Glucocorticoid pharmaceutical preparation as well as preparation method and application thereof

Abstract

The invention relates to a glucocorticoid pharmaceutical preparation as well as a preparation method and application thereof. The glucocorticoid pharmaceutical preparation mainly comprises a hydrocortisone derivative, an antioxidant, a cosolvent and a solvent, the invention relates to a hydrocortisone compound, which is prepared from the following components in parts by mass: 0.01 to 1 part of hydrocortisone derivative, 0.01 to 5 parts of antioxidant, 70 to 90 parts of solvent and 7 to 9 parts of cosolvent, the ratio of the solvent to the cosolvent is (9-11): 1. The hydrocortisone derivative spray disclosed by the invention is good in stability, high in safety, good in curative effect and simple and convenient in preparation method.

Description

Technical Field

[0001] The present invention relates to the technical field of veterinary drugs, and in particular to a glucocorticoid drug preparation and a preparation method and application thereof. Background Art

[0002] Hydrocortisone and its derivatives are medium-acting adrenocortical hormone drugs, which are widely used clinically. Its products include: hydrocortisone, hydrocortisone acetate, etc. Its curative effect is comparable to prednisone, and its anti-inflammatory effect is stronger, which is 3 to 5 times that of cortisone, but its water-salt metabolism is very weak, and it is generally not easy to cause side effects such as water-electrolyte disorders. Current products are oral and injection, and can also be used for skin. In a spray for eye diseases of cattle and sheep in patent CN116687957A, the preparation method is cumbersome, and there is also a requirement for shaking frequency, and sterilization treatment needs to be carried out separately. Therefore, simplifying the preparation method of hydrocortisone derivative preparations, and improving stability, safety, and curative effect are the directions of research worthwhile. Summary of the invention

[0003] Based on the above problems, the present invention provides a preparation for local administration by adding antioxidants and setting a specific ratio of solvents and co-solvents, which greatly expands the clinical application scope of hydrocortisone derivatives. The hydrocortisone derivative spray of the present invention has good stability, high safety, good efficacy, and a simple preparation method.

[0004] The first invention point of the present invention is: a glucocorticoid drug preparation, whose main components include hydrocortisone derivatives, antioxidants, cosolvents, and solvents; by mass, the hydrocortisone derivatives are 0.01-1 parts, the antioxidants are 0.01-5 parts, the solvents are 70-90 parts, and the cosolvents are 7-9 parts.

[0005] Furthermore, the ratio of the solvent to the co-solvent is (9-11):1.

[0006] Furthermore, the hydrocortisone derivative is selected from hydrocortisone acetonide.

[0007] Furthermore, the antioxidant is selected from anhydrous sodium sulfite, sodium metabisulfite, sodium thiosulfate, and vitamin E; preferably anhydrous sodium sulfite.

[0008] Furthermore, the solvent is selected from diethylene glycol monoethyl ether and propylene glycol methyl ether; preferably diethylene glycol monoethyl ether.

[0009] Furthermore, the co-solvent is selected from carbomer and polyethylene glycol 400; preferably polyethylene glycol 400.

[0010] Furthermore, the pharmaceutical preparation includes topical administration, and the dosage form for topical administration is selected from powders, sprays, ointments, pastes, creams, lotions, gels, solutions and patches, preferably sprays.

[0011] Furthermore, the pharmaceutical preparation includes a dermatological preparation.

[0012] The second invention of the present invention is: a method for preparing a glucocorticoid pharmaceutical preparation, the specific steps are as follows:

[0013] 1) Weigh the main ingredients of hydrocortisone derivative, antioxidant, cosolvent and solvent respectively;

[0014] 2) Add the solvent and co-solvent into the batching tank, and then add the antioxidant into the batching tank while stirring;

[0015] 3) Setting the temperature of the solution preparation, adding the hydrocortisone derivative into the preparation tank, stirring until dissolved, stirring for a while, filtering, and filling to obtain the hydrocortisone derivative preparation.

[0016] Furthermore, the solution preparation temperature in step 3) is 30-60 degrees.

