Prednisone acetate tablet and preparation method thereof

Abstract

The invention provides a prednisone acetate tablet and a preparation method thereof. The prednisone acetate tablet comprises the following components in percentage by weight: 0.5%-5% of prednisone acetate, 35%-45% of corn starch, 20%-25% of lactose, 10%-15% of internally added microcrystalline cellulose, 3%-5% of internally added carboxymethyl starch sodium, 0.6%-1.2% of polyvinylpyrrolidone, 10%-15% of externally added microcrystalline cellulose, 4.5%-7.5% of externally added carboxymethyl starch sodium and 0.1%-1.0% of magnesium stearate. The dissolution rates of the prednisone acetate tablet prepared by the invention in dissolution media with the pH value of 1.2, water and pH value of 7.8 are all greater than 85%, the dissolution rate is high, the prednisone acetate tablet can be placed for 6 months, and the dissolution is stable.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and particularly relates to a prednisone acetate tablet and a preparation method thereof. Background Art

[0002] Prednisone, also known as prednisone, has a chemical name of 17 α ,21-dihydroxypregnane-1,4-diene-3,11,20-trione, with the structural formula as follows, is a glucocorticoid with anti-inflammatory and anti-allergic effects. It can inhibit the proliferation of connective tissue, reduce the permeability of capillary walls and cell membranes, reduce inflammatory exudation, and inhibit the formation and release of histamine and other toxic substances, while increasing gastric juice secretion and promoting appetite. When there is a severe toxic infection, it can be used in combination with a large number of antibacterial drugs to have a good cooling, anti-toxic, anti-inflammatory, anti-shock and symptom relief effect. Its water and sodium retention and potassium excretion effects are smaller than those of cortisone, and its anti-inflammatory and anti-allergic effects are stronger, with fewer side effects.

[0003] Formula 1 Prednisone is commonly used in its acetate form. Prednisone acetate is a white or almost white crystalline powder; it is odorless and bitter. It is easily soluble in chloroform, slightly soluble in acetone, slightly soluble in ethanol or ethyl acetate, and almost insoluble in water. It is mainly used for various acute and severe bacterial infections, severe allergic diseases, collagen diseases (lupus erythematosus, periarteritis nodosa, etc.), rheumatism, rheumatoid arthritis, nephrotic syndrome, severe bronchial asthma, thrombocytopenic purpura, granulocytopenia, acute lymphocytic leukemia, various adrenal insufficiency, exfoliative dermatitis, pemphigus, neurodermatitis, eczema, etc.

[0004] Since prednisone acetate is used for acute allergies and acute inflammation, which are more urgent symptoms, it is very important to take the drug conveniently and quickly. Therefore, it is still necessary to improve the existing technology and develop a drug with stable quality and fast dissolution. Summary of the invention

[0005] The inventors of the present invention are committed to studying prednisone acetate tablets and a preparation method thereof. During the research, they unexpectedly found a tablet with improved content uniformity and a preparation method thereof, and at the same time, the solubility is significantly improved. The solubility in pH 1.2, water, and pH 7.8 dissolution media is greater than 85%, the solubility is high, and the dissolution is stable after accelerated placement for 6 months.

[0006] In a first aspect, the present invention provides a prednisone acetate tablet comprising the following components in percentage by weight: Furthermore, the particle size D of the prednisolone acetate is 501-2.5 μm, D 90 No higher than 5 microns Furthermore, in the added auxiliary materials, the microcrystalline cellulose is microcrystalline cellulose PH301.

[0007] Furthermore, in the added auxiliary materials, the microcrystalline cellulose is microcrystalline cellulose KG1000.

[0008] Furthermore, the adhesive is preferably polyvinyl pyrrolidone K25.

[0009] Internally added excipients are prepared into granules with active ingredients or other excipients using the "internal addition method".

[0010] Furthermore, the present invention provides a prednisone acetate tablet comprising the following components in percentage by weight: Furthermore, the prednisone acetate tablets contain 1-5 mg of prednisone, preferably 1 mg, 2.5 mg, or 5 mg.

[0011] In a second aspect, the present invention provides a method for preparing the prednisone acetate tablets.

[0012] A method for preparing prednisone acetate tablets, characterized in that it comprises the following steps: (1) Preparation of adhesive: dissolve the adhesive in water to prepare an adhesive solution with a concentration of 3%-6% (w / w), and control the temperature to 30-35°C for later use; (2) Premixing and wet granulation: first, add prednisone acetate, internal auxiliary materials sodium carboxymethyl starch, and microcrystalline cellulose into a wet mixer granulator and mix for 5-10 minutes, then add lactose and corn starch into the wet mixer granulator and mix for 3-5 minutes; add the binder solution under stirring conditions and wet granulate; (3) Drying: Dry the granules at 45-55°C until the moisture content is 1.0-2.5%; (4) Granulation: Add the dried granules into a granulator for granulation; (5) Mixing: Add external auxiliary materials, microcrystalline cellulose and sodium carboxymethyl starch, to the granules, mix for 5-10 minutes, then add magnesium stearate and mix for 5-10 minutes; after mixing, the moisture content of the granules is 1.0%-3.0%; (5) Tableting: obtaining prednisone acetate tablets.

