Didrogesterone tablet as well as preparation method and application thereof

Abstract

The invention discloses a didrogesterone tablet as well as a preparation method and application thereof. The preparation method of the didrogesterone tablet comprises the following steps: S1, spraying an ethanol solution of didrogesterone into a diluent, and drying to obtain a powdery mixture A; s2, spraying an aqueous solution of an adhesive into the mixture A in the step S1, and granulating to obtain particles B; s3, the mixture C is tableted, and the mixture C comprises the particles B in the step S2. The didrogesterone tablet disclosed by the invention has excellent dissolution rate and content uniformity.

Description

Technical Field

[0001] The present invention relates to a dydrogesterone tablet and a preparation method and application thereof, and specifically belongs to the technical field of medicine. Background Art

[0002] The chemical name of dydrogesterone is 9β,10α-pregnane-4,6-diene-3,20-dione. It is mainly used for diseases caused by endogenous progesterone deficiency, such as dysmenorrhea, endometriosis, secondary amenorrhea, irregular menstrual cycle, dysfunctional uterine bleeding, premenstrual syndrome, threatened abortion or habitual abortion caused by progesterone deficiency, infertility caused by corpus luteum deficiency, and can also be used for luteal support in assisted reproductive technology.

[0003] In 2002, SFDA approved the marketing of Dydrogesterone tablets of SOLVAY of the Netherlands in my country, with the trade name of "Duphaston". In September 2009, SOLVAY sold its pharmaceutical business to Abbott BV. Currently, Abbott is the only company selling Dydrogesterone tablets in China.

[0004] The Russian instructions for Dafutong clearly state that the prescription is: Tablet core: lactose, hydroxypropyl methylcellulose, magnesium stearate, corn starch, colloidal silicon dioxide; film coating powder: Opadry Y-1-7000 film coating premix (hydroxypropyl methylcellulose, polyethylene glycol 400 and titanium dioxide (E171)). The instructions for Dafutong state that the relative bioavailability of dydrogesterone tablets is only 28%. The low bioavailability affects the efficacy, so it is necessary to increase the dissolution rate of dydrogesterone tablets and thus increase the bioavailability.

[0005] In addition, the hydroxypropyl-beta-cyclodextrin inclusion technology used in the CN 116999399 A patent has a long process time, requiring 25 hours for material processing alone, which is not conducive to commercial production.

[0006] The dydrogesterone used in the patent CN 117180214 A needs to be micronized, but the disadvantage of micronized APIs is that there will be obvious agglomeration, which is not conducive to content uniformity, and APIs with more serious agglomeration need additional processing in production, which is not conducive to commercialization. Summary of the invention

[0007] The technical problem to be solved by the present invention is to overcome the defects of low dissolution and poor content uniformity of dydrogesterone tablets in the prior art, and provide a dydrogesterone tablet and a preparation method and application thereof. The dydrogesterone tablet of the present invention has excellent dissolution and content uniformity.

[0008] The present invention approaches the above technical problem through the following technical solutions.

[0009] The present invention provides a method for preparing a dydrogesterone tablet, which comprises the following steps:

[0010] S1, spraying the ethanol solution of dydrogesterone into a diluent, and drying to obtain a powdered mixture A;

[0011] S2, spraying the aqueous solution of the binder into the mixture A in step S1, granulating to obtain particles B;

[0012] S3, tableting the mixture C, wherein the mixture C includes the particles B in step S2.

[0013] In the present invention, preferably, the dydrogesterone tablets are used to prepare drugs for treating diseases caused by endogenous progesterone deficiency. The diseases caused by endogenous progesterone deficiency are, for example, dysmenorrhea, endometriosis, secondary amenorrhea, irregular menstrual cycle, dysfunctional uterine bleeding, premenstrual syndrome, threatened abortion or habitual abortion caused by progesterone deficiency, or infertility caused by corpus luteum deficiency.

[0014] In step S1 of the present invention, preferably, in the ethanol solution of dydrogesterone, the mass ratio of the dydrogesterone to the ethanol is 1:(60-90), more preferably 1:(50-70) or 1:90, for example 1:60.

[0015] In step S1 of the present invention, preferably, during the preparation of the ethanol solution of dydrogesterone, water bath heating is used to dissolve the dydrogesterone in the ethanol.

[0016] Preferably, the water bath heating temperature is 30-40°C.

[0017] Preferably, the water bath heating time is 20 to 60 minutes.

