Injection containing the active ingredient prucalopride succinate and its preparation method

Abstract

The present invention belongs to the technical field of pharmaceutical preparations for treating digestive system diseases, and relates to an injection containing the active ingredient prucalopride succinate and a preparation method thereof. The prucalopride succinate injection of the present invention comprises prucalopride succinate, an osmotic pressure regulator, a pH regulator, and water for injection. By optimizing the formulation, the present invention balances the relationship between the pain response of prucalopride succinate and the stability of prucalopride succinate, and provides a prucalopride succinate injection with high stability, high bioavailability, and low injection irritation.

Description

Technical Field

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

[0002] Disclosing the information of this background art section is only intended to enhance the overall understanding of the present invention, and is not necessarily to be regarded as an admission or any form of implication that this information constitutes the prior art already known to those of ordinary skill in the art.

[0003] Chronic constipation is a common gastrointestinal motility disorder clinically, which can affect the work and quality of life of modern people to varying degrees. With the change of people's diet structure and the influence of mental, psychological and social factors, the incidence of chronic constipation shows an increasing trend, and the prevalence rate in the population is as high as 27%. 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 and complex etiology of constipation, patients often have a lot of distress, and at the same time, it may also induce other serious diseases, such as causing hemorrhoids and anal fissures, damaging liver function, inducing myocardial infarction and cerebrovascular accidents, inducing pneumothorax, forming ventral hernia, etc., and the risks caused cannot be ignored.

[0004] Prucalopride succinate tablets are the world's first highly selective and highly affinity 5-HT4 receptor agonists, with no agonist effect on other 7 receptors such as 5-HT1, 2, etc., reducing the incidence of cardiovascular adverse events such as ischemic heart disease and severe arrhythmia. By specifically and selectively stimulating the intestinal 5-HT4 receptor, it induces high-amplitude propulsive contractions (HAPC) of the intestine, significantly promoting intestinal peristalsis, especially colonic peristalsis, and has a significant effect in improving intestinal motility and reconstructing intestinal function. It is used to treat chronic constipation symptoms that are difficult to fully relieve by laxatives, and a large amount of evidence-based medical data has proven that prucalopride has good tolerance and safety.

[0005] The existing marketed dosage form of prucalopride succinate is only 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. The existing public preparation technology shows that the production process is simple, which is conducive to large-scale production, and has high economy and stability. However, the main drug content of the tablets is less than 1% of the prescription amount, and the uniformity of powder mixing has certain industrial challenges, which in turn leads to problems with the content uniformity of the tablets.

[0006] In the existing prior art, a Chinese patent with the publication number CN103070865A discloses a solid preparation containing prucalopride succinate as an active ingredient and its application. The excipient contains 5% starch paste and the wet granulation process is used. The amino group in the excipient lactose and prucalopride succinate can produce the Maillard reaction at room temperature, generating toxic substances, and the drug has large toxic and side effects.

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

[0008] On the one hand, for people with postoperative gastrointestinal dysfunction and other conditions, it is not convenient to take the oral route, and injection can be selected; on the other hand, for intestinal preparation before intestinal examination or surgery, the oral administration of prucalopride succinate solid preparation has a slow onset and low bioavailability. Therefore, there is an urgent need to provide a prucalopride succinate injection that can achieve a rapid onset 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 its dosage form from the traditional tablet to an injection form. Existing tablets need to be digested and absorbed through the gastrointestinal tract to exert their effects, usually taking a long time to take effect. While the injection form can directly enter the blood circulation, avoiding the digestive process of the gastrointestinal tract, thus achieving faster absorption and more rapid drug efficacy.

[0010] To ensure that the prucalopride succinate injection meets the standards in terms of safety, effectiveness, quality control, and patient acceptance, this invention has conducted a series of studies. Through the analysis of the physicochemical properties, pharmacokinetics, etc. of the drug, especially when considering the requirement for rapid onset of the drug, intravenous injection becomes the most ideal administration method because the drug can directly enter the blood and quickly reach the 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:

[0017] (1) Add the osmotic pressure regulator to water and stir until dissolved;

[0018] (2) Add prucalopride succinate to (1) and stir until dissolved;

[0019] (3) Add a pH regulator to (2) to adjust the pH.

