A granule, solid preparation, tablet containing tibolone and a method for preparing the same

Abstract

This invention discloses granules, solid dosage forms, tablets containing tibolone, and their preparation methods. The tibolone-containing granules comprise 2.5 parts tibolone, 77-92 parts lactose-starch complex, 5-20 parts β-cyclodextrin and its derivatives, and a lubricant; wherein the tibolone and the β-cyclodextrin and its derivatives adhere to the surface of the lactose-starch complex to form a complex; the complex is prepared by spraying a solution containing the tibolone and the β-cyclodextrin and its derivatives onto the lactose-starch complex in a spray form. The tibolone-containing granules, solid dosage forms, and tablets provided by this invention significantly reduce content uniformity and improve product mixing uniformity; simultaneously, they ensure excellent dissolution behavior, guaranteeing the effectiveness of the product's absorption in vivo.

Description

Technical Field

[0001] This invention relates to granules, solid dosage forms, tablets containing tibolone, and methods for preparing the same, specifically belonging to the field of pharmaceutical technology. Background Technology

[0002] Tibolone tablets are a medication used to treat menopausal syndrome in women, with a strength of 2.5 mg. The active ingredient, tibolone, has the chemical name (7α,17α)-17-hydroxy-7-methyl-19-demethylpregn-5(10)-en-20-yn-3-one and the molecular formula C. 21 H 28 O2 is almost insoluble in water and is easily degraded, producing impurities.

[0003] The preparation process of tibolone tablets in the patent application "High-purity composition containing (7α,17α)-17-hydroxy-7-methyl-19-demethylpregn-5(10)-en-20-yn-3-one" (application number: 200510118666.8) filed by Organon Inc. is as follows: lactose and potato starch are granulated in a fluidized bed; granulation is performed, and the active pharmaceutical ingredient (hereinafter referred to as "API") and ascorbate palmitate are added and mixed. Finally, magnesium stearate is added and the mixture is compressed into tablets. Analysis shows that because the proportions of API (2.5%) and functional excipient ascorbate palmitate (0.2%) are very low, it is difficult to achieve uniform mixing. In addition, the particle size of the prepared particles differs greatly from that of API (based on the experience of developing poorly soluble drugs, it is speculated that the particle size D90 of the prepared particles is generally above 125μm, while the particle size D90 of poorly soluble API generally needs to be micronized to below 20μm), which also leads to a relatively high risk of uneven mixing. In addition, the micronized state of APIs can negatively affect product stability, and the uniformity of antioxidants can also significantly affect the overall stability of the product.

[0004] The patent application filed by Zhejiang Hemukang Pharmaceutical Technology Co., Ltd., entitled "A Tibolone Composition for Improving Stability and Dissolution Behavior and its Preparation Method" (application number: 202210475210.0), suggests adding colloidal silica during the preparation of a lactose-starch composition to participate in granulation, thereby improving the product's stability and dissolution behavior. This patent's process flow is similar to the patent mentioned above, both suffering from low API content, difficulty in achieving uniform mixing, and the API being added externally in solid micropowder form, making uniform mixing difficult and thus affecting the product's stability and efficacy. Furthermore, colloidal silica has extremely low density, easily separating from other heavier materials during granulation, posing a risk to granulation uniformity. In addition, the micropowder state of the API negatively impacts product stability, and the uniformity of colloidal silica also significantly affects the overall product stability.

[0005] In existing technologies, the preparation of tibolone-containing pharmaceutical compositions typically involves first producing tibolone micronized powder through a micronization process to ensure complete dissolution of the tibolone. The active pharmaceutical ingredient (API) is then added in micronized form to obtain the final pharmaceutical composition. However, the micronization process is highly invasive, posing significant risks to laboratory personnel and requiring costly occupational safety measures. Furthermore, the micronization process itself results in some material loss, and adding the API in micronized form can degrade the stability of the raw materials. In short, the existing micronization process for preparing tibolone-containing pharmaceutical compositions is complex, hazardous, costly, and can negatively impact product quality. Overcoming the shortcomings of poor stability and mixing uniformity in tibolone-containing pharmaceutical compositions, as well as the high risks, costs, and quality impacts of the micronization process, is urgently needed. Summary of the Invention

[0006] To address the aforementioned issues, this patent aims to provide tibolone-containing granules, solid dosage forms, tablets, and preparation methods that can reduce the risk of mixing uniformity and ensure excellent dissolution behavior of the product.

[0007] The technical problem to be solved by the present invention is achieved through the following technical solution.

[0008] The present invention provides granules containing tibolone, comprising 2.5 parts of tibolone, 77-92 parts of lactose-starch complex, 5-20 parts of β-cyclodextrin and its derivatives, and a lubricant;

[0009] The tibolone and the β-cyclodextrin and its derivatives adhere to the surface of the lactose-starch complex to form a complex;

[0010] The preparation process of the complex is as follows: a solution containing the tibolone and the β-cyclodextrin and its derivatives is sprayed onto the lactose-starch complex in the form of a spray.

[0011] In this invention, the tibolone can be a raw material that has not undergone a pulverization process.

[0012] In this invention, the tibolone can be a raw material with its original particle size that has not undergone micronization.

[0013] In this invention, the particle size distribution range (D90) of the tibolone is in the range of 40-80 μm.

[0014] In this invention, the lactose-starch complex can be a conventional lactose-starch complex in the art, preferably a lactose-starch complex composed of 85% alpha-water lactose and 15% corn starch.

[0015] In this invention, the lactose-starch complex can be a product manufactured by Roquette in France under the trade name [Brand Name Missing]. The lactose-starch complex has the CDE registration number F20190001406.

[0016] In this invention, the lactose-starch complex is preferably in the range of 84.5-89.5 parts by weight, for example, 77 parts, 89.5 parts or 92 parts.

[0017] In this invention, the β-cyclodextrin and its derivatives may be selected from one or more of β-cyclodextrin and hydroxypropyl-β-cyclodextrin.

