Injection containing active component prucalopride succinate and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations for treating digestive system diseases, and relates to an injection containing an active component prucalopride succinate and a preparation method of the injection. The prucalopride succinate injection provided by the invention comprises prucalopride succinate, an osmotic pressure regulator, a pH regulator and water for injection. According to the prucalopride succinate injection, by optimizing the prescription, the relationship between the pain reaction of prucalopride succinate and the stability of prucalopride succinate is balanced, and the prucalopride succinate injection which is high in stability, high in bioavailability and small in injection irritation is provided.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations for treating digestive system diseases, and particularly relates to an injection containing prucalopride succinate as an active ingredient and a preparation method thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Chronic constipation is a common gastrointestinal motility disease in clinical practice, which can affect the work and quality of life of modern people to varying degrees. With the changes in people's dietary structure and the influence of mental, psychological and social factors, the incidence of chronic constipation has an increasing trend, with a prevalence rate of up to 27% in the population. Constipation can affect people of all ages, more women than men, and more elderly than young and middle-aged people. Due to the high incidence of constipation and complex causes, patients often have many distresses. At the same time, it may also induce other serious diseases, such as hemorrhoids and anal fissures, damage liver function, induce myocardial infarction and cerebrovascular accident, induce pneumothorax, form abdominal hernia, etc. The risks caused cannot be ignored.

[0004] Prucalopride succinate tablets are the world's first highly selective, high-affinity 5-HT4 receptor agonist. It has no stimulatory effect on the other seven receptors such as 5-HT1, 2, etc., and reduces the incidence of adverse cardiovascular events such as ischemic heart disease and severe arrhythmias. It specifically and selectively stimulates the intestinal 5-HT4 receptors, induces high-amplitude propulsive contractions (HAPC) of the intestine, and significantly promotes the peristalsis of the intestine, especially the colon. It has a significant effect on improving intestinal motility and rebuilding intestinal function. It is used to treat chronic constipation symptoms that are difficult to fully relieve with laxatives. A large amount of evidence-based medical data has proved that prucalopride has good tolerability and safety.

[0005] The only marketed dosage form of prucalopride succinate is tablets. Prucalopride succinate tablets (trade name: Reslor) were launched in Germany in January 2010, in the UK in March 2010, and approved for marketing in China in December 2012. Existing public formulation technology shows that the production process is simple, conducive to large-scale production, and has high economy and stability. However, the content of the main drug in the tablets is less than 1% of the prescribed amount, and the uniformity of powder mixing has certain industrial challenges, which leads to problems with the uniformity of the tablet content.

[0006] In the existing public technology, a Chinese patent with publication number CN103070865A discloses a solid preparation with prucalopride succinate as an active ingredient and its application. The auxiliary material contains 5% starch slurry and uses a wet granulation process. The auxiliary material lactose and the amino group in prucalopride succinate can produce Maillard reaction at room temperature to produce toxic substances, and the drug has great toxic side effects.

[0007] Chinese patent publication number CN107582535A and Chinese patent publication number CN104069080A disclose prucalopride succinate tablets and a preparation method thereof and a prucalopride succinate tablet composition, respectively. Although the uniformity and toxicity problems are solved by special treatment methods, the bioavailability of the tablets is low and the application effect is poor.

[0008] On the one hand, for people with postoperative gastrointestinal dysfunction, it is not convenient to take the medicine orally, so injection can be used; on the other hand, for intestinal examination or intestinal preparation before surgery, oral solid preparations of prucalopride succinate have a slow onset of action and low bioavailability. Therefore, there is an urgent need to provide a prucalopride succinate injection that can achieve rapid onset of action and improve the flexibility of clinical application. Summary of the invention

[0009] In order to improve the clinical application effect of prucalopride succinate, this study is committed to improving it from the traditional tablet dosage form to an injection dosage form. Existing tablets need to be digested and absorbed through the gastrointestinal tract to work, and usually take a long time to take effect. The injection dosage form can directly enter the blood circulation and avoid the digestion process of the gastrointestinal tract, thereby achieving faster absorption and more rapid drug effect.

[0010] In order to ensure that prucalopride succinate injection meets the standards in terms of safety, efficacy, quality control and patient acceptance, the present invention has conducted a series of studies. Through the analysis of the physicochemical properties, pharmacokinetics and other aspects of the drug, especially considering the need for rapid onset of the drug, intravenous injection becomes the most ideal way of administration, because the drug can directly enter the blood and quickly reach a therapeutic concentration.