[0020] (4) Make up the volume of (3) with injection water, fill with nitrogen, filter, fill, and sterilize to obtain the product.

[0021] Through this series of research and development, the present invention has achieved the innovation and optimization of the dosage form of prucalopride succinate injection, and laid a solid foundation for its clinical promotion and application.

[0022] Compared with the prior art, the technical effects of the present invention are as follows:

[0023] (1) By changing the dosage form of prucalopride succinate from tablet to injection, prucalopride succinate can directly enter the blood circulation, avoiding the gastrointestinal digestion and absorption process, thus greatly accelerating the onset speed of the drug and enhancing the timeliness and effectiveness of clinical treatment.

[0024] (2) The present invention overcomes the contradiction between the pain reaction and stability of prucalopride succinate injection. The present invention first found that symptoms such as pain and swelling occurred in the animal experiments of prucalopride succinate injection, 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 reaction of the immune system by systematically screening the components of the injection and trying to replace some components. At the same time, continuously optimizing the prescription design, on the premise of ensuring the stability of the drug, the side effects are minimized, the safety of prucalopride succinate and the acceptance of patients are improved, and a prucalopride succinate injection with high stability, high bioavailability and small injection irritation is obtained, and the pH range of prucalopride succinate injection is broadened. Within the range of pH = 4.0 - 6.5, it can not only ensure the stability of prucalopride succinate injection to maintain the drug effect, but also reduce the irritation of prucalopride succinate. Description of the Drawings

[0025] Figure 1 : The stability of prucalopride succinate at different pH conditions on the 1st day and 6 months in the accelerated experiment.

[0026] Figure 2 : The sensitivity of the stability of prucalopride succinate injection in Examples 1 - 6 at different pH conditions. Detailed Embodiments

[0027] In order to make the purpose and technical solutions of the present invention clearer, the following further describes the present invention with reference to the embodiments. However, the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. Those skilled in the art should understand 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.

[0028] Pharmacodynamic experiment

[0029] 1. Experimental animals: Sprague-Dawley rats, SPF grade, 180 - 220 g, experimental animal license number: SYXK(Shandong) 20180008, provided by Lunan Pharmaceutical Group Co., Ltd., and adaptively fed for 1 week under standard conditions before the experiment;

[0030] 2. Modeling: For several rats, loperamide was formulated into a 1 ml dilution solution at a dose of 1.5 mg / kg. These dilution solutions were given to the rats by gavage, twice a day with an interval of 9 hours between each gavage, and continuously gavaged for 5 days. The successfully modeled rats were divided into 8 groups, with 10 rats in each group;

[0031] 3. Grouping

[0032] Model group: 10 successfully modeled rats, injected with normal saline via the tail vein;

[0033] Blank group: 10 normal rats, injected with normal saline via the tail vein;

[0034] Sample A group: 10 successfully modeled rats, injected with 0.01 mg prucalopride succinate prepared with normal saline via the tail vein, pH = 7.4;

[0035] Sample B group: 10 successfully modeled rats, injected with 0.20 mg prucalopride succinate prepared with normal saline via the tail vein, pH = 7.4;

[0036] Sample C group: 10 successfully modeled rats, injected with 0.01 mg prucalopride succinate prepared with normal saline via the tail vein, pH = 6.5;

[0037] Sample D group: 10 successfully modeled rats, injected with 0.20 mg prucalopride succinate prepared with normal saline via the tail vein, pH = 6.5;

[0038] Sample E group: 10 successfully modeled rats, injected with 0.01 mg prucalopride succinate prepared with normal saline via the tail vein, pH = 4.0;

[0039] Sample F group: 10 successfully modeled rats, injected with 0.20 mg prucalopride succinate prepared with normal saline via the tail vein, pH = 4.0.

