CN111529488A - Progesterone self-emulsifying composition and application thereof - Google Patents

Abstract

The invention discloses a progesterone self-emulsifying composition and application thereof, wherein the composition is prepared from the following raw materials in parts by mass: 1 part of progesterone, 2-15 parts of solvent, 6-75 parts of vitamin E polyethylene glycol succinate and 0.5-2 parts of stabilizer; the solvent is oleic acid or ethyl oleate; the stabilizer is one or a mixture of more of benzyl alcohol, sodium sulfite or disodium ethylene diamine tetraacetate in any proportion. The progesterone preparation composition disclosed by the invention is good in chemical stability, accelerated experiments are carried out according to the requirements of accelerated experiments in the four stability experiments of the national pharmacopoeia 2015 edition, the content of single impurities does not exceed 0.5%, the total impurities does not exceed 2.0%, the content is 93% -107%, the progesterone preparation composition meets the requirements of the content and impurity acceptance standards under the item of the progesterone injection of the national pharmacopoeia 2015 edition, the product stability is good, and the progesterone preparation composition is suitable for commercial production.

Description

Progesterone self-emulsifying composition and application thereof

(I) technical field

The invention relates to a progesterone self-emulsifying composition and application thereof.

(II) background of the invention

Progesterone, also known as progesterone, is a biologically active primary progestin secreted by the ovaries. Progesterone is widely used in the treatment of menstrual disorders such as amenorrhea, dysfunctional uterine bleeding, luteal function deficiency, threatened and recurrent abortion, premenstrual tension syndrome, climacteric syndrome, etc. However, progesterone is a steroid hormone, has low solubility, is poorly absorbed in vivo by oral administration, and is easily metabolized and inactivated by the liver, and the bioavailability of progesterone in human body is very low due to these factors, and the bioavailability of oral ordinary dosage forms is only about 10%. The non-absorbed progesterone is mainly metabolized by the liver, and the damage to the liver is large. The progesterone injection has large irritation during injection, causes discomfort for patients and brings inconvenience to clinical use. Therefore, there is an urgent need to develop a progesterone preparation with high bioavailability, which can reduce progesterone dosage, improve therapeutic effect, reduce side effects, facilitate clinical use, and improve patient compliance.

Currently, the non-injection dosage forms of progesterone on the market in China comprise tablets, capsules, vaginal gels and the like, but the bioavailability is low. US patent No. US4196188 proposes a progesterone capsule dispersed in an oil solution after micronization, which can increase absorption after oral administration by reducing the particle size of progesterone through micronization, and improve bioavailability, and Besins Healthcare Benelux corporation (angutan) and domestic zhejiang love crude drug industry limited corporation (qining) have also marketed progesterone micronized capsules. However, the effect of improving bioavailability by micronization is limited, 100mg still needs to be taken to achieve the curative effect, and the micronized progesterone has large variation among individuals and cannot avoid the side effect caused by the metabolism of the progesterone in the liver. Patent No. CN102091054 proposes a progesterone preparation composition with high solubility and a preparation method thereof. The progesterone preparation composition consists of progesterone, a nonpolar solvent and a solubilizer, wherein the nonpolar solvent is vegetable oil or animal oil, and the solubilizer is lecithin or beeswax. The bioavailability of 10mg of the progesterone preparation composition is equal to that of 100mg sold in the market, and the bioavailability is improved by ten times. However, the solubilization of lecithin or beeswax is limited and according to the patent it is disclosed that 10mg of progesterone requires about 500mg of oil and lecithin solvent, thus making the product too bulky to swallow. And according to the dissolution data of the formula in the artificial gastric juice and the artificial intestinal juice disclosed in the patent, the dissolution of the formula is still low, and the dissolution and the bioavailability still have room for improvement. In addition, the progesterone needs to be dissolved in an oily solvent, and according to our experience, the stability of the progesterone in the oily solvent is not good, so that the progesterone cannot meet the requirement of marketing of medicines. The patent with the patent number CN102415995 relates to a progesterone supersaturated and self-microemulsion composition with high oral bioavailability, which comprises progesterone, non-natural vegetable oil, an emulsifier, an auxiliary emulsifier and a stabilizer, wherein the emulsifier is polyoxyethylene castor oil or polyoxyethylene hydrogenated castor oil and polysorbate 80 or caprylic capric polyethylene glycol glyceride or medium-chain fatty acid triglyceride, glyceryl glycerate, polyoxyethylene castor oil and caprylic capric polyethylene glycol glyceride. Compared with the commercially available progesterone capsule product (Zhejiang love crude drug industry Co., Ltd., specification 100mg), the bioavailability of the progesterone self-microemulsion composition in Beagle dogs can be improved by six times. However, according to the laboratory's reproduction of the formulation, the solubilization effect of the formulation is still low, the particle size of the formed emulsion droplets is large, and thus the improvement of the solubility-enhancing effect and bioavailability effect of progesterone is still limited. And the patent does not carry out long-term research on physical and chemical stability, and according to the analysis of auxiliary materials used in the prescription in a laboratory, the prescription disclosed in the patent cannot meet the chemical stability requirement of commercial medicines on the market, and the product is not on the market at present.

Disclosure of the invention

The invention aims to overcome the defects of low dissolution rate and low bioavailability of non-injectable progesterone formulations in the current commercially available products, and provides a progesterone self-emulsifying composition which is suitable for commercialized non-injectable progesterone formulations, improves the bioavailability of progesterone and has good physicochemical stability.

The technical scheme adopted by the invention is as follows:

the invention provides a progesterone self-emulsifying composition, which comprises the following raw materials in parts by mass: 1 part of progesterone, 2-15 parts of solvent, 6-75 parts of vitamin E polyethylene glycol succinate and 0.05-2 parts of stabilizer; the solvent is oleic acid or ethyl oleate; the stabilizer is one or a mixture of more of benzyl alcohol, sodium sulfite or disodium ethylene diamine tetraacetate in any proportion.

Further, preferably, the progesterone self-emulsifying composition is prepared from the following raw materials in parts by mass: 1 part of progesterone, 3-10 parts of solvent, 8-50 parts of vitamin E polyethylene glycol succinate and 0.05-2 parts of stabilizer.

Further, it is preferable that the solvent is ethyl oleate.

Further, it is preferable that the stabilizer is benzyl alcohol.