[0011] On this basis, this study conducted animal experiments. The experimental results showed that the injection caused symptoms such as pain and swelling in rats, and the reaction was more severe when the pH value was lower than 7.0. However, through further optimization of drug preparations, formula design and stability studies, we found that prucalopride succinate has good stability in the pH range of 4.0-5.5. When the pH value of the drug solution is higher than 5.5, the generation of impurities increases significantly, which may affect the efficacy of the drug. Excessive impurities may not only reduce the active ingredients of the drug and reduce the therapeutic effect, but also interfere with the absorption and distribution of the drug and reduce its bioavailability. In addition, the increase in impurities may lead to enhanced side effects and toxicity, further aggravating the risk of clinical application.

[0012] During the development of prucalopride succinate injection, we were faced with the challenge of balancing the pain response of the drug with the stability of the drug. Generally, the irritation response of a drug is closely related to the use of solvents and excipients, but prucalopride succinate itself has a certain irritation, which makes it difficult to eliminate its irritation by changing solvents or excipients. Therefore, this study systematically screened the ingredients of the injection and tried to replace certain ingredients to reduce the irritation of prucalopride succinate to tissues and the response of the immune system.

[0013] At the same time, in order to ensure the stability of the drug under long-term storage and high temperature conditions, we continuously optimized the prescription design, striving to minimize the occurrence of irritation reactions and maintain the effectiveness of the drug. Ultimately, the study successfully overcame the contradiction between side effects and drug stability, providing strong support for the clinical application of prucalopride succinate injection.

[0014] Specifically, the prucalopride succinate injection comprises 0.1 to 5 parts by weight of prucalopride succinate, 2 to 70 parts by weight of an osmotic pressure regulator, a pH regulator, and 0.1 to 10 parts by weight of water for injection.

[0015] The osmotic pressure regulator is selected from one or more of sodium chloride, sodium phosphate, sodium citrate, potassium citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate; the pH regulator is selected from one or more of citric acid, sodium citrate, succinic acid, sodium succinate, hydrochloric acid, sodium hydroxide, phosphoric acid, and phosphates; the pH regulator adjusts the pH to 4.0-6.5.

[0016] Furthermore, the present invention also provides a method for preparing the above-mentioned prucalopride succinate injection: (1) Add the osmotic pressure regulator to water and stir until dissolved; (2) Add prucalopride succinate to (1) and stir until dissolved; (3) Adding a pH adjuster into (2) to adjust the pH; (4) Add injection water to (3) to make up the volume, fill with nitrogen, filter, fill and sterilize.

[0017] Through this series of research and development, the present invention realizes the innovation and optimization of the dosage form of prucalopride succinate injection and lays a solid foundation for its clinical promotion and application.

[0018] Compared with the prior art, the technical effects of the present invention are: (1) By changing the dosage form of prucalopride succinate from a tablet to an injection, prucalopride succinate can directly enter the blood circulation, avoiding the digestion and absorption process in the gastrointestinal tract, thereby greatly accelerating the drug's onset of action and improving the timeliness and effectiveness of clinical treatment; (2) The present invention overcomes the contradiction between the pain reaction and stability of prucalopride succinate injection. The present invention first discovered that prucalopride succinate injection caused pain, swelling and other symptoms in animal experiments, especially when the pH was lower than 7.0, the reaction was more severe. The present invention reduces the irritation of the drug to tissues and the response of the immune system by systematically screening the components of the injection and trying to replace certain components. At the same time, the prescription design is continuously optimized, and the side effects are minimized to the greatest extent while ensuring the stability of the drug, thereby improving the safety and patient acceptance of prucalopride succinate, and obtaining a prucalopride succinate injection with high stability, high bioavailability and low injection irritation. In addition, the pH range of prucalopride succinate injection is broadened. Within the range of pH = 4.0 ~ 6.5, the stability of prucalopride succinate injection can be ensured to maintain the efficacy, and the irritation of prucalopride succinate can be reduced. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 : Stability of prucalopride succinate under different pH conditions at 1 day and 6 months in an accelerated study.

[0020] Figure 2 : Example 1 to Example 6 The sensitivity of the stability of prucalopride succinate injection under different pH conditions. DETAILED DESCRIPTION

