Ranitidine combined medicine for injection and preparation method thereof

Abstract

The invention provides a ranitidine combined medicine for injection and a preparation method thereof, and the ranitidine combined medicine for injection is prepared by utilizing a cavity of cyclodextrin to clathrate ranitidine or a salt compound thereof in an aqueous solution state and further performing methods of sterilization filtration, freeze drying, nitrogen protection and the like. Compared with the prior art, the preparation method disclosed by the invention has the advantages that by utilizing a cyclodextrin inclusion technology, sulfobutyl-beta-cyclodextrin, sulfobutyl-gamma-cyclodextrin or carboxymethyl-beta-cyclodextrin is selected to encapsulate a ranitidine hydrochloride molecular structure or molecular fragment at a relatively low temperature under the protection of nitrogen and under a dark condition; the generation of NDMA and precursor compounds DMA and NO2 <-> thereof can be effectively controlled, the medication safety is guaranteed, and the application prospect and development potential are very good.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and particularly to a combination drug of ranitidine for injection and a preparation method thereof. Background Art

[0002] The chemical name of ranitidine is N'-Methyl-N-[2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]-2-nitro-1,1-ethenediamine. It is a white or light yellow crystalline powder. It is an H2 receptor antagonist developed by GlaxoSmithKline in the UK. It can effectively inhibit gastric acid secretion induced by histamine and pentagastrin. Clinically, it is mainly used to treat hyperacidity, heartburn, duodenal ulcer, benign gastric ulcer, postoperative ulcer, reflux esophagitis, and Zollinger-Ellison syndrome, etc.; intravenous injection can be used to treat upper gastrointestinal bleeding. Ranitidine hydrochloride is currently the most widely used drug for treating ulcer diseases.

[0003] On September 13, 2019, the U.S. Food and Drug Administration (FDA) website first issued a notice. Due to low concentrations of the genotoxic impurity N-nitrosodimethylamine (NDMA) being detected in multiple ranitidine drugs, it required the recall of related products; on April 1, 2020, the FDA again required the removal of all ranitidine drugs from the market; on May 8 of the same year, the "Technical Guidelines for the Study of Nitrosamine Impurities in Chemical Drugs (Trial)" issued by the National Medical Products Administration of China also required the traceability and control research on NDMA generated in ranitidine raw materials and their preparations.

[0004] Currently, it is generally believed that NDMA is generated due to the self-degradation of ranitidine. In October 2019, the Therapeutic Goods Administration of Australia found that the content of NDMA in related preparation products of ranitidine near the expiration date was significantly higher than that of newly produced samples. The Hunan Institute for Drug Control also confirmed that NDMA is a degradation impurity of ranitidine hydrochloride. Through stress tests in the early stage, it was further confirmed that under conditions such as high temperature, oxygen, moisture, or light, the generation of NDMA in ranitidine hydrochloride can be significantly promoted; and it was found that the amount of NDMA generated is related to its precursor compounds dimethylamine (DMA) and nitrite (NO2 -)The generated amounts show a positive correlation, and both of these precursor compounds are structural fragments of ranitidine hydrochloride. Thus, it is speculated that one of the possible mechanisms for the formation of NDMA from ranitidine hydrochloride may be the initial degradation to produce DMA and NO2 - , followed by further reaction to produce NDMA.

[0005] The patent with the publication number CN115518049A, which was published on December 27, 2022, discloses a ranitidine hydrochloride capsule and its preparation method. By the combination of anhydrous citric acid, maltol, and the stabilizer cyclodextrin derivative, it overcomes the difficulties in the preparation process caused by the poor fluidity and strong hygroscopicity of ranitidine hydrochloride, as well as the problem of poor stability, improves the smoothness in the preparation process, and increases the stability of the ranitidine hydrochloride capsule, avoiding problems such as discoloration during long-term storage of the drug. However, this preparation is an oral preparation and is not applicable to ranitidine hydrochloride injection; in addition, although the types of cyclodextrin derivatives used in this patent are hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dihydroxypropyl-β-cyclodextrin, and methyl-β-cyclodextrin as stabilizers, in the preparation process of this patent, only the solid of ranitidine hydrochloride and the cyclodextrin derivative are physically mixed, which cannot ensure that the ranitidine hydrochloride molecule or the fragment in the molecule can enter the cyclodextrin cavity, and thus cannot play a protective role.

[0006] The patent with the publication number CN 103330705A, which was published on October 2, 2013, discloses a ranitidine for injection composition. The prescription composition includes ranitidine, melatonin, and medium-substituted hydroxypropyl-β-cyclodextrin; in the preparation process, only hydroxypropyl-β-cyclodextrin is used to include melatonin, and ranitidine is not included, so the stability of ranitidine cannot be guaranteed. Summary of the Invention

[0007] The purpose of the present invention is to provide a combined drug of ranitidine for injection and its preparation method. By using the cavity of cyclodextrin, in the aqueous solution state, ranitidine or its salt compound is included, and further through methods such as sterile filtration, freeze-drying, and nitrogen protection, a combined drug of ranitidine for injection is prepared. The preparation method of the present invention can effectively control the generation of NDMA and its precursor compounds DMA and NO2 - , ensuring the safety of drug use and having good application prospects and development potential.

[0008] The specific technical solution of the present invention is as follows:

[0009] A combined drug of ranitidine for injection includes ranitidine or its salt compound, cyclodextrin, and a pH regulator.

[0010] The ranitidine or its salt compound in the combined drug of ranitidine for injection contains 50 mg / bottle of ranitidine (calculated based on C13 H 22 N4O3S meter).

