Pharmaceutical composition containing female progestational hormone, pharmaceutical preparation and preparation method and application thereof

Abstract

The invention discloses a pharmaceutical composition containing female progestational hormone, a pharmaceutical preparation and a preparation method and application thereof. The pharmaceutical composition is prepared from the following components in percentage by mass: 0.01 wt%-0.2 wt% of estetrol, 20 wt%-30 wt% of progesterone, 20 wt%-30 wt% of medium-chain fatty glyceride and 45 wt%-55 wt% of a solvent, the wt% is the mass percentage of the mass of each component in the total mass of the pharmaceutical composition. The pharmaceutical composition and the pharmaceutical preparation are good in pharmacokinetic property and high in bioavailability.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a pharmaceutical composition containing estrogen and progesterone, a pharmaceutical preparation, and a preparation method and application thereof. Background Art

[0002] After women enter menopause, due to the decline of ovarian function, the estrogen level in the body decreases, leading to a series of diseases caused by the decrease of estrogen level. The most common menopausal symptoms are: hot flashes, night sweats, insomnia, vaginal dryness, mood disorders, and weight gain. Women who enter menopause can effectively relieve these symptoms by supplementing exogenous estrogen. However, estrogen has the following disadvantages: ① It may cause endometrial cancer and breast cancer; ② It may increase the size of uterine fibroids and aggravate endometriosis; ③ It may cause thrombosis; ④ It may cause breast tenderness, nausea, edema, weight gain, increased leucorrhea, intermittent uterine bleeding, and increased blood pressure.

[0003] In order to overcome these shortcomings, the existing technology mainly adopts the combined use of estrogen and progesterone to treat menopausal syndrome. The main advantages are: 1. When using estrogen, adding progesterone to counteract the proliferative effect of estrogen on the endometrium, prevent the occurrence of endometrial cancer, and transform it into withdrawal bleeding after the secretory phase. 2. Continuous use of low-dose estrogen and progesterone has a low vaginal bleeding rate, which ensures the protective effect on preventing osteoporosis and cardiovascular diseases. It is currently the most widely used postmenopausal hormone replacement therapy.

[0004] However, the existing estrogen-progestin pharmaceutical compositions have defects such as low bioavailability. Therefore, there is an urgent need to develop a preparation with good pharmacokinetic properties and high bioavailability. Summary of the invention

[0005] The technical problem to be solved by the present invention is to overcome the defects of the prior art in the process of treating perimenopausal syndrome, such as low bioavailability of the estrogen-progesterone pharmaceutical composition, and to provide a pharmaceutical composition containing estrogen-progesterone, a pharmaceutical preparation, and a preparation method and application thereof. The pharmaceutical composition and the pharmaceutical preparation have good pharmacokinetic properties and further have high bioavailability.

[0006] The present invention solves the above technical problems through the following technical solutions:

[0007] The invention provides a pharmaceutical composition, which comprises the following components in mass fractions: 0.01wt%-0.2wt% of estetrol, 20wt%-30wt% of progesterone, 20wt%-30wt% of medium-chain fatty acid glyceride and 45wt%-55wt% of solvent; wt% is the mass percentage of the mass of each component to the total mass of the pharmaceutical composition.

[0008] Preferably, the progesterone is progesterone and / or dydrogesterone; more preferably, the progesterone is progesterone.

[0009] Preferably, the medium-chain fatty acid in the medium-chain fatty acid glyceride is a fatty acid having 6-12 carbon atoms in the carbon chain; preferably, the medium-chain fatty acid in the medium-chain fatty acid glyceride is caprylic acid and / or capric acid.

[0010] Further preferably, the medium-chain fatty acid glyceride is one or more of caprylic capric mono- and di-glycerides, tricaprylic glyceride and medium-chain triglycerides; preferably, the medium-chain fatty acid glyceride is caprylic capric mono- and di-glycerides, tricaprylic glyceride, or a mixture of caprylic capric mono- and di-glycerides and medium-chain triglycerides; more preferably, the medium-chain fatty acid glyceride is a mixture of caprylic capric mono- and di-glycerides and medium-chain triglycerides; further preferably, the mixture of caprylic capric mono- and di-glycerides and medium-chain triglycerides is a mixture of caprylic capric mono- and di-glycerides and medium-chain triglycerides in a mass ratio of (1.2-2):1; for example, a mixture of 1.4:1-1.5:1, and for example, a mixture of 1.495:1.

