Preparation method and application of phloroglucinol injection

Abstract

The invention discloses a preparation method and application of phloroglucinol injection, and belongs to the technical field of application of phloroglucinol injection. The method comprises the following steps: adding 70% * A * 4mL of water for injection at 80 DEG C, then introducing 0.02 Mpa of nitrogen into the water until the water is saturated, and keeping for more than 10 minutes at the temperature of 80-90 DEG C; adding 11.8 mol / L to 12.4 mol / L concentrated hydrochloric acid, adjusting the pH value to be less than or equal to 5, and keeping the pH value for more than 5 minutes; adding 40Amg of phloroglucinol hydrate and 28Amg of sodium chloride, stirring for 10 minutes at the speed of 800rpm, and controlling the temperature of the solution to be 80 DEG C; 0.04 Amg of trimethylphloroglucinol is added, stirring is conducted for 10 min at the speed of 800 rpm, and the temperature is reduced to 25 DEG C; adding 11.8 mol / L to 12.4 mol / L concentrated hydrochloric acid, adjusting the pH value to be less than or equal to 5, and keeping the pH value for more than 5 minutes; supplementing the water for injection until the volume of the solution is A * 4mL, and filtering the solution through a 0.22 mu m filter membrane; and introducing 0.02 Mpa of carbon dioxide, filling into a borosilicate glass ampoule, and carrying out moist heat sterilization at 120 DEG C for 15 minutes. According to the phloroglucinol injection, the storage stability of the phloroglucinol injection can be improved, the long-term stability is better, and the impurity reduction amplitude is larger.

Description

Technical Field

[0001] The invention belongs to the technical field of application of phloroglucinol injection, and more specifically, relates to a preparation method and application of phloroglucinol injection. Background Art

[0002] Phloroglucinol is an organic compound with the chemical formula C 6 H 5 (OH) 3 It is mainly used in medicine to treat acute spasmodic pain caused by digestive system and biliary dysfunction, acute spasmodic urethral, ​​bladder, and renal colic, and gynecological spasmodic pain. Phloroglucinol is easily oxidized in solution and can undergo multiple oxidation reactions with oxygen, causing the solution to change color, increase related substances, and change pH. High temperature will accelerate this reaction. At the same time, phloroglucinol solution is also unstable under light conditions. Long-term light exposure causes color changes and the increase of related substances.

[0003] In order to ensure the long-term stability of phloroglucinol injection, a protective gas (such as nitrogen or carbon dioxide) or an antioxidant sodium sulfite is usually added to the phloroglucinol injection. The addition of the protective gas determines the long-term stability of the phloroglucinol injection. However, in the preparation process of phloroglucinol injection in the prior art, the control of acidity and the selection of the order of adding phloroglucinol are not comprehensively considered, which leads to a decrease in the long-term stability of the phloroglucinol injection.

[0004] Therefore, it is necessary to prepare a phloroglucinol injection with high long-term stability and short-term stability. Summary of the invention

[0005] In view of the poor long-term storage stability of phloroglucinol injection in the prior art (manifested in a large growth rate of impurities during long-term storage), which affects the use of the drug, the present invention provides a preparation method and application of phloroglucinol injection.

[0006] In order to solve the above problems, the technical solution adopted by the present invention is as follows:

[0007] A method for preparing phloroglucinol injection of the present invention comprises the following steps:

[0008] (1) Add 70% × A × 4 mL of water for injection at 80°C, and then introduce 0.02 MPa nitrogen gas into the water to reach saturation;

[0009] (2) maintaining the solution of step (1) at a temperature of 80° C. to 90° C. for more than 10 minutes;

[0010] By optimizing the time of maintaining acidity, the acidity distribution of each interface of the solution can be better, forming a better uniform liquid environment. When other solutes are added later, the interfaces brought in can be more effectively maintained, so that during long-term storage, the activity of pyrogallol hydrate will not be too strong and cause the possibility of oxidation, thereby improving the long-term storage stability (in this application: storage for 16 days is long-term stability, storage for 8 days is short-term stability, the same below).