[0021] In order to make the purpose and technical solution of the present invention clearer, the present invention is further described below in conjunction with embodiments, but the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. It should be understood by those skilled in the art that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0022] Pharmacodynamics experiments 1. Experimental animals: SD rats, SPF grade, 180-220 g, experimental animal license number: SYXK (Lu) 20180008, provided by Lunan Pharmaceutical Group Co., Ltd., adaptively fed under standard conditions for 1 week before the experiment; 2. Modeling: Several rats were prepared with 1.5 mg / kg loperamide in 1 ml of diluent. The diluent was administered to the rats by gavage twice a day, 9 hours apart, for 5 consecutive days. The rats with successful modeling were divided into 8 groups, 10 rats in each group; 3. Grouping Model group: 10 rats with successful modeling were injected with normal saline through the tail vein; Blank group: 10 normal rats, injected with normal saline through the tail vein; Sample group A: 10 rats with successful modeling were injected with 0.01 mg of prucalopride succinate prepared with normal saline, pH = 7.4, through the tail vein; Sample group B: 10 rats with successful modeling were injected with 0.20 mg of prucalopride succinate prepared with normal saline, pH = 7.4, through the tail vein; Sample group C: 10 rats with successful modeling were injected with 0.01 mg of prucalopride succinate prepared with normal saline, pH = 6.5, through the tail vein; Sample group D: 10 rats with successful modeling were injected with 0.20 mg of prucalopride succinate prepared with normal saline, pH = 6.5, through the tail vein; Sample group E: 10 rats with successful modeling were injected with 0.01 mg of prucalopride succinate prepared with normal saline, pH = 4.0, through the tail vein; Sample group F: 10 rats with successful modeling were injected with 0.20 mg of prucalopride succinate prepared with normal saline, pH=4.0, through the tail vein.

[0023] Rats pain behavioral response scoring: The abnormal behaviors of rats in each group within 10 minutes after drug injection were recorded, including but not limited to tail swishing, licking the tail, curling up, leaning to the injured side, arching the back, drooping head and neck, hind limb tension, unnatural extension of hind limbs, shaking, tremor, unsteady walking, increased or irregular breathing rate, groaning, rolling, etc. 1 point was given for each occurrence of the above behaviors.

[0024] Table 1 Pain behavioral response scores of rats ( , n=10) ; Note: Compared with the blank group, *P<0.01; compared with the model group, *P<0.01.

[0025] As shown in Table 1, the scores of the model group and the blank group were similar and the values ​​were low, indicating that the simple modeling process (oral administration of loperamide) had little effect on the pain behavior response of rats. The modeling itself did not significantly increase the pain response of rats, and the injection method itself would not cause pain response in rats. The pain behavior performance of the two groups of rats was not significantly different under normal conditions, so the effects of the modeling itself and the administration method itself on the pain response of rats can be ruled out. However, the behavioral scores of sample groups A to F were significantly higher than those of the model group and the blank group, indicating that the injection of prucalopride succinate caused severe pain stimulation to rats. Comparing the sample groups with different doses at the same pH value, it can be seen that under the same pH value, with the increase of the dose of prucalopride succinate, the pain behavior response score of rats increased, indicating that the degree of pain response increased, indicating that the pain response may be positively correlated with the drug dose, which further verifies that prucalopride succinate has a more serious irritation. Comparing the sample groups with different pH values ​​at the same dose, as the pH value of the solution decreased, the pain behavior response score of the rats gradually increased, indicating that the degree of pain response intensified, indicating that the pain response may be related to the pH value of the solution. The lower pH value will enhance the pain stimulation of prucalopride succinate injection on rats. When the pH of the injection is close to the pH of the blood itself, the pain sensation is lower, but it is still higher than the pain score of the blank group and the model group rats, with a significant difference. Based on the above, it can be seen that prucalopride succinate itself has a more serious irritation and shows a more serious pH dependence.

[0026] The number of rat feces: The rats in each group were placed in metabolic cages without food or water. The number of feces particles discharged by the rats in each group within 12 hours was observed and recorded.

[0027] Table 2 Number of feces pellets discharged by rats in each group within 12 hours ( , n=10) ; Note: Compared with sample group A, *P<0.01; compared with sample group B, # P<0.01.

[0028] As shown in Table 2, the dose of prucalopride succinate is proportional to the therapeutic effect, but the effect of prucalopride succinate at different pH values ​​is different. When the pH is neutral, the same dose of prucalopride succinate is less effective in treating constipation, and the difference is significant. It is speculated that this may be due to the different stability of prucalopride succinate at different pH values. Prucalopride succinate may be more stable in an acidic environment, but will degrade in a neutral environment and cannot maintain biological activity.

[0029] The pharmacodynamic data of the present invention were statistically analyzed using SPSS 22.0 software, and the quantitative data were analyzed using ( ) indicated that the comparison among multiple groups was performed by one-way analysis of variance, and the comparison between two groups was performed by independent sample T test. P<0.05 was considered statistically significant.

[0030] Stability experiment of prucalopride succinate: prucalopride succinate was dissolved in buffer solutions with pH values ​​of 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, and 8.5 to prepare solutions of equal concentrations. The solutions were placed in a constant temperature and humidity chamber at 40℃±2℃\75±5%RH for 6 months. The content of prucalopride succinate was determined by HPLC to evaluate the dependence of prucalopride succinate on pH.