[0040] Rat pain behavior response score: The abnormal behaviors of rats in each group within 10 minutes after drug injection were counted, including but not limited to tail flicking, tail licking, curling up, leaning towards the injured side, arching the back, lowering the head and neck, tense hind limbs, unnatural extension of the hind limbs, shaking, tremors, unsteady walking, increased or irregular breathing rate, groaning, rolling, etc. Each occurrence of the above behaviors was counted as 1 point.

[0041] Table 1 Rat pain behavior response score ( , n = 10)

[0042] ;

[0043] Note: Compared with the blank group, *P < 0.01; compared with the model group, *P < 0.01.

[0044] As can be seen from Table 1, when comparing the model group with the blank group, the scores of the two groups were similar and relatively low, indicating that the simple modeling process (intragastric 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 this administration method itself did not cause pain response in rats. The pain behavior manifestations of rats in the two groups were not significantly different under normal conditions. Therefore, the effects of the modeling itself and the administration method itself on the pain response of rats can be excluded. However, the behavioral scores of the sample A group to the sample F group were significantly higher than those of the model group and the blank group, indicating that prucalopride succinate injection caused severe pain stimulation to rats. By comparing the sample groups with different doses under the same pH value, it can be seen that under the same pH value condition, as the dose of prucalopride succinate increased, the pain behavior response score of rats increased, suggesting that the degree of pain response increased, indicating that the pain response may be positively correlated with the drug dose, further verifying that prucalopride succinate has relatively severe irritation. By comparing the sample groups with different pH values under the same dose, as the pH value of the solution decreased, the pain behavior response score of rats gradually increased, indicating that the degree of pain response intensified, suggesting that the pain response may be related to the pH value of the solution. A lower pH value would enhance the pain stimulation of prucalopride succinate injection to rats. When the pH of the injection was close to the pH of the blood itself, the pain was lower, but still significantly higher than the pain scores of rats in the blank group and the model group. Based on the above, prucalopride succinate itself has relatively severe irritation and shows relatively severe pH dependence.

[0045] Number of rat feces: Rats in each group were placed in a metabolic cage, fasted but allowed to drink water, and the number of fecal pellets excreted by rats in each group within 12 hours was observed and recorded.

[0046] Table 2 Number of fecal pellets excreted by rats in each group within 12 hours ( , n = 10)

[0047] ;

[0048] Note: Compared with sample group A, *P < 0.01; compared with sample group B, # P < 0.01.

[0049] As can be seen from Table 2, the dose of prucalopride succinate is proportional to the efficacy. However, the effects of prucalopride succinate at different pH values are different. When the pH is neutral, the effect of treating constipation with the same dose of prucalopride succinate is poor, and the difference is significant. It is speculated that this may be due to the different stabilities of prucalopride succinate at different pH values. Prucalopride succinate may be more stable in an acidic environment and will degrade in a neutral environment, unable to maintain its biological activity.

[0050] In this invention, all the pharmacodynamic data were statistically analyzed using SPSS 22.0 software. Measurement data were expressed as ( ), one-way ANOVA was used for comparison among multiple groups, and independent sample T-test was used for analysis between two groups. P < 0.05 was considered statistically significant.

[0051] 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 with equal concentrations. They were placed in a constant temperature and humidity chamber at 40°C ± 2°C and 75 ± 5% RH for 6 months. The content of prucalopride succinate was determined by high performance liquid chromatography to evaluate the pH dependence of prucalopride succinate.

[0052] High performance liquid chromatography conditions: The chromatographic column was packed with octadecylsilane bonded silica gel; flow rate: 1.0 ml / ml; detection wavelength: 228 nm; column temperature: 25°C; injection volume: 20 μl; mobile phase: phosphate buffer solution (take 2.72 g of potassium dihydrogen phosphate, dissolve it in 900 ml of water, adjust the pH value to 6.0 with phosphoric acid, and dilute it to 1000 ml) as mobile phase A, and methanol as mobile phase B. Linear gradient elution is shown in Table 3.

[0053] Table 3 Linear gradient elution:

[0054] ;

[0055] Sample diluent: Phosphate buffer solution (take 2.72 g of potassium dihydrogen phosphate, dissolve it in 900 ml of water, adjust the pH value to 6.0 with sodium hydroxide, and dilute it to 1000 ml)-methanol (65:35).

