Ppenehyclidine hydrochloride injection and preparation method thereof

Abstract

The invention provides a penehyclidine hydrochloride injection and a preparation method thereof. The preparation method comprises the step of filling a polypropylene medicinal plastic ampoule bottle with a penehyclidine hydrochloride intermediate liquid medicine. According to the method, pre-acidification heat treatment does not need to be carried out on the inner packing material, and the intermediate liquid medicine does not need to be controlled within a narrow pH range. By adopting the technical scheme, the problems that the pH value of the liquid medicine is increased and the content of the liquid medicine is reduced in the high-temperature sterilization process and the stable placement process can be solved, meanwhile, a wider intermediate pH range (pH 4.5-6.0) is controlled in the production process, the operability of the production is more facilitated, the packaging material is easy to obtain, the production process is simple and convenient, and the production effect is improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to pentoxyverine hydrochloride injection and its preparation method. Background Technology

[0002] Pentylcholine hydrochloride is a novel selective anticholinergic drug that binds to both M and N cholinergic receptors, inhibiting the physiological functions of smooth muscle and glands innervated by postganglionic cholinergic nerves. It counteracts the muscarinic and nicotinic effects of acetylcholine and other cholinergic drugs. It can cross the blood-brain barrier, thus possessing both strong and comprehensive central and peripheral anticholinergic effects. Its structural formula is:

[0003]

[0004] Pentylcholine hydrochloride is commonly available in injection form. It is used for pre-anesthetic administration to inhibit salivary and airway gland secretion, and for emergency treatment of organophosphate poisoning (pesticide) and for maintaining atropinization in the later stages of poisoning or after cholinesterase (ChE) aging. National drug standards require that the pH of pentylcholine hydrochloride injection be controlled between 4.5 and 6.5.

[0005] Chinese patent CN102525909B discloses that: "The inventors' experimental research found that: when the pentoxyverine hydrochloride compound is dissolved in water and then directly filled into any commercially available untreated ampoules and vials, its stability is poor. After being stored for 8 months, there are significant changes in pH value and content. These changes in pH value and content cause instability in drug quality and efficacy, and may even exceed the acceptable limits, making it a substandard drug." To solve this problem, this application adjusts the pH value of the pentoxyverine hydrochloride intermediate solution to 4.6-4.8 before filling it into pharmaceutical glass ampoules or vials.

[0006] To address the issue of pH increase and content decrease in pentoxyverine hydrochloride injection during stable storage and prevent substandard products, Chinese patent CN102525910B proposes a pre-treatment method involving acidification and heat treatment of the inner packaging material (ampoules or vials) with different concentrations of acid before filling.

[0007] Chinese patent CN103271872B discloses a method for preparing pentoxyverine hydrochloride injection. The method involves dissolving pentoxyverine hydrochloride in water for injection, adding 0.01% activated carbon and stirring, then circulating the solution with a titanium rod for 15 minutes to remove carbon, adjusting the pH to 4.30 with hydrochloric acid solution, filtering the solution through a filter membrane, and then filling it into a low-borosilicate or medium-borosilicate ampoule.

[0008] Chinese patent CN103284943B discloses a preparation process for pentoxyverine hydrochloride injection. This preparation process involves heat-treating the inner packaging material (ampoules or vials) with hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, nitric acid, or oxalic acid solutions, and controlling the pH value of the intermediate drug solution to 4.6-4.8. This addresses the problem of pH increase and content decrease in pentoxyverine hydrochloride injection during stable storage, thus preventing the production of substandard products.

[0009] Chinese patent CN112716889B discloses a method for preparing pentoxyverine hydrochloride injection. The method involves adjusting the pH value of the pentoxyverine hydrochloride solution, filtering it once through a series of large-pore and small-pore filter cartridges until the pH value stabilizes, and then filtering it a second time to sterilize it before filling and sealing.

[0010] Given the existing technology, it is still necessary to provide a new solution that simplifies the formulation process of pentoxyverine hydrochloride injection and ensures product quality compliance throughout its shelf life. Summary of the Invention

[0011] The present invention provides a method for preparing pentoxyverine hydrochloride injection, the method comprising the step of filling pentoxyverine hydrochloride intermediate solution into pharmaceutical plastic ampoules.

[0012] In some specific embodiments, the pharmaceutical plastic ampoule is a polypropylene pharmaceutical plastic ampoule.

[0013] In some specific embodiments, the pH of the pentoxyverine hydrochloride intermediate solution is 4.5 to 6.0.

[0014] In some specific embodiments, the pentoxyverine hydrochloride intermediate solution is prepared by the following method: adding the prescribed amount of pentoxyverine hydrochloride raw material to 80% of the prescribed amount of water for injection, stirring to dissolve, adjusting the pH of the solution to 4.5-6.0 with a pH adjuster, adding water for injection to the prescribed amount, stirring to mix well, and obtaining the pentoxyverine hydrochloride intermediate solution.

