Stable danazol capsule and preparation thereof

Abstract

The invention relates to a stable danazol capsule and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations for treating endocrine system diseases. The danazol capsule disclosed by the invention is prepared from danazol, vanillin, a pH-regulated hydroxypropyl starch-glycerol matrix, a filling agent and a lubricating agent. The danazol and vanillin are co-ground, a hydroxypropyl starch-glycerol matrix with a specific pH value is combined, and a reasonable filling agent, a lubricant and a preparation process are matched, so that the danazol tablet is prepared, the problems of poor stability and low dissolution rate of an existing danazol preparation are solved, the raw materials are easy to obtain, the preparation process is simple, and industrial production is facilitated.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations for treating endocrine system diseases, and particularly relates to a stable danazol capsule and its preparation. Background Art

[0002] Disclosing the information of this background art section is only intended to increase the understanding of the overall background of the present invention, and is not necessarily regarded as an admission or an implication in any form that this information constitutes the prior art already known to those of ordinary skill in the art.

[0003] Danazol is a synthetic androgen, with the chemical name of 17α-pregna-2,4-diene-20-yn-3β-ol-17β-hydroxyisoandrosterone. Its main uses include treating diseases such as endometriosis, fibrocystic breast disease, hereditary angioedema, gynecomastia, precocious puberty, thrombocytopenic purpura, and hemophilia.

[0004] Chinese Patent No. CN108785264A discloses a danazol tablet composition, which contains danazol, lecithin, sodium dodecyl sulfate, lactose, low-substituted hydroxypropyl methylcellulose, sodium carboxymethyl starch, and magnesium stearate. Chinese Patent No. CN111588699A discloses an orally disintegrating tablet containing danazol. The solid pharmaceutical composition includes: danazol, cross-linked polyvinylpyrrolidone XL-108, colloidal silica, low-substituted hydroxypropyl methylcellulose, lactose, magnesium stearate, and an appropriate amount of 45% ethanol; the preparation method is: danazol and other excipients are sieved respectively, danazol, colloidal silica, and cross-linked polyvinylpyrrolidone XL-10 are weighed and moistened with 45% ethanol to make soft materials; the obtained mixture is added with lactose, low-substituted hydroxypropyl methylcellulose, and cross-linked polyvinylpyrrolidone XL-10, mixed evenly, moistened with 45% ethanol to make soft materials, granulated, sieved, added with magnesium stearate, and pressed into tablets.

[0005] However, the danazol preparations still have the following problems in the prior art:

[0006] (1) The stability of danazol in the preparation needs to be improved.

[0007] (2) The poor water solubility, low dissolution rate, and dissolution stability problems of danazol need to be solved. Summary of the Invention

[0008] The purpose of the present invention is to provide a stable danazol capsule and its preparation method, which can solve the problems of poor stability and low dissolution rate of danazol in the existing danazol preparations through a specific raw material formula and preparation process.

[0009] The danazol capsules provided by the present invention comprise the following components by weight: 50-150 parts of danazol, 10-30 parts of vanillyl alcohol (CAS: 498-00-0, content 98%), 50-150 parts of pH-adjusted hydroxypropyl starch-glycerol matrix, 50-150 parts of filler, and 5-20 parts of lubricant. Among them, in the pH-adjusted hydroxypropyl starch-glycerol matrix, there are 40-120 parts of hydroxypropyl starch and 10-30 parts of glycerol, and the pH of the matrix is 5.5 ± 0.5. Preferably, the weight ratio of danazol to vanillyl alcohol is 5:1. Preferably, the mass ratio of hydroxypropyl starch to glycerol is 4:1. The filler is selected from at least one of starch, microcrystalline cellulose, dextrin, sucrose, and mannitol; the lubricant is selected from at least one of magnesium stearate, colloidal silica, and talc powder; the capsule shell is one of No. 1, No. 2, No. 0, No. 00, and No. 000, and is assembled according to the weight, density, etc. of the actual content.

[0010] The specific preparation method thereof is as follows:

[0011] (1) Mix hydroxypropyl starch and glycerol, and adjust the pH to 5.5 ± 0.5 with citric acid-sodium citrate to obtain a pH-adjusted hydroxypropyl starch-glycerol matrix;

[0012] (2) Mix danazol and vanillyl alcohol, grind for 5-10 min, add to the pH-adjusted hydroxypropyl starch-glycerol matrix, and mix evenly to obtain a mixture;

[0013] (3) Mix the mixture with the filler and the lubricant, granulate, dry to obtain granules, and fill them into capsule shells to obtain the product.

