Solid preparation containing estradiol and production process thereof

Abstract

The invention discloses a solid preparation containing estradiol and a production process of the solid preparation. The solid preparation comprises estradiol, a filling agent, a disintegrating agent, an adhesive, a flow aid and a lubricant, the particle size of the estradiol is 5-30 [mu] m. The production process comprises the following steps: uniformly mixing an adhesive with other materials except a lubricant, and adding water into a granulator in a spraying manner for wet granulation; performing drying; adding a lubricant, and mixing to obtain total mixed powder; and tabletting and coating the total mixed powder. The solid preparation disclosed by the invention has the advantages of good stability, small inter-batch difference and more uniform in-batch dissolution.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a solid preparation containing estradiol and a commercial production process thereof. Background Art

[0002] Perimenopausal syndrome (MPS) refers to the decline of ovarian function before and after menopause in women, with a significant decrease in the secretion of estrogen and progesterone, hot flashes, insomnia, sweating, paranoia, irritability, anger, restlessness, and adverse effects on the cardiovascular, skeletal, and urinary systems. For example, the decrease in estrogen may lead to a large loss of bone minerals and prone to fractures. Postmenopausal hormone therapy (MHT) is the first-line medication recommended by the guidelines for patients with a uterus and no contraindications. Patients are advised to start MHT treatment as soon as possible, and it is recommended to use low-dose estrogen to reduce safety risks. It is recommended to take a sufficient course of progesterone to protect the endometrium. In addition to effectively relieving typical symptoms, long-term use also has additional benefits such as protecting the cardiovascular system, preventing osteoporosis, and reducing the incidence of type 2 diabetes. The hormone replacement therapy recommends the use of (quasi-) natural estrogen and progesterone because they can be used directly without conversion, reduce the burden on the liver, and have a lower risk of breast cancer.

[0003] Estradiol is a female hormone. Its English name is estradiol. Its chemical name is estradiol-1,3,5(10)-triene-3,17β-diol. Its structural formula is as follows:

[0004]

[0005] Dydrogesterone is a progestin, with the English name dydrogesterone, the chemical name is 9β,10α-pregnane-4,6-diene-3,20-dione, and the structural formula is as follows:

[0006]

[0007] As early as 1997, Femoston developed by Abbott was launched in the Netherlands for the treatment of perimenopausal syndrome. Because it can simulate the normal physiological cycle of women, it is often used beyond the instructions for the treatment of abnormal uterine bleeding, amenorrhea and other menstrual disorders. However, the applicant found in preliminary studies that Femoston had large batch differences, and some batches of its small-scale compound products had large dissolution RSD problems. The impurity content increased significantly during the stability test, which posed certain risks to the clinical treatment effect and safety. In addition, the product was launched at an early stage, and the equipment, technology and awareness of hormone protection for early drug production were relatively imperfect, and the process simplicity and safety and environmental protection may not be good. Summary of the invention

[0008] The object of the present invention is to provide a solid preparation containing estradiol, which uses estradiol or estradiol and dydrogesterone as active ingredients, has good preparation stability, small batch-to-batch differences, and more uniform dissolution within the batch.

[0009] Another object of the present invention is to provide a production process for the solid preparation containing estradiol, wherein the production process simplifies the method for adding the binder, replaces the coating powder of the Femoston small-size compound, and can obtain a solid preparation with good stability, small batch difference, and uniform dissolution within the batch.

[0010] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0011] The invention provides a solid preparation containing estradiol. The plain tablets in the solid preparation comprise the following components by weight: 0.4-4.0% of estradiol, 70.0-90.0% of a filler, 4.3-17.0% of a disintegrant, 1.0-6.0% of a binder, 0.1-3.0% of a glidant, and 0.1-3.0% of a lubricant; wherein the particle size of the estradiol is 5-30 μm.

[0012] The invention provides a solid preparation containing estradiol. The plain tablets in the solid preparation comprise the following components by weight: 0.6-2.5% of estradiol, 77.0-88.0% of a filler, 6.1-13.0% of a disintegrant, 1.0-3.5% of a binder, 0.1-2.0% of a glidant and 0.1-2.0% of a lubricant.

[0013] In some embodiments of the present invention, the plain tablet in the solid preparation further comprises 4.1-8.1% dydrogesterone by weight, preferably 6.1-8.1%, more preferably 7.1%.

[0014] In some embodiments of the present invention, the particle size Dv90 of estradiol is 5-10 μm, 10-20 μm, or 20-30 μm.

