Papaverine hydrochloride for injection and preparation method thereof

Abstract

The invention relates to papaverine hydrochloride for injection and a preparation method thereof. The papaverine hydrochloride is prepared from papaverine hydrochloride, mannitol, sodium citrate, sodium caprylate, a pH regulator and water for injection. The papaverine hydrochloride for injection obtained by the invention is good in stability, low in insoluble particle quantity and stable, and the effectiveness and safety of medication are greatly improved.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and in particular relates to papaverine hydrochloride for injection and a preparation method thereof. Background Art

[0002] Papaverine hydrochloride is a vasodilator that has a direct nonspecific relaxant effect on blood vessels, heart or other smooth muscles. Therefore, it is often used as a smooth muscle antispasmodic agent and is currently widely used in clinical practice. Its mechanism of action is to relax vascular smooth muscles, reduce peripheral vascular resistance, and directly dilate blood vessels by inhibiting the production of some vasoconstrictor substances. The commonly used dosage form of papaverine hydrochloride is injection, and the advantageous dosage form is lyophilized powder injection, which can alleviate the hydrolysis and oxidation problems of papaverine hydrochloride during the preparation process and storage. The papaverine hydrochloride in the prior art is easily degraded into substances such as papaverine alcohol during long-term storage, and its own stability is poor, which is easy to have adverse effects on drug efficacy. At the same time, due to degradation, excipients and other reasons, it is easy to produce more insoluble particles. Insoluble particles not only affect the normal progress of infusion therapy, but also long-term superposition of particles can lead to pathological changes in many tissues and organs, causing new diseases and even death. Infusion containing a large number of insoluble particles can directly cause pyrogenic reactions when entering the human body. Symptoms include fever, chills, rapid heartbeat, and rapid breathing. In severe cases, it can lead to shock and may cause safety problems. Summary of the invention

[0003] In view of the above technical problems, a method for improving the quality and stability of papaverine hydrochloride for injection is studied, and at the same time, the insoluble particles are low and stable, which has a positive effect on the application of papaverine hydrochloride for injection. The inventors have obtained a papaverine hydrochloride for injection in the process of long-term and extensive research on papaverine hydrochloride. The injection can maintain the extremely high stability of papaverine hydrochloride and has very low insoluble particles, which increases the safety of medication and is significantly better than the prior art.

[0004] The solution adopted by the present invention to solve the above technical problems is:

[0005] Papaverine hydrochloride for injection is prepared from papaverine hydrochloride, mannitol, sodium citrate, sodium caprylate, pH regulator and water for injection.

[0006] Preferably, the concentration of papaverine hydrochloride is 1.5%, the concentration of mannitol is 4%, the concentration of sodium citrate is 0.4%, and the concentration of sodium octanoate is 0.06%.

[0007] Preferably, the specification of papaverine hydrochloride for injection is 30 mg.

[0008] Preferably, the pH adjuster is 10% citric acid solution.

[0009] The present invention also provides a method for preparing papaverine hydrochloride for injection, the preparation method comprising the following steps:

[0010] (1) Add the prescribed amount of sodium citrate, mannitol, sodium caprylate, and papaverine hydrochloride to 1200 ml of water for injection in sequence and stir to dissolve. Add 10% citric acid solution dropwise to adjust the pH to 3.10-3.30, add water for injection to 2000 ml, and stir evenly.

[0011] (2) Filter the solution in step (1) through a 0.22 μm microporous filter membrane, determine the pH value and content of the filtrate, determine the filling volume according to the specifications, and divide the half-stoppered filling liquid into portions;

[0012] (3) Freeze-drying:

[0013] ① Prefreezing: Place the aliquoted liquid in a freezer that has been pre-cooled to -44℃~-40℃ for 4~6 hours;

[0014] ②Sublimation: Turn on the vacuum device, adjust the vacuum degree to 12Pa, increase the temperature at a uniform rate (2.0~2.2℃ / h) to -9℃~-7℃, and maintain this temperature for 5 hours;

[0015] ③ Drying: uniformly raise the temperature to 37°C, dry for 4 hours, and package and store after passing the test to obtain papaverine hydrochloride for injection.