[0018] The degree of substitution of the hydroxypropyl-β-cyclodextrin is preferably 4.5-6.0, more preferably 4.5-5.0.

[0019] In this invention, the weight fraction of the β-cyclodextrin is preferably 7.5-12.5 parts, for example 5 parts, 7.5 parts or 20 parts.

[0020] In this invention, the lubricant may be 0.5 parts.

[0021] In this invention, the lubricant may be magnesium stearate or stearic acid.

[0022] In a preferred embodiment of the present invention, the granules containing tibolone comprise the following components: tibolone, lactose-starch complex, hydroxypropyl-β-cyclodextrin, and magnesium stearate.

[0023] In a preferred embodiment of the present invention, the granules containing tibolone comprise the following components in parts by weight: 2.5 parts tibolone, 77-92 parts lactose-starch complex, 5-20 parts hydroxypropyl-β-cyclodextrin, and 0.5 parts magnesium stearate.

[0024] In one specific embodiment of the present invention, the granules containing tibolone comprise the following components in parts by weight: 2.5 parts tibolone, 92 parts lactose-starch complex, 5 parts hydroxypropyl-β-cyclodextrin, and 0.5 parts magnesium stearate.

[0025] In one specific embodiment of the present invention, the granules containing tibolone comprise the following components in parts by weight: 2.5 parts tibolone, 77 parts lactose-starch complex, 20 parts hydroxypropyl-β-cyclodextrin, and 0.5 parts magnesium stearate.

[0026] In one specific embodiment of the present invention, the granules containing tibolone comprise the following components in parts by weight: 2.5 parts tibolone, 89.5 parts lactose-starch complex, 7.5 parts hydroxypropyl-β-cyclodextrin, and 0.5 parts magnesium stearate.

[0027] In this invention, the preparation method of the tibolone-containing particles includes the following steps:

[0028] a. Dissolve the tibolone and the β-cyclodextrin and its derivatives in a solvent to obtain solution A;

[0029] The solvent may be anhydrous ethanol;

[0030] b. Using a portion of the lactose-starch complex as a carrier, spray the solution A obtained in step a onto the carrier to obtain material B;

[0031] Preferably, the spraying adopts a spray drying process. More preferably, the material temperature is controlled not to exceed 35°C during the spray drying process, and the final moisture content of the obtained material is 2%-5%. More preferably, the lactose-starch complex is placed in a fluidized bed as a carrier.

[0032] c. Mix the remaining lactose-starch complex, material B obtained in step b, and the lubricant.

[0033] Preferably, the mixing is carried out in a high-efficiency three-dimensional mixer, and the mixing time is preferably 10 minutes.

[0034] In some preferred embodiments of the present invention, the preparation method of the tibolone-containing particles includes the following steps:

[0035] a. Dissolve the tibolone and the β-cyclodextrin and its derivatives in anhydrous ethanol to obtain solution A;

[0036] b. Place 80% of the prescribed amount of the lactose-starch complex in a fluidized bed as a carrier, and spray the solution A obtained in step a onto the carrier to obtain material B;

[0037] c. Mix the remaining 20% ​​of the prescribed amount of the lactose-starch complex, material B obtained in step b, and magnesium stearate.

[0038] The present invention also provides a tibolone solid dosage form comprising the aforementioned tibolone-containing particles.

[0039] The present invention also provides a tibolone tablet comprising the aforementioned tibolone-containing particles.

[0040] In this invention, the granules are compressed into tablets using a tableting machine to obtain the tibolone tablets.

[0041] The tibolone tablet may weigh 100 mg, and each tibolone tablet may contain 2.5 mg of tibolone.

[0042] The present invention also provides a method for preparing granules containing tibolone, which includes the following steps:

[0043] Its raw materials include 2.5 parts tibolone, 77-92 parts lactose-starch complex, 5-20 parts β-cyclodextrin and its derivatives, and lubricant;

[0044] The tibolone and the β-cyclodextrin and its derivatives are dissolved in a solvent to obtain a solution; wherein, the solvent may be anhydrous ethanol;

[0045] The tibolone and the β-cyclodextrin and its derivatives are attached to the surface of the lactose-starch complex to form a complex; wherein the complex is prepared by spraying a solution containing the tibolone and the β-cyclodextrin and its derivatives onto the lactose-starch complex in a spray form.

[0046] In this invention, the spraying is preferably carried out using a spray drying process.

[0047] Preferably, the material temperature is controlled to not exceed 35°C during the spray drying process.

[0048] Preferably, the lactose-starch complex is placed in a fluidized bed.

[0049] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0050] The reagents and raw materials used in this invention are all commercially available.

[0051] The positive and progressive effects of this invention are as follows: This invention provides granules, solid dosage forms, tablets containing tibolone, and a method for preparing the same, resulting in the following positive and progressive effects:

[0052] (1) Based on the application of β-cyclodextrin and its derivatives, the selection of their specific contents, and the preparation process of adding the active pharmaceutical ingredient tibolone and hydroxypropyl-β-cyclodextrin solution in the form of spray, the present invention significantly reduces the content uniformity of the product and improves the mixing uniformity of the product; at the same time, it ensures the excellent dissolution behavior of the product and can ensure the effectiveness of the product in vivo absorption.

[0053] (2) When magnesium stearate is selected as the lubricant, the content of related substances in the product obtained by the present invention is lower, the product stability is higher, and the degradation risk is lower.

[0054] (3) The present invention avoids the micronization process of tibolone active pharmaceutical ingredient, reduces losses, reduces steps that may harm experimental personnel, reduces protection costs, and avoids the negative impact of the micronized state of tibolone active pharmaceutical ingredient on product stability, making it safer and more environmentally friendly. Detailed Implementation

[0055] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0056] Table 1 shows the information on the raw materials and auxiliary materials used in the examples and comparative examples.