[0011] Preferably, the fatty acids in the caprylic capric mono- and di-glycerides contain 50%-90% caprylic acid and 10%-50% capric acid; preferably, the fatty acids in the caprylic capric mono- and di-glycerides may also contain no more than 3% caproic acid, no more than 3% lauric acid and no more than 1% myristic acid; % is the mass percentage of various acids in the total mass of fatty acids; more preferably, the caprylic capric mono- and di-glycerides are caprylic capric mono- and di-glycerides with registration number F20180000680 (Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd.).

[0012] Preferably, the fatty acids in the medium chain triglycerides contain 50%-80% caprylic acid and 20%-50% capric acid; preferably, the fatty acids in the medium chain triglycerides may also contain no more than 2% caproic acid, no more than 3% lauric acid, no more than 1% myristic acid and no more than 1% fatty acids greater than or equal to hexadecene; % is the mass percentage of various acids in the total mass of fatty acids; more preferably, the medium chain triglycerides are medium chain triglycerides with registration number Y20230000156 (Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd.).

[0013] Preferably, the solvent is a vegetable oil, preferably one or more of sunflower oil, soybean oil and peanut oil; for example, sunflower oil or peanut oil.

[0014] The relative density of the sunflower seed oil can be 0.92; the refractive index can be 1.474; the acid value can be 0.06; the iodine value can be 128; preferably, the fatty acids in the sunflower seed oil can contain 6.8% hexadecanoic acid, 3.9% stearic acid, 25.6% oleic acid and 60.9% linoleic acid; more preferably, it also contains 0.3% arachidic acid, 0.2% eicosenoic acid, 0.8% behenic acid and 0.3% lignoceric acid; further preferably, the sunflower seed oil is a sunflower seed oil with registration number F20210000181 (Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd.).

[0015] The relative density of the peanut oil may be 0.914-0.917; the refractive index may be 1.462-1.464; the acid value may be ≤0.5; the iodine value may be 84-103; preferably, the fatty acids in the peanut oil may include 7%-16% palmitic acid, 35%-72% oleic acid and 13%-43% linoleic acid; more preferably, the peanut oil may also include ≤0.2% myristic acid, ≤1% palmitic acid, 1 .3%-6.5% stearic acid, ≤0.6% linolenic acid; 0.5%-3% arachidic acid, 0.5%-2.1% eicosenoic acid, 1%-5% behenic acid, ≤0.5% docosenoic acid and 0.5%-3% tetracosanoic acid; further preferably, the peanut oil is peanut oil with registration number F20180000683 (Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd.).

[0016] Preferably, the pharmaceutical composition satisfies one or more of the following conditions:

[0017] a. The mass fraction of estetrol is 0.03wt%-0.08wt%; for example, 0.05wt%;

[0018] b. The mass fraction of progesterone is 22wt%-28wt%; for example, 25wt%;

[0019] c. The mass fraction of the medium-chain fatty acid glyceride is 22wt%-28wt%, for example 24.95wt%;

[0020] d. The mass fraction of the solvent is 48wt%-52wt%; for example 50%.

[0021] Preferably, the pharmaceutical composition comprises the following components in mass fractions: 0.03wt%-0.08wt% of estetrol, 22wt%-28wt% of progesterone, 22wt%-28wt% of medium-chain fatty acid glycerides and 48wt%-52wt% of solvent; the definitions of the medium-chain fatty acid glycerides and the solvent are as described in any of the above items.

[0022] Preferably, the pharmaceutical composition consists of 0.03wt%-0.08wt% of estetrol, 22wt%-28wt% of progesterone, 22wt%-28wt% of medium-chain fatty acid glyceride and 48wt%-52wt% of solvent;

[0023] The medium-chain fatty acid glyceride and the solvent are defined as described in any one of the above items.

[0024] Further preferably, the pharmaceutical composition consists of 0.05wt% of estetrol, 25wt% of progesterone, 24.95% of medium-chain fatty acid glyceride and 50wt% of solvent;

[0025] The medium-chain fatty acid glyceride and the solvent are defined as described in any one of the above items.

[0026] Most preferably, the pharmaceutical composition is as described in any one of the following:

[0027] (1) The pharmaceutical composition is composed of 0.05 wt% of estetrol, 25 wt% of progesterone, 24.95 wt% of caprylic and capric mono- and di-glycerides, and 50 wt% of sunflower oil;

[0028] (2) The pharmaceutical composition is composed of 0.05 wt% of estetrol, 25 wt% of progesterone, 24.95 wt% of tricaprylin and 50 wt% of peanut oil;

[0029] (3) The pharmaceutical composition consists of 0.05 wt% of estetrol, 25 wt% of progesterone, 14.95 wt% of caprylic and capric mono- and di-glycerides, 10 wt% of medium-chain triglycerides and 50 wt% of sunflower seed oil.

