Stable estradiol valerate tablet and preparation method thereof

Abstract

The invention relates to a stable estradiol valerate tablet, the tablet comprises estradiol valerate, a filler, a disintegrating agent, an adhesive and a lubricant, in the preparation process of the tablet, the estradiol valerate is dispersed in a solvent to obtain a suspension, and then the suspension and the filler are subjected to fluidized bed granulation. According to the invention, the mode of preparing the API into the suspension and then carrying out fluidized bed granulation is adopted, so that the generation of estradiol valerate related impurities can be effectively controlled, and a guarantee is provided for clinical safe medication.

Description

Technical Field

[0001] The invention relates to the field of medicines, and in particular to an estradiol valerate tablet and a preparation method thereof. Background Art

[0002] Estradiol valerate is an estrogen drug, and its raw materials are mainly derived from sitosterol and cholesterol in soybean processing. Oral estradiol valerate is metabolized to produce natural estrogen-17-β-estradiol, that is, valeric acid is added to the 17th position of estradiol, which is basically the same as the estrogen produced by the human body, thus producing estrogen effects.

[0003] Currently, the commercially available estradiol valerate tablets are natural estrogen preparations with the pharmacological effects of estrogen. They can promote and regulate the normal development of female reproductive organs and secondary sexual characteristics, participate in the regulation of ovarian axis function, and are used to supplement estrogen deficiency, such as atrophic vaginitis, female gonadal insufficiency, vulvar dryness, menopausal vasomotor symptoms, oophorectomy, primary ovarian failure, and advanced prostate cancer. They are used in combination with progesterone as contraceptives. Because estradiol valerate tablets are safer and have fewer adverse reactions than other estrogen preparations, they are widely used in clinical practice.

[0004] Previous studies have shown that the estradiol valerate tablets prepared by conventional dry powder mixing processes have high levels of related substances and poor chemical stability, making it difficult to meet the requirements of safe clinical use. Therefore, the development of a stable estradiol valerate tablet that effectively controls related substances has become a common clinical need. Summary of the invention

[0005] To solve the above technical problems, the present invention includes the following aspects:

[0006] The first aspect of the present invention provides a stable estradiol valerate tablet, which comprises estradiol valerate, a filler, a disintegrant, a binder and a lubricant. The tablet preparation method comprises the following steps: firstly dispersing estradiol valerate in a solvent to obtain a suspension, and then fluidizing the suspension and the filler to granulate.

[0007] Preferably, the filler is selected from one or more of lactose, sucrose, and microcrystalline cellulose. More preferably, the filler is selected from one or more of lactose and microcrystalline cellulose. Most preferably, the filler is lactose.

[0008] Preferably, the disintegrant is one or more of starch, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinylpyrrolidone. More preferably, the disintegrant is one or more of starch and cross-linked polyvinylpyrrolidone. Most preferably, the disintegrant is starch.

[0009] Preferably, the binder is selected from one or more of povidone, hydroxypropyl cellulose, and hypromellose. More preferably, the binder is selected from one or more of povidone and hydroxypropyl cellulose. Most preferably, the binder is povidone.

[0010] Preferably, the lubricant is selected from one or more of magnesium stearate, micro powder silica gel, and talc. More preferably, the lubricant is selected from one or more of magnesium stearate and micro powder silica gel. Most preferably, the lubricant is magnesium stearate.

[0011] Preferably, the weight percentage of estradiol valerate in the tablet is 0.5-1%. More preferably, the weight percentage of estradiol valerate in the tablet is 0.6-0.9%. Most preferably, the weight percentage of estradiol valerate in the tablet is 0.7%.

[0012] Preferably, the weight percentage of the filler in the tablet is 65-90%. More preferably, the weight percentage of the filler in the tablet is 70-85%. Most preferably, the weight percentage of the filler in the tablet is 73.8-83.8%.

[0013] Preferably, the weight percentage of the disintegrant in the tablet is 5-25%. More preferably, the weight percentage of the disintegrant in the tablet is 8-22%. Most preferably, the weight percentage of the disintegrant in the tablet is 10-20%.

[0014] Preferably, the weight percentage of the binder in the tablet is 1-10%. More preferably, the weight percentage of the binder in the tablet is 3-8%. Most preferably, the weight percentage of the binder in the tablet is 5%.

[0015] Preferably, the weight percentage of the lubricant in the tablet is 0.2-1%. More preferably, the weight percentage of the lubricant in the tablet is 0.3-0.8%. Most preferably, the weight percentage of the lubricant in the tablet is 0.5%.