[0057]

[0058] In this invention, the molecular formula of the β-cyclodextrin is: C 42 H 70 O 35 The molecular weight of the β-cyclodextrin is 1134.98.

[0059] In this invention, the molecular formula of the hydroxypropyl-β-cyclodextrin is: C 42 H 70-n O 35 (C3H7O) n Where n is the degree of substitution, the molecular weight of the hydroxypropyl-β-cyclodextrin is 1134+58n, n is 4.5-6.0, and the specific degree of substitution of the hydroxypropyl-β-cyclodextrin used in the examples is 4.5-5.0.

[0060] Example 1

[0061] This embodiment prepares a tibolone tablet.

[0062] Formulation prescription:

[0063] raw materials Prescription quantity (10,000 tablets) Tibolone 25g lactose-starch complex 920g Hydroxypropyl-β-cyclodextrin 50g magnesium stearate 5g

[0064] Preparation process:

[0065] a. Preparation of API-cyclodextrin solution: Add 25g tibolone and 50g hydroxypropyl-β-cyclodextrin to 925g anhydrous ethanol, and stir at 25-35℃ until completely dissolved.

[0066] b. Spray drying: 80% lactose-starch complex (736g) was added to a fluidized bed as a carrier. The fluidization was started, and the solution obtained in step a was sprayed onto the lactose-starch carrier using a peristaltic pump and pressurized atomization. The parameters of the granulation process are shown in the table below:

[0067] parameter Preset parameters Control range Heating temperature / ℃ 35-45 30-50 Inlet air temperature / °C 40 40-60 Material temperature / °C 30 25-35 <![CDATA[Inlet air volume (m 3 / h)]]> 40-60 35-70 Peristaltic pump rate / rpm 20-30 10-30 Atomization pressure / MPa 0.2 0.2-0.6

[0068] The final moisture content of the particles was 2.9%.

[0069] c. Mixing: Add 20% lactose-starch complex (184g), 5g magnesium stearate and the material obtained in step b to a high-efficiency three-dimensional mixer and mix for 10 minutes.

[0070] d. Tableting: The material obtained in step c is tableted using a 6.0mm circular die, with a target tablet weight of 100mg and a hardness range of 30-60N.

[0071] Example 2

[0072] This embodiment prepares a tibolone tablet.

[0073] Formulation prescription:

[0074] raw materials Prescription quantity (10,000 tablets) Tibolone 25g lactose-starch complex 770g Hydroxypropyl-β-cyclodextrin 200g magnesium stearate 5g

[0075] Preparation process:

[0076] a. Preparation of API-cyclodextrin solution: Add 25g tibolone and 200g hydroxypropyl-β-cyclodextrin to 1225g anhydrous ethanol, and stir at 25-35℃ until completely dissolved.

[0077] b. Spray drying: 80% lactose-starch complex (616g) was added to a fluidized bed as a carrier. The fluidization was started, and the solution obtained in step a was sprayed onto the lactose-starch carrier using a peristaltic pump and pressurized atomization. The parameters of the granulation process are shown in the table below:

[0078] parameter Preset parameters Control range Heating temperature / ℃ 35-45 30-50 Inlet air temperature / °C 40 40-60 Material temperature / °C 35 25-35 <![CDATA[Inlet air volume (m 3 / h)]]> 40-60 35-70 Peristaltic pump rate / rpm 20-30 10-30 Atomization pressure / MPa 0.4 0.1-0.6

[0079] The final moisture content of the particles was 4.2%.

[0080] c. Mixing: Add 20% lactose-starch complex (154g), 5g magnesium stearate and the material obtained in step b to a high-efficiency three-dimensional mixer and mix for 10 minutes.

[0081] d. Tableting: The material obtained in step c is tableted using a 6.0mm circular die, with a target tablet weight of 100mg and a hardness range of 30-60N.

[0082] Example 3

[0083] This embodiment prepares a tibolone tablet.

[0084] Formulation prescription:

[0085] raw materials Prescription quantity (10,000 tablets) Tibolone 25g lactose-starch complex 895g Hydroxypropyl-β-cyclodextrin 75g magnesium stearate 5g

[0086] Preparation process:

[0087] a. Preparation of API-cyclodextrin solution: Add 25g tibolone and 100g hydroxypropyl-β-cyclodextrin to 1000g anhydrous ethanol, and stir at 25-35℃ until completely dissolved.

[0088] b. Spray drying: 80% lactose-starch complex (716g) was added to a fluidized bed as a carrier. The fluidization was started, and the solution obtained in step a was sprayed onto the lactose-starch carrier using a peristaltic pump and pressurized atomization. The parameters of the granulation process are shown in the table below:

[0089] parameter Preset parameters Control range Heating temperature / ℃ 35-45 30-50 Inlet air temperature / °C 40 40-60 Material temperature / °C 30 25-35 <![CDATA[Inlet air volume (m 3 / h)]]> 40-60 35-70 Peristaltic pump rate / rpm 20-30 10-30 Atomization pressure / MPa 0.6 0.1-0.6

[0090] The final moisture content of the particles was 3.0%.

[0091] c. Mixing: Add 20% lactose-starch complex (179g), 5g magnesium stearate and the material obtained in step b to a high-efficiency three-dimensional mixer and mix for 10 minutes.

[0092] d. Tableting: The material obtained in step c is tableted using a 6.0mm circular die, with a target tablet weight of 100mg and a hardness range of 30-60N.

[0093] Example 4:

[0094] The formulation and process of this comparative example are exactly the same as those of Example 1, except that magnesium stearate is replaced with stearic acid to prepare tibolone tablets.

[0095] Formulation prescription:

[0096]

[0097]

[0098] Preparation process:

[0099] a. Preparation of API-cyclodextrin solution: Add 25g tibolone and 50g hydroxypropyl-β-cyclodextrin to 925g anhydrous ethanol, and stir at 25-35℃ until completely dissolved.

