Propafenone hydrochloride injection and preparation method thereof

Abstract

The invention discloses a propafenone hydrochloride injection and a preparation method thereof, and relates to the technical field of medical preparations. The propafenone hydrochloride injection comprises the following components: propafenone hydrochloride, an osmotic pressure regulator sodium chloride, an acidic pH value regulator and water for injection. Wherein the content of propafenone hydrochloride is 3.5 mg / mL, the concentration of sodium chloride is 0.95%, the pH value regulator is hydrochloric acid, the pH value of the injection is 3.5-4.5, the pH value of the injection is 3.5-4.0, the pH value of the injection is 3.6-3.8, the osmotic pressure molar concentration of the injection is 0.29-0.31 Osmo l / L, and the injection does not generate 5-hydroxymethylfurfural (5-HMF) impurities after being sterilized. While the osmotic pressure safety is ensured, the pH stability and the long-term stability of the product quality can be remarkably improved, the generation of 5-HMF is reduced, the irritation of 5-HMF to eyes, mucous membranes and skin is weakened, the stability is superior to that of an original development agent and the stability of a commercially available product in China, and the safety of the product is ensured.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to a propafenone hydrochloride injection and a preparation method thereof. Background Art

[0002] Propafenone hydrochloride, chemical name: 3-phenyl-1-[2-[3-(propylamino)-2-hydroxypropoxy]phenyl]-1-propanone hydrochloride, molecular formula: C21H27NO3·HCl, molecular weight: 377.91; it is a white crystalline powder, odorless, slightly soluble in ethanol, chloroform or glacial acetic acid, and very slightly soluble in water. This product is mainly used for the treatment of diseases such as paroxysmal supraventricular tachycardia, supraventricular tachycardia associated with preexcitation syndrome, prevention of atrial flutter or atrial fibrillation, and various premature beats.

[0003] Currently, the commercially available propafenone hydrochloride injections mainly have the following two prescription compositions: ① The propafenone hydrochloride injection marketed in the European Union, with the trade name Its prescription contains glucose as an osmotic pressure regulator; ② The prescriptions of propafenone hydrochloride injections marketed in China mostly do not contain glucose. For example, the propafenone hydrochloride injection of Guangzhou Baiyunshan Mingxing Pharmaceutical Co., Ltd., and the Chinese invention patent with the publication number CN118021718A.

[0004] On May 12, 2023, the Expert Committee on the Consistency Evaluation of the Quality and Efficacy of Generic Drugs of the National Medical Products Administration reviewed and determined, and issued the Catalogue of Generic Drug Reference Preparations (the sixty-eighth batch). Among them, the propafenone hydrochloride injection licensed by Mylan Healthcare Gmbh / Viatris Healthcare Limited / Mylan

[0005] GmbH / Teva Italia S.r.l. and marketed in the European Union was published at No. 56-37, with the trade name as a reference preparation. The instruction manual marketed in the European Union (Italy) has a prescription composition of containing 70 mg of propafenone hydrochloride, 1.076 g of glucose (monohydrate) in every 20 ml of injection, and an appropriate amount of water for injection.

[0006] Glucose is often used as an osmotic pressure regulator in injections. Its long-term storage or heating can lead to an increase in 5-hydroxymethylfurfural (5-HMF) and related substances. Among them, 5-HMF is irritating to the eyes, mucous membranes, and skin, and has neurotoxicity and genotoxicity. It can be metabolically converted into 5-sulfoxymethylfurfural (5-SMF) in the body, which has strong carcinogenicity and genotoxicity. When 5-HMF exceeds a certain limit, it will affect human safety. Therefore, most of the propafenone hydrochloride injections marketed in China do not contain glucose. Although the safety hazard of 5-HMF is removed, the risk of osmotic pressure safety is increased.

[0007] Therefore, a propafenone hydrochloride injection and its preparation method are proposed. Summary of the Invention

[0008] The purpose of the present invention is to provide a propafenone hydrochloride injection and its preparation method to solve the problems mentioned in the above background technology.

