A stable pharmaceutical composition comprising drospirenone and estradiol and a preparation method thereof

Abstract

The present invention relates to a stable pharmaceutical composition comprising drospirenone and estradiol, wherein the pharmaceutical composition comprises drospirenone, estradiol, a filler, a disintegrant and a lubricant, wherein the filler is composed of a first filler and a second filler, wherein the first filler is lactose, and the second filler is selected from one or more of starch and microcrystalline cellulose. The pharmaceutical composition of the present invention can effectively control the related impurities generated by drospirenone during tableting, and stability studies show that the related impurities of the drospirenone do not increase, so the pharmaceutical composition of the present invention provides a guarantee for clinical safe medication.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a pharmaceutical composition comprising drospirenone and estradiol. Background Art

[0002] The decline in estrogen levels after menopause can lead to the onset of related symptoms. Currently, 130 million women in China are suffering from various menopausal symptoms, including hot flashes, night sweats, palpitations, mood swings, insomnia, vaginal dryness, and decreased libido. At the same time, the decline in estrogen levels after menopause can also have an adverse effect on the metabolism of blood lipids in the body, leading to an increased risk of cardiovascular disease. Menopausal hormone replacement therapy (HRT) is the most effective way to relieve menopausal symptoms. For women with a uterus who have been in menopause for more than one year and do not want menstruation, continuous combined estrogen and progesterone replacement therapy can be given.

[0003] Estradiol / drospirenone tablets (trade name: Anjinyi) are a low-dose continuous combined estrogen-progestin compound preparation containing a new progestin ingredient, drospirenone. Each tablet consists of 1 mg of estradiol and 2 mg of drospirenone. Estradiol is a natural estrogen, and there is sufficient evidence to show that it can effectively relieve menopausal symptoms, including vasomotor symptoms such as hot flashes and sweating, psychoneurological symptoms such as depression and anxiety, and symptoms of urogenital tract atrophy, improve the quality of life, and can effectively prevent osteoporosis and reduce the risk of pathological fractures.

[0004] Drospirenone is a derivative of 17α-spironolactone and a new type of progestin preparation with anti-mineralocorticoid activity. Its biochemical and pharmacological properties are very similar to those of natural progesterone. In addition to playing a reliable role in protecting the endometrium, drospirenone also has a certain anti-androgenic effect, and can act on the renin-angiotensin system by antagonizing aldosterone receptors, improve water and sodium retention, control body weight, lower blood pressure in patients with upper normal limits or mild hypertension, improve blood lipid metabolism, and reduce the risk of stroke and coronary heart disease.

[0005] For most active drugs, the tableting process generally does not cause the generation of impurities, so there is no need to examine the effect of excipients on product impurities during the tableting stage. However, during the study of drospirenone / estradiol compound preparations, it was unexpectedly discovered that during the tableting process, drospirenone produces related degradation impurities due to heat generated by pressure, thus affecting the safety of clinical medication. Therefore, drospirenone / estradiol compound preparations require extra attention to the stability of drospirenone in the tableting process to ensure the safety and effectiveness of the drug.

[0006] So far, there is no literature report on improving the chemical stability of compound drospirenone / estradiol preparations. Summary of the invention

[0007] To solve the above technical problems, the present invention includes the following aspects:

[0008] A first aspect of the present invention provides a stable pharmaceutical composition comprising drospirenone and estradiol, comprising drospirenone, estradiol, a filler, a disintegrant and a lubricant, wherein the filler consists of a first filler and a second filler.

[0009] Preferably, the pharmaceutical composition is a tablet.

[0010] Preferably, the weight percentage of drospirenone in the pharmaceutical composition is 0.5-1%, and the weight percentage of estradiol in the pharmaceutical composition is 1-2%. More preferably, the weight percentage of drospirenone in the pharmaceutical composition is 0.7-0.8%, and the weight percentage of estradiol in the pharmaceutical composition is 1.3-1.7%. Further preferably, the weight percentage of drospirenone in the pharmaceutical composition is 0.76%, and the weight percentage of estradiol in the pharmaceutical composition is 1.52%.

[0011] Preferably, the first filler is lactose.

[0012] Preferably, the first filler accounts for less than 90% of the weight of the pharmaceutical composition. More preferably, the first filler accounts for 70-85% of the weight of the pharmaceutical composition. Further preferably, the first filler accounts for 73.2-83.2% of the weight of the pharmaceutical composition.

[0013] Preferably, the second filler is selected from one or more of starch and microcrystalline cellulose. More preferably, the second filler is starch or microcrystalline cellulose. Further preferably, the second filler is microcrystalline cellulose.