[0018] In step S1 of the present invention, preferably, the ethanol solution of dydrogesterone is sprayed into the diluent through a fluidized bed.

[0019] In step S1 of the present invention, the injection time is, for example, 30 to 60 minutes, for example, 45 minutes.

[0020] In step S1 of the present invention, preferably, the mass ratio of the diluent to the dydrogesterone in step S1 is (10-15):1, more preferably (11-14):1, for example (12.51:1) or (12.41:1).

[0021] In step S1 of the present invention, the diluent is, for example, lactose and / or corn starch.

[0022] In a specific embodiment of the present invention, the manufacturer of the lactose is DFE Pharma GmbH & Co.KG., and the model is Pharmatose® 200M.

[0023] In a specific embodiment of the present invention, the manufacturer of the corn starch is Roquette Freres and the model is Maize Starch B.

[0024] In some preferred embodiments of the present invention, the diluent is lactose and corn starch, and the mass ratio of the lactose to the corn starch is 100:(10-60), for example, (111.1:14), (111.1:13), (100:25.1) or (80:45.1).

[0025] In step S1 of the present invention, preferably, during the drying process, the air volume is 60-80m 3 / h, for example 70m 3 / h.

[0026] In step S1 of the present invention, preferably, during the drying, the inlet air temperature is 40-60°C, for example, 50°C.

[0027] In step S1 of the present invention, preferably, the water content of the mixture A is ≤3.0%.

[0028] In step S2 of the present invention, preferably, the mass ratio of the adhesive to the dydrogesterone in step S1 is (0.1-0.5):1, more preferably (0.2-0.4):1, for example (0.28:1) or (0.38:1).

[0029] In step S2 of the present invention, preferably, the binder is selected from one or more of hydroxypropyl methylcellulose, corn starch and potato starch.

[0030] In a specific embodiment of the present invention, the manufacturer of the hypromellose is Nutrition & Biosciences USA 1, LLC, and the model is E5 PREMIUM LV.

[0031] In a specific embodiment of the present invention, the manufacturer of the corn starch is Roquette Freres and the model is Maize Starch B.

[0032] In a specific embodiment of the present invention, the manufacturer of the potato starch is Roquette Freres.

[0033] In a specific embodiment of the present invention, the aqueous solution of the binder is an aqueous solution of hypromellose, the concentration of the aqueous solution of hypromellose is 10% to 15%, for example 12%, and the percentage is the mass percentage of the hypromellose in the aqueous solution of hypromellose.

[0034] In a specific embodiment of the present invention, the aqueous solution of the adhesive is an aqueous solution of corn starch, the concentration of the aqueous solution of corn starch is 2% to 6%, for example 5%, and the percentage is the mass percentage of the corn starch in the aqueous solution of corn starch.

[0035] In a specific embodiment of the present invention, the aqueous solution of the adhesive is an aqueous solution of potato starch, the concentration of the potato starch aqueous solution is 2% to 6%, for example 5%, and the percentage is the mass percentage of the potato starch in the potato starch aqueous solution.

[0036] In step S2 of the present invention, preferably, the aqueous solution of the binder is sprayed into the mixture A in step S1 through a fluidized bed.

[0037] In step S2 of the present invention, preferably, during the granulation, the air volume of the air intake is 60-80m 3 / h, for example 70m 3 / h.

[0038] In step S2 of the present invention, preferably, during the granulation, the inlet air temperature is 40-60°C, for example, 50°C.

[0039] In step S2 of the present invention, the granulation time is, for example, 20 to 40 minutes, for example, 30 minutes.

[0040] In step S2 of the present invention, preferably, after the granulation, it also includes the steps of drying and granulation.

[0041] Preferably, the drying is carried out in a fluidized bed.

[0042] Herein, for example, a 1.0 mm sieve is used for the granulation.

[0043] In step S2 of the present invention, preferably, the moisture content of the particles B is ≤3.0%.

[0044] In step S2 of the present invention, preferably, the particle size of the particles B is ≤1.0 mm.

[0045] In step S3 of the present invention, preferably, the mixture C further comprises a glidant and / or a lubricant.

[0046] The glidant is, for example, colloidal silicon dioxide.

[0047] Preferably, the mass ratio of the glidant to the dydrogesterone in step S1 is (0.1-0.2):1, for example 0.14:1.

[0048] Wherein, the lubricant is, for example, magnesium stearate.