[0016] The invention has obtained the adjuvant composition and freeze-drying process of papaverine hydrochloride for injection through a large number of experiments and studies, and the adjuvant composition and freeze-drying process have an unexpected effect on improving the stability of papaverine hydrochloride. Common sense in the art, enlarging or reducing the same proportion of the prescription of the invention belongs to the essence and scope of the technical solution of the invention.

[0017] The following lists some parameters screening in some screening tests for illustrating the present invention:

[0018] 1. Selection of auxiliary materials:

[0019] The inventor of this patent application has unexpectedly discovered through extensive research that the use of mannitol as an excipient and sodium citrate and sodium octanoate as auxiliary materials can significantly improve the stability of papaverine hydrochloride, especially under the condition of a certain dosage, the stabilization effect is the best, and the pH value before and after freeze-drying can be kept relatively stable, which is conducive to maintaining the stability of papaverine hydrochloride. The test results are shown in Table 1:

[0020] Table 1 Comparative test results of different dosages of sodium citrate and sodium octanoate

[0021]

[0022] It can be seen from the test results in Table 1 that compared with the prior art, the combined use of sodium citrate and sodium octanoate can improve the stability of papaverine hydrochloride, especially adding 8g sodium citrate and 1.2g sodium octanoate per 2000ml has the best effect. Even if the dosage of sodium citrate and sodium octanoate changes slightly, the pH and stability of papaverine hydrochloride for injection before and after freeze-drying will change greatly. The sodium citrate and sodium octanoate used in the proportion of the present invention play an unexpected role in improving the stability of papaverine hydrochloride for injection.

[0023] 2. Selection of freeze-drying process

[0024] The freeze-drying process of freeze-dried preparations also has a decisive influence on product quality. In order to further improve the stability of the product, after a large number of experiments, the vacuum degree, sublimation heating temperature, drying temperature and drying time were selected and finally a freeze-dried preparation with good appearance, qualified quality and high stability was developed.

[0025] 2.1 Selection of vacuum degree

[0026] The vacuum degree in the freeze-drying process is generally controlled at 13Pa to 26Pa. In combination with the properties of the drug of the present invention and the characteristics of the drug solution and concentration, we screened the vacuum degree. The test results are shown in Table 2:

[0027] Table 2 Vacuum degree comparison test results

[0028]

[0029] From the test results in Table 2, it can be seen that conventional vacuum is not suitable for freeze-drying of this prescription. Under the condition of vacuum of 12Pa, the freeze-dried powder injection of this drug is well formed. (In order not to interfere with the test during the above screening process, the heating rate is set to a lower ≤2.0℃ / h.)

[0030] 2.2 Selection of sublimation heating rate

[0031] The speed of the temperature rise during the sublimation process in the freeze-drying process is also a major factor affecting the quality of freeze-drying. In the process of selecting the vacuum degree, we mainly examined the effects of freeze-drying with different vacuum degrees. In order not to interfere with the test, the temperature rise rate was set to a lower ≤2.0℃ / h. Here, we studied the sublimation temperature rise rate in combination with the characteristics of the composition of the present invention. The test results are shown in Table 3:

[0032] Table 3 Sublimation heating rate comparison test results

[0033]

[0034] It can be seen from the test results in Table 3 that when the heating rate is ≤2.2℃ / h, the freeze-dried product has good formation, and when the heating rate is ≥2.3℃ / h, bottle spraying occurs. Therefore, on the premise of ensuring the freeze-dried product quality and improving production efficiency, the sublimation heating rate is set to 2.0~2.2℃ / h.

[0035] 2.3 Selection of drying temperature and time

[0036] The drying temperature in the freeze-drying process generally does not exceed 38°C. In view of the characteristics of this drug, the drying temperature is set at 37°C. The drying time is studied, and the test results are shown in Table 4:

[0037] Table 4 Drying time comparison test results

[0038]

[0039] It can be seen from the test results in Table 4 that the moisture content is almost unchanged after drying for 4 hours. Under the premise of ensuring quality and improving efficiency, the drying time is set to 4 hours. Specific implementation method:

[0041] For a better understanding of the present invention, the following examples are provided to further illustrate the present invention, but the present invention is not limited to the following examples.