[0011] The ranitidine or its salt compound is selected from free ranitidine, ranitidine hydrochloride and ranitidine bismuth citrate, and preferably ranitidine hydrochloride.

[0012] The mass ratio of the cyclodextrin to ranitidine or its salt compound based on ranitidine is: 5 - 200:1;

[0013] The cyclodextrin is selected from one or more of sulfobutyl - β - cyclodextrin, sulfobutyl - γ - cyclodextrin or carboxymethyl - β - cyclodextrin, and preferably sulfobutyl - β - cyclodextrin or sulfobutyl - γ - cyclodextrin.

[0014] Among them, sulfobutyl - β - cyclodextrin is also known as sodium sulfobutyl ether - β - cyclodextrin, sulfobutyl ether - β - cyclodextrin or sodium sulfobutyl - β - cyclodextrin;

[0015] Sulfobutyl - γ - cyclodextrin is also known as sodium sulfobutyl ether - γ - cyclodextrin, sulfobutyl ether - γ - cyclodextrin or sodium sulfobutyl - γ - cyclodextrin.

[0016] Preferably, when the cyclodextrin is selected from sulfobutyl - β - cyclodextrin, the mass ratio of sulfobutyl - β - cyclodextrin to ranitidine or its salt compound based on ranitidine is: 5 - 200:1; preferably: 5 - 100:1;

[0017] Preferably, when the cyclodextrin is selected from sulfobutyl - γ - cyclodextrin, the mass ratio of sulfobutyl - γ - cyclodextrin to ranitidine or its salt compound based on ranitidine is: 5 - 200:1, preferably 10 - 100:1.

[0018] The dosage of the pH regulator is: to control the pH range of the ranitidine combined injection drug to be 5.0 - 8.0, preferably 5.0 - 7.4.

[0019] The pH regulator is selected from bases or acids acceptable for injections. Preferably, the pH regulator is selected from one or more of disodium hydrogen phosphate, sodium carbonate, sodium hydroxide, sodium citrate, phosphoric acid, citric acid, acetic acid and hydrochloric acid; more preferably sodium hydroxide and hydrochloric acid.

[0020] The encapsulation efficiency of the ranitidine combined injection drug is more than 85%.

[0021] A preparation method of a ranitidine combined injection drug provided by the present invention includes the following steps:

[0022] 1) Place the formulated amount of cyclodextrin in injection water and stir to dissolve;

[0023] 2) Place ranitidine or its salt compound into the solution obtained in step 1), and stir until completely dissolved to obtain a mixed solution;

[0024] 3) Add a pH regulator to adjust the pH of the mixed solution to 5.0 - 8.0;

[0025] 4) Under the protection of nitrogen filling, stir and complex the solution obtained in step 3) under light - proof conditions to obtain a clathrate;

[0026] 5) After filtering the clathrate obtained in step 4) to remove bacteria, sub - package, freeze - dry, fill with nitrogen, stopper, and crimp to obtain the combined ranitidine drug for injection.

[0027] In step 1), the conditions for stirring and dissolving are: under the constant temperature condition of 20°C - 80°C, stir until completely dissolved; after stirring and dissolving, lower the temperature to 10°C - 30°C, preferably lower the temperature to 15°C - 25°C;

[0028] In step 2), stirring until completely dissolved means: under the constant temperature condition of 10°C - 30°C, stir until completely dissolved;

[0029] Further, step 2) can also be: place ranitidine or its salt compound into water for injection, stir and dissolve, and then stir and mix with the solution of step 1) under the constant temperature condition of 10°C - 30°C to obtain a mixed solution;

[0030] In step 4), stirring and complexing under light - proof conditions means complexing by stirring at 200 - 800 rpm for 0.5 h - 24 h under the conditions of nitrogen protection, constant temperature of 10°C - 30°C, and light - proof; preferably complexing at 15°C - 25°C;

[0031] Further, in step 4), make up the water for injection to the full volume to obtain a clathrate;

[0032] In step 5), the bacteria - removing filtration means: filtering to remove bacteria successively through 0.45μm and 0.22μm filters;

[0033] In step 5), the sub - packaging means: filling the filtrate into glass - tube injection bottles; the filling amount is 25 mg / bottle, 50 mg / bottle, and 100 mg / bottle calculated by ranitidine, preferably 50 mg / bottle; the materials of the glass - tube injection bottles include high - borosilicate, medium - borosilicate, and low - borosilicate, preferably medium - borosilicate.

[0034] In step 5), the lyophilization means that after pre-freezing at -40°C to -20°C for 3 - 6 h, the parameters for the first drying are set as follows: the vacuum degree is 100 μbar to 200 μbar, and within 2 h to 6 h, the temperature rises from -40°C to -10°C and is maintained for 6 h to 12 h; the parameters for the second drying are set as follows: the vacuum degree is 100 μbar to 200 μbar, within 2 h to 4 h, the temperature rises from -10°C to 0°C, after being maintained for 4 h to 8 h, within 1 h, the temperature rises from 0°C to 20°C to 30°C and is maintained for 4 h to 6 h until completely dry.