Further, the stabilizer is preferably a mixture of benzyl alcohol, sodium sulfite and disodium ethylene diamine tetraacetate in a mass ratio of 5-20:0.5-1.5:1, preferably 10:0.7: 1.

Furthermore, the progesterone self-emulsifying composition is preferably prepared from the following raw materials in parts by mass: 1 part of progesterone, 3-8 parts of ethyl oleate, 10-30 parts of vitamin E polyethylene glycol succinate and 1.17 parts of a stabilizer; the stabilizer is a mixture of benzyl alcohol, sodium sulfite and disodium ethylene diamine tetraacetate in a mass ratio of 10:0.7: 1.

The invention also provides an application of the progesterone self-emulsifying composition in preparing a progesterone self-emulsifying preparation, wherein the preparation comprises tablets, capsules, soft capsules, oral liquid, gel or granules prepared by medical carriers.

The progesterone self-emulsifying composition can be prepared into medical carriers such as tablets, capsules, soft capsules, oral liquid, gels, granules and the like by adopting a method known in the field, wherein the medical carriers refer to conventional medicine carriers in the pharmaceutical field, and diluents, excipients and the like can be added when the progesterone self-emulsifying composition is prepared into the oral liquid; making into granule, optionally adding adsorbent, etc., and making into tablet, optionally adding binder, lubricant, etc.

The progesterone is dissolved in a mixed solution of an oily solvent (such as oleic acid esters or oleic acid salts), a solubilizer (vitamin E polyethylene glycol succinate) and a stabilizer, the composition is mixed with liquid in the gastrointestinal tract under the mild stirring action of the gastrointestinal tract in vivo after oral administration, and self-emulsified to form oil-in-water type microemulsion drops under the action of the vitamin E polyethylene glycol succinate and benzyl alcohol which can reduce the oil-water interfacial tension. The microemulsion drops are dispersed in a water phase in a liquid bead mode, vitamin E polyethylene glycol succinate and benzyl alcohol with oil-water amphiphilicity are distributed on an oil-water interface, an oil phase kernel formed by combining an oil solvent and a surfactant is arranged inside the microemulsion drops, and progesterone is dissolved in the oil phase kernel of the microemulsion drops. The self-emulsifying formulation can improve the bioavailability of progesterone in a variety of ways: 1. the microemulsion can greatly increase the concentration of water-insoluble progesterone in gastrointestinal fluids, and the microemulsion has low surface tension, is easy to pass through a hydration layer of a gastrointestinal wall and has large specific surface area, so that the contact rate of the progesterone and gastrointestinal epithelial cells is improved, and the absorption rate of the progesterone in the gastrointestinal tract is improved; 2. the microemulsion drops can be absorbed by the chylomicron tube to enter the lymphatic system for transportation, so that the first pass effect of progesterone in the hepatic portal vein is avoided; 3. the vitamin E polyethylene glycol succinate added in the prescription has the function of inhibiting the activity of efflux pump P-glycoprotein, thereby reducing the pumping of progesterone from blood plasma to gastrointestinal tract and improving the bioavailability of the progesterone.

Compared with the prior art, the invention has the following beneficial effects:

experiments prove that the absolute dissolution amount of the progesterone self-emulsifying composition in the artificial intestinal juice is between 6.5 and 8.6mg and can reach 8.6mg at most, and the absolute dissolution amount of each commercially available progesterone soft capsule product containing 100mg in the artificial intestinal juice is 1.9mg, so that the absolute dissolution amount of the self-emulsifying tablet in the artificial intestinal juice is far higher than that of each commercially available 100mg soft capsule product, so that the progesterone dissolution effect in body fluid can be improved, the bioavailability of the progesterone in a human body can be improved, meanwhile, the self-emulsifying composition can form an oil-in-water microemulsion in the intestinal tract, and microemulsion drops can be absorbed by a lymphatic system, the first pass effect of the liver after gastrointestinal tract vascular absorption is avoided, the metabolic burden of the liver is reduced, and the side effect is reduced.

Experiments prove that the progesterone preparation composition disclosed by the invention is good in chemical stability, accelerated experiments are carried out according to the requirements of accelerated experiments in the four stability experiments of the 2015 edition of Chinese pharmacopoeia, the content of single impurities does not exceed 0.5%, the total amount of impurities does not exceed 2.0%, the content is 93-107% at the end point of 6 months, the progesterone preparation composition meets the requirements of the content and impurity acceptance standards under the term of the 2015 edition progesterone injection of Chinese pharmacopoeia, the product stability is good, and the progesterone preparation composition is suitable for commercial production.

(IV) detailed description of the preferred embodiments

The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto:

example 1 Progesterone self-emulsifying composition

(1) The progesterone self-emulsifying composition comprises the following components in parts by weight: 1 part of progesterone, 15 parts of ethyl oleate, 75 parts of vitamin E polyethylene glycol succinate and 1.17 parts of stabilizer, wherein the stabilizer consists of benzyl alcohol, sodium sulfite and disodium ethylene diamine tetraacetate in a mass ratio of 10:0.7: 1.

(2) Preparation of progesterone self-emulsifying composition:

weighing 10.00g of benzyl alcohol, 150.00g of ethyl oleate and 750.00g of vitamin E polyethylene glycol succinate according to the formula amount, placing the materials into a beaker, and stirring and mixing the materials uniformly in a water bath at 60 ℃. Weighing 10.00g of progesterone, adding the progesterone into the solution, adding 0.70g of sodium sulfite and 1.00g of disodium ethylene diamine tetraacetate, and uniformly stirring to obtain 921.70g of the progesterone self-emulsifying composition with the drug content of 1.1%.

(3) Stability testing of progesterone self-emulsifying compositions

Placing the progesterone self-emulsifying composition prepared in the step (2) according to influence factor high-temperature test conditions (60 ℃ 60% RH) in appendix 9001 bulk drug and preparation stability test guiding principle of Chinese pharmacopoeia 2015 edition, sampling at zero, 1 week and 2 weeks, and detecting the content and impurities of the sample by adopting a high-performance liquid phase content and impurity method listed in British pharmacopoeia (BP 9.0) progesterone standard. The results are shown in table 1, and the experimental results show that the total impurity of the initial sample of the composition is 0.5%, the maximum single impurity is 0.3%, the total impurity amount does not exceed 2.0% in 2 weeks under the severe condition of high temperature, the maximum single impurity does not exceed 0.5%, the content is between 93% and 107%, the requirements of the content and impurity acceptance standards under the item of progesterone injection of the 2015 edition of Chinese pharmacopoeia are met, and the product stability is good.

