Preparation method of penehyclidine hydrochloride preparation

Abstract

The invention provides a preparation method of a penehyclidine hydrochloride preparation. The preparation method comprises the following steps: (1) adding preparation water accounting for 50-80% of the total preparation amount into a preparation container, introducing CO2 into the preparation water, and controlling the dissolved oxygen content to be below 6mg / L; (2) adding penehyclidine hydrochloride, uniformly stirring, then adding preparation water to the total amount, uniformly stirring, simultaneously introducing CO2, and controlling dissolved oxygen to be below 6mg / L to obtain a penehyclidine hydrochloride liquid with the pH of 4.5-6.5 and the concentration of 0.5-1.5 mg / mL; and (3) filtering the penehyclidine hydrochloride liquid medicine, filling a cleaned storage container with the filtered penehyclidine hydrochloride liquid medicine, filling CO2 into the headspace, and performing sealing and high-temperature sterilization to obtain the penehyclidine hydrochloride preparation. The preparation method provided by the invention can effectively improve the pH value stability of the penehyclidine hydrochloride preparation after long-term storage, and is beneficial to industrial large-scale production.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and more specifically, to a method for preparing a penehyclidine hydrochloride preparation. Technical Background

[0002] Penehyclidine hydrochloride is a new type of selective anticholinergic drug that can enter the brain through the blood-brain barrier. It can block the stimulatory effect of acetylcholine on muscarinic receptors (M receptors) and nicotinic receptors (N receptors) in the brain; therefore, it can be used to treat central poisoning symptoms caused by organophosphorus poisons (pesticides), such as convulsions, central respiratory and circulatory failure, and irritability. Currently, penehyclidine hydrochloride injection is mainly used clinically. Its usual preparation process is to dissolve the penehyclidine hydrochloride compound in water and fill it in an ampoule or a vial. The injection has the problem of poor stability. Long-term storage (such as more than 6 months) is prone to a significant increase in pH value, and a significant change in pH may cause unstable drug quality and efficacy.

[0003] Patent CN102525909B proposes to use hydrochloric acid aqueous solution to adjust the pH value of penehyclidine hydrochloride solution, and then fill it into a medicinal glass ampoule or glass vial, sterilize it at high temperature, and obtain penehyclidine hydrochloride injection with improved pH stability. However, the use of hydrochloric acid actually increases the types of preparation excipients, which is inconsistent with the principle of "the types and amounts of excipients used in injections should be as small as possible under the premise of meeting the needs" in the "Basic Technical Requirements for Chemical Injections". CN102525910B proposes that before bottling, the inner packaging material should be acidified and heat treated with acid solution in advance, and then the penehyclidine hydrochloride solution should be sealed in the spare inner packaging material; CN107638383A proposes that before bottling, the inner packaging material should be soaked in drinking water at 60 to 120°C. These two production methods are limited by equipment conditions and are not suitable for industrial scale-up production. Summary of the invention

[0004] In the present application, the inventors have developed a novel preparation method that can improve the pH stability of penehyclidine hydrochloride preparations and is suitable for industrial scale-up production. The dissolved oxygen content and pH value are adjusted by introducing CO2 during the preparation of penehyclidine hydrochloride solution, and CO2 is introduced as a protective gas after filling, so that the pH value of the penehyclidine hydrochloride preparation can remain stable after long-term storage, meeting the high quality requirements for use as injection and the like. The preparation method does not require the use of hydrochloric acid or other pH regulators or buffers to adjust the pH value, reduces the types of excipients, reduces the risks that may be caused by excipients, and does not require acidification heat treatment or soaking heat treatment of the inner packaging material before filling. It has the advantages of simple steps, low cost, and suitability for industrial scale-up production.

[0005] In some embodiments, the preparation method of the penehyclidine hydrochloride preparation comprises the following steps:

[0006] (1) Add 50%-80% of the total preparation water into the preparation container, introduce CO2 into the preparation water, and control the dissolved oxygen content to be below 6 mg / L;

[0007] (2) adding penehyclidine hydrochloride, stirring evenly, then adding preparation water to the full amount, stirring evenly, and introducing CO2 at the same time to control the dissolved oxygen below 6 mg / L to obtain a penehyclidine hydrochloride solution with a pH of 4.5 to 6.5, wherein the concentration of the penehyclidine hydrochloride solution is 0.5 to 1.5 mg / mL;

[0008] (3) filtering the penehyclidine hydrochloride liquid, filling it into a clean storage container, filling the headspace with CO2, sealing it, and sterilizing it at high temperature to obtain the penehyclidine hydrochloride preparation.

