CN102091054B - Progesterone preparation composite and preparation method thereof - Google Patents
Progesterone preparation composite and preparation method thereof Download PDFInfo
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- CN102091054B CN102091054B CN200910249693.7A CN200910249693A CN102091054B CN 102091054 B CN102091054 B CN 102091054B CN 200910249693 A CN200910249693 A CN 200910249693A CN 102091054 B CN102091054 B CN 102091054B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/56—Materials from animals other than mammals
- A61K35/63—Arthropods
- A61K35/64—Insects, e.g. bees, wasps or fleas
- A61K35/644—Beeswax; Propolis; Royal jelly; Honey
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4875—Compounds of unknown constitution, e.g. material from plants or animals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/06—Antiabortive agents; Labour repressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/34—Gestagens
Abstract
The invention discloses a progesterone preparation composite and a preparation method thereof, belonging to the field of chemical medicine preparations. The progesterone preparation composite comprises a progesterone oil solution containing substance, the progesterone oil solution containing substance is prepared from the following components by every 1000 progesterone preparation composites: 2-30 grams of progesterone, 75-1000 grams of nonpolar solvents and 0-180 grams of solubilizers, wherein the nonpolar solvent is vegetable oil or/and animal oil; and the solubilizer is lecithin or/and beewax. The reached progesterone preparation composite can be used for oral administration, is 10 times higher than a commercial progesterone capsule in dissolution rate and bioavailability, has the advantages of small taking dosage, high bioavailability, little adverse reaction, and the like and can be used for various diseases or symptoms, i.e. threatened abortion, habitual abortion, artificial insemination, sterility, premenstrual tension syndromes, anovulatory dysfunctional uterine bleeding, anovulatory amenorrhoea, endometriosis, climacteric syndromes, and the like which are caused by insufficient progestational hormones or corpus luteum functions.
Description
Technical field
The present invention relates to field of medicaments, particularly, relate to the progesterone preparation composition and method of making the same that a kind of dissolution is high.
Background technology
(English name is progesterone to Progesterone, chemical name is pregnant Gona-4-ene-3,20-diketone) be natural progestogen, there is the general action of progestogen, be widely used in disease or symptom due to the progestogen such as treatment threatened abortion, habitual abortion, artificial insemination, infertile, premenstrualtension syndrome, anovulatory functional bleeding, the amenorrhea of anovulation type, endometrium hyperplasia, adenocarcinoma of endometrium, endometriosis and climacteric syndrome or inadequate luteal function.
Progesterone is soluble in non-polar solven, almost insoluble in water.Existing progesterone preparation has Tablet and Capsula, but because absorbing under one's belt extreme difference after oral, and easily by the rapid metabolism of liver and inactivation cannot be used clinically substantially, so, clinically to use oily injection agent as main.But, because oleo-injection is difficult for being absorbed, after injection, easily cause that injection deposits in local muscle, form lump, virtually increased the weight of patient's misery.
The patent No. is that the United States Patent (USP) of US4196188 has proposed the oral soft gelatin capsule of a kind of Progesterone (being called for short UTROGESTAN), can replace above-mentioned injection, bioavailability than above-mentioned progesterone preparation is high, also has the oral soft gelatin capsule of Progesterone of similar dosage form in China market.Progesterone micropowder in above-mentioned soft gelatin capsule is suspended in oil solution, patient need take the oral soft gelatin capsule of Progesterone of 200mg every day, just can play effective therapeutical effect, the unnecessary Progesterone that wherein can not be absorbed by patient is mainly by liver metabolism, larger to the infringement of liver; Meanwhile, metabolite easily produces many untoward reaction in patient body, so this oral soft gelatin capsule is still subject to certain limitation in clinical practice.
Realizing in process of the present invention, inventor finds the above-mentioned medicine that contains Progesterone, and at least there are the following problems:
(1) taking dose is large: the oral soft gelatin capsule of Progesterone that is US4196188 for the patent No., and the oral soft gelatin capsule of Progesterone that patient need take 200mg every day just can play effective therapeutical effect, and taking dose is larger; The Progesterone that can not be absorbed by patient passes through the rapid metabolism of liver and inactivation;
(2) dissolution is low: the absorption extreme difference after the progesterone preparation of existing Tablet and Capsula type is oral in patient's the intestines and stomach;
(3) bioavailability is low: the dissolution of existing progesterone preparation in patient body is low, impact absorbs, the oral soft gelatin capsule of Progesterone of the 200mg that patient need take every day, the only 20mg of suitable injection, all the other Progesterone that can not be absorbed by patient pass through the rapid metabolism of liver and inactivation, and in visible above-mentioned progesterone preparation or the oral soft gelatin capsule of Progesterone, the utilization rate of Progesterone is lower;
(4) untoward reaction is many: the unnecessary Progesterone that can not be absorbed by patient in the oral soft gelatin capsule of above-mentioned progesterone preparation or Progesterone is by the rapid metabolism of liver, larger to liver injury.Adverse effect main manifestations is dizziness and mammary swelling, and dizzy incidence rate is 10.3%, and mammary swelling incidence rate is 17.2%.
Summary of the invention
The object of the invention is defect large for taking dose in prior art, that dissolution is low, bioavailability is low and untoward reaction is many, propose the progesterone preparation composition and method of making the same that a kind of dissolution is high, to realize, taking dose is little, dissolution is high, bioavailability is high and untoward reaction is few.
For achieving the above object, the invention provides a kind of progesterone preparation compositions, by including liquid solubilizing agent content and the outer covering material with pharmacologically active component, form, it is characterized in that: including the liquid solubilizing agent content with pharmacologically active component is the Progesterone oil solution of being made by Progesterone and adjuvant; Described adjuvant is non-polar solven and solubilizing agent, and described non-polar solven is vegetable oil or/and animal oil, and described solubilizing agent is that lecithin is or/and Cera Flava;
In every 1000 preparation compositions, containing Progesterone 2-30g, solubilizing agent is 0-180g, and non-polar solven is 75-1000g.