TABLE 1 stability data for high temperature influencing factors of progesterone self-emulsifying compositions

Impurities	Initial sample	1 week	2 weeks
				Maximum individual impurity (%)	0.3	0.3	0.3
Total miscellaneous	0.5	0.4	0.5
				Content (%)	99.8	100.1	102.2

Example 2 Progesterone self-emulsifying composition

(1) The progesterone self-emulsifying composition comprises the following components in parts by weight: 1 part of progesterone, 15 parts of oleic acid, 75 parts of vitamin E polyethylene glycol succinate and 1.17 parts of stabilizer, wherein the stabilizer consists of benzyl alcohol, sodium sulfite and disodium ethylene diamine tetraacetate in a mass ratio of 10:0.7: 1.

(2) Preparation of progesterone self-emulsifying composition:

weighing 10.00g of benzyl alcohol, 150.00g of oleic acid and 750.00g of vitamin E polyethylene glycol succinate according to the formula amount, placing the materials in a beaker, and stirring and mixing the materials uniformly in a water bath at 60 ℃. Weighing 10.00g of progesterone, adding the progesterone into the solution, stirring uniformly, adding 0.70g of sodium sulfite and 1.00g of disodium ethylene diamine tetraacetate, and stirring uniformly to obtain 921.70g of the progesterone self-emulsifying composition with the drug content of 1.1%. The impurity level and stability of the composition were tested by the method of example 1, and the results are shown in table 2, wherein the total impurity content of the composition is 0.2%, and the maximum single impurity content is 0.2%, which meets the impurity standard under the item of progesterone injection of 2015 edition of Chinese pharmacopoeia.

TABLE 2 stability data for high temperature influencing factors of progesterone self-emulsifying compositions

Impurities	Initial sample	1 week	2 weeks
				Maximum individual impurity (%)	0.2	0.4	0.5
Total miscellaneous	0.2	0.4	0.5
				Content (%)	101.3	101.9	101.9

Example 3 Progesterone self-emulsifying particles

1. Progesterone self-emulsifying composition

(1) The progesterone self-emulsifying composition comprises the following components in parts by weight: 1 part of progesterone, 2 parts of ethyl oleate, 6 parts of vitamin E polyethylene glycol succinate and 1.17 parts of stabilizer, wherein the stabilizer consists of benzyl alcohol, sodium sulfite and disodium ethylene diamine tetraacetate in a mass ratio of 10:0.7: 1.

(2) Preparation of progesterone self-emulsifying composition:

weighing 10.00g of benzyl alcohol, 20.00g of ethyl oleate and 60.00g of vitamin E polyethylene glycol succinate according to the formula amount, placing the materials into a beaker, and stirring and mixing the materials uniformly in a water bath at 60 ℃. Weighing 10.00g of progesterone, adding the progesterone into the solution, adding 0.70g of sodium sulfite and 1.00g of disodium ethylene diamine tetraacetate, and uniformly stirring to obtain 101.70g of the progesterone self-emulsifying composition.

2. Progesterone self-emulsifying particles

20.00g of mannitol and 95.00g of aerosil (specific surface area 175-²And/g), adding into a stirrer, stirring uniformly, adding 101.70g of the progesterone self-emulsifying composition prepared in the step 1, stirring uniformly by hand, starting the stirrer, and stirring uniformly to obtain 216.70g of progesterone self-emulsifying particles with the drug content of 4.6%. The particle size distribution is as follows: 4.4% of 40 meshes; 14.6 percent of 60 meshes; 80 meshes 39.5%; 16.1 percent of 100 meshes; 13.2 percent of 120 meshes; 12.2 percent above 120 meshes.

3. Stability testing of progesterone self-emulsifying particles

The progesterone self-emulsifying particles prepared in the step 1 are placed according to the influence factor high-temperature test condition (60 ℃ 60% RH) in the appendix 9001 bulk drug and preparation stability test guiding principle of Chinese pharmacopoeia 2015 edition, samples are taken at zero, 1 week and 2 weeks, and the content and impurities of the samples are detected by adopting the high performance liquid phase content and impurity method listed in British pharmacopoeia (BP 9.0) progesterone standard. The results are shown in table 3, and the experimental results show that the total impurity content of the initial sample of the progesterone self-emulsifying particles is 0.4%, the maximum single impurity content is 0.3%, the total impurity content does not exceed 2.0% in 2 weeks under the severe high-temperature condition, the maximum single impurity content does not exceed 0.5%, the content is 93% -107%, the requirements of the content and impurity acceptance standards under the item of progesterone injection of 2015 year edition of Chinese pharmacopoeia are met, and the product stability is good.

TABLE 3 stability data for high temperature influencing factors of progesterone self-emulsifying particles

Impurities	Initial sample	1 week	2 weeks
				Maximum individual impurity (%)	0.3	0.3	0.5
Total miscellaneous	0.4	0.8	1.2
				Content (%)	101.0	101.9	103.4

Example 4 Progesterone self-emulsifying particles

1. Progesterone self-emulsifying composition

(1) The progesterone self-emulsifying composition comprises the following components in parts by weight: 1 part of progesterone, 8 parts of ethyl oleate, 40 parts of vitamin E polyethylene glycol succinate and 1.17 parts of a stabilizer, wherein the stabilizer consists of benzyl alcohol, sodium sulfite and disodium ethylene diamine tetraacetate in a mass ratio of 10:0.7: 1.

(2) Preparation of progesterone self-emulsifying composition:

weighing 10.00g of benzyl alcohol, 80.00g of ethyl oleate and 400.00g of vitamin E polyethylene glycol succinate according to the formula amount, placing the materials into a beaker, and stirring and mixing the materials uniformly in a water bath at 60 ℃. Weighing 10.00g of progesterone, adding the progesterone into the solution, adding 0.70g of sodium sulfite and 1.00g of disodium ethylene diamine tetraacetate, and uniformly stirring to obtain 501.70g of the progesterone self-emulsifying composition.

