WO2024120399A1

WO2024120399A1 - Progesterone pharmaceutical composition

Info

Publication number: WO2024120399A1
Application number: PCT/CN2023/136525
Authority: WO
Inventors: 沈志群; 董永峰; 沈家林; 傅恩军; 应圣俊; 应子超; 张晓明
Original assignee: 杭州同惠医药科技有限公司; 浙江圣博康药业有限公司
Priority date: 2022-12-07
Filing date: 2023-12-05
Publication date: 2024-06-13
Also published as: CN118141823A

Abstract

A progesterone pharmaceutical composition. Specifically, provided is an oral formulation, comprising (a) progesterone; (b) an agent for promoting progesterone bio-utilization; and (c) a pharmaceutically acceptable oral formulation carrier. The agent for promoting progesterone bio-utilization is selected from one or more of sucrose fatty acid esters. The oral formulation is high in bioavailability and low in side effects, making it a superior progesterone oral product.

Description

A progesterone pharmaceutical composition

Technical Field

The invention belongs to the field of pharmaceutical preparations and relates to a progesterone pharmaceutical composition.

Background technique

Progesterone, also known as progesterone, is the main biologically active progestogen secreted by the ovaries. Progesterone is widely used clinically and is suitable for functional disorders caused by progesterone deficiency, such as menstrual disorders, amenorrhea, dysmenorrhea, premenstrual syndrome, menopausal syndrome, etc. At present, the main progesterone dosage forms available in China and abroad are: progesterone injection, progesterone vaginal preparations, oral progesterone preparations, etc. Among them, compared with injections, oral progesterone preparations have no pain, and the injection site is prone to hardening or even inflammation and other side effects; compared with vaginal administration dosage forms, it does not have the inconvenience of vaginal administration preparations, and has defects such as vaginal irritation, excessive vaginal secretions, and even vaginal bleeding. It is the dosage form with the highest patient compliance.

Besins Healthcare of Belgium has launched a micronized progesterone soft capsule preparation (trade name in China: Utrogestan; trade name in the United States: Prometrium). This product improves the bioavailability of oral progesterone by micronization and using oil as a carrier. However, the oral bioavailability of this product is extremely low, less than 5%, and more than 90% of the progesterone is converted into metabolites. The blood drug detection method used when this product was launched was an immunoassay (IA) with poor specificity, which could not distinguish between progesterone and other metabolites in plasma. Therefore, it was mistakenly believed that the blood concentration of progesterone after oral administration of low-dose micronized progesterone soft capsules (100mg-200mg) could reach a concentration that could produce physiological effects. This contradicts the results of its clinical trials: Prometrium FDA clinical application materials show that only 53% of patients with more than 300mg of this product have endometrial degeneration, and the proportion is only 24% with 200mg, and there is no significant difference between 100mg and placebo. At the same time, the product produces a large number of metabolites due to the first-pass effect when taken orally. Some of these metabolites, such as allopregnanolone, have known alcohol-like effects, which leads to dizziness, vertigo, drowsiness and other unbearable side effects of oral progesterone. The incidence of side effects increases with a single oral dose of 200 mg, and fatigue increases significantly with a single oral dose of more than 300 mg. In addition, micronized progesterone soft capsules also have defects such as great absorption variation between different patients, resulting in large differences in efficacy and side effects between patients, which greatly limits its application and brings inconvenience to patients' lives.

Therefore, there is an urgent need to develop an improved oral progesterone preparation that can improve bioavailability, reduce side effects, reduce inter-individual differences, facilitate clinical use, and improve patient compliance.

Summary of the invention

The purpose of the present invention is to provide an oral progesterone preparation with high bioavailability and low side effects.

In a first aspect, the present invention provides an oral preparation comprising

(a) progesterone;

(b) a progesterone bioavailability enhancer; and

(c) and a pharmaceutically acceptable carrier for oral preparation;

Wherein, the progesterone bioavailability promoter is selected from one or more of sucrose fatty acid esters, wherein the fatty acid is C12-C18 fatty acid; and

In the composition, the mass ratio of progesterone to the progesterone bioavailability promoter is 1:(0.1-250).

In another preferred embodiment, the mass ratio of progesterone to the progesterone bioavailability enhancer is 1:(0.25-50), preferably 1:(0.3-25) or 1:(0.5-10), such as 1:0.8, 1:1, 1:1.5, 1:2, 1:3, 1:4 or 1:5.

In another preferred embodiment, the dosage form of the oral preparation is selected from the following group: solid preparation and liquid preparation.

In another preferred embodiment, the dosage form of the oral preparation is selected from the following group: tablets, hard capsules, soft capsules, granules, pills, powders, suspensions, emulsions, oral solutions, syrups or elixirs.

In another preferred embodiment, the progesterone bioavailability promoter is selected from the following group: sucrose stearate, sucrose laurate, sucrose palmitate, sucrose oleate, or a combination thereof.

In another preferred embodiment, the pharmaceutically acceptable carrier is selected from the following group: disintegrant, filler, binder, humectant, inclusion agent, lubricant, sweetener, flavoring agent, colorant, diluent, or a combination thereof.

In another preferred embodiment, the oral preparation contains cyclodextrin, and the progesterone is included in the cyclodextrin. Preferably, the cyclodextrin is selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin sodium, methylated-β-cyclodextrin, or a combination thereof, preferably hydroxypropyl-β-cyclodextrin.

In another preferred embodiment, the mass ratio of progesterone to cyclodextrin in the pharmaceutical composition is 1:(1-1000), preferably 1:(5-100), and more preferably 1:(10-25).

In another preferred embodiment, the oral preparation is a soft capsule and comprises the following components:

In another preferred embodiment, in the soft capsule, geraniol is 1.5-2 parts by weight.

In another preferred embodiment, in the soft capsule, terpineol is 0.2-0.3 parts by weight.

In another preferred embodiment, in the soft capsule, the polyethylene glycol is 0.3-0.5 parts by weight.

In another preferred embodiment, in the soft capsule, the amount of monolinoleylglycerol is 8-12 parts by weight.

In another preferred embodiment, in the soft capsule, soybean oil is 4-6 parts by weight.