[0035] The combined drug of ranitidine for injection meets the following requirements: It is detected with reference to the guiding principles in the fourth part of the General Principles of the Chinese Pharmacopoeia (2020 Edition), and the results are as follows:

[0036] After being stored for 30 days under anaerobic conditions with light, NDMA is not detected; after being stored for 30 days under aerobic conditions with light, the NDMA content is less than 0.15 μg / g;

[0037] After being stored for 30 days under anaerobic conditions at 40°C, NDMA is not detected; after being stored for 30 days under aerobic conditions at 40°C, the NDMA content is not detected;

[0038] After being stored for 30 days under anaerobic conditions at 60°C, the NDMA content is less than 0.04 μg / g; after being stored for 30 days under aerobic conditions at 40°C, the NDMA content is less than 0.07 μg / g;

[0039] After being stored for 30 days under anaerobic conditions with light, the DMA content is less than 26 μg / g; after being stored for 30 days under aerobic conditions with light, the DMA content is less than 34 μg / g;

[0040] After being stored for 30 days under anaerobic conditions at 40°C, DMA is not detected; after being stored for 30 days under aerobic conditions at 40°C, the DMA content is not detected;

[0041] After being stored for 30 days under anaerobic conditions at 60°C, the DMA content is less than 11 μg / g; after being stored for 30 days under aerobic conditions at 40°C, the DMA content is less than 14 μg / g;

[0042] After being stored for 30 days under anaerobic conditions with light, NO2 - is not detected; after being stored for 30 days under aerobic conditions with light, NO2 - content is less than 40 μg / g;

[0043] After being stored for 30 days under anaerobic conditions at 40°C, NO2 - is less than 10 μg / g; after being stored for 30 days under aerobic conditions at 40°C, NO2 - content is less than 12 μg / g;

[0044] After being stored for 30 days under anaerobic conditions at 60 °C, the NO2 - content is less than 17 μg / g. After being stored for 30 days under aerobic conditions at 60 °C, the NO2 - content is less than 70 μg / g.

[0045] Ranitidine is unstable. Under conditions such as high temperature, oxygen, moisture or light, it can promote degradation to generate NDMA, DMA and NO2 - . During the preparation process, it is still an aqueous solution. Therefore, in order to avoid degradation, the temperature should be controlled and nitrogen protection should be adopted during the preparation process. In addition, in order to improve the encapsulation rate, the stirring speed and the inclusion time need to be controlled. Finally, it meets the requirement of being higher than 80% of the encapsulation rate in the pharmacopoeia. The present invention can achieve an encapsulation rate of more than 85%.

[0046] Compared with the prior art, the present invention uses the cyclodextrin inclusion technology. Under lower temperature, nitrogen protection and light avoidance conditions, sulfobutyl-β-cyclodextrin, sulfobutyl-γ-cyclodextrin or carboxymethyl-β-cyclodextrin is selected to encapsulate the molecular structure or molecular fragment of ranitidine hydrochloride, and through technologies such as sterile filtration and freeze-drying, it effectively controls the degradation of ranitidine hydrochloride to produce NDMA and its precursor compound DMA and NO2 - under conditions of light, high temperature, high oxygen content and high water content, better ensuring the drug safety of patients. Compared with traditional injections, the final product of this drug is freeze-dried to form a powder, which contains almost no water, thus improving the stability. Description of the Drawings

[0047] Figure 1 is a scanning electron microscopy image (SEM);

[0048] Figure 2 is an infrared spectroscopy image (FT-IR);

[0049] Figure 3 is a differential scanning calorimetry image (DSC);

[0050] Figure 4 is an X-ray diffraction image (XRD);

[0051] The drawings are used to provide a further understanding of the present invention, and constitute a part of the specification. Together with the embodiments of the present invention, they are used to explain the present invention and do not constitute a limitation to the present invention. Detailed Embodiments

[0052] To make the objectives, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the scope of protection of the present invention.

[0053] For the test materials, reagents, etc. used in the following embodiments, unless otherwise specified, they can all be obtained through commercial channels.

[0054] For those not specifying specific techniques or conditions in the embodiments, they can all be carried out according to the techniques or conditions described in the literature in this field or according to the product specifications.

[0055] Example 1

[0056] A preparation method of a ranitidine combined drug for injection. The preparation prescription (1000 bottles), and the main raw materials are shown in Table 1.

[0057] Table 1 Main raw materials of Example 1

[0058]

[0059]

[0060] The present invention uses a 1M sodium hydroxide solution. During the preparation process, solid NaOH needs to be first dissolved, and after being formulated into a solution, it is then added dropwise to the mixed solution containing ranitidine for four reasons: First, the dissolution process of solid sodium hydroxide takes a long time, and it cannot be directly added to the solution containing ranitidine to avoid affecting the inclusion efficiency. Second, solid sodium hydroxide releases heat during the dissolution process, resulting in a temperature rise, which may accelerate the degradation of ranitidine. Third, during the dissolution process of solid sodium hydroxide, it may cause a locally excessive concentration of sodium hydroxide in the tank, with too strong alkalinity, accelerating the reduction of ranitidine. Fourth, when adding solid sodium hydroxide, it is difficult to control the pH value.

[0061] In addition, the commercially available hydrochloric acid is concentrated hydrochloric acid, which also needs to be diluted before being added dropwise to the mixed solution containing ranitidine. Otherwise, it may also cause difficulty in controlling the pH and a locally excessive concentration in the tank. In addition, concentrated hydrochloric acid has strong volatility and corrosiveness. Using it to adjust the pH, if the time is too long, it will affect the health of production personnel.

[0062] Therefore, the above two reagents, namely the sodium hydroxide solution and the hydrochloric acid solution, need to be dissolved and diluted in advance.