2. Progesterone self-emulsifying particles

Weighing 50.00g of mannitol and 260.00g of aerosil (specific surface area 175-²/g) was added to a stirrer, and after stirring uniformly, 501.70g of the progesterone self-emulsifying composition prepared in example 4 was added, followed by granulation to obtain 1491.70g of progesterone self-emulsifying granules having a drug content of 0.67% and a particle size distribution of: 7.3 percent of 40 meshes, 35.1 percent of 60 meshes, 24.7 percent of 80 meshes, 8.7 percent of 100 meshes, 12.2 percent of 120 meshes and 12.2 percent above 120 meshes.

4. Degree of release in artificial intestinal fluids

The dissolution test of the progesterone self-emulsifying particles is carried out according to the second dissolution test method of appendix X of the second part of the year 2015 version of Chinese pharmacopoeia: measuring 900mL of the artificial intestinal juice, injecting the artificial intestinal juice into a dissolution cup, and heating in a water bath to keep the temperature of the artificial intestinal juice at 37 +/-0.5 ℃. Taking 4 tablets/capsule of the progesterone self-emulsifying granules prepared in the step 2 and commercially available progesterone soft capsules (Angel Tan 100mg Belgium Besins healthcare Benelux company), respectively putting one tablet or one capsule into each dissolution cup, immediately starting a rotating device and starting timing at the rotating speed of 50 r/min, respectively sampling from the dissolution cups at 0.5, 1, 2, 4, 6, 8 and 12 hours, filtering the absorbed dissolution liquid by a 0.45um microporous membrane, and measuring the subsequent filtrate by a high performance liquid chromatography, wherein the chromatographic conditions are that an octadecylsilane chemically bonded silica gel column is used for ethanol: water (55:45) as the mobile phase, a detection wavelength of 254nm, a release rate at each time point by an external standard method, and a cumulative dissolution percentage at each time point by the following formula were calculated, and the results are shown in Table 5:

in the formula: r_{General assembly}% is the total accumulated release degree when sampling at each time point; r_n% is the release at each time point; r₁% is the release at the first sampling time point; v_nVolume of dissolution medium (mL) for each time point; v₁Volume of dissolution medium (mL) at the first sampling time point; n is the number of times of sampling; PV is the sample volume (mL).

Table 4: dissolution percentage of commercially available soft capsules containing 100mg of progesterone in artificial intestinal juice

Time (h)	0.5h	1h	2h	4h	6h	8h	12h
								1	0.1	0.4	0.7	1.1	1.5	1.8	2.1
2	0.0	0.3	0.6	1.0	1.3	1.6	2.0
								3	0.1	0.4	0.7	1.1	1.4	1.7	2.0
4	0.1	0.3	0.6	0.9	1.1	1.3	1.5
								Mean value	0.1	0.3	0.6	1.0	1.3	1.6	1.9
RSD％	70.0	15.3	14.1	11.4	13.7	14.4	12.4

Table 5: dissolution percentage of progesterone self-emulsified particles in artificial intestinal juice

Time (h)	0.5h	1h	2h	4h	6h	8h	12h
								1	64.5	72.1	76.2	78.8	84.0	86.0	86.6
2	66.1	74.0	77.4	79.6	80.8	81.1	84.5
								3	56.8	69.6	75.2	78.8	81.3	83.5	84.3
4	63.4	73.7	77.3	78.9	79.9	80.7	85.3
								Mean value	62.7	72.3	76.5	79.0	81.5	82.8	85.2
RSD％	6.5	2.8	1.3	0.5	2.2	3.0	1.2

Example 5 Progesterone self-emulsifying particles

Weighing 70.00g of mannitol and 500.00g of aerosil (specific surface area 175-²/g) was added to a stirrer, and after stirring uniformly, 921.70g of the progesterone self-emulsifying composition prepared in example 1 was added and granulated to obtain 1491.70g of progesterone self-emulsifying granules having a drug content of 0.67% and a particle size distribution of: 40 meshes: 5 percent; 60 meshes: 34.4 percent; 80 meshes: 29.4 percent; 100 meshes: 10 percent; 120 meshes: 10.9 percent; more than 120 meshes: 10.4 percent. The release in artificial intestinal fluid was measured using the method of example 4 and the results are shown in table 6.

Table 6: dissolution percentage of progesterone self-emulsified particles in artificial intestinal juice

Time (h)	0.5h	1h	2h	4h	6h	8h	12h
								1	62.6	70.4	73.2	73.8	80.0	81.6	82.9
2	57.2	66.1	70.5	75.1	77.7	80.2	81.6
								3	58.6	66.0	70.0	71.9	77.4	80.8	82.2
4	60.4	68.0	71.0	75.5	79.6	81.7	82.4
								Mean value	59.7	67.6	71.2	74.1	78.7	81.1	82.3
RSD％	4.0	3.0	2.0	2.2	1.7	0.9	0.6

Example 6 Progesterone self-emulsifying particles

1. Progesterone self-emulsifying composition

(1) The progesterone self-emulsifying composition comprises the following components in parts by weight: 1 part of progesterone, 2 parts of oleic acid, 6 parts of vitamin E polyethylene glycol succinate and 1.17 parts of stabilizer, wherein the stabilizer consists of benzyl alcohol, sodium sulfite and disodium ethylene diamine tetraacetate in a mass ratio of 10:0.7: 1.

(2) Preparation of progesterone self-emulsifying composition:

weighing 10.00g of benzyl alcohol, 20.00g of oleic acid and 60.00g of vitamin E polyethylene glycol succinate according to the formula amount, placing the materials in a beaker, and stirring and mixing the materials uniformly in a water bath at 60 ℃. Weighing 10.00g of progesterone, adding the progesterone into the solution, uniformly stirring, adding 0.70g of sodium sulfite and 1.00g of disodium ethylene diamine tetraacetate, and uniformly stirring to obtain 101.70g of the progesterone self-emulsifying composition.

2. Progesterone self-emulsifying particles

20.00g of mannitol and 95.00g of aerosil (specific surface area 175-²And/g), adding the mixture into a stirrer, uniformly stirring, adding 101.70g of the progesterone self-emulsifying composition prepared in the step 1, and granulating to obtain 216.70g of progesterone self-emulsifying granules with the drug content of 4.6 percent and the particle size distribution of: 4.3 percent of 40 meshes, 22.0 percent of 60 meshes, 8.5 percent of 80 meshes, 7.9 percent of 100 meshes, 20.1 percent of 120 meshes and 37.2 percent above 120 meshes. The impurity level and stability of the self-emulsifying particles were tested by the method of example 1, the total impurity was 0.4%, the maximum single impurity was 0.3%, the standards for impurities under the term "progesterone injection prepared in 2015 by chinese pharmacopoeia" were met, and the stability results are shown in table 7.