[0011] (3) adding 11.8 mol / L to 12.4 mol / L concentrated hydrochloric acid to the solution in step (2), adjusting the pH to less than or equal to 5 and maintaining the pH for more than 5 minutes;

[0012] (4) Add 40A mg of pyrogallol hydrate and 28A mg of sodium chloride to the solution of step (3), stir at 800 rpm for 10 min, and control the solution temperature at 80° C.

[0013] (5) adding 0.04A mg of trimethylphloroglucinol to the solution obtained in step (4), stirring at 800 rpm for 10 min, and cooling to 25° C.;

[0014] Since pyrogallol hydrate is easily oxidized, it is necessary to provide it with a sufficiently acidic environment first. After it is stabilized, when trimethylpyrogallol is added, the molecular attraction between the two substances will cause part of the pyrogallol hydrate to be oxidized. If they are added sequentially, the acidic environment can provide stable conditions for pyrogallol hydrate.

[0015] (6) adding 11.8 mol / L to 12.4 mol / L concentrated hydrochloric acid to the solution in step (5), adjusting the pH to less than or equal to 5 and maintaining the pH for more than 5 minutes;

[0016] Due to the preparation process and the addition of some substances to the solution, the acidity of the solution is unevenly distributed. The uneven distribution causes the oxygen content of the solution to change and the number of impurities to increase. Therefore, the pH value of the solution needs to be adjusted in time.

[0017] (7) Adding water for injection to the solution in step (6) to a solution volume of A×4 mL, and filtering the solution through a 0.22 μm filter membrane;

[0018] (8) Pass 0.02 MPa carbon dioxide into the solution of step (7) and seal it in a borosilicate glass ampoule, and sterilize it by wet heat at 120° C. for 15 min.

[0019] Without carbon dioxide filling conditions and moist heat sterilization, the acidity may weaken with dilution, and the liquid surface may contain some oxygen, causing certain oxidation. Because the contact area is limited, it affects the long-term stability.

[0020] Preferably, the value of A is greater than or equal to 1.

[0021] Preferably, the value of A is 1 or 10. When the value of A is 10, the general prescription volume is 4 mL, but it can be configured more by expanding it 10 times, so that the error is smaller when more samples are weighed, and there is more solution, the acidic environment formed by stirring is more uniform, and the antioxidant capacity is better. However, when A is infinite, because the contact area of ​​the stirring device is limited, the acidic environment of each interface with different liquid heights is different, which will cause an increase in impurities. Therefore, when the value of A is 10, the impurity content is controlled to the minimum, and the drug impurity content is lower.

[0022] Preferably, in step (2), the solution of step (1) is kept at a temperature of 80° C. to 90° C. for more than 20 minutes.

[0023] Preferably, in step (3), the pH is adjusted to 5 and maintained for more than 10 min.

[0024] Preferably, in step (3), the pH is adjusted to 4 and maintained for more than 5 minutes.

[0025] Preferably, in step (4), stirring is carried out at 700 rpm for 10 min.

[0026] Preferably, the absolute value of the difference between the pH value in step (3) and the pH value in step (6) is 1.

[0027] The present invention also protects a phloroglucinol injection, which is prepared by any of the above-mentioned preparation methods of the phloroglucinol injection.

[0028] The invention also protects the use of phloroglucinol injection, which is a drug with antispasmodic activity and can directly act on smooth muscles.

[0029] Beneficial Effects

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] (1) A method for preparing phloroglucinol injection of the present invention. The novel preparation method of the present invention can effectively reduce the content of impurity B and the content of total impurities in phloroglucinol injection. This is largely due to the fact that concentrated hydrochloric acid is added in advance and carbon dioxide is not introduced at the beginning. The addition of strong acid can maintain acidity more stably and is more compatible with other corresponding substances. Carbon dioxide filling during filling can further form an acidic environment after the solution is prepared, thereby improving the long-term storage stability of the solution, thereby avoiding excessive generation of impurity B and total impurities in phloroglucinol injection, and improving the purity of the drug.