[0014] Preferably, the second filler accounts for more than 5% of the weight of the pharmaceutical composition. More preferably, the second filler accounts for 5-25% of the weight of the pharmaceutical composition. Further preferably, the second filler accounts for 10-20% of the weight of the pharmaceutical composition.

[0015] Preferably, the disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose. More preferably, the disintegrant is cross-linked sodium carboxymethyl cellulose.

[0016] Preferably, the weight percentage of the disintegrant in the pharmaceutical composition is 1-10%. More preferably, the weight percentage of the disintegrant in the pharmaceutical composition is 2-5%. Further preferably, the weight percentage of the disintegrant in the pharmaceutical composition is 4%.

[0017] Preferably, the lubricant is selected from one or more of magnesium stearate, micro-powdered silica gel, and talc. More preferably, the lubricant is magnesium stearate.

[0018] Preferably, the lubricant accounts for 0.1-1% by weight of the pharmaceutical composition. More preferably, the lubricant accounts for 0.3-0.8% by weight of the pharmaceutical composition. Further preferably, the lubricant accounts for 0.52% by weight of the pharmaceutical composition.

[0019] Preferably, the pharmaceutical composition is a tablet prepared from the following weight percentages of drugs and excipients: 0.76% drospirenone, 1.52% estradiol, 83.2% lactose, 10% starch, 4% cross-linked sodium carboxymethyl cellulose and 0.52% magnesium stearate.

[0020] Preferably, the pharmaceutical composition is a tablet prepared from the following weight percentages of drugs and excipients: 0.76% drospirenone, 1.52% estradiol, 73.2% lactose, 20% starch, 4% cross-linked sodium carboxymethyl cellulose and 0.52% magnesium stearate.

[0021] Preferably, the pharmaceutical composition is a tablet prepared from the following weight percentages of drugs and excipients: 0.76% drospirenone, 1.52% estradiol, 83.2% lactose, 10% microcrystalline cellulose, 4% cross-linked sodium carboxymethyl cellulose and 0.52% magnesium stearate.

[0022] Preferably, the pharmaceutical composition is a tablet prepared from the following weight percentages of drugs and excipients: 0.76% drospirenone, 1.52% estradiol, 73.2% lactose, 20% microcrystalline cellulose, 4% cross-linked sodium carboxymethyl cellulose and 0.52% magnesium stearate.

[0023] Preferably, the impurity content of drospirenone generated by the pharmaceutical composition after tableting is less than 1%. More preferably, the impurity content of drospirenone generated by the pharmaceutical composition after tableting is less than 0.5%. Further preferably, the impurity content of drospirenone generated by the pharmaceutical composition after tableting is less than 0.1%. Most preferably, the impurity content of drospirenone generated by the pharmaceutical composition after tableting is less than 0.05%.

[0024] Preferably, the retention time of the impurity relative to drospirenone is 0.16±0.02.

[0025] The second aspect of the present invention provides a method for preparing a stable pharmaceutical composition comprising drospirenone and estradiol, comprising the following steps:

[0026] (1) dissolving drospirenone and estradiol in an organic solvent to obtain a main drug solution;

[0027] (2) sieving the filler;

[0028] (3) placing the filler obtained in step (2) into a fluidized bed granulator, and spraying the main drug solution 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;

[0029] (4) mixing the drug-containing granules obtained in step (3), a disintegrant and a lubricant, and tableting to obtain a composite tablet containing drospirenone and estradiol.

[0030] Preferably, the organic solvent in step (1) is dichloromethane.

[0031] Preferably, the sieve used for screening in step (2) is 20 mesh.

[0032] Preferably, the drying in step (3) is carried out at 45°C.

[0033] Preferably, the fluidized liquid spraying parameters in step (3) are: liquid spraying speed is 100 g / min, air inlet volume is 200 cfm, air inlet temperature is 40° C., and atomization pressure is 4.0 bar.

[0034] Preferably, the rotation speed during mixing in step (4) is 20 rpm and the mixing time is 5 min.

[0035] Preferably, in step (4), a round punch with a diameter of 5 mm is used for tableting.

[0036] Preferably, the main pressure used for tableting in step (4) is 5-10 KN. More preferably, the main pressure used for tableting is 7 KN.

[0037] The third aspect of the present invention provides use of the above-mentioned pharmaceutical composition in the preparation of a drug for treating symptoms of estrogen deficiency.

[0038] Preferably, the estrogen deficiency symptoms are vasomotor symptoms caused by menopause and / or vulvar and vaginal atrophy symptoms caused by menopause.

[0039] A fourth aspect of the present invention provides a use of a filler composition for improving the chemical stability of drospirenone in a pharmaceutical composition comprising drospirenone and estradiol, wherein the filler composition consists of a first filler and a second filler.