[0017] The stirring temperature should not exceed 60 degrees, otherwise it will lead to a decrease in the content of hydrocortisone derivatives.

[0018] Furthermore, the stirring time in step 3) is 1-4 hours.

[0019] Furthermore, the filtration membrane in step 3) is selected from polytetrafluoroethylene, nylon, and polyethersulfone, and the pore size of the filtration membrane is 0.22 μm or 0.45 μm; the pore size is preferably 0.22 μm.

[0020] The third invention of the present invention is: use of the above-mentioned pharmaceutical preparation or the above-prepared pharmaceutical preparation in the preparation of drugs for preventing and treating canine allergic and pruritic skin diseases.

[0021] Compared with the prior art, the advantages of the present invention are:

[0022] The material compatibility of the invention is good. Since an antioxidant is added and the ratio of the solvent and the cosolvent is adjusted, the product has good stability under high temperature, high humidity and light conditions. Hydrocortisone is a drug that is insoluble in water. Clinical application is relatively troublesome. Therefore, after the hydrocortisone derivative spray is prepared by using a solvent and a cosolvent, the hydrocortisone derivative in the spray will not precipitate, and the hydrocortisone derivative can be better absorbed by the dog's skin, and the hydrocortisone is released for symptomatic treatment of dog allergic and itchy skin diseases; after filtering through a filter membrane, the sterilization effect is achieved, and the sterilization effect does not need to be performed separately; a simpler hydrocortisone derivative preparation suitable for industrial large-scale production is provided.

[0023] Specific implementation method

[0024] In order to make the purpose, technical solution and advantages of the present application more clear, the present application is further described in detail below. However, it should be understood that the description here is only used to explain the present application and is not used to limit the scope of the present application.

[0025] Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present application, and the terms used herein in the specification of the present application are only for the purpose of describing specific embodiments and are not intended to limit the present application. The reagents and instruments used herein are all commercially available, and the characterization means involved can refer to the relevant descriptions in the prior art, which will not be repeated herein.

[0026] In order to further understand the present application, the present application is further described in detail below in conjunction with the best embodiment.

[0027] Example 1

[0028] The present embodiment provides a glucocorticoid drug preparation, the main ingredients of which include hydrocortisone derivatives, antioxidants, cosolvents, and solvents; by weight, the hydrocortisone derivatives are 0.01-1 parts, the antioxidants are 0.01-5 parts, the solvents are 70-90 parts, and the cosolvents are 7-9 parts.

[0029] As a further embodiment, the ratio of the solvent to the co-solvent is (9-11):1.

[0030] Hydrocortisone is a drug that is insoluble in water. Clinical application is relatively troublesome. Therefore, by using solvents and co-solvents to prepare hydrocortisone derivative sprays, the hydrocortisone derivatives in the sprays will not precipitate. According to the results of clinical efficacy trials, by determining the ratio of solvents to co-solvents to be 10:1, the hydrocortisone derivatives can be better absorbed by the dog's skin and release hydrocortisone for the symptomatic treatment of allergic and itchy skin diseases in dogs.

[0031] The following is a further description of the above main components and their mass fractions:

[0032] The hydrocortisone derivative is selected from hydrocortisone acetonide;

[0033] Hydrocortisone acetonide, chemical name: 11β, 17α, 21-trihydroxypregnane-4-ene-3, 20-dione-21-acetoxy-17α-propionate, molecular formula: C 26 H 36 O7. The structural formula is as follows:

[0034]

[0035] Hydrocortisone acetonide is a glucocorticoid drug with glucocorticoid activity. The ester bond in its structure has strong lipophilicity, which enhances its penetration into the skin and reduces its plasma utilization rate, so low doses can exert local effects. This product is transported within the skin structure, the ester bond is hydrolyzed and inactivated, and hydrocortisone is released. It has the same metabolic pathway as hydrocortisone (or endogenous cortisol). The absorption effect of this product is better than that of hydrocortisone. Preferably, the amount of hydrocortisone derivative by mass is, for example, 0.01, 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00 part or any value between any two values.