[0013] Furthermore, in step (1), a binder solution with a concentration of 4%-5% (w / w) is prepared.

[0014] Furthermore, in the step (4), the particles are granulated, and the particle size distribution of the particles after granulation is: The present invention has achieved beneficial technical effects: (1) The prednisone acetate tablets of the present invention have stable quality, and the solubility in the dissolution medium of pH 1.2, water, and pH 7.8 is greater than 85%, the solubility is high, and the clinical efficacy is stable.

[0015] (2) The prednisone acetate tablets of the present invention have stable dissolution after accelerated storage for 6 months. DETAILED DESCRIPTION

[0016] The present invention discloses a prednisone acetate tablet and a preparation method. Those skilled in the art can refer to the content of the present invention, combine the relevant principles of pharmaceutical preparations, and appropriately improve the process parameters to achieve the present invention. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the scope of the present invention. The application of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit and scope of the present invention to achieve and apply the technology of the present invention.

[0017] In order to better understand the present invention but not to limit the scope of the present invention, all the numbers expressing the amount, percentage, and other numerical values ​​used in this application should be understood to be modified by the word "about" in all cases. Each numerical parameter should at least be considered to be obtained based on the reported significant figures and by conventional rounding methods.

[0018] The present invention is further described below by way of examples, but the examples do not limit the present invention in any way.

[0019] Content uniformity: Take 10 tablets of this product, place each tablet in a 50ml volumetric flask, add appropriate amount of methanol, dissolve the prednisone acetate by ultrasound, cool, dilute to the scale with methanol, shake well, filter, and take the filtrate as the test solution. Determine according to the method under the content determination item. Calculate the content of each tablet by peak area using the external standard method, which should comply with the regulations (General Rule 0941).

[0020] Dissolution test method: (1) Dissolution medium: pH 7.8 phosphate buffer (900 ml): Take 0.58 g of potassium dihydrogen phosphate and 22.34 g of disodium hydrogen phosphate, add 1000 ml of water, shake to dissolve, then add 2.5 g of sodium dodecyl sulfate, stir well, and adjust the pH to 7.80±0.05 with 10% phosphoric acid solution or 1 mol / L sodium hydroxide solution.

[0021] pH 1.2 hydrochloric acid solution (900 ml): Use a measuring cylinder to measure 7.65 ml of hydrochloric acid and dilute it to 1000 ml with water. Then add 2.5 g of sodium dodecyl sulfate and stir well.

[0022] Aqueous solution (600 ml): Use a measuring cylinder to measure 1000 ml of water, then add 2.5 g of sodium dodecyl sulfate and stir well.

[0023] (2) Dissolution apparatus: paddle method; rotation speed: 50 rpm; temperature: 37.0°C ± 0.5°C; sampling volume: 7 ml; The particle size D of prednisolone acetate used in the embodiment of the present invention is 50 1-2.5 μm, D 90 No higher than 5 microns.

[0024] Example 1-3: Prednisone acetate tablets 1. Prescription composition: The materials were added according to the prescription quantity of 1,000,000 tablets to prepare prednisone acetate tablets, the same below.

[0025] 2. Preparation method: (1) Preparation of adhesive: dissolve polyvinyl pyrrolidone K25 in water to prepare a 5.0% (w / w) adhesive solution, and control the temperature to 33-35°C for later use; (2) Premixing and wet granulation: first add prednisone acetate, internal auxiliary materials sodium carboxymethyl starch, and microcrystalline cellulose PH301 into a wet mixer granulator and mix for 5-8 minutes, then add lactose and corn starch into the wet mixer granulator and mix for 3-4 minutes; add the binder solution under stirring conditions and wet granulate; (3) Drying: Dry the granules at 50-53°C to a moisture content of 1.8%; (4) Granulation: The dried granules are added to the granulator for granulation. After granulation, the particle size distribution is as follows: (5) Mixing: Add the external auxiliary materials microcrystalline cellulose KG1000 and sodium carboxymethyl starch to the granules, mix for 5-10 minutes, then add magnesium stearate and mix for 5-10 minutes; the moisture content of the granules after mixing is 2.1%; (6) Tablet compression: Tablets containing 1 mg, 2.5 mg, and 5 mg of prednisolone acetate are obtained respectively.

[0026] 3. Test results: The prepared prednisone acetate tablets were tested for content uniformity and the results are shown in Table 1.