[0009] The present invention specifically adopts the following technical solutions to achieve the above purpose:

[0010] A propafenone hydrochloride injection, comprising the following components: propafenone hydrochloride, osmotic pressure regulator sodium chloride, acidic pH regulator, and water for injection. Among them, the content of propafenone hydrochloride is 3.5 mg / mL, the concentration of sodium chloride is 0.95%, the pH regulator is hydrochloric acid, and the pH value of the injection is 3.5 - 4.5.

[0011] Further, the pH value of the injection is 3.5 - 4.0.

[0012] Further, the pH value of the injection is 3.6 - 3.8.

[0013] Further, the osmotic pressure molar concentration of the injection is 0.29 - 0.31 Osmol / L.

[0014] Further, the injection does not produce 5-hydroxymethylfurfural (5-HMF) impurities after sterilization.

[0015] Further, the pH value of the injection fluctuates no more than ±0.2 within 30 days under light and high temperature conditions, the maximum single impurity ≤ 0.2%, and the total impurity ≤ 0.5%.

[0016] A preparation method of a propafenone hydrochloride injection, comprising the following steps:

[0017] Add 90% of the prescription amount of water for injection and control the temperature at 45°C - 55°C;

[0018] Add the prescription amount of propafenone hydrochloride and stir until dissolved;

[0019] Add sodium chloride and stir until completely dissolved;

[0020] Use a pH regulator to adjust the pH of the liquid medicine to 3.6 - 3.8;

[0021] Make up the volume to the prescription amount with additional injection water;

[0022] Through filtration, nitrogen filling, sealing, and sterilization, propafenone hydrochloride injection is obtained.

[0023] Furthermore, the filtration uses a 0.22 μm polyethersulfone filter element.

[0024] Furthermore, in the nitrogen filling step, control the residual oxygen content < 5%.

[0025] Furthermore, the sterilization conditions are sterilization at 121 °C for 12 minutes, and the F value ≥ 12.

[0026] The beneficial effects of the present invention are as follows:

[0027] While ensuring the safety of osmotic pressure, the present invention can significantly improve the pH stability of this product and the long-term stability of product quality, reduce the generation of 5-HMF, and weaken the irritation of 5-HMF to eyes, mucous membranes, and skin; this technical solution consists of propafenone hydrochloride, osmotic pressure regulator (sodium chloride), pH value regulator (hydrochloric acid), and injection water. Under the condition of ensuring the stable osmotic pressure of the product, by strictly controlling the pH range of this product to be 3.6 - 3.8, the generation of 5-HMF and other related substances is significantly reduced, and the stability is better than that of the original research preparation and domestic commercial products, ensuring the safety of the product. Description of the Drawings

[0028] Figure 1 It is a schematic flow chart of the preparation method of the present invention; Detailed Embodiments

[0029] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are some, but not all, of the embodiments of the present invention. Usually, the components of the embodiments of the present invention described and shown herein can be arranged and designed in various different configurations.

[0030] Therefore, the following detailed description of the embodiments of the present invention provided in the drawings is not intended to limit the scope of the claimed present invention, but merely represents selected embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts fall within the scope of protection of the present invention.

[0031] It should be noted that like reference numerals and letters refer to like items in the following figures. Therefore, once an item is defined in one figure, it does not need to be further defined and explained in subsequent figures. In addition, the terms "first", "second", etc. are only used for descriptive distinction and should not be construed as indicating or implying relative importance.

[0032] The electrical components appearing in this text are all electrically connected to an external main controller and 220V mains power, and the main controller can be a conventional known device such as a computer for control.

[0033] In the description of the embodiments of the present invention, it should be noted that the orientation or positional relationship indicated by the terms "inner", "outer", "upper", etc. is based on the orientation or positional relationship shown in the drawings, or the orientation or positional relationship in which the inventive product is customarily placed during use. It is only for the convenience of describing the present invention and simplifying the description, rather than indicating or implying that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore should not be construed as a limitation of the present invention.