Preferred: in every 1000 preparation compositions, containing Progesterone 5-20g, solubilizing agent is 0-100g, and non-polar solven is 80-800g.
Preferred: in every 1000 preparation compositions, contain Progesterone 5g, solubilizing agent is 0-50g, and non-polar solven is 80-200g.
Preferred: in every 1000 preparation compositions, contain Progesterone 10g, solubilizing agent is 0-80g, and non-polar solven is 100-500g.
Preferred: every 1000 preparation compositions meters, contain Progesterone 20g, solubilizing agent is 0-100g, non-polar solven is 400-800g.
Described vegetable oil is that vegetable oil is one or more in Oleum Arachidis hypogaeae semen, soybean oil, Oleum Brassicae campestris, Semen Maydis oil, olive oil, Oleum Helianthi, Oleum sesami, Semen Lini oil, Oleum Gossypii semen, Testa oryzae oil, Oleum Cocois, camellia seed oil, low erucic acid rapeseed oil, Fructus Zanthoxyli oil, Fructus Capsici wet goods.
Described animal oil is one or more in Adeps Sus domestica, Adeps Bovis seu Bubali, Adeps Caprae seu ovis, chicken oil, duck wet goods Animal fat oil.
Described lecithin is soybean lecithin or Ovum Gallus domesticus Flavus lecithin.
In described Progesterone micropowder, the particle diameter of 90% Progesterone micropowder is less than 10 μ m.
Its preparation formulation is soft capsule, liquid capsule or drop pill, and its outer wrapping is gelatin or gelatin and glycerol or other acceptable capsule outer covering material clinically.
The preparation method of above-mentioned progesterone preparation compositions, comprising: take in proportion the each component of content, its mixing stirred evenly, obtain Progesterone oil solution, by Progesterone oil solution mean cut-off in soft capsule or hard capsule or drop pill.
Described mixing adopts ultrasonic assist in dissolving while stirring evenly.
Generally, the water solublity that increases medicine just can increase its trap, but for fat-soluble medicine, liposoluble diffusion is the main mode of transport of drug, fat-soluble medicine can directly be dissolved in lipid and by cell membrane, so mainly fat-soluble relevant, fat-soluble larger with medicine of its transport speed, more easily diffusion, is more easily absorbed by the quasi-lipid film of blood capillary; The fat content of fat-soluble medicine preparation affects its degree of absorption, and Progesterone is fat-soluble medicine, and in non-polar solven, dissolubility is higher.Progesterone compositions in the present invention, adopt lecithin or Cera Flava and vegetable oil or the animal oil non-polar solven as Progesterone, by a large amount of evidences, by adjusting three's ratio, when Progesterone compositions presents oil solution state, its bioavailability is higher.Owing to being vegetable oil or animal oil containing being useful on the non-polar solven that dissolves Progesterone micropowder, with the solubilizing agent of the dissolubility for increasing Progesterone micropowder be lecithin or Cera Flava, thereby can improve dissolution and the bioavailability of Progesterone in patient body in Progesterone compositions of the present invention, can improve Progesterone in gastrointestinal dissolution and the trap in patient body, thereby be conducive to improve the bioavailability of preparation, improve the burden of patient to the trap of Progesterone and the unnecessary Progesterone of minimizing liver metabolism, thereby it is little to realize taking dose, dissolution is high, bioavailability height and the few advantage of untoward reaction.
Prove by experiment, soft gelatin capsule dissolution of the present invention is higher than the more than 10 times of commercially available prod, human experimentation shows, the soft gelatin capsule of 10mg/ grain of the present invention and commercially available 100mg/ grain has bioequivalence, greatly reduced dosage, alleviate the metabolism burden of liver simultaneously, reduced the bad harm of liver metabolism product to patient.
The specific embodiment
Below the preferred embodiments of the present invention are described, should be appreciated that preferred embodiment described herein, only for description and interpretation the present invention, is not intended to limit the present invention.
Progesterone micropowder (commercially available, particle diameter is less than 10 μ m micropowders and accounts for more than 90%)
Soybean lecithin, Ovum Gallus domesticus Flavus lecithin, Cera Flava
Vegetable oil (Oleum Arachidis hypogaeae semen, soybean oil, Oleum Brassicae campestris, Semen Maydis oil, olive oil, Oleum Helianthi, Oleum sesami, Semen Lini oil, Oleum Gossypii semen, Testa oryzae oil, Oleum Cocois, camellia seed oil, low erucic acid rapeseed oil, Fructus Zanthoxyli oil, chilli oil) is commercially available
Animal oil (Adeps Sus domestica, Adeps Bovis seu Bubali, Adeps Caprae seu ovis, chicken oil, duck oil) is commercially available
Basic thought of the present invention: every 1000 compositions meters, take the Progesterone 2-30g with pharmacologically active, add pharmaceutic adjuvant lecithin or Cera Flava 0-180g, all the other are the mixture 75-1000g of vegetable oil or animal oil or the non-polar solven that both are above, carry out again ultrasonic dissolution, obtain Progesterone oil solution, this Progesterone oil solution mean cut-off, in soft capsule, is made to Progesterone soft gelatin capsule of the present invention.In an embodiment, Progesterone micropowder has pharmacologically active, is soluble in non-polar solven, is insoluble in water; Vegetable oil is non-polar solven, for dissolving Progesterone micropowder; Lecithin or Cera Flava can be used as solubilizing agent or surfactant, the dissolubility for increasing Progesterone microgranule in vegetable oil.