[0032] (2) The application of the phloroglucinol injection of the present invention has all the beneficial effects of the present invention. DETAILED DESCRIPTION

[0033] The more detailed description of the embodiments of the present invention below is not intended to limit the scope of the claimed invention, but is merely for illustration and not to limit the description of the features and characteristics of the present invention, so as to propose the best mode for performing the present invention, and to be sufficient to enable those skilled in the art to implement the present invention. However, it should be understood that various modifications and variations may be made without departing from the scope of the present invention as defined by the appended claims. The detailed description should be considered only as illustrative, not restrictive, and if there are any such modifications and variations, they will all fall within the scope of the present invention described herein. In addition, the background technology is intended to illustrate the current status and significance of the research and development of the present technology, and is not intended to limit the present invention or the application field of the present application and the present invention.

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs; the terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0035] It is worth noting that the raw materials used in the present invention are all common commercially available products, among which trimethylphloroglucinol was purchased from Sigma-Aldrich; phloroglucinol hydrate (CAS RN: 6099-90-7) was purchased from TCI (Shanghai) Chemical Industry Development Co., Ltd.; impurity B is resorcinol, batch number 100389-201903, purchased from China Food and Drug Inspection Institutes.

[0036] The present invention is further described below in conjunction with specific embodiments.

[0037] Example 1

[0038] This embodiment provides a phloroglucinol injection, and the preparation method thereof specifically comprises the following steps:

[0039] (1) Add 28 mL of 80°C water for injection, and then introduce 0.02 MPa nitrogen gas into the water to reach saturation;

[0040] (2) maintaining the solution of step (1) at a temperature of 80° C. to 90° C. for 10 min;

[0041] (3) adding 11.8 mol / L-12.4 mol / L concentrated hydrochloric acid to the solution in step (2), adjusting the pH to 5 and maintaining for 5 min;

[0042] (4) adding 400 mg of pyrogallol hydrate and 280 mg of sodium chloride to the solution of step (3), stirring at 800 rpm for 10 min, and controlling the solution temperature at 80° C.;

[0043] (5) adding 0.4 mg of trimethylphloroglucinol to the solution obtained in step (4), stirring at 800 rpm for 10 min, and cooling to 25° C.;

[0044] (6) adding 11.8 mol / L-12.4 mol / L concentrated hydrochloric acid to the solution in step (5), adjusting the pH to 5 and maintaining for 5 min;

[0045] (7) Adding water for injection to the solution in step (6) until the solution volume is 40 mL, and filtering the solution through a 0.22 μm filter membrane;

[0046] (8) Pass 0.02 MPa carbon dioxide into the solution of step (7) and seal it in a borosilicate glass ampoule, and sterilize it by wet heat at 120° C. for 15 min.

[0047] This embodiment also provides an application of phloroglucinol injection, which is a drug with antispasmodic activity and can directly act on smooth muscle.

[0048] Test method:

[0049] The results obtained in this example are recorded in Table 1.

[0050] The steps include:

[0051] 1. Dilution solution: Take the phloroglucinol injection samples prepared in Examples 1 to 4 and Comparative Examples 1 to 5, and add purified water to quantitatively dilute them to obtain a 4 mg / mL phloroglucinol solution (for example: Example 1 is 400 mg / 40 mL = 10 mg / mL, so Example 1 needs to be diluted 2.5 times).

[0052] 2. Control solution: Accurately measure 1 mL of the diluted solution, place it in a 100 mL volumetric flask, dilute it to the mark with purified water, and shake well; accurately measure 1 mL again, place it in a 10 mL volumetric flask, dilute it to the mark with purified water, and shake well.

[0053] 3. System suitability solution: Accurately weigh appropriate amounts of impurity B and phloroglucinol standard (phloroglucinol dihydrate), place in the same volumetric flask, add purified water to dissolve and dilute to make a mixed solution containing 10 μg impurity B and 4 mg phloroglucinol standard per 1 mL.

