Estradiol tablet and estradiol didrogesterone tablet combined package and preparation method thereof

Abstract

The invention discloses a combined package of an estradiol tablet and an estradiol didrogesterone tablet and a preparation method of the combined package. The package is composed of an estradiol tablet and an estradiol didrogesterone tablet. The combined package of the estradiol tablets and the estradiol digestrol tablets comprises the estradiol tablets and the estradiol digestrol tablets which are equal in tablet number, each of the estradiol tablets and the estradiol digestrol tablets comprises a tablet core and a coating layer, the tablet cores are prepared by a high-speed shearing granulation and tabletting process, and the prepared tablets are consistent with an originally developed agent Femoston in in-vitro release behavior, and have the advantages that the estradiol tablets and the estradiol digestrol tablets are combined, so that the estradiol and the estradiol digestrol tablets can be used for preparing the estradiol digestrol tablets; and in-vivo bioequivalence can be achieved. The high-speed shearing granulation mode is used for improving the particle mixing uniformity, so that the medicine content is more uniform, the in-vitro dissolution is stable, and the inter-batch difference is reduced. According to the invention, estradiol with a particle size of less than 20 [mu] m and didrogesterone with a particle size of less than 30 [mu] m are selected, high-speed shearing granulation is carried out by using a high stirring frequency, a special water adding device with a specific opening angle is selected, and the water adding amount, the water adding time and the stirring frequency are controlled at the same time, so that the tablets with rapid dissolution, uniform content and stable quality can be obtained.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to an estradiol tablet / estradiol dydrogesterone tablet and its preparation method. Background Technology

[0002] Estradiol is an important estrogen and the most active ovarian hormone. Dydrogesterone is an orally administered progestin with activity equivalent to parenteral progesterone.

[0003] Estradiol is used to supplement the decreased estrogen levels caused by ovarian dysfunction, while dydrogesterone is used to protect the endometrium and reduce the risk of endometrial hyperplasia that estradiol may cause.

[0004] Femoston is administered in a 28-day cycle. The first 14 days contain only estradiol, mimicking the follicular phase of the menstrual cycle; the following 14 days involve a combination of estradiol and dydrogesterone, mimicking the luteal phase of the menstrual cycle. This combination packaging allows for convenient administration.

[0005] Femoston has been approved by the Dutch Medicines Agency for the treatment of perimenopausal syndrome in women due to its proven efficacy in treating natural or postoperative menopausal syndrome, and for the prevention of osteoporosis in postmenopausal women (it should only be used in patients who are not permitted to use other products for the treatment of osteoporosis). Femoston is currently available in tablet form and is primarily used in hormone replacement therapy (HST) to supplement estrogen and progesterone in perimenopausal women.

[0006] Estradiol has poor solubility, being slightly soluble in ethanol and insoluble in water; its absorption depends on particle size. Dydrogesterone is slightly soluble in ethanol (96%) and almost insoluble in water; it is rapidly absorbed after oral administration. Particle size selection directly affects absorption in the body.

[0007] In the combination packaging of estradiol tablets / estradiol-dydrogesterone tablets, the estradiol component is small, accounting for only 0.1-1 parts by weight of the tablet core, and its proportion in the prescription is extremely low. Therefore, the uniformity of mixing and the uniformity of content are key technical issues. Summary of the Invention

[0008] A first aspect of the present invention provides a combined packaging of estradiol tablets and estradiol dydrogesterone tablets, wherein each tablet in the combined packaging consists of a tablet core and a coating layer, the tablet core comprising an active pharmaceutical ingredient, a filler, a binder, a disintegrant, a flow aid, and a lubricant, and the combined packaging of estradiol tablets and estradiol dydrogesterone tablets is bioequivalent to the original formulation Femoston.

[0009] In view of the shortcomings of the prior art, the object of the present invention is to provide estradiol tablets and estradiol-dydrogesterone tablets that dissolve rapidly, have uniform content, and stable quality. To achieve this object, the following two problems need to be solved:

[0010] A first aspect of the present invention provides a composite packaging for estradiol tablets and estradiol-dydrogesterone tablets, both of which consist of a core and a coating layer. The estradiol tablet core includes estradiol, a filler, a binder, a disintegrant, a flow aid, and a lubricant. The estradiol-dydrogesterone tablet core comprises estradiol and dydrogesterone, a filler, a binder, a disintegrant, a flow aid, and a lubricant.

[0011] In the estradiol tablets described above, the tablet core comprises a combination of the following parts by weight: 0.1-2 parts estradiol, 40-47 parts filler, 0.7-1.5 parts binder, 1.7-6.5 parts disintegrant, 0.3-0.6 parts flow aid, and 0.07-0.2 parts lubricant; preferably, the estradiol accounts for 0.3-0.4 parts by weight of the tablet core. More preferably, the estradiol accounts for 0.1-1 parts by weight of the tablet core.