[0042] Example 1 Preparation of Papaverine Hydrochloride for Injection (Specification: 30 mg)

[0043] prescription:

[0044] Papaverine hydrochloride: 30 g

[0045] Mannitol: 80g

[0046] Sodium citrate: 8.0g

[0047] Sodium octanoate: 1.2g

[0048] Add water for injection to 2000ml

[0049] Made into 1000 pieces

[0050] (1) Add the prescribed amount of sodium citrate, mannitol, sodium caprylate, and papaverine hydrochloride to 1200 ml of water for injection in sequence and stir to dissolve. Add 10% citric acid solution dropwise to adjust the pH to 3.20, add water for injection to 2000 ml, and stir evenly.

[0051] (2) Filter the solution in step (1) through a 0.22 μm microporous filter membrane, determine the pH value and content of the filtrate, determine the filling volume according to the specifications, and divide the half-stoppered filling liquid into portions;

[0052] (3) Freeze-drying:

[0053] ① Pre-freezing: Place the aliquoted liquid in a freezer that has been pre-cooled to -42°C for 5 hours;

[0054] ② Sublimation: Turn on the vacuum device, adjust the vacuum degree to 12Pa, increase the temperature at a constant rate (2.1℃ / h) to -8℃, and maintain this temperature for 5 hours;

[0055] ③ Drying: uniformly raise the temperature to 37°C, dry for 4 hours, and package and store after passing the test to obtain papaverine hydrochloride for injection.

[0056] Example 2 Preparation of Papaverine Hydrochloride for Injection (Specification: 30 mg)

[0057] prescription:

[0058] Papaverine hydrochloride: 30 g

[0059] Mannitol: 80g

[0060] Sodium citrate: 8.0g

[0061] Sodium octanoate: 1.2g

[0062] Add water for injection to 2000ml

[0063] Made into 1000 pieces

[0064] (1) Add the prescribed amount of sodium citrate, mannitol, sodium caprylate, and papaverine hydrochloride to 1200 ml of water for injection in sequence and stir to dissolve. Add 10% citric acid solution dropwise to adjust the pH to 3.10, add water for injection to 2000 ml, and stir evenly.

[0065] (2) Filter the solution in step (1) through a 0.22 μm microporous filter membrane, determine the pH value and content of the filtrate, determine the filling volume according to the specifications, and divide the half-stoppered filling liquid into portions;

[0066] (3) Freeze-drying:

[0067] ① Pre-freezing: Place the aliquot in a freezer that has been pre-cooled to -44°C for 4 hours;

[0068] ② Sublimation: Turn on the vacuum device, adjust the vacuum degree to 12Pa, increase the temperature at a constant rate (2.0 / h) to -9°C, and maintain this temperature for 5 hours;

[0069] ③ Drying: uniformly raise the temperature to 37°C, dry for 4 hours, and package and store after passing the test to obtain papaverine hydrochloride for injection.

[0070] Example 3 Preparation of Papaverine Hydrochloride for Injection (Specification: 30 mg)

[0071] prescription:

[0072] Papaverine hydrochloride: 30 g

[0073] Mannitol: 80g

[0074] Sodium citrate: 8.0g

[0075] Sodium octanoate: 1.2g

[0076] Add water for injection to 2000ml

[0077] Made into 1000 pieces

[0078] (1) Add the prescribed amount of sodium citrate, mannitol, sodium caprylate, and papaverine hydrochloride to 1200 ml of water for injection in sequence and stir to dissolve. Add 10% citric acid solution dropwise to adjust the pH to 3.30, add water for injection to 2000 ml, and stir evenly.

