Amino caproic acid injection and its preparation method

Abstract

The application discloses an amino hexanoic acid injection and a preparation method thereof, and belongs to the technical field of medicines.The technical problem to be solved is to provide an amino hexanoic acid injection with lower initial impurities, higher high-temperature stability, better light stability and better freeze-thaw stability.The technical solution is characterized in that the amino hexanoic acid injection comprises amino hexanoic acid, ectoine, a pH regulator and water for injection, and the pH of the amino hexanoic acid injection is 6.0-7.6.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to an aminocaproic acid injection and its preparation method. Background Technology

[0002] 6-Aminocaproic acid (EACA), chemically known as 6-aminocaproic acid, has the molecular formula C6H12O. 13 NO2, with a molecular weight of 131.17, is a linear amino acid derivative with both amino (-NH2) and carboxyl (-COOH) groups. It is a commonly used antifibrinolytic hemostatic drug in clinical practice, mainly used to treat various types of bleeding caused by excessive primary fibrinolysis.

[0003] Relevant patent documents retrieved: Patent document CN107115280A (publication date September 1, 2017) discloses an aminocaproic acid injection and its preparation method. The method includes the following steps: (1) Add 50% of freshly boiled water for injection to a concentrated solution tank, add aminocaproic acid, stir and dissolve; filter back to clear using a Suzhou sand filter rod, and then filter into a diluted solution tank; (2) Add water for injection to the total volume, stir for 15 minutes to make it uniform, and adjust the pH; (3) Filter back to clear using a Suzhou sand filter rod, 0.45μm and 0.22μm polyethersulfone fins; (4) Take samples to test the content of intermediates and pH value. After all items are qualified, filter the drug solution into a storage tank; (5) After the drug solution in the storage tank is filtered multiple times by 0.22μm polyethersulfone fins, it is input into a filling buffer tank for filling; (6) Filling and sealing; (7) Sterilize at 100℃ for 30 minutes. This invention employs a secondary sterilization filtration process, ensuring sterility throughout the entire process, reducing visible foreign matter in the medicine, and guaranteeing product quality.

[0004] Patent document CN112516082A (publication date March 19, 2021) discloses an aminocaproic acid injection solution and its preparation method, comprising: ① adding 50-80% water for injection to a dilution tank, then adding aminocaproic acid, heating to 75-90℃ and stirring until completely dissolved, adding water for injection to 90-98%, and filtering with a 1.0μm titanium rod; ② adjusting the pH to 6.2-7.4, adding water for injection to the full volume, then passing through 0.45μm and 0.22μm polyethersulfone filters for precision reflux, and then filtering to a storage tank; ③ passing through 0.22μm and 0.10μm polyethersulfone filters for final filtration, and finally filling into ampoules and sterilizing. This invention does not use activated carbon to adsorb pyrogens, thus effectively avoiding impurities introduced by activated carbon. Furthermore, the five-stage filtration, especially the final filtration using a 0.10μm polyethersulfone filter, effectively controls the bacterial endotoxin content.

[0005] Patent document CN116549386A (publication date August 8, 2023) discloses an aminocaproic acid injection and its preparation method, including the following steps: S1. Processing of raw materials: The aminocaproic acid raw material is dissolved in purified water at high temperature, decolorized with pharmaceutical charcoal, then distilled under reduced pressure to crystallize, recrystallized by ethanol, and then vacuum dried to obtain refined aminocaproic acid; S2. Preparation of injection solution: S21. The refined aminocaproic acid is added to a concentration tank, and 40-50 wt% of water for injection is added to the concentration tank. The mixture is heated, stirred, and circulated for 5-15 min; S22. The solution in the concentration tank is filtered through a 0.22 μm filter and then pumped into a dilution tank. Water for injection is added to the concentration tank twice, and the concentration tank and the solution pipeline are rinsed several times before being filtered and pumped into the dilution tank. The dilution tank is stirred for 5-15 min; S23. Add 5-6 Adjust the pH with wt% hydrochloric acid, add the remaining water for injection to the total volume, and stir for 5-15 minutes after making up to the final volume; S24. Circulate the drug solution in the dilution tank through a 0.22μm filter, first circulating it for 5-15 minutes on a small scale, then opening the valve from the dilution tank to the filling tank for a large scale circulation of 5-10 minutes. The temperature of the drug solution should not exceed 50℃ during storage; S25. Fill, seal, and sterilize to obtain aminocaproic acid injection. This invention, on the one hand, provides special treatment for aminocaproic acid raw material, improving raw material quality control and reducing formulation risks; on the other hand, by controlling the temperature range during the filtration stage, it significantly reduces the content of related substances in the finished product.