[0012] The coating layer is Opadry. The coating layer accounts for 0.7-2 parts by weight of the core.

[0013] Preferably, the estradiol dydrogesterone tablet core contains a combination of the following parts by weight: 0.1-2 parts estradiol, 40-47 parts filler, 0.7-1.5 parts binder, 1.7-6.5 parts disintegrant, 0.3-0.6 parts flow aid, and 0.07-0.2 parts lubricant; preferably, the estradiol accounts for 0.1-1 parts by weight of the tablet core.

[0014] In the estradiol dydrogesterone tablets, the estradiol dydrogesterone tablet core contains a combination of the following parts by weight: 0.1-1 parts estradiol, 0.5-4 parts dydrogesterone, 37-45 parts filler, 0.7-1.5 parts binder, 3.5-6 parts disintegrant, 0.3-0.6 parts flow aid, and 0.15-0.4 parts lubricant; the coating layer is Opadry; the coating layer accounts for 0.7-2 parts by weight of the tablet core.

[0015] The filler is one or more of lactose, microcrystalline cellulose, and micronized silica gel.

[0016] The adhesive is one or more of hydroxypropyl methylcellulose, polyvinyl chloride, and starch.

[0017] The disintegrant is one or more of corn starch, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose.

[0018] The flow aid is colloidal silica.

[0019] The lubricant is one or more of magnesium stearate, zinc stearate, sodium stearate fumarate, polyethylene glycol, and hydrogenated vegetable oil.

[0020] A second aspect of the present invention provides a method for preparing the above-mentioned combined packaging of estradiol tablets and estradiol dydrogesterone tablets, wherein the preparation methods of the estradiol tablets and estradiol dydrogesterone tablets in the combined packaging are the same, and the preparation method includes the following steps:

[0021] Step 1, Granulation: Granulation of estradiol tablets: Estradiol, filler, binder, flow aid, disintegrant and purified water are granulated into granules by high-speed shear granulation process;

[0022] Granulation of estradiol dydrogesterone tablets: Dydrogesterone and a portion of the filler are mixed and sieved to obtain a preliminary mixture; estradiol, the preliminary mixture, the remaining filler, binder, flow aid, disintegrant, and purified water are granulated into granules using a high-speed shear granulation process.

[0023] The second step is granulation: the granules obtained in the first step are sieved and granulated. The granulated granules are then mixed with the gliding agent and lubricant in a mixer to obtain the final mixtures.

[0024] The third step is tablet core compression: the final mixture obtained in the second step is compressed into tablets using a high-speed rotary tablet press to obtain estradiol tablet cores and estradiol-dydrogesterone tablet cores.

[0025] Step 4, Coating: Prepare a suspension of the coating powder with purified water, and coat the estradiol tablet core and estradiol dydrogesterone tablet core obtained in step 3 in a high-efficiency coating pan to obtain estradiol tablets and estradiol dydrogesterone tablets.

[0026] During the granulation process of estradiol dydrogesterone tablets, when preparing the initial mixture, mix for 3 minutes and use a sieve with a mesh size of 40.

[0027] During the granulation process, the high-speed shearing stirring frequency is 10-30Hz, the cutting frequency is 30-40Hz, purified water is added using a special water adding device, the water adding time is 1-2 minutes, the mixing time is 5-15 minutes, after granulation, the material is sized by passing it through an 18-mesh sieve, the material temperature is heated to 50℃ and maintained for 40-60 minutes, and then dried until the moisture content is no more than 2.0%.

[0028] During the granulation process, the sieve mesh size is 20 mesh.

[0029] During the granulation process, the granulated particles are mixed with a flow aid and a lubricant in a mixer for 5-15 minutes to obtain the final mixture.

[0030] During the tableting process, the hardness of the obtained estradiol tablet core and estradiol dydrogesterone tablet core is controlled at 50-100N, and the brittleness does not exceed 1.0%.

[0031] During the coating process, the temperature of the air entering the coating chamber during the spraying process is controlled between 50-99℃.

[0032] Conventional wet granulation machines have no timed water inlet valve, making it impossible to control the water addition time. The water addition time is closely related to the granulation formability. Using a circulating pump for water addition results in unstable water flow. Using a pressurized spray water device for water addition can lead to poor water addition effect and poor granulation formability when the batch size is small.