[0100] b. Spray drying: 80% lactose-starch complex (736g) was added to a fluidized bed as a carrier. The fluidization was started, and the solution obtained in step a was sprayed onto the lactose-starch carrier using a peristaltic pump and pressurized atomization. The parameters of the granulation process are shown in the table below:

[0101] parameter Preset parameters Control range Inlet air temperature / °C 40 40-60 Material temperature / °C 30 25-35 <![CDATA[Inlet air volume (m 3 / h)]]> 40-60 35-70 Peristaltic pump rate / rpm 20-30 10-30 Atomization pressure / MPa 0.2 0.2-0.6

[0102] The final moisture content of the particles was 2.9%.

[0103] c. Mixing: Add 20% lactose-starch complex (184g), 5g stearic acid and the material obtained in step b to a high-efficiency three-dimensional mixer and mix for 10 minutes.

[0104] d. Tableting: The material obtained in step c is tableted using a 6.0mm circular die, with a target tablet weight of 100mg and a hardness range of 30-60N.

[0105] Comparative Example 1

[0106] This comparative example is based on the formulation and process described in Organon Inc.'s patent application (application number: 200510118666.8) to prepare tibolone tablets.

[0107] Formulation prescription:

[0108]

[0109]

[0110] Preparation process:

[0111] a. Preparation of starch slurry: Prepare 400g of potato starch slurry solution with a weight percentage of 2.5% (w / w) by mixing 10g of potato starch in the prescription with boiling water.

[0112] b. Fluidized bed preparation of the carrier: 871.2g of lactose and 86.8g of potato starch were placed in a fluidized bed, fluidization was started, and the starch slurry solution obtained in step a was added to the fluidized bed by spraying to prepare lactose-starch carrier particles. The granulation parameters are as follows:

[0113] parameter Preset parameters Control range Heating temperature / ℃ 65-75 60-75 Inlet air temperature / °C 60 55-65 Material temperature / °C 40 35-45 <![CDATA[Inlet air volume (m 3 / h)]]> 50-70 40-80 Peristaltic pump rate / rpm 10-20 10-20 Atomization pressure / MPa 0.05 0.01-0.2

[0114] The final moisture content of the particles was 5.8%.

[0115] c. Premixing: Take 10% of the lactose-starch carrier particles obtained in step b and premix them together with tibolone and ascorbate palmitate using a dry granulator. Tibolone is a micronized active pharmaceutical ingredient with a particle size D90 of 12 μm.

[0116] d. Total mixing: Add 5g of magnesium stearate, the premixed material obtained in step c, and the remaining lactose-starch carrier particles obtained in step b to a high-efficiency three-dimensional mixer for mixing for 10 minutes.

[0117] e. Tableting: The material obtained in step d is tableted using a 6.0mm circular die, with a target tablet weight of 100mg and a hardness range of 30-60N.

[0118] Comparative Example 2

[0119] This comparative example is based on the prescription and process disclosed in the patent application (application number: 202210475210.0) filed by Zhejiang Hemukang Pharmaceutical Technology Co., Ltd., to prepare tibolone tablets.

[0120] Formulation prescription:

[0121] raw materials Prescription quantity (10,000 tablets) Tibolone 25g lactose 873g Potato starch 87.3g colloidal silica 9.7g magnesium stearate 5g

[0122] Preparation process:

[0123] a. Preparation of starch slurry: Prepare 908g of potato starch slurry solution with a weight percentage of 2.5% (w / w) by mixing 22.7g of potato starch in the prescription with boiling water.

[0124] b. Preparation of lactose-starch granules: Add the prescribed amount of lactose, the remaining starch, and silica to a fluidized bed. Spray the starch slurry solution obtained in step a into the fluidized bed while the material is in a fluidized state to prepare lactose-starch carrier granules. Granulation parameters are as follows:

[0125] parameter Preset parameters Control range Inlet air temperature / °C 60-80 60 Material temperature / °C 30-45 30 <![CDATA[Inlet air volume (m 3 / h)]]> 70-90 70 Peristaltic pump rate / rpm 3-20 8 <![CDATA[Atomization pressure / kg / cm 3 > 1～5 2

[0126] The material lost weight during drying was 2.8%.

[0127] c. Premixing: Tibolone and the lactose-starch granules obtained in step b are mixed for 10 minutes. Tibolone is a micronized active pharmaceutical ingredient with a particle size D90 of 12 μm.

[0128] d. Total mixing: Add magnesium stearate and mix it with the material obtained in c for 5 minutes.

[0129] e. Tableting: The material obtained in step d is tableted using a 6.0mm circular die, with a target tablet weight of 100mg and a hardness range of 70-80N.

[0130] Comparative Example 3

[0131] This embodiment prepares a tibolone tablet.

[0132] Formulation prescription:

[0133] raw materials Prescription quantity (10,000 tablets) Tibolone 25g lactose-starch complex 950g Hydroxypropyl-β-cyclodextrin 20g magnesium stearate 5g

[0134] Preparation process:

[0135] a. Preparation of API-cyclodextrin solution: Add 25g tibolone and 20g hydroxypropyl-β-cyclodextrin to 900g anhydrous ethanol, and stir at 25-35℃ until completely dissolved.

[0136] b. Spray drying: 80% lactose-starch complex (760g) was added to a fluidized bed as a carrier. The fluidization was started, and the solution obtained in step a was sprayed onto the lactose-starch carrier using a peristaltic pump and pressurized atomization. The parameters of the granulation process are shown in the table below:

[0137] parameter Preset parameters Control range Heating temperature / ℃ 35-45 30-50 Inlet air temperature / °C 40 40-60 Material temperature / °C 35 25-35 <![CDATA[Inlet air volume (m 3 / h)]]> 40-60 35-70 Peristaltic pump rate / rpm 20-30 10-30 Atomization pressure / MPa 0.4 0.1-0.6

[0138] The final moisture content of the particles was 3.1%.