[0031] HPLC chromatographic conditions: chromatographic column with octadecylsilane bonded silica as filler; flow rate: 1.0 ml / ml; detection wavelength: 228 nm; column temperature: 25 °C; injection volume: 20 μl; mobile phase: phosphate buffer (take 2.72 g of potassium dihydrogen phosphate, add 900 ml of water to dissolve, adjust the pH value to 6.0 with phosphoric acid, and dilute to 1000 ml with water) as mobile phase A, methanol as mobile phase B, linear gradient elution see Table 3.

[0032] Table 3 Linear gradient elution: ; Sample diluent: phosphate buffer (take 2.72 g of potassium dihydrogen phosphate, add 900 ml of water to dissolve, adjust the pH value to 6.0 with sodium hydroxide, and dilute to 1000 ml with water)-methanol (65:35).

[0033] Figure 1 The stability results of prucalopride succinate under different pH conditions at day 1 and 6 months in the accelerated experiment. The experiment showed that prucalopride succinate showed the best stability between pH = 4.0 and 5.5, and the content of the drug remained almost unchanged after 6 months, still maintaining above 99%. In contrast, when the pH value was close to neutral or alkaline, the stability of prucalopride succinate decreased significantly, especially at pH 6.0 and higher, the degree of drug degradation was more obvious. This change indicates that higher pH values ​​may accelerate the degradation of the drug, thereby affecting its efficacy. The results of the stability experiment of prucalopride succinate are consistent with the results of the pharmacodynamic experiment, further verifying that the stability of prucalopride succinate does depend on the change of pH value, and its stability is most superior within a specific pH range.

[0034] Based on the above, during the development of prucalopride succinate injection, the stability of prucalopride succinate and the pain response during injection became difficult problems to adjust. The research team tried to balance the above problems by adding solvents, optimizing buffer solutions, adding stabilizers, adjusting osmotic pressure, screening osmotic pressure regulators, and using sustained-release technology.

[0035] Example 1 Prucalopride succinate injection Table 4 Example 1 Formula:

[0036] Preparation method: Add the prescribed amount of osmotic pressure regulator to room temperature water for injection and stir until dissolved. Add the prescribed amount of prucalopride succinate and stir until dissolved. Add the prescribed amount of pH regulator to adjust the pH value. Finally, dilute it to the prescribed amount with water for injection, fill it with nitrogen to protect the liquid, filter it through a 0.22μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to a sterilizer and sterilize it at 121℃ for 30 minutes.

[0037] Example 2 Prucalopride succinate injection Table 5 Example 2 Formula:

[0038] Preparation method: Add the prescribed amount of osmotic pressure regulator to room temperature water for injection and stir until dissolved. Add the prescribed amount of prucalopride succinate and stir until dissolved. Add the prescribed amount of pH regulator to adjust the pH value. Finally, dilute it to the prescribed amount with water for injection, fill it with nitrogen to protect the liquid, filter it through a 0.22μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to a sterilizer and sterilize it at 121℃ for 20 minutes.

[0039] Example 3 Prucalopride succinate injection Table 6 Example 3 Formula:

[0040] Preparation method: Add the prescribed amount of osmotic pressure regulator to room temperature water for injection and stir until dissolved. Add the prescribed amount of prucalopride succinate and stir until dissolved. Add the prescribed amount of pH regulator to adjust the pH value. Finally, dilute it to the prescribed amount with water for injection, fill it with nitrogen to protect the liquid, filter it through a 0.22μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to a sterilizer and sterilize it at 121℃ for 15 minutes.

[0041] Example 4 Prucalopride succinate injection Table 7 Example 4 Formula:

[0042] Preparation method: Add the prescribed amount of osmotic pressure regulator to room temperature water for injection and stir until dissolved. Add the prescribed amount of prucalopride succinate and stir until dissolved. Add the prescribed amount of pH regulator to adjust the pH value. Finally, dilute it to the prescribed amount with water for injection, fill it with nitrogen to protect the liquid, filter it through a 0.22μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to a sterilizer and sterilize it at 121℃ for 30 minutes.

[0043] Example 5 Prucalopride succinate injection Table 8 Example 5 Formula:

[0044] Preparation method: Add the prescribed amount of osmotic pressure regulator to room temperature water for injection and stir until dissolved. Add the prescribed amount of prucalopride succinate and stir until dissolved. Add the prescribed amount of pH regulator to adjust the pH value. Finally, dilute it to the prescribed amount with water for injection, fill it with nitrogen to protect the liquid, filter it through a 0.22μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to a sterilizer and sterilize it at 121℃ for 30 minutes.