[0033] The specialized water supply device is a modification of the original water inlet of a conventional wet granulation machine: a water supply pipe is added to the inlet, and a control valve is installed on the pipe. A water tank is installed at the top of the pipe. During operation, a certain amount of water is added to the tank, and the water flow rate is controlled by opening and closing the valve. The water in the tank is completely added to the wet granulation machine within 1-2 minutes. The water-to-material mass ratio is 1:82-1:84.

[0034] A third aspect of the present invention provides the use of the above-mentioned combination packaging of estradiol tablets and estradiol dydrogesterone tablets in the preparation of a treatment for perimenopausal syndrome caused by natural or postoperative menopause.

[0035] Furthermore, the perimenopausal period is characterized by symptoms such as neuropsychiatric symptoms, sleep disorders, menstrual irregularities, vasomotor symptoms, and atrophy of the urogenital organs.

[0036] A fourth aspect of the invention provides the use of the above-described combination of estradiol tablets and estradiol dydrogesterone tablets in the preparation of a formulation for the prevention of osteoporosis in postmenopausal women.

[0037] The technical effects of this invention are as follows: The combined packaging of estradiol tablets and estradiol dydrogesterone tablets of this invention includes an equal number of estradiol tablets and estradiol dydrogesterone tablets. Both types of tablets contain a core and a coating layer. The core is prepared using a high-speed shear granulation and tableting process. The resulting tablets not only exhibit consistent in vitro release behavior with the original formulation Femoston but also achieve in vivo bioequivalence. This invention uses high-speed shear granulation to improve particle mixing uniformity, resulting in more uniform drug content, stable in vitro dissolution, and reduced batch-to-batch variation. Through extensive experimental research and tireless exploration, the inventors have discovered that by selecting estradiol particles with a diameter <30 μm, preferably 10-20 μm, and dydrogesterone particles with a diameter <50 μm, preferably <30 μm, and using high stirring frequency for mixing and low stirring frequency for granulation, along with the use of a dedicated water addition device with a specific opening and closing angle, and simultaneous control of the water addition amount, time, and stirring frequency, tablets with rapid dissolution, uniform content, and stable quality can be obtained. Attached Figure Description

[0038] Figure 1 This is a dissolution curve of estradiol particle size screening in this invention.

[0039] Figure 2 This is a dissolution curve of dydrogesterone particle size screening in this invention.

[0040] Figure 3 This is a dissolution curve of estradiol tablets (2mg) in this invention and the original formulation in a medium of pH 6.8.

[0041] Figure 4 This is a dissolution curve of estradiol dydrogesterone tablets (2 / 10 mg) in this invention and the original formulation in a medium of pH 6.8.

[0042] Figure 5 This is a dissolution curve of estradiol tablets (1mg) in this invention and the original formulation in a medium of pH 6.8.

[0043] Figure 6 This is a dissolution curve of estradiol dydrogesterone tablets (1 / 10 mg) in this invention and the original formulation in a medium of pH 6.8. Detailed Implementation

[0044] The present invention will be further described below with reference to the following embodiments and accompanying drawings, but is not limited to the scope of protection of the present invention.

[0045] The present invention will be further described in detail below with reference to experimental examples, but the embodiments of the present invention are not limited thereto. Unless otherwise specified, the experimental methods used in the following experimental examples are conventional methods.

[0046] Example 1

[0047] Preparation of estradiol tablets:

[0048] Step 1: Mix lactose, estradiol raw material, 50% colloidal silica, corn starch, and hydroxypropyl methylcellulose at high speed using a stirring frequency of 30-40 Hz and a cutting frequency of 30-40 Hz. Add purified water evenly and granulate the mixture into wet granules using a high-speed shearing granulation process. During granulation, the stirring frequency is 10-30 Hz and the cutting frequency is 30-40 Hz. Mix and granulate for 5-10 minutes. Then, pass the wet granules through an 18-mesh sieve for wet granulation. Heat the material to 50°C for drying and maintain the temperature for 40-60 minutes to ensure that the moisture content of the granules is no more than 2.0%.

[0049] Step 2: The particles obtained in Step 1 are granulated by passing them through a 20-mesh sieve. The granulated particles are then mixed with the remaining 50% silica and magnesium stearate in a mixer for 5 minutes to obtain the final mixture.

[0050] Step 3: Compress the final mixture obtained in Step 2 into tablets using a high-speed rotary tablet press to obtain estradiol tablet cores; the hardness of the tablet cores is controlled at 50-100N, and the brittleness does not exceed 1.0%;

[0051] Step 4: Prepare a suspension using purified water and coat the estradiol tablet cores obtained in step (3) in a high-efficiency coating pan. The inlet air temperature is controlled at 50℃ during the coating process. The final coating weight gain is 1.4-3.5% of the tablet core weight.

[0052] Estradiol-dydrogesterone tablets manufacturing process:

[0053] Step 1: Mix dydrogesterone and some lactose for 3 minutes, then pass through a 40-mesh sieve.