In another preferred embodiment, in the soft capsule, Tween-20 is 0.2-0.3 parts by weight.

In another preferred embodiment, in the soft capsule, sucrose stearate and/or sucrose laurate is 0.8-1.2 parts by weight.

In another preferred embodiment, the oral preparation is a tablet and comprises the following components:

In another preferred embodiment, in the tablet, hydroxypropyl-beta-cyclodextrin is 10-20 parts by weight.

In another preferred embodiment, in the tablet, lactose is 1.5-3 parts by weight.

In another preferred embodiment, in the tablet, PVPk30 is 0.2-0.3 parts by weight.

In another preferred embodiment, in the tablet, Tween-20 is 0.2-0.3 parts by weight.

In another preferred embodiment, in the tablet, sucrose stearate and/or sucrose laurate is 0.5-2.5 parts by weight, such as 1, 1.5 or 2 parts by weight.

The second aspect of the present invention provides a composition comprising:

(a) progesterone; and

(b) a progesterone bioavailability enhancer;

Wherein, the progesterone bioavailability promoter is selected from the following group: one or more of sucrose fatty acid esters, wherein the fatty acid is C12-C18 fatty acid; and

In another preferred embodiment, the mass ratio of progesterone to progesterone bioavailability enhancer is 1:(0.25-50), preferably 1:(0.3-25) or 1:(0.5-10), such as 1:0.8, 1:1, 1:1.5, 1:2, 1:3, 1:4 or 1:5.

The third aspect of the present invention provides use of the oral preparation according to the first aspect of the present invention or the composition according to the second aspect of the present invention in the preparation of a medicament for preventing and/or treating diseases related to progesterone deficiency.

In another preferred embodiment, the progesterone deficiency-related disease is selected from the group consisting of menstrual disorders, amenorrhea, dysmenorrhea, premenstrual syndrome, menopausal syndrome, or a combination thereof.

The fourth aspect of the present invention provides a method for preventing and/or treating a disease associated with progesterone deficiency, comprising the steps of: administering to a subject in need thereof an oral preparation as described in the first aspect of the present invention or a composition as described in the second aspect of the present invention, thereby preventing and/or treating the disease associated with progesterone deficiency.

In another preferred embodiment, the subject is a mammal, such as a human, mouse, monkey or dog.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the following (such as implementation) The various technical features specifically described in the example) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here.

Detailed ways

The inventors have conducted extensive and in-depth research, and through a large number of screenings and tests, provided an oral progesterone preparation with excellent bioavailability. The inventors unexpectedly found that the progesterone bioavailability enhancer of the present invention can selectively improve the absorption effect of progesterone in the gastrointestinal tract, while having no obvious promoting effect on progesterone metabolites such as allopregnanolone, and can reduce the side effects of progesterone administration, thereby providing the progesterone preparation of the present invention that is suitable for oral administration, has high bioavailability, and has low side effects.

the term

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

As used herein, when used in reference to a specific recited numerical value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

As used herein, the term "comprising" or "including (comprising)" may be open, semi-closed and closed. In other words, the term also includes "consisting essentially of" or "consisting of".

As used in the present invention, the terms “oral preparation of the present invention”, “oral progesterone preparation”, “progesterone pharmaceutical composition” and “pharmaceutical composition of the present invention” can be used interchangeably to refer to the oral progesterone preparation of the present invention.

Active ingredients

Progesterone, also known as progesterone and luteinizing hormone, is the main biologically active progestogen secreted by the ovaries. Its structural formula is as follows:

Progesterone Bioavailability Enhancer

The inventors unexpectedly discovered that sucrose fatty acid esters can be used as progesterone bioavailability promoters, which can significantly improve the absorption effect of progesterone in the gastrointestinal tract and thus improve its bioavailability, while for allopregnanolone The promoting effect of progesterone metabolites such as progesterone is not obvious, which can reduce the side effects of progesterone administration. Therefore, the composition including progesterone and sucrose fatty acid ester is very suitable for preparing various progesterone drugs for gastrointestinal administration, especially oral preparations.

In the present invention, the progesterone bioavailability promoter can be selected from one or more combinations of sucrose fatty acid esters, wherein the fatty acid is preferably C12-C18 fatty acid.

As used herein, the term "sucrose fatty acid ester" is prepared by esterification of sucrose and fatty acids, including monoesters, diesters, triesters and polyesters, i.e., one molecule of sucrose is respectively composed of one, two, three or more fatty acid molecules. Preferably, the sucrose fatty acid ester is selected from: sucrose mono-fatty acid ester, sucrose di-fatty acid ester, sucrose tri-fatty acid ester, or a combination thereof.

Preferably, the content of sucrose monofatty acid ester in the sucrose fatty acid ester is ≥wt20%, more preferably ≥wt40%, ≥wt50% or ≥wt70%, such as 55wt%, 60wt%, 70wt%, 75wt%, 80wt%, 85wt%, 90wt%, 95wt% or 98wt%.

As in the present invention, the term "C12-C18 fatty acid" refers to a saturated or unsaturated straight or branched fatty acid comprising 12-18 carbon atoms, such as 12, 13, 14, 15, 16, 17 or 18 carbon atoms. Typical C12-C18 fatty acids include (but are not limited to): stearic acid, palmitic acid, lauric acid, oleic acid, or a combination thereof. Preferably, the stearic acid content in the C12-C18 fatty acid is ≥wt20%, more preferably ≥wt40%, ≥wt50% or ≥wt70%, such as 55wt%, 60wt%, 70wt%, 75wt%, 80wt%, 85wt%, 90wt%, 95wt% or 98wt%.

Preferably, the hydrophile-lipophile balance (HLB) of the sucrose fatty acid ester is 3-16, preferably, the HLB is 7-16, more preferably 10-16, such as 11, 12, 13, 14 or 15.

combination

The present invention provides a composition comprising: (a) progesterone; (b) a progesterone bioavailability promoter,

Wherein, the progesterone bioavailability promoter is selected from the following group: the progesterone bioavailability promoter is selected from one or more of sucrose fatty acid esters, wherein the fatty acid is a C12-C18 fatty acid. Preferably, in the composition, the mass ratio of progesterone to the progesterone bioavailability promoter is 1:(0.1-250).