[0045] Example 6 Prucalopride succinate injection Table 9 Example 6 Formula:

[0046] Preparation method: Add the prescribed amount of osmotic pressure regulator to room temperature water for injection and stir until dissolved. Add the prescribed amount of prucalopride succinate and stir until dissolved. Add the prescribed amount of pH regulator to adjust the pH value. Finally, dilute it to the prescribed amount with water for injection, fill it with nitrogen to protect the liquid, filter it through a 0.22μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to a sterilizer and sterilize it at 121℃ for 30 minutes.

[0047] Example 7 Prucalopride succinate injection Table 10 Example 7 Formula:

[0048] Preparation method: Add the prescribed amount of osmotic pressure regulator to room temperature water for injection and stir until dissolved. Add the prescribed amount of prucalopride succinate and stir until dissolved. Add the prescribed amount of pH regulator to adjust the pH value. Finally, dilute it to the prescribed amount with water for injection, fill it with nitrogen to protect the liquid, filter it through a 0.22μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to a sterilizer and sterilize it at 121℃ for 30 minutes.

[0049] Example 8 Prucalopride succinate injection Table 11 Example 8 Formula:

[0050] Preparation method: Add the prescribed amount of osmotic pressure regulator to room temperature water for injection and stir until dissolved. Add the prescribed amount of prucalopride succinate and stir until dissolved. Add the prescribed amount of pH regulator to adjust the pH value. Finally, dilute it to the prescribed amount with water for injection, fill it with nitrogen to protect the liquid, filter it through a 0.22μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to a sterilizer and sterilize it at 121℃ for 30 minutes.

[0051] Example 9 Prucalopride succinate injection Table 12 Example 9 Formula:

[0052] Preparation method: Add the prescribed amount of osmotic pressure regulator to room temperature water for injection and stir until dissolved. Add the prescribed amount of prucalopride succinate and stir until dissolved. Add the prescribed amount of pH regulator to adjust the pH value. Finally, dilute it to the prescribed amount with water for injection, fill it with nitrogen to protect the liquid, filter it through a 0.22μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to a sterilizer and sterilize it at 121℃ for 20 minutes.

[0053] Example 10 Prucalopride succinate injection Table 13 Example 10 Formulation:

[0054] Preparation method: Add the prescribed amount of osmotic pressure regulator to room temperature water for injection and stir until dissolved. Add the prescribed amount of prucalopride succinate and stir until dissolved. Add the prescribed amount of pH regulator to adjust the pH value. Finally, dilute it to the prescribed amount with water for injection, fill it with nitrogen to protect the liquid, filter it through a 0.22μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to a sterilizer and sterilize it at 121℃ for 15 minutes.

[0055] Example 11 Prucalopride succinate injection Table 14 Example 11 Formula:

[0056] Preparation method: Add the prescribed amount of osmotic pressure regulator to room temperature water for injection and stir until dissolved. Add the prescribed amount of prucalopride succinate and stir until dissolved. Add the prescribed amount of pH regulator to adjust the pH value. Finally, dilute it to the prescribed amount with water for injection, fill it with nitrogen to protect the liquid, filter it through a 0.22μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to a sterilizer and sterilize it at 121℃ for 30 minutes.

[0057] Example 12 Prucalopride succinate injection Table 15 Example 12 Formula:

[0058] Preparation method: Add the prescribed amount of osmotic pressure regulator to room temperature water for injection and stir until dissolved. Add the prescribed amount of prucalopride succinate and stir until dissolved. Add the prescribed amount of pH regulator to adjust the pH value. Finally, dilute it to the prescribed amount with water for injection, fill it with nitrogen to protect the liquid, filter it through a 0.22μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to a sterilizer and sterilize it at 121℃ for 30 minutes.

[0059] Example 13 Prucalopride succinate injection Table 16 Example 13 Formula:

[0060] Preparation method: Add the prescribed amount of osmotic pressure regulator to room temperature water for injection and stir until dissolved. Add the prescribed amount of prucalopride succinate and stir until dissolved. Add the prescribed amount of pH regulator to adjust the pH value. Finally, dilute it to the prescribed amount with water for injection, fill it with nitrogen to protect the liquid, filter it through a 0.22μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to a sterilizer and sterilize it at 121℃ for 30 minutes.

[0061] Example 14 Prucalopride succinate injection Table 17 Example 14 Formula:

[0062] Preparation method: Add the prescribed amount of osmotic pressure regulator to room temperature water for injection and stir until dissolved. Add the prescribed amount of prucalopride succinate and stir until dissolved. Add the prescribed amount of pH regulator to adjust the pH value. Finally, dilute it to the prescribed amount with water for injection, fill it with nitrogen to protect the liquid, filter it through a 0.22μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to a sterilizer and sterilize it at 121℃ for 30 minutes.