[0049] Preferably, the mass ratio of the lubricant to the dydrogesterone in step S1 is (0.05-0.1):1, for example 0.07:1.

[0050] Among them, when the mixture C also includes a flow aid and a lubricant, preferably, the granules B after granulation in step S2 are first mixed with the flow aid, and the mixing speed is 15 rpm; then the lubricant is added and mixed, and the mixing speed is 15 rpm.

[0051] In step S3 of the present invention, preferably, the tableting further includes coating.

[0052] Among them, the coating agent used in the coating is, for example, a film coating premix, and the concentration of the aqueous solution of the film coating premix is ​​preferably 9%-15%, for example, 12%, and the percentage is the mass percentage of the film coating premix in the aqueous solution of the film coating premix.

[0053] Preferably, the mass ratio of the coating agent used in the coating to the dydrogesterone in step S1 is (0.2-0.6):1, for example 0.4:1.

[0054] In a specific embodiment of the present invention, in the preparation method of the dydrogesterone tablets, the raw material composition is selected from one of the following schemes:

[0055] Solution 1:

[0056] Dydrogesterone 100 parts,

[0057] Lactose 1111 parts,

[0058] 140 parts corn starch,

[0059] 6000 parts of anhydrous ethanol,

[0060] 28 parts of hypromellose, wherein the concentration of the aqueous solution of hypromellose is 12%, and the percentage is the mass percentage of the hypromellose in the aqueous solution of the hypromellose,

[0061] 14 parts of colloidal silicon dioxide,

[0062] 7 parts of magnesium stearate,

[0063] 40 parts of film coating premix, wherein the concentration of the aqueous solution of the film coating premix is ​​12%, and the percentage is the mass percentage of the film coating premix in the aqueous solution of the film coating premix;

[0064] Option 2:

[0065] Dydrogesterone 100 parts,

[0066] Lactose 1111 parts,

[0067] 140 parts corn starch,

[0068] 9000 parts of anhydrous ethanol,

[0069] 28 parts of hypromellose, wherein the concentration of the aqueous solution of hypromellose is 12%, and the percentage is the mass percentage of the hypromellose in the aqueous solution of hypromellose,

[0070] 14 parts of colloidal silicon dioxide,

[0071] 7 parts of magnesium stearate,

[0072] 40 parts of film coating premix, wherein the concentration of the aqueous solution of the film coating premix is ​​12%, and the percentage is the mass percentage of the film coating premix in the aqueous solution of the film coating premix;

[0073] Option 3:

[0074] Dydrogesterone 100 parts,

[0075] Lactose 1111 parts,

[0076] 130 parts corn starch,

[0077] 6000 parts of anhydrous ethanol,

[0078] 38 parts of corn starch, wherein the concentration of the aqueous solution of corn starch is 5%, and the percentage is the mass percentage of the corn starch in the aqueous solution of corn starch,

[0079] 14 parts of colloidal silicon dioxide,

[0080] 7 parts of magnesium stearate,

[0081] 40 parts of film coating premix, wherein the concentration of the aqueous solution of the film coating premix is ​​12%, and the percentage is the mass percentage of the film coating premix in the aqueous solution of the film coating premix;

[0082] Option 4:

[0083] Dydrogesterone 100 parts,

[0084] Lactose 1111 parts,

[0085] 130 parts corn starch,

[0086] 6000 parts of anhydrous ethanol,

[0087] 38 parts of potato starch, wherein the concentration of the aqueous solution of the potato starch is 5%, and the percentage is the mass percentage of the potato starch in the aqueous solution of the potato starch,

[0088] 14 parts of colloidal silicon dioxide,

[0089] 7 parts of magnesium stearate,

[0090] 40 parts of film coating premix, wherein the concentration of the aqueous solution of the film coating premix is ​​12%, and the percentage is the mass percentage of the film coating premix in the aqueous solution of the film coating premix;

[0091] Option 5:

[0092] Dydrogesterone 100 parts,

[0093] Lactose 1000 parts,

[0094] 251 parts corn starch,

[0095] 6000 parts of anhydrous ethanol,

[0096] 28 parts of hypromellose, wherein the concentration of the aqueous solution of hypromellose is 12%, and the percentage is the mass percentage of the hypromellose in the aqueous solution of the hypromellose,

[0097] 14 parts of colloidal silicon dioxide,

[0098] 7 parts of magnesium stearate,

[0099] 40 parts of film coating premix, wherein the concentration of the aqueous solution of the film coating premix is ​​12%, and the percentage is the mass percentage of the film coating premix in the aqueous solution of the film coating premix;