[0034] A propafenone hydrochloride injection, comprising the following components: propafenone hydrochloride, osmotic pressure regulator sodium chloride, acidic pH regulator, and water for injection; wherein, the content of propafenone hydrochloride is 3.5 mg / mL, the concentration of sodium chloride is 0.95%, the pH regulator is hydrochloric acid, and the pH value of the injection is 3.5 - 4.5. The osmotic molality of the injection is 0.29 - 0.31 Osmol / L. The osmotic molality of the injection is 0.29 - 0.31 Osmol / L. The injection does not produce 5-hydroxymethylfurfural (5-HMF) impurities after sterilization. The pH value of the injection fluctuates by no more than ±0.2 within 30 days under light and high temperature conditions, the maximum single impurity ≤ 0.2%, and the total impurity ≤ 0.5%.

[0035] A preparation method of a propafenone hydrochloride injection, comprising the following steps:

[0036] Add 90% of the prescription amount of water for injection and control the temperature at 45°C - 55°C;

[0037] Add the prescription amount of propafenone hydrochloride and stir until dissolved;

[0038] Add sodium chloride and stir until completely dissolved;

[0039] Use a pH regulator to adjust the pH of the liquid medicine to 3.6 - 3.8;

[0040] Make up the volume to the prescription amount with water for injection;

[0041] After filtration, nitrogen filling, sealing, and sterilization, a propafenone hydrochloride injection is obtained.

[0042] The filtration uses a 0.22 μm polyethersulfone filter element. In the nitrogen filling step, the residual oxygen content is controlled to be <5%. The sterilization condition is sterilization at 121 °C for 12 minutes, and the F value ≥ 12.

[0043] While ensuring the osmotic pressure safety, the present invention can significantly improve the pH stability of this product and the long-term stability of the product quality, reduce the generation of 5-HMF, and weaken the irritation of 5-HMF to the eyes, mucous membranes and skin; this technical solution consists of propafenone hydrochloride, an osmotic pressure regulator (sodium chloride), a pH value regulator (hydrochloric acid), and water for injection. Under the condition of ensuring the stable osmotic pressure of the product, by strictly controlling the pH range of this product to be 3.6 - 3.8, the generation of 5-HMF and other related substances is significantly reduced, and the stability is better than that of the original research preparation and domestic market products, ensuring the safety of the product.

[0044] Example 1

[0045] Prescription composition:

[0046]

[0047]

[0048] The dosage of propafenone hydrochloride is 35 mg, the dosage of sodium chloride is 95 mg, the pH regulator is hydrochloric acid, the pH value of the prepared solution is adjusted to 3.6, and the water for injection is added to 10 ml.

[0049] The preparation method of the propafenone hydrochloride injection: Add about 90% of the prescription amount of water for injection, and control the temperature at 45 °C. Add propafenone hydrochloride, stir until dissolved, then add sodium chloride and stir until completely dissolved. Use an acidic pH regulator (hydrochloric acid in this example) to adjust the pH value of the medicinal solution to 3.6, and make up the water for injection to the prescription amount. After volume fixation, filter through a 0.22 μm filter element (the filter element material is polyethersulfone), fill with nitrogen (control the residual oxygen content <0.5%), fill, and sterilize (the sterilization temperature is 121 °C, the sterilization time is 12 minutes, and the F0 value ≥ 12) to obtain the finished product of propafenone hydrochloride injection.

[0050] Example 2

[0051] The prescription composition is the same as that of Example 1. Preparation method: Add about 90% of the injection water in the prescription amount, control the temperature at 55 °C. Add propafenone hydrochloride, stir until dissolved, then add sodium chloride and stir until completely dissolved. Use an acidic pH regulator (hydrochloric acid in this example) to adjust the pH value of the liquid medicine to 3.8, and make up the injection water to the prescription amount. After volume fixation, filter through a 0.22 μm filter element (the filter element material is polyethersulfone), fill with nitrogen (control the residual oxygen content < 0.5%), fill, and sterilize (the sterilization temperature is 121 °C, the sterilization time is 12 minutes, and the F0 value ≥ 12) to obtain the finished product of propafenone hydrochloride injection.