[0015] In some embodiments of the present invention, the plain tablets in the solid preparation include the following components by weight: estradiol 0.4-2.0%, filler 70.0-90.0%, disintegrant 6.0-14.0%, binder 1.0-5.0%, glidant 0.1-2.0%, lubricant 0.1-2.0%, dydrogesterone 4.1-8.1% (preferably 6.1-8.1%, more preferably 7.1%).

[0016] In some embodiments of the present invention, the plain tablets in the solid preparation include the following components by weight: estradiol 0.6-1.5%, filler 75.0-88.0%, disintegrant 8.0-12.0%, binder 1.0-3.0%, glidant 0.1-1.5%, lubricant 0.1-1.5%, dydrogesterone 4.1-8.1% (preferably 6.1-8.1%, more preferably 7.1%).

[0017] In some embodiments of the present invention, the plain tablet of the solid preparation comprises the following components by weight: 1.4% estradiol, 85.8% filler, 10.0% disintegrant, 1.4% binder, 1.1% glidant, and 0.4% lubricant;

[0018] Or comprising the following components: estradiol 0.7%, dydrogesterone 7.1%, filler 80.3%, disintegrant 8.9%, binder 1.5%, glidant 1.1%, lubricant 0.4%;

[0019] Or include the following components: estradiol 1.4%, dydrogesterone 7.1%, filler 79.4%, disintegrant 8.6%, binder 1.9%, glidant 1.1%, lubricant 0.4%.

[0020] In some embodiments of the present invention, the filler comprises at least one of lactose, mannitol, and microcrystalline cellulose.

[0021] In some embodiments of the present invention, the disintegrant includes at least one of starch, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, and low-substituted hydroxypropyl cellulose, preferably corn starch.

[0022] In some embodiments of the present invention, the binder includes at least one of hypromellose and polyvinyl pyrrolidone.

[0023] In some embodiments of the present invention, the glidant includes at least one of colloidal silicon dioxide and talc.

[0024] In some embodiments of the present invention, the lubricant includes at least one of magnesium stearate, talc, and sodium stearyl fumarate.

[0025] In some embodiments of the present invention, the filler is lactose, preferably lactose monohydrate;

[0026] In some embodiments of the present invention, the disintegrant is starch, preferably corn starch.

[0027] In some embodiments of the present invention, the binder is hypromellose.

[0028] In some embodiments of the present invention, the glidant is colloidal silicon dioxide.

[0029] In some embodiments of the present invention, the lubricant is magnesium stearate.

[0030] In some embodiments of the present invention, the solid preparation is a tablet.

[0031] In some embodiments of the present invention, the tablet is a coated tablet.

[0032] In some embodiments of the present invention, the coating material of the tablet is selected from coating powder whose main component is polyvinyl alcohol or hypromellose.

[0033] The present invention provides a production process of a solid preparation containing estradiol, comprising the following steps:

[0034] Step 1. After the binder and other materials except the lubricant are uniformly mixed, water is added into the granulator in a spraying manner for wet granulation to obtain wet granules;

[0035] Step 2. Drying the wet granules to obtain dry granules;

[0036] Step 3. Adding a lubricant to the dry particles and mixing to obtain a total mixed material;

[0037] Step 4. Take the total mixed material and compress it into tablets to obtain plain tablets;

[0038] Step 5. Coat the plain tablets to obtain coated tablets.

[0039] In some embodiments of the present invention, in step 1, the amount of water added is 10%-20% by weight of the mixed material, preferably 12-16%.

[0040] In some embodiments of the present invention, in step 2, fluidized bed drying is used.

[0041] In some embodiments of the present invention, in step 2, the air inlet temperature is controlled to be 40°C to 65°C, preferably 40°C to 50°C during drying.

[0042] In some embodiments of the present invention, in step 2, drying is stopped when the moisture content of the particles is ≤3.5%.

[0043] In some embodiments of the present invention, in step 5, the amount of the coating powder is 2.0-7.0% by weight of the plain tablet.

[0044] In some embodiments of the present invention, in step 5, coating is performed using a coating powder whose main component is polyvinyl alcohol or hydroxypropyl methylcellulose to obtain a coated tablet.