[0009] In some embodiments, the dissolved oxygen content in step (1) and step (2) can be monitored in real time, and CO2 can be introduced to control the dissolved oxygen level.

[0010] In some embodiments, step (2) further comprises monitoring the pH value of the penehyclidine hydrochloride solution in real time to obtain a penehyclidine hydrochloride solution that meets the desired pH value requirement.

[0011] In some embodiments, the dissolved oxygen content in step (1) and step (2) is controlled to be 4 mg / L to 6 mg / L, and the pH value of the penehyclidine hydrochloride solution is 4.5 to 5.5.

[0012] In some embodiments, the dissolved oxygen content in step (1) and step (2) is controlled to be 4 mg / L to 5.8 mg / L, and the pH value of the penehyclidine hydrochloride solution is 4.5 to 5.3.

[0013] In some embodiments, the dissolved oxygen content in step (1) and step (2) is controlled to be 1 mg / L to 3 mg / L, and the pH value of the penehyclidine hydrochloride solution is 4.5 to 5.0.

[0014] In some embodiments, the dissolved oxygen content in step (1) and step (2) is controlled to be 1 mg / L to 3 mg / L, and the pH value of the penehyclidine hydrochloride solution is 4.5 to 4.8.

[0015] In some embodiments, the temperature of step (1) and step (2) is controlled at 30-90° C., and the penehyclidine hydrochloride solution needs to be controlled at room temperature before filtering in step (3).

[0016] In some embodiments, the high temperature sterilization conditions are: sterilization temperature of about 121°C, time of about 12 minutes; sterilization temperature of about 121°C, time of about 15 minutes; sterilization temperature of about 115°C, time of about 30 minutes; or sterilization temperature of about 121°C, time of about 8 minutes.

[0017] In some embodiments, the penehyclidine hydrochloride preparation is penehyclidine hydrochloride injection, and the preparation water is water for injection. In some embodiments, the storage container is an ampoule or a vial.

[0018] In some embodiments, the preparation water added in step (1) is 60-80% of the total preparation amount; preferably, the preparation water added in step (1) is 80% of the total preparation amount.

[0019] In some embodiments, the filter membrane used for filtration in step (3) is 0.1-0.45 μm, preferably 0.22 μm.

[0020] In some embodiments, when CO2 is charged into the headspace in step (3), the residual oxygen concentration in the headspace needs to be controlled to be less than 9%. For example, the residual oxygen concentration in the headspace is less than 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%.

[0021] In some embodiments, the concentration of the penehyclidine hydrochloride solution in step (2) is 1 mg / mL. The national drug standard content range of this product is 90-110%, and the concentration and labeled content are as follows.

[0022] As used herein, the term "about" refers to a value or composition within an acceptable error range for a particular value or composition determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. In this article, when "about" is used to describe a measurable value (e.g., concentration of a substance, time, temperature, etc.), it means a range of ±5% of a given value, e.g., the expression "about 10 mM" means 9.5-10.5 mM.

[0023] As used herein, the term "comprising" or "including" means including the stated elements, integers or steps, but does not exclude any other elements, integers or steps. In this article, when the term "comprising" or "including" is used, unless otherwise indicated, the situation consisting of the stated elements, integers or steps is also covered. For example, when referring to an antibody variable region "comprising" a specific sequence, it is also intended to cover the antibody variable region consisting of the specific sequence.

[0024] Embodiments of the present invention will be described in detail below in conjunction with examples, but it will be appreciated by those skilled in the art that the following examples are only used to illustrate the present invention, rather than to limit the scope of the present invention. According to the following detailed description of preferred embodiments, various objects and advantages of the present invention will become implementable for those skilled in the art. DETAILED DESCRIPTION

[0025] The present invention is now described with reference to the following examples which are intended to illustrate the present invention (but not to limit the present invention). It is known to those skilled in the art that the examples describe the present invention by way of example and are not intended to limit the scope of the present invention.

[0026] Materials and Equipment

[0027] Penehyclidine hydrochloride: purchased from Jiangsu Enhua Pharmaceutical Co., Ltd.

[0028] Water for injection: Henan Kelun Pharmaceutical Co., Ltd.

[0029] CO2: purchased from Sichuan Qiaoyuan Gas Co., Ltd., concentration ≥99.999%.

[0030] The dissolved oxygen measuring instrument was purchased from Yidian Scientific Instruments (Lecithin) Company.

[0031] The headspace gas mass analyzer was purchased from Dansensor.