Oral preparations/pharmaceutical compositions

Furthermore, the present invention provides an oral preparation, comprising the above composition and a pharmaceutically acceptable oral preparation carrier.

In the present invention, there is no particular requirement for the specific dosage form of the oral preparation, and it can be any oral dosage form commonly used in the art, such as (but not limited to) solid preparations and liquid preparations.

Typically, solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrators, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Preferably, the active ingredient of the present invention is included in cyclodextrin and then mixed with a bioavailability enhancer or other carrier. The cyclodextrin can be selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin sodium, methylated-β-cyclodextrin, preferably hydroxypropyl-β-cyclodextrin.

As required, the solid preparation of the present invention, such as granules or plain tablets, can be further coated, and the coating material is typically selected from but not limited to water-insoluble polymers or enteric polymers. Water-insoluble polymers, such as ethyl cellulose, vinyl acetate polymers, aminoalkyl methacrylate copolymers, ethyl acrylate-methyl methacrylate copolymer dispersions; enteric polymers, such as enteric cellulose esters such as cellulose acetate propionate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxymethyl ethylcellulose phthalate, carboxymethyl ethylcellulose, cellulose acetate, phthalate, methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, and mixtures thereof.

In some embodiments, the coating is an enteric coating selected from cellulose acetate propionate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethylethylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, and mixtures thereof.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances. Compounds, etc.

In a non-limiting embodiment, the pharmaceutical composition of the present invention further comprises an oil solvent or an emulsifier, so as to prepare the pharmaceutical composition of the present invention into an emulsion.

The oil solvent is selected from vegetable oils, such as cocoa butter, soybean oil, olive oil, cottonseed oil, sunflower oil, peanut oil, corn oil, castor oil, palm oil, rapeseed oil, peppermint oil, geraniol, pineneol, etc.; fatty acids, such as oleic acid, linolenic acid, linoleic acid, stearic acid, lauric acid, palmitic acid, caprylic acid, caprylic acid, etc.; fatty acid esters, such as oleic acid glyceride, linoleic acid glyceride, caprylic acid glyceride, capric acid glyceride, caprylic acid capric acid glyceride, ethyl oleate, decyl oleate, etc.

The emulsifier is selected from polyoxyethylene sorbitan fatty acid condensates, such as Tween 20, Tween 60, Tween 80, etc.; sorbitan fatty acid esters, such as Span 20, Span 60, Span 80, etc.; glycerol fatty acid esters, such as oleic acid glyceride, linoleic acid glyceride, caprylic acid glyceride, capric acid glyceride, caprylic acid capric acid glyceride, etc.; polyoxyethylene fatty oil condensates, such as polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, etc.; phospholipids, such as soybean lecithin, lecithin, etc., alkyl sulfates, such as sodium lauryl sulfate; vitamin E succinate polyethylene glycol ester.

The pharmaceutical composition of the present invention comprises the active ingredient of the present invention or its pharmacologically acceptable salt within the range of safe and effective amount and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the active ingredient is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the active ingredient of the present invention/dose, and more preferably, contains 10-500 mg of the active ingredient of the present invention/dose. Preferably, the "one dose" is a capsule or tablet.

use

The present invention also provides the oral preparation or composition as described above or use thereof in preparing a drug for treating and/or preventing diseases related to progesterone deficiency.

Those skilled in the art will appreciate that the oral preparation or composition of the present invention can be used for all known diseases or symptoms that can be prevented or treated by progesterone.

Typically, the progesterone deficiency-related disease is selected from the group consisting of menstrual disorders, amenorrhea, dysmenorrhea, premenstrual syndrome, menopausal syndrome, or a combination thereof.

Preparation

The present invention has no special requirements on the preparation method of the oral preparation, and the preparation method commonly used in the art can be used to prepare the desired dosage form, or it can be prepared by referring to the method of the present invention.

Preferably, the method comprises the step of mixing the active ingredient with the bioavailability enhancer. Furthermore, before the active ingredient is mixed with the bioavailability enhancer, the method may comprise the step of encapsulating the active ingredient in cyclodextrin to obtain a cyclodextrin inclusion complex of the active ingredient.

Furthermore, the preparation method also includes the steps of mixing the cyclodextrin inclusion compound with the bioavailability enhancer and the pharmaceutically acceptable excipient, and then preparing the corresponding dosage form, such as granulation, tablet compression or capsule filling, direct tablet compression or direct capsule filling.

Typically, the preparation method of the emulsion may include: dissolving the active ingredient in an oil solvent and/or an emulsifier, and then mixing with the bioavailability enhancer.

The main advantages of the present invention include:

Experiments have shown that the progesterone preparation of the present invention can significantly improve the bioavailability of oral progesterone, and the bioavailability in beagle dogs can be up to 10 times that of the original product on the market (progesterone soft capsule trade name: Anqitan). It was unexpectedly found that the progesterone preparation of the present invention can significantly reduce the exposure of the progesterone metabolite-allopregnanolone while having the same exposure amount as the commercially available progesterone soft capsule, thereby reducing the side effects of dizziness, drowsiness, etc. related to the metabolites, and reducing the burden on the liver.

The oral progesterone preparation of the present invention has good absorption, low side effects, and low liver burden, and provides patients with a better oral progesterone product.

The present invention will be further described below in conjunction with specific implementation. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

Embodiment 1: Progesterone self-emulsifying soft capsule

(1) Prescription of progesterone self-emulsifying soft capsules

(2) Preparation method

According to the formula ratio, 50 g of benzyl alcohol, 150 g of ethyl oleate, 5 g of disodium ethylenediaminetetraacetate, 3.5 g of sodium sulfite, and 50 g of progesterone were weighed and placed in a conical flask, placed in an 80°C water bath and stirred to mix evenly, 600 g of melted vitamin E polyethylene glycol succinate was added, and stirred in a water bath for 1 hour to obtain 858.5 g of a progesterone self-emulsifying composition.