[0014] In this technical solution, the addition of vanillyl alcohol and co-grinding with danazol can improve the dispersion state of danazol and enhance its stability; the pH-adjusted hydroxypropyl starch-glycerol matrix provides a suitable microenvironment for danazol, and vanillyl alcohol and the matrix play a positive role in the stability of the overall structure of the capsule.

[0015] Compared with the prior art, the technical effects of the present invention are as follows:

[0016] (1) High stability: By co-grinding danazol and vanillyl alcohol and combining with the pH-adjusted hydroxypropyl starch-glycerol matrix, the present invention significantly improves the stability of danazol in the capsule. The results of the accelerated test show that when placed at 40°C ± 2°C and a relative humidity of 75 ± 5% for 6 months, the decline in the content of danazol in Examples 1-3 is extremely small, far superior to the comparative examples, which can ensure the stability of the content of the active ingredient during storage and guarantee the quality and efficacy of the drug.

[0017] (2) Good dissolution performance: The unique formulation and preparation process endow the danazol capsules with excellent dissolution performance. In the dissolution test, the dissolution degrees of the examples at different time points are significantly higher than those of the comparative examples. The dissolution degrees reach over 90% at 30 minutes, far exceeding the specified minimum limit (70% of the labeled amount), enabling the drug to be released faster, improving bioavailability, and exerting the drug effect more quickly.

[0018] (3) Stable dissolution degree: The danazol capsules prepared by the present invention exhibit excellent performance in terms of dissolution stability. After a 6-month accelerated test, the changes in the dissolution degrees of Examples 1 to 3 are minimal, while those of the comparative examples decrease significantly. This indicates that the danazol capsules of the present invention can still maintain stable drug release performance under long-term storage conditions, providing a reliable guarantee for the stability and effectiveness of clinical medication.

[0019] (4) Advantages of raw materials and process: The raw materials used in the formulation are all common pharmaceutical excipients, with wide sources and controllable costs. The preparation process is relatively simple, easy to industrialize, and no complex technologies and equipment are introduced during the production process, which is conducive to reducing production costs, improving production efficiency, and facilitating popularization and application. Description of the Drawings

[0020] Figure 1 : Content stability of the danazol capsules of Examples 1 to 3 and Comparative Examples 1 to 5.

[0021] Figure 2 : Dissolution degrees of the danazol capsules of Examples 1 to 3 and Comparative Examples 1 to 5. Detailed Embodiments

[0022] In order to make the objectives and technical solutions of the present invention clearer, the following further illustrates the present invention with reference to the 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.

[0023] Example 1 Danazol Capsules

[0024] Formulation:

[0025]

[0026] Preparation method:

[0027] (1) Mix hydroxypropyl starch and glycerol, and adjust the pH to 5.5 with citric acid - sodium citrate to obtain a pH-adjusted hydroxypropyl starch - glycerol matrix.

[0028] (2) Mix danazol with vanillyl alcohol, grind in a mortar for 8 min, add to the pH-adjusted hydroxypropyl starch-glycerol matrix, and mix well to obtain a mixture.

[0029] (3) Mix the mixture with a filler and a lubricant, granulate, and dry (temperature ≤ 40 °C, time 3 hours) to obtain granules, and fill them into No. 0 capsule shells to obtain the product.

[0030] Example 2 Danazol Capsules

[0031] Formulation:

[0032]

[0033] Preparation method:

[0034] (1) Mix hydroxypropyl starch with glycerol, adjust the pH to 5.0 with citric acid-sodium citrate to obtain a pH-adjusted hydroxypropyl starch-glycerol matrix.

[0035] (2) Mix danazol with vanillyl alcohol, grind in a mortar for 5 min, add to the pH-adjusted hydroxypropyl starch-glycerol matrix, and mix well to obtain a mixture.

[0036] (3) Mix the mixture with a filler and a lubricant, granulate, and dry (temperature ≤ 40 °C, time 2 hours) to obtain granules, and fill them into No. 1 or No. 2 capsule shells to obtain the product.

[0037] Example 3 Danazol Capsules

[0038] Formulation:

[0039]

[0040]

[0041] Preparation method:

[0042] (1) Mix hydroxypropyl starch with glycerol, adjust the pH to 6.0 with citric acid-sodium citrate to obtain a pH-adjusted hydroxypropyl starch-glycerol matrix.

[0043] (2) Mix danazol with vanillyl alcohol, grind in a mortar for 10 min, add to the pH-adjusted hydroxypropyl starch-glycerol matrix, and mix well to obtain a mixture.

[0044] (3) Mix the mixture with a filler and a lubricant, granulate, and dry (temperature ≤ 40 °C, time 4 hours) to obtain granules, and fill them into No. 000 capsule shells to obtain the product.

