Famotidine injection and preparation method thereof

Abstract

The invention belongs to the technical field of injection production processes, and particularly relates to a famotidine injection and a preparation method thereof. According to the famotidine injection disclosed by the invention, dendrobium nobile is fermented by using lactic acid bacteria ATCC 8008 and saccharomycetes ATCC 918, and chlorogenic acid and ilaprazole are added to prepare the famotidine injection. According to the method for fermenting by using the lactic acid bacteria ATCC 8008 and the saccharomycetes ATCC 918, not only can the curative effect of famotidine be improved, but also the effect of the dendrobium is enhanced due to the modification of the dendrobium, and more beneficial substances in the dendrobium are obtained. The Chinese yam and the lotus seeds used in the famotidine have good body building effects, have the advantages of tonifying the spleen and nourishing the stomach and can also enter the heart and the spleen, and the medicine effect of the prepared famotidine is enhanced. The famotidine prepared by the invention can be used for treating peptic ulcer, and has a great development prospect in the field of first aid.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical production technology, and particularly relates to a famotidine injection for injection and a preparation method thereof. Background Art

[0002] Famotidine is a third-generation histamine H2 receptor antagonist of the piperidine thiazole class. It was first discovered and synthesized by the Central Research Institute of Yamanouchi Pharmaceutical Co., Ltd. in Japan in the 1970s. Clinically, famotidine is mainly used to treat upper gastrointestinal bleeding caused by peptic ulcers and diseases such as gastric and duodenal erosion and bleeding caused by tumors, esophageal or gastric fundus varices. Due to the particularity of the structure of famotidine, the long-term use of famotidine alone will bring certain adverse reactions. The use of traditional Chinese medicine to treat peptic ulcers is effective, but it takes a long time for patients to improve their symptoms, but it does not increase the risk of adverse reactions. After the state promulgated the "Guidelines for the Clinical Application of Proton Pump Inhibitors (2020 Edition)" and strengthened the control of its rational clinical application, the use of H2RA has surged. At present, famotidine has been combined with licorice and ginseng to treat peptic ulcers, and the prepared famotidine has obvious advantages. Therefore, the motidine injection and preparation method for treating peptic ulcer developed in this article not only have significant therapeutic effects, but also shorten the time required for improvement of patients' symptoms, and can be widely used in clinical practice.

[0003] In addition, due to the poor solubility of famotidine, its stability after dissolving in water is extremely poor and it is insoluble in cold water. It is generally dissolved with an acidic solution, and Chinese medicine assists in improving its efficacy. In view of this, this paper developed a famotidine injection to solve the above technical problems. Summary of the invention

[0004] Based on the above reasons, the present invention provides famotidine for injection and a preparation method thereof, and the specific preparation method is as follows:

[0005] S1. Weigh 0.4-0.6 g of aspartic acid and 0.03-0.06 g of disodium ethylenediaminetetraacetic acid powder into a 250 mL beaker, add 75 mL of ionized water, heat to 75-85 ° C, stir until completely dissolved, and when the temperature drops to 55-65 ° C, add 1.0 g of famotidine, 10 mg of ilaprazole and 0.02-0.04 g of chlorogenic acid to the beaker, and stir until completely dissolved;

[0006] S2, washing Chinese yam, lotus seeds and Ophiopogon japonicus, removing impurities and drying them, grinding the dried Chinese yam, lotus seeds and Ophiopogon japonicus into powder for later use, and mixing the powders of 4-8g Chinese yam, 6-12g lotus seeds and 2-4g Ophiopogon japonicus;

[0007] S3, boil the mixed Chinese medicinal materials at 95°C for 3 times, add 6 times the amount of water each time, and the boiling time is 1h, 0.5h, and 0.5h respectively; collect and combine the boiled liquid and centrifuge to obtain a supernatant; evaporate and concentrate the supernatant under reduced pressure to a relative density of 1.15 (60°C), bring to room temperature, add 95% ethanol to adjust the alcohol content to 70%, seal, maintain the temperature at 10°C, let stand for 48 hours for alcohol precipitation, take the supernatant and filter it, concentrate the filtrate until there is no alcohol taste, and obtain a Chinese medicinal material extract for standby use;

[0008] S4. Preparation of bacterial solution: Preparation of Lactobacillus ATCC 8008 bacterial solution: The concentration of preparation is 1.2×10 8 -1.21×10 8 cfu / mL; Preparation of yeast ATCC 918 bacterial solution: the preparation concentration is 1.7×10 9 -1.72×10 9 cfu / mL of yeast culture solution is placed in a culture solution tank for later use;