[0015] In some specific embodiments, the prescription is 0.5 mg or 1 mg of pentoxyverine hydrochloride, diluted with water for injection to 1.0 ml.

[0016] In some specific embodiments, the pH of the drug solution is adjusted using hydrochloric acid aqueous solution or sodium hydroxide aqueous solution, preferably with a concentration of 0.1-0.5 mol / L for the hydrochloric acid aqueous solution and a concentration of 0.1-0.5 mol / L for the sodium hydroxide aqueous solution.

[0017] In some specific embodiments, the preparation method of the pentoxyverine hydrochloride injection further includes the step of filtering the pentoxyverine hydrochloride intermediate solution through a filter membrane before filling, preferably the filter membrane has a pore size of 0.22 μm.

[0018] In some specific embodiments, the preparation method of the pentoxyverine hydrochloride injection further includes the steps of filling, sealing and sterilization; preferably, the sterilization is a high-temperature sterilization treatment at 121℃-124℃ for 12-15 minutes.

[0019] Another aspect of the present invention provides a pentoxyverine hydrochloride injection solution, wherein the injection solution is composed of pentoxyverine hydrochloride raw material, a pH adjuster, and water for injection, and has a pH value of 4.5 to 6.5. The inner packaging material of the injection solution is a polypropylene pharmaceutical plastic ampoule. Preferably, the pH adjuster is an aqueous solution of hydrochloric acid or an aqueous solution of sodium hydroxide.

[0020] Using the preparation method of this invention, the pH of the pentoxyverine hydrochloride intermediate solution is controlled to 4.5–6.0, and the solution is filled into polypropylene pharmaceutical plastic ampoules. After high-temperature sterilization, the product is placed under accelerated conditions for 6 months, and the content and pH of the product show no significant changes. This invention does not require pretreatment of the inner packaging material, nor does it require controlling the pH of the intermediate solution within a narrower range. With the development of blow-fill-seal (BFS) integrated equipment and technology in my country, polypropylene pharmaceutical plastic ampoules have been widely used in injectable products, and the packaging material is readily available.

[0021] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0022] (1) This invention eliminates the need for pre-acidification heat treatment of the inner packaging material and the need to control the intermediate drug solution within a narrow pH range. By adopting the technical solution of this invention, the problems of pH increase and content decrease of the drug solution during high-temperature sterilization and stable storage can be solved. At the same time, controlling a wider pH range of intermediates (pH 4.5 to 6.0) during production is more conducive to the operability of production. Furthermore, the packaging material is readily available, the production process is simple, and it is beneficial to improve the production efficiency.

[0023] (2) The pentoxyverine hydrochloride injection provided by the present invention not only has stable product quality during production and stable storage, but also has no upward trend in pH value during storage, ensuring product quality and medication safety during shelf life. Detailed Implementation

[0024] The specific embodiments of the present invention will be described in further detail below with reference to the examples. These examples are for illustrative purposes only and are not intended to limit the scope of the invention.

[0025] All ranges described in this invention include the endpoints of the range between two values, whether or not indicated. All values ​​listed in this invention include the degree of expected experimental error, technical error, and instrumental error of the given technique used to measure that value. When the degree of error is not stated, all values ​​listed in this invention encompass a range of ±10% of the stated value.

[0026] In this invention, unless otherwise stated, % is a percentage of weight / weight (w / w).

[0027] Unless otherwise specified, all materials used in this invention are commercially available.

[0028] In this invention, "pentoxyverine hydrochloride intermediate solution" means a pharmaceutical intermediate, referring to a solution that has been prepared but not sterilized at high temperature.

[0029] The method for determining the pH value of pentoxyverine hydrochloride injection is as follows: Determined according to General Chapter 0631 of Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0030] HPLC conditions for determining the content of pentoxyverine hydrochloride injection:

[0031] Instrument: High-performance liquid chromatograph equipped with a DAD detector

[0032] Column: SHIMADZU Inertsil ODS-3V, 4.6*250mm, 5μm

[0033] Mobile phase A: 0.02 mol / L dipotassium hydrogen phosphate buffer (weigh 3.48 g of anhydrous dipotassium hydrogen phosphate, dissolve in 1000 ml of water, add 10.0 ml of triethylamine, and adjust the pH to 5.0 with phosphoric acid): acetonitrile = 80:20 (v / v)

[0034] Mobile phase B: 80% acetonitrile aqueous solution

[0035] Wavelength: 206nm; Flow rate: 1.0ml / min

[0036] Injection volume: 10 μl; Column temperature: 35℃; Run time: 22 min

[0037] gradient:

