A veterinary dexamethasone sodium phosphate injection and its preparation method

Abstract

The present invention belongs to the technical field of animal medicine, and particularly relates to a veterinary dexamethasone sodium phosphate injection and a preparation method thereof. The veterinary dexamethasone sodium phosphate injection of the present invention comprises dexamethasone sodium phosphate, sodium octadecenoate, a pH regulator, a cosolvent, and injection water. By optimizing excipients and preparation processes, the problem of poor preparation stability caused by the extremely unstable nature of dexamethasone sodium phosphate to light, moisture, and air is solved. The visible foreign matters of the veterinary dexamethasone sodium phosphate injection prepared by the present invention are qualified, the insoluble particles are few, and it remains basically unchanged in the accelerated test. In the light test and the accelerated test, the related substance content of the veterinary dexamethasone sodium phosphate injection of the present invention is low and the stability is high.

Description

Technical Field

[0001] The present invention belongs to the technical field of animal medicine, and particularly relates to a veterinary dexamethasone sodium phosphate injection and a preparation method thereof. Background Art

[0002] Dexamethasone sodium phosphate, with the chemical formula C 22 H 28 FNa2O8P, is a white or almost white crystalline powder, soluble in water, its aqueous solution is a colorless clear liquid, slightly soluble in ethanol, odorless and easy to absorb moisture. It belongs to adrenal cortical hormone drugs, has anti-inflammatory, anti-allergic, anti-rheumatic and immunosuppressive effects, is commonly used in allergic and autoimmune diseases, and is widely used in veterinary clinics. It has good effects in the treatment of postpartum acute metritis, severe septicemia, peritonitis, etc.; it also has good treatment effects on allergic diseases such as edema and allergic congestion; it has a certain protective effect on traumatic shock, cardiogenic shock, allergic shock, toxic shock, etc.

[0003] Chinese Patent with the publication number CN1559413A discloses a dexamethasone sodium phosphate freeze-dried powder injection and a preparation method provided by the present invention, including 1 part of dexamethasone sodium phosphate, 0 - 500 parts of freeze-dried powder support agents (mannitol, sorbitol, lactose), 1 part of antioxidant (sodium bisulfite, sodium sulfite, sodium thiosulfate, cysteine hydrochloride), and an appropriate amount of pH regulator. This solution solves to a certain extent the problem that due to the extremely unstable nature of dexamethasone sodium phosphate to light, moisture and air, the stability of its preparation is poor. However, for the dexamethasone sodium phosphate freeze-dried powder injection, the related substance content reaches 1.41% after 10 days of light exposure, 6.64% after 10 days at 60°C, 1.68% after 10 days of high humidity, and as high as 2.58% after 3 months at 40°C, indicating that the effect of making the dexamethasone sodium phosphate preparation stable by this solution is not good and the related substance content is high.

[0004] Chinese Patent with the publication number CN112245386A discloses a dexamethasone sodium phosphate injection and a preparation method thereof. By weight percentage, the dexamethasone sodium phosphate injection includes 1.04% - 1.14% of dexamethasone sodium phosphate, 2.56% - 2.598% of sodium citrate dihydrate, 0.007% - 0.010% of citric acid, and the balance is injection water. By using the amounts of sodium citrate dihydrate and citric acid to ensure the osmotic pressure and pH value of the preparation, and the preparation process ensures the stability of the preparation by adopting a lower liquid preparation temperature, nitrogen filling and sterilization process. However, its stability effect is slightly unsatisfactory, and the related substance content is relatively high when stored at room temperature for 0 months and at 40°C for 1 month. Summary of the Invention

[0005] Overcoming the deficiencies of the prior art, the present invention provides a stable dexamethasone sodium phosphate injection for veterinary use, solves the problems of high content of related substances and easy decomposition upon exposure to light in dexamethasone sodium phosphate preparations, and provides a dexamethasone sodium phosphate injection for veterinary use that is stable to light, heat, and humidity.

[0006] Specifically, the technical solution of the present invention is as follows:

[0007] The present invention provides a dexamethasone sodium phosphate injection for veterinary use, and the dexamethasone sodium phosphate injection for veterinary use includes: dexamethasone sodium phosphate, sodium octadecenoate, pH regulator, cosolvent, and injection water. The CAS of the sodium octadecenoate is 143-19-1.

[0008] The preparation method of the dexamethasone sodium phosphate injection for veterinary use is as follows:

[0009] (1) Grind dexamethasone sodium phosphate and sodium octadecenoate together in the dark, add the cosolvent and dissolve it fully, filter, and let it stand;

[0010] (2) Add an appropriate amount of pH regulator to the solution obtained in step (1) to adjust the pH, make up the volume to the full amount with injection water, stir evenly, filter, fill, sterilize, and package to obtain the finished product.