[0006] Currently, there is relatively little research on aminocaproic acid injections, and providing an aminocaproic acid injection with lower initial impurities, better high-temperature stability, light stability, and freeze-thaw stability remains a very challenging task. Summary of the Invention

[0007] To address the aforementioned technical problems, this invention provides an aminocaproic acid injection solution and its preparation method.

[0008] Terminology Explanation: Unless otherwise defined, all technical terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this subject matter pertains. Unless otherwise stated, all patents, patent inventions, and disclosures cited throughout this document are incorporated herein by reference in their entirety. Where multiple definitions exist for terms herein, the definitions provided in this chapter shall prevail.

[0009] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention in any way. In this invention, the singular is used in conjunction with the plural unless otherwise specifically stated. It should also be noted that, unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “contains” are not limiting.

[0010] Definitions of standard chemical terms can be found in the references Chinese Pharmacopoeia 2025 edition and Complete Explanation of Pharmacological Terminology.

[0011] Unless otherwise stated, conventional methods within the scope of the art, such as drug dissolution testing, accelerated stability testing under extreme conditions, and long-term stability testing, shall be used.

[0012] Unless specifically defined herein, the use of all commercially available products herein employs standard techniques. For example, it may be carried out using the manufacturer's instructions for use with the kit, or in accordance with methods known in the art or the description of this invention. The techniques and methods described herein can generally be implemented according to conventional methods well known in the art, based on the descriptions in the various summary and more specific documents cited and discussed in this specification.

[0013] The “range” disclosed in this document takes the form of a lower limit and an upper limit. It can be one or more lower limits and one or more upper limits, respectively. A given range is defined by selecting a lower limit and an upper limit. The selected lower and upper limits define the boundaries of the particular range. All ranges that can be defined in this way are inclusive and composable; that is, any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60-120 and 80-110 are listed for a specific parameter, it is also expected that ranges of 60-110 and 80-120 are also expected. Furthermore, if the minimum range values ​​are listed as 1 and 2, and if the maximum ranges are listed as 3, 4, and 5, then the following ranges are all expected: 1-2, 1-4, 1-5, 2-3, 2-4, and 2-5.

[0014] In this invention, unless otherwise specified, the numerical range "ab" represents a shortened representation of any combination of real numbers from a to b, where a and b are both real numbers. For example, the numerical range "0-5" means that all real numbers between "0-5" have been listed in this document, and "0-5" is simply a shortened representation of these numerical combinations.

[0015] As used herein, the term "about" refers to a quantity or range of values ​​that is an approximation within experimental variability (or within statistical experimental error). In this invention, the term "about" shall have the meaning of being within 10% of the specified value or range, preferably within 5%.

[0016] The term "water for injection" as used in this article refers to sterile water for injection that meets the quality standards for water for injection stipulated in the current edition of the Chinese Pharmacopoeia, wherein the content of heavy metal ions meets the relevant limit requirements.

[0017] The term "pH adjuster" as used in this article refers to injectable pH-adjusting pharmaceutical excipients that can adjust and maintain the stability of the acid-base environment of a drug solution system, keep the active ingredient in a stable pH range, inhibit the degradation of active ingredients, and reduce local irritation during administration.

[0018] The term "sterilization" as used in this article refers to the routine operation of using appropriate physical or chemical methods to kill or remove all microorganisms and their spores in preparations, excipients, solvents or packaging containers to make the product meet sterility requirements and ensure the safety of clinical drug use, including but not limited to moist heat sterilization, dry heat sterilization, radiation sterilization, filtration sterilization and other methods.