Embodiment 1
Take Progesterone micropowder 2g, soybean lecithin 8g and soybean oil 92g, the Progesterone micropowder taking, soybean lecithin and soybean oil are mixed and shaken up, carry out ultrasonic dissolution, obtain Progesterone oil solution; Use soft mode formula capsule maker, the Progesterone oil solution mean cut-off obtaining, in 1000 soft capsules, is made to Progesterone soft gelatin capsule.
Embodiment 2
Take Progesterone microgranule 5g, Cera Flava 30g and Oleum Brassicae campestris 110g and Fructus Zanthoxyli oil 60g, the Progesterone microgranule taking, soybean lecithin and Oleum Brassicae campestris are mixed and shaken up, carry out ultrasonic dissolution, obtain Progesterone oil solution; Use soft mode formula capsule maker, the Progesterone oil solution mean cut-off obtaining, in 1000 soft capsules, is made to Progesterone soft gelatin capsule.
Embodiment 3
Take Progesterone micropowder 10g, Ovum Gallus domesticus Flavus lecithin 100g and Semen Maydis oil 400g, the Progesterone micropowder taking, Ovum Gallus domesticus Flavus lecithin and Semen Maydis oil are mixed and shaken up, carry out ultrasonic dissolution, obtain Progesterone oil solution; Use soft mode formula capsule maker, the Progesterone oil solution mean cut-off obtaining, in 1000 soft capsules, is made to Progesterone soft gelatin capsule.
Embodiment 4
Take Progesterone micropowder 20g and Adeps Sus domestica 700g, the Progesterone micropowder taking, Adeps Sus domestica are mixed and shaken up, carry out ultrasonic dissolution, obtain Progesterone oil solution; Use soft mode formula capsule maker, the Progesterone oil solution mean cut-off obtaining, in 1000 soft capsules, is made to Progesterone soft gelatin capsule.
Embodiment 5
Take Progesterone micropowder 5g, Ovum Gallus domesticus Flavus lecithin 5g, Oleum Arachidis hypogaeae semen 30g and Oleum Helianthi 65g, the Progesterone micropowder taking, Ovum Gallus domesticus Flavus lecithin, Oleum Arachidis hypogaeae semen and soybean oil are mixed and shaken up, carry out ultrasonic dissolution, obtain Progesterone oil solution; Use soft mode formula capsule maker, the Progesterone oil solution mean cut-off obtaining, in 1000 soft capsules, is made to this Progesterone soft gelatin capsule.
Embodiment 6
Take Progesterone micropowder 2g, Cera Flava 10g and chicken oil 90g, the Progesterone micropowder taking, Cera Flava and Oleum Helianthi are mixed and shaken up, carry out ultrasonic dissolution, obtain Progesterone oil solution; Use soft mode formula capsule maker, the Progesterone oil solution mean cut-off obtaining, in 1000 soft capsules, is made to Progesterone soft gelatin capsule.
Embodiment 7
Take Progesterone micropowder 30g, Cera Flava 150g and Oleum sesami 850g, the Progesterone micropowder taking, Cera Flava and Oleum sesami are mixed and shaken up, carry out ultrasonic dissolution, obtain Progesterone oil solution; Use soft mode formula capsule maker, the Progesterone oil solution mean cut-off obtaining, in 1000 soft capsules, is made to Progesterone soft gelatin capsule.
Embodiment 8
Take Progesterone micropowder 4g, Cera Flava 40g and Adeps Bovis seu Bubali 80g and Adeps Caprae seu ovis 80g, the Progesterone micropowder taking, Cera Flava and Semen Maydis oil are mixed and shaken up, carry out ultrasonic dissolution, obtain Progesterone oil solution; Use soft mode formula capsule maker, the Progesterone oil solution mean cut-off obtaining, in 1000 soft capsules, is made to Progesterone soft gelatin capsule.
In the various embodiments described above, at least one in the animal oil such as at least one in Oleum Arachidis hypogaeae semen, soybean oil, Oleum Brassicae campestris and Semen Maydis wet goods vegetable oil or Adeps Sus domestica, Adeps Bovis seu Bubali, Adeps Caprae seu ovis, can be used for dissolving Progesterone micropowder, soybean lecithin, Ovum Gallus domesticus Flavus lecithin or Cera Flava can be used as the solubilizing agent that Progesterone micropowder dissolve in above-mentioned vegetable oil, also can be used for doing the surfactant of Progesterone compositions of the present invention.
In sum, various embodiments of the present invention are mixed in proportion Progesterone micropowder, lecithin or Cera Flava and vegetable oil or animal oil to shake up, and carry out ultrasonic dissolution, obtain Progesterone oil solution, Progesterone oil solution are filled in soft capsule to the Progesterone soft gelatin capsule making; Wherein, non-polar solven is used for dissolving Progesterone micropowder, and solubilizing agent, for increasing the dissolubility of Progesterone, can improve dissolution and the bioavailability of Progesterone in patient body in Progesterone soft gelatin capsule, to improve the trap of patient to Progesterone, reduce the burden of the unnecessary Progesterone of liver metabolism; Thereby the defect such as can overcome that in prior art, taking dose is large, dissolution is low, bioavailability is low and untoward reaction is many, to realize, taking dose is little, dissolution is high, bioavailability is high and untoward reaction is few.
Finally it should be noted that: the foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, although the present invention is had been described in detail with reference to previous embodiment, for a person skilled in the art, its technical scheme that still can record aforementioned each embodiment is modified, or part technical characterictic is wherein equal to replacement.Within the spirit and principles in the present invention all, any modification of doing, be equal to replacement, improvement etc., within all should being included in protection scope of the present invention.
Below by experiment, the pharmaceutical properties of Progesterone soft gelatin capsule of the present invention is tested.