[0063] The specific preparation method of Example 1 includes the following steps:

[0064] (1) Take 70% of the injection water in the prescription of Table 1, heat it to 50°C - 60°C, take the sulfobutyl-β-cyclodextrin in the prescription amount, slowly add it to the injection water, stir until completely dissolved, and then cool it to 20°C ± 5°C;

[0065] (2) Take the solid powder of ranitidine hydrochloride in the prescription amount of Table 1, weigh it precisely, and slowly add it to the solution obtained in step (1) under the constant temperature condition of 20°C ± 5°C, and stir until completely dissolved;

[0066] (3) In the solution obtained in step (2), dropwise add 1M sodium hydroxide solution or 1M hydrochloric acid solution to adjust the pH to 6.5;

[0067] (4) After filling nitrogen into the solution obtained in step (3), seal it and protect it from light. Under the condition of 20°C ± 2°C, stir at 400 rpm for 6 hours, make up to the full prescription volume with injection water, and then stir evenly;

[0068] (5) Filter the medicinal liquid through 0.45μm and 0.22μm filter cartridges in sequence for sterilization. For the obtained filtrate, calculated based on 50 mg / vial of ranitidine, aliquot it into middle-borosilicate glass injection vials, semi-plug the vials and send them into the freeze-drying equipment. Pre-freeze at -40°C for 4 hours. Set the parameters for the first drying: the vacuum degree is 100 μbar, and within 4 hours, the temperature rises from -40°C to -10°C and is maintained for 12 hours; Set the parameters for the second drying: the vacuum degree is 100 μbar, within 3 hours, the temperature rises from -10°C to 0°C, after maintaining for 4 hours, within 1 hour, the temperature rises from 0°C to 25°C and is maintained for 6 hours, fill nitrogen, crimp the stopper, and prepare ranitidine for injection.

[0069] Example 2

[0070] A preparation method of a combined drug of ranitidine for injection, with a preparation prescription (1000 vials), and the main raw materials are shown in Table 2.

[0071] Table 2 Main raw materials of Example 2

[0072] Component Dosage Ranitidine Hydrochloride 55.6g Sulfobutyl-β-cyclodextrin 3433.3g 1M Sodium Hydroxide Solution Appropriate amount 1M Hydrochloric Acid Solution Appropriate amount Water for Injection 5000g

[0073] The specific preparation method of Example 2 includes the following steps:

[0074] (1) Take 70% of the injection water in the prescription, heat it to 50°C - 60°C, take the sulfobutyl-β-cyclodextrin in the prescription amount, slowly add it to the injection water, stir until completely dissolved, and cool it to 20°C ± 5°C;

[0075] (2) Take the solid powder of ranitidine hydrochloride in the prescription amount, weigh it precisely, and slowly add it to the solution in step (1) under the constant temperature condition of 20°C ± 5°C, and stir until completely dissolved;

[0076] (3) In the solution obtained in step (2), add 1M sodium hydroxide solution or 1M hydrochloric acid solution dropwise to adjust the pH to 6.5;

[0077] (4) After filling nitrogen into the solution obtained in step (3), seal it and avoid light. Stir at 500 rpm for 6 hours under the condition of 20°C ± 2°C, make up to the full volume of the prescription with water for injection, and stir evenly;

[0078] (5) Filter the medicinal liquid obtained in step (4) through 0.45μm and 0.22μm filter elements in sequence for sterilization. For the obtained filtrate, calculate by 50mg / vial of ranitidine, dispense it into medium-borosilicate glass control injection vials, semi-plug it and then send it into the freeze-drying equipment. Pre-freeze at -40°C for 4h. The set parameters for the first drying are: the vacuum degree is 100μbar, and within 4h, the temperature rises from -40°C to -10°C and is maintained for 12h; the set parameters for the second drying are: the vacuum degree is 100μbar, within 3h, the temperature rises from -10°C to 0°C, after maintaining for 4h, within 1h, the temperature rises from 0°C to 25°C and is maintained for 6h. Fill nitrogen, plug the vial and crimp the cap to prepare ranitidine for injection.

[0079] Example 3

[0080] A preparation method of a combined drug of ranitidine for injection. The preparation prescription (1000 vials), and the main raw materials are shown in Table 3.

[0081] Table 3 Main raw materials of Example 3

[0082]

[0083]

[0084] The specific preparation method of Example 3 includes the following steps:

[0085] (1) Take 90% of the water for injection in the prescription amount, heat it to 50°C - 60°C, take the sulfobutyl-β-cyclodextrin in the prescription amount, slowly add it to the water for injection, and stir until completely dissolved, then cool it to 20°C ± 5°C;

[0086] (2) Take the solid powder of ranitidine hydrochloride in the prescription amount, weigh it precisely, and slowly add it to the solution obtained in step (1) under the constant temperature condition of 20°C ± 5°C, and stir until completely dissolved;

[0087] (3) In the solution obtained in step (2), add 1M sodium hydroxide or 1M hydrochloric acid solution dropwise to adjust the pH to 6.5;

[0088] (4) After filling nitrogen into the solution obtained in step (3), seal it and avoid light, stir at 600 rpm for 6 hours under the condition of 20°C ± 2°C, make up to the full prescription volume with water for injection, and stir evenly;

[0089] (5) Filter the medicinal liquid obtained in step (4) through 0.45μm and 0.22μm filters in sequence for sterile filtration. The obtained filtrate, calculated based on 50 mg of ranitidine per vial, is dispensed into medium-borosilicate glass ampoules for injections. After half-capping, it is sent into the freeze-drying equipment and pre-frozen at -40°C for 4 hours. The parameters set for the primary drying are: the vacuum degree is 100 μbar, and within 4 hours, the temperature rises from -40°C to -10°C and is maintained for 12 hours; the parameters set for the secondary drying are: the vacuum degree is 100 μbar, within 3 hours, the temperature rises from -10°C to 0°C, after maintaining for 4 hours, within 1 hour, the temperature rises from 0°C to 25°C and is maintained for 6 hours, then fill with nitrogen, cap and crimp, and prepare the ranitidine for injection.