[0040] Preferably, the pharmaceutical composition is a tablet.

[0041] Preferably, the first filler is lactose.

[0042] Preferably, the first filler accounts for less than 90% of the weight of the pharmaceutical composition. More preferably, the first filler accounts for 70-85% of the weight of the pharmaceutical composition. Further preferably, the first filler accounts for 73.2-83.2% of the weight of the pharmaceutical composition.

[0043] Preferably, the second filler is selected from one or more of starch and microcrystalline cellulose. More preferably, the second filler is starch or microcrystalline cellulose. Further preferably, the second filler is microcrystalline cellulose.

[0044] Preferably, the second filler accounts for more than 5% of the weight of the pharmaceutical composition. More preferably, the second filler accounts for 5-25% of the weight of the pharmaceutical composition. Further preferably, the second filler accounts for 10-20% of the weight of the pharmaceutical composition.

[0045] Preferably, the improving the chemical stability of drospirenone in the pharmaceutical composition comprising drospirenone and estradiol is to reduce the content of impurities generated by drospirenone during tableting.

[0046] Preferably, the retention time of the impurity relative to drospirenone is 0.16±0.02.

[0047] The technical effects produced by the present invention are:

[0048] The present invention unexpectedly found that during the tableting process of the drospirenone / estradiol compound tablet, drospirenone generates heat due to pressure and produces related degradation impurities. The present invention selects a specific filler (microcrystalline cellulose or starch) and optimizes its content ratio, not only to obtain tablets with qualified hardness and in vitro release, but also to effectively control the above-mentioned drospirenone-related impurities generated during the tableting process. At the same time, stability studies show that the drospirenone-related impurities have not increased. The tablets of the present invention provide a guarantee for clinical safe medication. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 It is an HPLC chromatogram of active ingredients and impurities in the drospirenone / estradiol tablet of Comparative Example 1 of the present invention. DETAILED DESCRIPTION

[0050] Experimental Example 1: Effect of excipient types on the amount of impurities generated during tablet compression of compound tablets

[0051] 1. Test methods

[0052] 1.1. Preparation of tablets

[0053] 1.1.2 Prescription

[0054]

[0055] 1.1.2 Preparation process

[0056] The invention discloses a compound tablet containing drospirenone and estradiol prepared by fluidized bed wet granulation tableting technology. The specific preparation method comprises the following steps: (1) dissolving drospirenone and estradiol in dichloromethane; (2) passing a filler through a 20-mesh screen; (3) placing the filler obtained in step (2) into a fluidized bed granulator, and spraying the main drug solution obtained in step (1) onto the filler in a fluidized state by fluidized spraying; drying the material obtained after the spraying at a temperature of 45°C to obtain a granulated tablet. to obtain drospirenone and estradiol drug particles, wherein the fluidized spray parameters are as follows: spray speed of 100 g / min, air volume of 200 cfm, air temperature of 40°C, and atomization pressure of 4.0 bar; (4) mixing the drug-containing particles obtained in step (3) with cross-linked sodium carboxymethyl cellulose and magnesium stearate at a rotation speed of 20 rpm for 5 min, and tableting with a round punch having a diameter of 5 mm and a main pressure of 7 KN to obtain the composite tablets containing drospirenone and estradiol.

[0057] 1.2. Detection of impurities

[0058] The unknown degradation impurities related to drospirenone produced in the granule mixtures (before tableting) and tablets (after tableting) obtained in Examples 1-4 and Comparative Example 1 were determined.

[0059] Sample processing method: Weigh an appropriate amount of the above-mentioned granular mixture or compound tablet containing drospirenone and estradiol, place it in a volumetric bottle, measure an appropriate amount of water, add it to the above-mentioned volumetric bottle, and make the granular mixture or compound tablet completely dispersed or disintegrated. Then measure an appropriate amount of acetonitrile (the volume ratio of water to acetonitrile is 1:4), place it in the above-mentioned volumetric bottle, then ultrasonicate, shake it on a shaker, transfer the solution to a centrifuge tube, centrifuge it, and take the supernatant for sampling and analysis.

[0060] HPLC chromatographic conditions: the chromatographic column is YMC-Pack Pro C18; acetonitrile-water (50:50) is used as mobile phase A, acetonitrile is used as mobile phase B, and linear gradient elution is performed according to the following table; the detection wavelength is UV 245nm; the injection volume is 20μL; and the flow rate is 1.0ml / min.