(3) Release in simulated intestinal fluid

Progesterone self-emulsification was carried out according to the "Appendix X Dissolution Test Method 2 of Part II of the Chinese Pharmacopoeia 2015 Edition" Particle dissolution test: 900 mL of simulated artificial intestinal fluid was measured and injected into the dissolution cup, and the simulated artificial intestinal fluid was kept at 37 ± 0.5 ° C by water bath heating. Then, the progesterone self-emulsifying soft capsule (20 mg) and the reference preparation (100 mg of Anqitan) prepared in step 2 were taken, and one capsule was put into each dissolution cup, and the rotating device was immediately started and the timing was started. The speed was 50 rpm, and samples were taken from the dissolution cup at 0.5, 1, 2, 4, 6, 8, and 12 hours, respectively. The absorbed dissolution solution was filtered through a 0.45um microporous filter membrane, and the filtrate was taken and determined by high performance liquid chromatography. The chromatographic conditions were: octadecylsilane bonded silica gel column, ethanol: water (55:45) as the mobile phase, the detection wavelength was 254 nm, and the release at each time point was calculated by the external standard method, and then the cumulative dissolution percentage at each time point was calculated according to the following formula. The results are shown in Table 1:

Wherein: _Rtotal % is the total cumulative release rate at each time point; _Rn % is the release rate at each time point; _R1 % is the release rate at the first sampling time point; _Vn is the volume of dissolution medium at each time point (mL); _V1 is the volume of dissolution medium at the first sampling time point (mL); n is the number of samplings; PV is the sampling volume (mL).

Table 1: Dissolution percentage of progesterone self-emulsifying soft capsule (20 mg) and reference preparation (Anqitan 100 mg) in artificial intestinal fluid

The dissolution test results show that the progesterone self-emulsifying soft capsules of Example 1 can significantly improve the in vitro release of progesterone.

(4) Pharmacokinetic test on the progesterone self-emulsifying soft capsule of Example 1 and the commercially available progesterone soft capsule (Anqitan).

Test method: 8 healthy male beagles were divided into 2 groups, 4 in each group, and 2 cycles of tests were carried out respectively, with a wash-out period of 5 days. The test samples were commercially available progesterone soft capsules (Anqitan), each containing 100 mg of progesterone; and the progesterone self-emulsifying soft capsules provided in Example 1, each containing 20 mg of progesterone. Administration route and dosage: Oral, one capsule of the reference preparation at a time, one capsule of the preparation of Example 1 at a time. Sampling design: Before administration (0h) and 0.33h, 0.67h, 1.0h, 1.5h, 2.0h, 2.5h, Blood was collected at 3.0h, 3.5h, 4.0h, 4.5h, 5.0h, 5.5h, 6.0h, 6.5h, 7.0h, 7.5h, 8.0h, 8.5h, 9.0h, 10.0h, 12h, 14h, and 24h, for a total of 23 blood collection points.

Table 2: Pharmacokinetic results of the self-emulsifying soft capsule of Example 1 and commercially available progesterone soft capsule (Anqitan)

The experimental results show that the absorption of the self-emulsifying soft capsule of Example 1 is similar to that of the reference preparation in terms of dose conversion, and no significant improvement is observed. At the same time, the variation of Cmax and AUC _(0-t) of the self-emulsifying soft capsule of Example 1 is greater than that of the reference preparation, and no improvement is observed. This indicates that although the self-emulsifying preparation of Example 1 can significantly increase the release of progesterone in vitro, it cannot increase or improve its absorption in vivo.

Embodiment 2: Progesterone self-emulsifying soft capsule

(1) Prescription of progesterone self-emulsifying soft capsules

(2) Preparation method:

According to the formula, weigh 20g of progesterone, 100g of olive oil, 160g of oleic acid, and 5g of benzyl alcohol and place them in a beaker, stir and mix them evenly in a 60°C water bath. Then add 60g of Tween-80 and 60g of polyoxyethylene 40 hydrogenated castor oil, stir evenly, and the progesterone self-emulsifying composition is obtained, and the drug content is 4.9%. The above-mentioned progesterone self-emulsifying composition is filled into soft capsules, and each soft capsule contains about 506mg of the self-emulsifying composition.

(4) Release in simulated intestinal fluid

According to the "Dissolution Determination Method 2 of Appendix X of Part II of the 2015 Edition of the Chinese Pharmacopoeia", the dissolution test of progesterone self-emulsifying granules was carried out: 900 mL of artificial intestinal fluid was measured and injected into the dissolution cup, and the artificial intestinal fluid was heated in a water bath to maintain at 37 ± 0.5 ° C. Then, the progesterone self-emulsifying soft capsule (25 mg) prepared in step 2 was taken, and one capsule was placed in each dissolution cup, and the rotating device was immediately started and the timing was started, with a speed of 50 rpm. Samples were taken from the dissolution cup at 0.5, 1, and 2 hours respectively, and the absorbed dissolution solution was filtered through a 0.45um microporous filter membrane, and the filtrate was then taken for determination by high performance liquid chromatography. The chromatographic conditions were: octadecylsilane bonded silica gel column, ethanol: water (55:45) as the mobile phase, and the detection wavelength was 254nm. The release at each time point was calculated by the external standard method, and then the cumulative dissolution percentage at each time point was calculated according to the following formula. The results are shown in Table 3:

Table 3: Dissolution percentage of progesterone self-emulsifying soft capsule (25 mg) in artificial intestinal fluid of Example 2

The dissolution test results show that the progesterone self-emulsifying soft capsules of Example 2 can significantly improve the in vitro release of progesterone.

(4) Pharmacokinetic test on the progesterone self-emulsifying soft capsule of Example 2 and the commercially available progesterone soft capsule (Anqitan).

Test method: 8 healthy beagles were divided into 2 groups, 4 in each group, and 2 cycles of tests were performed respectively, with a washout period of 5 days. The test samples were commercially available progesterone soft capsules (Angita), each containing 100 mg of progesterone; and the progesterone self-emulsifying soft capsules provided in Example 2, each containing 25 mg of progesterone. Administration route and dosage: Oral, one capsule of the reference preparation at a time, and two capsules of the preparation of Example 2 at a time. Sampling design: Blood was collected before administration (0h) and 0.33h, 0.67h, 1.0h, 1.5h, 2.0h, 2.5h, 3.0h, 3.5h, 4.0h, 4.5h, 5.0h, 5.5h, 6.0h, 6.5h, 7.0h, 7.5h, 8.0h, 8.5h, 9.0h, 10.0h, 12h, 14h, and 24h after administration to detect the progesterone concentration in plasma, with a total of 23 blood collection points.

