A chemical drug composition for treating digestive tract diseases and its preparation process

Abstract

The present invention relates to the technical field of pharmaceutical compositions, in particular to a chemical pharmaceutical composition for treating digestive tract diseases and a preparation process thereof, including preparation and treatment of lactic acid solution, pipeline deoxygenation, injection water deoxygenation, sodium hydroxide solution preparation, liquid preparation, and filtration sterilization. The self-made preparation provided by the present invention has a stable production process, good product quality stability, and all indicators of the famotidine injection prepared by the present invention are similar or close to those of a reference preparation, so the quality level of the self-developed famotidine injection is consistent with that of the reference preparation.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical compositions, and in particular to a chemical pharmaceutical composition for treating digestive tract diseases and a preparation process thereof. Background Art

[0002] Famotidine injection The original formulation was developed by Yamanouchi Pharmaceutical (now Astellas) and marketed in Japan by LTL Pharmaceuticals Co., Ltd. Famotidine is a histamine H2 receptor antagonist indicated for the treatment of duodenal and gastric ulcers, esophageal reflux disease (GERD), and pathological hypersecretion disorders.

[0003] Famotidine injection It was first launched in Japan in July 2005, with specifications of 1ml: 10mg and 2ml: 20mg. In January 2022, Towa Pharmaceutical of Japan launched a generic drug with the same prescription, famotidine injection (trade name: Specifications: 1ml: 10mg and 2ml: 20mg). There are no generic drugs with the same prescription on the market in Europe and the United States.

[0004] At present, the original preparation has not been launched in China. Many domestic companies, including Yintao Pharmaceutical (approval number: National Medicine Standard H20046327), have launched famotidine injection, with a specification of 2ml:20mg. The National Medical Products Administration (NMPA) has clearly stated the reference preparation information of this product in the "Catalogue of Reference Preparations for Chemical Generic Drugs (25th Batch)", that is, LTL ファーマ Co., Ltd., No. 25-7, has launched the original drug famotidine injection (trade name: Specification: 2ml:20mg)

[0005] The prescription composition and dosage of the famotidine injection currently approved for marketing are inconsistent with the reference preparation, so the prescription of famotidine injection is re-developed. Summary of the invention

[0006] The invention provides a chemical medicine composition for treating digestive tract diseases. A single famotidine injection comprises 15-24 mg of famotidine, 80-110 mg of nicotinamide, 30-45 mg of mannitol, 1.5-2.5 mg of vitamin C, 6-8 mg of lactic acid, 1-1.5 mg of sodium hydroxide and 1-3 mg of water for injection.

[0007] In one possible implementation, a single famotidine injection includes 20 mg famotidine, 100 mg niacinamide, 40 mg mannitol, 2 mg vitamin C, 7.03 mg lactic acid, 1.1 mg sodium hydroxide and 2 mg water for injection.

[0008] The present invention also provides a preparation process of a chemical drug composition for treating digestive tract diseases, comprising the following steps: S1, preparing and treating a lactic acid solution

[0009] Place lactic acid in a clean container and add water for injection to prepare a lactic acid solution with a concentration of 100 mg / ml. Transfer the prepared lactic acid solution to a reactor and heat it for 7 to 9 hours. During this period, the temperature of the lactic acid solution is maintained at 100±5℃. After the lactic acid solution is cooled, seal it in a sterilized stainless steel barrel with a cover, weigh it, and add water for injection to make it consistent with the weight of the solution before treatment.

[0010] S2. Pipeline deoxygenation

[0011] S3, deoxygenation of water for injection

[0012] Add 350L of water for injection into the concentration tank and stir. Pass steam into the interlayer to boil the water for injection for 100 minutes. Turn off the steam, pass nitrogen, and cool the water for injection through the interlayer to reduce the temperature of the water for injection to below 35°C.

[0013] S4. Preparation of sodium hydroxide solution

[0014] The concentrated preparation tank is rinsed with cooled injection water, and 0.2 kg NaOH is added to the cooled injection water in the 5 kg concentrated preparation tank, and stirred to dissolve to obtain 1 mol / L NaOH solution for use.

[0015] S5. Preparation of drug solution

[0016] S51. Transfer 80% of the prescribed amount of cooled water for injection from the concentrated preparation tank to the diluted preparation tank, start stirring and fill with nitrogen throughout the process, add nicotinamide and mannitol while stirring, and stir for 15 minutes to completely dissolve nicotinamide and mannitol.

[0017] S52. Add famotidine and stir for 30 minutes to ensure uniform dispersion.