[0054] Compared with Comparative Examples 1 to 5, the new preparation method of Example 1 can effectively reduce the content of impurity B and the content of total impurities in phloroglucinol injection. This is largely due to the addition of concentrated hydrochloric acid in advance and the lack of carbon dioxide at the beginning. The addition of strong acid can maintain better acidity and be more compatible with other corresponding substances. The carbon dioxide filling during filling can further form an acidic environment after the solution is configured, thereby improving the long-term storage stability of the solution, thereby avoiding excessive generation of impurity B and total impurities in phloroglucinol injection, and improving the purity of the drug.

[0055] Table 1. Comparison of application performance of phloroglucinol injection prepared in various embodiments

[0056]

[0057] Example 2

[0058] This comparative example provides a phloroglucinol injection, the specific preparation method of which is basically the same as that of Example 1, except that in step (2), the solution of step (1) is kept at a temperature of 80° C. to 90° C. for 20 min. The corresponding test results are recorded in Table 1.

[0059] This embodiment also provides an application of phloroglucinol injection, which is a drug with antispasmodic activity and can directly act on smooth muscle.

[0060] Example 3

[0061] This comparative example provides a phloroglucinol injection, the specific preparation method of which is basically the same as that of Example 1, the main difference being that in step (3), the pH is adjusted to 5 and maintained for more than 10 minutes. The corresponding test results are recorded in Table 1.

[0062] This embodiment also provides an application of phloroglucinol injection, which is a drug with antispasmodic activity and can directly act on smooth muscle.

[0063] Compared with Example 1, the schemes of Example 2 and Example 3 can optimize the time for maintaining acidity, so that the acidity distribution of each interface of the solution can be better, forming a better uniform liquid environment. When other solutes are added later, the interfaces brought in can be more effectively maintained, so that during long-term storage, the activity of benzyltriol hydrate will not be too strong, causing the possibility of oxidation, thereby improving the stability of long-term storage (in this application: storage for 16 days is long-term stability, storage for 8 days is short-term stability, the same below).

[0064] Example 4

[0065] This comparative example provides a phloroglucinol injection, and its specific preparation method is basically the same as that of Example 1, except that the pH is adjusted to 4 and maintained for 5 minutes in step (3). The corresponding test results are recorded in Table 1. This example also provides an application of phloroglucinol injection, a drug with antispasmodic activity, which can directly act on smooth muscle.

[0066] Compared with Example 1, Example 4 can provide a more acidic environment by lowering the pH value, thereby improving the long-term stability after storage for 16 days. Compared with the impurity content of short-term stability after storage for 8 days, the impurity content of long-term stability in Example 4 is lower.

[0067] Comparative Example 1

[0068] This comparative example provides a conventional phloroglucinol injection prepared by protection with carbon dioxide / nitrogen: 80% of the prescription amount of water for injection at 80°C is added, and carbon dioxide / nitrogen is introduced to saturate the water. The prescription amount of trimethyl phloroglucinol, phloroglucinol hydrate and sodium chloride are added and stirred for 5 minutes, the pH is adjusted to 4.00 with hydrochloric acid, and water for injection is added to a sufficient amount and stirred for 10 minutes, the solution is filtered through a 0.22μm filter membrane, and carbon dioxide / nitrogen is used for sealing.

[0069] By comparison, the phloroglucinol injection of comparative example 1 basically meets the design requirements, while the application performance of the phloroglucinol injection prepared in the embodiment is significantly improved, and the long-term stability (16 days) can still have a lower impurity mass after storage, which improves its long-term stability (16 days of long-term stability, comparative example 1 compared with Example 1, the 16-day long-term stability of impurity B deteriorates more seriously, reaching 0.029%), among which the application performance of the phloroglucinol injection of Example 1 is the best, indicating that the new preparation method of the present invention can effectively reduce the content of impurity B and the content of total impurities in the phloroglucinol injection, which is largely due to the addition of concentrated hydrochloric acid in advance, and the introduction of carbon dioxide at the beginning. The addition of strong acid can maintain better stability of acidity and is more compatible with other corresponding substances. The carbon dioxide encapsulation during encapsulation can further form an acidic environment after the solution is configured, thereby improving the long-term storage stability of the solution, thereby avoiding excessive generation of impurity B and total impurities in the phloroglucinol injection.