[0009] S5, placing 10-15g of washed and cut dendrobium in a fermentation tank containing 10-15mL of lactobacillus ATCC8008, 12-17mL of yeast ATCC 918 bacterial solution and 15mL of basal culture medium prepared in step S4, fermenting at 35°C for 12-24 hours, and turning over every two hours. After the fermentation is completed, the lactobacillus and yeast bacterial solution are inactivated with a 3% H2O2 solution by mass fraction to obtain a dendrobium fermentation product, and the fermentation product is boiled at 95°C for 3 times, with 6 times the amount of water added each time, and the boiling time is 1h, 0.5h, and 0.5h respectively; collecting and merging the boiled liquid and centrifuging to obtain a supernatant; separating the supernatant from the supernatant; The liquid was evaporated under reduced pressure and concentrated to a relative density of 1.15 (60°C), cooled to room temperature, 95% ethanol was added to adjust the alcohol content to 70%, sealed, maintained at 10°C, and allowed to stand for 48 hours for alcohol precipitation, the supernatant was filtered, and the filtrate was concentrated until there was no alcohol taste, to obtain the fermented water extract of Dendrobium officinale for standby use; wherein the basic culture medium: casein peptone 10.0g, beef extract 10.0g, yeast powder 5.0g, glucose 5.0g, sodium acetate 5.0g, diammonium citrate 2.0g, Tween 801.0g, K2HPO42.0g, MgSO4.7H2O 0.2g, MnSO4·H2O 0.05g, CaCO320.0g, distilled water 1.0L, pH 6.8;

[0010] S6. Preparation of buffer solution: Prepare solution A: weigh 2.10g of citric acid crystals, add the citric acid crystals to 8-10mL of deionized water, stir until completely dissolved, transfer the dissolved citric acid solution to a 100mL volumetric flask, dilute to the mark with distilled water, shake well, and obtain a 0.1moL / L citric acid aqueous solution, i.e., solution A; Prepare solution B: weigh 2.94g of trisodium citrate crystals, add the trisodium citrate crystals to 8-10mL of deionized water, stir until completely dissolved; transfer the dissolved trisodium citrate solution to a 100mL volumetric flask, dilute to the mark with distilled water, shake well, and obtain a 0.1moL / L trisodium citrate aqueous solution, i.e., solution B; take 8.2mL of solution A and 11.2mL of solution B, add them to a beaker, stir thoroughly with a glass rod to ensure uniform mixing; adjust the pH to 5 with solution A, transfer to a 100mL volumetric flask, and dilute to the mark with distilled water;

[0011] S7, preparation of famotidine injection: when the solution prepared in S1 is cooled to 25-35°C, the buffer solution prepared in step S6 is added to a beaker, the pH of the solution is adjusted to 5.6-6.2, and then the Chinese medicinal material extract prepared in step S3 and the fermented water extract of Dendrobium officinale prepared in step S5 are added, and the buffer solution is continued to be added to adjust the pH to 5.6-5.8, and the volume is made up to 100 ml with distilled water, and the famotidine injection is obtained after sterilization at 115°C for 30 min.

[0012] Preferably: in step S1, 0.5 g of aspartic acid and 0.045 g of disodium ethylenediaminetetraacetic acid powder are weighed into a 250 mL beaker, 90 mL of ionized water is added, and the mixture is heated to 80° C. and stirred until completely dissolved. When the temperature drops to 60° C., 1.0 g of famotidine, 10 mg of ilaprazole and 0.03 g of chlorogenic acid are added to the beaker and stirred until completely dissolved.

[0013] Preferably, the concentration of the lactic acid bacteria ATCC 8008 liquid used in step S4 is 1.2×10 8 cfu / mL, the concentration of yeast ATCC 918 bacterial solution was 1.71×10 9 cfu / mL.

[0014] Preferably, in step S2, the powders of yam, lotus seeds and ophiopogon japonicus are crushed in a mass ratio of 2:3:1 and then mixed evenly.

[0015] Preferably, in step S5, lactic acid bacteria ATCC 8008 and yeast ATCC 918 are used to ferment and modify the dendrobium.

[0016] Preferably, in step S5, the amount of Dendrobium officinale used is 12.5 g, the amount of Lactobacillus ATCC 8008 and the amount of Saccharomyces ATCC 918 bacterial solution used are both 12.5 mL, and the fermentation time is 18 h.

[0017] Preferably, the amount of distilled water used in step S6 is 9 mL.

[0018] Preferably: in step S7, the temperature is lowered to 30°C.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] 1. Famotidine can reduce the secretion of gastric acid, thereby reducing the erosion of gastric acid on the gastric mucosa, and help to reduce the inflammatory response of the gastric mucosa; by reducing gastric acid secretion, famotidine helps the healing of peptic ulcers and indirectly relieves the symptoms of inflammation. Esomeprazole can inhibit the activity of hydrogen-potassium-ATPase in the gastric mucosal parietal cells, thereby strongly inhibiting gastric acid secretion, lowering the pH value in the gastric cavity, and helping to reduce the damage of gastric acid to the gastric mucosa. Protect gastric mucosa: by inhibiting gastric acid secretion, esomeprazole can protect the gastric mucosa from gastric acid erosion, thereby reducing the inflammatory response of the gastric mucosa; both famotidine and esomeprazole can inhibit gastric acid secretion, and the combined use of the two further enhances the acid suppression effect, thereby more effectively reducing the damage and inflammatory response of gastric acid to the gastric mucosa; at the same time, by synergistically inhibiting gastric acid secretion, famotidine and esomeprazole will accelerate the healing process of peptic ulcers and relieve inflammatory symptoms.