Table 4: Pharmacokinetic results of the self-emulsifying soft capsule of Example 2 and commercially available progesterone soft capsule (Anqitan)

The experimental results show that the self-emulsifying soft capsule of Example 2 does not improve absorption, indicating that although the self-emulsifying preparation can significantly improve the release of progesterone in vitro, it cannot improve its absorption in vivo.

For the promoters that promote the absorption of progesterone in vivo, the inventors selected vitamin E succinate polyethylene glycol ester, Tween 80, Span 80, sodium lauryl sulfate, soybean lecithin, lecithin, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, sucrose stearate and sucrose laurate and conducted in vitro release studies; then, based on the in vitro release results, vitamin E succinate polyethylene glycol ester (Example 1), polyoxyethylene hydrogenated castor oil and Tween 80 (Example 2), sucrose stearate and sucrose laurate were selected for animal (dog) pharmacokinetic studies. The experimental results show that vitamin E succinate polyethylene glycol ester, polyoxyethylene hydrogenated castor oil and Tween 80 cannot promote the improvement of progesterone bioavailability.

Embodiment 3: Progesterone self-emulsifying soft capsule

(1) Prescription of progesterone self-emulsifying soft capsules:

*Sucrose stearate S-15: HLB: 15; fatty acid composition: total amount of palmitic acid and stearic acid ≥ 90.0%; monoester content ≥ 65%.

(2) Preparation method:

According to the formula, 43g of geraniol, 6g of pinene alcohol, 10g of polyethylene glycol, 255g of monolinoleyl glyceride, and 120g of soybean oil were weighed and placed in a beaker, and stirred and mixed evenly in a 60°C water bath. 25g of progesterone was weighed and added to the above solution, and then 7g of Tween-20 and 25g of sucrose stearate were added and stirred evenly to obtain a progesterone self-emulsifying composition with a drug content of 5.1%. The above progesterone self-emulsifying composition was filled into soft capsules, and each soft capsule contained about 491mg of the self-emulsifying composition.

Embodiment 4: Progesterone self-emulsifying soft capsule

(2) Prescription of progesterone self-emulsifying soft capsules:

*Sucrose laurate: HLB: 15-16; fatty acid composition: lauric acid; monoester content: 96.5%.

(2) Preparation method:

According to the formula, 43g of geraniol, 6g of pinene alcohol, 10g of polyethylene glycol, 255g of monolinoleyl glyceride, and 120g of soybean oil were weighed and placed in a beaker. Sucrose laurate was stirred in a water bath at 60°C until evenly stirred to obtain a progesterone self-emulsifying composition with a drug content of 5.1%. The above progesterone self-emulsifying composition was filled into soft capsules, and each soft capsule contained about 491mg of the self-emulsifying composition.

Example 5

Release in simulated intestinal fluid

According to the second method of dissolution determination method of Appendix X of Part II of the 2015 edition of the Chinese Pharmacopoeia, the dissolution test of progesterone self-emulsifying soft capsules was carried out: 900 mL of simulated artificial intestinal fluid was measured and injected into the dissolution cup, and the simulated artificial intestinal fluid was kept at 37±0.5°C by water bath heating. Then the progesterone self-emulsifying soft capsules (25 mg) of Example 3 and Example 4 were taken, and one capsule was put into each dissolution cup respectively, and the rotating device was immediately started and the timing was started, the speed was 50 rpm, and samples were taken from the dissolution cup at 0.5, 1, 1.5, and 2 hours respectively, and the absorbed dissolution solution was filtered through a 0.45um microporous filter membrane, and then the filtrate was taken and determined by high performance liquid chromatography, and the chromatographic conditions were: octadecylsilane bonded silica gel column, ethanol: water (55:45) as the mobile phase, the detection wavelength was 254nm, and the release at each time point was calculated by the external standard method, and then the cumulative dissolution percentage at each time point was calculated according to the following formula, and the results are shown in Table 5:

Table 5: Dissolution percentage of progesterone self-emulsifying soft capsules (25 mg) of Example 3 and Example 4 in simulated artificial intestinal fluid

The dissolution test results show that the progesterone self-emulsifying soft capsules of Example 3 and Example 4 can improve the progesterone In vitro release of ketone.

Example 6

The pharmacokinetic test of the progesterone self-emulsifying soft capsules of Example 3 and Example 4 and the commercially available progesterone soft capsules (Anqitan) was conducted.

Test method: 12 healthy beagle dogs were divided into 3 groups, 4 in each group, and 3 cycles of tests were carried out respectively, with a washout period of 5 days. The test samples were commercially available progesterone soft capsules (Angita), each containing 100 mg of progesterone; and the progesterone self-emulsifying soft capsules provided in Example 3 or 4, each containing 25 mg of progesterone. Administration route and dosage: Oral, 1 capsule of the reference preparation at a time, 4 capsules of the example preparation at a time. Sampling design: Blood was collected before administration (0h) and 0.33h, 0.67h, 1.0h, 1.25h, 1.5h, 1.75h, 2.0h, 2.25h, 2.5h, 2.75h, 3.0h, 3.33h, 3.67h, 4.0h, 4.25h, 4.5h, 4.75h, 5.0h, 5.25h, 5.5h, 6.0h, 6.5h, 7.0h, 8.0h, 9.0h, 10.0h, 12h, 14h, and 24h after administration to detect the progesterone concentration in plasma, with a total of 30 blood collection points.

Table 6: Pharmacokinetic results of self-emulsifying soft capsules of Example 3 and Example 4 and commercially available progesterone soft capsules (Anqitan)

The experimental results show that the self-emulsifying soft capsules of Example 3 containing sucrose stearate and Example 4 containing sucrose laurate can significantly improve the absorption of progesterone in the body compared with the reference preparation, wherein the absorption of Example 3 is about 4.78 times that of the reference preparation, and the absorption of Example 4 is about 2.29 times that of the reference preparation.