[0016] Preferably, the contents of the components in the tablet are as follows: 0.7% estradiol valerate, 73.8% lactose, 20% starch, 5% povidone and 0.5% magnesium stearate, all in weight percentage.

[0017] Preferably, the contents of the components in the tablet are as follows: 0.7% estradiol valerate, 83.8% lactose, 10% starch, 5% povidone and 0.5% magnesium stearate, all in weight percentage.

[0018] Preferably, in the tablet preparation method, the solvent for dispersing estradiol valerate is purified water.

[0019] Preferably, the weight ratio of estradiol valerate to purified water is 1:(50-100). More preferably, the weight ratio of estradiol valerate to purified water is 1:(65-85). Most preferably, the weight ratio of estradiol valerate to purified water is 1:75.

[0020] A second aspect of the present invention provides a method for preparing the above-mentioned tablet, comprising the following steps:

[0021] (1) dispersing a prescribed amount of estradiol valerate in a solvent to obtain a main drug suspension;

[0022] (2) sieving the prescribed amount of filler;

[0023] (3) placing the material obtained in step (2) into a fluidized bed granulator, and spraying the main drug suspension obtained in step (1) into the filler in a fluidized state by fluidized spraying; drying the material obtained after the spraying to obtain drug-containing granules;

[0024] (4) mixing the drug-containing granules obtained in step (3) with a prescribed amount of a disintegrant, a binder and a lubricant, and tableting to obtain estradiol valerate tablets.

[0025] Preferably, the solvent for dispersing estradiol valerate in step (1) is purified water.

[0026] Preferably, the weight ratio of estradiol valerate to purified water in step (1) is 1:(50-100). More preferably, the weight ratio of estradiol valerate to purified water in step (1) is 1:(65-85). Most preferably, the weight ratio of estradiol valerate to purified water in step (1) is 1:75.

[0027] Preferably, in step (2), the filler is passed through a 20-mesh sieve.

[0028] Preferably, the fluidized liquid spraying parameters in step (3) are as follows: liquid spraying speed is 20 g / min, air inlet volume is 80 cfm, air inlet temperature is 45° C., and atomization pressure is 2 bar.

[0029] Preferably, in step (4), the drug-containing particles are mixed with the disintegrant, binder and lubricant at a rotation speed of 20 rpm for 10 min.

[0030] Preferably, in step (4), a round punch with a diameter of 7 mm is used to press the tablet at a pressure of 10 KN.

[0031] The third aspect of the present invention provides the use of the above-mentioned tablet in the preparation of a medicament for treating dysfunctional uterine bleeding in adolescence, estrogen deficiency in perimenopausal women, or estrogen deficiency after hysterectomy.

[0032] A fourth aspect of the present invention provides a method for improving the chemical stability of the above-mentioned estradiol valerate tablet, the method comprising the following steps:

[0033] (1) dispersing a prescribed amount of estradiol valerate in a solvent to obtain a main drug suspension;

[0034] (2) sieving the prescribed amount of filler;

[0035] (3) placing the material obtained in step (2) into a fluidized bed granulator, and spraying the main drug suspension obtained in step (1) into the filler in a fluidized state by fluidized spraying; drying the material obtained after the spraying to obtain drug-containing granules;

[0036] (4) mixing the drug-containing granules obtained in step (3) with a prescribed amount of a disintegrant, a binder and a lubricant, and tableting to obtain estradiol valerate tablets.

[0037] Preferably, the solvent for dispersing estradiol valerate in step (1) is purified water.

[0038] Preferably, the weight ratio of estradiol valerate to purified water in step (1) is 1:(50-100). More preferably, the weight ratio of estradiol valerate to purified water in step (1) is 1:(65-85). Most preferably, the weight ratio of estradiol valerate to purified water in step (1) is 1:75.

[0039] Preferably, the improvement of chemical stability is to reduce the content of related substances in the estradiol valerate tablets.

[0040] Preferably, the related substances are selected from one or more of impurity C, unknown impurity 1 or unknown impurity 2. More preferably, the related substances include impurity C, unknown impurity 1 and unknown impurity 2.

[0041] Preferably, the impurity C is 3-hydroxyestrast-1,3,5(10),9(11)-tetraene-17β-valerate, the unknown impurity 1 is a compound having a retention time of 0.34±0.02 relative to estradiol valerate, and the unknown impurity 2 is a compound having a retention time of 0.56±0.02 relative to estradiol valerate.