[0045] Comparative Example 1 Danazol Capsules

[0046] Formulation:

[0047]

[0048] Preparation method:

[0049] (1) Mix hydroxypropyl starch and glycerol, and adjust the pH to 5.5 with citric acid - sodium citrate to obtain a pH - adjusted hydroxypropyl starch - glycerol matrix.

[0050] (2) Add danazol to the pH - adjusted hydroxypropyl starch - glycerol matrix, mix well to obtain a mixture.

[0051] (3) Mix the mixture with a filler and a lubricant, granulate, and dry (temperature ≤ 40 °C, time 3 hours) to obtain granules, and fill them into capsules to obtain the product.

[0052] Control Example 2 Danazol Capsules

[0053] Formula:

[0054]

[0055] Preparation method:

[0056] (1) Mix hydroxypropyl starch and glycerol, and adjust the pH to 5.5 with citric acid - sodium citrate to obtain a pH - adjusted hydroxypropyl starch - glycerol matrix.

[0057] (2) Add danazol and vanillyl alcohol to the pH - adjusted hydroxypropyl starch - glycerol matrix, mix well to obtain a mixture.

[0058] (3) Mix the mixture with a filler and a lubricant, granulate, and dry (temperature ≤ 40 °C, time 3 hours) to obtain granules, and fill them into capsules to obtain the product.

[0059] Control Example 3 Danazol Capsules

[0060] Formula:

[0061]

[0062] Preparation method:

[0063] Mix danazol and vanillyl alcohol, grind them in a mortar for 8 min, mix with a filler and a lubricant, granulate, and dry (temperature ≤ 40 °C, time 3 hours) to obtain granules, and fill them into capsules to obtain the product.

[0064] Control Example 4 Danazol Capsules

[0065] Formula:

[0066]

[0067] Preparation method:

[0068] (1) Mix hydroxypropyl starch and glycerol to obtain a hydroxypropyl starch - glycerol matrix (pH measured to be 6.8 - 7.0).

[0069] (2) Mix danazol and vanillyl alcohol, grind in a mortar for 8 min, add to the pH - adjusted hydroxypropyl starch - glycerol matrix, and mix evenly to obtain a mixture.

[0070] (3) Mix the mixture with a filler and a lubricant, granulate, and dry (temperature ≤ 40°C, time 3 hours) to obtain granules, which are then filled into capsules to obtain the product.

[0071] Danazol Capsule of Comparative Example 5

[0072] Formulation:

[0073]

[0074] Preparation method:

[0075] Mix danazol with a filler and a lubricant, granulate, and dry (temperature ≤ 40°C, time 3 hours) to obtain granules, which are then filled into capsules to obtain the product.

[0076] Stability experiment of danazol content

[0077] The content of danazol is determined by the high - performance liquid chromatography method (General Rule 0512) in the Chinese Pharmacopoeia 2020 Edition. Test solution: Weigh an appropriate amount of danazol accurately, dissolve it in the mobile phase and quantitatively dilute it to prepare a solution containing about 0.2 mg per 1 ml. Reference solution: Weigh an appropriate amount of the test substance accurately, dissolve it in the mobile phase and quantitatively dilute it to prepare a solution containing about 0.2 mg per 1 ml. System suitability solution: Weigh an appropriate amount of danazol, dissolve it in the mobile phase and dilute it to prepare a solution containing about 0.2 mg per 1 ml. Chromatographic conditions: Use octadecylsilane chemically bonded silica gel as the filler; use acetonitrile - methanol - water (4:4:3) as the mobile phase; the detection wavelength is 270 nm; the injection volume is 10 μl. System suitability requirements: In the chromatogram of the system suitability solution, the number of theoretical plates calculated based on the danazol peak is not less than 2500. Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram. Calculate by the external standard method based on the peak area. (Accelerated test: Test conditions: 40°C ± 2°C, relative humidity 75 ± 5%, 6 months.)

[0078] Table 1 Content stability of danazol capsules

[0079]

[0080] Table 1, Figure 1It shows that under the accelerated test conditions, the content of danazol in Examples 1 to 3 decreased by a relatively small amount and still maintained a relatively high content at the end of the 6th month, indicating that the danazol capsules prepared according to the formula and preparation method of the present invention have good stability of danazol content. The content of danazol in Comparative Examples 1 to 5 decreased relatively significantly within 6 months. In particular, in Comparative Examples 1, 2 and 5, the content at the end of the 6th month was significantly lower than that in the examples, indicating that changes in factors such as the matrix, vanillin, and preparation process have a significant impact on the stability of danazol content.