[0090] Comparative Example 1

[0091] A preparation method of a combined drug of ranitidine for injection, the preparation prescription (1000 vials), and the main raw materials are shown in Table 4.

[0092] Table 4 Main raw materials of Comparative Example 1

[0093] Component Dosage Ranitidine Hydrochloride 55.6g Hydroxypropyl-β-cyclodextrin 244.7g 1M Sodium Hydroxide Solution Appropriate amount 1M Hydrochloric Acid Solution Appropriate amount Water for Injection 1000g

[0094] The specific preparation method of Comparative Example 1 includes the following steps:

[0095] (1) Take 70% of the water for injection in the prescription amount, heat it to 50°C - 60°C, take the hydroxypropyl-β-cyclodextrin in the prescription amount, slowly add it to the water for injection, stir until completely dissolved, and cool to 20°C ± 5°C;

[0096] (2) Take the solid powder of ranitidine hydrochloride in the prescription amount, accurately weigh it, and slowly add it to the solution obtained in step (1) under the constant temperature condition of 20°C ± 5°C, and stir until completely dissolved;

[0097] (3) In the solution obtained in step (2), dropwise add 1M sodium hydroxide solution or 1M hydrochloric acid solution to adjust the pH to 6.5;

[0098] (4) After filling nitrogen into the solution obtained in step (3), seal it and avoid light, stir at 400 rpm for 6 hours under the condition of 20°C ± 2°C, then make up to the full prescription volume with water for injection, and stir evenly;

[0099] (5) The liquid medicine obtained in step (4) is sequentially subjected to sterilizing filtration through 0.45 μm and 0.22 μm filters. The obtained filtrate, calculated based on 50 mg of ranitidine per vial, is dispensed into medium-borosilicate glass ampoules for injections. After semi-capping, it is sent into the freeze-drying equipment and pre-frozen at -40°C for 4 h. The parameters for the first drying are set as follows: the vacuum degree is 100 μbar, and within 4 h, the temperature is raised from -40°C to -10°C and maintained for 12 h. The parameters for the second drying are set as follows: the vacuum degree is 100 μbar, within 3 h, the temperature is raised from -10°C to 0°C, maintained for 4 h, then within 1 h, the temperature is raised from 0°C to 25°C and maintained for 6 h. Nitrogen is filled in, the vials are capped and crimped to prepare ranitidine for injection.

[0100] Comparative Example 2

[0101] A preparation method of a combined drug of ranitidine for injection. The preparation prescription (1000 vials), and the main raw materials are shown in Table 5.

[0102] Table 5 Main raw materials of Comparative Example 2

[0103] Component Dosage Ranitidine Hydrochloride 55.6g Hydroxypropyl-β-cyclodextrin 1223.5g 1M Sodium Hydroxide Appropriate amount 1M Hydrochloric Acid Appropriate amount Add Water for Injection 5000g

[0104] The specific preparation method of Comparative Example 2 includes the following steps:

[0105] (1) Take 70% of the injection water in the prescription amount, heat it to 50°C - 60°C, take the hydroxypropyl-β-cyclodextrin in the prescription amount, slowly add it to the injection water, stir until completely dissolved, and cool to 20°C ± 5°C;

[0106] (2) Take the solid powder of ranitidine hydrochloride in the prescription amount, accurately weigh it, and slowly add it to the solution obtained in step (1) under the constant temperature condition of 20°C ± 5°C, and stir until completely dissolved;

[0107] (3) In the solution obtained in step (2), dropwise add 1M sodium hydroxide solution or 1M hydrochloric acid solution to adjust the pH to 6.5;

[0108] (4) In the solution obtained in step (3), fill in nitrogen, seal and protect from light, under the condition of 20°C ± 2°C, stir at 500 rpm for 6 hours, make up to the full prescription amount with injection water, stir evenly, and the liquid medicine is sequentially subjected to sterilizing filtration through 0.45 μm and 0.22 μm filters;

[0109] (5) The liquid medicine obtained in step (4) is sequentially subjected to sterile filtration through 0.45 μm and 0.22 μm filter elements. The filtrate is filled into medium-borosilicate glass injection vials at a rate of 50 mg of ranitidine per vial. After semi-capping, it is sent into a freeze-drying device and pre-frozen at -40 °C for 4 h. The parameters for the first drying are set as follows: the vacuum degree is 100 μbar, and within 4 h, the temperature is raised from -40 °C to -10 °C and maintained for 12 h. The parameters for the second drying are set as follows: the vacuum degree is 100 μbar, and within 3 h, the temperature is raised from -10 °C to 0 °C and maintained for 4 h. Then, within 1 h, the temperature is raised from 0 °C to 25 °C and maintained for 6 h. Nitrogen is filled in, the vials are stoppered and crimped to obtain ranitidine for injection.

[0110] Comparative Example 3

[0111] A preparation method of a combined drug of ranitidine for injection. The preparation prescription (1000 vials), and the main raw materials are shown in Table 6.