[0063] Example 15 Prucalopride succinate injection Table 18 Example 15 Formulation:

[0064] Preparation method: Add the prescribed amount of osmotic pressure regulator to room temperature water for injection and stir until dissolved. Add the prescribed amount of prucalopride succinate and stir until dissolved. Add the prescribed amount of pH regulator to adjust the pH value. Finally, dilute it to the prescribed amount with water for injection, fill it with nitrogen to protect the liquid, filter it through a 0.22μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to a sterilizer and sterilize it at 121℃ for 30 minutes.

[0065] Example 16 Prucalopride succinate injection Table 19 Example 16 Formula:

[0066] Preparation method: Add the prescribed amount of osmotic pressure regulator to room temperature water for injection and stir until dissolved. Add the prescribed amount of prucalopride succinate and stir until dissolved. Add the prescribed amount of pH regulator to adjust the pH value. Finally, dilute it to the prescribed amount with water for injection, fill it with nitrogen to protect the liquid, filter it through a 0.22μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to a sterilizer and sterilize it at 121℃ for 30 minutes.

[0067] Example 17 Prucalopride succinate injection Table 20 Example 17 Formula:

[0068] Preparation method: Add the prescribed amount of osmotic pressure regulator to room temperature water for injection and stir until dissolved. Add the prescribed amount of prucalopride succinate and stir until dissolved. Add the prescribed amount of pH regulator to adjust the pH value. Finally, dilute it to the prescribed amount with water for injection, fill it with nitrogen to protect the liquid, filter it through a 0.22μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to a sterilizer and sterilize it at 121℃ for 30 minutes.

[0069] Example 18 Prucalopride succinate injection Table 21 Example 18 Formula:

[0070] Preparation method: Add the prescribed amount of osmotic pressure regulator to room temperature water for injection and stir until dissolved. Add the prescribed amount of prucalopride succinate and stir until dissolved. Add the prescribed amount of pH regulator to adjust the pH value. Finally, dilute it to the prescribed amount with water for injection, fill it with nitrogen to protect the liquid, filter it through a 0.22μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to a sterilizer and sterilize it at 121℃ for 30 minutes.

[0071] Example 19 Prucalopride succinate injection Table 22 Example 19 Formula:

[0072] Preparation method: Add the prescribed amount of osmotic pressure regulator to room temperature water for injection and stir until dissolved. Add the prescribed amount of prucalopride succinate and stir until dissolved. Add the prescribed amount of pH regulator to adjust the pH value. Finally, dilute it to the prescribed amount with water for injection, fill it with nitrogen to protect the liquid, filter it through a 0.22μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to a sterilizer and sterilize it at 121℃ for 30 minutes.

[0073] Example 20 Prucalopride succinate injection Table 23 Example 20 Formulation:

[0074] Preparation method: Add the prescribed amount of osmotic pressure regulator to room temperature water for injection and stir until dissolved. Add the prescribed amount of prucalopride succinate and stabilizer and stir until dissolved. Add the prescribed amount of pH regulator to adjust the pH value. Finally, dilute it to the prescribed amount with water for injection, fill it with nitrogen to protect the liquid, filter it through a 0.22μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to a sterilizer and sterilize it at 121℃ for 30 minutes.

[0075] Example 21 Prucalopride succinate injection Table 24 Example 21 Formula:

[0076] Preparation method: Add the prescribed amount of osmotic pressure regulator to room temperature water for injection and stir until dissolved. Add the prescribed amount of prucalopride succinate and stabilizer and stir until dissolved. Add the prescribed amount of pH regulator to adjust the pH value. Finally, dilute it to the prescribed amount with water for injection, fill it with nitrogen to protect the liquid, filter it through a 0.22μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to a sterilizer and sterilize it at 121℃ for 30 minutes.

[0077] Example 22 Prucalopride succinate injection Table 25 Example 22 Formula:

[0078] Preparation method: Add the prescribed amount of osmotic pressure regulator to room temperature water for injection and stir until dissolved. Add the prescribed amount of prucalopride succinate and stabilizer and stir until dissolved. Add the prescribed amount of pH regulator to adjust the pH value. Finally, dilute it to the prescribed amount with water for injection, fill it with nitrogen to protect the liquid, filter it through a 0.22μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to a sterilizer and sterilize it at 121℃ for 30 minutes.