[0027] Table 1: Content uniformity results of prednisone acetate tablets of Examples 1-3 2. The dissolution of the prepared prednisone acetate tablets was tested. The results are shown in Table 2.

[0028] Table 2: Dissolution results of prednisone acetate tablets of Examples 1-3 Example 4-6: Prednisone acetate tablets 1. Prescription composition: 2. Preparation method: (1) Preparation of adhesive: dissolve polyvinyl pyrrolidone K25 in water to prepare a 4.0% (w / w) adhesive solution, and control the temperature to 30-33°C for later use; (2) Premixing and wet granulation: first add prednisone acetate, internal auxiliary materials sodium carboxymethyl starch, and microcrystalline cellulose PH301 into a wet mixer granulator and mix for 8-10 minutes, then add lactose and corn starch into the wet mixer granulator and mix for 4-5 minutes; add the binder solution under stirring conditions and wet granulate; (3) Drying: Dry the granules at 48-50°C until the moisture content is 1.9%; (4) Granulation: The dried granules are added to the granulator for granulation. After granulation, the particle size distribution is as follows: (5) Mixing: Add the external auxiliary materials microcrystalline cellulose KG1000 and sodium carboxymethyl starch to the granules, mix for 5-10 minutes, then add magnesium stearate and mix for 5-10 minutes; the moisture content of the granules after mixing is 2.2%; (6) Tablet compression: Tablets containing 1 mg, 2.5 mg, and 5 mg of prednisolone acetate are obtained respectively.

[0029] 3. Test results: 1. The prepared prednisone acetate tablets were subjected to content uniformity and determination, and the results are shown in Table 3.

[0030] Table 3: Content uniformity of prednisone acetate tablets in Example 4-6, results 2. The dissolution of the prepared prednisone acetate tablets was tested. The results are shown in Table 4.

[0031] Table 4: Dissolution results of prednisone acetate tablets of Example 4-6 Comparative Examples 1-9: Effect of Type of Microcrystalline Cellulose 1. Prescription composition: The types of microcrystalline cellulose are as follows: 2. Preparation method: Same as Example 1-3.

[0032] 3. Test results: 1. The content uniformity and content uniformity of the prednisone acetate tablets prepared in Comparative Examples 1-9 were measured. The results are shown in Table 5.

[0033] Table 5: Comparative Examples 1-9 Prednisone Acetate Tablets Content Uniformity, Results Comparative analysis of Examples 1 to 3 and Comparative Examples 1 to 9 shows that different types of microcrystalline cellulose have different densities, which affects the content uniformity of prednisone acetate tablets.

[0034] (1) Comparative analysis of Examples 1-3 and Comparative Examples 1-3 shows that in terms of content uniformity, the internally added excipient microcrystalline cellulose PH301 is significantly better than microcrystalline cellulose PH101.

[0035] (2) Comparative analysis of Examples 1-3 and Comparative Examples 4-9 showed that in terms of content uniformity, the internal excipient microcrystalline cellulose PH301 was significantly better than microcrystalline cellulose KG1000; the external excipient microcrystalline cellulose KG1000 was significantly better than microcrystalline cellulose KG301.

[0036] In summary, the preferred internal auxiliary material microcrystalline cellulose is microcrystalline cellulose PH301; the preferred external auxiliary material microcrystalline cellulose is microcrystalline cellulose KG1000.

[0037] Comparative Examples 10-15: Effect of Dosage and Addition Method of Sodium Carboxymethyl Starch 1. Prescription composition: The dosage of sodium carboxymethyl starch is as follows: 2. Preparation method: Same as Example 1-3.

[0038] 3. Test results: 1. The content uniformity and content uniformity of the prednisone acetate tablets prepared in Comparative Examples 10-15 were measured. The results are shown in Table 6.

[0039] Table 6: Comparative Example 10-15 Prednisone Acetate Tablets Content Uniformity, Results 2. The dissolution of the prepared prednisone acetate tablets was tested. The results are shown in Table 7.

[0040] Table 7: Dissolution results of prednisone acetate tablets of comparative examples 10-15 Comparative analysis of Examples 1-3 and Comparative Examples 10-15 shows that sodium carboxymethyl starch is a disintegrant, and the addition method and amount affect the dissolution rate of prednisone acetate tablets.

[0041] (1) When sodium carboxymethyl starch is added internally (such as in Comparative Example 13), the dissolution rate of prednisone acetate tablets is affected. In water at pH 1.2, the dissolution rate is lower than 85%, which does not meet the requirements.

[0042] (2) When sodium carboxymethyl starch is added externally (such as in Comparative Example 15), the solubility of prednisone acetate tablets is affected. In pH 1.2, water, and pH 7.8, the solubility is lower than 85%, which does not meet the requirements.