Commercially available Progesterone soft gelatin capsule, trade name: fine jade is peaceful, manufacturer: Aisheng Pharmaceutical Co., Ltd., Zhejiang,
Lot number: 20080301
Specification: 100mg/ grain
Experimental example 1: the stability to Progesterone soft gelatin capsule of the present invention is investigated:
It is 3500LX that the Progesterone soft gelatin capsule making respectively in the above embodiment of the present invention is exposed to illumination, and temperature is respectively room temperature, 40 ℃ and 25 ℃, and humidity is respectively under the condition of RH92.5% and RH75% each 10 days.From character, content color and luster, cracked property, disintegration, assay and chromatograph, check with the Progesterone soft gelatin capsule of the present invention of sealing preservation that respectively the aspects such as degradation product contrast again, comparing result shows, the each character of Progesterone soft gelatin capsule of the present invention exposed under illumination and different temperatures, damp condition is basicly stable.
In addition, Progesterone soft gelatin capsule of the present invention is packed, in temperature, be to accelerate transhipment six months under 40 ℃, the humidity condition that is RH75%, store at ambient temperature 24 months simultaneously, and regularly according to default matter temperature criterion index, sample is carried out to Observe and measure, find that the each character of sample is basicly stable.
Experimental example 2: dissolution and commercially available Progesterone soft gelatin capsule by Progesterone soft gelatin capsule of the present invention (embodiment 1,2,4,5,7, every specification is respectively 2mg, 5mg, 20mg, 5mg, 30mg) in simulated gastric fluid contrast investigation at the dissolution of simulated gastric fluid:
Progesterone soft gelatin capsule of the present invention and commercially available Progesterone soft gelatin capsule are carried out to dissolution contrast test by two appendix X dissolution methods of < < Chinese Pharmacopoeia version in 2005 the second method > > respectively: respectively measure the simulated gastric fluid 900ml through degassed processing, inject sequence number and be followed successively by the container of 1-6, can make simulated gastric fluid remain on 37 ± 0.5 ℃ by the mode of heating, take respectively again Progesterone soft gelatin capsule content of the present invention and the each 0.5g of commercially available Progesterone soft gelatin capsule (fine jade is peaceful) content as test liquid, accurately weighed, inject respectively in 6 corresponding process containers, start immediately rotary container and start timing, rotating speed is 50 revs/min, respectively 30, 60, 90, 120, 150, in the time of 180 minutes, each 20ml solution of drawing from 6 containers, and the blank solution that fills into immediately equivalent is the simulated gastric fluid of equal character, respectively by draw dissolution fluid through 0.45 μ m filtering with microporous membrane, get again subsequent filtrate according to determined by ultraviolet spectrophotometry, at 241nm wavelength place, measure trap, by the absorptance of Progesterone, be 540 calculating, calculate each stripping percentage rate.The results are shown in following table.Here, Progesterone soft gelatin capsule of the present invention (embodiment 1,2,4,5,7, every specification is respectively 2mg, 5mg, 20mg, 5mg, 30mg) in the percentage by weight of Progesterone for being respectively 1.96%, 2.44%, 2.78%, 4.76%, 2.91%, in commercially available Progesterone soft gelatin capsule, the percentage by weight of Progesterone is 37%, so, in the Progesterone soft gelatin capsule of the present invention of 0.5g, containing Progesterone, be respectively 9.8mg, 12.2mg, 13.9mg, 23.8mg, 14.55mg, contain Progesterone 185mg in the commercially available Progesterone soft gelatin capsule of 0.5g.
Table one: every Progesterone soft gelatin capsule day part containing Progesterone 2mg stripping percentage rate (%) in simulated gastric fluid
| Container sequence number | 30min | 60min | 90min | 120min | 150min | 180min |
| 1 | 7.13 | 11.91 | 19.27 | 24.02 | 31.1 | 39.06 |
| 2 | 9.71 | 14.1 | 19.44 | 23.75 | 32.47 | 37.2 |
| 3 | 8.3 | 13.18 | 19.87 | 25.08 | 33.86 | 40.22 |
| 4 | 7.41 | 12.75 | 23.17 | 29.86 | 36.25 | 43.36 |
| 5 | 8.7 | 11.87 | 21.69 | 26.63 | 34.14 | 41.18 |
| 6 | 9.07 | 13.14 | 25.73 | 29.21 | 33.63 | 39.97 |
| Average | 8.39 | 12.83 | 21.53 | 26.43 | 33.58 | 40.17 |
| SD | 0.99 | 0.85 | 2.55 | 2.62 | 1.73 | 2.06 |
| Every 0.5g is containing Progesterone 9.8mg average absolute stripping quantity (mg) | 0.82 | 1.26 | 2.11 | 2.59 | 3.29 | 3.94 |
Table two: every Progesterone soft gelatin capsule day part containing Progesterone 5mg stripping percentage rate (%) in simulated gastric fluid
| Container sequence number | 30min | 60min | 90min | 120min | 150min | 180min |
| 1 | 9.31 | 12.91 | 23.27 | 29.02 | 35.1 | 40.06 |