Comparative Example 1: Progesterone self-emulsifying soft capsule

(1) Prescription of progesterone self-emulsifying soft capsules:

(2) Preparation method:

According to the formula, 43g of geraniol, 6g of pinene alcohol, 10g of polyethylene glycol, 255g of monolinoleyl glyceride, and 120g of soybean oil were weighed and placed in a beaker, and stirred and mixed evenly in a 60°C water bath. 25g of progesterone was weighed and added to the above solution, and then 7g of Tween-20 was added and stirred evenly to obtain a progesterone self-emulsifying composition with a drug content of 5.4%. The above progesterone self-emulsifying composition was filled into soft capsules, and each soft capsule contained about 466mg of the self-emulsifying composition.

(3) Release in simulated intestinal fluid

According to the second method of dissolution determination method of Appendix X of Part II of the 2015 edition of the Chinese Pharmacopoeia, the dissolution test of progesterone self-emulsifying soft capsules was carried out: 900 mL of simulated artificial intestinal fluid was measured and injected into the dissolution cup, and the simulated artificial intestinal fluid was kept at 37±0.5°C by water bath heating. Then the progesterone self-emulsifying soft capsules (25 mg) of Comparative Example 1 were taken, and one capsule was put into each dissolution cup, and the rotating device was immediately started and the timing was started, with a speed of 50 rpm. Samples were taken from the dissolution cup at 0.5, 1, 2, 4, and 6 hours, respectively, and the absorbed dissolution solution was filtered through a 0.45um microporous filter membrane, and then the filtrate was taken for determination by high performance liquid chromatography. The chromatographic conditions were: octadecylsilane bonded silica gel column, ethanol: water (55:45) as the mobile phase, and the detection wavelength was 254 nm. The release at each time point was calculated by the external standard method, and then the cumulative dissolution percentage at each time point was calculated according to the following formula. The results are shown in Table C1:

Wherein: Rtotal% is the total cumulative release at each time point; Rn% is the release at each time point; R1% is the release at the first sampling time point; Vn is the volume of dissolution medium at each time point (mL); V1 is the volume of dissolution medium at the first sampling time point (mL); n is the number of samplings; PV is the sampling volume (mL).

Table C1: Dissolution percentage of progesterone self-emulsifying soft capsule (25 mg) of Comparative Example 1 in simulated artificial intestinal fluid

The dissolution test results show that the progesterone self-emulsifying soft capsules of Comparative Example 1 can improve the in vitro release of progesterone.

(4) Comparison of the progesterone self-emulsifying soft capsules of Example 1 and the commercially available progesterone soft capsules (Anqitan) Metabolic kinetics testing.

Test method: 2 healthy beagles were divided into 2 groups, 1 in each group, and 2 cycles of tests were performed, with a washout period of 5 days. The test samples were commercially available progesterone soft capsules (Angita), each containing 100 mg of progesterone; and the progesterone self-emulsifying soft capsules provided in comparative example 1, each containing 25 mg of progesterone. Administration route and dosage: Oral, 1 capsule of the reference preparation at a time, 4 capsules of the comparative example 1 preparation at a time. Sampling design: Blood was collected before administration (0h) and 0.33h, 0.67h, 1.0h, 1.25h, 1.5h, 1.75h, 2.0h, 2.25h, 2.5h, 2.75h, 3.0h, 3.33h, 3.67h, 4.0h, 4.25h, 4.5h, 4.75h, 5.0h, 5.25h, 5.5h, 6.0h, 6.5h, 7.0h, 8.0h, 9.0h, 10.0h, 12h, 14h, and 24h after administration to detect the progesterone concentration in plasma, with a total of 30 blood collection points.

Table C2: Pharmacokinetic results of the self-emulsifying soft capsule of Comparative Example 1 and the commercially available progesterone soft capsule (Anqitan)

The experimental results show that the bioavailability of the self-emulsifying soft capsule of Comparative Example 1 is lower than the bioavailability of the commercially available progesterone soft capsule (Anqitan).

Example 7: Progesterone Tablets

(1) Prescription of progesterone tablets:

(2) Preparation method:

Preparation of progesterone granules

Take 400g of Hydroxypropyl Beta-Cyclodextrin according to the prescription, add it to 800g of water, and stir until it is completely dissolved. Add progesterone raw material, stir until it is completely dissolved. Add 7g of Povidone and 7g of Tween-20, stir until it is completely dissolved. Dissolve to obtain a progesterone-hydroxypropyl beta-cyclodextrin aqueous solution. Take 53g of lactose and add it to the fluidized bed. Use the above-mentioned progesterone-hydroxypropyl beta-cyclodextrin aqueous solution 1239g to granulate by top spraying. Set the fluidized bed air volume to 20-50HZ, the spray speed to 30-100g/min, the atomization pressure to 1.0bar, and adjust the inlet air temperature to maintain the material temperature at 40-45°C to obtain progesterone particles. The obtained particles are granulated with a pulverizer, the screen used is a 1.8mm screen, and the rotation speed is 300rpm.

Preparation of progesterone tablets

Weigh 492 g of the above progesterone granules and 30 g of sucrose stearate, add them into a three-dimensional motion mixer and mix for 20 minutes. Use 7.5*16 mm oval punching tablets.

(6) Release in simulated intestinal fluid

The dissolution test of progesterone tablets was carried out according to the second method of dissolution determination method of Appendix X of Part II of the 2015 edition of the Chinese Pharmacopoeia: 900 mL of simulated artificial intestinal fluid was measured and injected into the dissolution cup, and the simulated artificial intestinal fluid was kept at 37±0.5°C by water bath heating. Then the progesterone tablets (25 mg) of Example 7 were taken, and one tablet was put into each dissolution cup, and the rotating device was immediately started and the timing was started, with a speed of 50 rpm. Samples were taken from the dissolution cup at 0.5, 1, 1.5, and 2 hours, respectively, and the absorbed dissolution solution was filtered through a 0.45um microporous filter membrane, and then the filtrate was taken for high performance liquid chromatography determination. The chromatographic conditions were: octadecylsilane bonded silica gel column, ethanol: water (55:45) as the mobile phase, and the detection wavelength was 254 nm. The release at each time point was calculated by the external standard method, and then the cumulative dissolution percentage at each time point was calculated according to the following formula. The results are shown in Table 7:

Table 7: Dissolution percentage of progesterone tablets (25 mg) of Example 7 in simulated artificial intestinal fluid

The dissolution test results show that the progesterone tablet of Example 7 can significantly improve the in vitro release of progesterone.