[0042] Preferably, the HPLC chromatographic conditions for the detection of the content of related substances are as follows: the chromatographic column is YMC-Pack ProC18; acetonitrile-water (80:20) is used as mobile phase A, acetonitrile is used as mobile phase B, linear gradient elution is performed according to the following table, the detection wavelength is UV 220nm, the injection volume is 10μL, and the flow rate is 1.0ml / min;

[0043] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 100 0 15 100 0 20 0 100 50 0 100 51 100 0 55 100 0 .

[0044] The technical effects produced by the present invention are:

[0045] The present invention unexpectedly discovered that, in the preparation process of estradiol valerate tablets, compared with a dry powder mixing process or fluidized bed granulation after completely dissolving the API, fluidized bed granulation after the API is made into a suspension can effectively control the generation of estradiol valerate related impurities, thereby providing a guarantee for clinical safe drug use. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 This is a high performance liquid chromatogram of the tablets of Example 1 measured after being placed for 3 months;

[0047] Figure 2 This is the HPLC chromatogram of the tablets of Comparative Example 3 after being placed for 3 months. DETAILED DESCRIPTION

[0048] Preparation of Examples 1-2 and Comparative Examples 1-4

[0049] 1. Tablet prescription

[0050] Table 1 Tablet prescription of Examples 1-2 and Comparative Examples 1-4 (mg / tablet)

[0051]

[0052]

[0053] 2. Tablet preparation process

[0054] 2.1. Fluidized bed granulation process (API suspension)

[0055] The batch size is 20,000 tablets, and the materials are added according to the prescription in Table 1. The specific preparation method is as follows: (1) The prescribed amount of estradiol valerate is dispersed in 1.5 kg of purified water by stirring to obtain a main drug suspension; (2) The prescribed amount of lactose is passed through a 20-mesh sieve; (3) The material obtained in step (2) is placed in a fluidized bed granulator, and the main drug suspension obtained in step (1) is sprayed onto the lactose in a fluidized state by fluidized spraying; the material obtained after the spraying is dried at a temperature of 45° C. to obtain estradiol valerate drug particles, wherein the fluidized spraying parameters are as follows: spraying speed is 20 g / min, air volume is 80 cfm, air temperature is 45° C., and atomization pressure is 2 bar; (4) The drug-containing particles obtained in step (3), the prescribed amount of starch, povidone and magnesium stearate are mixed at a rotation speed of 20 rpm for 10 min, and tableted using a round punch with a diameter of 7 mm and a main pressure of 10 KN to obtain the estradiol valerate tablet embodiment 1-2.

[0056] 2.2 Dry powder mixing process

[0057] The batch size is 20,000 tablets. The materials are added according to the prescription in Table 1. The specific preparation method is as follows: (1) Passing the prescribed amount of estradiol valerate, lactose, starch, and povidone through a 40-mesh sieve; (2) Mixing the material in step (1) at a speed of 20 rpm for 25 minutes; (3) Mixing the material in step (2) with magnesium stearate at a speed of 20 rpm for 5 minutes, and using a round punch with a diameter of 7 mm to press the tablets at a main pressure of 10 KN to obtain the estradiol valerate tablet comparative example 1-2.

[0058] 2.3. Fluidized bed granulation process (API is completely dissolved)

[0059] The batch size is 20,000 tablets. The materials are added according to the above prescription. The specific preparation method is as follows: (1) the prescribed amount of estradiol valerate is completely dissolved in 1.5 kg of ethanol to obtain a main drug solution; (2) the prescribed amount of lactose is passed through a 20-mesh sieve; (3) the material obtained in step (2) is placed in a fluidized bed granulator, and the main drug solution obtained in step (1) is sprayed onto the lactose in a fluidized state by a fluidized spray; the material obtained after the spraying is dried at a temperature of 45° C. to obtain estradiol valerate drug particles, wherein the fluidized spray parameters are as follows: the spraying speed is 25 g / min, the air volume is 80 cfm, the air temperature is 45° C., and the atomization pressure is 2 bar; (4) the drug-containing particles obtained in step (3), the prescribed amount of starch, povidone and magnesium stearate are mixed at a rotation speed of 20 rpm for 10 min, and a round punch with a diameter of 7 mm is used to press the tablets at a main pressure of 10 KN to obtain the estradiol valerate tablet comparative example 3-4.

[0060] Test Example 1: Chemical stability test of estradiol valerate tablets of the present invention

[0061] 1. Test methods

[0062] The tablets prepared in Examples 1-2 of the present invention and Comparative Examples 1-4 were packaged in HDPE bottles and stored under accelerated conditions (45±2°C / 75±5%RH) for 3 months. The contents of estradiol valerate-related impurities in the tablets on day 0 and after 3 months were determined according to the following method.