TABLE 7 stability data for high temperature influencing factors of progesterone self-emulsifying particles

Impurities	Initial sample	1 week	2 weeks
				Maximum individual impurity (%)	0.3	0.5	0.5
Total miscellaneous	0.4	1.1	1.6
				Content (%)	102.3	100.3	100.9

Example 7 Progesterone self-emulsifying oral tablets

216.70g of progesterone self-emulsifying granules prepared by the method of example 3, 100.00g of aerosil, 61.50g of mannitol, 14.00g of talcum powder (particle size of 100 meshes), 196.40g of low-substituted hydroxypropyl cellulose, 13.60g of povidone K30 and 10.24g of magnesium stearate are weighed, placed in a V-shaped mixer to be uniformly mixed and tabletted to obtain progesterone self-emulsifying oral tablets, wherein the dosage of the tablets is 1.6%. The release in artificial intestinal fluid was measured using the method of example 4 and the results are shown in Table 8.

TABLE 8 dissolution percentage of progesterone self-emulsifying oral tablets in artificial intestinal juice

Time (h)	0.5h	1h	2h	4h	6h	8h	12h
								1	45.5	58.9	65.8	71.0	74.3	75.9	77.6
2	45.7	62.0	68.0	72.6	75.6	76.7	77.6
								3	45.2	59.9	66.6	71.9	74.9	76.4	78.0
4	45.8	60.1	67.3	72.3	75.0	76.4	77.8
								Mean value	45.6	60.2	66.9	71.9	74.9	76.4	77.8
RSD％	0.5	2.2	1.4	1.0	0.7	0.4	0.2

Example 8 Progesterone self-emulsifying oral tablets

1. Progesterone self-emulsifying composition

(1) The progesterone self-emulsifying composition comprises the following components in parts by weight: 1 part of progesterone, 3 parts of ethyl oleate, 12 parts of vitamin E polyethylene glycol succinate and 1.17 parts of stabilizer, wherein the stabilizer consists of benzyl alcohol, sodium sulfite and disodium ethylene diamine tetraacetate in a mass ratio of 10:0.7: 1.

(2) Preparation of progesterone self-emulsifying composition:

weighing 10.00g of benzyl alcohol, 30.00g of oleic acid and 120.00g of vitamin E polyethylene glycol succinate according to the formula amount, placing the materials in a beaker, and stirring and mixing the materials uniformly in a water bath at 60 ℃. Weighing 10.00g of progesterone, adding the progesterone into the solution, uniformly stirring, adding 0.70g of sodium sulfite and 1.00g of disodium ethylene diamine tetraacetate, and uniformly stirring to obtain 171.70g of the progesterone self-emulsifying composition.

2. Progesterone self-emulsifying particles

Weighing 7.71g mannitol, 36.63g aerosil (specific surface)Volume 175-²And/g), adding the mixture into a stirrer, uniformly stirring, adding 66.22g of the progesterone self-emulsifying composition prepared in the step 1, manually stirring, starting the stirrer, and uniformly stirring to obtain 110.56g of progesterone self-emulsifying particles.

3. Progesterone self-emulsifying oral tablet

110.56g of progesterone self-emulsifying granules, 2.74g of aerosil, 50.13g of mannitol, 7.71g of talcum powder (particle size is 100 meshes), 65.55g of low-substituted 2-hydroxypropyl ether cellulose and 2.39g of magnesium stearate are weighed and placed in a V-shaped mixer to be uniformly mixed and tabletted to obtain the progesterone self-emulsifying oral tablet, wherein the drug content of the tablet is 1.6%. The release in artificial intestinal fluids was tested using the methods of the examples, see table 9.

TABLE 9 dissolution percentage of progesterone self-emulsifying oral tablets in artificial intestinal juice

Time (h)	0.5h	1h	2h	4h	6h	8h	12h
								1	58.8	73.2	78.8	83.1	84.9	86.0	88.1
2	58.2	71.5	77.6	81.4	83.0	84.8	86.5
								3	57.6	70.3	76.2	80.6	82.8	84.1	85.4
4	58.5	72.4	78.3	82.2	84.1	85.2	86.2
								Mean value	58.3	71.9	77.7	81.8	83.7	85.0	86.5
RSD％	0.9	1.8	1.5	1.4	1.1	1.0	1.3

Example 9 Progesterone self-emulsifying oral tablets

1. Progesterone self-emulsifying composition

(1) The progesterone self-emulsifying composition comprises the following components in parts by weight: 1 part of progesterone, 10 parts of ethyl oleate, 20 parts of vitamin E polyethylene glycol succinate and 1.17 parts of stabilizer, wherein the stabilizer consists of benzyl alcohol, sodium sulfite and disodium ethylene diamine tetraacetate in a mass ratio of 10:0.7: 1.

(2) Preparation of progesterone self-emulsifying composition:

weighing 10.00g of benzyl alcohol, 100.00g of ethyl oleate and 200.00g of vitamin E polyethylene glycol succinate according to the formula amount, placing the materials into a beaker, and stirring and mixing the materials uniformly in a water bath at 60 ℃. Weighing 10.00g of progesterone, adding the progesterone into the solution, adding 0.70g of sodium sulfite and 1.00g of disodium ethylene diamine tetraacetate, and uniformly stirring to obtain 321.70g of the progesterone self-emulsifying composition.

2. Progesterone self-emulsifying particles

20.00g of mannitol and 95.00g of aerosil (specific surface area 175-²And/g), adding the mixture into a stirrer, uniformly stirring, adding 321.70g of the progesterone self-emulsifying composition prepared in the step 1, manually stirring uniformly, starting the stirrer, and uniformly stirring to obtain 436.70g of progesterone self-emulsifying particles with the particle size distribution: 1.1 percent of 40 meshes; 8.4% of 60 meshes, 16.7% of 80 meshes, 18.2% of 100 meshes, 20.7% of 120 meshes and more than 120 meshesThe upper 34.9 percent.