[0036] Antioxidant: Antioxidant is a substance that prevents the adverse effects of oxygen. It is a type of substance that can help capture and neutralize free radicals, thereby removing the damage of free radicals to the human body. Preferably, the antioxidant can be taken as 0.1, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0 parts by mass or any value between any two values.

[0037] Preferably, the antioxidant is selected from anhydrous sodium sulfite, sodium metabisulfite, sodium thiosulfate, and vitamin E; preferably anhydrous sodium sulfite.

[0038] Solvent: A liquid (gas, or solid) that can dissolve a solid, liquid or gaseous solute (both the solvent and the solute can be solid, liquid or gas) to form a solution. The most common solvent in daily life is water. So-called organic solvents are organic compounds containing carbon atoms. Solvents usually have a relatively low boiling point and are easy to evaporate. Or they can be removed by distillation, leaving behind the dissolved substances. Therefore, solvents cannot react chemically with solutes. They must be inert. Solvents can extract soluble compounds from a mixture, the most common example being brewing coffee or tea with hot water. Solvents are usually clear, colorless liquids, most of which have a distinctive smell. Preferably, the solvent can be taken by mass as: for example, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90 parts or any value between any two values.

[0039] Preferably, the solvent is selected from diethylene glycol monoethyl ether and propylene glycol methyl ether; preferably diethylene glycol monoethyl ether.

[0040] Cosolvent: The poorly soluble drug and the added third substance form a complex, an association compound or a double salt between soluble molecules in the solvent to increase the solubility of the drug in the solvent. This third substance is called a cosolvent. Preferably, the cosolvent can be taken as: for example, 7, 8, 9 parts by mass or any value between any two values.

[0041] Preferably, the cosolvent is selected from carbomer and polyethylene glycol 400; preferably polyethylene glycol 400.

[0042] As a further embodiment, the pharmaceutical preparation includes topical administration, and the dosage form for topical administration is selected from powders, sprays, ointments, pastes, creams, lotions, gels, solutions and patches, preferably sprays.

[0043] For topical (including buccal and sublingual) administration, powders, sprays, ointments, pastes, creams, lotions, gels, solutions and patches may be acceptable dosage forms.

[0044] As a further embodiment, the pharmaceutical preparation comprises a skin medication.

[0045] Example 2

[0046] This embodiment provides a method for preparing a glucocorticoid pharmaceutical preparation, and the specific steps are as follows:

[0047] 1) Weigh the main ingredients of hydrocortisone derivative, antioxidant, cosolvent and solvent respectively;

[0048] 2) Add the solvent and co-solvent into the batching tank, and then add the antioxidant into the batching tank while stirring;

[0049] 3) Setting the temperature of the solution preparation, adding the hydrocortisone derivative into the preparation tank, stirring until dissolved, stirring for a while, filtering, and filling to obtain the hydrocortisone derivative preparation.

[0050] As a further embodiment, the solution preparation temperature in step 3) is 30-60 degrees.

[0051] The stirring temperature should not exceed 60 degrees, otherwise it will lead to a decrease in the content of hydrocortisone derivatives.

[0052] As a further embodiment, the stirring time in step 3) is 1-4 hours.

[0053] As a further embodiment, the filtration membrane in step 3) is selected from polytetrafluoroethylene, nylon or polyethersulfone, and the pore size of the filtration membrane is 0.22 μm or 0.45 μm; the pore size is preferably 0.22 μm.

[0054] After filtering through a filter membrane with a pore size of 0.22μm, the sterilization effect is achieved, and there is no need to sterilize separately. Hydrocortisone derivatives should be added last to ensure that they are completely dissolved, and the order of addition cannot be changed.

[0055] Example 3

[0056] A use of the above-mentioned pharmaceutical preparation or the above-prepared pharmaceutical preparation in preparing drugs for preventing and treating canine allergic and pruritic skin diseases.