[0112] Table 6 Main raw materials of Comparative Example 3

[0113] Component Dosage Ranitidine Hydrochloride 55.6g Hydroxypropyl-β-cyclodextrin 4893.8g 1M Sodium Hydroxide Appropriate amount 1M Hydrochloric Acid Appropriate amount Add Water for Injection 10000g

[0114] The specific preparation method of Comparative Example 3 includes the following steps:

[0115] (1) Take 90% of the prescribed amount of injection water and heat it to 50 °C - 60 °C. Take the prescribed amount of hydroxypropyl-β-cyclodextrin and slowly add it to the injection water, stir until completely dissolved, and cool to 20 °C ± 5 °C.

[0116] (2) Take the prescribed amount of solid powder of ranitidine hydrochloride, accurately weigh it, and slowly add it to the solution obtained in step (1) under the constant temperature condition of 20 °C ± 25 °C, and stir until completely dissolved.

[0117] (3) In the solution obtained in step (2), dropwise add 1M sodium hydroxide solution or 1M hydrochloric acid solution to adjust the pH to 6.5.

[0118] (4) In the solution obtained in step (3), fill in nitrogen, seal and protect from light, stir at 600 rpm for 6 h under the condition of 20 °C ± 2 °C, make up to the full prescribed amount with injection water, stir evenly, and the liquid medicine is sequentially subjected to sterile filtration through 0.45 μm and 0.22 μm filter elements.

[0119] (5) The filtrate obtained in step (4) is filled into neutral borosilicate glass vials for injection, with 50 mg of ranitidine per vial. After semi-capping, it is sent into a freeze-drying device and pre-frozen at -40°C for 4 h. The parameters for the first drying are set as follows: the vacuum degree is 100 μbar, and within 4 h, the temperature is raised from -40°C to -10°C and maintained for 12 h. The parameters for the second drying are set as follows: the vacuum degree is 100 μbar, and within 3 h, the temperature is raised from -10°C to 0°C and maintained for 4 h. Then, within 1 h, the temperature is raised from 0°C to 25°C and maintained for 6 h. Nitrogen is filled in, the vials are capped and crimped to obtain ranitidine for injection.

[0120] The following tests are carried out on the above examples and comparative examples

[0121] I. Determination of encapsulation percentage (EP%)

[0122] Appropriately weigh the ranitidine for injection of Examples 1 to 3 and Comparative Examples 1 to 3 respectively, and place them in ampoules. Precisely add 10 mL of dichloromethane respectively, seal with a rubber stopper, shake vigorously with a shaker for 1 min, take 5 mL of the solution, centrifuge at 10000 rpm for 10 min, precisely transfer 2 mL of the supernatant, dry it with nitrogen, and make up the volume to 10 mL with 50% methanol. Determine the amount of unencapsulated ranitidine by high performance liquid chromatography, and calculate the encapsulation percentage according to the following formula. Table 7 shows the results of the encapsulation percentage determination.

[0123]

[0124] Table 7 Results of encapsulation percentage determination of samples of Examples 1 to 3 and Comparative Examples 1 to 3

[0125]

[0126]

[0127] As can be seen from Table 7, the encapsulation percentages of Examples 1 to 3 are all greater than 80%, reaching over 85%, and the higher the ratio of sulfobutyl-β-cyclodextrin, the greater the encapsulation percentage. Although the encapsulation percentages of Comparative Examples 1 to 3 increase with hydroxypropyl-β-cyclodextrin, they are all lower than those of sulfobutyl-β-cyclodextrin and also lower than 80%. In the chemical structural formula of sulfobutyl-β-cyclodextrin used in the present invention, a negatively charged sulfonic acid group is introduced, which produces electrostatic interaction with ranitidine containing nitrogen element, thus significantly improving the encapsulation percentage.

[0128] II. Scanning Electron Microscope (SEM) analysis:

[0129] Appropriately take appropriate amounts of ranitidine hydrochloride raw material, sulfobutyl-β-cyclodextrin, and select the samples of Examples 1 to 3, fix them on the sample stage, and perform vacuum sputtering to improve the conductivity. Observe the surface morphology of the samples through a scanning electron microscope at an accelerating voltage.

[0130] Figure 1 In A, it is the SEM image of ranitidine hydrochloride raw material, showing a columnar crystal structure; Figure 1 In B, it is the SEM image of sulfobutyl-β-cyclodextrin, showing a spherical or fragmented structure; Figure 1 In C-E are the inclusion compounds of Examples 1 to 3 respectively. The structures of both ranitidine hydrochloride and sulfobutyl-β-cyclodextrin disappear, generating a smooth spherical or irregular blocky structure. This indicates that ranitidine hydrochloride and sulfobutyl-β-cyclodextrin interact, demonstrating the formation of an inclusion compound.

[0131] III. Infrared Fourier Transform Infrared Spectroscopy (FT-IR) analysis:

[0132] Use a Fourier transform infrared spectrometer to analyze ranitidine hydrochloride raw material, sulfobutyl-β-cyclodextrin, the physical mixture of ranitidine hydrochloride and sulfobutyl-β-cyclodextrin, and the samples of Examples 1 to 3 (wherein, the physical mixture is the solid of two substances, ranitidine hydrochloride and sulfobutyl-β-cyclodextrin, which are mixed by a vortex shaker. Since there is no inclusion process, ranitidine hydrochloride cannot enter the cavity of sulfobutyl-β-cyclodextrin. Therefore, the physical mixture is compared with the inclusion compound to confirm whether ranitidine hydrochloride in the examples enters the cavity of sulfobutyl-β-cyclodextrin). Appropriately take the above samples and mix them thoroughly with potassium bromide (KBr) powder and grind them into tablets. Set the wavenumber range to 4000 - 400 cm -1 , the number of scans is 32, and the resolution is 2 cm -1 .