[0139] c. Mixing: Add 20% lactose-starch complex (190g), 5g magnesium stearate and the material obtained in step b to a high-efficiency three-dimensional mixer and mix for 10 minutes.

[0140] d. Tableting: The material obtained in step c is tableted using a 6.0mm circular die, with a target tablet weight of 100mg and a hardness range of 30-60N.

[0141] Comparative Example 4

[0142] This embodiment prepares a tibolone tablet.

[0143] Formulation prescription:

[0144] raw materials Prescription quantity (10,000 tablets) Tibolone 25g lactose-starch complex 720g Hydroxypropyl-β-cyclodextrin 250g magnesium stearate 5g

[0145] Preparation process:

[0146] a. Preparation of API-cyclodextrin solution: Add 25g tibolone and 250g hydroxypropyl-β-cyclodextrin to 1500g anhydrous ethanol, and stir at 25-35℃ until completely dissolved.

[0147] b. Spray drying: 80% lactose-starch complex (576g) was added to a fluidized bed as a carrier. The fluidization was started, and the solution obtained in step a was sprayed onto the lactose-starch carrier using a peristaltic pump and pressurized atomization. The parameters of the granulation process are shown in the table below:

[0148] parameter Preset parameters Control range Heating temperature / ℃ 35-45 30-50 Inlet air temperature / °C 40 40-60 Material temperature / °C 35 25-35 <![CDATA[Inlet air volume (m 3 / h)]]> 40-60 35-70 Peristaltic pump rate / rpm 20-30 10-30 Atomization pressure / MPa 0.4 0.1-0.6

[0149] The final moisture content of the particles was 3.5%.

[0150] c. Mixing: Add 20% lactose-starch complex (144g), 5g magnesium stearate and the material obtained in step b to a high-efficiency three-dimensional mixer and mix for 10 minutes.

[0151] d. Tableting: The material obtained in step c is tableted using a 6.0mm circular die, with a target tablet weight of 100mg and a hardness range of 30-60N.

[0152] Comparative Example 5

[0153] This embodiment prepares a tibolone tablet.

[0154] Formulation prescription:

[0155] raw materials Prescription quantity (10,000 tablets) Tibolone 25g lactose-starch complex 895g Hydroxypropyl-β-cyclodextrin 75g magnesium stearate 5g

[0156] Preparation process:

[0157] a. Mixing: Add 25g tibolone, 75g hydroxypropyl-β-cyclodextrin, 895g lactose-starch complex, and 5g magnesium stearate to a high-efficiency three-dimensional mixer and mix for 10 minutes.

[0158] b. Tableting: The material obtained in step a is tableted using a 6.0mm circular die, with a target tablet weight of 100mg and a hardness range of 30-60N.

[0159] Comparative Example 6

[0160] This embodiment prepares a tibolone tablet.

[0161] Formulation prescription:

[0162] raw materials Prescription quantity (10,000 tablets) Tibolone 25g lactose-starch complex 895g Hydroxypropyl-β-cyclodextrin 75g magnesium stearate 5g

[0163] Preparation process:

[0164] a. Preparation of API solution: Add 25g of tibolone to 900g of anhydrous ethanol and stir at 25-35℃ until completely dissolved.

[0165] b. Spray drying: 80% lactose-starch complex (716g) and 75g hydroxypropyl-β-cyclodextrin were added to a fluidized bed as a carrier. The fluidization was started, and the solution obtained in step a was sprayed onto the lactose-starch carrier using a peristaltic pump and pressurized atomization. The parameters of the granulation process are shown in the table below:

[0166] parameter Preset parameters Control range Heating temperature / ℃ 35-45 30-50 Inlet air temperature / °C 40 40-60 Material temperature / °C 35 25-35 <![CDATA[Inlet air volume (m 3 / h)]]> 40-60 35-70 Peristaltic pump rate / rpm 20-30 10-30 Atomization pressure / MPa 0.4 0.1-0.6

[0167] The final moisture content of the particles was 3.7%.

[0168] a. Mixing: Add 20% lactose-starch complex (179g), 5g magnesium stearate and the material obtained in step b to a high-efficiency three-dimensional mixer and mix for 10 minutes.

[0169] b. Tableting: The material obtained in step c is tableted using a 6.0mm circular die, with a target tablet weight of 100mg and a hardness range of 30-60N.

[0170] Comparative Example 7

[0171] This embodiment prepares a tibolone tablet.

[0172] Formulation prescription:

[0173]

[0174]

[0175] Preparation process:

[0176] a. Preparation of hydroxypropyl-β-cyclodextrin solution: Add 75g of hydroxypropyl-β-cyclodextrin to 900g of anhydrous ethanol and stir at 25-35℃ until completely dissolved.

[0177] b. Spray drying: 80% lactose-starch complex (716g) and 25g tibolone were added to a fluidized bed as a carrier. The fluidization was started, and the solution obtained in step a was sprayed onto the lactose-starch carrier using a peristaltic pump and pressurized atomization. The parameters of the granulation process are shown in the table below:

[0178] parameter Preset parameters Control range Heating temperature / ℃ 35-45 30-50 Inlet air temperature / °C 40 40-60 Material temperature / °C 35 25-35 <![CDATA[Inlet air volume (m 3 / h)]]> 40-60 35-70 Peristaltic pump rate / rpm 20-30 10-30 Atomization pressure / MPa 0.4 0.1-0.6

[0179] The final moisture content of the particles was 3.8%.

[0180] a. Mixing: Add 20% lactose-starch complex (179g), 5g magnesium stearate and the material obtained in step b to a high-efficiency three-dimensional mixer and mix for 10 minutes.

[0181] b. Tableting: The material obtained in step c is tableted using a 6.0mm circular die, with a target tablet weight of 100mg and a hardness range of 30-60N.