[0063] Weigh an appropriate amount of estradiol valerate tablets and place them in a volumetric bottle. Measure an appropriate amount of water and add it to the above volumetric bottle to completely disperse the tablets. Then measure an appropriate amount of acetonitrile (the volume ratio of water to acetonitrile is 1:4) and place it in the above volumetric bottle. Then transfer the solution to a centrifuge tube after ultrasonication, centrifuge, and take the supernatant for injection analysis in a high performance liquid chromatography.

[0064] HPLC chromatographic conditions: the chromatographic column is YMC-Pack Pro C18; acetonitrile-water (80:20) is used as mobile phase A, acetonitrile is used as mobile phase B, linear gradient elution is performed according to the table below, the detection wavelength is UV 220nm, the injection volume is 10μL, and the flow rate is 1.0ml / min.

[0065] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 100 0 15 100 0 20 0 100 50 0 100 51 100 0 55 100 0

[0066] 2. Test results

[0067] The results of the determination of the contents of related substances in the tablets of Examples 1-2 and Comparative Examples 1-4 on day 0 and after 3 months of storage under accelerated conditions are shown in Tables 2 and 3, respectively.

[0068] Table 2 Determination results of related substances in the tablets of the present invention

[0069]

[0070] Table 3 Determination results of related substance contents in comparative tablets of the present invention

[0071]

[0072] As shown in Table 3 above, impurity C (3-hydroxyestra-1,3,5(10),9(11)-tetraene-17β-valerate, molecular formula C 23 H 30 O3, molecular weight 354.5, structural formula ), unknown impurity 1 (retention time relative to estradiol valerate is 0.34±0.02), and unknown impurity 2 (retention time relative to estradiol valerate is 0.56±0.02) increased significantly than that of Example 1-2. In particular, for unknown impurity 1, each comparative example increased to 0.16-0.41% after 3 months of accelerated testing, while this impurity was hardly detected in Example 1-2 under the same test conditions. The above test results show that the fluidized bed granulation process in which the API is formulated into a suspension can effectively control the formation of the main related substances of the API (especially the unknown impurity 1) in the tablets, thereby improving the clinical drug safety of estradiol valerate tablets.

[0073] Although specific embodiments of the present invention have been described, it will be appreciated by those skilled in the art that various changes and modifications may be made to the present invention without departing from the scope or spirit of the present invention. Therefore, the present invention is intended to cover all such changes and modifications that fall within the scope of the appended claims and their equivalents.

Claims

1. A stable estradiol valerate tablet, characterized in that: The tablet comprises estradiol valerate, a filler, a disintegrant, a binder and a lubricant. The tablet preparation method comprises the following steps: firstly dispersing estradiol valerate in a solvent to obtain a suspension, and then subjecting the suspension and the filler to fluidized bed granulation.

2. The tablet according to claim 1, characterized in that The filler is selected from one or more of lactose, sucrose and microcrystalline cellulose.

3. The tablet according to claim 1, characterized in that The disintegrant is one or more of starch, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinylpyrrolidone.

4. The tablet according to claim 1, characterized in that The binder is selected from one or more of povidone, hydroxypropyl cellulose and hypromellose.

5. The tablet according to claim 1, characterized in that The lubricant is selected from one or more of magnesium stearate, micro powder silica gel and talc.

6. The tablet according to any one of claims 1 to 5, characterized in that The solvent for dispersing estradiol valerate in the tablet preparation method is purified water.

7. The tablet according to claim 6, characterized in that The weight ratio of estradiol valerate to purified water is 1:(50-100).

8. The method for preparing the tablet according to any one of claims 1 to 7, characterized in that: The following steps are involved: (1) dispersing a prescribed amount of estradiol valerate in a solvent to obtain a main drug suspension; (2) sieving the prescribed amount of filler; (3) placing the material obtained in step (2) into a fluidized bed granulator, and spraying the main drug suspension obtained in step (1) into the filler in a fluidized state by fluidized spraying; drying the material obtained after the spraying to obtain drug-containing granules; (4) mixing the drug-containing granules obtained in step (3) with a prescribed amount of a disintegrant, a binder and a lubricant, and tableting to obtain estradiol valerate tablets.

9. The preparation method according to claim 8, characterized in that: The solvent for dispersing estradiol valerate in step (1) is purified water.

10. Use of the tablet according to any one of claims 1 to 7 in the preparation of a medicament for treating dysfunctional uterine bleeding in adolescence, estrogen deficiency in perimenopausal women, or estrogen deficiency after hysterectomy.

Images