[0081] Determination of dissolution of danazol capsules

[0082] The dissolution was determined according to the dissolution and release determination method (General Rule 0931, Method 2) in the Chinese Pharmacopoeia 2020 Edition. Dissolution conditions: Using 1000 ml of 0.1 mol / L hydrochloric acid solution - isopropanol (3:2) as the dissolution medium, the rotation speed was 80 revolutions per minute. The operation was carried out according to the law, and samples were taken after 30 minutes. Test solution: Take 25 ml of the dissolution solution, filter it, accurately measure an appropriate amount of the continued filtrate, and quantitatively dilute it with the dissolution medium to prepare a solution containing about 20 μg of danazol per 1 ml. Reference solution: Take an appropriate amount of danazol reference substance, accurately weigh it, dissolve it with the dissolution medium and quantitatively dilute it to prepare a solution containing about 20 μg per 1 ml. Determination method: Take the test solution and the reference solution, and according to the ultraviolet-visible spectrophotometry (General Rule 0401), measure the absorbance at the wavelength of 286 nm respectively, and calculate the dissolution amount per capsule. Minimum limit: 70% of the labeled amount, and it should meet the requirements.

[0083] Table 2 Dissolution of danazol capsules

[0084]

[0085] Table 2, Figure 2 It shows that the dissolution of Examples 1 to 3 at different time points was relatively high, and the dissolution reached more than 90% at 30 minutes, which was far higher than the minimum limit (70% of the labeled amount), indicating that the formula and preparation process of the examples are beneficial to the dissolution of danazol. The dissolution of Comparative Examples 1 to 5 was generally lower than that of the examples at each time point. In particular, in Comparative Examples 3 to 5, the dissolution at 30 minutes was significantly lower than that of the examples, indicating that factors such as the matrix, filler, and preparation process will affect the dissolution of danazol capsules.

[0086] Dissolution stability of danazol capsules

[0087] The danazol capsules of Examples 1 to 3 and the danazol capsules of Comparative Examples 1 to 5 were placed at 40°C ± 2°C and a relative humidity of 75 ± 5% for 6 months, and the dissolution at 30 min was measured.

[0088] Table 3 Dissolution stability of danazol capsules

[0089]

[0090]

[0091] Table 3 shows that after 6 months of accelerated testing, the dissolution of Examples 1 to 3 changed little, indicating good dissolution stability. This is related to the formulation and preparation process of the examples, which make the capsule structure stable and not easily affected by environmental factors. Due to the defects in the formulation or preparation process of Comparative Examples 1 to 5, the structure of the capsules changed under the accelerated test conditions, affecting the dissolution of danazol, and the dissolution decreased relatively significantly after 6 months.

Claims

1. A danazol capsule, characterized in that, The danazol capsules comprise the following components by weight: 50 - 150 parts of danazol, 10 - 30 parts of vanillyl alcohol, 50 - 150 parts of pH-adjusted hydroxypropyl starch-glycerol matrix, 50 - 150 parts of filler, and 5 - 20 parts of lubricant; the preparation method is: after co-grinding danazol and vanillyl alcohol, mixing with the pH-adjusted hydroxypropyl starch-glycerol matrix, adding the filler and the lubricant, granulating, drying, and then filling into capsule shells.

2. The danazol capsule according to claim 1, characterized in that, In the pH-adjusted hydroxypropyl starch-glycerol matrix, there are 40 - 120 parts of hydroxypropyl starch and 10 - 30 parts of glycerol.

3. The danazol capsule according to claim 1, wherein, The pH of the pH-adjusted hydroxypropyl starch-glycerol matrix is 5.5 ± 0.

5.

4. The danazol capsule according to claim 1, characterized in that, The weight ratio of danazol to vanillyl alcohol is 5:

1.

5. The danazol capsule according to claim 1, wherein The mass ratio of hydroxypropyl starch to glycerol is 4:

1.

6. The danazol capsule according to claim 1, wherein The filler is selected from at least one of starch, microcrystalline cellulose, dextrin, sucrose, and mannitol.

7. The danazol capsule according to claim 1, characterized in that, The lubricant is selected from at least one of magnesium stearate, colloidal silicon dioxide, and talc powder.

8. The danazol capsule according to claim 1, wherein The capsule shell is one of No. 1, No. 2, No. 0, No. 00, and No.

000.

9. A method for preparing the danazol capsules according to claim 1, characterized in that, The method is as follows: (1) Mix hydroxypropyl starch and glycerol, and adjust the pH to 5.5 ± 0.5 with an acid to obtain the pH-adjusted hydroxypropyl starch-glycerol matrix; (2) Mix danazol and vanillyl alcohol, grind for 5 - 10 min, add to the pH-adjusted hydroxypropyl starch-glycerol matrix, and mix evenly to obtain a mixture; (3) Mix the mixture with the filler and the lubricant, granulate, dry to obtain granules, and fill into capsule shells to obtain the product.

10. The method according to claim 9, characterized in that, The acid is citric acid-sodium citrate.

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