[0032] Method Description

[0033] Determination of penehyclidine hydrochloride content

[0034] Test sample solution: Take the test sample and measure it directly.

[0035] Reference solution: Take an appropriate amount of penehyclidine hydrochloride reference substance, weigh accurately, dissolve in water and quantitatively dilute to make a solution of about 1 mg per 1 ml.

[0036] Chromatographic conditions: octadecylsilane bonded silica gel was used as filler, 0.02 mol / L potassium dihydrogen phosphate solution-methanol-triethylamine (50:50:0.5) was used as mobile phase with pH value adjusted to 5.0 with phosphoric acid; detection wavelength was 254 nm; column temperature was 35°C; injection volume was 20 μl.

[0037] System suitability requirements: In the chromatogram of the reference solution, the theoretical plate numbers of the two peaks of penehyclidine hydrochloride racemate Ⅰ and Ⅱ should not be less than 3000.

[0038] Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, record the chromatogram, and calculate according to the external standard method with the sum of the peak areas of the two main peaks.

[0039] Sterility test

[0040] Take a sample, treat it by membrane filtration, and then rinse it with 0.1% sterile peptone aqueous solution containing 0.1% polysorbate 80 for at least 3 times, 100 ml each time. Use Staphylococcus aureus as the positive control bacteria and test it in accordance with the method in 1101 of the General Rules of Part IV of the 2020 edition of the "Chinese Pharmacopoeia". If it meets the requirements, it is deemed to be qualified.

[0041] Bacterial endotoxin qualified test

[0042] Take samples and test them according to the bacterial endotoxin test method in General Chapter 1143 of Part IV of the 2020 edition of the Chinese Pharmacopoeia. If the amount of endotoxin contained in each 1 mg of penehyclidine hydrochloride is less than 0.5EU, it is considered qualified.

[0043] Example 1

[0044] Weigh 1.0g of penehyclidine hydrochloride. Add about 800ml of water for injection into a clean beaker, pass CO2, control the dissolved oxygen to 5.8mg / L, add 1.0g of penehyclidine hydrochloride, stir and dissolve at 60-80℃, add water for injection to 1000ml, stir well, pass CO2 at the same time, control the dissolved oxygen to 5.8mg / L, and test the pH value and content of the liquid. After cooling to room temperature, filter the liquid through a 0.22um filter membrane, fill it into a clean ampoule, fill it with CO2, melt-seal it, and sterilize it at 121℃ for 12 minutes to obtain penehyclidine hydrochloride injection, and test its pH value.

[0045] Example 2

[0046] Weigh 1.0g of penehyclidine hydrochloride. Add about 800ml of water for injection into a clean beaker, add CO2, control the dissolved oxygen to 4.0mg / L, add 1.0g of penehyclidine hydrochloride, stir and dissolve at 60-80℃, add water for injection to 1000ml, stir well, pass CO2 at the same time, control the dissolved oxygen to 4.0mg / L, and test the pH value and content of the liquid. After cooling to room temperature, filter the liquid through a 0.22um filter membrane, fill it into a clean ampoule, add CO2, melt-seal it, and sterilize it at 121℃ for 12 minutes to obtain penehyclidine hydrochloride injection, and test its pH value.

[0047] Example 3

[0048] Weigh 1.0g of penehyclidine hydrochloride. Add about 800ml of water for injection into a clean beaker, add CO2, control the dissolved oxygen to 3.0mg / L, add 1.0g of penehyclidine hydrochloride, stir and dissolve at 60-80℃, add water for injection to 1000ml, stir well, pass CO2 at the same time, control the dissolved oxygen to 3.0mg / L, and test the pH value and content of the liquid. After cooling to room temperature, filter the liquid through a 0.22um filter membrane, fill it into a clean ampoule, add CO2, melt-seal it, and sterilize it at 121℃ for 12 minutes to obtain penehyclidine hydrochloride injection, and test its pH value.

[0049] Example 4

[0050] Weigh 1.0g of penehyclidine hydrochloride. Add about 800ml of water for injection into a clean beaker, add CO2, control the dissolved oxygen to 2.0mg / L, add 1.0g of penehyclidine hydrochloride, stir and dissolve at 60-80℃, add water for injection to 1000ml, stir well, pass CO2 at the same time, control the dissolved oxygen to 2.0mg / L, and test the pH value and content of the liquid. After cooling to room temperature, filter the liquid through a 0.22um filter membrane, fill it into a clean ampoule, add CO2, melt-seal it, and sterilize it at 121℃ for 12 minutes to obtain penehyclidine hydrochloride injection, and test its pH value.