[0057] Example 4

[0058] According to the content of this application, the pharmaceutical preparation of the example is prepared, and the specific description is as follows:

[0059] If no specific experimental steps or conditions are specified in the examples, the conventional experimental steps or conditions described in the literature in the field can be used. If no manufacturer is specified for the reagents or instruments used, they are all conventional reagent products that can be obtained commercially.

[0060] The present invention is further described in detail below in conjunction with specific embodiments. These embodiments should not be construed as limiting the scope of protection claimed by the present invention.

[0061] Test Example 1

[0062] Weigh the main ingredients of hydrocortisone acetonide 0.1g, anhydrous sodium sulfite 1g, diethylene glycol monoethyl ether 90g, and 9g polyethylene glycol 400 respectively. Add diethylene glycol monoethyl ether and polyethylene glycol 400 to the batching tank, add anhydrous sodium sulfite to the batching tank, stir while adding, the solution preparation temperature is 40 degrees, add hydrocortisone derivatives to the batching tank, stir until dissolved, stir for another hour, filter, the filter membrane is polytetrafluoroethylene, the pore size of the filter membrane is 0.22μm, fill, and get 100ml hydrocortisone derivative spray.

[0063] Test Example 2

[0064] Weigh the main ingredients of hydrocortisone acetonide 0.05g, sodium thiosulfate 3g, diethylene glycol monoethyl ether 100g, and carbomer 10g respectively. Add diethylene glycol monoethyl ether and carbomer to the batching tank, add sodium thiosulfate to the batching tank, stir while adding, the solution preparation temperature is 60 degrees, add hydrocortisone derivatives to the batching tank, stir until dissolved, stir for another 2 hours, filter, the filter membrane is polyethersulfone, the pore size of the filter membrane is 0.45μm, fill, and obtain 110ml of hydrocortisone derivative spray.

[0065] Test Example 3

[0066] Weigh the main ingredients of hydrocortisone acetonide 0.1g, vitamin E 3g, propylene glycol methyl ether 88g, and polyethylene glycol 400 respectively. Add propylene glycol methyl ether and polyethylene glycol 400 to the batching tank, add vitamin E, and stir while adding. The solution preparation temperature is 30 degrees. Add hydrocortisone derivatives to the preparation tank, stir until dissolved, stir for another 4 hours, filter, the filter membrane is nylon, and the pore size of the filter membrane is 0.22μm, fill, and get 98ml of hydrocortisone derivative spray.

[0067] Comparative Example 1: (The recommended ratio of the solvent and the co-solvent of the present invention is not used in this experiment)

[0068] Weigh the main ingredients of hydrocortisone acetonide 0.1g, anhydrous sodium sulfite 1g, diethylene glycol monoethyl ether 96g, and polyethylene glycol 400 3g respectively. Other experimental conditions and steps are the same as those in Experimental Example 1, and 98ml of hydrocortisone derivative spray is obtained.

[0069] Comparative Example 2: (The recommended ratio of the solvent and the co-solvent of the present invention is not used in this experiment)

[0070] Weigh the main ingredients of hydrocortisone acetonide 0.05g, sodium thiosulfate 3g, diethylene glycol monoethyl ether 80g, and polyethylene glycol 400 20g respectively. Other experimental conditions and steps are the same as those in Experimental Example 1, and 98ml of hydrocortisone derivative spray is obtained.

[0071] Comparative Example 3: (This experiment does not adopt the solution preparation temperature range recommended by the present invention)

[0072] During the experiment, the solution preparation temperature was 70 degrees, and other test conditions and steps were the same as those in Test Example 1, and 100 ml of hydrocortisone derivative spray was obtained.

[0073] Comparative Example 4: (The stirring time recommended by the present invention is not used in this experiment)

[0074] During the experiment, stir until dissolved and then stir for 10 minutes. Other test conditions and steps are the same as those in Test Example 1, and 100 ml of hydrocortisone derivative spray is obtained.