[0011] In multiple embodiments, the weight ratio of dexamethasone sodium phosphate to sodium octadecenoate is 10:0.5 to 1.3.

[0012] In a preferred embodiment, the weight ratio of dexamethasone sodium phosphate to sodium octadecenoate is 10:0.9.

[0013] In multiple embodiments, the pH regulator is selected from one of acetate buffer solution, citrate buffer solution, tartrate buffer solution, phosphate buffer solution, and carbonate buffer solution.

[0014] In a preferred embodiment, the pH regulator is citrate buffer solution.

[0015] In multiple embodiments, the cosolvent is a mixed solution of ethanol and tert-butanol.

[0016] Among them, the cosolvent is a mixed solution of ethanol and tert-butanol with a volume ratio of 3:1 to 2.

[0017] In a preferred embodiment, the cosolvent is a mixed solution of ethanol and tert-butanol with a volume ratio of 3:1.5.

[0018] The ethanol is ethanol with a mass fraction of 95%.

[0019] Further, the content of dexamethasone sodium phosphate in the veterinary dexamethasone sodium phosphate injection is 1 mg / ml to 5 mg / ml. The content of dexamethasone sodium phosphate in the veterinary dexamethasone sodium phosphate injection is 1 mg / ml; the content of dexamethasone sodium phosphate in the veterinary dexamethasone sodium phosphate injection is 2 mg / ml; the content of dexamethasone sodium phosphate in the veterinary dexamethasone sodium phosphate injection is 5 mg / ml.

[0020] In multiple embodiments, the co-grinding time in the preparation method of the veterinary dexamethasone sodium phosphate injection is 10 to 20 minutes; in a preferred embodiment, the co-grinding time is 15 minutes.

[0021] In multiple embodiments, the standing time in the preparation method of the veterinary dexamethasone sodium phosphate injection is 10 to 20 minutes; in a preferred embodiment, the co-grinding time is 15 minutes.

[0022] In multiple embodiments, the pH is adjusted to 7.0 to 8.5 in the preparation method of the veterinary dexamethasone sodium phosphate injection.

[0023] In a preferred embodiment, the pH is adjusted to 7.5 to 8.0 in the preparation method of the veterinary dexamethasone sodium phosphate injection.

[0024] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0025] The present invention optimizes excipients and preparation processes, solves the problem of poor preparation stability caused by the extremely unstable nature of dexamethasone sodium phosphate to light, moisture, and air. The visible foreign matters of the veterinary dexamethasone sodium phosphate injection prepared by the present invention are qualified, the number of insoluble particles is small, and it remains basically unchanged in the accelerated test. In the light test and accelerated test, the related substance content of the veterinary dexamethasone sodium phosphate injection of the present invention is low and the stability is high. Description of the Drawings

[0026] Figure 1 : Curves of related substance content in the light test of the veterinary dexamethasone sodium phosphate injection in Examples 1 to 3 and Comparative Examples 1 to 3

[0027] Figure 2 : Curves of related substance content in the light test of the veterinary dexamethasone sodium phosphate injection in Examples 4 to 6 and Comparative Examples 4 to 6

[0028] Figure 3 : Curves of related substance content in the accelerated test of the veterinary dexamethasone sodium phosphate injection in Examples 1 to 3 and Comparative Examples 1 to 3

[0029] Figure 4:Accelerated test related substance content curve of dexamethasone sodium phosphate injection for veterinary use in Examples 4 - 6 and Comparative Examples 4 - 6 Detailed implementation manners

[0030] In order to make the objectives and technical solutions of the present invention clearer, the following further describes the present invention in conjunction with embodiments. However, the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. Those skilled in the art should understand that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0031] Example 1 Dexamethasone sodium phosphate injection for veterinary use

[0032] (1) Grind 10 parts by weight of dexamethasone sodium phosphate and 0.9 parts by weight of sodium octadecenoate in the dark for 15 min, add them to a mixed solution of ethanol and tert-butanol with a volume ratio of 3:1.5, fully dissolve, filter, and let stand for 15 min;

[0033] (2) Add an appropriate amount of citrate buffer solution to the solution obtained in step (1) to adjust the pH to 7.8, make up the volume to the full volume with injection water, stir evenly, filter, fill, sterilize, and package to obtain the finished product.