[0056] Figure 1This is the stability results of prucalopride succinate on the 1st day and after 6 months under different pH conditions in the accelerated experiment. The experiment shows that prucalopride succinate exhibits the best stability between pH = 4.0 and 5.5. After 6 months, the drug content hardly changes and remains above 99%. In contrast, when the pH value approaches neutral or is slightly alkaline, the stability of prucalopride succinate significantly decreases. Especially at pH 6.0 and higher pH values, the degradation degree of the drug is more obvious. This change indicates that a higher pH value may accelerate the degradation of the drug, thus affecting its efficacy. The stability experiment results of prucalopride succinate are consistent with the pharmacodynamic experiment results, further verifying that the stability of prucalopride succinate indeed depends on the change of pH value and its stability is most excellent within a specific pH range.

[0057] Based on the above, during the development process of prucalopride succinate injection, the stability of prucalopride succinate and the pain reaction during injection become difficult problems to adjust. The scientific research team tries to balance the above problems by methods such as increasing the solvent, optimizing the buffer solution, adding stabilizers, adjusting the osmotic pressure, screening osmotic pressure regulators, and using sustained-release technology.

[0058] Example 1 Prucalopride Succinate Injection

[0059] Table 4 Formula of Example 1:

[0060]

[0061] Preparation method:

[0062] Add the prescribed amount of osmotic pressure regulator to the room-temperature injection water 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, make up the volume to the prescribed amount with injection water, protect the liquid medicine with nitrogen, filter through a 0.22μm PES filter membrane, fill with nitrogen, and seal. Transfer to the sterilization cabinet, sterilize at 121°C for 30 minutes to obtain the product.

[0063] Example 2 Prucalopride Succinate Injection

[0064] Table 5 Formula of Example 2:

[0065]

[0066] Preparation method:

[0067] Add the prescribed amount of osmotic pressure regulator to the room-temperature injection water 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, make up the volume to the prescribed amount with injection water, protect the liquid medicine with nitrogen filling, filter it through a 0.22μm PES filter membrane, fill with nitrogen, and seal. Transfer it to the sterilization cabinet, sterilize at 121°C for 20 minutes to obtain the product.

[0068] Example 3 Prucalopride Succinate Injection

[0069] Table 6 Formulation of Example 3:

[0070]

[0071] Preparation method:

[0072] Add the prescribed amount of osmotic pressure regulator to the room-temperature injection water 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, make up the volume to the prescribed amount with injection water, protect the liquid medicine with nitrogen filling, filter it through a 0.22μm PES filter membrane, fill with nitrogen, and seal. Transfer it to the sterilization cabinet, sterilize at 121°C for 15 minutes to obtain the product.

[0073] Example 4 Prucalopride Succinate Injection

[0074] Table 7 Formulation of Example 4:

[0075]

[0076] Preparation method:

[0077] Add the prescribed amount of osmotic pressure regulator to the room-temperature injection water 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, make up the volume to the prescribed amount with injection water, protect the liquid medicine with nitrogen filling, filter it through a 0.22μm PES filter membrane, fill with nitrogen, and seal. Transfer it to the sterilization cabinet, sterilize at 121°C for 30 minutes to obtain the product.

[0078] Example 5 Prucalopride Succinate Injection

[0079] Table 8 Formulation of Example 5:

[0080]

[0081] Preparation method:

[0082] Add the prescribed amount of osmotic pressure regulator to the room-temperature injection water 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, make up the volume to the prescribed amount with injection water, protect the liquid medicine with nitrogen, filter it through a 0.22-μm PES filter membrane, then fill it with nitrogen and seal it. Transfer it to the sterilization cabinet, sterilize it at 121 °C for 30 minutes to obtain the product.