[0051] Example 5

[0052] Weigh 1.0g of penehyclidine hydrochloride. Add about 800ml of water for injection into a clean beaker, add CO2, control the dissolved oxygen to 1.0mg / L, add 1.0g of penehyclidine hydrochloride, stir and dissolve at 60-80℃, add water for injection to 1000ml, stir well, pass CO2 at the same time, control the dissolved oxygen to 1.0mg / L, and test the pH value and content of the liquid. After cooling to room temperature, filter the liquid through a 0.22um filter membrane, fill it into a clean ampoule, add CO2, melt-seal it, and sterilize it at 121℃ for 12 minutes to obtain penehyclidine hydrochloride injection, and test its pH value.

[0053] Example 6

[0054] Weigh 1.0g of penehyclidine hydrochloride. Add about 800ml of water for injection into a clean beaker, add CO2, control the dissolved oxygen to 4.0mg / L, add 1.0g of penehyclidine hydrochloride, stir and dissolve at 60-80℃, add water for injection to 1000ml, stir well, introduce CO2 at the same time, control the dissolved oxygen to 4.0mg / L, and test the pH value and content of the liquid. After cooling to room temperature, filter the liquid through a 0.22um filter membrane, fill it into a clean ampoule, add CO2, melt-seal it, and sterilize it at 121℃ for 15 minutes to obtain penehyclidine hydrochloride injection, and test its pH value.

[0055] Example 7

[0056] Weigh 1.0g of penehyclidine hydrochloride. Add about 800ml of water for injection into a clean beaker, add CO2, control the dissolved oxygen to 4.0mg / L, add 1.0g of penehyclidine hydrochloride, stir and dissolve at 60-80℃, add water for injection to 1000ml, stir well, introduce CO2 at the same time, control the dissolved oxygen to 4.0mg / L, and test the pH value and content of the liquid. After cooling to room temperature, filter the liquid through a 0.22um filter membrane, fill it into a clean ampoule, add CO2, melt-seal it, and sterilize it at 115℃ for 30 minutes to obtain penehyclidine hydrochloride injection, and test its pH value.

[0057] Example 8

[0058] Weigh 1.0g of penehyclidine hydrochloride. Add about 800ml of water for injection into a clean beaker, add CO2, control the dissolved oxygen to 4.0mg / L, add 1.0g of penehyclidine hydrochloride, stir and dissolve at 60-80℃, add water for injection to 1000ml, stir well, pass CO2 at the same time, control the dissolved oxygen to 4.0mg / L, and test the pH value and content of the liquid. After cooling to room temperature, filter the liquid through a 0.22um filter membrane, fill it into a clean ampoule, add CO2, melt-seal it, and sterilize it at 121℃ for 8 minutes to obtain penehyclidine hydrochloride injection, and test its pH value.

[0059] Example 9

[0060] Weigh 1.0g of penehyclidine hydrochloride. Add about 800ml of water for injection into a clean beaker, add CO2, control the dissolved oxygen to 4.0mg / L, add 1.0g of penehyclidine hydrochloride, stir and dissolve at 60-80℃, add water for injection to 1000ml, stir well, pass CO2 at the same time, control the dissolved oxygen to 4.0mg / L, and test the pH value and content of the liquid. After cooling to room temperature, filter the liquid through a 0.22um filter membrane, fill it into a cleaned vial, add CO2, add a stopper and cap, sterilize at 121℃ for 12 minutes, and obtain penehyclidine hydrochloride injection, and test its pH value.

[0061] Example 10

[0062] Weigh 1.0g of penehyclidine hydrochloride. Add about 800ml of water for injection into a clean beaker, add CO2, control the dissolved oxygen to 4.0mg / L, add 1.0g of penehyclidine hydrochloride, stir and dissolve at 60-80℃, add water for injection to 1000ml, stir well, pass CO2 at the same time, control the dissolved oxygen to 4.0mg / L, and test the pH value and content of the liquid. After cooling to room temperature, filter the liquid through a 0.22um filter membrane, fill it into a cleaned vial, add CO2, add a stopper and cap, sterilize at 121℃ for 15 minutes, and obtain penehyclidine hydrochloride injection, and test its pH value.