[0182] Example 1

[0183] The content uniformity of the products in Examples 1-4, Comparative Examples 1-7, and Organon's commercially available 2.5mg tibolone tablets (Livial) was tested according to the inspection method under the content uniformity item in the import registration standard JX20120192 for tibolone tablets. The results are shown in Table 1 below.

[0184] Table 1 Content Uniformity

[0185]

[0186]

[0187] As shown in Table 1, Examples 1-4, Comparative Examples 1, 2, 3, and 6, and the commercially available Livialtibolone tablets all meet the requirements of A+2.2S≤15 in the 2020 edition of the Chinese Pharmacopoeia. However, Comparative Examples 4, 5, and 7 do not meet the requirements of A+2.2S≤15. The evaluation data shows that the content uniformity of Examples 1-4 is significantly better than that of Comparative Examples 1, 2, 3, and 6, and the commercially available Livialtibolone tablets. Furthermore, the content uniformity of Comparative Examples 3 and 6 is significantly worse than that of Examples 1-4 and the commercially available Livialtibolone tablets.

[0188] The formulations and preparation processes of Comparative Examples 1 and 2 are based on existing technologies: Patent Document 1 (Application No.: 200510118666.8) and Patent Document 2 (Application No.: 202210475210.0), respectively. The main difference between Comparative Examples 1 and 2 and the present invention lies in the application of "β-cyclodextrin and its derivatives" and the resulting difference in the addition process of the active pharmaceutical ingredient tibolone. The results are shown in Table 1. The content uniformity of Examples 1-4 is significantly better than that of Comparative Examples 1 and 2, and significantly better than that of commercially available Livial tibolone tablets. This indicates that the application of "β-cyclodextrin and its derivatives" in the present invention, and its combined use with the preparation process, results in tibolone tablets with better mixing uniformity compared to tibolone tablets in the prior art.

[0189] Furthermore, considering the ease of operation and loss of tibolone raw material in the micronization process of Comparative Examples 1 and 2, the formulation process of Examples 1 to 4 of this invention is better than Comparative Examples 1 to 2 and commercially available Livial tibolone tablets in achieving the mixing uniformity of small-sized tibolone tablets.

[0190] Comparative Examples 3 and 4 followed the same preparation process as Examples 1-4, with the main difference being the amount of β-cyclodextrin and its derivatives in the formulation, as shown in Table 2. Examples 1-4 used 5-20 parts, while Comparative Example 3 used 2 parts, and Comparative Example 4 used 25 parts. The results are shown in Table 1. The content uniformity of Examples 1-4 was significantly better than that of Comparative Examples 3 and 4. This indicates that in the preparation of tibolone-containing particles, it is necessary to control the content of β-cyclodextrin and its derivatives to achieve the best mixing uniformity of the tibolone-containing particles.

[0191] Table 2 Dosage of β-cyclodextrin and its derivatives

[0192] Example 1 5 copies Example 2 20 copies Example 3 7.5 copies Example 4 5 copies Comparative Example 3 2 copies Comparative Example 4 25 copies

[0193] Comparative Examples 5-7 had identical formulations to Example 3, differing primarily in their preparation processes. The methods of adding the active pharmaceutical ingredient tibolone and β-cyclodextrin and its derivatives differed, as shown in Table 3. In Example 3, tibolone and hydroxypropyl-β-cyclodextrin were first prepared into a solution and then added via spray. In Comparative Example 5, both tibolone and hydroxypropyl-β-cyclodextrin were added in solid form. In Comparative Example 6, tibolone was first prepared into a solution separately and then added via spray, while hydroxypropyl-β-cyclodextrin was added in solid form. In Comparative Example 7, hydroxypropyl-β-cyclodextrin was first prepared into a solution and then added via spray, while tibolone was added in solid form. The results are shown in Table 1. Comparative Examples 5 and 7 did not meet the pharmacopoeia requirement of A+2.2S≤15, while Comparative Example 6, although meeting the requirement of A+2.2S≤15, still showed significantly lower content uniformity than Example 3. This indicates that in the preparation of tibolone-containing granules, the active pharmaceutical ingredient tibolone can only meet the pharmacopoeia-sprayed content uniformity requirements if it is added in the form of a solution spray. Furthermore, only when tibolone and hydroxypropyl-β-cyclodextrin are prepared into a solution and the solution of the active pharmaceutical ingredient tibolone and hydroxypropyl-β-cyclodextrin is added in the form of a spray can the resulting tibolone-containing granules achieve the best mixing uniformity.

[0194] Table 3. Methods of adding tibolone active pharmaceutical ingredient to β-cyclodextrin and its derivatives

[0195]

[0196] Example 2

[0197] Tibolone tablets will develop degradation products after prolonged storage. The main degradation products are:

[0198] OM 38: (7α,17α)-17-hydroxy-7-methyl-19-nor-17-pregn-4-en-20-yn-3-one;

[0199] OM 06: (10,17)-Dihydroxy-7α-methyl-19-nor-10ξ,17α-pregn-4-en-20-yn-3-one;

[0200] OM 08: 10-peroxy-7α-methyl-19-nor-10ξ,17α-pregn-4-en-20-yn-3-one.

[0201] The related substances tests were conducted on the products of Examples 1-4, Comparative Examples 1-7, and Organon's commercially available 2.5mg tibolone tablets (Livial) according to the test methods under the Related Substances section of the import registration standard JX20120192 for tibolone tablets. The results are shown in Table 4 below.

[0202] Table 4 Content of related substances

[0203]

[0204]

[0205] As shown in Table 4, the content of related substances and total impurities of the tibolone tablets obtained in Examples 1-3 of this invention are significantly lower than those in Comparative Examples 1-7 and commercially available Livial tibolone tablets.

[0206] The main difference between Comparative Examples 1 and 2 and the present invention lies in the application of "β-cyclodextrin and its derivatives" in the present invention and the resulting difference in the addition process of the active pharmaceutical ingredient tibolone. The results are shown in Table 4. The contents of related substances in Examples 1-3 of the present invention are significantly lower than those in Comparative Examples 1 and 2 and commercially available Livial tibolone tablets. This indicates that the application of "β-cyclodextrin and its derivatives" in the present invention, and its combined use with the preparation process, results in tibolone tablets with higher stability and lower degradation risk compared to tibolone tablets of the prior art.