[0021] 2. The preparation process of famotidine is mature, feasible, safe and effective, and suitable for large-scale, industrialized production of famotidine injection products.

[0022] 3. Both Chinese yam and lotus seeds have a good effect on strengthening the body. They not only have the benefits of nourishing the spleen and stomach, but also can enter the heart and spleen. Ophiopogon japonicus is sweet and cold in nature and enters the heart, lung and stomach meridians. Eating it in moderation can help reduce the body's heat and has a certain effect of nourishing yin and promoting body fluid. Chinese yam and lotus seeds are combined with famotidine to treat patients with post-inflammatory diseases, which enhances the role of famotidine in protecting the gastric mucosa and improves the efficacy of the injection.

[0023] 4. The use of yeast and lactobacillus to ferment traditional Chinese medicine and the addition of appropriate culture medium resulted in a fast fermentation speed and good effect, which enhanced the effect of Dendrobium and had a significant therapeutic effect on TNBS-induced colitis in rats. The mechanism may be related to reducing the release of inflammatory cytokines and improving immune regulation disorders. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative labor.

[0025] Figure 1 This is a bar graph comparing the colon tissue morphology scores of rats in the experimental study on the therapeutic effect of famotidine prepared in Example 1 and Comparative Examples 1 to 3 on TNBS-induced colitis in rats.

[0026] Figure 2 This is a bar graph comparing the colon tissue morphology scores of rats in the specific test of the therapeutic effect of famotidine prepared in Example 2, Comparative Example 4 and Comparative Example 5 on TNBS-induced colitis in rats.

[0027] Figure 3 The double Y-axis bar graph is a comparison of the gastric juice test result data of Example 3 and Comparative Example 6. DETAILED DESCRIPTION

[0028] The following describes the embodiments of the present invention by 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 embodiments, 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. It should be noted that the following embodiments and features in the embodiments can be combined with each other without conflict.

[0029] In the present invention, famotidine (purchased from Shanghai Shikangte Pharmaceutical Co., Ltd., national medicine standard H20067930), ilaprazole (purchased from Livzon Pharmaceutical Factory of Livzon Group, national medicine standard H20070256), chlorogenic acid (purchased from Shaanxi Hongyi Kaiyuan Biotechnology Co., Ltd., 98% food-grade health-care raw materials), lactic acid bacteria ATCC 8008 was purchased from Beijing Biobowei Biotechnology Co., Ltd., and yeast ATCC 918 was purchased from Shanghai Gaining Biotechnology Co., Ltd.

[0030] Example 1

[0031] This example demonstrates that lactic acid bacteria ATCC 8008 and yeast ATCC 918 have a synergistic effect on the fermentation of Dendrobium officinale, and the Dendrobium officinale fermentation water extract obtained by using the two together can effectively enhance the therapeutic effect of famotidine.

[0032] The production steps are as follows:

[0033] S1. Weigh 0.4 g of aspartic acid and 0.03 g of disodium ethylenediaminetetraacetic acid powder into a 250 mL beaker, add 75 mL of ionized water, heat to 75°C, and stir until completely dissolved. When the temperature drops to 55°C, add 1.0 g of famotidine, 10 mg of ilaprazole, and 0.02 g of chlorogenic acid into the beaker, and stir until completely dissolved.

[0034] S2. Wash Chinese yam, lotus seeds and Ophiopogon japonicus, remove impurities and dry them, grind the dried Chinese yam, lotus seeds and Ophiopogon japonicus into powder for later use, and mix the powders of 4g Chinese yam, 6g lotus seeds and 2g Ophiopogon japonicus;

[0035] S3, boil the mixed Chinese medicinal materials at 95°C for 3 times, add 6 times the amount of water each time, and the boiling time is 1h, 0.5h, and 0.5h respectively; collect and combine the boiled liquid and centrifuge to obtain a supernatant; evaporate and concentrate the supernatant under reduced pressure to a relative density of 1.15 (60°C), bring to room temperature, add 95% ethanol to adjust the alcohol content to 70%, seal, maintain the temperature at 10°C, let stand for 48 hours for alcohol precipitation, take the supernatant and filter it, concentrate the filtrate until there is no alcohol taste, and obtain a Chinese medicinal material extract for standby use;

[0036] S4. Preparation of bacterial solution: Preparation of Lactobacillus ATCC 8008 bacterial solution: The concentration of preparation is 1.2×10 8 cfu / mL; Preparation of yeast ATCC 918 bacterial solution: the preparation concentration is 1.7×10 9 cfu / mL of yeast culture solution is placed in a culture solution tank for later use;