[0030] The present invention also provides a method for preparing the pharmaceutical composition, which specifically comprises the following steps:

[0031] The components of the pharmaceutical composition as described above are mixed evenly.

[0032] Preferably, the mixing process is stirring.

[0033] More preferably, the stirring temperature is 30-60°C, such as 40°C.

[0034] The present invention also provides a pharmaceutical preparation, which comprises the pharmaceutical composition as described above.

[0035] Preferably, the pharmaceutical preparation is a capsule.

[0036] More preferably, the capsule uses the above-mentioned pharmaceutical composition as a core material.

[0037] In the present invention, the capsule shell of the capsule is a pharmaceutically acceptable capsule shell, such as a gelatin capsule shell.

[0038] The present invention also provides a use of the above-mentioned pharmaceutical composition or pharmaceutical preparation in preparing a drug for treating perimenopausal syndrome.

[0039] Terminology explanation:

[0040] In the present invention, the term "medium-chain fatty acid" in "medium-chain fatty acid glyceride" refers to fatty acids with 6 to 12 carbon atoms in the carbon chain, and the main components are caprylic acid (C8) and capric acid (C 10 ).

[0041] The positive and progressive effects of the present invention are:

[0042] (1) The pharmaceutical composition and pharmaceutical preparation of the present invention possess the advantages of both estetrol and progesterone, can effectively treat perimenopausal syndrome, and have few toxic and side effects.

[0043] (2) The half-life of the pharmaceutical composition and pharmaceutical preparation of the present invention is up to 28 hours, which can reduce the number of dosing times; the bioavailability is high, which can reduce the daily dosage; the safety is high, which can reduce the potential risk of venous thromboembolism; and the effect of treating perimenopausal syndrome is better than that of the drugs already on the market.

[0044] (3) The preparation method of the pharmaceutical preparation of the present invention is relatively simple and suitable for industrial production. DETAILED DESCRIPTION

[0045] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples.

[0046] The reagents used in the following examples are shown in Table 1.

[0047] Table 1

[0048]

[0049]

[0050] The solution of the present application can be prepared with existing commercially available capsule shells to obtain the pharmaceutical preparation of the present invention. The following preparation method of gelatin capsule shells is selected in the examples of the present application, but those skilled in the art need to understand that the use of this gelatin capsule shell does not mean that the present application can only be applied to the following gelatin capsule shells.

[0051] Example 1

[0052] Weigh estetrol, progesterone, caprylic and capric mono- and di-glycerides, dissolve them in sunflower oil at 40° C., stir evenly, and fill them into gelatin capsule shells to prepare a pharmaceutical preparation.

[0053] Preparation method of gelatin capsule shell:

[0054] Mix 530g titanium dioxide and 1.06kg glycerol, pass through a 100-mesh sieve, and mix the titanium dioxide and glycerol thoroughly to obtain a uniform mixture. Add the sieved material, 5.3kg purified water and 1.14kg glycerol to the sol bucket, stir for 10 minutes and heat to 70°C. Add the weighed 6.39kg gelatin to the sol bucket and stir for about 20 minutes. Connect a vacuum pump to evacuate and stir until there are no bubbles in the glue. Keep the glue at 55°C and heat it to 60-65°C before pressing.

[0055] The raw materials used are as follows:

[0056] Table 2

[0057] Raw materials Dosage / per tablet Estetrol 0.1mg Progesterone 50mg Caprylic / capric mono- and di-glycerides 49.9mg Sunflower Oil 100mg total 200mg

[0058] The fatty acid composition of caprylic and capric mono- and di-glycerides is as follows:

[0059] Hexanoic acid: ≤3.0%

[0060] Caprylic acid: 50%-90%

[0061] Capric acid: 10%-50%

[0062] Lauric acid: ≤3.0%

[0063] Myristic acid: ≤1.0%.