[0038] Time (minutes) Mobile phase A (v / v, %) Mobile phase B (v / v, %) 0 78 22 5 78 22 10 70 30 11 10 90 16 10 90 17 78 22 22 78 22

[0039] Example 1

[0040] Prescription: Pentyl quinone hydrochloride 1g

[0041] Appropriate amount of hydrochloric acid / sodium hydroxide

[0042] Add water for injection to 1000ml

[0043] Preparation process:

[0044] Weigh 80% of the prescribed amount of water for injection, add the prescribed amount of pentoxyverine hydrochloride raw material, stir to dissolve, adjust the pH of the solution to 4.5 with 0.2 mol / L hydrochloric acid solution, and then add water for injection to the prescribed amount; filter through a 0.22 μm PES filter membrane to obtain the pentoxyverine hydrochloride intermediate solution, and measure the pH value; fill the above intermediate solution into polypropylene plastic ampoules, and sterilize at 121°C for 12 min to obtain pentoxyverine hydrochloride injection.

[0045] Different pH values ​​of pentoxyverine hydrochloride raw materials were taken, and the pH values ​​of the pentoxyverine hydrochloride intermediate drug solution were adjusted to different ranges by adding 0.2 mol / L hydrochloric acid solution or 0.2 mol / L sodium hydroxide solution to prepare different pentoxyverine hydrochloride injection solutions. The preparation process was the same as in Example 1. Table 1 shows the pentoxyverine hydrochloride injection solutions prepared under different conditions.

[0046] Table 1

[0047]

[0048] Comparative Example 1

[0049] Prescription: Pentyl quinone hydrochloride 1g

[0050] Appropriate amount of hydrochloric acid / sodium hydroxide

[0051] Add water for injection to 1000ml

[0052] Weigh 80% of the prescribed amount of water for injection, add the prescribed amount of pentoxyverine hydrochloride (the same batch of raw material as in Example 1, pH 6.0), stir to dissolve, adjust the pH of the solution to 4.5 with 0.2 mol / L hydrochloric acid solution, and then add water for injection to the prescribed amount; filter through a 0.22 μm PES filter membrane to obtain the pentoxyverine hydrochloride intermediate solution, and measure the pH value; fill the above intermediate solution into untreated glass ampoules, and sterilize at 121°C for 12 min to obtain pentoxyverine hydrochloride injection.

[0053] Comparative Example 2

[0054] Weigh 80% of the prescribed amount of water for injection, add the prescribed amount of pentoxyverine hydrochloride (the same batch of raw material as in Example 3, pH 6.0), stir to dissolve, adjust the pH of the solution to 5.7 using 0.2 mol / L hydrochloric acid solution or sodium hydroxide solution, and then add water for injection to the prescribed amount; filter through a 0.22 μm PES filter membrane to obtain the pentoxyverine hydrochloride intermediate solution, and measure the pH value; fill the above intermediate solution into untreated glass ampoules, and sterilize at 121°C for 12 min to obtain pentoxyverine hydrochloride injection.

[0055] Comparative Example 3

[0056] This comparative example refers to the inner packaging material pretreatment process described in Chinese Patent CN103284943B, which involves acidification and heat treatment of glass ampoules: the glass ampoules are filled with 0.1mol / L hydrochloric acid solution (prepared with water for injection, temperature 75℃), soaked for 1 hour, then dried, washed with purified water and water for injection, sterilized and dried at high temperature, and then ready for use.

[0057] Weigh 80% of the prescribed amount of water for injection, add the prescribed amount of pentoxyverine hydrochloride (the same batch of raw material as in Example 1, pH 6.0), stir to dissolve, adjust the pH of the solution to 4.5 with 0.2 mol / L hydrochloric acid solution, and then add water for injection to the prescribed amount; filter through a 0.22 μm PES filter membrane to obtain the pentoxyverine hydrochloride intermediate solution, and measure the pH value; fill the above intermediate solution into the above-mentioned acidified heat-treated spare glass ampoules, and sterilize at 121°C for 12 min to obtain pentoxyverine hydrochloride injection.

[0058] Comparative Example 4

[0059] This comparative example uses the inner packaging material pretreatment process described in Chinese patent CN103284943B to perform acidification and heat treatment on the glass ampoules: fill the glass ampoules with 0.1mol / L hydrochloric acid solution (prepared with water for injection, temperature 75℃), soak for 1 hour, spin dry, wash with purified water and water for injection, sterilize and dry at high temperature, and set aside for use.

[0060] Weigh 80% of the prescribed amount of water for injection, add the prescribed amount of pentoxyverine hydrochloride (the same batch of raw material as in Example 3, pH 6.0), stir to dissolve, adjust the pH of the solution to 6.0 using 0.2 mol / L hydrochloric acid solution or sodium hydroxide solution, and then add water for injection to the prescribed amount; filter through a 0.22 μm PES filter membrane to obtain the pentoxyverine hydrochloride intermediate solution, and measure the pH value; fill the above intermediate solution into the above-mentioned acidified heat-treated spare glass ampoules, and sterilize at 121°C for 12 min to obtain pentoxyverine hydrochloride injection.