[0083] Example 6 Prucalopride Succinate Injection

[0084] Table 9 Formulation of Example 6:

[0085]

[0086] Preparation method:

[0087] Add the prescribed amount of osmotic pressure regulator to the room-temperature injection water 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, make up the volume to the prescribed amount with injection water, protect the liquid medicine with nitrogen, filter it through a 0.22-μm PES filter membrane, then fill it with nitrogen and seal it. Transfer it to the sterilization cabinet, sterilize it at 121 °C for 30 minutes to obtain the product.

[0088] Example 7 Prucalopride Succinate Injection

[0089] Table 10 Formulation of Example 7:

[0090]

[0091] Preparation method:

[0092] Add the prescribed amount of osmotic pressure regulator to the room-temperature injection water 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, make up the volume to the prescribed amount with injection water, protect the liquid medicine with nitrogen, filter it through a 0.22-μm PES filter membrane, then fill it with nitrogen and seal it. Transfer it to the sterilization cabinet, sterilize it at 121 °C for 30 minutes to obtain the product.

[0093] Example 8 Prucalopride Succinate Injection

[0094] Table 11 Formulation of Example 8:

[0095]

[0096] Preparation method:

[0097] Add the prescribed amount of osmotic pressure regulator to the room-temperature injection water 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, make up the volume to the prescribed amount with injection water, protect the liquid medicine by filling it with nitrogen, filter it through a 0.22-μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to the sterilization cabinet, sterilize it at 121 °C for 30 minutes to obtain the product.

[0098] Example 9 Prucalopride Succinate Injection

[0099] Table 12 Example 9 Formula:

[0100]

[0101] Preparation method:

[0102] Add the prescribed amount of osmotic pressure regulator to the room-temperature injection water 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, make up the volume to the prescribed amount with injection water, protect the liquid medicine by filling it with nitrogen, filter it through a 0.22-μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to the sterilization cabinet, sterilize it at 121 °C for 20 minutes to obtain the product.

[0103] Example 10 Prucalopride Succinate Injection

[0104] Table 13 Example 10 Formula:

[0105]

[0106] Preparation method:

[0107] Add the prescribed amount of osmotic pressure regulator to the room-temperature injection water 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, make up the volume to the prescribed amount with injection water, protect the liquid medicine by filling it with nitrogen, filter it through a 0.22-μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to the sterilization cabinet, sterilize it at 121 °C for 15 minutes to obtain the product.

[0108] Example 11 Prucalopride Succinate Injection

[0109] Table 14 Example 11 Formula:

[0110]

[0111] Preparation method:

[0112] Add the prescribed amount of osmotic pressure regulator to the room-temperature injection water 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, make up the volume to the prescribed amount with injection water, protect the liquid medicine by filling it with nitrogen, filter it through a 0.22-μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to the sterilization cabinet, sterilize it at 121°C for 30 minutes to obtain the product.

[0113] Example 12 Prucalopride Succinate Injection

[0114] Table 15 Formulation of Example 12:

[0115]

[0116] Preparation method:

[0117] Add the prescribed amount of osmotic pressure regulator to the room-temperature injection water 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, make up the volume to the prescribed amount with injection water, protect the liquid medicine by filling it with nitrogen, filter it through a 0.22-μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to the sterilization cabinet, sterilize it at 121°C for 30 minutes to obtain the product.

[0118] Example 13 Prucalopride Succinate Injection

[0119] Table 16 Formulation of Example 13:

[0120]

[0121] Preparation method:

[0122] Add the prescribed amount of osmotic pressure regulator to the room-temperature injection water 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, make up the volume to the prescribed amount with injection water, protect the liquid medicine by filling it with nitrogen, filter it through a 0.22-μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to the sterilization cabinet, sterilize it at 121°C for 30 minutes to obtain the product.

[0123] Example 14 Prucalopride Succinate Injection

[0124] Table 17 Formulation of Example 14:

[0125]

[0126] Preparation method:

[0127] Add the prescribed amount of osmotic pressure regulator to the room-temperature injection water 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, make up the volume to the prescribed amount with injection water, protect the liquid medicine with nitrogen filling, filter through a 0.22-μm PES filter membrane, fill with nitrogen, and seal. Transfer to the sterilization cabinet, sterilize at 121°C for 30 minutes to obtain the product.