[0045] Compared with the prior art, the present invention has the following beneficial effects:

[0046] The invention is scientifically designed and ingeniously conceived. By controlling the particle size of raw materials, simplifying the method of adding adhesives, selecting coating powders with suitable ingredients, and strictly controlling the temperature and moisture in the preparation process, smaller batch differences and dissolution RSDs are achieved than those of Femoston, and impurities are reduced and stability is improved, thereby providing patients with higher quality and safer alternative drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Attached Figure 1 The dissolution curves of three batches of estradiol preparations with a particle size Dv90 of 5-30 μm in Test Example 1;

[0048] Attached Figure 2 The dissolution curves of three batches of preparations granulated with a binder solution in Test Example 2;

[0049] Attached Figure 3 The dissolution curves of three batches of reference products in Test Example 1;

[0050] Attached Figure 4 This is the structural formula of impurity II and C of this product. DETAILED DESCRIPTION

[0051] The invention of the present application is further explained below through specific examples, but it should not be understood that the scope of the present application is limited to the following examples. According to the inventive ideas and the full content of the present application, the raw materials, solvents, reagents, operating steps, reaction conditions, etc. in the following examples can be appropriately combined / replaced / adjusted / modified, which is obvious to those skilled in the art and still falls within the scope of protection of the present application.

[0052] In the following examples, as well as in the specification and claims of this application, the following abbreviations have the following meanings, and for undefined abbreviations, they have generally recognized meanings.

[0053] Example 1

[0054] This embodiment discloses the production process of the estradiol tablets of the present invention, and the prescription is shown in Table 1:

[0055] Table 1 Prescription table of Example 1

[0056]

[0057] The specific process steps are as follows:

[0058] Step 1. After the binder and other materials except magnesium stearate are uniformly mixed, water is added into the granulator in a spraying manner for wet granulation, and the amount of water is 15% of the weight of the mixed materials;

[0059] Step 2: Use fluidized bed drying method, control the air inlet temperature to 40℃~55℃, and stop drying until the moisture content of the particles is ≤3.5%;

[0060] Step 3. adding magnesium stearate and mixing to obtain a total mixed material;

[0061] Step 4. tableting;

[0062] Step 5. Coating with coating powder whose main component is hydroxypropyl methylcellulose, the amount of coating powder used is 5.0% of the weight of the plain tablet, to obtain coated tablets.

[0063] Example 2

[0064] This embodiment discloses the production process of the estradiol dydrogesterone tablets of the present invention, and the prescription is shown in Table 2:

[0065] Table 2 Prescription table of Example 2

[0066]

[0067]

[0068] The process steps of this embodiment are to add dydrogesterone to step 1 of embodiment 1, and the other steps are the same as those of embodiment 1.

[0069] Example 3

[0070] Compared with Example 1, this example has the same formulation prescription and process route, but the difference lies in the different specific process parameters.

[0071] In step 2, the air inlet temperature during drying is set to 40°C to 50°C.

[0072] Example 4

[0073] Compared with Example 1, the present embodiment has the same formulation prescription, and the difference in the process route is that the binder is added in a different way. In the present embodiment, the binder is not added in step 1, but the binder is prepared into an aqueous solution, replacing the purified water used for granulation in step 1 of Example 1, that is, the aqueous solution of the binder (12.5%, w / w) is sprayed in step 1.

[0074] Example 5

[0075] This embodiment discloses the production process of the estradiol dydrogesterone tablets of the present invention, and the prescription is shown in Table 3:

[0076] Table 3 Prescription table of Example 5

[0077]

[0078] The process steps of this embodiment are to add dydrogesterone to step 1 of embodiment 1, and the other steps are the same as those of embodiment 1.

[0079] Test example

[0080] The dissolution curve in the test example of the present invention was detected with reference to the dissolution method of estradiol tablets in the United States Pharmacopoeia USP43. The standard curve determination method is as follows:

[0081] Table 4 Standard dissolution curve determination method

[0082] Dissolution method Speed medium Medium volume temperature Detection Methods Paddle 100rpm Water + 0.3% SDS 500ml 37℃ HPLC

[0083] The present application found that Femoston and the preparations of the present invention dissolved faster (15min>85%) when the standard curve was measured. Considering that Femoston is a rapid-release preparation, in order to simulate the gastric fluid absorption environment, the invention preparations consistent with the in vivo behavior of Femoston were screened out. When the dissolution curves of the preparations 1-4 of the present invention and the reference product (Femoston) in Table 5 of Test Example 1 were measured, the dissolution medium was set to pH 1.2 (gastric fluid environment), and the concentration of SDS was reduced to 0.1% to enhance the discrimination of the dissolution curves.

[0084] Reference products 1, 2, and 3 described in the test examples of the present invention are all Femoston (estradiol 2 mg / tablet) developed by Abbott BV; reference product 4 is Femoston (estradiol 2 mg / tablet, dydrogesterone 10 mg / tablet) developed by Abbott BV; reference product 5 is Femoston (estradiol 1 mg / tablet, dydrogesterone 10 mg / tablet) developed by Abbott BV.

[0085] Test Example 1

[0086] This test example is to control the particle size of estradiol and reduce the batch-to-batch difference.