[0061] Example 10: Stability test:

[0062] The pentoxyverine hydrochloride injection solutions prepared according to the methods of Examples 1-9 and Comparative Examples 1-4 were placed in constant temperature and humidity chambers under influencing conditions (60±2℃ / 75±5%RH) and accelerated conditions (40±2℃ / 75±5%RH), respectively. Samples were taken after 10 days and 30 days under influencing conditions (60±2℃ / 75±5%RH), and after 1 month, 3 months, and 6 months under accelerated conditions (40±2℃ / 75±5%RH). The pH value and pentoxyverine hydrochloride content of the products were measured, and the results are shown in Table 2.

[0063] Table 2. Results of stability study of pentoxyverine hydrochloride injection

[0064]

[0065] As can be seen from the stability data in Table 2, based on the data from Comparative Examples 1-2, when the pentoxyverine hydrochloride intermediate solution was filled into untreated glass ampoules and sterilized at high temperature, the content of pentoxyverine hydrochloride injection showed a decreasing trend, and the pH value changed significantly. During the stabilization process, the pH value of the solution increased and exceeded the upper limit of the pH value standard for the preparation (the pH value standard for the preparation is 4.5 to 6.5), which did not meet the product quality requirements.

[0066] According to the data from Comparative Examples 3-4, after the pentoxyverine hydrochloride intermediate solution was filled into pre-acidified and heat-treated glass ampoules and sterilized at high temperature, the pH value and content of the pentoxyverine hydrochloride injection met the product quality standards. However, during the stability storage process, the pH of the solution still showed an upward trend, indicating a risk of product non-compliance.

[0067] The pentoxyverine hydrochloride injection prepared according to the preparation process of the present invention was tested and found that: the pH value and content both met the quality standards for pentoxyverine hydrochloride injection; the pH value showed no upward trend, and the content showed no downward trend.

[0068] The specific embodiments described in this invention are merely illustrative of the spirit of the invention. Those skilled in the art can make various modifications or additions to the described specific embodiments or use similar methods to substitute them, without departing from the spirit of the invention or exceeding the scope defined by the appended claims.

Claims

1. A method for preparing pentoxyverine hydrochloride injection, characterized in that: The method includes the step of filling a solution of pentoxyverine hydrochloride intermediate into pharmaceutical plastic ampoules.

2. The preparation method according to claim 1, characterized in that, The pharmaceutical plastic ampoule is a polypropylene plastic ampoule.

3. The preparation method according to claim 1, characterized in that, The pH of the pentoxyverine hydrochloride intermediate solution is 4.5–6.

0.

4. The preparation method according to claim 1, characterized in that, The pentoxyverine hydrochloride intermediate solution is prepared by the following method: 80% of the prescribed amount of water for injection is added to the prescribed amount of pentoxyverine hydrochloride raw material, stirred and dissolved, the pH of the solution is adjusted to 4.5-6.0 with a pH adjuster, water for injection is added to the prescribed amount, and the mixture is stirred until homogeneous to obtain the pentoxyverine hydrochloride intermediate solution.

5. The preparation method according to claim 4, characterized in that, The prescription is 0.5 mg or 1 mg of pentoxyverine hydrochloride, diluted with water for injection to 1.0 ml.

6. The preparation method according to claim 4, characterized in that, The pH adjuster is an aqueous solution of hydrochloric acid or an aqueous solution of sodium hydroxide; preferably, the concentration of the aqueous solution of hydrochloric acid is 0.1-0.5 mol / L, and the concentration of the aqueous solution of sodium hydroxide is 0.1-0.5 mol / L.

7. The preparation method according to claim 4, characterized in that, The preparation method of the pentoxyverine hydrochloride injection further includes the step of filtering the pentoxyverine hydrochloride intermediate solution through a filter membrane before filling; preferably, the pore size of the filter membrane is 0.22 μm.

8. The preparation method according to claim 4, characterized in that, The preparation method of the pentoxyverine hydrochloride injection further includes the steps of filling, sealing and sterilization; preferably, the sterilization is performed at a high temperature of 121℃-124℃ for 12-15 minutes.

9. A pentoethione hydrochloride injection, characterized in that, The injection solution is composed of pentoxyverine hydrochloride raw material, pH adjuster and water for injection, with a pH value of 4.5 to 6.

5. The inner packaging material of the injection solution is a polypropylene pharmaceutical plastic ampoule.

10. The injection solution according to claim 9, characterized in that, The pH adjuster is an aqueous solution of hydrochloric acid or an aqueous solution of sodium hydroxide.

Images