[0018] S53. Add lactic acid solution and stir for 30 minutes to dissolve the API.

[0019] S54. Add 1 mol / L NaOH solution to adjust the pH and stir for 15 minutes until the pH value detected at the sampling port of the dilution tank is 6.0±0.2 and the dissolved oxygen content is ≤3 ppm.

[0020] S55. Add vitamin C and stir for 15 minutes to completely dissolve it.

[0021] S56. Add 1 mol / L NaOH solution again to adjust the pH and stir for 15 minutes until the pH value detected at the sampling port of the dilution tank is 6.0±0.2 and the dissolved oxygen content is ≤3 ppm.

[0022] S57. Turn off the stirring in the dilution tank, add the cooled water for injection in the concentration tank to make up the weight of the dilution tank, turn on the stirring for 15 minutes to obtain the drug solution.

[0023] S6, filtering and sterilizing, the liquid medicine obtained in step S5 is circulated in multiple stages and sterilized.

[0024] In a possible implementation, the nitrogen source pressure in all nitrogen filling and deoxygenation operations is greater than 0.1 MPa, and the stirring frequency of the stirring operation in step S5 is 25 to 30 Hz.

[0025] In one possible implementation, step S2 is specifically as follows: before preparation, the filter pipeline of the dilution tank is first purged with nitrogen for about 60 seconds each through a titanium rod section, a 0.45 μm filter section, a 0.22 μm sterilizing filter section, a 0.22 μm terminal filter section, and a circulating reflux section, and the dilution tank and the buffer tank are continuously filled with nitrogen 30 minutes in advance.

[0026] In one possible implementation, step S6 is specifically as follows: the drug solution is filtered through a 0.45μm precision filter and a 0.22μm sterilizing filter and circulated to a dilution tank. After circulating for 30 minutes, the drug solution is tested. After the semi-finished product is inspected and qualified, the drug solution passes through a 0.45μm precision filter, a 0.22μm sterilizing filter, and a 0.22μm terminal sterilizing filter, and enters a buffer tank for filling.

[0027] In one possible implementation, the items tested for the drug solution include properties, pH value, content, color, insoluble particles and visible foreign matter tested by sampling at a 0.45 μm precision filter sampling port, and bacterial endotoxin testing by sampling at a 0.22 μm sterilizing filter sampling port.

[0028] The above one or more technical solutions in the embodiments of the present invention have at least one of the following technical effects: the production process of the homemade preparation provided by the present invention is stable, the product quality stability is good, and the various indicators of the famotidine injection prepared by the present invention are similar or close to those of the reference preparation, so the quality level of the self-developed famotidine injection and the reference preparation is consistent. DETAILED DESCRIPTION

[0029] The following describes the implementation of the present invention through specific examples, and those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. The present invention can also be implemented or applied through other different specific implementations, and the details in this specification can also be modified or changed in various ways based on different viewpoints and applications without departing from the spirit of the present invention.

[0030] Before further describing the specific embodiments of the present invention, it should be understood that the scope of protection of the present invention is not limited to the specific embodiments described below; it should also be understood that the terms used in the examples of the present invention are for describing specific embodiments rather than for limiting the scope of protection of the present invention.

[0031] When the embodiments give a numerical range, it should be understood that, unless otherwise specified in the present invention, both endpoints of each numerical range and any value between the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by ordinary technicians in the technical field to which the present invention belongs.

[0032] A preparation process of a chemical drug composition for treating digestive tract diseases, comprising the following steps:

[0033] S1. Preparation and treatment of lactic acid solution

[0034] Place lactic acid in a clean container and add water for injection to prepare a lactic acid solution with a concentration of 100 mg / ml. Transfer the prepared lactic acid solution to a reactor and heat it for 7 to 9 hours. During this period, the temperature of the lactic acid solution is maintained at 100±5℃. After the lactic acid solution is cooled, seal it in a sterilized stainless steel barrel with a cover, weigh it, and add water for injection to make it consistent with the weight of the solution before treatment.

[0035] S2. Pipeline deoxygenation

[0036] Before preparation, the filter pipeline of the dilution tank is first purged with nitrogen for about 60 seconds each through the titanium rod section, 0.45μm filter section, 0.22μm sterilizing filter section, 0.22μm terminal filter section, and circulating reflux section. The dilution tank and buffer tank are continuously filled with nitrogen 30 minutes in advance.

[0037] S3, deoxygenation of water for injection

[0038] Add 350L of water for injection into the concentration tank and stir. Pass steam into the interlayer to boil the water for injection for 100 minutes. Turn off the steam, pass nitrogen, and cool the water for injection through the interlayer to reduce the temperature of the water for injection to below 35°C.