[0037] S5, placing 10-15g of washed and cut Dendrobium in a fermentation tank containing 10mL of Lactobacillus ATCC 8008, 12mL of yeast ATCC 918 bacterial solution and 15mL of basal culture medium prepared in step S4, fermenting at 35°C for 12 hours, and turning over every two hours. After the fermentation is completed, the Lactobacillus and yeast bacterial solution are inactivated with a 3% H2O2 solution by mass to obtain a Dendrobium fermentation product, and the fermentation product is boiled at 95°C for 3 times, with 6 times the amount of water added each time, and the boiling time is 1h, 0.5h, and 0.5h respectively; collecting and merging the boiled liquid and centrifuging to obtain a supernatant; and separating the supernatant from the supernatant. The mixture was concentrated by evaporation under reduced pressure to a relative density of 1.15 (60° C.), cooled to room temperature, 95% ethanol was added to adjust the alcohol content to 70%, the mixture was sealed, the temperature was maintained at 10° C., the mixture was allowed to stand for 48 hours for alcohol precipitation, the supernatant was filtered, and the filtrate was concentrated until there was no alcohol taste, thereby obtaining a fermented water extract of Dendrobium officinale for standby use; wherein the basal culture medium comprises: casein peptone 10.0 g, beef extract 10.0 g, yeast powder 5.0 g, glucose 5.0 g, sodium acetate 5.0 g, diammonium citrate 2.0 g, Tween 80 1.0 g, K2HPO4 2.0 g, MgSO4.7H2O 0.2 g, MnSO4·H2O 0.05 g, CaCO3 20.0 g, distilled water 1.0 L, pH 6.8;

[0038] S6. Preparation of buffer solution: Prepare solution A: weigh 2.10g of citric acid crystals, add the citric acid crystals to 8mL of deionized water, stir until completely dissolved, transfer the dissolved citric acid solution to a 100mL volumetric flask, dilute to the mark with distilled water, shake well, and obtain a 0.1moL / L citric acid aqueous solution, i.e., solution A; Prepare solution B: weigh 2.94g of trisodium citrate crystals, add the trisodium citrate crystals to 8mL of deionized water, stir until completely dissolved; transfer the dissolved trisodium citrate solution to a 100mL volumetric flask, dilute to the mark with distilled water, shake well, and obtain a 0.1moL / L trisodium citrate aqueous solution, i.e., solution B; take 8.2mL of solution A and 11.2mL of solution B, add them to a beaker, stir thoroughly with a glass rod to ensure uniform mixing; adjust the pH to 5 with solution A, transfer to a 100mL volumetric flask, and dilute to the mark with distilled water;

[0039] S7, preparation of famotidine injection: when the solution prepared in S1 is cooled to 25°C, the buffer solution prepared in step S6 is added to a beaker, the pH of the solution is adjusted to 5.6, and then the Chinese medicinal material extract prepared in step S3 and the fermented water extract of Dendrobium officinale prepared in step S5 are added, and the buffer solution is continued to be added to adjust the pH to 5.6, and the volume is made up to 100 ml with distilled water, and the famotidine injection is obtained after sterilization at 115°C for 30 min.

[0040] Comparative Example 1: Except that lactic acid bacteria ATCC 8008 liquid is not added in step S5, the remaining steps are the same as those in Example 1.

[0041] Comparative Example 2: Except that yeast ATCC 918 bacterial solution is not added in step S5, the remaining steps are the same as those in Example 1.

[0042] Comparative Example 3: In step S7, non-fermented Dendrobium officinale was used, and the remaining steps were the same as those in Example 1.

[0043] Experimental study on the therapeutic effect on TNBS-induced colitis in rats

[0044] Material

[0045] 1.1 Animals: SD rats weighing 180-200 g were provided by the Experimental Animal Center of Nanjing Medical University.

[0046] 1.2 Drugs and reagents: trinitrobenzenesulfonic acid (246-trinitrobenzenesulphonic acid, TNBS), Sigma; famotidine injection prepared in Example 1 and Comparative Examples 1 to 3;

[0047] 2.1 Establishment of animal model: SD rats were fasted for 24 h before modeling. During the experiment, ether anesthesia was performed first, and a catheter was inserted into the colon through the anus 8 cm away from the anus and 15% TBNS prepared with ethanol was injected at a dosage of 100 mg / kg to complete the modeling.

[0048] 2.2 Experimental grouping and treatment: The SD rats with the above model were randomly divided into 5 groups, each with 10 rats (half male and half female). The drug was administered once a day for 7 days starting from the 14th day after TNBS administration. The experimental group was intravenously injected with 10 mg / kg of the famotidine injection prepared in Example 1 and Comparative Examples 1 to 3, and the model group was intravenously injected with the same volume of normal saline; 10 SD rats without modeling were set as the normal control group (administered with the same volume of normal saline).

[0049] The effect of experimental pathological examination scores on the acute injury of colonic membrane was evaluated according to Table 1. The higher the score, the more serious the injury. Figure 1

[0050] Table 1 Scoring criteria for colon mucosal injury

[0051]

[0052] Figure 1 This is a bar graph comparing the colon tissue morphology scores of rats in the experimental study on the therapeutic effect of famotidine prepared in Example 1 and Comparative Examples 1 to 3 on TNBS-induced colitis in rats. Figure 1The experimental results show that lactic acid bacteria ATCC8008 and yeast ATCC918 have a synergistic effect on fermented Chinese medicine. The fermented water extract of Dendrobium obtained by using the two together can effectively enhance the efficacy of famotidine.

[0053] Example 2

[0054] This example demonstrates that both lactic acid bacteria ATCC8008 and yeast ATCC918 have specificity, and when lactic acid bacteria ATCC8008 and yeast ATCC918 are used simultaneously, the therapeutic effect of famotidine is significantly improved.

