rolled, and sterilized at 121° C. for 15 min.

[0077] Comparative Example 7 Effect of water addition at different stages on stability

[0078] The preparation process is changed by adding water in different sections.

[0079] (1) Take 3 L of water for injection in a non-stainless steel container, cool it to 0-5°C, add 48.0 g of sodium chloride, stir at 5 rpm until the sodium chloride is completely dissolved, and filter through a 0.2 μm filter membrane.

[0080] (2) Add 1.2 L of 30° C. water for injection to the filtrate obtained in step (1), add 9.6 g of moxifloxacin hydrochloride (calculated as moxifloxacin), stir at a stirring speed of 5 rpm until the moxifloxacin hydrochloride is completely dissolved, and filter through a 0.2 μm filter membrane.

[0081] (3) Add 5°C water for injection to 6 L of the filtrate obtained in step (2), cool to 5-8°C, stir at 5 rpm for 1 hour, and filter through a 0.2 μm filter membrane.

[0082] (4) Nitrogen is introduced into the filtrate obtained in step (3).

[0083] (5) The solution obtained in step (4) is filled into 250 ml glass bottles, 250 ml per bottle, the headspace is filled with nitrogen, stoppers are added, caps are rolled, and sterilized at 121° C. for 15 min.

[0084] Stability test

[0085] The samples of Examples 1-3 and Comparative Examples 1-7 were subjected to accelerated stability tests to examine the stability of the samples.

[0086] Test method: Place at a temperature of 40±2°C and a relative humidity of 75±5% for 6 months, take samples once in the 0th, 1st, 2nd, 3rd, 4th, 5th and 6th month of the experiment, check visible foreign particles, and determine the content and total impurities by high performance liquid chromatography, and compare with the results of the 0th month. The results are shown in Table 1. The results in Table 1 show that the stability of moxifloxacin hydrochloride sodium chloride injection is affected by the preparation process parameters such as dissolution temperature, stirring speed, whether nitrogen is filled, feeding sequence and water addition amount at different stages. The inventor finally obtained the best synergistic process parameters and the best feeding sequence and water segment addition combination after a lot of practice and research on combination technology, and obtained the preparation method of the present invention.

[0087] Table 1. Accelerated stability test results

[0088]

[0089]

[0090]

[0091] The above embodiments are only representative of the present invention. Any simple variation, combination, modification, etc. of the present invention without departing from the spirit and purpose of the present invention shall fall within the scope of the present invention.

Claims

1. A method for preparing moxifloxacin hydrochloride and sodium chloride injection, comprising the following steps: (1) Take 20% of the prepared water for injection in a non-stainless steel container, cool it to 0-5°C, add sodium chloride, stir at a stirring speed of 5-15 rpm until the sodium chloride is completely dissolved, and filter through a 0.2 μm filter membrane; (2) adding 50-70% injection water at 25-30° C. to the filtrate obtained in step (1), adding moxifloxacin hydrochloride, stirring at a stirring speed of 5-15 rpm until the moxifloxacin hydrochloride is completely dissolved, and filtering through a 0.2 μm filter membrane; (3) adding the remaining amount of water for injection at 5-25° C. to the filtrate obtained in step (2) to 6 L, cooling to 5-8° C., stirring at a stirring speed of 5-15 rpm for not less than 0.5 hour, and filtering with a 0.2 μm filter membrane; (4) introducing nitrogen into the filtrate obtained in step (3); (5) The filtered solution of step (4) is filled into 250 ml glass bottles, 250 ml per bottle, the headspace is filled with nitrogen, stoppered, capped, and sterilized.

2. The preparation method according to claim 1, wherein the stirring speed in step (1) is 5 to 8 rpm.

3. The preparation method according to claim 1, wherein the amount of water for injection added in step (2) is 50-55% of the preparation amount.

4. The preparation method according to claim 1, wherein the stirring speed in step (2) is 5 to 8 rpm.

5. The preparation method according to claim 1, wherein the temperature of the water for injection added in step (3) is 5 to 15°C.

6. The preparation method according to claim 1, wherein the stirring speed in step (3) is 5 to 8 rpm.

7. The preparation method according to claim 1, wherein in step (5), the sterilization temperature is 121°C and the sterilization time is 15 min.

8. The preparation method according to any one of claims 1 to 7, wherein the moxifloxacin hydrochloride and sodium chloride injection contains 0.16% g / ml of moxifloxacin hydrochloride and 0.8% g / ml of sodium chloride based on moxifloxacin.

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