[0207] Furthermore, the active pharmaceutical ingredients in Comparative Examples 1 and 2 were added in solid micronized form, and their stability was significantly lower than that in Examples 1-4 of this invention. This indicates that the preparation process of this invention does not require a micronized process for tibolone active pharmaceutical ingredient, reducing losses, minimizing steps that could harm laboratory personnel, lowering protective costs, and avoiding the negative impact of the micronized state of tibolone on product stability.

[0208] Compared with Example 1, Example 4 of this invention differs only in that the lubricant is replaced with stearic acid instead of magnesium stearate. As shown in Table 4, although the related substances in Example 4 are higher than those in Examples 1-3, Comparative Example 1, and commercially available tibolone tablets, the related substances in Example 4 are still lower than those in Comparative Examples 2-7, while the related substance content of the formulations prepared in Example 1 is lower than that in Example 4. This indicates that the stability of tibolone-containing particles and the risk of degradation can be maximized and reduced only when "β-cyclodextrin and its derivatives" and "magnesium stearate" work together.

[0209] Comparative Examples 3 and 4, compared to Examples 1-4, used the same preparation process, the main difference being the amount of β-cyclodextrin and its derivatives in the formulation, as shown in Table 2. The results are shown in Table 4; the content of related substances in Comparative Examples 3 and 4 was almost 10 times that of Examples 1-3 of this invention. This indicates that in the preparation of tibolone-containing particles, it is necessary to control the content of β-cyclodextrin and its derivatives to improve the stability of the tibolone-containing particles and reduce the risk of degradation.

[0210] Comparative Examples 5-7 had identical formulations to Example 3, differing primarily in their preparation processes. The methods of adding the active pharmaceutical ingredient tibolone and β-cyclodextrin and its derivatives differed, as detailed in Table 3. The results, shown in Table 4, indicated that the contents of related substances in Comparative Examples 5, 6, and 7 were significantly higher than those in Examples 1-3. This demonstrates that only by preparing tibolone and hydroxypropyl-β-cyclodextrin into a solution, and then adding the solution of the active pharmaceutical ingredient tibolone and hydroxypropyl-β-cyclodextrin via spraying, can the stability of tibolone-containing particles be improved and the risk of degradation reduced.

[0211] Example 3

[0212] The dissolution of the products of Examples 1-4, Comparative Examples 1-7, and Organon's commercially available 2.5mg tibolone tablets (Livial) was tested according to the dissolution test method in the import registration standard JX20120192 for tibolone tablets. The results are shown in Table 5 below.

[0213] Table 5 Dissolution

[0214]

[0215]

[0216] The "similar factor f2" in the table above is based on dissolution data at 10 min, 20 min, 30 min, and 45 min. Following the "Announcement of the State Food and Drug Administration on Issuing Three Technical Guidance Principles for the Selection and Determination of Reference Preparations for Ordinary Oral Solid Dosage Forms (No. 61 of 2016)," the similarity of dissolution curves was compared to derive the similarity factor f2. According to the announcement, a similarity factor f2 of not less than 50 indicates similarity in dissolution curves; a higher similarity factor f2 indicates greater similarity to the reference preparation (100). More similar dissolution curves indicate a lower risk of clinical efficacy differences between the generic and reference preparations.

[0217] As shown in Table 5, the similarity factor f2 of Examples 1-4 in this application is greater than 50, indicating similar dissolution curves, and the similarity factor f2 is much higher than 50. The similarity factor f2 of Examples 1-4 is not lower than 75, with Example 2 even reaching 92. However, the similarity factor f2 of Comparative Examples 1-7 is lower than 50, indicating dissimilar dissolution curves. According to import registration standards, the dissolution rate at 45 minutes should not be less than 75%. The closer the dissolution rate at 45 minutes is to that of the reference formulation, commercially available Livialtebolone tablets, the better. As shown in Table 5, the 45-minute dissolution rates of Examples 1-4, Comparative Examples 1, 2, 4, 6, and the commercially available Livialtebolone tablets all meet the import registration standards. However, Comparative Examples 3, 5, and 7 do not meet the standard requirements, and the dissolution rates of Comparative Examples 4 and 6 are significantly inferior to those of the Examples and the commercially available product.

[0218] Comparative Examples 3 and 4, compared to Examples 1-4, had the same preparation process, the main difference being the different amounts of β-cyclodextrin and its derivatives in the formulation, as shown in Table 2. Comparative Examples 5-7, compared to Example 3, had completely identical formulations, the main difference being the different preparation processes, specifically the different methods of adding the active pharmaceutical ingredient tibolone and β-cyclodextrin and its derivatives, as shown in Table 3. The results are shown in Table 5. The 45-minute dissolution rates of Comparative Examples 3, 5, and 7 did not meet the standard requirements. The 45-minute dissolution rates of Comparative Examples 4 and 6 were significantly worse than those of Examples 1-4 and the commercially available product, Livial tibolone tablets. Furthermore, the similarity factor f2 of Comparative Examples 3-7 was less than 50, failing to meet the similarity conditions for dissolution curves. This indicates that in the preparation of tibolone-containing particles, it is necessary to control the content of β-cyclodextrin and its derivatives, and to add the active pharmaceutical ingredient tibolone and the hydroxypropyl-β-cyclodextrin solution in a spray form to achieve excellent dissolution behavior in the resulting tibolone-containing particles.

[0219] The evaluation data shows that the 45-minute dissolution of Examples 1-4 is significantly better than that of Comparative Example 2, better than that of Comparative Example 1, and no worse than that of the original commercially available formulation, Livialtebolone tablets. Furthermore, the similarity factor f2 of Comparative Example 1 and Comparative Example 2 is less than 50, which does not meet the similarity condition of the dissolution curve.