[0128] Example 15 Prucalopride Succinate Injection

[0129] Table 18 Example 15 Formula:

[0130]

[0131] Preparation method:

[0132] Add the prescribed amount of osmotic pressure regulator to the room-temperature injection water 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, make up the volume to the prescribed amount with injection water, protect the liquid medicine with nitrogen filling, filter through a 0.22-μm PES filter membrane, fill with nitrogen, and seal. Transfer to the sterilization cabinet, sterilize at 121°C for 30 minutes to obtain the product.

[0133] Example 16 Prucalopride Succinate Injection

[0134] Table 19 Example 16 Formula:

[0135]

[0136] Preparation method:

[0137] Add the prescribed amount of osmotic pressure regulator to the room-temperature injection water 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, make up the volume to the prescribed amount with injection water, protect the liquid medicine with nitrogen filling, filter through a 0.22-μm PES filter membrane, fill with nitrogen, and seal. Transfer to the sterilization cabinet, sterilize at 121°C for 30 minutes to obtain the product.

[0138] Example 17 Prucalopride Succinate Injection

[0139] Table 20 Example 17 Formula:

[0140]

[0141] Preparation method:

[0142] Add the prescribed amount of osmotic pressure regulator to the room-temperature injection water 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, make up the volume to the prescribed amount with injection water, protect the liquid medicine with nitrogen filling, filter through a 0.22-μm PES filter membrane, fill with nitrogen, and seal. Transfer it to the sterilization cabinet, sterilize at 121 °C for 30 minutes to obtain the product.

[0143] Example 18 Prucalopride Succinate Injection

[0144] Table 21 Example 18 Formula:

[0145]

[0146] Preparation method:

[0147] Add the prescribed amount of osmotic pressure regulator to the room-temperature injection water 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, make up the volume to the prescribed amount with injection water, protect the liquid medicine with nitrogen filling, filter through a 0.22-μm PES filter membrane, fill with nitrogen, and seal. Transfer it to the sterilization cabinet, sterilize at 121 °C for 30 minutes to obtain the product.

[0148] Example 19 Prucalopride Succinate Injection

[0149] Table 22 Example 19 Formula:

[0150]

[0151] Preparation method:

[0152] Add the prescribed amount of osmotic pressure regulator to the room-temperature injection water 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, make up the volume to the prescribed amount with injection water, protect the liquid medicine with nitrogen filling, filter through a 0.22-μm PES filter membrane, fill with nitrogen, and seal. Transfer it to the sterilization cabinet, sterilize at 121 °C for 30 minutes to obtain the product.

[0153] Example 20 Prucalopride Succinate Injection

[0154] Table 23 Example 20 Formula:

[0155]

[0156] Preparation method:

[0157] Add the prescribed amount of osmotic pressure regulator to the room-temperature injection water and stir until dissolved. Add the prescribed amount of prucalopride succinate and stabilizer, stir until dissolved, add the prescribed amount of pH regulator, and adjust the pH value. Finally, make up the volume to the prescribed amount with injection water, protect the liquid medicine by filling it with nitrogen, filter it through a 0.22-μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to the sterilization cabinet, sterilize it at 121 °C for 30 minutes to obtain the product.

[0158] Example 21 Prucalopride Succinate Injection

[0159] Table 24 Example 21 Formula:

[0160]

[0161] Preparation method:

[0162] Add the prescribed amount of osmotic pressure regulator to the room-temperature injection water and stir until dissolved. Add the prescribed amount of prucalopride succinate and stabilizer, stir until dissolved, add the prescribed amount of pH regulator, and adjust the pH value. Finally, make up the volume to the prescribed amount with injection water, protect the liquid medicine by filling it with nitrogen, filter it through a 0.22-μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to the sterilization cabinet, sterilize it at 121 °C for 30 minutes to obtain the product.