[0064] Physical and chemical parameters of sunflower oil:

[0065] Relative density (20℃): 0.92;

[0066] Refractive index (20℃): 1.474;

[0067] Acid value: 0.06;

[0068] Iodine value: 128;

[0069] Fatty acid composition of sunflower oil:

[0070] Table 3

[0071]

[0072]

[0073] Example 2

[0074] On the basis of Example 1, caprylic and capric mono- and diglycerides were replaced by tricaprylic glyceride, and sunflower oil was replaced by peanut oil. The rest was the same as in Example 1, to obtain a pharmaceutical preparation.

[0075] The raw materials used are as follows:

[0076] Table 4

[0077]

[0078]

[0079] Physical and chemical parameters of peanut oil:

[0080] Table 5

[0081]

[0082] Fatty acid composition of peanut oil:

[0083] Table 6

[0084]

[0085] Example 3

[0086] On the basis of Example 1, caprylic capric mono- and di-glycerides were replaced with a mixture of caprylic capric mono- and di-glycerides and medium-chain triglycerides, and the rest were the same as in Example 1, to obtain a pharmaceutical preparation.

[0087] The raw materials used are as follows:

[0088] Table 7

[0089] Raw materials Dosage / per tablet Estetrol 0.1mg Progesterone 50mg Caprylic / capric mono- and di-glycerides 29.9mg Medium Chain Triglycerides 20mg Sunflower Oil 100mg total 200mg

[0090] The fatty acid composition of medium-chain triglycerides is as follows:

[0091] Hexanoic acid: ≤2.0%

[0092] Caprylic acid: 50.0%-80.0%

[0093] Capric acid: 20.0%-50.0%

[0094] Lauric acid: ≤3.0%

[0095] Myristic acid: ≤1.0%

[0096] Fatty acids with carbon numbers greater than or equal to 16: ≤1.0%

[0097] Comparative Examples 1-4

[0098] Comparative Examples 1-4 are based on Example 1, except that only the amounts of raw materials and auxiliary materials are changed, and the rest are the same as Example 1, to obtain pharmaceutical preparations.

[0099] The raw materials used are as follows:

[0100] Table 8

[0101]

[0102] Comparative Example 5

[0103] Only the caprylic and capric mono- and di-glycerides in Example 1 were replaced with an equal amount of lecithin, and the rest were the same as in Example 1.

[0104] Comparative Example 6

[0105] The other steps are the same as those in Example 1, except that the types and amounts of the raw and auxiliary materials are changed, and the other steps are the same as those in Example 1, to obtain a pharmaceutical preparation.

[0106] The raw materials used are as follows:

[0107] Table 9

[0108] Raw materials Dosage / per tablet Estetrol 15mg Dydroprogesterone 10mg Sunflower Oil 175mg total 200mg

[0109] Comparative Example 7

[0110] Only the caprylic and capric mono- and di-glycerides in Example 1 were replaced with an equal amount of glyceryl monooleate, and the rest were the same as in Example 1.

[0111] Monoolein is mainly composed of C18 long-chain glycerides, the detailed information is as follows:

[0112] Table 10

[0113] Carbon chain length Number of double bonds Percentage content (%) 16 0 ≤12.0 18 0 ≤6.0 18 1 ≥60.0 18 2 ≤35.0 18 3 ≤2.0 20 0 ≤2.0 20 1 ≤2.0

[0114] Effect Example 1: Pharmacokinetic Test

[0115] The pharmaceutical preparations prepared in Examples 1-3 and Comparative Examples 1-6 of the present invention were used for pharmacokinetic experiments. Six male beagles (weight 10-15 kg, Beijing Mas Biotechnology Co., Ltd.) in each group were used as test subjects, and commercially available estradiol progesterone soft capsules (trade name: BIJUVA) were used as reference preparations (estradiol: 1 mg; progesterone: 100 mg; caprylic and capric mono- and diglycerides: 196 mg; lauroyl polyoxyethylene glyceride: 3 mg in a single estradiol progesterone soft capsule) were used for a single-dose, two-cycle crossover test.

[0116] For each example, male beagle dogs were divided into two groups, each with 6 dogs. In the first cycle, the first group was given a reference preparation (one tablet) once, and the second group was given an example pharmaceutical preparation (one tablet) once; in the second cycle, the first group was given an example pharmaceutical preparation (one tablet) once, and the second group was given a reference preparation (one tablet) once. The blood sampling time for each cycle was 0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 7.0, 8.0, 9.0, 10.0, 11.0, 12.0, 14.0, 24.0, 26.0, 48.0, 72.0 (h), and the washout period was 14 days.