[0055] The production steps are as follows:

[0056] S1. Weigh 0.5 g of aspartic acid and 0.045 g of disodium ethylenediaminetetraacetic acid powder into a 250 mL beaker, add 75 mL of ionized water, heat to 80°C, and stir until completely dissolved. When the temperature drops to 60°C, add 1.0 g of famotidine, 10 mg of ilaprazole, and 0.03 g of chlorogenic acid into the beaker, and stir until completely dissolved.

[0057] S2. Wash Chinese yam, lotus seeds and Ophiopogon japonicus, remove impurities and dry them, grind the dried Chinese yam, lotus seeds and Ophiopogon japonicus into powder for later use, and mix the powders of 6g Chinese yam, 9g lotus seeds and 3g Ophiopogon japonicus;

[0058] S3, boil the mixed Chinese medicinal materials at 95°C for 3 times, add 6 times the amount of water each time, and the boiling time is 1h, 0.5h, and 0.5h respectively; collect and combine the boiled liquid and centrifuge to obtain a supernatant; evaporate and concentrate the supernatant under reduced pressure to a relative density of 1.15 (60°C), bring to room temperature, add 95% ethanol to adjust the alcohol content to 70%, seal, maintain the temperature at 10°C, let stand for 48 hours for alcohol precipitation, take the supernatant and filter it, concentrate the filtrate until there is no alcohol taste, and obtain a Chinese medicinal material extract for standby use;

[0059] S4. Preparation of bacterial solution: Preparation of Lactobacillus ATCC 8008 bacterial solution: The concentration of preparation is 1.2×10 8 ; Preparation of yeast ATCC 918 bacterial solution: the preparation concentration is 1.71×10 9 cfu / mL of yeast culture solution is placed in a culture solution tank for later use;

[0060] S5, placing 12.5g of washed and cut dendrobium in a fermentation tank containing 12.5mL of lactobacillus ATCC8008, 12.5mL of yeast ATCC 918 bacterial solution and 15mL of basal culture medium prepared in step S4, fermenting at 35°C for 18 hours, and turning over every two hours. After the fermentation is completed, the lactobacillus and yeast bacterial solution are inactivated with a 3% H2O2 solution by mass fraction to obtain a dendrobium fermentation product, and the fermentation product is boiled at 95°C for 3 times, with 6 times the amount of water added each time, and the boiling time is 1h, 0.5h, and 0.5h respectively; collecting and merging the boiled liquid and centrifuging to obtain a supernatant; and separating the supernatant from the supernatant. The mixture was concentrated by evaporation under reduced pressure to a relative density of 1.15 (60° C.), cooled to room temperature, 95% ethanol was added to adjust the alcohol content to 70%, the mixture was sealed, the temperature was maintained at 10° C., the mixture was allowed to stand for 48 hours for alcohol precipitation, the supernatant was filtered, and the filtrate was concentrated until there was no alcohol taste, thereby obtaining a fermented water extract of Dendrobium officinale for standby use; wherein the basal culture medium comprises: casein peptone 10.0 g, beef extract 10.0 g, yeast powder 5.0 g, glucose 5.0 g, sodium acetate 5.0 g, diammonium citrate 2.0 g, Tween 80 1.0 g, K2HPO4 2.0 g, MgSO4.7H2O 0.2 g, MnSO4·H2O 0.05 g, CaCO3 20.0 g, distilled water 1.0 L, pH 6.8;

[0061] S6. Preparation of buffer solution: Prepare solution A: weigh 2.10g of citric acid crystals, add the citric acid crystals to 9mL of deionized water, stir until completely dissolved, transfer the dissolved citric acid solution to a 100mL volumetric flask, dilute to the mark with distilled water, shake well, and obtain a 0.1moL / L citric acid aqueous solution, i.e., solution A; Prepare solution B: weigh 2.94g of trisodium citrate crystals, add the trisodium citrate crystals to 9mL of deionized water, stir until completely dissolved; transfer the dissolved trisodium citrate solution to a 100mL volumetric flask, dilute to the mark with distilled water, shake well, and obtain a 0.1moL / L trisodium citrate aqueous solution, i.e., solution B; take 8.2mL of solution A and 11.2mL of solution B, add them to a beaker, stir thoroughly with a glass rod to ensure uniform mixing; adjust the pH to 5 with solution A, transfer to a 100mL volumetric flask, and dilute to the mark with distilled water;

[0062] S7, preparation of famotidine injection: when the solution prepared in S1 is cooled to 30°C, the buffer solution prepared in step S6 is added to a beaker, the pH of the solution is adjusted to 5.8, and then the Chinese medicinal material extract prepared in step S3 and the fermented water extract of Dendrobium officinale prepared in step S5 are added, and the buffer solution is continued to be added to adjust the pH to 5.8, and the volume is made up to 100 ml with distilled water, and the famotidine injection is obtained after sterilization at 115°C for 30 min.