[0034] Example 2 Dexamethasone sodium phosphate injection for veterinary use

[0035] (1) Grind 10 parts by weight of dexamethasone sodium phosphate and 0.5 parts by weight of sodium octadecenoate in the dark for 10 min, add them to a mixed solution of ethanol and tert-butanol with a volume ratio of 3:1, fully dissolve, filter, and let stand for 10 min;

[0036] (2) Add an appropriate amount of citrate buffer solution to the solution obtained in step (1) to adjust the pH to 7.5, make up the volume to the full volume with injection water, stir evenly, filter, fill, sterilize, and package to obtain the finished product.

[0037] Example 3 Dexamethasone sodium phosphate injection for veterinary use

[0038] (1) Grind 10 parts by weight of dexamethasone sodium phosphate and 1.3 parts by weight of sodium octadecenoate in the dark for 20 min, add them to a mixed solution of ethanol and tert-butanol with a volume ratio of 3:2, fully dissolve, filter, and let stand for 20 min;

[0039] (2) Add an appropriate amount of acetate buffer solution to the solution obtained in step (1) to adjust the pH to 8.0, make up the volume to the full volume with injection water, stir evenly, filter, fill, sterilize, and package to obtain the finished product.

[0040] Example 4 Dexamethasone sodium phosphate injection for veterinary use

[0041] (1) Grind 10 parts by weight of sodium dexamethasone phosphate and 0.9 parts by weight of sodium octadecenoate in the dark for 15 min, add them to a mixed solution of ethanol and tert-butanol with a volume ratio of 3:1.5, dissolve them fully, filter, and let stand for 15 min;

[0042] (2) Add an appropriate amount of tartrate buffer solution to the solution obtained in step (1) to adjust the pH to 7.0, make up the volume to the full volume with injection water, stir evenly, filter, fill, sterilize, and package to obtain the finished product.

[0043] Example 5 Veterinary Sodium Dexamethasone Phosphate Injection

[0044] (1) Grind 10 parts by weight of sodium dexamethasone phosphate and 0.9 parts by weight of sodium octadecenoate in the dark for 15 min, add them to a mixed solution of ethanol and tert-butanol with a volume ratio of 3:1.5, dissolve them fully, filter, and let stand for 15 min;

[0045] (2) Add an appropriate amount of phosphate buffer solution to the solution obtained in step (1) to adjust the pH to 8.0, make up the volume to the full volume with injection water, stir evenly, filter, fill, sterilize, and package to obtain the finished product.

[0046] Example 6 Veterinary Sodium Dexamethasone Phosphate Injection

[0047] (1) Grind 10 parts by weight of sodium dexamethasone phosphate and 0.9 parts by weight of sodium octadecenoate in the dark for 15 min, add them to a mixed solution of ethanol and tert-butanol with a volume ratio of 3:1.5, dissolve them fully, filter, and let stand for 15 min;

[0048] (2) Add an appropriate amount of carbonate buffer solution to the solution obtained in step (1) to adjust the pH to 7.7, make up the volume to the full volume with injection water, stir evenly, filter, fill, sterilize, and package to obtain the finished product.

[0049] Comparative Example 1 Veterinary Sodium Dexamethasone Phosphate Injection

[0050] (1) Add 10 parts by weight of sodium dexamethasone phosphate to a mixed solution of ethanol and tert-butanol with a volume ratio of 3:1.5, dissolve them fully, filter, and let stand for 15 min;

[0051] (2) Add an appropriate amount of citrate buffer solution to the solution obtained in step (1) to adjust the pH to 7.8, make up the volume to the full volume with injection water, stir evenly, filter, fill, sterilize, and package to obtain the finished product.

[0052] Comparative Example 2 Veterinary Sodium Dexamethasone Phosphate Injection

[0053] (1) Grind 10 parts by weight of sodium dexamethasone phosphate and 2 parts by weight of sodium octadecenoate together in the dark for 15 min, add them to a mixed solution of ethanol and tert-butanol with a volume ratio of 3:1.5, dissolve them completely, filter, and let stand for 15 min;

[0054] (2) Add an appropriate amount of citrate buffer solution to the solution obtained in step (1) to adjust the pH to 7.8, make up the volume to the full volume with injection water, stir evenly, filter, fill, sterilize, and package to obtain the finished product.