[0054] Step 2: The mixed powder obtained in Step 1, estradiol raw material, 50% colloidal silica, corn starch, hydroxypropyl methylcellulose, and remaining lactose are mixed at high speed with stirring at 30-40 Hz and cutting frequency at 30-40 Hz. Purified water is added evenly, and wet granules are made by high-speed shear granulation. During granulation, the stirring frequency is 25-30 Hz and the cutting frequency is 32-38 Hz. Mixing and granulating is carried out for 10 minutes. The wet granules are then wet-sized by passing them through an 18-mesh sieve. The material temperature is heated to 50℃ for drying and maintained for 40 minutes to ensure that the moisture content of the granules is no more than 2.0%.

[0055] Step 3: The particles obtained in Step 2 are granulated by passing them through a 20-mesh sieve. The granulated particles are then mixed with the remaining 50% colloidal silica and magnesium stearate in a mixer for 5 minutes to obtain the final mixture.

[0056] Step 4: Compress the final mixture obtained in Step 2 into tablets using a high-speed rotary tablet press to obtain estradiol dydrogesterone tablet cores; the hardness of the tablet cores is controlled at 50-100N, and the brittleness does not exceed 1.0%;

[0057] Step 5: Prepare a suspension using purified water, and coat the estradiol-dydrogesterone tablet core obtained in step (4) in a high-efficiency coating pan. The air inlet temperature is controlled at 50℃ during the coating process. The final coating weight gain is 1.4-3.5% of the tablet core weight.

[0058] Examples 2-7

[0059] Screening of water addition method and granulation parameters

[0060] Referring to the estradiol tablet process steps in Example 1, this product has a small specification, with the raw material accounting for a minimum of nearly 0.71%, and the raw material has a small particle size. Conventional wet granulation parameters cannot granulate evenly. By using appropriate stirring and shearing parameters, and with appropriate water addition methods and times, the uniformity of particle mixing and tablet content can be ensured.

[0061] The mixed powder was prepared into soft mass using different water addition methods and granulation parameters (see Table 1). The granules were wet-granulated through an 18-mesh woven sieve, dried at 50℃ until the moisture content was less than 2.0%, and then dry-granulated through a 20-mesh woven sieve. The granules were mixed with magnesium stearate and colloidal silica for 10 minutes, then compressed into tablets and coated. The particle mixing uniformity, coating tablet content uniformity, and dissolution under different media were tested. (See Table 1).

[0062] Table 1. Study on different water addition methods and granulation parameters

[0063]

[0064]

[0065] In the process research, by using a stirring frequency of 20-25Hz, a cutter frequency of 35Hz, and a dedicated water addition device for granulation, and by controlling the amount and time of water addition, estradiol tablets with good particle mixing uniformity, uniform tablet content, high dissolution similarity to the original drug, and stable quality were obtained.

[0066] Example 8

[0067] Referring to the process steps of estradiol dydrogesterone tablets in Example 1, a stirring frequency of 25Hz and a cutter frequency of 35Hz were used. Water was added and granulated using a special water adding device, and the amount and time of water addition were controlled to be 1-2 minutes. Granules were prepared, compressed into tablets, and coated.

[0068] Comparative Example 1

[0069] Estradiol tablets and estradiol dydrogesterone tablets were prepared by high-speed shear granulation using conventional parameters.

[0070] Preparation of estradiol tablets:

[0071] Step 1: Add hydroxypropyl methylcellulose to purified water at 80℃ while stirring, stir to dissolve, and cool to below 35℃ to obtain the adhesive solution;

[0072] Step 2: Mix lactose, corn starch, estradiol, and colloidal silica using a stirring frequency of 10Hz and a shearing frequency of 15Hz. Add the binder solution obtained in Step 1 directly during stirring. During granulation, maintain a stirring frequency of 35Hz and a shearing frequency of 35Hz for 5 minutes. Heat the material to 50℃ for drying and maintain this temperature for 40 minutes, ensuring the granule moisture content is no more than 2.0%.

[0073] Step 3: Mix the particles obtained in Step 2 with the remaining 50% silica and magnesium stearate to obtain the final mixture;

[0074] Step 4: Compress the final mixture obtained in Step 3 into tablets using a high-speed rotary tablet press to obtain estradiol tablet cores; the tablet core hardness is >50N and the brittleness does not exceed 1.0%.

[0075] Step 5: Prepare a suspension using purified water and coat the estradiol tablet cores obtained in Step 4 in a high-efficiency coating pan. Spray the coating suspension onto the tablet cores until the average weight of the dry tablets increases by about 2%-4%. During the coating process, the temperature is maintained at 45℃.