[0063] Comparative Example 4: Except that lactic acid bacteria ATCC 8008 is replaced by lactic acid bacteria ATCC 33222 (Hubei Rishengchang New Material Technology Co., Ltd.) in step S5, the remaining steps are the same as those in Example 2.

[0064] Comparative Example 5: Except that yeast ATCC 918 was replaced by yeast ACCC 6633 (purchased from Weifang Yihao Biotechnology Co., Ltd.) in step S5, the remaining steps were the same as those in Example 2.

[0065] Experimental study on the therapeutic effect on TNBS-induced colitis in rats

[0066] Material

[0067] 1.1 Animals: SD rats, weighing 180-200 g, were provided by the Experimental Animal Center of Nanjing Medical University.

[0068] 1.2 Drugs and reagents: trinitrobenzenesulfonic acid (246-trinitrobenzenesulphonic acid, TNBS), Sigma; famotidine injection prepared in Example 2 and Comparative Examples 4-5;

[0069] 2.1. Establishment of animal model: SD rats were fasted for 24 hours before modeling. After ether anesthesia, a catheter was inserted into the colon through the anus to a depth of 8 cm and 15% TBNS prepared with ethanol was injected at a dosage of 100 mg / kg to complete the modeling.

[0070] 2.2 Experimental grouping and treatment: The SD rats with the above model were randomly divided into 4 groups with 10 rats in each group (half male and half female). The drug was administered once a day for 7 days starting from the 14th day after TNBS administration. The experimental group was intravenously injected with 10 mg / kg of the famotidine injection prepared in Example 2, Comparative Example 4 and Comparative Example 5, and the model group was intravenously injected with the same volume of normal saline; 10 SD rats without modeling were set as the normal control group (administered with the same volume of normal saline).

[0071] The effect of experimental pathological examination scores on the acute injury of colonic membrane was evaluated according to Table 1. The higher the score, the more serious the injury. Figure 2 .

[0072] Figure 2 This is a bar graph comparing the colon tissue morphology scores of rats in the specific test of the therapeutic effect of famotidine prepared in Example 2, Comparative Example 4 and Comparative Example 5 on TNBS-induced colitis in rats. Figure 2The experimental results show that both lactic acid bacteria ATCC 8008 and yeast ATCC 918 are specific to the fermentation of Dendrobium officinale. When lactic acid bacteria ATCC8008 and yeast ATCC 918 are used to ferment Dendrobium officinale at the same time, the obtained Dendrobium officinale fermentation water extract significantly improves the efficacy of famotidine.

[0073] Example 3

[0074] This example demonstrates that both famotidine and ilaprazole can inhibit gastric acid secretion, and their combined use further enhances the acid-suppressing effect.

[0075] The production steps are as follows:

[0076] S1. Weigh 0.6 g of aspartic acid and 0.06 g of disodium ethylenediaminetetraacetic acid powder into a 250 mL beaker, add 75 mL of ionized water, heat to 85°C, and stir until completely dissolved. When the temperature drops to 65°C, add 1.0 g of famotidine, 10 mg of ilaprazole, and 0.04 g of chlorogenic acid into the beaker, and stir until completely dissolved.

[0077] S2. Wash Chinese yam, lotus seeds and Ophiopogon japonicus, remove impurities and dry them, grind the dried Chinese yam, lotus seeds and Ophiopogon japonicus into powder for later use, and mix 8g of Chinese yam, 12g of lotus seeds and 4g of Ophiopogon japonicus powder;

[0078] S3, boil the mixed Chinese medicinal materials at 95°C for 3 times, add 6 times the amount of water each time, and the boiling time is 1h, 0.5h, and 0.5h respectively; collect and combine the boiled liquid and centrifuge to obtain a supernatant; evaporate and concentrate the supernatant under reduced pressure to a relative density of 1.15 (60°C), bring to room temperature, add 95% ethanol to adjust the alcohol content to 70%, seal, maintain the temperature at 10°C, let stand for 48 hours for alcohol precipitation, take the supernatant and filter it, concentrate the filtrate until there is no alcohol taste, and obtain a Chinese medicinal material extract for standby use;

[0079] S4. Preparation of bacterial solution: Preparation of Lactobacillus ATCC 8008 bacterial solution: The concentration of preparation is 1.21×10 8 cfu / mL; Preparation of yeast ATCC 918 bacterial solution: the preparation concentration is 1.72×10 9 cfu / mL of yeast culture solution is placed in a culture solution tank for later use;