| 2 | 7.64 | 14.28 | 22.44 | 28.75 | 37.47 | 43.2 |
| 3 | 8.33 | 10.18 | 20.87 | 24.08 | 35.86 | 39.22 |
| 4 | 7.41 | 12.75 | 23.17 | 30.76 | 41.25 | 42.36 |
| 5 | 10.84 | 14.89 | 19.79 | 25.63 | 34.14 | 40.18 |
| 6 | 9.07 | 13.14 | 20.84 | 29.91 | 37.63 | 41.97 |
| Average | 7.05 | 11.83 | 20.33 | 25.86 | 37.74 | 41.33 |
| Average | 8.77 | 13.03 | 21.73 | 28.03 | 36.91 | 41.17 |
| SD | 1.26 | 1.63 | 1.43 | 2.60 | 2.52 | 1.56 |
| Every 0.5g is containing Progesterone 12.2mg average absolute stripping quantity (mg) | 1.07 | 1.59 | 2.65 | 3.42 | 4.50 | 5.02 |
Table three: every Progesterone soft gelatin capsule day part containing Progesterone 20mg stripping percentage rate (%) in simulated gastric fluid
| Container sequence number | 30min | 60min | 90min | 120min | 150min | 180min |
| 1 | 8.31 | 12.91 | 19.27 | 28.02 | 33.1 | 42.06 |
| 2 | 9.64 | 13.28 | 21.44 | 30.75 | 35.47 | 39.2 |
| 3 | 7.33 | 10.18 | 20.87 | 23.08 | 34.86 | 38.22 |
| 4 | 8.41 | 12.75 | 24.17 | 30.76 | 37.25 | 41.36 |
| 5 | 7.84 | 13.89 | 23.79 | 27.63 | 35.14 | 40.18 |
| 6 | 10.07 | 14.14 | 21.84 | 29.91 | 33.63 | 42.97 |
| Average | 8.60 | 12.86 | 21.90 | 28.36 | 34.91 | 40.67 |
| SD | 1.05 | 1.42 | 1.84 | 2.91 | 1.47 | 1.79 |
| Every 0.5g is containing Progesterone 13.9mg average absolute stripping quantity (mg) | 1.20 | 1.79 | 3.04 | 3.94 | 4.85 | 5.65 |
Table four: every Progesterone soft gelatin capsule day part containing Progesterone 5mg stripping percentage rate (%) in simulated gastric fluid
| Container sequence number | 30min | 60min | 90min | 120min | 150min | 180min |
| 1 | 8.31 | 12.91 | 22.27 | 27.52 | 38.1 | 41.06 |
| 2 | 9.64 | 13.28 | 21.44 | 31.75 | 37.47 | 39.2 |
| 3 | 9.33 | 14.18 | 20.87 | 27.58 | 35.86 | 43.22 |
| 4 | 8.41 | 13.75 | 21.17 | 27.76 | 33.25 | 40.36 |
| 5 | 6.84 | 10.89 | 19.79 | 23.63 | 30.14 | 38.18 |
| 6 | 10.07 | 13.14 | 25.84 | 28.91 | 33.63 | 46.97 |
| Average | 8.77 | 13.03 | 21.90 | 27.86 | 34.74 | 41.50 |
| SD | 1.17 | 1.14 | 2.09 | 2.62 | 2.99 | 3.18 |
| Every 0.5g is containing Progesterone 23.8mg average absolute stripping quantity (mg) | 2.09 | 3.10 | 5.21 | 6.63 | 8.27 | 9.88 |
Table five: every Progesterone soft gelatin capsule day part containing Progesterone 30mg stripping percentage rate (%) in simulated gastric fluid
| Container sequence number | 30min | 60min | 90min | 120min | 150min | 180min |
| 1 | 7.31 | 10.91 | 20.27 | 29.02 | 38.1 | 42.06 |
| 2 | 8.64 | 13.28 | 22.44 | 30.75 | 31.47 | 38.2 |
| 3 | 9.33 | 12.18 | 23.87 | 29.08 | 34.86 | 40.22 |
| 4 | 7.41 | 13.75 | 19.17 | 28.76 | 39.25 | 41.36 |
| 5 | 8.84 | 13.89 | 21.79 | 27.63 | 32.14 | 41.18 |
| 6 | 10.07 | 14.14 | 21.84 | 25.91 | 33.63 | 39.97 |
| Average | 8.60 | 13.03 | 21.56 | 28.53 | 34.91 | 40.50 |
| SD | 1.08 | 1.25 | 1.65 | 1.62 | 3.17 | 1.36 |
| Every 0.5g is containing Progesterone 14.55mg average absolute stripping quantity (mg) | 1.25 | 1.90 | 3.14 | 4.15 | 5.08 | 5.89 |
Table six: the stripping percentage rate (%) of commercially available every Progesterone soft gelatin capsule day part containing Progesterone 100mg in simulated gastric fluid
| Container sequence number | 30min | 60min | 90min | 120min | 150min | 180min |
| 1 | 0.46 | 1.12 | 1.39 | 1.61 | 1.59 | 1.91 |
| 2 | 1.46 | 1.91 | 1.79 | 2.08 | 2.17 | 1.86 |
| 3 | 0.41 | 0.95 | 1.03 | 1.44 | 1.57 | 1.48 |
| 4 | 0.97 | 0.99 | 1.07 | 1.21 | 1.50 | 1.43 |
| 5 | 1.17 | 0.81 | 1.10 | 1.10 | 1.27 | 1.32 |
| 6 | 0.64 | 1.09 | 1.18 | 1.33 | 1.84 | 1.49 |
| Average | 0.85 | 1.15 | 1.26 | 1.46 | 1.65 | 1.58 |
| SD | 0.42 | 0.39 | 0.29 | 0.35 | 0.31 | 0.24 |
| Every 0.5g is containing Progesterone 185mg average absolute stripping quantity | 1.74 | 2.33 | 2.57 | 2.98 | 3.37 | 3.22 |
| (mg) | ||||||
| Containing Progesterone 100mg average absolute stripping quantity (mg) | 0.94 | 1.26 | 1.39 | 1.61 | 1.82 | 1.74 |
From table one, two, three, four, five, six, in simulated gastric fluid, the present invention containing the dissolution of the Progesterone soft gelatin capsule of 2mg, 5mg, 20mg, 30mg in 40% left and right than commercially available Progesterone soft gelatin capsule dissolution 1.58% height, and, As time goes on, Progesterone soft gelatin capsule stripping quantity of the present invention is also many than commercially available Progesterone soft gelatin capsule stripping quantity.During with 180 minutes, the dissolution that Progesterone soft gelatin capsule 5mg of the present invention is example is 41.17 ± 1.56%, containing the absolute stripping quantity of content of Progesterone 12.2mg, is 5.02mg; The dissolution of commercially available Progesterone soft gelatin capsule is 1.58 ± 0.24%, containing the absolute stripping quantity of content of Progesterone 100mg, is 1.74mg; Visible, in simulated gastric fluid, the absolute stripping quantity of Progesterone soft gelatin capsule of the present invention is 23 times of commercially available Progesterone soft gelatin capsule stripping quantity, can show that Progesterone soft gelatin capsule of the present invention is high-efficiency preparation.