[0220] The above results indicate that the formulation of this invention, especially the application of specific amounts of β-cyclodextrin and its derivatives, and the preparation process of adding the active pharmaceutical ingredient in the form of solution spray, together produce tibolone-containing particles with excellent dissolution behavior, ensuring the effectiveness of product absorption in vivo and high clinical efficacy and safety. This is of significant importance for tibolone products belonging to BCS Class II (low solubility, high permeability).

[0221] In summary, as demonstrated in Examples 1-4, the tibolone-containing granules, solid dosage forms, tablets, and their preparation methods provided by this invention, on the one hand, significantly reduce content uniformity and improve mixing uniformity by employing the application of β-cyclodextrin and its derivatives, the selection of their specific content, and the spray-addition of the active pharmaceutical ingredient tibolone and hydroxypropyl-β-cyclodextrin solution. Simultaneously, excellent dissolution behavior is ensured, guaranteeing the product's effectiveness in in vivo absorption. Furthermore, when magnesium stearate is chosen as the lubricant, the related substances content of the product obtained by this invention is lower, resulting in higher product stability and a lower risk of degradation. On the other hand, this invention eliminates the need for a micronization process on the tibolone raw material, reducing waste, minimizing harmful steps for laboratory personnel, lowering protective costs, and avoiding the negative impact of the micronized state of the active pharmaceutical ingredient tibolone on product stability, thus enhancing safety and environmental friendliness.

Claims

1. A granule containing tibolone, characterized in that, It consists of 2.5 parts tibolone, 77-92 parts lactose-starch complex, 5-20 parts hydroxypropyl-β-cyclodextrin and magnesium stearate; The tibolone and the hydroxypropyl-β-cyclodextrin adhere to the surface of the lactose-starch complex to form a complex; The preparation process of the complex is as follows: The solution containing the tibolone and the hydroxypropyl-β-cyclodextrin is sprayed onto the lactose-starch complex in a spray form to obtain the product. The method for preparing the tibolone-containing particles includes the following steps: a. Dissolve the tibolone and the hydroxypropyl-β-cyclodextrin in anhydrous ethanol, and stir at 25-35°C until completely dissolved to obtain solution A; b. Add 80% of the lactose-starch complex to a fluidized bed as a carrier, start fluidization, and spray the solution A obtained in step a onto the lactose-starch carrier using a peristaltic pump and pressurized atomization to obtain material B. Control the material temperature not to exceed 35°C throughout the spray drying process. c. Mix 20% of the lactose-starch complex, material B obtained in step b, and the magnesium stearate; d. Tableting.

2. The granules containing tibolone as described in claim 1, characterized in that, The particle size distribution range (D90) of the tibolone is in the range of 40-80 μm; And / or, the tibolone is an active pharmaceutical ingredient that has not undergone micronization.

3. The granules containing tibolone as described in claim 1, characterized in that, The lactose-starch complex consists of 85% alpha-hydrate lactose and 15% corn starch; And / or, the lactose-starch complex is present in parts by weight of 84.5-89.

5.

4. The granules containing tibolone as described in claim 1, characterized in that, The lactose-starch complex is a lactose-starch complex with the trade name STARLAC® produced by Roquette, France, and the CDE registration number of the lactose-starch complex is F20190001406. And / or, the lactose-starch complex is present in parts by weight of 77, 89.5, or 92.

5. The granules containing tibolone as described in claim 1, characterized in that, The degree of substitution of the hydroxypropyl-β-cyclodextrin is 4.5-6.0; And / or, the hydroxypropyl-β-cyclodextrin is present in parts by weight of 7.5-12.5 parts; And / or, the magnesium stearate is 0.1-10 parts by weight.

6. The granules containing tibolone as described in claim 1, characterized in that, The degree of substitution of the hydroxypropyl-β-cyclodextrin is 4.5-5.0; And / or, the hydroxypropyl-β-cyclodextrin is present in parts by weight of 5, 7.5, or 20; And / or, the magnesium stearate is 0.5 parts by weight.

7. The granules containing tibolone as described in claim 1, characterized in that, The granules containing tibolone are composed of the following components in parts by weight: 2.5 parts tibolone, 77-92 parts lactose-starch complex, 5-20 parts hydroxypropyl-β-cyclodextrin, and 0.5 parts magnesium stearate; Alternatively, the granules containing tibolone are composed of the following components in parts by weight: 2.5 parts tibolone, 84.5-89.5 parts lactose-starch complex, 7.5-12.5 parts hydroxypropyl-β-cyclodextrin, and 0.5 parts magnesium stearate.

8. The granules containing tibolone as described in claim 1, characterized in that, The granules containing tibolone are composed of the following components in parts by weight: 2.5 parts tibolone, 92 parts lactose-starch complex, 5 parts hydroxypropyl-β-cyclodextrin, and 0.5 parts magnesium stearate; Alternatively, the granules containing tibolone are composed of the following components in parts by weight: 2.5 parts tibolone, 77 parts lactose-starch complex, 20 parts hydroxypropyl-β-cyclodextrin, and 0.5 parts magnesium stearate; Alternatively, the granules containing tibolone are composed of the following components in parts by weight: 2.5 parts tibolone, 89.5 parts lactose-starch complex, 7.5 parts hydroxypropyl-β-cyclodextrin, and 0.5 parts magnesium stearate.

9. A tibolone solid dosage form comprising tibolone-containing particles as described in any one of claims 1 to 8.

10. A tibolone tablet, characterized in that, It comprises particles containing tibolone as described in any one of claims 1 to 8.

11. The tibolone tablet as described in claim 10, characterized in that, The tibolone tablets weigh 100 mg each.

12. The tibolone tablet as described in claim 11, characterized in that, Each of the tibolone tablets contains 2.5 mg of tibolone.

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