[0087] The applicant found that the dissolution rate of different batches of Femoston tablets varies greatly. After a large number of experiments, the applicant was surprised to find that by controlling the particle size of estradiol, the batch difference of tablet dissolution rate can be reduced. This test example selects estradiol of different particle sizes to prepare tablets, and compares the dissolution curve of Femoston in pH1.2+0.1% SDS for similarity, and simultaneously investigates the mixing uniformity of the total mixed material during the preparation process, determines the acceptable range of the particle size of estradiol, and avoids the batch difference problem introduced by the particle size exceeding the limit, as shown in Table 5, wherein the prescription and production process of the preparations 1-4 of the present invention are the same as those of Example 1. The particle size of estradiol in the preparations 1-4 of the present invention is shown in Table 5.

[0088] Table 5 Particle size range study results

[0089]

[0090]

[0091] As shown in Table 5, when the particle size Dv90 of estradiol is 5-30 μm, the dissolution curve of the preparation of the present invention is similar to that of the reference product (f2>50), the mixing uniformity content of the total mixed material is 98%-102%, and the uniformity RSD is <1.5%. The particle size Dv90 of the raw materials of each batch of products is controlled to be within this range. Three batches of preparations are prepared using the prescription and steps in Example 1, namely, preparations 5, 6, and 7 of the present invention. The dissolution inter-batch RSD of the three batches of preparations is determined by the pharmacopoeia standard release method and compared with the dissolution RSD of the three batches of reference products. The results are shown in Table 6 and Figure 1 , Figure 3 .

[0092] As shown in Table 6, the preparation of the present invention prepared by controlling the raw material particle size Dv90 in the range of 5-30 μm can significantly improve the RSD of batch dissolution and reduce batch differences compared with the reference product.

[0093] Test Example 2

[0094] This test example uses the dissolution curve as an indicator to examine the effect of the binder addition method on the batch-to-batch differences of the preparation.

[0095] Preparations 8, 9, and 10 of the present invention are three batches of preparations prepared with the same prescription and process using the prescription and steps of Example 4, and the particle size Dv90 of the estradiol raw material used is 5-30 μm. The dissolution inter-batch RSD of preparations 8, 9, and 10 of the present invention was measured and compared with the dissolution RSD of preparations 5, 6, and 7 of the present invention and three batches of reference products. The results are shown in Tables 6 and Figure 1 , Figure 2 , Figure 3 shown.

[0096] Table 6 Dissolution batch differences between the preparation of the present invention and the reference product (n=12)

[0097]

[0098]

[0099] As can be seen from the above table, the RSD of dissolution batches of preparations 8, 9, and 10 of the present invention is less than that of the three batches of reference products, but greater than that of preparations 5, 6, and 7 of the present invention, indicating that the particle size of the estradiol raw material is controlled to be 5-30 μm, and the binder is prepared into an aqueous solution and added to the granulation to reduce the batch difference, but it is not as significant as the effect of directly mixing the binder with other materials in step 1 of Example 1 and spraying purified water for granulation to reduce the batch difference. In addition, the operation of spraying purified water for granulation after uniform mixing with other materials is simpler and faster, and the production efficiency is higher.

[0100] Test Example 3

[0101] This test example discloses the stability test of the preparation of the present invention and the reference product. This test example is prepared according to the method of Example 5. The reference product of this test example is Reference Product 4, and the results are shown in Table 7 below:

[0102] Table 7 Stability of the preparation of the present invention and the reference product at 0 day and under the conditions of influencing factors

[0103]

[0104] “-” indicates not detected. The structural formulas of impurities Ⅱ and C are attached. Figure 4 .

[0105] As can be seen from the above table, the reference product has relatively high content of impurity II and impurity C at 0 days. The above impurities are easily affected by temperature and moisture, which poses certain hidden dangers to the safety of patients' medication. In the preparation process of the present invention, the drying temperature is strictly controlled not to exceed 65°C, and the particle moisture is ≤3.5%. The impurities of the preparation of the present invention are measured, and impurity II is not detected. When the preparation of the present invention and the reference product are placed under the conditions of influencing factors, the impurities of the preparation of the present invention do not increase. The reference product has obvious impurity II growth at 10 days under high humidity conditions. It can be seen that better impurity control can be achieved by controlling the temperature and moisture of the preparation process.

[0106] Test Example 4

[0107] In this test example, different coating materials were investigated.