(5) Pharmacokinetic test on the progesterone tablet of Example 7 and commercially available progesterone soft capsule (Anqitan).

Test method: 8 healthy beagle dogs were divided into 2 groups, 4 in each group, and 2 cycles of tests were performed, with a washout period of 7 days. The test samples were commercially available progesterone soft capsules (Anqitan), each containing 100 mg of progesterone; and the progesterone tablets provided in Example 7, each containing 25 mg of progesterone. Administration route and dosage: Oral, 2 capsules of the reference preparation at a time, 2 tablets of the Example 7 tablet at a time. Sampling design: respectively at the time of giving Blood was collected before medication (0h) and 0.25h, 0.5h, 0.75h, 1.0h, 1.5h, 2.0h, 2.5h, 3.0h, 3.5h, 4.0h, 4.5h, 5.0h, 6.0h, 8.0h, 12h, and 24h after administration to detect the concentration of progesterone in plasma and the main metabolite causing side effects-allopregnanolone, a total of 17 blood sampling points. The comparison results between the reference preparation and the preparation of Example 7 are shown in the following table.

Table 8: Pharmacokinetic results of the progesterone tablets of Example 7 and commercially available progesterone soft capsules (Anqitan)

The experimental results show that the progesterone tablet of Example 7 can significantly improve the bioavailability of progesterone in vivo. The bioavailability of the progesterone tablet converted by the dosage is about 10 times that of the reference preparation, and the variation of _Cmax and AUC _(0-t) of the progesterone tablet of the present invention is significantly less than that of the reference preparation, which indicates that the progesterone tablet significantly reduces the difference between individuals. And surprisingly, while the progesterone tablet of the present invention significantly improves the bioavailability of progesterone, the bioavailability of its metabolite allopregnanolone that causes side effects is similar to that of the reference preparation, which indicates that the progesterone tablet of the present invention selectively improves the bioavailability of progesterone without increasing side effects.

Example 8: Progesterone Tablets

(1) Prescription of progesterone tablets:

(2) Preparation method:

Preparation of progesterone granules

Take 363g of hydroxypropyl beta-cyclodextrin according to the prescription, add it to 800g of water, and stir until completely dissolved. Add progesterone raw material and stir until completely dissolved. Add 7g of povidone and 7g of Tween-20, stir until completely dissolved, and obtain a progesterone-hydroxypropyl beta-cyclodextrin aqueous solution. Take 54g of lactose and add it to the fluidized bed, and use the above-mentioned progesterone-hydroxypropyl beta-cyclodextrin aqueous solution 1202g to top spray granulate, set the fluidized bed air volume to 20-50HZ, the spray speed to 30-100g/min, the atomization pressure to 1.0bar, adjust the inlet temperature to maintain the material temperature at 40-45°C, and obtain progesterone particles. The obtained particles are granulated with a crushing and granulating machine, the screen used is a 1.8mm screen, and the rotation speed is 300rpm.

Preparation of progesterone tablets

Weigh 456 g of the above progesterone granules and 50 g of sucrose stearate, add them into a three-dimensional motion mixer and mix for 20 minutes. Use 7.5*16 mm oval punching tablets.

(7) Release in simulated intestinal fluid

The dissolution test of progesterone tablets was carried out according to the second method of dissolution determination method of Appendix X of Part II of the 2015 edition of the Chinese Pharmacopoeia: 900 mL of simulated artificial intestinal fluid was measured and injected into the dissolution cup, and the simulated artificial intestinal fluid was kept at 37±0.5°C by water bath heating. Then the progesterone tablets (25 mg) of Example 8 were taken, and one tablet was put into each dissolution cup, and the rotating device was immediately started and the timing was started, with a speed of 50 rpm. Samples were taken from the dissolution cup at 0.5, 1, 1.5, and 2 hours, respectively, and the absorbed dissolution solution was filtered through a 0.45um microporous filter membrane, and then the filtrate was taken for high performance liquid chromatography determination. The chromatographic conditions were: octadecylsilane bonded silica gel column, ethanol: water (55:45) as the mobile phase, and the detection wavelength was 254 nm. The release at each time point was calculated by the external standard method, and then the cumulative dissolution percentage at each time point was calculated according to the following formula. The results are shown in Table 9:

Table 9: Dissolution percentage of progesterone tablets (25 mg) of Example 8 in simulated artificial intestinal fluid

The dissolution test results show that the progesterone tablet of Example 8 can significantly improve the in vitro release of progesterone.

(5) Pharmacokinetic test on the progesterone tablet of Example 8 and commercially available progesterone soft capsule (Anqitan).

Test method: 2 healthy beagles were divided into 2 groups, 1 in each group, and 2 cycles of tests were performed respectively, with a washout period of 5 days. The test samples were commercially available progesterone soft capsules (Anqitan), each containing 100 mg of progesterone; and the progesterone tablets provided in Example 8, each containing 25 mg of progesterone. Administration route and dosage: oral, 1 tablet of the reference preparation at a time, 1 tablet of the Example 8 tablet at a time. Sampling design: Blood was collected before administration (0h) and 0.25h, 0.5h, 0.75h, 1.0h, 1.5h, 2.0h, 2.5h, 3.0h, 3.5h, 4.0h, 4.5h, 5.0h, 6.0h, 8.0h, 12h, and 24h after administration to detect the progesterone concentration in plasma, with a total of 17 blood collection points. The comparison results of the reference preparation and the preparation of Example 8 are shown in the following table.

Table 10: Pharmacokinetic results of the progesterone tablets of Example 8 and commercially available progesterone soft capsules (Anqitan)

The experimental results show that the progesterone of Example 8 can significantly improve the absorption of progesterone in the body. The bioavailability of progesterone in the tablet of Example 8 is about 3 times that of the reference preparation according to the administered dosage.