[0080] S5, placing 15g of washed and cut Dendrobium in a fermentation tank containing 15mL of Lactobacillus ATCC 8008, 17mL of Saccharomyces ATCC 918 bacterial solution and 15mL of basal culture medium prepared in step S4, fermenting at 35°C for 24 hours, and turning over every two hours. After the fermentation is completed, the Lactobacillus and the Saccharomyces cerevisiae are inactivated with a 3% H2O2 solution to obtain a Dendrobium fermentation product, boiling the fermentation product at 95°C for 3 times, adding 6 times the amount of water each time, and the boiling time is 1h, 0.5h, and 0.5h respectively; collecting and combining the boiled liquid and centrifuging to obtain a supernatant; separating the supernatant The mixture was concentrated by evaporation under reduced pressure to a relative density of 1.15 (60° C.), cooled to room temperature, 95% ethanol was added to adjust the alcohol content to 70%, the mixture was sealed, the temperature was maintained at 10° C., the mixture was allowed to stand for 48 hours for alcohol precipitation, the supernatant was filtered, and the filtrate was concentrated until there was no alcohol taste, thereby obtaining a fermented water extract of Dendrobium officinale for standby use; wherein the basal culture medium comprises: casein peptone 10.0 g, beef extract 10.0 g, yeast powder 5.0 g, glucose 5.0 g, sodium acetate 5.0 g, diammonium citrate 2.0 g, Tween 80 1.0 g, K2HPO4 2.0 g, MgSO4.7H2O 0.2 g, MnSO4·H2O 0.05 g, CaCO3 20.0 g, distilled water 1.0 L, pH 6.8;

[0081] S6. Preparation of buffer solution: Prepare solution A: weigh 2.10g of citric acid crystals, add the citric acid crystals to 10mL of deionized water, stir until completely dissolved, transfer the dissolved citric acid solution to a 100mL volumetric flask, dilute to the mark with distilled water, shake well, and obtain a 0.1moL / L citric acid aqueous solution, i.e., solution A; Prepare solution B: weigh 2.94g of trisodium citrate crystals, add the trisodium citrate crystals to 10mL of deionized water, stir until completely dissolved; transfer the dissolved trisodium citrate solution to a 100mL volumetric flask, dilute to the mark with distilled water, shake well, and obtain a 0.1moL / L trisodium citrate aqueous solution, i.e., solution B; take 8.2mL of solution A and 11.2mL of solution B, add them to a beaker, stir thoroughly with a glass rod to ensure uniform mixing; adjust the pH to 5 with solution A, transfer to a 100mL volumetric flask, and dilute to the mark with distilled water;

[0082] S7, preparation of famotidine injection: when the solution prepared in S1 is cooled to 35°C, the buffer solution prepared in step S6 is added to a beaker, the pH of the solution is adjusted to 6.2, and then the Chinese medicinal material extract prepared in step S3 and the fermented water extract of Dendrobium officinale prepared in step S5 are added, and the pH is adjusted to 5.8 by adding buffer solution, and the volume is made up to 100 ml by adding distilled water, and the famotidine injection is obtained after sterilization at 115°C for 30 min.

[0083] Comparative Example 6: Except that iprazol was not added in step S1, the remaining steps were the same as those in Example 3.

[0084] Gastric acid secretion inhibition test

[0085] Experimental animals: SD rats, weighing 180-200 g, were provided by the Experimental Animal Center of Nanjing Medical University.

[0086] Experimental method: 30 SD rats were randomly divided into 3 groups, 10 rats in each group, namely the control group, Example 3 and Comparative Example 6. Example 3 and Comparative Example 6 were intravenously injected with 10 mg / kg of famotidine injection prepared in Example 3 and Comparative Example 6, respectively. The control group was intravenously injected with distilled water. The administration was intravenously injected once every 6 hours for a total of 4 times. After ether anesthesia 1 hour after the last administration, the pylorus was surgically ligated. After 6 hours, the stomach was removed to collect gastric juice, and the total volume, total acidity and total acid excretion of gastric juice were measured. The results are shown in Table 2 and Figure 3 .

[0087] Table 2 Gastric juice test results

[0088] Test items Gastric juice volume mL Total acidity mmoL / L Total acid discharge mmoL / L Control group 7.2±0.4 68.8±12.1 0.41±0.04 Example 3 3.2±1.6 42.5±5.6 0.08±0.03 Comparative Example 6 5.6±1.2 56.4±4.8 0.21±0.09

[0089] From Table 2 and Figure 3 The experimental results show that both famotidine and ilaprazole can inhibit gastric acid secretion, and their combined use further enhances the acid suppression effect.