Experimental example 3: the dissolution by Progesterone soft gelatin capsule of the present invention in simulated intestinal fluid and commercially available Progesterone soft gelatin capsule contrast investigation at the dissolution of simulated intestinal fluid:
Operational approach according to experiment 2 contrasts investigation by Progesterone soft gelatin capsule of the present invention and commercially available Progesterone soft gelatin capsule at the dissolution of simulated intestinal fluid, the results are shown in following table.
Table seven: the stripping percentage rate (%) containing the Progesterone soft gelatin capsule day part of Progesterone 2mg in simulated intestinal fluid
| Container sequence number | 30min | 60min | 90min | 120min | 150min | 180min |
| 1 | 43.12 | 50.02 | 49.73 | 51.89 | 49.1 | 49.72 |
| 2 | 38.45 | 43.8 | 42.51 | 49.64 | 44.13 | 46.17 |
| 3 | 46.59 | 49.71 | 52.76 | 58.19 | 55.42 | 57.97 |
| 4 | 51.27 | 53.42 | 54.75 | 57.45 | 54.57 | 54.07 |
| 5 | 41.98 | 51.41 | 52.4 | 57.19 | 56.48 | 54.14 |
| 6 | 47.78 | 49.06 | 48.62 | 53.15 | 50.19 | 52.09 |
| Average | 44.87 | 49.57 | 50.13 | 54.59 | 51.65 | 52.36 |
| SD | 4.58 | 3.22 | 4.33 | 3.51 | 4.72 | 4.07 |
| Every 0.5g is containing Progesterone 9.8mg average absolute stripping quantity (mg) | 4.40 | 4.86 | 4.91 | 5.35 | 5.06 | 5.13 |
Table eight: the stripping percentage rate (%) containing the Progesterone soft gelatin capsule day part of Progesterone 5mg in simulated intestinal fluid
| Container sequence number | 30min | 60min | 90min | 120min | 150min | 180min |
| 1 | 44.12 | 51.02 | 49.73 | 49.89 | 50.1 | 51.72 |
| 2 | 38.45 | 54.8 | 52.51 | 52.64 | 52.13 | 50.17 |
| 3 | 46.59 | 50.71 | 48.76 | 48.19 | 50.42 | 56.97 |
| 4 | 39.27 | 47.42 | 53.75 | 51.45 | 53.57 | 54.07 |
| 5 | 49.98 | 53.41 | 50.4 | 50.19 | 56.48 | 57.14 |
| 6 | 49.78 | 50.06 | 48.62 | 52.15 | 59.19 | 60.09 |
| Average | 44.70 | 51.24 | 50.63 | 50.75 | 53.65 | 55.03 |
| SD | 5.02 | 2.60 | 2.08 | 1.65 | 3.58 | 3.72 |
| Every 0.5g is containing Progesterone 12.2mg average absolute stripping quantity (mg) | 5.45 | 6.25 | 6.18 | 6.19 | 6.55 | 6.71 |
Table nine: the stripping percentage rate (%) containing the Progesterone soft gelatin capsule day part of Progesterone 20mg in simulated intestinal fluid
| Container sequence number | 30min | 60min | 90min | 120min | 150min | 180min |
| 1 | 50.12 | 52.02 | 51.73 | 52.89 | 52.1 | 52.72 |
| 2 | 43.45 | 51.8 | 50.51 | 53.64 | 52.13 | 52.17 |
| 3 | 43.59 | 51.71 | 50.76 | 52.19 | 51.42 | 50.97 |
| 4 | 46.27 | 49.42 | 51.75 | 54.45 | 54.57 | 53.07 |
| 5 | 42.98 | 52.41 | 51.4 | 52.19 | 53.48 | 55.14 |
| 6 | 44.78 | 53.06 | 50.62 | 56.15 | 54.19 | 50.09 |
| Average | 45.20 | 51.74 | 51.13 | 53.59 | 52.98 | 52.36 |
| SD | 2.69 | 1.24 | 0.57 | 1.53 | 1.28 | 1.76 |
| Every 0.5g is containing Progesterone 13.9mg average absolute stripping quantity (mg) | 6.28 | 7.19 | 7.11 | 7.45 | 7.36 | 7.28 |
Table ten: the stripping percentage rate (%) containing the Progesterone soft gelatin capsule day part of Progesterone 5mg in simulated intestinal fluid
| Container sequence number | 30min | 60min | 90min | 120min | 150min | 180min |
| 1 | 44.12 | 50.02 | 49.73 | 55.89 | 55.1 | 53.72 |
| 2 | 42.45 | 52.8 | 52.51 | 53.64 | 50.13 | 50.17 |
| 3 | 46.59 | 48.71 | 49.76 | 55.19 | 53.42 | 52.97 |
| 4 | 44.27 | 50.42 | 49.75 | 54.45 | 54.57 | 51.07 |
| 5 | 45.98 | 54.41 | 50.4 | 56.19 | 55.48 | 54.14 |
| 6 | 48.78 | 53.06 | 51.62 | 51.15 | 50.19 | 53.09 |
| Average | 45.37 | 51.57 | 50.63 | 54.42 | 53.15 | 52.53 |
| SD | 2.23 | 2.18 | 1.18 | 1.85 | 2.42 | 1.56 |
| Every 0.5g is containing Progesterone 23.8mg average absolute stripping quantity (mg) | 10.80 | 12.27 | 12.05 | 12.95 | 12.65 | 12.50 |
Table ten one: the stripping percentage rate (%) containing the Progesterone soft gelatin capsule day part of Progesterone 30mg in simulated intestinal fluid
| Container sequence number | 30min | 60min | 90min | 120min | 150min | 180min |
| 1 | 42.12 | 48.02 | 51.73 | 53.89 | 51.1 | 51.72 |
| 2 | 41.45 | 50.8 | 49.51 | 52.64 | 51.13 | 51.17 |
| 3 | 45.59 | 47.71 | 50.76 | 53.19 | 50.42 | 51.97 |
| 4 | 43.27 | 48.42 | 51.75 | 55.45 | 52.57 | 52.07 |
| 5 | 44.98 | 52.41 | 50.4 | 53.19 | 51.48 | 52.14 |
| 6 | 47.78 | 51.06 | 50.62 | 54.15 | 51.19 | 51.09 |
| Average | 44.20 | 49.74 | 50.80 | 53.75 | 51.32 | 51.69 |
| SD | 2.37 | 1.94 | 0.85 | 0.99 | 0.71 | 0.46 |
| Every 0.5g is containing Progesterone 14.55mg average absolute stripping quantity (mg) | 6.43 | 7.24 | 7.39 | 7.82 | 7.47 | 7.52 |