[0070] Comparative Example 2

[0071] This comparative example provides a phloroglucinol injection, and its specific preparation method is basically the same as that of Example 1, except that 0.02Mpa nitrogen and carbon dioxide are introduced in step (1). The corresponding test results are recorded in Table 1.

[0072] By comparison, the long-term stability (16 days) of the phloroglucinol injection of Comparative Example 2 is significantly reduced compared with that of Example 1, and the reduction is greater than that of 8 days. This may be due to the premature introduction of carbon dioxide in (1), which causes the corresponding concentrated hydrochloric acid to be introduced again. Because carbon dioxide is a reversible reaction, at this time, because the addition of phloroglucinol hydrate causes contact in the solution, the surface of some phloroglucinol hydrates is not completely and uniformly in contact with the acidic environment, and subsequently cannot be stably and uniformly dispersed with trimethyl phloroglucinol, thereby affecting the long-term stability (especially the impurity content after 16 days of storage is greatly increased), thereby reducing the cycle life of the phloroglucinol injection.

[0073] Comparative Example 3

[0074] This comparative example provides a phloroglucinol injection, and its specific preparation method is basically the same as that of Example 1, with the main difference that: in step (4) and step (5), 40A mg of phloroglucinol hydrate, 28A mg of sodium chloride and 0.04A mg of trimethylphloroglucinol are directly mixed, and stirred at 800 rpm for 10 min, and the solution temperature is controlled at 80°C and then reduced to 25°C.

[0075] By comparison, the long-term stability of the 16-day storage of the phloroglucinol injection of Comparative Example 3 will also be greatly reduced, and compared with the 8-day storage, the increase in impurities during the 16-day storage is greater. This is probably because phloroglucinol hydrate is easily oxidized. Only by providing it with a sufficient acidic environment and stabilizing it, and then adding trimethylphloroglucinol, the molecular attraction of the two substances themselves will cause part of the phloroglucinol hydrate to be oxidized. If added sequentially, the acidic environment can provide stable conditions for the phloroglucinol hydrate.

[0076] Comparative Example 4

[0077] This comparative example provides a phloroglucinol injection, and its specific preparation method is basically the same as that of Example 1, with the main difference being that: there is no step (8).

[0078] By comparison, the long-term stability of the phloroglucinol injection in Comparative Example 4 decreases after 16 days compared with Example 1 (i.e., after 16 days of storage, the impurity content increases more significantly). This may be due to the absence of carbon dioxide sealing conditions and moist heat sterilization. The acidity may weaken with dilution, and the liquid surface may contain some oxygen, causing certain oxidation. Because the contact area is limited, the long-term stability is affected.

[0079] Comparative Example 5

[0080] This comparative example provides a phloroglucinol injection, and its specific preparation method is basically the same as that of Example 1, with the main difference being that: there is no step (6).

[0081] By comparison, the long-term stability of the phloroglucinol injection of Comparative Example 5 is lower than that of Example 1 after 16 days (i.e., after 16 days of storage, the impurity content increases more significantly). This may be due to the fact that the acidity of the solution is unevenly distributed due to the preparation process and the addition of some substances to the solution. The uneven distribution causes the oxygen content of the solution to change, and the number of impurities may increase.

[0082] In some specific embodiments, the value of A is 1 or 10. When the value of A is 10, the general prescription volume is 4 mL, but it can be configured more by expanding it 10 times, so that more samples are weighed, the error is smaller, and there is more solution, the acidic environment formed by stirring is more uniform, and the antioxidant capacity is better, but when A is infinite, because the contact area of ​​the stirring device is limited, the acidic environment of each interface with different liquid heights is different, which will cause an increase in impurities. Therefore, when the value of A is 10, the impurity content is controlled to the minimum, and the drug impurity content is lower.

[0083] The present invention has been described in detail above in conjunction with specific exemplary embodiments. However, it should be understood that various modifications and variations may be made without departing from the scope of the present invention as defined by the appended claims. The detailed description should be considered only as illustrative, not restrictive, and any such modifications and variations, if any, will fall within the scope of the present invention described herein. In addition, the background art is intended to illustrate the current status and significance of the research and development of the present technology and is not intended to limit the present invention or the application field of the present application and the present invention.