[0052] Comparative Example 1: The reference preparation of propafenone hydrochloride injection (20 ml: 70 mg) marketed in Italy (Holder: Teva Italia S.r.l.).

[0053] Comparative Example 2: The reference preparation of propafenone hydrochloride injection (20 ml: 70 mg) marketed in Italy (Holder: Teva Italia S.r.l.), and perform terminal sterilization under the conditions of 121 °C for 12 min.

[0054] Comparative Example 3: The commercially available product of propafenone hydrochloride injection (10 ml: 35 mg) marketed in China (manufacturer: Guangzhou Baiyunshan Mingxing Pharmaceutical Co., Ltd.).

[0055] Comparative Example 4: The commercially available product of propafenone hydrochloride injection (10 ml: 35 mg) marketed in China (manufacturer: Guangzhou Baiyunshan Mingxing Pharmaceutical Co., Ltd.), and perform terminal sterilization under the conditions of 121 °C for 12 min.

[0056] Comparative Example 5: The formula and preparation method of propafenone hydrochloride injection are basically the same as those in the implementation manner, except that terminal sterilization is not performed.

[0057] Comparative Example 6: The formula and preparation method of propafenone hydrochloride injection are basically the same as those in the implementation manner, except that propafenone hydrochloride is not added and terminal sterilization is not performed.

[0058] Comparative Example 7: The formula and preparation method of propafenone hydrochloride injection are basically the same as those in the implementation manner, except that propafenone hydrochloride is not added.

[0059] Comparative Example 8: The formula and preparation method of propafenone hydrochloride injection are basically the same as those in the implementation manner, except that the pH value range of the prepared solution is adjusted to 3.5 ± 0.2.

[0060] Comparative Example 9: The formula and preparation method of propafenone hydrochloride injection are basically the same as those in the implementation manner, except that the pH value range of the prepared solution is adjusted to 4.0 ± 0.2.

[0061] Comparative Example 10: The formulation and preparation method of propafenone hydrochloride injection are basically the same as those in the embodiment. The difference is that the pH value range of the prepared solution is adjusted to 4.5 ± 0.2.

[0062] Comparative Example 11: The formulation and preparation method of propafenone hydrochloride injection are basically the same as those in the embodiment. The difference is that the pH value range of the prepared solution is adjusted to 5.0 ± 0.2.

[0063] Comparison results of Example 1 under different conditions with each comparative example:

[0064] Table 1 Terminal sterilization results of propafenone hydrochloride injection

[0065]

[0066]

[0067] The above experimental results show that a certain amount of related substances are generated before sterilization of the reference preparation, and the related substances increase significantly after sterilization, especially the 5-HMF impurity increases significantly; the commercially available product and the self-made preparation do not contain glucose, and 5-HMF is not detected before and after sterilization, and there is no significant change in other related substances, indicating that the raw material propafenone hydrochloride is stable to high temperature, and the related substances mainly come from the auxiliary material glucose. For the commercially available product without adding the osmotic pressure regulators glucose and sodium chloride, there is a certain risk of osmotic pressure, which may cause certain irritation to the drug administration site during use and bring adverse effects to patients. For the self-made preparation added with the osmotic pressure regulator sodium chloride, there is no significant change in the related substances before and after sterilization, 5-HMF is not detected before and after sterilization, and the osmotic pressure concentration is within the effective control range, which will not cause irritation to patients.