3. Progesterone self-emulsifying oral tablet

436.70g of progesterone self-emulsifying granules, 100.00g of aerosil, 61.50g of mannitol, 14.00g of talcum powder (particle size is 100 meshes), 196.40g of low-substituted 2-hydroxypropyl ether cellulose, 13.60g of povidone K30 and 10.24g of magnesium stearate are weighed and placed in a V-shaped mixer to be uniformly mixed and tabletted to obtain 832.44g of progesterone self-emulsifying oral tablet with the drug content of 1.2%. The release in the artificial intestinal juice was measured by the method of example 4 and is shown in Table 10.

Table 10: dissolution percentage of progesterone self-emulsifying oral tablet in artificial intestinal juice

Example 10 Progesterone self-emulsifying oral tablets

215.00g of progesterone self-emulsifying particles prepared by the method of example 6 and 100.00g of aerosil (specific surface area 175-225 m)²61.50g of mannitol, 14.00g of talcum powder (particle size is 100 meshes), 196.40g of low-substituted 2-hydroxypropyl ether cellulose, 13.60g of povidone K30 and 10.24g of magnesium stearate are placed in a V-shaped mixer to be uniformly mixed and tabletted to obtain 610.74g of the progesterone self-emulsifying oral tablet, and the content of the obtained tablet is 1.6%. The release in the artificial intestinal juice was measured by the method of example 4 and is shown in Table 11.

Table 11: dissolution percentage of progesterone self-emulsifying oral tablet in artificial intestinal juice

Time (h)	0.5h	1h	2h	4h	6h	8h	12h
								1	41.6	58.5	70.1	79.1	83.2	87.4	89.9
2	39.7	55.1	66.1	74.9	79.1	81.9	84.8
								3	41.1	57.4	65.5	73.3	78.1	80.7	83.3
4	40.2	55.6	66.0	73.2	77.8	81.3	84.1
								Mean value	40.7	56.6	66.9	75.1	79.6	82.8	85.5
RSD％	2.2	2.8	3.2	3.7	3.1	3.7	3.5

Example 11 Progesterone self-emulsifying oral tablets

1. Progesterone self-emulsifying composition

(1) The progesterone self-emulsifying composition comprises the following components in parts by weight: 1 part of progesterone, 10 parts of oleic acid, 20 parts of vitamin E polyethylene glycol succinate and 1 part of benzyl alcohol.

(2) Preparation of progesterone self-emulsifying composition:

weighing 10.00g of benzyl alcohol, 100.00g of oleic acid and 200.00g of vitamin E polyethylene glycol succinate according to the formula amount, placing the materials in a beaker, and stirring and mixing the materials uniformly in a water bath at 60 ℃. Weighing 10.00g of progesterone, adding the progesterone into the solution, and uniformly stirring to obtain 320.00g of the progesterone self-emulsifying composition.

2. Progesterone self-emulsifying particles

20.00g of mannitol and 95.00g of aerosil (specific surface area 175-²And/g), adding the mixture into a stirrer, uniformly stirring, adding 320.00g of the progesterone self-emulsifying composition prepared in the step 1, manually stirring uniformly, starting the stirrer, and uniformly stirring to obtain 435.00g of progesterone self-emulsifying particles with the particle size: 2.2 percent of 40 meshes; 27.6 percent of 60 meshes, 21.3 percent of 80 meshes, 7.1 percent of 100 meshes, 10.0 percent of 120 meshes and 31.8 percent above 120 meshes.

3. Progesterone self-emulsifying oral tablet

435.00g of progesterone self-emulsifying particles and 100.00g of aerosil (specific surface area 175-225 m)²61.50g of mannitol, 14.00g of talcum powder (particle size is 100 meshes), 196.40g of low-substituted 2-hydroxypropyl ether cellulose, 13.60g of povidone K30 and 10.24g of magnesium stearate are placed in a V-shaped mixer to be uniformly mixed and tabletted to obtain 830.74g of the progesterone self-emulsifying oral tablet, and the content of the obtained tablet is 1.2%. The release in artificial intestinal fluids was tested using the method of example 4, see table 12.

Table 12: dissolution percentage of progesterone self-emulsifying oral tablet in artificial intestinal juice

Time (h)	0.5h	1h	2h	4h	6h	8h	12h
								1	4.3	9.1	18.7	36.4	48.5	56.9	66.7
2	4.8	9.5	19.4	39.8	49.7	57.2	66.5
								3	4.7	8.5	13.6	30.9	43.1	53.2	74.1
4	6.6	14.4	22.1	37.2	50.8	58.3	67.1
								Mean value	5.1	10.4	18.4	36.1	48.0	56.4	68.6
RSD％	20.1	26.0	19.1	10.3	7.1	3.9	5.4

As can be seen from tables 5-12, the release rate of the self-emulsifying preparation containing 10mg of progesterone in the artificial intestinal juice is 65-90%, which is much higher than that of the commercially available soft capsule containing 100mg of progesterone by 1.9%. The absolute dissolution amount of the 10mg progesterone self-emulsifying oral tablet in the artificial intestinal juice is also 6.5-9mg, and the absolute dissolution amount of each commercially available 100mg progesterone soft capsule product in the artificial intestinal juice is 1.9mg, so the absolute dissolution amount of the self-emulsifying tablet in the artificial intestinal juice is also far higher than that of the commercially available 100mg soft capsule product.

Example 12 progesterone self-emulsifying oral tablets

1. Progesterone self-emulsifying composition

(1) The progesterone self-emulsifying composition comprises the following components in parts by weight: 1 part of progesterone, 4 parts of ethyl oleate, 10 parts of vitamin E polyethylene glycol succinate and 0.5 part of ethylene diamine tetraacetic acid.

(2) Preparation of progesterone self-emulsifying composition:

weighing 3.2g of ethyl oleate, 0.4g of disodium ethylene diamine tetraacetate, 0.8g of progesterone and 8.0g of vitamin E polyethylene glycol succinate according to the formula amount, placing the mixture in a beaker, and stirring and mixing the mixture uniformly in a water bath at 60 ℃ to obtain 12.4g of the progesterone self-emulsifying composition.