[0163] Example 22 Prucalopride Succinate Injection

[0164] Table 25 Example 22 Formula:

[0165]

[0166] Preparation method:

[0167] Add the prescribed amount of osmotic pressure regulator to the room-temperature injection water and stir until dissolved. Add the prescribed amount of prucalopride succinate and stabilizer, stir until dissolved, add the prescribed amount of pH regulator, and adjust the pH value. Finally, make up the volume to the prescribed amount with injection water, protect the liquid medicine by filling it with nitrogen, filter it through a 0.22-μm PES filter membrane, fill it with nitrogen, and seal it. Transfer it to the sterilization cabinet, sterilize it at 121 °C for 30 minutes to obtain the product.

[0168] Example 23 Prucalopride Succinate Injection

[0169] Table 26 Example 23 Formula:

[0170]

[0171] Preparation method:

[0172] Add the prescribed amount of osmotic pressure regulator to the room-temperature injection water 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, make up the volume to the prescribed amount with injection water, protect the liquid medicine with nitrogen filling, filter through a 0.22-μm PES filter membrane, fill with nitrogen, and seal. Transfer to the sterilization cabinet, sterilize at 121 °C for 30 minutes to obtain the product.

[0173] Example 24 Prucalopride Succinate Injection

[0174] Table 27 Example 24 Formula:

[0175]

[0176] Preparation method:

[0177] Add the prescribed amount of osmotic pressure regulator to the room-temperature injection water 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, make up the volume to the prescribed amount with injection water, protect the liquid medicine with nitrogen filling, filter through a 0.22-μm PES filter membrane, fill with nitrogen, and seal. Transfer to the sterilization cabinet, sterilize at 121 °C for 30 minutes to obtain the product.

[0178] Example 25 Prucalopride Succinate Injection

[0179] Table 28 Example 25 Formula:

[0180]

[0181] Preparation method:

[0182] Add the prescribed amount of osmotic pressure regulator to the room-temperature injection water and stir until dissolved. Add the prescribed amount of prucalopride succinate and sustained-release material, stir until dissolved, add the prescribed amount of pH regulator, and adjust the pH value. Finally, make up the volume to the prescribed amount with injection water, protect the liquid medicine with nitrogen filling, filter through a 0.22-μm PES filter membrane, fill with nitrogen, and seal. Transfer to the sterilization cabinet, sterilize at 121 °C for 30 minutes to obtain the product.

[0183] Example 26 Prucalopride Succinate Injection

[0184] Table 29 Example 26 Formula:

[0185]

[0186] Preparation method:

[0187] Add the prescribed amount of osmotic pressure regulator to the room temperature injection water and stir until dissolved. Add the prescribed amount of prucalopride succinate and sustained-release material, stir until dissolved, add the prescribed amount of pH regulator, and adjust the pH value. Finally, make up the volume to the prescribed amount with injection water, protect the liquid medicine with nitrogen filling, filter through a 0.22μm PES filter membrane, fill with nitrogen, and seal. Transfer to the sterilization cabinet, sterilize at 121°C for 30 minutes to obtain the product.

[0188] Comparative Example 1 Prucalopride Succinate Tablets

[0189] Table 30 Formula of Comparative Example 1:

[0190]

[0191] Preparation method:

[0192] Put the prescribed amount of microcrystalline cellulose, prucalopride succinate (screened through 80-mesh sieve), lactose (screened through 80-mesh sieve), and microcrystalline cellulose into a wet granulator, mix for 18 minutes at a mixing speed of 150 rpm to obtain material a; put material a, the prescribed amount of silicon dioxide, and magnesium stearate into a total mixer, mix for 8 minutes at a mixing speed of 150 rpm to obtain material b; press the material b into tablets, check the weight difference once every 10 minutes during the pressing process, and check the appearance quality of the semi-finished product at any time; weigh the prescribed amount of Opadry, add purified water, stir and swell, sieve, and prepare a coating solution with a solid content of about 12.5%; after screening out the fine powder of the obtained tablets, put them into a coating pan, control the inlet air temperature at 55°C and the material temperature at 40°C, start coating, stop coating when the coating weight gain reaches 3%-5%, reduce the main machine speed and dry for 30 minutes, then let it cool, take it out, and package to obtain the product.