[0068] Table 2 Detection results of propafenone hydrochloride injection with different pH values

[0069]

[0070]

[0071] To determine the effect of the pH of the liquid medicine on the stability of propafenone hydrochloride injection, the quality of propafenone hydrochloride injection products with different pH values was tested respectively. From the above data, it can be seen that with the increase of pH (pH 3.5 - 5.0), 5-HMF was not detected in the self-made preparations, the maximum single impurity and total impurities gradually increased, and the stability gradually decreased. When pH ≥ 4.5, the maximum single impurity exceeded the quality standard range, and the total impurities were close to or even exceeded the control limit; when the pH of the self-made preparation ≤ 4.0, the self-made preparation was still relatively stable after 30 days of investigation under the conditions of light and high temperature, and the maximum single impurity and total impurities of the self-made preparation were both small; while the pH of the reference preparation showed obvious fluctuations after 30 days of investigation under the conditions of light and high temperature, and 5-HMF, the maximum single impurity and total impurities all increased significantly and exceeded the control limit. Therefore, the pH control range is very important for ensuring the quality of this product and improving the stability. In this technical solution, it is required that the pH of the preparation liquid be controlled within 3.6 - 3.8, and its beneficial effect is significantly better than the existing technical solution.

[0072] To sum up: while ensuring the safety of osmotic pressure, the present invention can significantly improve the pH stability of this product and the long-term stability of product quality, reduce the generation of 5-HMF, and weaken the irritation of 5-HMF to the eyes, mucous membranes and skin; this technical solution is composed of propafenone hydrochloride, osmotic pressure regulator (sodium chloride), pH regulator (hydrochloric acid) and water for injection. Under the condition of ensuring the stability of the osmotic pressure of the product, by strictly controlling the pH range of this product to be 3.6 - 3.8, the generation of 5-HMF and other related substances is significantly reduced, and the stability is better than that of the original research preparation and domestic market products, ensuring the safety of the product.

[0073] The above shows and describes the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments. What is described in the above embodiments and the specification is only the principle of the present invention. Without departing from the spirit and scope of the present invention, the present invention will have various changes and improvements, and these changes and improvements all fall within the scope of the present invention claimed. The scope of protection claimed by the present invention is defined by the appended claims and their equivalents.

Claims

1. A propafenone hydrochloride injection, characterized in that: The invention comprises the following components: propafenone hydrochloride, osmotic pressure regulator sodium chloride, acidic pH regulator and water for injection; wherein the content of propafenone hydrochloride is 3.5 mg / mL, the concentration of sodium chloride is 0.95%, the pH regulator is hydrochloric acid, and the pH value of the injection is 3.5-4.

5.

2. A propafenone hydrochloride injection according to claim 1, characterized in that: The pH value of the injection is 3.5-4.

0.

3. A propafenone hydrochloride injection according to claim 1, characterized in that: The pH value of the injection is 3.6-3.

8.

4. The propafenone hydrochloride injection according to any one of claims 1 to 3, characterized in that: The osmotic pressure molar concentration of the injection is 0.29-0.31 Osmol / L.

5. The propafenone hydrochloride injection according to any one of claims 1 to 3, characterized in that: The injection does not generate 5-hydroxymethylfurfural (5-HMF) impurities after sterilization.

6. The propafenone hydrochloride injection according to any one of claims 1 to 3, characterized in that: The pH value of the injection under light and high temperature conditions fluctuates within ±0.2 within 30 days, the maximum single impurity is ≤0.2%, and the total impurity is ≤0.5%.

7. A method for preparing the propafenone hydrochloride injection according to any one of claims 1 to 3, characterized in that: The following steps are involved: Add 90% of the prescribed amount of water for injection and control the temperature at 45℃~55℃; Add the prescribed amount of propafenone hydrochloride and stir until dissolved; Add sodium chloride and stir until completely dissolved; Use a pH adjuster to adjust the pH of the solution to 3.6-3.8; Add water for injection to make up to the prescribed amount; The propafenone hydrochloride injection is obtained through filtration, nitrogen filling, sealing and sterilization.

8. The method for preparing propafenone hydrochloride injection according to claim 4, characterized in that: The filtration uses a 0.22 μm polyethersulfone filter element.

9. The method for preparing propafenone hydrochloride injection according to claim 4, characterized in that: In the nitrogen filling step, the residual oxygen content is controlled to be less than 5%.

10. The method for preparing propafenone hydrochloride injection according to claim 4, characterized in that: The sterilization condition is sterilization at 121° C. for 12 minutes, with an F value ≥12.

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