[0079] (2) Filter the solution in step (1) through a 0.22 μm microporous filter membrane, determine the pH value and content of the filtrate, determine the filling volume according to the specifications, and divide the half-stoppered filling liquid into portions;

[0080] (3) Freeze-drying:

[0081] ① Pre-freezing: Place the aliquoted liquid in a freezer that has been pre-cooled to -40°C for 6 hours;

[0082] ② Sublimation: Turn on the vacuum device, adjust the vacuum degree to 12Pa, increase the temperature at a constant rate (2.2℃ / h) to -7℃, and maintain this temperature for 5 hours;

[0083] ③ Drying: uniformly raise the temperature to 37°C, dry for 4 hours, and package and store after passing the test to obtain papaverine hydrochloride for injection.

[0084] The present invention also provides the following stability test data:

[0085] Sample 1: papaverine hydrochloride for injection prepared in Invention Example 1;

[0086] Sample 2: papaverine hydrochloride for injection prepared according to Example 1 of Chinese application No. 202010822021.7;

[0087] Sample 3: Papaverine hydrochloride for injection prepared according to Example 2 of Chinese application No. 202110233742.9;

[0088] Samples 1-3 and commercially available products were subjected to accelerated stability tests (40°C ± 2°C, RH 75% ± 5%). The specific test method refers to: National Standard for Papaverine Hydrochloride for Injection WS1-XG-023-2015. The results are shown in Table 5:

[0089] Table 5 Accelerated test results

[0090]

[0091] It can be seen from Table 5 that the papaverine hydrochloride for injection prepared by the present invention has very stable indicators, which are significantly improved compared with the prior art, and the insoluble particles are low and stably maintained at a low level, which reduces the risk of medication. The same test was also conducted in other embodiments of the present application, and similar results were obtained. The above is only a preferred embodiment of the present invention, and of course it cannot be used to limit the scope of the rights of the present invention. It should be pointed out that for ordinary technicians in this technical field, without departing from the principle of the present invention, several improvements and changes can be made, and these improvements and changes are also regarded as the protection scope of the present invention.

Claims

1. A papaverine hydrochloride for injection, characterized in that: In addition to papaverine hydrochloride, it also contains: mannitol, sodium citrate, sodium caprylate, pH adjuster, and is prepared by adding water for injection.

2. Papaverine hydrochloride for injection as claimed in claim 1, characterized in that The concentration of papaverine hydrochloride is 1.5%, the concentration of mannitol is 4%, the concentration of sodium citrate is 0.4%, and the concentration of sodium octanoate is 0.06%.

3. Papaverine hydrochloride for injection according to claim 1 or 2, characterized in that, The specification of the papaverine hydrochloride for injection is 30 mg.

4. Papaverine hydrochloride for injection according to claim 1 or 2, characterized in that, The pH regulator is 10% citric acid solution.

5. The method for preparing papaverine hydrochloride for injection according to claim 1 or 2, comprising the following steps: (1) Add the prescribed amount of sodium citrate, mannitol, sodium caprylate, and papaverine hydrochloride to 1200 ml of water for injection in sequence and stir to dissolve. Add 10% citric acid solution dropwise to adjust the pH. Add water for injection to 2000 ml and stir evenly. (2) Filter the solution in step (1) through a 0.22 μm microporous filter membrane, determine the pH value and content of the filtrate, determine the filling volume according to the specifications, and divide the half-stoppered filling liquid into portions; (3) Freeze-drying: ① Prefreezing: Place the aliquoted liquid in a freezer that has been pre-cooled to -44℃~-40℃ for 4~6 hours; ②Sublimation: Turn on the vacuum device, adjust the vacuum degree, and uniformly raise the temperature to -9℃~-7℃, and maintain this temperature for 5 hours; ③ Drying: uniformly heat to 37°C, dry, and package and store after passing the test to obtain papaverine hydrochloride for injection.

6. The method for preparing papaverine hydrochloride for injection as claimed in claim 5, characterized in that: Adjust pH to 3.10-3.

30.

7. The method for preparing papaverine hydrochloride for injection as claimed in claim 5, characterized in that: Adjust the vacuum degree to 12Pa.

8. The method for preparing papaverine hydrochloride for injection as claimed in claim 5, characterized in that: The sublimation uniform temperature rise rate is 2.0~2.2℃ / h.

9. The method for preparing papaverine hydrochloride for injection as claimed in claim 5, characterized in that: Drying time is 4 hours.

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