[0055] Comparative Example 3 Veterinary Sodium Dexamethasone Phosphate Injection

[0056] (1) Add 10 parts by weight of sodium dexamethasone phosphate and 0.9 parts by weight of sodium octadecenoate to a mixed solution of ethanol and tert-butanol with a volume ratio of 3:1.5, dissolve them completely, filter, and let stand for 15 min;

[0057] (2) Add an appropriate amount of citrate buffer solution to the solution obtained in step (1) to adjust the pH to 7.8, make up the volume to the full volume with injection water, stir evenly, filter, fill, sterilize, and package to obtain the finished product.

[0058] Comparative Example 4 Veterinary Sodium Dexamethasone Phosphate Injection

[0059] (1) Grind 10 parts by weight of sodium dexamethasone phosphate and 0.9 parts by weight of sodium octadecenoate together in the dark for 15 min, add ethanol, dissolve them completely, filter, and let stand for 15 min;

[0060] (2) Add an appropriate amount of citrate buffer solution to the solution obtained in step (1) to adjust the pH to 7.8, make up the volume to the full volume with injection water, stir evenly, filter, fill, sterilize, and package to obtain the finished product.

[0061] Comparative Example 5 Veterinary Sodium Dexamethasone Phosphate Injection

[0062] (1) Grind 10 parts by weight of sodium dexamethasone phosphate and 0.9 parts by weight of sodium octadecenoate together in the dark for 15 min, add them to a mixed solution of ethanol and tert-butanol with a volume ratio of 1:1, dissolve them completely, filter, and let stand for 15 min;

[0063] (2) Add an appropriate amount of citrate buffer solution to the solution obtained in step (1) to adjust the pH to 7.8, make up the volume to the full volume with injection water, stir evenly, filter, fill, sterilize, and package to obtain the finished product.

[0064] Comparative Example 6 Sodium Dexamethasone Phosphate Injection (Veterinary Drug Approval Number: 040622530)

[0065] Stability Verification of the Veterinary Sodium Dexamethasone Phosphate Injection of the Present Invention

[0066] 1. Visual inspection and insoluble particle inspection of dexamethasone sodium phosphate injection for veterinary use

[0067] Accelerated test: According to the commercial package, 5 vials (bottles) of the test article are placed at a temperature of 40 ± 2°C and a relative humidity of 75% ± 5% for 6 months. Samples are taken at the end of the 0th month and the 6th month during the test period for visual inspection under a light intensity of 1000 - 1500 lx and for insoluble particle inspection under a microscope.

[0068] Table 1 Visual inspection and insoluble particle inspection of dexamethasone sodium phosphate injection for veterinary use

[0069]

[0070] Visual inspection and insoluble particle inspection are carried out on the dexamethasone sodium phosphate injection for veterinary use in Examples 1 - 6 and Comparative Examples 1 - 6. Table 1 shows that the visual inspection and insoluble particle inspection of the dexamethasone sodium phosphate injection in the examples of the present invention are qualified. As the solution is placed, the number of insoluble particles basically does not increase, indicating high stability.

[0071] 2. Content of related substances in the light exposure test

[0072] The dexamethasone sodium phosphate injection for veterinary use in Examples 1 - 6 and Comparative Examples 1 - 6 are used as test articles respectively, and are placed with the openings facing upwards in a light exposure chamber equipped with fluorescent lamps under the condition of an illuminance of 4500 lx ± 500 lx for 90 days. Samples are taken on the 0th day, 10th day, 30th day, 60th day, and 90th day respectively, and the total content of related substances in the dexamethasone sodium phosphate injection for veterinary use is detected by high performance liquid chromatography.

[0073] Determination of related substance content in dexamethasone sodium phosphate injection by high performance liquid chromatography: Take this product and quantitatively dilute it with the mobile phase to prepare a solution containing about 0.5 mg of dexamethasone sodium phosphate per 1 ml as the test solution; accurately measure 1 ml and place it in a 100-ml volumetric flask, dilute it to the mark with the mobile phase, shake well, and use it as the control solution; take dexamethasone reference substance, accurately weigh it, dissolve it with methanol and quantitatively dilute it to prepare a solution containing about 0.5 mg per 1 ml, accurately measure 1 ml, place it in a 100-ml volumetric flask, dilute it to the mark with the mobile phase, shake well, and use it as the reference solution; determine according to the method under the item of related substances of dexamethasone sodium phosphate in "Chinese Veterinary Pharmacopoeia 2015 Edition". If there is a peak in the chromatogram of the test solution with the same retention time as the dexamethasone peak in the chromatogram of the reference solution, calculate by the external standard method based on the peak area, and it shall not exceed 0.5% of the labeled amount; if other impurity peaks appear, for the impurity (impurity I) peak with a relative retention time of about 0.25 to the dexamethasone sodium phosphate peak, the peak area shall not be greater than the main peak area of the control solution (1.0%), and the peak area of other single impurity peaks shall not be greater than 0.5 times the main peak area of the control solution (0.5%), and the sum of the peak areas of impurity I and other impurity peaks shall not be greater than 2 times the main peak area of the control solution (2.0%). The excipient peaks with a relative retention time of less than 0.2 to the dexamethasone sodium phosphate peak in the chromatogram of the test solution shall be ignored.