2. Progesterone self-emulsifying particles

Weighing 1.6g of mannitol and 3.76g of aerosil (specific surface area 175-²And/g) and 8.0g of anhydrous calcium hydrogen phosphate, adding into a stirrer, uniformly stirring, adding 12.4g of the progesterone self-emulsifying composition prepared in the step 1, manually stirring uniformly, starting the stirrer, and uniformly stirring to obtain 25.76g of progesterone self-emulsifying particles.

3. Progesterone self-emulsifying oral tablet

Weighing the above 22.54g progesterone self-emulsifying particles, 1.05g silica gel micropowder (specific surface area 175-²(g), 9.10g of mannitol, 1.40g of talcum powder (particle size is 100 meshes), 8.40g of low-substituted 2-hydroxypropyl ether cellulose and 0.434g of magnesium stearate are placed and mixed uniformly and tabletted to obtain 42.924g of progesterone self-emulsifying oral tablet, wherein the drug content of the tablet is 1.6%. The impurity level and stability of the self-emulsifying oral tablet are tested by the method of example 1, the total impurity is 0.6%, the impurity level and stability meet the impurity standard under the item of progesterone injection of 2015 year version of Chinese pharmacopoeia, and the stability result is shown in table 13.

TABLE 13 stability data of high temperature influencing factors of progesterone self-emulsifying oral tablets

Impurities	Initial sample	1 week	2 weeks
				Maximum individual impurity (%)	0.3	0.3	0.2
Total miscellaneous	0.4	0.5	0.5

Example 13 Progesterone self-emulsifying oral tablets

1. Progesterone self-emulsifying composition

(1) The progesterone self-emulsifying composition comprises the following components in parts by weight: 1 part of progesterone, 4 parts of ethyl oleate, 10 parts of vitamin E polyethylene glycol succinate and 1 part of benzyl alcohol.

(2) The preparation process comprises the following steps:

weighing 3.2g of ethyl oleate, 0.8g of benzyl alcohol, 0.8g of progesterone and 8.0g of vitamin E polyethylene glycol succinate according to the formula amount, placing the mixture in a beaker, and stirring and mixing the mixture uniformly in a water bath at 60 ℃ to obtain 12.8g of the progesterone self-emulsifying composition.

2. Progesterone self-emulsifying particles

Weighing 1.6g of mannitol and 3.76g of aerosil (specific surface area 175-²And/g) and 8.0g of anhydrous calcium hydrogen phosphate, adding into a stirrer, uniformly stirring, adding 12.8g of the progesterone self-emulsifying composition prepared in the step 1, manually stirring uniformly, starting the stirrer, and uniformly stirring to obtain 26.16g of progesterone self-emulsifying particles.

3. Progesterone self-emulsifying oral tablet

Weighing the 22.89g of progesterone self-emulsifying granules, 1.05g of aerosil, 9.10g of mannitol, 1.40g of talcum powder (the particle size is 100 meshes), 8.40g of low-substituted 2-hydroxypropyl ether cellulose and 0.434g of magnesium stearate, uniformly mixing, and tabletting to obtain 43.274g of progesterone self-emulsifying oral tablets, wherein the medicine content of the tablets is 1.6%. The impurity level and stability of the self-emulsifying oral tablet are detected by the method of example 1, the total impurity is 0.5%, the impurity level and stability meet the impurity standard under the item of progesterone injection of 2015 year version of Chinese pharmacopoeia, and the stability result is shown in table 14.

TABLE 14 stability data for high temperature influencing factors of progesterone self-emulsifying oral tablets

Impurities	Initial sample	1 week	2 weeks
				Maximum individual impurity (%)	0.2	0.2	0.2
Total miscellaneous	0.5	0.4	0.4

Example 14 Progesterone self-emulsifying oral tablets

1. Progesterone self-emulsifying composition

(1) The progesterone self-emulsifying composition comprises the following components in parts by weight: 1 part of progesterone, 4 parts of ethyl oleate, 10 parts of vitamin E polyethylene glycol succinate and 0.07 part of sodium sulfite.

(2) Preparation of progesterone self-emulsifying composition:

weighing 3.2g of ethyl oleate, 0.056g of sodium sulfite, 0.8g of progesterone and 8.0g of vitamin E polyethylene glycol succinate according to the formula amount, placing the mixture in a beaker, and stirring and mixing the mixture uniformly in a water bath at 60 ℃ to obtain 12.056g of the progesterone self-emulsifying composition.

2. Progesterone self-emulsifying particles

Weighing 1.6g of mannitol and 3.76g of aerosil (specific surface area 175-²And/g) and 8.0g of anhydrous calcium hydrogen phosphate, adding the mixture into a stirrer, uniformly stirring, adding 12.056g of the progesterone self-emulsifying composition prepared in the step 1, manually uniformly stirring, starting the stirrer, and uniformly stirring to obtain 25.416g of progesterone self-emulsifying particles.

3. Progesterone self-emulsifying oral tablet

22.239g of progesterone self-emulsifying granules, 1.05g of aerosil, 9.10g of mannitol, 1.40g of talcum powder (particle size is 100 meshes), 8.40g of low-substituted 2-hydroxypropyl ether cellulose and 0.434g of magnesium stearate are weighed, mixed uniformly and tabletted to obtain 42.623g of progesterone self-emulsifying oral tablets, and the content of the tablets is 1.6%. The impurity level and stability of the self-emulsifying oral tablet are tested by the method of example 1, the total impurity is 0.4%, the impurity level and stability meet the impurity standard under the item of progesterone injection of 2015 year version of Chinese pharmacopoeia, and the stability result is shown in table 15.

TABLE 15 stability data of high temperature influencing factors of progesterone self-emulsifying oral tablets

Impurities	Initial sample	1 week	2 weeks
				Maximum individual impurity (%)	0.2	0.2	0.2
Total miscellaneous	0.6	0.5	0.5

Example 15 self-emulsifying enteric coated tablets of Progesterone

1. Progesterone self-emulsifying composition:

(1) the progesterone self-emulsifying composition comprises the following components in parts by weight: 1 part of progesterone, 3 parts of ethyl oleate, 12 parts of vitamin E polyethylene glycol succinate and 1.17 parts of stabilizer, wherein the stabilizer consists of benzyl alcohol, sodium sulfite and disodium ethylene diamine tetraacetate in a mass ratio of 10:0.7: 1.