[0133] Figure 2 In A is the infrared spectrum of un-included ranitidine hydrochloride, showing multiple characteristic absorption peaks at 3258 cm -1 (N-H stretching vibration), 3196 cm -1 and 3104 cm -1 (C-H stretching vibration on the alkene and furan rings), 2975 cm -1 - 2908 cm -1 (C-H stretching vibration of methyl and methylene) and 2563 cm -1 - 2468 cm -1 (N + -H stretching vibration). Figure 2 In B is the infrared spectrum of sulfobutyl-β-cyclodextrin, at 3437 cm-1 (O-H stretching vibration) and 2939 cm -1 ~2870 cm -1 (C-H stretching vibrations of the cyclodextrin backbone and sulfobutyl side chains) show characteristic absorption peaks. Figure 2 In C is the infrared spectrum of the physical mixture of ranitidine hydrochloride and sulfobutyl-β-cyclodextrin. The results show that characteristic absorption peaks related to both substances appear simultaneously, indicating that ranitidine hydrochloride and sulfobutyl-β-cyclodextrin only undergo simple mixing and their chemical properties remain unchanged. Figure 2 In D are the infrared spectra of Examples 1-3 of the inclusion complex of ranitidine hydrochloride and sulfobutyl-β-cyclodextrin. The results show that the characteristic absorption peaks related to ranitidine hydrochloride disappear, indicating that ranitidine hydrochloride and sulfobutyl-β-cyclodextrin react to form an inclusion complex.

[0134] IV. Differential Scanning Calorimetry (DSC) analysis:

[0135] Weigh the ranitidine hydrochloride raw material, sulfobutyl-β-cyclodextrin, the physical mixture of ranitidine hydrochloride and sulfobutyl-β-cyclodextrin, and the samples of Examples 1-3 respectively, place them in an aluminum crucible, use a sealed empty crucible as the blank, and perform analysis using a differential scanning calorimeter. The measurement parameter settings are as follows: nitrogen gas volume flow rate 10 mL / min, heating rate 10 °C / min, and temperature range 30-400 °C.

[0136] Figure 3 In ranitidine hydrochloride has endothermic peaks at 151.1 °C and 270.3 °C, which are its melting peak and decomposition peak respectively; sulfobutyl-β-cyclodextrin shows a melting peak and a decomposition peak at 268.8 °C and 360.2 °C respectively; the physical mixture of ranitidine hydrochloride and sulfobutyl-β-cyclodextrin is basically similar to the superposition peak of the two peaks; the peaks of ranitidine hydrochloride in the samples of Examples 1-3 completely disappear, and the generated peaks are similar to those of sulfobutyl-β-cyclodextrin. This indicates that ranitidine hydrochloride and sulfobutyl-β-cyclodextrin react to form an inclusion complex.

[0137] V. X-ray Diffraction (XRD) analysis:

[0138] Weigh the ranitidine hydrochloride raw material, sulfobutyl-β-cyclodextrin, the physical mixture of ranitidine hydrochloride and sulfobutyl-β-cyclodextrin, and the samples of Examples 1-3 respectively, and detect them using an X-ray diffractometer. Set the fixed wavelength of Cu Kα radiation to The voltage and current are 40 kV and 40 mA respectively, the scanning angle is 5°-30°, and the scanning speed is 0.1 ° / s.

[0139] Figure 4 Ranitidine Hydrochloride showed multiple diffraction peaks, among which the strongest were at 8.4°, 20.3° and 23.5°; Sulfobutyl-β-cyclodextrin did not show obvious diffraction peaks and was an amorphous powder. The diffraction peaks of the physical mixture corresponded to those of Ranitidine Hydrochloride, while the diffraction peaks of the main drug Ranitidine Hydrochloride in the samples of Examples 1-3 completely disappeared and were similar to those of Sulfobutyl-β-cyclodextrin. It indicated that Ranitidine Hydrochloride and Sulfobutyl-β-cyclodextrin interacted to form an inclusion compound.

[0140] VI. Stability Investigation:

[0141] Samples of Example 2 and Comparative Example 2 were selected, together with commercially available Ranitidine Hydrochloride Injection as test samples. Referring to the guiding principle 9001 "Guiding Principles for the Stability Testing of Drug Substances and Preparations" in the fourth part of the Chinese Pharmacopoeia (2020 Edition), the stress testing was carried out to investigate the stability under light, high temperature, anaerobic and aerobic conditions. Experimental conditions: Under the light intensity of 4500lx±500lx (temperature 25±2°C), high temperatures of 40°C±2°C and 60°C±5°C, and the above conditions were divided into those containing air (aerobic) and nitrogen (anaerobic) conditions, and placed for 30 days (d). Samples were taken on the 5th day, 10th day and 30th day during the test period, and ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS / MS), cation and anion chromatography were used to determine the contents of NDMA and its precursor compounds dimethylamine (DMA) and nitrite ion (NO2 - ) respectively.