[0100] Option 6:

[0101] Dydrogesterone 100 parts,

[0102] Lactose 800 parts,

[0103] 451 parts corn starch,

[0104] 9000 parts of anhydrous ethanol,

[0105] 28 parts of hypromellose, wherein the concentration of the aqueous solution of hypromellose is 12%, and the percentage is the mass percentage of the hypromellose in the aqueous solution of the hypromellose,

[0106] 14 parts of colloidal silicon dioxide,

[0107] 7 parts of magnesium stearate,

[0108] 40 parts of film coating premix, wherein the concentration of the aqueous solution of the film coating premix is ​​12%, and the percentage is the mass percentage of the film coating premix in the aqueous solution of the film coating premix.

[0109] The present invention also provides a dydrogesterone tablet, which is prepared by the above-mentioned preparation method of the dydrogesterone tablet.

[0110] In the present invention, preferably, the dydrogesterone tablets are used to prepare drugs for treating diseases caused by endogenous progesterone deficiency. The diseases caused by endogenous progesterone deficiency are, for example, dysmenorrhea, endometriosis, secondary amenorrhea, irregular menstrual cycle, dysfunctional uterine bleeding, premenstrual syndrome, threatened abortion or habitual abortion caused by progesterone deficiency, or infertility caused by corpus luteum deficiency.

[0111] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0112] The reagents and raw materials used in the present invention are commercially available.

[0113] The positive and progressive effects of the present invention are:

[0114] The dydrogesterone tablets of the present invention have improved dissolution and content uniformity. The preparation method of the dydrogesterone tablets of the present invention has a short production process time, is easy to operate, does not require micronization of the raw material drug, and is suitable for dydrogesterone general powder. BRIEF DESCRIPTION OF THE DRAWINGS

[0115] Figure 1 The dissolution rate of Examples 1 to 6 and Comparative Examples 1 to 4 varies with time. DETAILED DESCRIPTION

[0116] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0117] The raw material information involved in the examples and comparative examples of the present invention is shown in Table 1:

[0118] Table 1

[0119]

[0120] Embodiment 1-2

[0121] The raw material components of the dydrogesterone tablets of Examples 1 and 2 are as shown in Table 2:

[0122] Table 2

[0123]

[0124] The preparation method is as follows:

[0125] Dissolve dydrogesterone in anhydrous ethanol, then spray the dydrogesterone-ethanol solution into the diluent through a fluidized bed, control the time within 45±15min, and then dry to a moisture content of ≤3.0%. The parameters during drying are: air volume of 70m 3 / h, the inlet air temperature is 50℃; a 12% hydroxypropyl methylcellulose solution is sprayed into the diluent through a fluidized bed for granulation. The granulation parameters are: the inlet air volume is 70m 3 / h, the inlet air temperature is 50℃, and the granulation time is controlled to be 30±10min; after fluidized bed drying to a moisture content of ≤3.0%, a 1.0mm sieve is used for granulation; the granulated particles are then mixed with colloidal silicon dioxide for 10min at a speed of 15rpm; magnesium stearate is added and mixed for 3min at a speed of 15rpm; finally, tableting is performed, and the film coating premix is ​​prepared with water to form a film coating premix aqueous solution with a mass fraction of 12%, and film coating is performed to obtain dydrogesterone tablets.

[0126] Embodiment 3-4

[0127] The raw material components of the dydrogesterone tablets of Examples 3 and 4 are as shown in Table 3:

[0128] Table 3

[0129]

[0130] The difference between Examples 3 and 4 and Example 1 is that the diluents are different, wherein the mass concentration of corn starch in Example 3 is 5%, and the mass concentration of potato starch in Example 4 is 5%, and the remaining operations and conditions are the same as those in Example 1.

[0131] Embodiment 5-6

[0132] The raw material components of the dydrogesterone tablets of Examples 5 to 6 are shown in Table 4 below:

[0133] Table 4

[0134]

[0135] The difference between Examples 5 and 6 and Example 1 is that the ratio of lactose to corn starch in the diluent is different, and the other operations and conditions are the same as those in Example 1.

[0136] Comparative Example 1

[0137] Purchase Duphaston from the market, batch number 368860.