[0061] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 100 0 4 100 0 10 80 20 20 80 20 30 30 70 39 30 70 40 100 0 49 100 0

[0062] 2. Test results

[0063] 2.1 Effects of tableting and formulation on impurities

[0064] Figure 1The chromatographic peaks and retention times of the unknown degradation impurities, estradiol and drospirenone in the HPLC chromatogram of Comparative Example 1 are shown, wherein the retention times of the unknown degradation impurities related to drospirenone and drospirenone in the chromatogram are 3.540 min and 22.617 min, respectively. The retention time of the unknown impurity relative to drospirenone is 0.16±0.02. The determination results of the impurity amounts of the granular mixtures and the composite tablets of Examples 1-4 and Comparative Example 1 are shown in Table 1 below.

[0065] Table 1 Impurities generated before and after tableting in the present invention

[0066]

[0067] As can be seen from Table 1 above, no drospirenone-related impurities (retention time relative to drospirenone is 0.16±0.02) were detected in Examples 1-4 and Comparative Example 1 before tableting (granular state). After tableting, the amount of this impurity produced by the composite tablets of Comparative Example 1 without starch and microcrystalline cellulose increased significantly to 1.02%, which exceeded the limit of unknown impurities set by ICH (not more than 0.5%). In comparison, 10% and 20% microcrystalline cellulose were added to the prescriptions of Examples 1 and 2, respectively, and the unknown impurity was not detected; 10% and 20% starch were added to the prescriptions of Examples 3 and 4, and the amount of this unknown impurity was only 0.02%, which was much less than the limit of unknown impurities (not more than 0.5%).

[0068] The above test results show that adding 10% microcrystalline cellulose or starch to the formulation can significantly or completely eliminate the relevant impurities generated during the tableting process.

[0069] 2.2. Study on impurity stability

[0070] The tablets prepared in Examples 1-4 and Comparative Example 1 were packaged in aluminum plastic packaging and subjected to an impurity stability study at 40°C / 75%. The results of the determination of the initial impurities and the impurities after 6 months of storage under accelerated conditions (40±2°C / 75±5%RH) are shown in Table 2.

[0071] Table 2 Impurity results of the present invention examples and comparative examples under stability study conditions

[0072]

[0073] It can be seen from Table 2 above that when 10% or 20% microcrystalline cellulose or starch is added to the formulation, the impurities do not increase after being stored under accelerated conditions for 6 months, indicating that the formulations of Examples 1-4 can ensure the long-term stability of the product.

[0074] 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 pharmaceutical composition comprising drospirenone and estradiol, characterized in that: The pharmaceutical composition comprises drospirenone, estradiol, a filler, a disintegrant and a lubricant, wherein the filler consists of a first filler and a second filler, wherein the first filler is lactose, and the second filler is selected from starch or microcrystalline cellulose. The pharmaceutical composition is a tablet, wherein the first filler accounts for 70-85% of the weight of the pharmaceutical composition, the second filler accounts for 5-25% of the weight of the pharmaceutical composition, the drospirenone accounts for 0.5-1% of the weight of the pharmaceutical composition, and the estradiol accounts for 1-2% of the weight of the pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, characterized in that The disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose.

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

4. The method for preparing the stable pharmaceutical composition comprising drospirenone and estradiol according to any one of claims 1 to 3, characterized in that: The steps include: (1) dissolving drospirenone and estradiol in an organic solvent to obtain a main drug solution; (2) sieving the filler; (3) placing the filler obtained in step (2) into a fluidized bed granulator, and spraying the main drug solution 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) The drug-containing granules obtained in step (3), a disintegrant and a lubricant are mixed and tableted to obtain a compound tablet containing drospirenone and estradiol.

5. The method according to claim 4, characterized in that The fluidized liquid spraying parameters in step (3) are: liquid spraying speed is 100 g / min, air inlet volume is 200 cfm, air inlet temperature is 40°C, and atomization pressure is 4.0 bar.

6. Use of the pharmaceutical composition according to any one of claims 1 to 3 in the preparation of a medicament for treating symptoms of estrogen deficiency.

7. Use of a filler composition for improving the chemical stability of drospirenone in a pharmaceutical composition comprising drospirenone and estradiol, characterized in that: The filler composition consists of a first filler and a second filler, the first filler is lactose, the second filler is selected from starch or microcrystalline cellulose, the first filler accounts for 70-85% of the weight percentage of the pharmaceutical composition, the second filler accounts for 5-25% of the weight percentage of the pharmaceutical composition, the drospirenone accounts for 0.5-1% of the weight percentage of the pharmaceutical composition, the estradiol accounts for 1-2% of the weight percentage of the pharmaceutical composition, and the improvement of the chemical stability of drospirenone in the pharmaceutical composition containing drospirenone and estradiol is to reduce the impurity content generated by drospirenone during the tableting process.

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