[0019] To achieve the above objectives, the present invention provides the following technical solution: In a first aspect, the present invention provides: an aminocaproic acid injection solution comprising aminocaproic acid, ectoine, a pH adjuster and water for injection; wherein the pH of the aminocaproic acid injection solution is 6.0-7.6.

[0020] In some embodiments, the aminocaproic acid injection solution contains, per 1000 mL, 200-300 g of aminocaproic acid, 0.01-0.05 g of ectoine, a pH adjuster, and the remainder of water for injection.

[0021] In some embodiments, the pH adjuster is at least one of hydrochloric acid, citric acid, and sodium citrate; preferably, the pH adjuster is hydrochloric acid; more preferably, the concentration of the hydrochloric acid is 1-2 mol / L.

[0022] In some embodiments, the pH of the aminocaproic acid injection is 6.5-6.7.

[0023] In some embodiments, the aminocaproic acid injection solution contains, per 1000 mL, 250.0 g of aminocaproic acid, 0.02-0.04 g of ectoine, a pH adjuster, and the remainder of water for injection.

[0024] In some embodiments, the aminocaproic acid injection solution contains, per 1000 mL, 250.0 g of aminocaproic acid, 0.03 g of ectoine, a pH adjuster, and the remainder of water for injection.

[0025] Secondly, the present invention provides a method for preparing the above-mentioned aminocaproic acid injection, comprising the following steps: (1) Add ectoine to water for injection and stir to dissolve, then add aminocaproic acid and continue stirring until completely dissolved to obtain a solution; (2) The solution is cooled, and a pH adjuster is added to adjust the pH to 6.0-7.6; (3) Add the remaining water for injection and stir well. After filtering, fill, sterilize, check for leaks and inspect with a light, and then package.

[0026] In some implementations, the temperature of the water for injection in step (1) is 65-75°C, preferably 68-72°C.

[0027] In some implementations, the amount of water for injection used in step (1) is 50%-70% of the total amount of water for injection; preferably 55%-65%.

[0028] In some implementations, the cooling in step (2) is cooling to a temperature not exceeding 40°C.

[0029] In some implementations, the filtration in step (3) is a three-stage filtration; preferably, it is filtered sequentially through a 0.45μm polyethersulfone filter, a 0.22μm PES filter, and a 0.22μm polyethersulfone filter.

[0030] Thirdly, the present invention provides the use of the above-mentioned aminocaproic acid injection in the preparation of drugs for the prevention and treatment of bleeding.

[0031] In some implementations, the bleeding is various types of bleeding caused by hyperfibrinolysis.

[0032] In some embodiments, the bleeding includes traumatic or surgical bleeding from organs rich in plasminogen activator, or bleeding caused by an overdose of tissue plasminogen activator, streptokinase, or urokinase; preferably, the organ includes at least one of the prostate, urethra, lung, liver, pancreas, brain, uterus, adrenal gland, and thyroid gland.

[0033] Fourthly, the present invention provides the application of ectoine in improving the quality of aminocaproic acid injection.

[0034] In some embodiments, the quality includes drug safety and stability, and preferably, the stability includes at least one of high temperature stability, light stability and freeze-thaw stability.

[0035] In some embodiments, the amount of ectoine in aminocaproic acid injection is 0.01-0.05 g per 1000 mL.

[0036] Fifthly, the present invention provides a method for improving the quality of aminocaproic acid injection, comprising preparing aminocaproic acid injection using the above-described preparation method.

[0037] The beneficial effects of this invention are as follows: 1. This invention stabilizes the molecular structure of aminocaproic acid by adding ectoine, significantly inhibiting cyclization degradation and polymerization reactions. Compared with existing technologies, the aminocaproic acid injection prepared by this invention has better drug safety. Specifically, the caprolactam content of the aminocaproic acid injection prepared in Examples 1-3 is 0.002%-0.005% on day 0, which is more than 54% lower than the 0.011% of the reference preparation; the glycine dimer content is 0.007%-0.009%, which is more than 85% lower than the 0.067% of the reference preparation.