[0117] The total estrone concentration in plasma was determined by high performance liquid chromatography-tandem mass spectrometry, and the maximum concentration of the drug in plasma after administration was calculated. max , the area under the curve (AUC) of the drug in plasma after administration, the results are shown in Table 11. (“AUC 0-∞ "AUC is the area under the concentration-time curve extrapolated to infinity after a certain dose is administered. 0-t " is the area under the concentration-time curve from time zero to time t after a certain dose is administered, where t refers to Tmax, i.e. the time (horizontal axis) corresponding to the maximum blood drug concentration (vertical axis)

[0118] Chromatographic conditions

[0119] Column: Ultimate XB-C18, 2.1*50mm, 5μm, Welch

[0120] Mobile phase A: aqueous solution containing 100 μM ammonium fluoride

[0121] Mobile phase B: 5% 100 μM ammonium fluoride in water and 95% methanol

[0122] Flow rate: 1.00mL / min

[0123] Injection volume: 20.0 μL

[0124] Elution gradient: as shown in Table 11.

[0125] Table 11

[0126] Time (minutes) Mobile phase B ratio (%) 0.01 48.0 1.20 90.0 1.30 100 2.00 100 2.10 48.0

[0127] Mass spectrometry conditions

[0128] Ion source: ESI

[0129] Ionization mode: Negative ion mode

[0130] The test results are shown in Table 12.

[0131] Table 12

[0132]

[0133]

[0134] *: F represents relative bioavailability, F = (AUC 0-∞实施例药物制剂 *Reference preparation specification) / (AUC 0-∞参比制剂 *Specifications of the pharmaceutical preparation in the example)*100%.

[0135] As can be seen from the above table, compared with the commercially available preparation BIJUVA, the pharmaceutical preparation of the present invention greatly improves the bioavailability of the pharmaceutical preparation, and Examples 1 to 3 all increase the bioavailability by at least 18 times, among which Example 3 has the best effect, increasing by nearly 30 times. In addition, the half-life of the pharmaceutical preparation of the present invention is significantly prolonged compared with the commercially available BIJUVA.

[0136] The bioavailability of Comparative Examples 1-7 of the present application is also far inferior to that of Examples 1-3 of the present application. The dosage of excipients used in Comparative Examples 1-4 is different from that of the present application, and the ratio of the components is not appropriate, resulting in poor effects; the lecithin used in Comparative Example 5 cannot achieve the effect of the fatty acid glyceride of the present application; the raw materials and dosages and excipients used in Comparative Examples 6-7 are different from those of the present application, and the synergistic effect of the components of the drug is not as good as that of the examples of the present application, and the effects are also poor.

[0137] Although the specific embodiments of the present invention are described above, it should be understood by those skilled in the art that this is only for illustration and the protection scope of the present invention is defined by the appended claims. Those skilled in the art may make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but these changes and modifications all fall within the protection scope of the present invention.

Claims

1. A pharmaceutical composition, characterized in that The drug composition comprises the following components in mass fractions: 0.01wt%-0.2wt% of estetrol, 20wt%-30wt% of progesterone, 20wt%-30wt% of medium-chain fatty acid glyceride and 45wt%-55wt% of solvent; wt% is the mass percentage of the mass of each component to the total mass of the drug composition.

2. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition satisfies one or more of the following conditions: a. The progesterone is progesterone and / or dydroprogesterone; preferably, the progesterone is progesterone; b. The medium-chain fatty acid in the medium-chain fatty acid glyceride is a fatty acid having 6-12 carbon atoms on the carbon chain; preferably, the medium-chain fatty acid in the medium-chain fatty acid glyceride is caprylic acid and / or capric acid; more preferably, the medium-chain fatty acid glyceride is one or more of caprylic capric acid mono- and di-glycerides, tricaprylic acid glyceride and medium-chain triglycerides; further preferably, the medium-chain fatty acid glyceride is caprylic capric acid mono- and di-glycerides, tricaprylic acid glyceride, or a mixture of caprylic capric acid mono- and di-glycerides and medium-chain triglycerides; further more preferably, the medium-chain fatty acid glyceride is a mixture of caprylic capric acid mono- and di-glycerides and medium-chain triglycerides; optimally, the mixture of caprylic capric acid mono- and di-glycerides and medium-chain triglycerides is a mixture of caprylic capric acid mono- and di-glycerides and medium-chain triglycerides in a mass ratio of (1.2-2):1; for example, a mixture of 1.4:1-1.5:1; c. The solvent is a vegetable oil, preferably one or more of sunflower oil, soybean oil and peanut oil; for example, sunflower oil or peanut oil.