[0193] Pharmacodynamic experiment and stability experiment of prucalopride succinate:

[0194] Conduct pharmacodynamic experiments (0.20 mg) and stability experiments of prucalopride succinate injection for Examples 1 to 26 according to the aforementioned method. Table 31 Scoring of rat pain behavior response ( , n = 10)

[0195] ;

[0196] Note: Compared with any group in Examples 1 to 11, *P < 0.01; compared with any group in Examples 1 to 4, # P < 0.05.

[0197] As can be seen from Table 31, Examples 1 to 26 are a large number of experiments conducted by screening osmotic pressure regulators, pH regulators, stabilizers, solvents, drug release methods, etc. Among them, the pain response scores of the rats in Groups 1 to 11 of Examples 1 to 11 are at a relatively low level, indicating that the optimization of the formulation has a significant effect on reducing the irritation response of prucalopride succinate.

[0198] Table 32 Stability of Prucalopride Succinate Injection:

[0199] ;

[0200] Note: The control group is prucalopride succinate in the control group dissolved in water for injection; Example 12 (pH = 7.4) refers to the formulation in Example 12 except for the buffer solution, but the pH of the injection solution is adjusted to 7.4, and the same applies to others.

[0201] As can be seen from the stability test results of Prucalopride Succinate Injection in Table 32, the Prucalopride Succinate Injection in Examples 20 to 22 contains stabilizers, which can improve the stability of Prucalopride Succinate Injection to a certain extent. However, according to the experimental results of injection pain response in Table 4, the rats injected with Prucalopride Succinate Injection in Examples 12 to 16 and Examples 20 to 22 had severe injection pain responses, and the problems of the stability and pain response of Prucalopride Succinate were not solved.

[0202] Effect of pH on the Stability of Prucalopride Succinate Injection in Examples 1 to 11

[0203] 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 in Examples 1 to 11 to pH. Experimental conditions: 25°C ± 2°C, relative humidity 60% ± 5%, 12 months. Figure 2 For the sensitivity of the stability of Prucalopride Succinate Injection in Examples 1 to 6 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 of Examples 5 to 6. Based on the above experimental results, it shows that the Prucalopride Succinate Injection in Examples 1 to 11 of the present invention solves both the irritation response problem of Prucalopride Succinate Injection and the defect of the instability of Prucalopride Succinate in a neutral environment through formula optimization.

[0204] Stability of the Preparation Properties of Prucalopride Succinate Injection

[0205] Table 33 Preparation Properties of Prucalopride Succinate Injection

[0206] ;

[0207] Table 33 shows that for the preparations of prucalopride succinate injection in Examples 1 to 11, the appearance was colorless and clear liquid under the conditions of 6-month accelerated test and 24-month long-term test, with no obvious change, and the visible foreign matters met the requirements.

[0208] Bioavailability test: To investigate the absolute bioavailability of the prucalopride succinate injection in Examples 1 - 11 of the present invention and the prucalopride succinate tablets in Comparative Example 1. Table 34 Absolute bioavailability:

[0209] ;

[0210] Note: The samples in Examples 1 - 11 were administered by intravenous bolus injection, and the sample in Comparative Example 1 was administered orally.

[0211] The results of the absolute bioavailability of the prucalopride succinate injection in Examples 1 - 11 and the prucalopride succinate tablets in Comparative Example 1 are shown in Table 34. The bioavailability of the prucalopride succinate injection in Examples 1 to 11 was all 100%, while that of Comparative Example 1 (prucalopride succinate tablets) was 90%. The intravenous administration form can provide higher drug bioavailability compared to oral administration, 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-phosphate; The pH regulator adjusts the pH to 4.0-5.

5.

2. The injection containing the active ingredient prucalopride succinate according to claim 1, characterized in that: The prucalopride succinate is 0.5-3 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 any one of claims 1 to 7, characterized in that: The osmotic pressure regulator is sodium chloride.

9. The injection containing prucalopride succinate as an active ingredient according to any one of claims 1 to 7, characterized in that: The pH regulators are citric acid and sodium citrate.

10. 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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