[0038] 2. Meanwhile, the aminocaproic acid injection prepared by this invention has good high temperature stability, light stability and freeze-thaw stability, making it suitable for long-distance transportation and long-term storage. Detailed Implementation

[0039] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, and such changes should also fall within the scope of protection claimed by the present invention.

[0040] The present invention will be further described below by way of specific embodiments. All instruments, devices, equipment, reagents, products, etc., used in the embodiments of the present invention were obtained through conventional commercial channels unless otherwise specified. Ectoin (for injection) was purchased from Aivito (Jiangsu) Pharmaceutical Technology Co., Ltd., and aminocaproic acid was purchased from Zhejiang Saimo Pharmaceutical Co., Ltd., registration number Y20210001094.

[0041] Examples 1-3 and Comparative Examples 1-3 Aminocaproic acid injection According to the prescription in Table 1, the corresponding aminocaproic acid injection solution was prepared using the following preparation method.

[0042] Table 1

[0043] Note: 1. In the table, "#" represents trehalose instead of ectoine; 2. "-" represents no addition.

[0044] The preparation method of the aminocaproic acid injection is as follows: (1) Take 60% of the prescription amount of water for injection, heat it to 70°C, add ectoine and stir for 5 minutes to dissolve, then add aminocaproic acid and stir for 5 minutes to dissolve, and obtain a solution; (2) Cool the solution to room temperature and adjust the pH to 6.5-6.7 with 1 mol / L hydrochloric acid; (3) Add the remaining amount of water for injection and stir for 10 minutes. The solution is filtered through a 0.45μm polyethersulfone filter, a 0.22μm PES filter and a 0.22μm polyethersulfone filter. The filtrate is then filled, sterilized, leak-tested, inspected by light, and packaged to obtain the final product.

[0045] The preparation method of Comparative Example 1, aminocaproic acid injection, is as follows: (1) Take 60% of the prescribed amount of water for injection, heat it to 70°C, add aminocaproic acid and stir for 5 minutes to dissolve it, and obtain a solution; (2) Cool the solution to room temperature and adjust the pH to 6.5-6.7 with 1 mol / L hydrochloric acid; (3) Add the remaining amount of water for injection and stir for 10 minutes. The solution is filtered through a 0.45μm polyethersulfone filter, a 0.22μm PES filter and a 0.22μm polyethersulfone filter. The filtrate is then filled, sterilized, leak-tested, inspected by light, and packaged to obtain the final product.

[0046] The preparation method of comparative example 3 aminocaproic acid injection is as follows: (1) Take 60% of the prescribed amount of water for injection, heat it to 70°C, add trehalose and stir for 5 minutes to dissolve, then add aminocaproic acid and stir for 5 minutes to dissolve, and obtain a solution; (2) Cool the solution to room temperature and adjust the pH to 6.5-6.7 with 1 mol / L hydrochloric acid; (3) Add the remaining amount of water for injection and stir for 10 minutes. The solution is filtered through a 0.45μm polyethersulfone filter, a 0.22μm PES filter and a 0.22μm polyethersulfone filter. The filtrate is then filled, sterilized, leak-tested, inspected by light, and packaged to obtain the final product.

[0047] Detection example The aminocaproic acid injection solutions prepared in the examples and comparative examples were placed at high temperature (60±2℃) for 10 days and 30 days, and exposed to light (without packaging, with a total illuminance of not less than 1.2×10⁻⁶). 6 Lux / hr, near-ultraviolet energy not less than 200w.hr / m 2 The samples were subjected to freeze-thaw cycles (placed at -20 to -10℃ for 2 days, then placed at 40℃ for 2 days, repeated 3 times), and samples were taken for analysis of properties, pH value, related substances, etc. The results were compared with those of day 0. The results are shown in Table 2.

[0048] Among them, the detection of related substances is performed by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0631) for related substance I.