[0084] More specifically, although exemplary embodiments of the present invention have been described herein, the present invention is not limited to these embodiments, but includes any and all embodiments that are recognizable by those skilled in the art based on the foregoing detailed description, such as combinations between the various embodiments, adaptive changes and / or replacements. The limitations in the claims may be interpreted broadly based on the language used in the claims and are not limited to the examples described in the foregoing detailed description or during the implementation of the application, which examples should be considered non-exclusive. Any steps listed in any method or process claim may be performed in any order and are not limited to the order presented in the claim. Therefore, the scope of the present invention should be determined solely by the attached claims and their legal equivalents, rather than by the description and examples given above.

[0085] Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those of ordinary skill in the art to which the present invention belongs. When there is a conflict, the definitions in this specification shall prevail. When flow, power, refractive index, time, or other values ​​or parameters are expressed as ranges, preferred ranges, or a series of upper preferred values ​​and lower preferred values, this should be understood to specifically disclose all ranges formed by any pairing of any upper range limit or preferred value with any lower range limit or preferred value, regardless of whether the range is disclosed separately. For example, a range of 1-50 is understood to include any number, combination of numbers, or subrange selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, and all decimal values ​​between the above integers, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to subranges, "nested subranges" extending from any endpoint within the range are specifically contemplated. For example, nested sub-ranges of the exemplary range 1-50 may include 1-10, 1-20, 1-30, and 1-40 in one direction, or 50-40, 50-30, 50-20, and 50-10 in the other direction.

Claims

1. A method for preparing phloroglucinol injection, characterized in that: The steps include: (1) Add 70% × A × 4 mL of water for injection at 80°C, and then introduce 0.02 MPa nitrogen gas into the water to reach saturation; (2) maintaining the solution of step (1) at a temperature of 80° C. to 90° C. for more than 10 minutes; (3) adding 11.8 mol / L to 12.4 mol / L concentrated hydrochloric acid to the solution in step (2), adjusting the pH to less than or equal to 5 and maintaining the pH for more than 5 minutes; (4) Add 40A mg of pyrogallol hydrate and 28A mg of sodium chloride to the solution of step (3), stir at 800 rpm for 10 min, and control the solution temperature at 80° C. (5) adding 0.04A mg of trimethylphloroglucinol to the solution obtained in step (4), stirring at 800 rpm for 10 min, and cooling to 25° C.; (6) adding 11.8 mol / L to 12.4 mol / L concentrated hydrochloric acid to the solution in step (5), adjusting the pH to less than or equal to 5 and maintaining the pH for more than 5 minutes; (7) Adding water for injection to the solution in step (6) to a solution volume of A×4 mL, and filtering the solution through a 0.22 μm filter membrane; (8) Pass 0.02 MPa carbon dioxide into the solution of step (7) and seal it in a borosilicate glass ampoule, and sterilize it by wet heat at 120° C. for 15 min.

2. The method for preparing phloroglucinol injection according to claim 1, characterized in that: The absolute value of the difference between the pH value in step (3) and the pH value in step (6) is 1.

3. The method for preparing phloroglucinol injection according to claim 1, characterized in that: The value of A is 1 or 10.

4. The method for preparing phloroglucinol injection according to claim 1, characterized in that: In the step (2), the solution of step (1) is kept at a temperature of 80° C. to 90° C. for more than 20 minutes.

5. The method for preparing phloroglucinol injection according to claim 1, characterized in that: In the step (3), the pH is adjusted to 5 and maintained for more than 10 minutes.

6. The method for preparing phloroglucinol injection according to claim 1, characterized in that: In step (3), the pH is adjusted to 4 and maintained for more than 5 minutes.

7. The method for preparing phloroglucinol injection according to claim 1, characterized in that: In step (4), the mixture was stirred at 700 rpm for 10 min.

8. The method for preparing phloroglucinol injection according to claim 1, characterized in that: The value of A is greater than or equal to 1.

9. Use of phloroglucinol injection prepared by the preparation method according to any one of claims 1 to 8 in the preparation of spasmolytic drugs.

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