[0076] Estradiol-dydrogesterone tablets manufacturing process:

[0077] Step 1: Add hydroxypropyl methylcellulose to purified water at 80℃ while stirring, stir to dissolve, and cool to below 35℃ to obtain the adhesive solution;

[0078] Step 2: Mix lactose, corn starch, estradiol raw material, dydrogesterone, and colloidal silica using a stirring frequency of 10Hz and a shearing frequency of 15Hz. Add the binder solution obtained in Step 1 directly during stirring. During granulation, maintain a stirring frequency of 35Hz and a shearing frequency of 35Hz for 5 minutes. Heat the material to 50℃ for drying and hold for 40 minutes to ensure the granule moisture content is no more than 2.0%.

[0079] Step 3: Mix the particles obtained in Step 2 with the remaining 50% silica and magnesium stearate to obtain the final mixture;

[0080] Step 4: Compress the final mixture obtained in Step 3 into tablets using a high-speed rotary tablet press to obtain estradiol dydrogesterone tablet cores; the tablet core hardness is >50N and the brittleness does not exceed 1.0%.

[0081] Step 5: Prepare a suspension using purified water and coat the estradiol dydrogesterone tablet cores obtained in Step 4 in a high-efficiency coating pan. Spray the coating suspension onto the tablet cores until the average weight of the dry tablets increases by about 2%-4%. During the coating process, the temperature is maintained at 45℃.

[0082] The particle mixing uniformity, coating tablet content uniformity, and dissolution in different media were tested, and the results are shown in Table 2.

[0083] Table 2 shows the test results of Comparative Example 1, Example 5, and Example 8.

[0084]

[0085] It can be seen that when the stirring frequency is 25Hz, the cutter frequency is 35Hz, and a special water adding device is used for water addition and granulation, and the water addition amount and time are controlled within 1-2 minutes, the resulting granules have good mixing uniformity, uniform tablet content, high dissolution similarity to the original drug, and stable quality.

[0086] Example 9

[0087] Study on the combined packaging formulation of estradiol tablets and estradiol dydrogesterone tablets

[0088] Prescription 1

[0089]

[0090]

[0091] Prescription 2

[0092]

[0093] Prescription 3

[0094]

[0095]

[0096] Prescription 4

[0097]

[0098] Tablets were prepared according to the formulations 1-4 above, following the process described in Example 1:

[0099] Tablets prepared according to the four formulations in Example 9 were taken, along with the corresponding original formulation of Femoston. Dissolution testing was performed using the second dissolution method (paddle method) according to the Chinese Pharmacopoeia 2020 edition, Part IV, General Chapter 0931. The dissolution medium was phosphate solution (pH 6.8), with a volume of 500 ml, and a temperature of 37℃ ± 0.5℃. Samples were taken at 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 90 min, 120 min, 180 min, 240 min, 300 min, and 360 min, with 10 ml samples taken at each time point. The chromatographic conditions are shown in Table 3. The drug release at different time points was calculated. The results are shown in Table 4.

[0100] Table 3 Dissolution curves and chromatographic conditions for estradiol / estradiol-dydrogesterone combination packaging

[0101]

[0102] Table 4. Similarity results of in vitro release

[0103]

[0104] As can be seen from Table 4, for each formulation, this product and the reference formulation have high in vitro dissolution similarity in pH 6.8 medium.

[0105] Example 10

[0106] Estradiol Particle Size Study

[0107] Following the formulation and process steps in Example 1, estradiol tablets (2 mg) of different particle sizes were prepared. Dissolution testing was performed using the second dissolution method (paddle method) according to the Chinese Pharmacopoeia 2020 edition, Part IV, General Chapter 0931. The dissolution medium was phosphate solution (pH 6.8), with a volume of 500 ml, and a temperature of 37℃ ± 0.5℃. Samples were taken at 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 90 min, 120 min, 180 min, 240 min, 300 min, and 360 min, with 10 ml samples taken at each time point. The results of the estradiol particle size study for the 2 mg estradiol tablets are shown in Table 5, and the dissolution curves are attached. Figure 1 .

[0108] Table 5. Results of in vitro dissolution test for estradiol particle size study.

[0109]

[0110] In the process study of estradiol tablets (2mg), tablets with higher similarity to the original formulation in in vitro dissolution were obtained when the estradiol particle size was 10-20μm.

[0111] Dydrogesterone particle size study

[0112] Following the formulation and process steps in Example 1, estradiol dydrogesterone tablets (2 / 10 mg) were prepared using dydrogesterone with different particle sizes. Dissolution testing was performed according to the method described in the Chinese Pharmacopoeia 2020 edition, Part IV, General Chapter 0931, using a dissolution test apparatus (paddle method) at 50 rpm. The dissolution medium was a phosphate solution (pH 6.8) with a volume of 500 ml and a temperature of 37℃ ± 0.5℃. Samples were taken at 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 90 min, 120 min, 180 min, 240 min, 300 min, and 360 min, with each sample being 10 ml.