Example 9: Progesterone Tablets

(1) Progesterone tablet prescription:

(2) Preparation method:

Preparation of progesterone granules

Take 400g of hydroxypropyl beta-cyclodextrin according to the prescription, add it to 800g of water, and stir until it is completely dissolved. Add progesterone raw material, stir until it is completely dissolved. Add 7g of povidone and 7g of Tween-20, stir Until completely dissolved, a progesterone-hydroxypropyl beta-cyclodextrin aqueous solution was obtained. 53g of lactose was added to the fluidized bed, and 1239g of the above-mentioned progesterone-hydroxypropyl beta-cyclodextrin aqueous solution was used for top spray granulation. The fluidized bed air volume was set to 20-50HZ, the spray speed was 30-100g/min, the atomization pressure was 1.0bar, and the inlet air temperature was adjusted to maintain the material temperature at 40-45°C to obtain progesterone particles. The obtained particles were granulated with a pulverizer, the screen used was a 1.8mm screen, and the rotation speed was 300rpm.

Preparation of progesterone tablets

Weigh 492 g of the above progesterone granules and 12.5 g of sucrose stearate, add them into a three-dimensional motion mixer and mix for 20 minutes. Use 7.5*16 mm oval punching tablets.

(5) Release in simulated intestinal fluid

The dissolution test of progesterone tablets was carried out according to the second method of dissolution determination method of Appendix X of Part II of the 2015 edition of the Chinese Pharmacopoeia: 900 mL of simulated artificial intestinal fluid was measured and injected into the dissolution cup, and the simulated artificial intestinal fluid was kept at 37±0.5°C by water bath heating. Then the progesterone tablets (25 mg) of Example 9 were taken, and one tablet was put into each dissolution cup, and the rotating device was immediately started and the timing was started, with a speed of 50 rpm. Samples were taken from the dissolution cup at 0.5, 1, and 2 hours, respectively, and the absorbed dissolution solution was filtered through a 0.45um microporous filter membrane, and then the filtrate was taken for high performance liquid chromatography determination. The chromatographic conditions were: octadecylsilane bonded silica gel column, ethanol: water (55:45) as the mobile phase, and the detection wavelength was 254 nm. The release at each time point was calculated by the external standard method, and then the cumulative dissolution percentage at each time point was calculated according to the following formula. The results are shown in Table 5:

Table 11: Dissolution percentage of the progesterone tablet (25 mg) of Example 9 in simulated artificial intestinal fluid

The dissolution test results show that the progesterone tablet of Example 9 can significantly improve the in vitro release of progesterone.

discuss

The present invention aims to provide a progesterone composition to solve the problems of low bioavailability, large inter-patient variability, and large liver burden in the oral progesterone dosage forms currently available on the market. The composition contains progesterone and sucrose fatty acid ester. Progesterone is a BCS2 drug, that is, a low-solubility, high-permeability drug with extremely low oral bioavailability. The marketed drugs have improved the oral bioavailability of progesterone by using oil solvents to improve the solubility of progesterone, but the bioavailability of the product is still extremely low (<5%). During the research process, we found that a substance with a gastrointestinal absorption-sucrose fatty acid ester can significantly improve the bioavailability of oral progesterone. In addition, in some prescriptions, it can also reduce the differences in progesterone absorption between individual patients and reduce the exposure of metabolites that cause side effects. Therefore, the oral progesterone composition of the present invention has the advantages of improving bioavailability, reducing medication dosage, reducing individual variation, and reducing the exposure of metabolites, and can provide patients with a convenient, more stable and safer oral progesterone dosage form. There is no teaching in previous literature that sucrose fatty acid esters can improve the absorption of progesterone or other BCS2 drugs.

All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

An oral preparation comprising

(a) progesterone;

(b) a progesterone bioavailability enhancer; and

(c) and a pharmaceutically acceptable carrier for oral preparation;

Wherein, the progesterone bioavailability promoter is selected from one or more of sucrose fatty acid esters, wherein the fatty acid is C12-C18 fatty acid; and

In the composition, the mass ratio of progesterone to the progesterone bioavailability promoter is 1:(0.1-250).
The oral preparation according to claim 1, characterized in that the dosage form of the oral preparation is selected from the following group: solid preparations and liquid preparations, preferably, selected from the following group: tablets, hard capsules, soft capsules, granules, pills, powders, suspensions, emulsions, oral liquids, syrups or elixirs.
The oral preparation according to claim 1, characterized in that the progesterone bioavailability enhancer is selected from the group consisting of sucrose stearate, sucrose laurate, sucrose palmitate, sucrose oleate, or a combination thereof.
The oral preparation according to claim 1, characterized in that the pharmaceutically acceptable carrier is selected from the group consisting of a disintegrant, a filler, a binder, a humectant, a inclusion agent, a lubricant, a sweetener, a flavoring agent, a colorant, a diluent, or a combination thereof.
The oral preparation according to claim 1, characterized in that the oral preparation contains cyclodextrin, and the progesterone is included in the cyclodextrin, preferably, the cyclodextrin is selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin sodium, methylated-β-cyclodextrin, or a combination thereof, preferably hydroxypropyl-β-cyclodextrin.
The oral preparation according to claim 1, characterized in that the oral preparation is a soft capsule and comprises the following components:
The oral preparation according to claim 1, characterized in that the oral preparation is a tablet and comprises the following components:
The oral preparation according to claim 1, characterized in that the oral preparation is a tablet and comprises the following components:
A composition comprising:

(a) progesterone; and

(b) a progesterone bioavailability enhancer;

Wherein, the progesterone bioavailability promoter is selected from the following group: one or more of sucrose fatty acid esters, wherein the fatty acid is C12-C18 fatty acid; and

In the composition, the mass ratio of progesterone to the progesterone bioavailability promoter is 1:(0.1-250).
Use of the oral preparation according to claim 1 in the preparation of a medicament for treating and/or preventing a progesterone deficiency-related disease, preferably, the progesterone deficiency-related disease is selected from the group consisting of menstrual disorders, amenorrhea, dysmenorrhea, premenstrual syndrome, menopausal syndrome, or a combination thereof.