Table ten two: the stripping percentage rate (%) of commercially available each time period of Progesterone soft gelatin capsule in simulated intestinal fluid
| Container sequence number | 30min | 60min | 90min | 120min | 150min | 180min |
| 7 | 2.13 | 2.49 | 3.70 | 3.41 | 2.33 | 2.94 |
| 8 | 2.08 | 3.52 | 3.78 | 3.72 | 3.26 | 3.31 |
| 9 | 2.67 | 3.57 | 5.42 | 3.71 | 4.02 | 3.76 |
| 10 | 4.27 | 4.78 | 3.73 | 4.37 | 4.47 | 4.10 |
| 11 | 2.02 | 3.55 | 3.64 | 2.96 | 3.26 | 4.64 |
| 12 | 2.54 | 4.37 | 4.25 | 2.83 | 4.32 | 4.51 |
| Average | 2.62 | 3.71 | 4.09 | 3.50 | 3.61 | 3.88 |
| SD | 0.85 | 0.79 | 0.69 | 0.57 | 0.82 | 0.67 |
| Every 0.5g is containing Progesterone 185mg average absolute stripping quantity (mg) | 4.77 | 6.76 | 7.44 | 6.38 | 6.58 | 7.06 |
| Containing the average absolute stripping quantity (mg) of Progesterone 100mg | 2.58 | 3.65 | 4.02 | 3.45 | 3.56 | 3.82 |
From table six, seven, eight, nine, ten, 11,12, in simulated intestinal fluid, the present invention containing the dissolution of the Progesterone soft gelatin capsule of 2mg, 5mg, 20mg, 30mg in 50% left and right than commercially available Progesterone soft gelatin capsule dissolution 3.88% height, and, As time goes on, Progesterone soft gelatin capsule stripping quantity of the present invention is also many than commercially available Progesterone soft gelatin capsule stripping quantity.During with 180 minutes, the dissolution that Progesterone soft gelatin capsule 5mg of the present invention is example is 55.03 ± 3.72%, containing the absolute stripping quantity of content of Progesterone 12.2mg, is 6.71mg; The dissolution of commercially available Progesterone soft gelatin capsule is 3.88 ± 0.67%, containing the absolute stripping quantity of content of Progesterone 100mg, is 3.82mg; Visible, in simulated intestinal fluid, the absolute stripping quantity of Progesterone soft gelatin capsule of the present invention is 14 times of commercially available Progesterone soft gelatin capsule stripping quantity, can show that Progesterone soft gelatin capsule of the present invention is high-efficiency preparation.
Experimental example 4: the Progesterone soft gelatin capsule of 10mg Progesterone soft gelatin capsule of the present invention and commercially available 100mg is carried out to Bioequivalence Test research below:
This research is take 6 male as subjects, single dose oral Progesterone ball of the present invention (specification 10mg) and commercially available Progesterone ball (specification 100mg) on an empty stomach respectively, adopt radioimmunoassay method different time blood plasma Chinese medicine concentration, according to blood drug level-time data, tried to achieve main pharmacokinetic parameter.
In Progesterone ball of the present invention, the Cmax of Progesterone is 2.73 ± 0.77 (ng/ml), and Tmax is 1.5 (h), and AUC0～48 are 42.38 ± 6.33 (ng/ml.h).The Cmax of commercially available Progesterone ball is 2.78 ± 0.17 (ng/ml), and Tmax is 2.5 ± 1 (h), and AUC0～48 are 44.42 ± 6.12 (ng/ml.h).Above-mentioned main pharmacokinetic parameter is carried out to the evaluation of statistical analysis and bioequivalence, result shows: Progesterone soft gelatin capsule of the present invention is that the average relative bioavailability of commercially available Progesterone soft gelatin capsule is 95.46 ± 12.67%, between two kinds of preparations, Cmax, the Tmax of Progesterone and AUC0～48 are all without significant significant difference (P > 0.05), 90% the fiducial limit of preparation AUC of the present invention drops within the scope of the 76-132% of commercial preparation, and Cmax is within the scope of 81%-125%.
Can find out that thus Progesterone ball of the present invention (specification 10mg) and commercially available Progesterone soft gelatin capsule (specification 100mg) are bioequivalence at human body.
Below by model case, further illustrate the pharmaceutical properties of the Progesterone soft gelatin capsule that dissolution of the present invention is high.
Case one: Wang Jinhua, 47 years old, is diagnosed as and encloses menopause anovulation.Accept Progesterone soft gelatin capsule 10mg of the present invention treatment, be used in conjunction 3 months after menstrual blood volume and menstruation natural law recover normal; From in the period the 17th day, add with Progesterone soft gelatin capsule 10mg of the present invention, be used in conjunction 10 days after drug withdrawal.This patient does not take other medicines before taking Progesterone soft gelatin capsule of the present invention, does not take Alora while taking Progesterone soft gelatin capsule of the present invention yet.