[0113] The particle size study results of estradiol dydrogesterone tablets (2 / 10mg) and the in vitro dissolution test results of the original formulation are shown in Table 6. The dissolution curves are attached. Figure 2 .

[0114] Table 6. Results of in vitro dissolution test for dydrogesterone particle size study.

[0115]

[0116] In the process research of estradiol dydrogesterone tablets (2 / 10mg), tablets with higher similarity to the original formulation in in vitro dissolution were obtained when the particle size of dydrogesterone was <30μm.

[0117] Example 11

[0118] Following the process described in Example 1, smaller estradiol dydrogesterone tablets were prepared according to the following formulation. A stirring frequency of 25 Hz and a cutting frequency of 35 Hz were used. Water was added using a dedicated water-adding device for granulation, controlling the water addition amount and time to 1-2 minutes. Granules were then prepared, compressed into tablets, and coated. Estradiol dydrogesterone tablets (0.5 / 2.5 mg)

[0119]

[0120] Estradiol dydrogesterone tablets (1 / 5mg)

[0121]

[0122] The uniformity of particle mixing and the uniformity of coating tablet content were tested. The results are shown in Table 7.

[0123] Table 7. Detection results of estradiol and dydrogesterone tablets

[0124]

[0125]

[0126] It can be seen that this process can also meet the requirements for the preparation of smaller estradiol dydrogesterone tablets, with good particle uniformity, RSD < 1%, and good tablet content uniformity.

[0127] Example 12

[0128] Comparison of in vitro dissolution of the products prepared in Examples 5 and 8 with the original formulation

[0129] According to the dissolution assay method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931), the dissolution method II apparatus (paddle method) was used, with a rotation speed of 50 rpm, a phosphate solution (pH 6.8) as the dissolution medium, a medium volume of 500 ml, and a dissolution medium temperature of 37℃±0.5℃. Samples were taken at 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 90 min, 120 min, 180 min, 240 min, 300 min, and 360 min, and 10 ml of sample was taken.

[0130] The in vitro dissolution test results of the self-developed tablets and the original formulation of estradiol tablets / estradiol dydrogesterone tablets (2 / 10) are shown in Tables 8 and 9. The dissolution curves are attached. Figure 3 and attached Figure 4 :

[0131] Table 8. In vitro dissolution test results of estradiol tablets (2mg) – self-developed tablets and original formulation.

[0132]

[0133]

[0134] Note: / No relevant information.

[0135] Table 9. In vitro dissolution test results of estradiol dydrogesterone tablets (2 / 10mg) compared with the original formulation.

[0136]

[0137] Note: / No relevant information.

[0138] The in vitro dissolution test results of the product prepared by Formula 3 in Example 9 and the original formulation are shown in Tables 10 and 11. The dissolution curves are attached. Figure 5 and attached Figure 6 :

[0139] Table 10. In vitro dissolution test results of estradiol tablets (1 mg) for self-developed tablets and original formulations.

[0140]

[0141]

[0142] Note: / No relevant information.

[0143] Table 11. In vitro dissolution test results of estradiol dydrogesterone tablets (1 / 10mg) compared with the original formulation.

[0144]

[0145]

[0146] Note: / No relevant information.

[0147] A comparison of in vitro dissolution tests between the original and self-developed formulations showed that the RSD (%) value of the original formulation was higher than that of the self-developed formulation, with greater intra-batch and inter-tablet differences. The RSD (%) values ​​of the self-developed formulation all met the requirements, with smaller intra-batch and inter-tablet differences. The in vitro dissolution test results showed that the f2 values ​​of both the self-developed and original formulations were greater than 50, indicating consistency in in vitro dissolution with the original formulation.

[0148] Example 13

[0149] Bioequivalence studies

[0150] 1. Test Methods

[0151] All subjects were divided into two groups and fasting trials of Examples 5 and 8 with the original formulation Femoston (2mg / 2 / 10mg) were conducted in a randomized, open-label, crossover manner. At the start of each cycle, one tablet of the estradiol / estradiol dydrogesterone tablet of this invention (2mg / 2 / 10mg) or the original formulation Femoston (2mg / 2 / 10mg) was orally administered. Venous blood was collected at 1 hour, 0.5 hours, 0 hours before administration, and at 5 minutes, 10 minutes, 20 minutes, 40 minutes, 1 hour, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 8 hours, 9 hours, 10 hours, 10.5 hours, 11 hours, 11.5 hours, 12 hours, 12.5 hours, 13 hours, 14 hours, 24 hours, 48 ​​hours, and 72 hours after administration. Approximately 4 mL of blood was collected at each point. Various pharmacokinetic parameters of the embodiments and the original formulation under fasting conditions were calculated.