[0142] Tables 8-10 were respectively the detection results of the contents of NDMA, DMA and NO2 - in the stability samples. The results showed that under light, high temperature, aerobic and anaerobic conditions, the amounts of the above three substances produced by the commercially available Ranitidine Hydrochloride Injection were significantly higher than those of Example 2 and Comparative Example 2; in addition, when comparing Example 2 and Comparative Example 2, the contents of the three substances in the sample of Example 2 were lower. Combining with the determination results of the encapsulation efficiency, because Sulfobutyl-β-cyclodextrin was used as the inclusion excipient and the encapsulation efficiency was higher, the stability of Ranitidine was significantly improved. By cyclodextrin inclusion, especially Sulfobutyl-β-cyclodextrin, and using technologies such as freeze-drying and nitrogen protection, the generation of genotoxic impurities NDMA and its precursor compounds DMA and NO2 - can be effectively controlled.

[0143] Table 8 Detection Results of NDMA in the Stability Samples of Example 2, Comparative Example 2 and Commercially Available Ranitidine Hydrochloride Injection

[0144]

[0145]

[0146] Note: 1 N / D indicates that the target substance was not detected; 2 LOQ indicates below the lower limit of quantification. The same applies hereinafter.

[0147] Table 9 DMA detection results in the stability samples of Example 2, Comparative Example 2, and commercially available ranitidine hydrochloride injection

[0148]

[0149]

[0150] Table 10 NO2 in the stability samples of Example 2, Comparative Example 2, and commercially available ranitidine hydrochloride injection - Detection results

[0151]

[0152]

[0153] In addition, the following experiments were also conducted in the present invention:

[0154] Carried out according to Example 2, except that in step 3), the pH was adjusted to 5.0 and 8.0 respectively and carried out under the above two pH conditions. The product performance stability still meets the requirements of the present invention.

[0155] This project was supported by the "Key R & D and Achievement Transformation Project" of Wuhu City, and the project number is 2023yf001.

[0156] The descriptions of the above embodiments are for the convenience of those of ordinary skill in the art to understand and use the invention. Those skilled in the art can obviously make various modifications to these embodiments easily and apply the general principles described herein to other embodiments without creative labor. Therefore, the present invention is not limited to the above embodiments, and the improvements and modifications made by those skilled in the art without departing from the scope of the present invention according to the disclosure of the present invention should be within the protection scope of the present invention.

Claims

1. A combined drug of ranitidine for injection, characterized in that, The combined ranitidine for injection comprises ranitidine or its salt compound, cyclodextrin and a pH regulator; the cyclodextrin is selected from one or more of sulfobutyl-β-cyclodextrin, sulfobutyl-γ-cyclodextrin or carboxymethyl-β-cyclodextrin.

2. The combined drug of ranitidine for injection according to claim 1, characterized in that, The ranitidine or its salt compound is selected from free ranitidine, ranitidine hydrochloride and ranitidine bismuth citrate.

3. The combined drug of ranitidine for injection according to claim 1 or 2, characterized in that, The mass ratio of the cyclodextrin and ranitidine or its salt compound calculated based on ranitidine is: 5-200:

1.

4. The combined drug of ranitidine for injection according to claim 1 or 3, characterized in that, When the cyclodextrin is selected from sulfobutyl-γ-cyclodextrin, the mass ratio of sulfobutyl-γ-cyclodextrin and ranitidine or its salt compound calculated based on ranitidine is: 10-100:

1.

5. The combined drug of ranitidine for injection according to claim 1 or 3, characterized in that, The encapsulation efficiency of the combined ranitidine for injection is more than 85%.

6. A preparation method of the ranitidine combined drug for injection according to any one of claims 1-5, characterized in that, The preparation method comprises the following steps: 1) Place the formula amount of cyclodextrin into water for injection and stir to dissolve; 2) Place ranitidine or its salt compound into the solution obtained in step 1) and stir until completely dissolved to obtain a mixed solution; 3) Add a pH regulator to adjust the pH of the mixed solution to 5.0-8.0; 4) Under the protection of nitrogen, the solution obtained in step 3) is stirred and included under light-shielded conditions to obtain an inclusion compound; 5) After the inclusion compound obtained in step 4) is sterilized and filtered, it is subpackaged, freeze-dried, filled with nitrogen, stoppered and crimped to obtain the combined ranitidine for injection.

7. The preparation method according to claim 6, characterized in that, In step 1), the conditions for stirring and dissolving are: under the constant temperature condition of 20°C - 80°C, stir until completely dissolved; after stirring and dissolving, lower the temperature to 10°C - 30°C.

8. The preparation method according to claim 6 or 7, characterized in that, Step 2) can also be: Place ranitidine or its salt compound into water for injection, stir to dissolve, and then stir and mix with the solution in step 1) under the constant temperature condition of 10°C - 30°C to obtain a mixed solution.

9. The preparation method according to claim 6 or 7, characterized in that, In step 4), stirring and inclusion under light-shielded conditions means stirring and including at 200 - 800 rpm for 0.5 h - 24 h under the protection of nitrogen, under the constant temperature and light-shielded conditions of 10°C - 30°C.

10. The preparation method according to claim 6 or 7, characterized in that, In step 5), the freeze-drying means pre-freezing at -40°C - -20°C for 3 - 6 h, and the parameters for the first drying are set as: the vacuum degree is 100 μbar - 200 μbar, within 2 h - 6 h, the temperature rises from -40°C to -10°C and is maintained for 6 h - 12 h; the parameters for the second drying are set as: the vacuum degree is 100 μbar - 200 μbar, within 2 h - 4 h, the temperature rises from -10°C to 0°C, is maintained for 4 h - 8 h, and then within 1 h, the temperature rises from 0°C to 20°C - 30°C and is maintained for 4 h - 6 h until completely dry.

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