3. The pharmaceutical composition according to claim 2, characterized in that The pharmaceutical composition satisfies one or more of the following conditions: a. The fatty acids in the caprylic capric acid mono- and di-glycerides contain 50%-90% caprylic acid and 10%-50% capric acid; preferably, the caprylic capric acid mono- and di-glycerides are caprylic capric acid mono- and di-glycerides with registration number F20180000680; b. The fatty acids in the medium chain triglycerides include 50%-80% caprylic acid and 20%-50% capric acid; preferably, the medium chain triglycerides are medium chain triglycerides with registration number Y20230000156; c. The relative density of the sunflower oil is 0.92; the refractive index may be 1.474; the acid value may be 0.06; The iodine value may be 128; preferably, the fatty acids in the sunflower oil may contain 6.8% hexadecanoic acid, 3.9% stearic acid, 25.6% oleic acid and 60.9% linoleic acid; further preferably, the sunflower oil is a sunflower oil with registration number F20210000181; d. The relative density of the peanut oil is 0.914-0.917; the refractive index may be 1.462-1.464; the acid value may be ≤0.5; the iodine value may be 84-103; preferably, the fatty acids in the peanut oil may contain 7%-16% palmitic acid, 35%-72% oleic acid and 13%-43% linoleic acid; further preferably, the peanut oil is peanut oil with registration number F20180000683.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The pharmaceutical composition satisfies one or more of the following conditions: a. The mass fraction of estetrol is 0.03wt%-0.08wt%; for example, 0.05wt%; b. The mass fraction of progesterone is 22wt%-28wt%; for example, 25wt%; c. The mass fraction of the medium-chain fatty acid glyceride is 22wt%-28wt%, for example 24.95wt%; d. The mass fraction of the solvent is 48wt%-52wt%; for example 50%.

5. The pharmaceutical composition according to claim 4, characterized in that The invention comprises the following components in mass fractions: 0.03wt%-0.08wt% of estetrol, 22wt%-28wt% of progesterone, 22wt%-28wt% of medium-chain fatty acid glyceride and 48wt%-52wt% of solvent; The definitions of the medium-chain fatty acid glyceride and the solvent are as described in claim 2 or 3.

6. The pharmaceutical composition according to claim 5, characterized in that The pharmaceutical composition is composed of 0.03wt%-0.08wt% of estetrol, 22wt%-28wt% of progesterone, 22wt%-28wt% of medium-chain fatty acid glyceride and 48wt%-52wt% of solvent; Preferably, the pharmaceutical composition consists of 0.05wt% estetrol, 25wt% progesterone, 24.95% medium-chain fatty acid glyceride and 50wt% solvent; Wherein, the definitions of the medium-chain fatty acid glyceride and the solvent are as described in claim 2 or 3.

7. The pharmaceutical composition according to claim 6, characterized in that The pharmaceutical composition is as described in any of the following: (1) The pharmaceutical composition is composed of 0.05wt% of estetrol, 25wt% of progesterone, 24.95wt% of caprylic and capric mono- and di-glycerides, and 50wt% of sunflower oil; (2) The pharmaceutical composition is composed of 0.05wt% estetrol, 25wt% progesterone, 24.95wt% tricaprylin and 50wt% peanut oil; (3) The pharmaceutical composition is composed of 0.05wt% estetrol, 25wt% progesterone, 14.95wt% caprylic and capric mono- and diglycerides, 10wt% medium chain triglycerides and 50wt% sunflower oil; Wherein, the definitions of the caprylic capric mono- and diglycerides, the medium-chain triglycerides, the peanut oil and the sunflower oil are as described in claim 3.

8. A method for preparing a pharmaceutical composition, characterized in that: The specific steps include: The components of the pharmaceutical composition according to any one of claims 1 to 7 are mixed evenly; Preferably, the mixing process is stirring; More preferably, the stirring temperature is 30-60°C, such as 40°C.

9. A pharmaceutical preparation, characterized in that It comprises the pharmaceutical composition according to any one of claims 1 to 7; Preferably, the pharmaceutical preparation is a capsule; More preferably, the capsule uses the pharmaceutical composition according to any one of claims 1 to 7 as a core material.

10. Use of the pharmaceutical composition according to any one of claims 1 to 7 or the pharmaceutical preparation according to claim 9 in the preparation of a drug for treating perimenopausal syndrome.

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