[0152] 2. Test Results

[0153] Using the original formulation Femoston estradiol tablets 2mg and estradiol / dydrogesterone tablets 2 / 10mg as controls, the bioequivalence results of Example 5 with the original formulation under fasting conditions (baseline corrected estradiol / dydrogesterone) are as follows:

[0154] Table 17 Bioequivalence data of estradiol tablets and the original formulation estradiol tablets under fasting conditions in Example 5.

[0155]

[0156] Using the original formulation Femoston (2mg / 2 / 10mg) as a control, the bioequivalence results of Example 8 under fasting conditions are as follows:

[0157] Table 18. Bioequivalence data of estradiol dydrogesterone tablets and the original formulation estradiol dydrogesterone tablets under fasting conditions in Example 8.

[0158]

[0159]

[0160] As can be seen from Tables 17 and 18 above, the tablets of Example 1 of the present invention are all equivalent to the corresponding original formulations in vivo.

[0161] Example 14

[0162] In vitro stability test

[0163] 1. Test Methods

[0164] Different specifications of estradiol / estradiol-dydrogesterone tablets were prepared from formulations 1 and 3 of Example 9 and packaged in PVC blister packs, with a packaging specification of 28 tablets / blister. These were compared with the original formulation and stored for 6 months at 40°C / 75% relative humidity.

[0165] Accurately weigh 20 tablets each under initial conditions and after 6 months of storage. Place them in a 200ml volumetric flask, add mobile phase to dissolve and dilute to the mark. Filter, and use the filtrate as the estradiol test solution. Accurately measure an appropriate amount of the estradiol test solution and quantitatively dilute with mobile phase to prepare a solution containing approximately 0.1mg of dydrogesterone per ml. Filter, and use the filtrate as the dydrogesterone test solution. The content of the main active ingredients and impurities in the estradiol tablets / estradiol-dydrogesterone tablets before and after storage was determined by high performance liquid chromatography (HPLC). The HPLC conditions were as follows: column: C18, 4.6mm × 150mm, 5μm; mobile phase: acetonitrile-water (40:60); column temperature: 40℃; detection wavelength: 220nm for estradiol, 310nm for dydrogesterone; run time: 40min.

[0166] 2. Test Results

[0167] Table 12 Accelerated stability data of Formula 1 (2 mg) for Example 9 and the original formulation

[0168]

[0169] Table 13 Accelerated stability data of Formula 1 (Estradiol Dydrogesterone Tablets 2 / 10mg) and the original formulation in Example 9

[0170]

[0171]

[0172] Table 14 Accelerated stability data of Formula 3 (1 mg) for Example 9 and the original formulation

[0173]

[0174] Table 15 Accelerated stability data of Formula 3 (1 / 10 mg) for Example 9 compared with the original formulation.

[0175]

[0176] As can be seen from Tables 12-15, the self-developed formulations of Formula 1 and Formula 3 in Examples 9 have comparable stability to the original formulations, with no significant difference, confirming that the tablets of the present invention have good chemical stability.

[0177] Of course, it should be understood that the above description is merely for illustrating the application of the principles of the present invention. Those skilled in the art can devise various modifications and alternatives without departing from the spirit and scope of the invention, and the appended claims are intended to encompass these modifications and alternatives. Thus, although the features and details of the invention have been described above in conjunction with what are currently considered to be the most practical and preferred embodiments, it will be apparent to those skilled in the art that many modifications can be made without departing from the principles and concepts set forth herein, including but not limited to changes in size, material, shape, form, operational function and mode of operation, components, and uses.

Claims

1. A combination package of estradiol tablets and estradiol dydrogesterone tablets, characterized in that, The package consists of estradiol tablets and estradiol-dydrogesterone tablets, each containing a core and a coating. The estradiol tablet core comprises the following components in parts by weight: 0.1-2 parts estradiol, 40-47 parts filler, 0.7-1.5 parts binder, 1.7-6.5 parts disintegrant, 0.3-0.6 parts flow aid, and 0.07-0.2 parts lubricant; preferably, the estradiol accounts for 0.1-1 parts by weight of the tablet core. The coating layer is Opadry; the coating layer accounts for 0.7-2 parts by weight of the core material; The core of estradiol dydrogesterone tablets contains the following components in parts by weight: The tablet contains 0.1-1 parts estradiol, 0.5-4 parts dydrogesterone, 37-45 parts filler, 0.7-1.5 parts binder, 3.5-6 parts disintegrant, 0.3-0.6 parts flow aid, and 0.15-0.4 parts lubricant; the coating layer is Opadry; the coating layer accounts for 0.7-2 parts by weight of the tablet core.