Case two: Chen Xiulian, 50 years old, menstruation was not risen for nearly 4 months, and B ultrasonic endometrium EN > 13mm, is diagnosed as menopause.Accept Progesterone soft gelatin capsule 10mg of the present invention treatment, be used in conjunction 10 days after endometrium strip off; After cycle therapy 3 months, it is normal that menstrual blood volume and menstruation natural law recover.This patient takes before Progesterone soft gelatin capsule of the present invention and does not take other medicines, does not also take Alora while taking the high Progesterone soft gelatin capsule of dissolution of the present invention.
Case three: Ye Lei, 32 years old, the following tide of menstruation in 3 months, got rid of gestation, is diagnosed as amenorrhea.Accept Progesterone soft gelatin capsule 10mg of the present invention treatment, be used in conjunction 2 months after menstrual blood volume and menstruation natural law recover normal; From in the period the 17th day, add with dissolution of the present invention high Progesterone soft gelatin capsule 10mg, be used in conjunction 10 days after drug withdrawal.This patient does not take other medicines before taking the Progesterone soft gelatin capsule that dissolution of the present invention is high, does not take Alora while taking Progesterone soft gelatin capsule of the present invention yet; The time that this patient takes the Progesterone soft gelatin capsule that dissolution of the present invention is high is about 3 months.
Case four: Lu little Jie, 40 years old, is diagnosed as premature ovarian failure.Accept Progesterone soft gelatin capsule 10mg of the present invention treatment, taking Progesterone soft gelatin capsule of the present invention February, it is normal that menstrual blood volume and menstruation natural law recover; If cooperation progynova, therapeutic effect is better, concrete, can rise and take progynova in the 5th of menstruation day, is used in conjunction 21 days; And menstruation within the 17th day, play and take Progesterone soft gelatin capsule of the present invention, be used in conjunction 10 days.Treatment cycle is 3 months.
Through clinical verification, patient only need take the Progesterone soft gelatin capsule of 20mg every day, can reach effective therapeutic dose, and taking convenience, also without any untoward reaction.
Claims (8)
1. a progesterone preparation compositions, by including liquid solubilizing agent content and the outer covering material with pharmacologically active component, form, it is characterized in that: including the liquid solubilizing agent content with pharmacologically active component is the Progesterone oil solution of being made by Progesterone and adjuvant; Described adjuvant is non-polar solven and solubilizing agent, and described non-polar solven is vegetable oil or/and animal oil, described solubilizing agent be lecithin or/and Cera Flava:
In every 1000 preparation compositions, contain Progesterone 5g, solubilizing agent is 0-50g, and non-polar solven is 80-200g, or in every 1000 preparation compositions, contain Progesterone 10g, solubilizing agent is 0-80g, and non-polar solven is 100-500g, or in every 1000 preparation compositions, contain Progesterone 20g, solubilizing agent is 0-100g, and non-polar solven is 400-800g.
2. progesterone preparation compositions according to claim 1, described vegetable oil is one or more in Oleum Arachidis hypogaeae semen, soybean oil, Oleum Brassicae campestris, Semen Maydis oil, olive oil, Oleum Helianthi, Oleum sesami, Semen Lini oil, Oleum Gossypii semen, Testa oryzae oil, Oleum Cocois, camellia seed oil, low erucic acid rapeseed oil, Fructus Zanthoxyli oil, Fructus Capsici wet goods.
3. progesterone preparation compositions according to claim 1, described animal oil is one or more in Adeps Sus domestica, Adeps Bovis seu Bubali, Adeps Caprae seu ovis, chicken oil, duck wet goods Animal fat oil.
4. progesterone preparation compositions according to claim 1, described lecithin is soybean lecithin or Ovum Gallus domesticus Flavus lecithin.
5. progesterone preparation compositions according to claim 1, described Progesterone is Progesterone micropowder, and in Progesterone micropowder, the particle diameter of 90% Progesterone micropowder is less than 10 μ m.
6. progesterone preparation compositions according to claim 1, its preparation formulation is soft capsule, liquid capsule or drop pill, its outer covering material is gelatin or gelatin and glycerol or other acceptable capsule outer covering material clinically.
7. the preparation method of progesterone preparation compositions described in claim 6, comprising: take in proportion the each component of content, its mixing stirred evenly, obtain Progesterone oil solution, by Progesterone oil solution mean cut-off in soft capsule or hard capsule or drop pill.
8. preparation method claimed in claim 7, described mixing adopts ultrasonic assist in dissolving while stirring evenly.
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| CN1446540A (en) * | 2003-04-03 | 2003-10-08 | 上海医药工业研究院 | Combination of semisolid framework preparation of progesterone |
| CN1585644A (en) * | 2001-11-13 | 2005-02-23 | 培新国际比利时公司 | Pharmaceutical composition based on micronized progesterone, preparation method and uses thereof |
| CN1589801A (en) * | 2004-02-24 | 2005-03-09 | 范敏华 | Progesterone liquid capsule and its preparation method |
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| CN1585644A (en) * | 2001-11-13 | 2005-02-23 | 培新国际比利时公司 | Pharmaceutical composition based on micronized progesterone, preparation method and uses thereof |
| CN1398590A (en) * | 2002-08-20 | 2003-02-26 | 杭州容立医药科技有限公司 | Recipe and prepn of progesterone capsule |
| CN1446540A (en) * | 2003-04-03 | 2003-10-08 | 上海医药工业研究院 | Combination of semisolid framework preparation of progesterone |
| CN1589801A (en) * | 2004-02-24 | 2005-03-09 | 范敏华 | Progesterone liquid capsule and its preparation method |
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