[0043] (3) When sodium carboxymethyl starch is added externally (such as in Comparative Examples 10-12), the dissolution rate of prednisone acetate tablets is affected. The dissolution rate at pH 1.2 is less than 85%, which does not meet the requirements.

[0044] Comparative Examples 16-20: Effects of adhesive type, adhesive concentration and temperature.

[0045] 1. Prescription composition: The type and dosage of adhesive are as follows: 2. Preparation method: The preparation method of Comparative Examples 16-18 is the same as that of Examples 1-3; Comparative Examples 19-20 Preparation method, step (1) is as follows, and the remaining steps are the same as in Example 3. Comparative Example 19 Step (1): Preparation of adhesive: dissolve polyvinyl pyrrolidone K25 in water to prepare a 4.0% (w / w) adhesive solution, and control the temperature to 33-35° C.; set aside; Comparative Example 20 Step (1): Preparation of adhesive: dissolve polyvinyl pyrrolidone K25 in water to prepare a 5.0% (w / w) adhesive solution, and control the temperature to 20-25° C.; set aside; 3. Test results 1. The content uniformity and content uniformity of the prednisone acetate tablets prepared in Comparative Examples 16-20 were measured. The results are shown in Table 8.

[0046] Table 8: Comparative Examples 16-20 Prednisone Acetate Tablets Content Uniformity Results 2. The dissolution of the prepared prednisone acetate tablets was tested. The results are shown in Table 9.

[0047] Table 9: Dissolution results of prednisone acetate tablets of comparative examples 16-20 It can be seen from Examples 1-6 and Comparative Examples 16-20 that the amount and concentration of the binder have an effect on the dissolution of the prednisone acetate tablets. The dissolution of the prednisone acetate tablets just prepared meets the requirements, but after accelerated storage for 1-6 months, the dissolution slows down and does not meet the requirements (see Example 7 for details). Therefore, polyvinyl pyrrolidone K25 is preferably used as the binder.

[0048] Example 7: Stability Test The prednisone acetate tablets prepared in Examples 1 to 6, Comparative Example 14 and Comparative Examples 16 to 20 were placed at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% (accelerated) for 6 months. Samples were taken at the end of 6 months and their dissolution was measured. The results are shown in Table 10.

[0049] Table 10: Stability test results The prednisone acetate tablets prepared by the invention are placed under accelerated conditions for 6 months, and their dissolution and release rates meet the standards. The prednisone acetate tablets prepared by the invention have stable quality.

Claims

1. A prednisone acetate tablet comprising the following components in percentage by weight: The particle size D of the prednisolone acetate 50 1-2.5 μm, D 90 Not higher than 5 microns; Among the added excipients, the microcrystalline cellulose is microcrystalline cellulose PH301; Among the added excipients, the microcrystalline cellulose is microcrystalline cellulose KG1000; The adhesive is preferably polyvinyl pyrrolidone K25.

2. The prednisone acetate tablet according to claim 1, characterized in that Contains the following components in percentage by weight: 。 3. The prednisone acetate tablet according to claim 2, characterized in that: The prednisone acetate tablets contain 1-5 mg of prednisone.

4. The prednisone acetate tablet according to claim 3, characterized in that: The prednisone acetate tablets contain 1 mg of prednisone.

5. The prednisone acetate tablet according to claim 3, characterized in that: The prednisone acetate tablets contain 2.5 mg of prednisone.

6. The prednisone acetate tablet according to claim 3, characterized in that: The prednisone acetate tablets contain 5 mg of prednisone.

7. A method for preparing the prednisone acetate tablets according to any one of claims 1 to 6, characterized in that: The steps include: (1) Preparation of adhesive: dissolve the adhesive in water to prepare an adhesive solution with a concentration of 3%-6%, and control the temperature at 30-35°C for later use; (2) Premixing and wet granulation: first, add prednisone acetate, internal auxiliary materials sodium carboxymethyl starch, and microcrystalline cellulose into a wet mixer granulator and mix for 5-10 minutes, then add lactose and corn starch into the wet mixer granulator and mix for 3-5 minutes; add the binder solution under stirring conditions and wet granulate; (3) Drying: Dry the granules at 45-55°C until the moisture content is 1.0-2.5%; (4) Granulation: Add the dried granules into a granulator for granulation; (5) Mixing: Add external auxiliary materials, microcrystalline cellulose and sodium carboxymethyl starch, to the granules, mix for 5-10 minutes, then add magnesium stearate and mix for 5-10 minutes; after mixing, the moisture content of the granules is 1.0%-3.0%; (5) Tableting: obtaining prednisone acetate tablets.

8. The preparation method according to claim 7, characterized in that: In the step (1), a binder solution with a concentration of 4%-5% is prepared.

9. The preparation method according to claim 7, characterized in that: In the step (4), the particles are granulated, and the particle size distribution of the particles after granulation is: 。

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