2. The combined packaging of estradiol tablets and estradiol dydrogesterone tablets according to claim 1, characterized in that, The estradiol-dydrogesterone tablet core contains the following components in parts by weight: 0.1-1 parts estradiol, 0.5-4 parts dydrogesterone, 37-45 parts filler, 0.7-1.5 parts binder, 3.5-6 parts disintegrant, 0.3-0.6 parts flow aid, and 0.15-0.4 parts lubricant. The coating layer is Opadry; the coating layer comprises 0.7-2 parts by weight of the tablet core.

3. The combined packaging of estradiol tablets and estradiol dydrogesterone tablets according to claim 1, characterized in that, The filler is one or more of lactose, microcrystalline cellulose, and micronized silica gel. The adhesive is one or more of hydroxypropyl methylcellulose, polyvinyl ketone, and starch; The disintegrant is one or more of corn starch, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose. The flow aid is silicon dioxide, which may be amorphous or crystalline, or a combination thereof. The lubricant is one or more of magnesium stearate, zinc stearate, sodium stearate fumarate, polyethylene glycol, or hydrogenated vegetable oil.

4. The combined packaging of estradiol tablets and estradiol dydrogesterone tablets according to claim 1, characterized in that, The estradiol raw material has a particle size of less than 30 μm, preferably 10-20 μm; the dydrogesterone raw material has a particle size of less than 50 μm, preferably less than 30 μm.

5. A preparation process for a combined packaging of estradiol tablets and estradiol dydrogesterone tablets as described in any one of claims 1-4, characterized in that, Includes the following steps: Step 1, Granulation: Granulation of estradiol tablets: Estradiol, filler, binder, flow aid, disintegrant and purified water are granulated into granules by high-speed shear granulation process; Granulation of estradiol dydrogesterone tablets: Mix dydrogesterone with 10-20 parts of filler and sieve to obtain a preliminary mixture; granulate estradiol, preliminary mixture, remaining filler, binder, flow aid, disintegrant and purified water by high-speed shear granulation process. The second step is granulation: the granules obtained in the first step are sieved and granulated. The granulated granules are then mixed with the gliding agent and lubricant in a mixer to obtain the final mixtures. The third step is tablet core compression: the final mixture obtained in the second step is compressed into tablets using a high-speed rotary tablet press to obtain estradiol tablet cores and estradiol-dydrogesterone tablet cores. Step 4, Coating: Prepare a suspension of the coating powder with purified water, and coat the estradiol tablet core and estradiol dydrogesterone tablet core obtained in step 3 in a high-efficiency coating pan to obtain estradiol tablets and estradiol dydrogesterone tablets.

6. The preparation process of the combined packaging of estradiol tablets and estradiol dydrogesterone tablets according to claim 5, characterized in that, During the granulation process of estradiol dydrogesterone tablets, when preparing the initial mixture, mix for 3 minutes and use a sieve with a mesh size of 40.

7. The preparation process of the combined packaging of estradiol tablets and estradiol dydrogesterone tablets according to claim 5, characterized in that, In the high-speed shear granulation process, the stirring frequency of the high-speed shear is 10-30Hz, the cutting frequency is 30-40Hz, and the mixing time is 5-15 minutes. During the granulation process, purified water is added through a dedicated water adding device, and the water adding time of the dedicated water adding device is 1-2 minutes. The mass ratio of water added to material is 1:82-1:

84. After granulation, the material is sieved through an 18-mesh sieve for granulation. The material temperature is heated to 50℃ and maintained for 40-60 minutes, and then dried until the moisture content is no more than 2.0%.

8. The preparation process of the combined packaging of estradiol tablets and estradiol dydrogesterone tablets according to claim 3, characterized in that, During the granulation process, the sieve mesh size is 20 mesh.

9. The preparation process of the combined packaging of estradiol tablets and estradiol dydrogesterone tablets according to claim 3, characterized in that, During the granulation process, the granulated particles are mixed with a flow aid and a lubricant in a mixer for 5-15 minutes to obtain the final mixture.

10. The preparation process of the combined packaging of estradiol tablets and estradiol dydrogesterone tablets according to claim 3, characterized in that, During the tableting process, the hardness of the obtained estradiol tablet core and estradiol dydrogesterone tablet core is controlled at 50-100N, and the brittleness does not exceed 1.0%; in the fourth step of the coating process, the coating air temperature is controlled at 50-60℃ during the liquid spraying process.

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