[0138] Comparative Example 2

[0139] The raw material components of the dydrogesterone tablets of Comparative Example 2 are shown in Table 5 below:

[0140]

[0141] Among them, dydrogesterone was micronized and agglomerated, and the particle size distribution was as shown in Table 6:

[0142] Table 6

[0143]

[0144] Comparative Example 2: Dydrogesterone tablets were prepared by high shear wet granulation. The specific preparation method is as follows:

[0145] Lactose, dydrogesterone and corn starch were added to the high shear wet granulation pot in sequence. After dry mixing for 10 minutes, 12% hydroxypropyl methylcellulose solution was added to the granulation pot through a peristaltic pump. The slurry addition time was controlled to be 1-3 minutes, and the stirring speed was 100 rpm. Then the cutter was turned on and stirred for 1 minute at a cutter speed of 2000 rpm. The granulated wet granules were transferred to a fluidized bed for drying until the moisture content was ≤3.0%, and then granulated using a 1.0 mm sieve; the granulated granules were then mixed with colloidal silicon dioxide for 10 minutes at a speed of 15 rpm; magnesium stearate was added and mixed for 3 minutes at a speed of 15 rpm; finally, tablets were pressed, and the film coating premix was prepared with water to prepare a film coating premix aqueous solution with a mass fraction of 12%, and film coating was performed to obtain dydrogesterone tablets.

[0146] Comparative Example 3

[0147] The prescription composition of the dydrogesterone tablets in Comparative Example 3 is exactly the same as that in Comparative Example 2, except that the specific preparation method is different. Comparative Example 3 uses high shear wet granulation to prepare dydrogesterone tablets, and the specific preparation method is as follows:

[0148] After part of lactose and dydrogesterone were mixed in a ratio of 2:1, the mixture was passed through a 50-mesh sieve, and then lactose, dydrogesterone-lactose mixture, and corn starch were added to the high shear wet granulation pot in sequence. After dry mixing for 10 minutes, 12% hydroxypropyl methylcellulose solution was added to the granulation pot through a peristaltic pump, and the slurry addition time was controlled to be 1-3 minutes, and the stirring speed was 100 rpm. Then, the cutter was turned on and stirred for 1 minute at a cutter speed of 2000 rpm. The granulated wet granules were transferred to a fluidized bed for drying until the moisture content was ≤3.0%, and then granulated using a 1.0 mm sieve; the granulated granules were then mixed with colloidal silicon dioxide for 10 minutes at a speed of 15 rpm; magnesium stearate was added and mixed for 3 minutes at a speed of 15 rpm; finally, tablets were pressed, and the film coating premix was prepared with water to prepare a film coating premix aqueous solution with a mass fraction of 12%, and film-coated to obtain dydrogesterone tablets.

[0149] Comparative Example 4

[0150] The prescription composition of the dydrogesterone tablets of Comparative Example 4 is exactly the same as that of Comparative Example 2, except that the specific preparation method is different. Comparative Example 4 uses high shear wet granulation to prepare dydrogesterone tablets, and the specific preparation method is as follows:

[0151] Lactose, dydrogesterone and corn starch were added to the high shear wet granulation pot in sequence. After dry mixing for 10 minutes, 12% hydroxypropyl methylcellulose solution was atomized by a peristaltic pump and added to the granulation pot. The atomization pressure was 0.1MPa, the slurry addition time was controlled to be 1-3 minutes, the stirring speed was 100rpm, and then the cutter was turned on and stirred for 1 minute at a cutter speed of 2000rpm. The granulated wet granules were transferred to a fluidized bed for drying until the moisture content was ≤3.0%, and then granulated using a 1.0mm sieve; the granulated granules were then mixed with colloidal silicon dioxide for 10 minutes at a speed of 15rpm; magnesium stearate was added and mixed for 3 minutes at a speed of 15rpm; finally, tablets were pressed, and the film coating premix was prepared with water to prepare a film coating premix aqueous solution with a mass fraction of 12%, and film coating was performed to obtain dydrogesterone tablets.

[0152] Effect Example 1

[0153] (1) Content mean and content uniformity

[0154] Test methods for content mean and content uniformity:

[0155] Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0512).

[0156] Solution preparation

[0157] Test solution: Take 1 dydrogesterone tablet, place it in a 20ml volumetric bottle, add an appropriate amount of mobile phase, ultrasonicate for 15 minutes until completely disintegrated, cool to room temperature, dilute to scale with mobile phase, shake well, and then filter with a 0.45μm polytetrafluoroethylene filter membrane, and take the filtrate as the test solution; prepare 10 portions in parallel. (about 0.5mg / ml)

[0158] Reference solution: Take about 25 mg of dydrogesterone reference substance, weigh accurately, place in a 50 ml volumetric flask, add appropriate amount of mobile phase, ultrasonicate for 15 minutes, cool to room temperature, dilute to scale with mobile phase, shake well, and prepare a solution containing about 0.5 mg of dydrogesterone per 1 ml as the reference solution.