[0075] Comparative Example 5: (This experiment does not adopt the experimental step sequence recommended by the present invention)

[0076] Weigh the main ingredients of hydrocortisone acetonide 0.1g, anhydrous sodium sulfite 1g, diethylene glycol monoethyl ether 90g, and 9g polyethylene glycol 400 respectively. Add hydrocortisone derivatives, diethylene glycol monoethyl ether and polyethylene glycol 400 into the batching tank, add anhydrous sodium sulfite into the batching tank, stir while adding, the solution preparation temperature is 60 degrees, stir until dissolved, filter, the filter membrane is polytetrafluoroethylene, the pore size of the filter membrane is 0.22μm, fill, and get 100ml hydrocortisone derivative spray.

[0077] Experimental Example 1

[0078] The water solubility of the samples of Test Examples 1-3 was investigated. Take 4 portions of 10 ml of each sample from Test Examples 1-3, add 10 ml, 50 ml, 100 ml, and 500 ml of water respectively, shake well, and observe the phenomenon. Specific experimental group settings: Group 1: No. 1: 10 ml of sample 1 of Test Example 1 + 10 ml of water, No. 2: 10 ml of sample 1 of Test Example 1 + 50 ml of water, No. 3: 10 ml of sample 1 of Test Example 1 + 100 ml of water, No. 4: 10 ml of sample 1 of Test Example 1 + 500 ml of water;

[0079] Group 2: No. 1: 10 ml of sample 2 of Test Example + 10 ml of water, No. 2: 10 ml of sample 2 of Test Example + 50 ml of water, No. 3: 10 ml of sample 2 of Test Example + 100 ml of water, No. 4: 10 ml of sample 2 of Test Example + 500 ml of water;

[0080] 3 groups: No. 1: Test Example 3 sample 10ml + water 10ml, No. 2: Test Example 3 sample 10ml + water 50ml, No. 3: Test Example 3 sample 10ml + water 100ml, No. 4: Test Example 3 sample 10ml + water 500ml.

[0081] It can be seen from Table 1 that the test sample is miscible with water in any ratio.

[0082] Table 1 Solubility of samples in water

[0083] Group No. 1 No. 2 No.3 No. 4 1 group Colorless clear solution Colorless clear solution Colorless clear solution Colorless clear solution 2 groups Colorless clear solution Colorless clear solution Colorless clear solution Colorless clear solution 3 groups Colorless clear solution Colorless clear solution Colorless clear solution Colorless clear solution

[0084] Experimental Example 2

[0085] The stability of the influencing factors of the samples of Test Example 1 and Comparative Examples 3-5 was investigated, as shown in Table 2.

[0086] High temperature test: Take the samples of Test Example 1 and Comparative Examples 3-5, place them in a constant temperature box at 60°C for 10 days with the opening opened, and take samples for testing on the 5th and 10th days.

[0087] High humidity test: Take the samples of Test Example 1 and Comparative Examples 3-5, open them and place them in a stabilization box with a humidity of 75% for 10 days, and take samples for testing on the 5th and 10th days.

[0088] Light test: Samples of Test Example 1 and Comparative Examples 3-5 were placed under an illumination of 4500 lx ± 500 lx for 10 days, and samples were taken for testing on the 5th and 10th days. The results showed that the sample of Test Example 1 had good stability under high temperature, high humidity and light conditions, and the content of the samples of Comparative Examples 3-5 was less than 91% on day 0, proving that the stirring temperature, stirring time and the order of preparation steps had a great influence on the content.

[0089] Table 2 Stability effect of samples

[0090]

[0091]

[0092] Experimental Example 3

[0093] This product is used for the symptomatic treatment of allergic and pruritic skin diseases in dogs.

[0094] Only dogs with a history and clinical signs of allergic and pruritic skin diseases were included in this study. The 96 test dogs were beagles between 6 and 8 years old. All dogs had moderate to severe pruritus at the time.

[0095] The rats were randomly divided into 8 groups, each with 12 rats, and the samples of Test Examples 1 and 2 and Comparative Examples 1, 2, 3, 4, and 5 and an existing product (Cortavance of Virbac Co., Ltd., France, with a bottle volume of 76 ml and 0.584 mg of hydrocortisone acetonide per 1 ml) were used for the test.