[0039] S4. Preparation of sodium hydroxide solution

[0040] The concentrated preparation tank is rinsed with cooled injection water, and 0.2 kg NaOH is added to the cooled injection water in the 5 kg concentrated preparation tank, and stirred to dissolve to obtain 1 mol / L NaOH solution for use.

[0041] S5. Preparation of drug solution

[0042] S51. Transfer 80% of the prescribed amount of cooled water for injection from the concentrated preparation tank to the diluted preparation tank, start stirring and fill with nitrogen throughout the process, add nicotinamide and mannitol while stirring, and stir for 15 minutes to completely dissolve nicotinamide and mannitol.

[0043] S52. Add famotidine and stir for 30 minutes to ensure uniform dispersion.

[0044] S53. Add lactic acid solution and stir for 30 minutes to dissolve the API.

[0045] S54. Add 1 mol / L NaOH solution to adjust the pH and stir for 15 minutes until the pH value detected at the sampling port of the dilution tank is 6.0±0.2 and the dissolved oxygen content is ≤3 ppm.

[0046] S55. Add vitamin C and stir for 15 minutes to completely dissolve it.

[0047] S56. Add 1 mol / L NaOH solution again to adjust the pH and stir for 15 minutes until the pH value detected at the sampling port of the dilution tank is 6.0±0.2 and the dissolved oxygen content is ≤3 ppm.

[0048] S57. Turn off the stirring in the dilution tank, add the cooled water for injection in the concentration tank to make up the weight of the dilution tank, turn on the stirring for 15 minutes to obtain the drug solution.

[0049] S6. Filtration and sterilization

[0050] The drug solution is filtered through a 0.45μm precision filter and a 0.22μm sterilizing filter and circulated to the dilution tank. After circulating for 30 minutes, the drug solution is tested. Samples are taken from the sampling port of the 0.45μm precision filter for properties, pH value, content, color, insoluble particles and visible foreign matter. Samples are taken from the sampling port of the 0.22μm sterilizing filter for bacterial endotoxin testing. After the semi-finished product is inspected and qualified, the drug solution passes through a 0.45μm precision filter, a 0.22μm sterilizing filter and a 0.22μm terminal sterilizing filter and enters the buffer tank for filling.

[0051] Quality attribute comparison experiment

[0052] The information tables of the reference preparation (control group) and the homemade preparation (experimental group) are shown in Tables 1 and 2, respectively. At least two batches are selected for both homemade preparations and reference preparations. The information indicators of each batch of homemade preparations (experimental group one, experimental group two and experimental group three) are compared, and the comparison results are shown in Table 3. The various information indicators of the reference preparation (control group) and the homemade preparation (experimental group) are tested and compared, and the test results are shown in Table 4.

[0053] Table 1

[0054]

[0055] Table 2

[0056]

[0057]

[0058] Table 3

[0059]

[0060]

[0061] Among them, impurity A is famotidine EP impurity A; its chemical name is N-(2-[[[5-(dimethylamino)methyl]-1H-benzimidazol-2-yl]thio]ethyl]-N'-methylurea;

[0062] Impurity C is famotidine EP impurity C; its chemical name is N-(2-[[[5-(dimethylamino)methyl]-1H-benzimidazol-2-yl]thio]ethyl]-N'-methylguanidine;

[0063] Impurity D is famotidine EP impurity D, N-(2-[[[5-(dimethylamino)methyl]-1H-benzimidazol-2-yl]thio]ethyl]-N'-methylguanidine hydrochloride;

[0064] Impurity F is famotidine EP impurity F, and its chemical name is N-(2-[[[5-(dimethylamino)methyl]-1H-benzimidazol-2-yl]thio]ethyl]-N'-methylguanidine.

[0065] From the above results, it can be seen that there are no significant differences in the various indicators of the three batches of process verification products of famotidine injection, indicating that the production process is stable and the product quality is stable.

[0066] Table 4

[0067]

[0068]

[0069]

[0070] By comparing the results, it can be seen that the indicators of the famotidine injection produced by our company are similar or close to those of the reference preparation. This shows that the quality level of our self-developed famotidine injection is consistent with that of the reference preparation.

Claims

1. A chemical pharmaceutical composition for treating digestive tract diseases, characterized in that: A single famotidine injection includes 15-24 mg of famotidine, 80-110 mg of niacinamide, 30-45 mg of mannitol, 1.5-2.5 mg of vitamin C, 6-8 mg of lactic acid, 1-1.5 mg of sodium hydroxide and 1-3 mg of water for injection.