[0079] Example 23 Prucalopride succinate injection Table 26 Example 23 Formula:

[0080] Preparation method: Add the prescribed amount of osmotic pressure regulator to room temperature water for injection and stir until dissolved. Add the prescribed amount of prucalopride succinate and solvent, stir until dissolved, add the prescribed amount of pH regulator, and adjust the pH value. Finally, dilute it to the prescribed amount with water for injection, fill it with nitrogen to protect the liquid, filter it through a 0.22μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to a sterilizer and sterilize it at 121℃ for 30 minutes.

[0081] Example 24 Prucalopride succinate injection Table 27 Example 24 Formula:

[0082] Preparation method: Add the prescribed amount of osmotic pressure regulator to room temperature water for injection and stir until dissolved. Add the prescribed amount of prucalopride succinate and solvent, stir until dissolved, add the prescribed amount of pH regulator, and adjust the pH value. Finally, dilute it to the prescribed amount with water for injection, fill it with nitrogen to protect the liquid, filter it through a 0.22μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to a sterilizer and sterilize it at 121℃ for 30 minutes.

[0083] Example 25 Prucalopride succinate injection Table 28 Example 25 Formulation:

[0084] Preparation method: Add the prescribed amount of osmotic pressure regulator to room temperature water for injection and stir until dissolved. Add the prescribed amount of prucalopride succinate and sustained-release material and stir until dissolved. Add the prescribed amount of pH regulator to adjust the pH value. Finally, dilute it to the prescribed amount with water for injection, fill it with nitrogen to protect the liquid, filter it through a 0.22μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to a sterilizer and sterilize it at 121℃ for 30 minutes.

[0085] Example 26 Prucalopride succinate injection Table 29 Example 26 Formula:

[0086] Preparation method: Add the prescribed amount of osmotic pressure regulator to room temperature water for injection and stir until dissolved. Add the prescribed amount of prucalopride succinate and sustained-release material and stir until dissolved. Add the prescribed amount of pH regulator to adjust the pH value. Finally, dilute it to the prescribed amount with water for injection, fill it with nitrogen to protect the liquid, filter it through a 0.22μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to a sterilizer and sterilize it at 121℃ for 30 minutes.

[0087] Comparative Example 1 Prucalopride succinate tablets Table 30 Comparative Example 1 Formula:

[0088] Preparation method: The prescribed amount of microcrystalline cellulose, prucalopride succinate (passed through an 80-mesh sieve), lactose (passed through an 80-mesh sieve), and microcrystalline cellulose are placed in a wet mixing granulator, mixed for 18 minutes, and mixed at a speed of 150 rpm to obtain material a; material a, the prescribed amount of silicon dioxide, and magnesium stearate are placed in a total mixer, mixed for 8 minutes, and mixed at a speed of 150 rpm to obtain material b; material b is tableted, the weight difference is checked once every 10 minutes during the tableting process, and the appearance quality of the semi-finished product is checked at any time; the prescribed amount of Opadry is weighed, purified water is added, stirred to swell, sieved, and prepared into a coating solution with a solid content of about 12.5%; the obtained tablets are sieved to remove fine powder, placed in a coating pot, the inlet air temperature is controlled at 55°C, the material temperature is controlled at 40°C, and coating is started. When the coating weight increases by 3%-5%, the coating is stopped, the main engine speed is reduced to dry for 30 minutes, cooled, taken out, and packaged to obtain the product.

[0089] Pharmacodynamics and stability experiments of prucalopride succinate: According to the above method, the pharmacodynamics experiment (0.20 mg) and stability experiment of prucalopride succinate injection of Examples 1 to 26 were carried out. Table 31 Rats pain behavior response score ( , n=10) ; Note: Compared with any group of Examples 1 to 11, *P < 0.01; Compared with any group of Examples 1 to 4, # P<0.05.

[0090] As shown in Table 31, Examples 1 to 26 are a large number of experiments conducted to screen osmotic pressure regulators, pH regulators, stabilizers, solvents, drug release methods, etc., among which the pain response scores of rats in the Example 1 to Example 11 groups are at a relatively low level, indicating that the optimization of the formula has a significant effect on reducing the irritation response of prucalopride succinate.

[0091] Table 32 Stability of Prucalopride Succinate Injection: ; Note: The control group is a control group in which prucalopride succinate is dissolved in water for injection; Example 12 (pH=7.4) refers to the formulation of Example 12 except for the buffer solution, but the pH of the injection solution is adjusted to 7.4, and the others are similar.

[0092] From the experimental results of stability of prucalopride succinate injection in Table 32, it can be seen that the prucalopride succinate injections in Examples 20 to 22 contain stabilizers, which can improve the stability of prucalopride succinate injection to a certain extent. However, from the experimental results of injection pain response in Table 4, the rats injected with prucalopride succinate injections in Examples 12 to 16 and Examples 20 to 22 had severe pain responses, which failed to solve the problems of stability and pain response of prucalopride succinate.