Claims

1. A method for preparing famotidine for injection, characterized in that: The specific preparation method is as follows: S1. Weigh 0.4-0.6 g of aspartic acid and 0.03-0.06 g of disodium ethylenediaminetetraacetic acid powder into a 250 mL beaker, add 75 mL of ionized water, heat to 75-85 ° C, stir until completely dissolved, and when the temperature drops to 55-65 ° C, add 1.0 g of famotidine, 10 mg of ilaprazole and 0.02-0.04 g of chlorogenic acid to the beaker, and stir until completely dissolved; S2. Wash Chinese yam, lotus seeds and Ophiopogon japonicus, remove impurities and dry them, grind the dried Chinese yam, lotus seeds and Ophiopogon japonicus into powder for later use, and mix the powders according to 4-8 g of Chinese yam, 6-12 g of lotus seeds and 2-4 g of Ophiopogon japonicus; S3. Boil the mixed Chinese medicinal materials at 95°C for 3 times, adding 6 times the amount of water each time, and the boiling time is 1h, 0.5h, and 0.5h respectively; collect and combine the boiled liquid and centrifuge to obtain the supernatant; evaporate and concentrate the supernatant under reduced pressure to a relative density of 1.15 (60°C), bring it to room temperature, add 95% ethanol to adjust the alcohol content to 70%, seal it, maintain the temperature at 10°C, let it stand for 48 hours for alcohol precipitation, take the supernatant and filter it, concentrate the filtrate until there is no alcohol taste, and obtain the Chinese medicinal material extract for standby use; S4. Preparation of bacterial solution: Preparation of Lactobacillus ATCC 8008 bacterial solution: The concentration of preparation is 1.2×10 8 -1.21×10 8 cfu / mL; Preparation of yeast ATCC 918 bacterial solution: the preparation concentration is 1.7×10 9 -1.72×10 9 cfu / mL of yeast culture solution is placed in a culture solution tank for later use; S5, place 10-15 g of washed and cut Dendrobium officinale in a container containing 10-15 mL of Lactobacillus ATCC 8008 and 12-17 mL of Saccharomyces ATCC prepared in step S4. 918 bacterial liquid and 15mL basic culture medium were added to the fermentation tank at 35°C for 12-24 hours, and the mixture was stirred every two hours. After the fermentation, the lactobacillus and yeast liquid were inactivated with a 3% H2O2 solution to obtain the Dendrobium fermented product. The fermented product was boiled at 95°C for 3 times, and 6 times the amount of water was added each time. The boiling time was 1h, 0.5h, and 0.5h respectively. The boiled liquid was collected and combined and centrifuged to obtain the supernatant. The supernatant was evaporated and concentrated under reduced pressure to a relative density of 1.15 (60°C), cooled to room temperature, 95% ethanol was added to adjust the alcohol content to 70%, sealed, maintained at 10°C, and allowed to stand for 48 hours for alcohol precipitation. The supernatant was filtered and the filtrate was concentrated to no alcohol taste to obtain the Dendrobium fermented water extract for standby use. S6. Preparation of buffer solution: Prepare solution A: weigh 2.10g of citric acid crystals, add the citric acid crystals to 8-10 mL of deionized water, stir until completely dissolved, transfer the dissolved citric acid solution to a 100mL volumetric flask, dilute to the mark with distilled water, shake well, and obtain a 0.1moL / L citric acid aqueous solution, i.e., solution A; Prepare solution B: weigh 2.94g of trisodium citrate crystals, add the trisodium citrate crystals to 8-10 mL of deionized water, stir until completely dissolved; transfer the dissolved trisodium citrate solution to a 100mL volumetric flask, dilute to the mark with distilled water, shake well, and obtain a 0.1moL / L trisodium citrate aqueous solution, i.e., solution B; take 8.2mL of solution A and 11.2mL of solution B and add them to a beaker, stir thoroughly with a glass rod to ensure uniform mixing; adjust the pH to 5 with solution A, transfer to a 100mL volumetric flask, and dilute to the mark with distilled water; S7, preparation of famotidine injection: when the solution prepared in S1 is cooled to 25-35°C, the buffer solution prepared in step S6 is added to a beaker, the pH of the solution is adjusted to 5.6-6.2, and then the Chinese medicinal material extract prepared in step S3 and the fermented water extract of Dendrobium officinale prepared in step S5 are added, and the buffer solution is continued to be added to adjust the pH to 5.6-5.8, and the volume is made up to 100 ml with distilled water, and the famotidine injection is obtained after sterilization at 115°C for 30 min.

2. A method for preparing famotidine for injection according to claim 1, characterized in that: In step S1, 0.5 g of aspartic acid and 0.045 g of disodium ethylenediaminetetraacetic acid powder were weighed into a 250 mL beaker, 90 mL of ionized water was added, and the mixture was heated to 80° C. and stirred until completely dissolved. When the temperature dropped to 60° C., 1.0 g of famotidine, 10 mg of ilaprazole and 0.03 g of chlorogenic acid were added to the beaker and stirred until completely dissolved.

3. A method for preparing famotidine for injection according to claim 2, characterized in that: The concentration of the lactic acid bacteria ATCC 8008 liquid used in step S4 was 1.2×10 8 cfu / mL, the concentration of yeast ATCC 918 bacterial solution was 1.71×10 9 cfu / mL.

4. A method for preparing famotidine for injection according to claim 3, characterized in that: In the step S2, the powders of Chinese yam, lotus seeds and Radix Ophiopogonis are crushed in a mass ratio of 2:3:1 and then mixed evenly.

5. A method for preparing famotidine for injection according to claim 3, characterized in that: In step S5, lactic acid bacteria ATCC 8008 and yeast ATCC 918 are used to ferment and modify the dendrobium.

6. A method for preparing famotidine for injection according to claim 1, characterized in that: In step S5, the amount of Dendrobium officinale used is 12.5 g, the amount of Lactobacillus ATCC 8008 and the amount of yeast ATCC 918 bacterial liquid used are both 12.5 mL, and the fermentation time is 18 hours.

7. A method for preparing famotidine for injection according to claim 1, characterized in that: The amount of distilled water used in step S6 is 9 mL.

8. A method for preparing famotidine for injection according to claim 1, characterized in that: In step S7, the temperature is lowered to 30°C.

9. Famotidine for injection prepared by the preparation method according to any one of claims 1 to 8.

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