[0063] Comparison Example

[0064] Weigh 1.0 g of penehyclidine hydrochloride. Add about 800 ml of water for injection into a clean beaker, add 1.0 g of penehyclidine hydrochloride, stir and dissolve at 60-80°C, add water for injection to make up to 1000 ml, and test the pH value and content of the solution. After cooling to room temperature, filter the solution through a 0.22 um filter membrane, fill it into a clean glass ampoule, add a stopper and cap, and sterilize at 121°C for 12 minutes to obtain penehyclidine hydrochloride injection, and test its pH value.

[0065] Test example:

[0066] The penehyclidine hydrochloride injection obtained based on the above Examples 1-10 and the control example was placed at 40°C ± 2°C to investigate its stability. Samples were taken regularly to detect the pH value, the content of penehyclidine hydrochloride, whether it met the sterility standard, whether it met the endotoxin standard, and whether there were visible foreign matter in the appearance. The results are shown in Table 1.

[0067] Table 1 Stability test results of penehyclidine hydrochloride injection

[0068]

[0069]

[0070] According to the above results, the pH value of the control example penehyclidine hydrochloride injection without adjusting the pH value changed greatly before and after sterilization; after being placed for 6 months, the pH value increased by 0.5, showing a significant change. The initial pH value of the penehyclidine hydrochloride injection obtained in Examples 1-10 was between 4.5 and 5.3, and the pH value did not change significantly before and after sterilization. After being placed for 6 months, the pH value did not change by more than 0.3, and the content decreased by less than 1.5%. The results of sterility test and endotoxin test were qualified, and the stability was relatively high.

[0071] Although the specific embodiments of the present invention have been described in detail, it will be understood by those skilled in the art that various modifications and changes may be made to the details according to all the teachings that have been published, and these changes are within the scope of protection of the present invention. The entire invention is given by the attached claims and any equivalents thereof.

Claims

1. A method for preparing a penehyclidine hydrochloride preparation, characterized in that: The preparation method comprises the following steps: (1) Add 50%-80% of the total preparation water into the preparation container, introduce CO2 into the preparation water, and control the dissolved oxygen content to be below 6 mg / L; (2) adding penehyclidine hydrochloride, stirring evenly, then adding preparation water to the full amount, stirring evenly, and introducing CO2 at the same time to control the dissolved oxygen below 6 mg / L to obtain a penehyclidine hydrochloride solution with a pH of 4.5 to 6.5, wherein the concentration of the penehyclidine hydrochloride solution is 0.5 to 1.5 mg / mL; (3) filtering the penehyclidine hydrochloride liquid, filling it into a clean storage container, filling the headspace with CO2, sealing it, and sterilizing it at high temperature to obtain the penehyclidine hydrochloride preparation.

2. The preparation method according to claim 1, characterized in that: The dissolved oxygen content in the steps (1) and (2) is controlled to be 4 mg / L to 6 mg / L, and the pH value of the penehyclidine hydrochloride solution is 4.5 to 5.

5.

3. The preparation method according to claim 1, characterized in that: The dissolved oxygen content in the steps (1) and (2) is controlled to be 4 mg / L to 5.8 mg / L, and the pH value of the penehyclidine hydrochloride solution is 4.5 to 5.

3.

4. The preparation method according to claim 1, characterized in that: The dissolved oxygen content in the steps (1) and (2) is controlled to be 1 mg / L to 3 mg / L, and the pH value of the penehyclidine hydrochloride solution is 4.5 to 5.

0.

5. The preparation method according to claim 1, characterized in that: The dissolved oxygen content in the steps (1) and (2) is controlled to be 1 mg / L to 3 mg / L, and the pH value of the penehyclidine hydrochloride solution is 4.5 to 4.

8.

6. The preparation method according to claim 1, characterized in that: The conditions for high temperature sterilization are: Sterilization temperature: 121°C, time: 12 minutes; Sterilization temperature: 121°C, time: 15 minutes; Sterilization temperature 115℃, time 30 minutes; or Sterilization temperature is 121°C and time is 8 minutes.

7. The preparation method according to claim 1, characterized in that: The penehyclidine hydrochloride preparation is penehyclidine hydrochloride injection, the preparation water is water for injection, and the storage container is an ampoule or a vial.

8. The preparation method according to claim 1, characterized in that: The amount of preparation water added in step (1) is 60-80% of the total preparation amount; preferably, the amount of preparation water added in step (1) is 80% of the total preparation amount.

9. The preparation method according to claim 1, characterized in that: The filter membrane used for filtration in step (3) is 0.1-0.45 μm, preferably 0.22 μm.

10. The preparation method according to claim 1, characterized in that: The concentration of the penehyclidine hydrochloride solution in the step (2) is about 1 mg / mL.

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