2. A chemical pharmaceutical composition for treating digestive tract diseases according to claim 1, characterized in that: A single famotidine injection includes 20 mg of famotidine, 100 mg of niacinamide, 40 mg of mannitol, 2 mg of vitamin C, 7.03 mg of lactic acid, 1.1 mg of sodium hydroxide and 2 mg of water for injection.

3. A process for preparing the chemical pharmaceutical composition for treating digestive tract diseases as claimed in claim 1, characterized in that: The following steps are involved: S1. Preparation and treatment of lactic acid solution Put lactic acid in a clean container and add water for injection to prepare a lactic acid solution with a concentration of 100 mg / ml. Transfer the prepared lactic acid solution to a reactor and heat it for 7 to 9 hours. During this period, the temperature of the lactic acid solution is maintained at 100±5℃. After the lactic acid solution is cooled, seal it in a sterilized stainless steel barrel with a cover, weigh it, and add water for injection until the weight is consistent with the solution before treatment. S2. Pipeline deoxygenation S3, deoxygenation of water for injection Add 350L of injection water into the concentrated preparation tank, stir, and pass steam into the interlayer to boil the injection water for 100 minutes. Turn off the steam, pass nitrogen, and cool the injection water through the interlayer to reduce the temperature of the injection water to below 35°C; S4. Preparation of sodium hydroxide solution The concentrated preparation tank is rinsed with cooled injection water, and 0.2 kg NaOH is added to the cooled injection water in the 5 kg concentrated preparation tank, and stirred to dissolve to obtain a 1 mol / L NaOH solution for standby use; S5. Preparation of drug solution S51, transfer 80% of the prescribed amount of cooled water for injection from the concentrated preparation tank to the diluted preparation tank, start stirring and fill with nitrogen throughout the process, add nicotinamide and mannitol under stirring, and stir for 15 minutes to completely dissolve nicotinamide and mannitol; S52, add famotidine, and stir for 30 minutes to make it evenly dispersed; S53, adding lactic acid solution, stirring for 30 minutes to dissolve the API; S54, add 1 mol / L NaOH solution to adjust the pH, stir for 15 minutes, until the pH value detected at the sampling port of the dilution tank is 6.0±0.2, and the dissolved oxygen content is ≤3ppm; S55, add vitamin C and stir for 15 minutes to completely dissolve; S56. Add 1 mol / L NaOH solution again to adjust the pH, and stir for 15 min until the pH value detected at the sampling port of the dilution tank is 6.0±0.2, and the dissolved oxygen content is ≤3 ppm; S57, turn off the stirring of the dilution tank, add the injection water after cooling in the concentration tank to make up the weight of the dilution tank, turn on the stirring for 15 minutes, and prepare the drug solution; S6, filtering and sterilizing, the liquid medicine obtained in step S5 is circulated in multiple stages and sterilized.

4. The preparation process of a chemical pharmaceutical composition for treating digestive tract diseases according to claim 3, characterized in that: The nitrogen source pressure in all nitrogen filling and deoxygenation operations is greater than 0.1 MPa, and the stirring frequency of the stirring operation in step S5 is 25 to 30 Hz.

5. The preparation process of a chemical pharmaceutical composition for treating digestive tract diseases according to claim 3, characterized in that: The step S2 is specifically as follows: before preparation, the filter pipeline of the dilution tank is first purged with nitrogen for about 60 seconds each through the titanium rod section, 0.45 μm filter section, 0.22 μm sterilizing filter section, 0.22 μm terminal filter section, and circulating reflux section, and the dilution tank and buffer tank are continuously filled with nitrogen 30 minutes in advance.

6. The preparation process of a chemical pharmaceutical composition for treating digestive tract diseases according to claim 3, characterized in that: The specific step S6 is as follows: the drug liquid is filtered through a 0.45μm precision filter and a 0.22μm sterilizing filter and circulated to the dilution tank. After circulating for 30 minutes, the drug liquid is tested. After the semi-finished product is inspected and qualified, the drug liquid passes through a 0.45μm precision filter, a 0.22μm sterilizing filter, and a 0.22μm terminal sterilizing filter, and enters the buffer tank for filling.

7. The preparation process of a chemical pharmaceutical composition for treating digestive tract diseases according to claim 6, characterized in that: The test items for the drug solution include properties, pH value, content, color, insoluble particles and visible foreign matter testing by sampling at the 0.45μm precision filter sampling port, and bacterial endotoxin testing by sampling at the 0.22μm sterilizing filter sampling port.

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