[0159] Chromatographic conditions

[0160] Chromatographic column: Octadecylsilane bonded silica column as filler (Hypersil ODS (C18) or Agilent ZORBAX Extend-C18, 150*4.6mm, 5μm or other chromatographic columns with equivalent performance)

[0161] Mobile phase: acetonitrile-water (40:60)

[0162] Flow rate: 1.0mL / min

[0163] Column temperature: 40°C

[0164] Injection volume: 10µL

[0165] Detection wavelength: 310nm

[0166] Run until 1.5 times the retention time of the main component chromatographic peak (the recommended column peak time is about 18 minutes, and the recommended running time is 25 minutes)

[0167] The system suitability requires that the number of theoretical plates calculated based on the dydrogesterone peak should be no less than 4000, and the asymmetry of the dydrogesterone peak should be 0.7~1.4.

[0168] Determination method: Accurately measure 10 μL of the test solution and the reference solution, respectively, inject them into the liquid chromatograph, record the chromatogram, and calculate the content of each tablet by the peak area according to the external standard method, which should comply with the regulations (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0941)

[0169] The content mean and content uniformity of Examples 1 to 6 and Comparative Examples 1 to 4 are shown in Table 7:

[0170] Table 7

[0171]

[0172] As shown in Table 7, the content uniformity A+2.2S of Examples 1 to 6 is less than that of Comparative Examples 1 to 4, and the results of Comparative Examples 2 to 4 are the worst, indicating that the use of spray coating and one-step granulation process can effectively improve the content uniformity.

[0173] (2) Dissolution

[0174] The dissolution was determined according to the dissolution test method (Method 0931, General Rules of Part IV of the 2020 Edition of the Chinese Pharmacopoeia).

[0175] The dissolution conditions are: water as the dissolution medium, the rotation speed is 50 rpm, and the operation is carried out according to the law, and samples are taken after 10, 15, 30, and 45 minutes respectively.

[0176] The dissolution rates of Examples 1 to 6 and Comparative Examples 1 to 4 vary with time as shown in Tables 8 and Figure 1 As shown:

[0177] Table 8

[0178]

[0179] As can be seen from Table 8, the solubility of Examples 1 to 6 is higher than that of Comparative Example 1, and higher than that of Comparative Examples 2 to 4, indicating that the use of spray-coating and one-step granulation process can effectively improve the solubility of dydrogesterone.

Claims

1. A method for preparing a dydrogesterone tablet, characterized in that: It includes the following steps: S1, spraying the ethanol solution of dydrogesterone into a diluent, and drying to obtain a powdered mixture A; S2, spraying the aqueous solution of the binder into the mixture A in step S1, granulating to obtain particles B; S3, tableting the mixture C, wherein the mixture C includes the particles B in step S2.

2. The method for preparing the dydrogesterone tablets according to claim 1, characterized in that: The dydrogesterone tablets are used to prepare drugs for treating diseases caused by endogenous progesterone deficiency, such as dysmenorrhea, endometriosis, secondary amenorrhea, irregular menstrual cycle, dysfunctional uterine bleeding, premenstrual syndrome, threatened abortion or habitual abortion caused by progesterone deficiency, or infertility caused by corpus luteum deficiency.

3. The method for preparing the dydrogesterone tablets according to claim 1, characterized in that: It meets one or more of the following conditions: (1) In step S1, in the ethanol solution of dydrogesterone, the mass ratio of dydrogesterone to ethanol is 1:(60-90), preferably 1:(50-70) or 1:90, for example 1:60; (2) In step S1, during the preparation of the ethanol solution of dydrogesterone, heating in a water bath is used to dissolve the dydrogesterone in the ethanol; (3) In step S1, the ethanol solution of dydrogesterone is sprayed into the diluent through a fluidized bed; (4) In step S1, the injection time is 30 to 60 minutes, for example, 45 minutes; (5) In step S1, the mass ratio of the diluent to the dydrogesterone in step S1 is (10-15):1, preferably (11-14):1, for example (12.51:1) or (12.41:1); (6) In step S1, the diluent is lactose and / or corn starch; (7) In step S1, during the drying process, the air volume is 60-80m 3 / h, for example 70m 3 / h; (8) In step S1, during the drying process, the air inlet temperature is 40-60°C, for example, 50°C; (9) In step S1, the moisture content of the mixture A is ≤3.0%.