[0108] According to the instructions for the original research products, the small-sized compound products (estradiol 1mg / tablet, dydrogesterone 10mg / tablet) use film coating powder whose main ingredient is polyvinyl alcohol. The applicant found in the previous research that the dissolution RSD of this specification product is large. After a large number of experiments, the applicant found that the coating material of the original research product has a great influence on its dissolution. The applicant was surprised to find that the original research product using polyvinyl alcohol film coating powder has weak adhesion of the coating film. When conducting dissolution tests, it is easy to slide to various places in the dissolution cup after the tablet is inserted, and the uneven force leads to large differences in the dissolution results.

[0109] In this test example, polyvinyl alcohol (PVA) coating powder (the main component of which is polyvinyl alcohol) is used. Products) and Hydroxypropyl methylcellulose (HPMC) coating powder (the main ingredient of which is Hydroxypropyl methylcellulose product) for coating.

[0110] The specific operation is: prepare plain tablets according to the method of Example 2, and coat them with the above two coating powders respectively, examine the dissolution curves of the coated tablets obtained with different coating powders, and compare them with the reference preparation. The results are shown in Table 8 below.

[0111] Table 8 Dissolution data of samples with different coating powder compositions

[0112]

[0113]

[0114] It can be seen from the above table that when using coating powder whose main ingredient is hydroxypropyl methylcellulose, the dissolution RSD is significantly reduced and the dissolution within the product batch is more uniform.

[0115] Finally, it should be noted that the above embodiments are only preferred embodiments of the present invention to illustrate the technical solutions of the present invention, rather than limiting them, and certainly not limiting the patent scope of the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions recorded in the aforementioned embodiments, or replace some or all of the technical features therein by equivalents. These modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention. In other words, any changes or modifications made to the main design concept and spirit of the present invention that have no substantive significance, and the technical problems they solve are still consistent with the present invention, should be included in the protection scope of the present invention. In addition, the direct or indirect application of the technical solutions of the present invention in other related technical fields is also included in the patent protection scope of the present invention.

Claims

1. A solid preparation containing estradiol, It is characterized in that The plain tablets in the solid preparation include the following components by weight: 0.4-4.0% estradiol, 70.0-90.0% filler, 4.3-17.0% disintegrant, 1.0-6.0% binder, 0.1-3.0% glidant, and 0.1-3.0% lubricant; wherein the particle size Dv90 of estradiol is 5-30 μm.

2. A solid preparation containing estradiol according to claim 1, It is characterized in that The plain tablet in the solid preparation further comprises 4.1-8.1% dydrogesterone by weight, preferably 7.1%.

3. A solid preparation containing estradiol according to claim 1 or 2, It is characterized in that The plain tablets in the solid preparation include the following components by weight: 0.6-2.5% of estradiol, 77.0-88.0% of filler, 6.1-13.0% of disintegrant, 1.0-3.5% of binder, 0.1-2.0% of glidant, and 0.1-2.0% of lubricant.

4. A solid preparation containing estradiol according to claim 1, It is characterized in that The filler comprises at least one of lactose, mannitol, microcrystalline cellulose, and pregelatinized starch; or / and the disintegrant comprises at least one of starch, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, and low-substituted hydroxypropyl cellulose, preferably corn starch; or / and the binder comprises at least one of hydroxypropyl methylcellulose and polyvinyl pyrrolidone; or / and the glidant includes at least one of colloidal silicon dioxide and talc; or / and the lubricant includes at least one of magnesium stearate, talc, and sodium stearyl fumarate; Preferably, the solid preparation is a tablet; More preferably, the tablet is a coated tablet; Further preferably, the coating material of the tablet is selected from coating powder whose main component is polyvinyl alcohol or hypromellose.

5. A process for producing a solid preparation containing estradiol according to any one of claims 1 to 4, It is characterized in that The following steps are involved: Step 1. After the binder and other materials except the lubricant are uniformly mixed, water is added into the granulator in a spraying manner for wet granulation to obtain wet granules; Step 2. Drying the wet granules to obtain dry granules; Step 3. Adding a lubricant to the dry particles and mixing to obtain a total mixed material; Step 4. Take the total mixed material, press it into tablets, and obtain plain tablets; Step 5. Coat the plain tablets to obtain coated tablets.

6. A process for producing a solid preparation containing estradiol according to claim 5, It is characterized in that In step 1, the amount of water added is 10%-20% by weight of the mixed material, preferably 12-16%.

7. A process for producing a solid preparation containing estradiol according to claim 5 or 6, It is characterized in that In the step 2, fluidized bed drying is adopted.

8. A process for producing a solid preparation containing estradiol according to any one of claims 5 to 7, wherein in step 5, coating is performed using a coating powder whose main component is polyvinyl alcohol or hydroxypropyl methylcellulose to obtain a coated tablet; and / or the amount of the coating powder is 2.0-7.0% of the weight of the plain tablet.

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