[0074] Figure 1 It is a curve graph of the related substance content in the light exposure test of veterinary dexamethasone sodium phosphate injection in Examples 1 to 3 and Comparative Examples 1 to 3. Figure 2 It is a curve graph of the related substance content in the light exposure test of dexamethasone sodium phosphate injection in Examples 4 to 6 and Comparative Examples 4 to 6. It shows that the veterinary dexamethasone sodium phosphate injection of the present invention is not easily decomposed when exposed to light, overcomes the defect of light instability of dexamethasone sodium phosphate, and has strong light stability.

[0075] 3. Related substance content in accelerated test

[0076] Accelerated test: According to the commercial package, place it at 40 ± 2 °C and relative humidity of 75% ± 5% for 6 months. Samples are taken at the end of the 1st month, 2nd month, 3rd month, and 6th month during the test, and the related substances of the veterinary dexamethasone sodium phosphate injection in the examples and comparative examples are inspected, and the detection method is the above-mentioned high performance liquid chromatography.

[0077] Figure 3 It is a curve graph of the related substance content in the accelerated test of veterinary dexamethasone sodium phosphate injection in Examples 1 to 3 and Comparative Examples 1 to 3. Figure 4Graph of the content of related substances in the accelerated test of dexamethasone sodium phosphate injection for veterinary use in Examples 4 to 6 and Comparative Examples 4 to 6. The results show that the dexamethasone sodium phosphate injection for veterinary use of the present invention has high stability and low content of related substances. Through the accelerated test, the total content of related substances changes little.

Claims

1. A veterinary dexamethasone sodium phosphate injection, characterized in that, The dexamethasone sodium phosphate injection for animals comprises: dexamethasone sodium phosphate, sodium octadecenoate, pH regulator, cosolvent, and injection water; The preparation method of the dexamethasone sodium phosphate injection for animals is as follows: (1) Grind 10 parts by weight of dexamethasone sodium phosphate and 0.5 - 1.3 parts by weight of sodium octadecenoate together in the dark, add an ethanol and tert-butanol mixed solution with a volume ratio of 3:1 - 2 as a cosolvent and dissolve it fully, filter, and let it stand; (2) Add an appropriate amount of pH regulator to the solution obtained in step (1) to adjust the pH, make up the volume to the full volume with injection water, stir evenly, filter, fill, sterilize, and package to obtain the finished product.

2. The dexamethasone sodium phosphate injection for veterinary use according to claim 1, characterized in that, The weight ratio of dexamethasone sodium phosphate to sodium octadecenoate is 10:0.

9.

3. The dexamethasone sodium phosphate injection for veterinary use according to claim 1, wherein The pH regulator is selected from one of acetate buffer solution, citrate buffer solution, tartrate buffer solution, phosphate buffer solution, and carbonate buffer solution.

4. The dexamethasone sodium phosphate injection for animals according to claim 3, wherein, The pH regulator is citrate buffer solution.

5. The dexamethasone sodium phosphate injection for veterinary use according to claim 1, wherein, The cosolvent is an ethanol and tert-butanol mixed solution with a volume ratio of 3:1.

5.

6. The dexamethasone sodium phosphate injection for veterinary use according to claim 1, characterized in that, The content of dexamethasone sodium phosphate in the dexamethasone sodium phosphate injection for animals is 1 mg / ml - 5 mg / ml.

7. The veterinary dexamethasone sodium phosphate injection according to claim 6, characterized in that, The content of dexamethasone sodium phosphate in the dexamethasone sodium phosphate injection for animals is 1 mg / ml; the content of dexamethasone sodium phosphate in the dexamethasone sodium phosphate injection for animals is 2 mg / ml; the content of dexamethasone sodium phosphate in the dexamethasone sodium phosphate injection for animals is 5 mg / ml.

8. The dexamethasone sodium phosphate injection for veterinary use according to claim 1, wherein The co-grinding time is 10 - 20 minutes, and the standing time is 10 - 20 minutes.

9. The dexamethasone sodium phosphate injection for veterinary use according to claim 1, wherein, The pH adjustment is to 7.0 - 8.5.

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