[0096] All dogs were treated with this product, and the dosage was: 1.524g per square centimeter of skin area per day, equivalent to spraying twice in a square area of ​​10cm×10cm. The drug was used once a day for 7 consecutive days and the degree of clinical improvement and side effects were recorded.

[0097] The observation of treatment response was divided into three categories: significant efficacy, effective and ineffective. Significant efficacy means that the itching has been eliminated or reduced to a very mild level, effective means that the itching has been significantly reduced (at least 50%), and ineffective means that the itching has not changed or has worsened, or the dog has an adverse reaction that requires discontinuation of the drug. In this study, the test results are shown in Table 3 below.

[0098] Table 3 The therapeutic effect of the preparation

[0099]

[0100] This study proves that this product can be used for symptomatic treatment of allergic and pruritic skin diseases in dogs. It also proves that the ratio of solvent to cosolvent of 10:1 has no effect on the preparation of hydrocortisone derivative preparations, but has a great impact on the efficacy. Only by adopting this ratio can the efficacy of this product be guaranteed to be better. In addition, the test results can prove that this product is slightly better than the existing product (Cortavance of Virbac Co., Ltd., France).

[0101] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present application should be included in the protection scope of the present application.

Claims

1. A glucocorticoid pharmaceutical preparation, characterized in that: Its main components include hydrocortisone derivatives, antioxidants, cosolvents and solvents; by weight, the hydrocortisone derivatives are 0.01-1 parts, the antioxidants are 0.01-5 parts, the solvents are 70-90 parts and the cosolvents are 7-9 parts.

2. The pharmaceutical preparation according to claim 1, characterized in that The ratio of the solvent to the co-solvent is (9-11):

1.

3. The pharmaceutical preparation according to claim 1, characterized in that The hydrocortisone derivative is selected from hydrocortisone acetonide.

4. The pharmaceutical preparation according to claim 1, characterized in that The antioxidant is selected from anhydrous sodium sulfite, sodium metabisulfite, sodium thiosulfate, and vitamin E; preferably anhydrous sodium sulfite.

5. The pharmaceutical preparation according to claim 1, characterized in that The solvent is selected from diethylene glycol monoethyl ether and propylene glycol methyl ether; preferably diethylene glycol monoethyl ether; The cosolvent is selected from carbomer and polyethylene glycol 400, preferably polyethylene glycol 400.

6. The pharmaceutical preparation according to claim 1, characterized in that The pharmaceutical preparation includes topical administration, and the dosage form for topical administration is selected from powders, sprays, ointments, pastes, creams, lotions, gels, solutions and patches, preferably sprays.

7. The pharmaceutical preparation according to claim 6, characterized in that The pharmaceutical preparations include skin preparations.

8. A method for preparing the glucocorticoid pharmaceutical preparation according to any one of claims 1 to 7, characterized in that: The specific steps are as follows: 1) Weigh the main ingredients of hydrocortisone derivative, antioxidant, cosolvent and solvent respectively; 2) adding the solvent and the co-solvent into the batching tank under stirring, and then adding the antioxidant into the batching tank; 3) Setting the temperature of the solution preparation, adding the hydrocortisone derivative into the preparation tank, stirring until dissolved, stirring for a while, filtering, and filling to obtain the hydrocortisone derivative preparation.

9. The preparation method according to claim 8, characterized in that: The solution preparation temperature in step 3) is 30-60 degrees; The stirring time in step 3) is 1-4 hours; The filtering membrane in step 3) is selected from polytetrafluoroethylene, nylon, and polyethersulfone; the pore size of the filtering membrane is 0.22 μm or 0.45 μm; the pore size is preferably 0.22 μm.

10. Use of the pharmaceutical preparation according to any one of claims 1 to 7 or the pharmaceutical preparation prepared according to any one of claims 8 to 9 in the preparation of drugs for preventing and treating allergic and pruritic skin diseases in dogs.

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