[0093] Effect of pH on the stability of prucalopride succinate injection in Examples 1 to 11 Since the stability of prucalopride succinate injection is closely related to pH, it is necessary to verify the sensitivity of the stability of prucalopride succinate injection to pH in Examples 1 to 11. Experimental conditions: 25°C±2°C, relative humidity 60%±5%, 12 months. Figure 2 The stability of prucalopride succinate injection in Examples 1 to 6 is sensitive to pH. The same experiment was also carried out on prucalopride succinate injection in Examples 7 to 11, and the stability was similar to that in Examples 5 to 6. In summary, the above experimental results show that the prucalopride succinate injection in Examples 1 to 11 of the present invention not only solves the irritation reaction problem of prucalopride succinate injection by optimizing the formula, but also solves the defect that prucalopride succinate is unstable in a neutral environment.

[0094] Stability of preparation properties of prucalopride succinate injection Table 33 Properties of Prucalopride Succinate Injection Preparation ; Table 33 shows that the properties of the prucalopride succinate injection preparations of Examples 1 to 11 were all colorless clear liquids under accelerated 6-month and long-term 24-month conditions, without significant changes, and visible foreign matter met the requirements.

[0095] Bioavailability test: The absolute bioavailability of the prucalopride succinate injection of Examples 1 to 11 of the present invention and the prucalopride succinate tablet of Comparative Example 1 was investigated. Table 34 Absolute bioavailability: ; Note: The samples of Examples 1 to 11 were injected intravenously, and the sample of Comparative Example 1 was administered orally.

[0096] The absolute bioavailability results of prucalopride succinate injections of Examples 1 to 11 and prucalopride succinate tablets of Comparative Example 1 are shown in Table 34. The bioavailability of prucalopride succinate injections of Examples 1 to 11 is 100%, while that of Comparative Example 1 (prucalopride succinate tablets) is 90%. Compared with oral administration, intravenous administration can provide higher drug bioavailability, which may lead to faster onset of drug effect and better control of drug concentration.

Claims

1. An injection containing the active ingredient prucalopride succinate, characterized in that: The structural formula of the active ingredient prucalopride succinate is: ； The injection comprises 0.1 to 5 parts by weight of prucalopride succinate, 2 to 140 parts by weight of an osmotic pressure regulator, a pH regulator, and 0.1 to 10 parts by weight of water for injection; The osmotic pressure regulator is selected from one or more of sodium chloride, sodium phosphate, sodium citrate, potassium citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate; The pH regulator is selected from one or more of citric acid, sodium citrate, succinic acid, sodium succinate, hydrochloric acid, sodium hydroxide, phosphoric acid, and phosphates.

2. The injection containing the active ingredient prucalopride succinate according to claim 1, characterized in that: The prucalopride succinate is 0.5 to 3 parts by weight.

3. The injection containing prucalopride succinate as an active ingredient according to claim 1, characterized in that: The osmotic pressure regulator is 4.5 to 25 parts by weight.

4. The injection containing prucalopride succinate as an active ingredient according to claim 1, characterized in that: The water for injection is 0.5 to 3 parts by weight.

5. The injection containing prucalopride succinate as an active ingredient according to claim 2, characterized in that: The prucalopride succinate is 1 to 2 parts by weight.

6. The injection containing prucalopride succinate as an active ingredient according to claim 3, characterized in that: The osmotic pressure regulator is 9 to 18 parts by weight.

7. The injection containing prucalopride succinate as an active ingredient according to claim 4, characterized in that: The water for injection is 1 to 2 parts by weight.

8. The injection containing prucalopride succinate as an active ingredient according to claim 1, characterized in that: The pH regulator adjusts the pH to 4.0-6.

5.

9. The injection containing prucalopride succinate as an active ingredient according to claim 1, characterized in that: The pH regulator adjusts the pH to 4.0-5.

5.

10. The injection containing prucalopride succinate as an active ingredient according to any one of claims 1 to 9, characterized in that: The osmotic pressure regulator is sodium chloride.

11. The injection containing prucalopride succinate as an active ingredient according to any one of claims 1 to 9, characterized in that: The pH regulators are citric acid and sodium citrate.

12. A method for preparing the injection containing the active ingredient prucalopride succinate according to claim 1, characterized in that: The method is: (1) Add the osmotic pressure regulator to water and stir until dissolved; (2) Add prucalopride succinate to (1) and stir until dissolved; (3) Adding a pH adjuster into (2) to adjust the pH; (4) Add injection water to (3) to make up the volume, fill with nitrogen, filter, fill and sterilize.

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