(2) Preparation method

Weighing 50g of benzyl alcohol, 150g of ethyl oleate, 5g of ethylene diamine tetraacetic acid, 3.5g of sodium sulfite and 50g of progesterone in a triangular flask according to the formula amount, placing the mixture in a water bath at 80 ℃, uniformly stirring and mixing, adding 600g of melted vitamin E polyethylene glycol succinate, and stirring in the water bath for 1h to obtain 858.5g of the progesterone self-emulsifying composition.

2. Progesterone self-emulsifying particles:

weighing 100g of mannitol and 475g of aerosil (specific surface area 175-225 m)²And/g), adding into a granulator, uniformly stirring, adding 858.5g of the progesterone self-emulsifying composition prepared in the step 1, and stirring and granulating to obtain 1433.5g of progesterone self-emulsifying granules.

3. Progesterone self-emulsifying tablet

573.4g of progesterone self-emulsifying particles prepared in step 2 and 199.41g of aerosil (specific surface area 175-²123g of mannitol, 27.75g of talcum powder (particle size 100 meshes), 274.55g of low-substituted 2-hydroxypropyl ether cellulose and 20.3g of magnesium stearate, uniformly mixing in a V-shaped mixer, and tabletting to obtain corpus luteum1218.41g of ketone self-emulsifying tablet, wherein the drug content of the tablet is 1.6%.

4. Progesterone self-emulsifying enteric-coated tablet

TABLE 16

(1) Preparing an isolating layer coating solution:

weighing 400g of 95% ethanol and 107g of water, uniformly mixing, adding 18g of Opadry, stirring until the mixture is completely dissolved, adding 18g of talcum powder and micro silica gel (the specific surface area is 175-²And/g) 9g, and stirring uniformly to obtain 552g of the isolating layer coating solution.

(2) Preparation of isolation layer tablets:

weighing 700g of the progesterone self-emulsifying tablet prepared in the step 3, adding into a coating pan, weighing 551.42g of the above isolating layer coating solution, spraying slurry and coating to obtain isolating layer tablet.

(3) Preparing enteric-coated layer coating liquid:

weighing 21g of 95% ethanol, adding 21g of polypropylene resin II and 13g of polypropylene resin III, stirring until the mixture is completely dissolved, adding 3g of triethyl citrate, 1013g of Tween 80 and 7g of talcum powder, and uniformly stirring to obtain 1078g of enteric-coated solution.

(4) Preparation of enteric layer tablets:

weighing 720.8g of the isolating layer tablet prepared in the step (2), adding into a coating pan, weighing 1077.2g of the enteric coating solution, spraying and coating to obtain 1798g of enteric layer tablet.

(5) Preparing a coating solution of the coloring layer:

the water was weighed to 130g and opadry 23g, and the opadry was added to the water and stirred uniformly to obtain 153g of a coating solution for a coloring layer.

(6) Preparation of colored layer tablet:

764.4g of enteric-coated tablet is weighed and added into a coating pan, 152.9g of the coating liquid of the coloring layer is weighed and sprayed with slurry to coat, and the finished product is prepared, wherein the drug content of the finished product is 1.3 percent.

5. Stability testing of progesterone self-emulsifying enteric tablets

And (3) reserving the sample of the progesterone self-emulsifying enteric-coated tablet prepared in the step (4) according to acceleration test conditions (75% RH at 40 ℃) in appendix 9001 of Chinese pharmacopoeia 2015 edition of pharmaceutical raw materials and preparation stability test guiding principles, sampling at zero, 1 month, 2 months, 3 months and 6 months at 12 months, and detecting the content and impurities of the sample by adopting a high-efficiency liquid phase content and impurity method listed in British pharmacopoeia (BP 9.0) progesterone standard. The results are shown in table 17, and the experimental results show that the total impurity of the initial sample of the progesterone self-emulsifying oral tablet is 0.5%, the maximum single impurity is 0.2%, the single impurities in 6 months under the acceleration condition do not exceed 0.5%, the total impurity amount does not exceed 2.0%, the content is 93-107%, the requirements of the content and the impurity acceptance standard under the item of progesterone injection published in 2015 of China pharmacopoeia are met, and the stability of the product is good.

TABLE 17

Impurities	Initial sample	1 month	2 months old	3 months old	6 months old
						Maximum individual impurity (%)	0.2	0.2	0.2	0.3	0.3
Total miscellaneous	0.5	0.7	0.7	0.6	0.9
						Content (%)	102.0	102.6	98.7	102.8	101.4

Claims (8)

1. A progesterone self-emulsifying composition is characterized by comprising the following raw materials in parts by mass: 1 part of progesterone, 2-15 parts of solvent, 6-75 parts of vitamin E polyethylene glycol succinate and 0.5-2 parts of stabilizer; the solvent is oleic acid or ethyl oleate; the stabilizer is one or a mixture of more of benzyl alcohol, sodium sulfite or disodium ethylene diamine tetraacetate in any proportion.

2. The progesterone self-emulsifying composition according to claim 1, wherein the progesterone self-emulsifying composition comprises the following raw materials by mass: 1 part of progesterone, 3-10 parts of solvent, 8-50 parts of vitamin E polyethylene glycol succinate and 0.5-2 parts of stabilizer.

3. The progesterone self-emulsifying composition of claim 1, wherein the solvent is ethyl oleate.

4. The progesterone self-emulsifying composition of claim 1, wherein the stabilizer is benzyl alcohol.

5. The progesterone self-emulsifying composition of claim 1, wherein the stabilizer is a mixture of benzyl alcohol, sodium sulfite and disodium edetate in a mass ratio of 5-20:0.5-1.5: 1.

6. The progesterone self-emulsifying composition according to claim 1, wherein the progesterone self-emulsifying composition comprises the following raw materials by mass: 1 part of progesterone, 3-8 parts of ethyl oleate, 10-30 parts of vitamin E polyethylene glycol succinate and 1.17 parts of a stabilizer; the stabilizer is a mixture of benzyl alcohol, sodium sulfite and disodium ethylene diamine tetraacetate in a mass ratio of 10:0.7: 1.

7. Use of a progesterone self-emulsifying composition of claim 1 in the preparation of a progesterone self-emulsifying formulation.

8. The use of claim 7, wherein the formulation comprises a tablet, capsule, soft capsule, oral liquid, gel or granule prepared with a medical carrier.