[0049] Table 2. Stability study of the aminocaproic acid injection prepared in Example 1

[0050] Table 3. Stability study of the aminocaproic acid injection prepared in Example 2

[0051] Table 4. Stability study of the aminocaproic acid injection prepared in Example 3

[0052] Table 5. Stability study of the aminocaproic acid injection prepared in Comparative Example 1

[0053] Table 6. Stability study of the aminocaproic acid injection prepared in Comparative Example 2

[0054] Table 7. Stability study of the aminocaproic acid injection prepared in Comparative Example 3

[0055] Verification of technical effectiveness and / or analysis of technical problem solving The results showed that the caprolactam content of the aminocaproic acid injection prepared in Examples 1-3 of this invention was 0.002%-0.005% on day 0, the glycine dimer content was 0.007%-0.009%, and the total impurity content was 0.009%-0.014%. Compared with the reference preparation (caprolactam content 0.011%, glycine dimer content 0.067%, total impurity content 0.078%), the caprolactam content of the aminocaproic acid injection prepared in these examples was reduced by more than 54%, the glycine dimer content by more than 85%, and the total impurity content by more than 82%. This indicates that the aminocaproic acid injection prepared in this invention has better drug safety compared with the prior art.

[0056] Meanwhile, the aminocaproic acid injection prepared in the embodiments of the present invention has good high temperature stability, light stability and freeze-thaw stability.

[0057] Based on the aminocaproic acid injection prepared in Comparative Example 1, the aminocaproic acid injection without ectoine had essentially the same 0-day caprolactam content, glycine dimer content, and total impurity content as the reference formulation. This suggests that the addition of ectoine can stabilize the molecular structure of aminocaproic acid and significantly inhibit cyclization degradation and polymerization reactions.

[0058] According to the aminocaproic acid injection prepared in Comparative Example 2, increasing the amount of ectoine in the aminocaproic acid injection will significantly worsen the freeze-thaw stability of the aminocaproic acid injection.

[0059] According to the aminocaproic acid injection prepared in Comparative Example 3, the aminocaproic acid injection using trehalose instead of ectoine had caprolactam content, glycine dimer content, and total impurity content that were basically the same as the reference preparation, and the freeze-thaw stability of the aminocaproic acid injection was significantly worse.

[0060] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. An aminocaproic acid injection solution, characterized in that, It contains aminocaproic acid, ectoine, a pH adjuster, and water for injection; the pH of the aminocaproic acid injection solution is 6.0-7.

6.

2. The aminocaproic acid injection solution according to claim 1, characterized in that, Each 1000mL contains 200-300g of aminocaproic acid, 0.01-0.05g of ectoine, pH adjuster, and the remainder of water for injection.

3. The aminocaproic acid injection solution according to claim 1, characterized in that, The pH of the aminocaproic acid injection solution is 6.5-6.

7.

4. The aminocaproic acid injection solution according to claim 1, characterized in that, Each 1000 mL contains 250 g of aminocaproic acid, 0.02-0.04 g of ectoine, pH adjuster, and the remainder of water for injection.

5. The method for preparing the aminocaproic acid injection solution according to any one of claims 1-4, characterized in that, Includes the following steps: (1) Add ectoine to water for injection and stir to dissolve, then add aminocaproic acid and continue stirring until completely dissolved to obtain a solution; (2) After the solution is cooled, a pH adjuster is added to adjust the pH to 6.0-7.6; (3) Add the remaining water for injection and stir well. After the solution is filtered through three stages, fill, sterilize, check for leaks, inspect with a light, and package.

6. The preparation method according to claim 5, characterized in that, The temperature of the water for injection in step (1) is 65-75℃.

7. The preparation method according to claim 5, characterized in that, The three-stage filtration in step (3) involves sequential filtration through a 0.45μm polyethersulfone filter, a 0.22μm PES filter, and a 0.22μm polyethersulfone filter.

8. The use of the aminocaproic acid injection solution according to any one of claims 1-4 or the aminocaproic acid injection solution prepared by the preparation method according to any one of claims 5-7 in the preparation of a drug for the prevention and treatment of bleeding.

9. The application of ectoine in improving the quality of aminocaproic acid injection, characterized in that, The dosage of ectoine in the aminocaproic acid injection is 0.01-0.05g per 1000mL.

10. A method for improving the quality of aminocaproic acid injection, characterized in that, This includes preparing aminocaproic acid injection using the preparation method described in any one of claims 5-7.

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