4. The method for preparing the dydrogesterone tablets according to claim 3, characterized in that: It meets one or more of the following conditions: (1) In step S1, the water bath heating temperature is 30-40°C; (2) In step S1, the water bath heating time is 20 to 60 minutes; (3) In step S1, the manufacturer of the lactose is DFE Pharma GmbH & Co.KG., and the model is Pharmatose®200M; (4) In step S1, the manufacturer of the corn starch is Roquette Freres and the model is Maize Starch B.

5. The method for preparing the dydrogesterone tablets according to claim 1, characterized in that: It meets one or more of the following conditions: (1) In step S2, the mass ratio of the adhesive to the dydrogesterone in step S1 is (0.1-0.5):1, preferably (0.2-0.4):1, for example (0.28:1) or (0.38:1); (2) In step S2, the binder is selected from one or more of hypromellose, corn starch and potato starch; (3) In step S2, the aqueous solution of the binder is sprayed into the mixture A in step S1 through a fluidized bed; (4) In step S2, during the granulation, the air volume is 60-80m 3 / h, for example 70m 3 / h; (5) In step S2, during the granulation, the inlet air temperature is 40-60°C, for example, 50°C; (6) In step S2, the granulation time is 20 to 40 minutes, for example, 30 minutes; (7) In step S2, after the granulation, the steps of drying and granulation are also included; (8) In step S2, the moisture content of the particles B is ≤3.0%; (9) In step S2, the particle size of the particles B is ≤1.0 mm; (10) In step S3, the mixture C further comprises a glidant and / or a lubricant; (11) In step S3, the tableting further includes coating.

6. The method for preparing the dydrogesterone tablets according to claim 5, characterized in that: It meets one or more of the following conditions: (1) In step S2, the manufacturer of the hypromellose is Nutrition & Biosciences USA 1, LLC, and the model is E5 PREMIUM LV; (2) In step S2, the manufacturer of the corn starch is Roquette Freres and the model is Maize Starch B; (3) In step S2, the manufacturer of the potato starch is Roquette Freres; (4) In step S2, the drying is carried out using a fluidized bed; (5) In step S2, a 1.0 mm sieve is used for granulation; (6) In step S3, the glidant is colloidal silicon dioxide; (7) In step S3, the mass ratio of the glidant to the dydrogesterone in step S1 is (0.1-0.2):1, for example 0.14:1; (8) In step S3, the lubricant is magnesium stearate; (9) In step S3, the mass ratio of the lubricant to the dydrogesterone in step S1 is (0.05-0.1):1, for example 0.07:1; (10) In step S3, the mixture C further includes a flow aid and a lubricant. The granules B after granulation in step S2 are first mixed with the flow aid at a mixing speed of 15 rpm. The lubricant is then added and mixed at a mixing speed of 15 rpm. (11) The coating agent used in the coating is a film coating premix, and the concentration of the aqueous solution of the film coating premix is ​​preferably 9%-15%, for example, 12%, and the percentage is the mass percentage of the film coating premix in the aqueous solution of the film coating premix; (12) The mass ratio of the coating agent used in the coating to the dydrogesterone in step S1 is (0.2-0.6):1, for example 0.4:

1.

7. The method for preparing the dydrogesterone tablets according to claim 1, characterized in that: It satisfies conditions (1) and / or (2): (1) The diluent is lactose and corn starch, and the mass ratio of the lactose to the corn starch is 100:(10-60), for example, (111.1:14), (111.1:13), (100:25.1) or (80:45.1); (2) The aqueous solution of the binder is an aqueous solution of hypromellose, the concentration of the aqueous solution of hypromellose is 10% to 15%, for example, 12%, and the percentage is the mass percentage of the hypromellose in the aqueous solution of hypromellose; Or, the aqueous solution of the adhesive is an aqueous solution of corn starch, the concentration of the aqueous solution of corn starch is 2% to 6%, for example 5%, and the percentage is the mass percentage of the corn starch in the aqueous solution of corn starch; Or, the aqueous solution of the adhesive is an aqueous solution of potato starch, the concentration of the potato starch aqueous solution is 2% to 6%, for example 5%, and the percentage is the mass percentage of the potato starch in the potato starch aqueous solution.

8. The method for preparing the dydrogesterone tablets according to claim 1, characterized in that: In the preparation method of the dydrogesterone tablets, the raw material composition is selected from one of the following schemes: Solution 1: Dydrogesterone 100 parts, Lactose 1111 parts, 140 parts corn starch, 6000 parts of anhydrous ethanol, 28 parts of hypromellose, wherein the concentration of the aqueous solution of hypromellose is 12%, and the percentage is the mass percentage of the hypromellose in the aqueous solution of hypromellose, 14 parts of colloidal silicon dioxide, 7 parts of magnesium stearate, 40 parts of film coating premix, wherein the concentration of the aqueous solution of the film coating premix is ​​12%, and the percentage is the mass percentage of the film coating premix in the aqueous solution of the film coating premix; Option 2: Dydrogesterone 100 parts, Lactose 1111 parts, 140 parts corn starch, 9000 parts of anhydrous ethanol, 28 parts of hypromellose, wherein the concentration of the aqueous solution of hypromellose is 12%, and the percentage is the mass percentage of the hypromellose in the aqueous solution of hypromellose, 14 parts of colloidal silicon dioxide, 7 parts of magnesium stearate, 40 parts of film coating premix, wherein the concentration of the aqueous solution of the film coating premix is ​​12%, and the percentage is the mass percentage of the film coating premix in the aqueous solution of the film coating premix; Option 3: Dydrogesterone 100 parts, Lactose 1111 parts, 130 parts corn starch, 6000 parts of anhydrous ethanol, 38 parts of corn starch, wherein the concentration of the aqueous solution of corn starch is 5%, and the percentage is the mass percentage of the corn starch in the aqueous solution of corn starch, 14 parts of colloidal silicon dioxide, 7 parts of magnesium stearate, 40 parts of film coating premix, wherein the concentration of the aqueous solution of the film coating premix is ​​12%, and the percentage is the mass percentage of the film coating premix in the aqueous solution of the film coating premix; Option 4: Dydrogesterone 100 parts, Lactose 1111 parts, 130 parts corn starch, 6000 parts of anhydrous ethanol, 38 parts of potato starch, wherein the concentration of the aqueous solution of the potato starch is 5%, and the percentage is the mass percentage of the potato starch in the aqueous solution of the potato starch, 14 parts of colloidal silicon dioxide, 7 parts of magnesium stearate, 40 parts of film coating premix, wherein the concentration of the aqueous solution of the film coating premix is ​​12%, and the percentage is the mass percentage of the film coating premix in the aqueous solution of the film coating premix; Option 5: Dydrogesterone 100 parts, Lactose 1000 parts, 251 parts corn starch, 6000 parts of anhydrous ethanol, 28 parts of hypromellose, wherein the concentration of the aqueous solution of hypromellose is 12%, and the percentage is the mass percentage of the hypromellose in the aqueous solution of hypromellose, 14 parts of colloidal silicon dioxide, 7 parts of magnesium stearate, 40 parts of film coating premix, wherein the concentration of the aqueous solution of the film coating premix is ​​12%, and the percentage is the mass percentage of the film coating premix in the aqueous solution of the film coating premix; Option 6: Dydrogesterone 100 parts, Lactose 800 parts, 451 parts corn starch, 9000 parts of anhydrous ethanol, 28 parts of hypromellose, wherein the concentration of the aqueous solution of hypromellose is 12%, and the percentage is the mass percentage of the hypromellose in the aqueous solution of hypromellose, 14 parts of colloidal silicon dioxide, 7 parts of magnesium stearate, 40 parts of film coating premix, wherein the concentration of the aqueous solution of the film coating premix is ​​12%, and the percentage is the mass percentage of the film coating premix in the aqueous solution of the film coating premix.

9. A dydrogesterone tablet, characterized in that: The dydrogesterone tablet is prepared by the preparation method of the dydrogesterone tablet according to any one of claims 1 to 8.

10. The dydrogesterone tablet according to claim 9, characterized in that The dydrogesterone tablets are used to prepare drugs for treating diseases caused by endogenous progesterone deficiency, such as dysmenorrhea, endometriosis, secondary amenorrhea, irregular menstrual cycle, dysfunctional uterine bleeding, premenstrual syndrome, threatened abortion or habitual abortion caused by progesterone deficiency, or infertility caused by corpus luteum deficiency.

Images